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Pharmaceutical
Ingredients
Second Edition
Edited by
Ira R. Berry and Daniel Harpaz
informa
healthcare
New York London
CRC Press
Taylor & Francis Group
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© 2001 by Taylor & Francis Group, LLC
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CONTENTS
1. INTRODUCTION 1
Daniel Harpaz
GMP Concepts 2
Regulatory 3
FDA Site Inspections 4
References 7
iii
iv Validation of Active Pharmaceutical Ingredients
API Inspections 21
History of API Inspections 21
Reasonable Inspections Under Section 374(a) 22
Scope of FDA lnspectional Authority over APis 23
Inspection Priorities: Active Drug Substances Versus Excipients 25
Foreign Versus Domestic Plant Inspection 26
Other Inspection Issues 30
Enforcement Tools Against APis 32
Administrative Tools 32
Judicial Tools 34
FDA Import/Export Authority over APis 37
Drug Master Files for APis 42
DMFTypes 42
DMF Holder Obligations 43
Status of DMFs as Records 44
Conclusion 45
Notes 45
References 52
Approval of DMFs 89
Types of DMFs 89
Manufacturing Performed at More Than One Site 91
Intermediates 93
Rereview of DMFs for APis 93
Changing the Manufacturing Procedure in a DMF 95
Summary 96
INDEX 573
PREFACE 2001
Since publication of the first edition, there has been continuous activity in
the subject areas of bulk pharmaceutical Good Manufacturing Practice (GMP)
and validation. The basic philosophy and principles of GMP and validation
have not changed. New terminology has been introduced, and old terminol-
ogy has been better defined so as to improve the understanding of related
concepts and principles. For example, the term active pharmaceutical ingredi-
ent (API) has been introduced to replace the older term bulk pharmaceutical
chemical (BPC).
The continuous activity referred to has resulted in considerable new in-
formation and global regulatory guidance that has been made available in
the form of guidances and guidelines written by the U.S. Food and Drug Ad-
ministration and by ICH (International Conference on the Harmonisation of
Technical Requirements for Registration of Pharmaceuticals for Human Use).
These guidances and guidelines cover current Good Manufacturing Practices
(cGMPs), stability, product quality requirements, and postapproval changes
-all of which are discussed in this book.
This second edition includes updates to the chapters in the first edition
and several additional chapters on pertinent subjects, including postapproval
changes, technology transfer, international cGMP guidelines/FDA guidance
progress and fadlity inspectional issues. The book is intended to provide bet-
ter clarity and understanding of the regulatory process so as to facilitate com-
pliance by the regulated pharmaceutical industry.
Spedal thanks are given to the contributing authors, who have given of
their personal time to write this book, while continuing their very busy work
schedules. These people have provided extensive effort to create this
book and to help maintain the high quality of products that the industry
manufactures, while also striving to create a more productive regulatory
environment.
Ira R. Berry
Daniel Harpaz
xvii
AUTHOR BIOGRAPHIES
BOOK EDITORS
Ira R. Berry
Ira R. Berry is executive vice president of Wockhardt Americas Inc. He is
responsible for global regulatory affairs and quality assurance, the U.S. oper-
ation, and establishing new manufacturing and technical operations world-
wide. He has a BS in biology and chemistry from Queens College of the City
University of New York, an MA in biology from Hofstra University, and an
MBA from Adelphi University.
Previously, Mr. Berry was a manager at Pfizer, Inc., in product and
process development and production. At Denver Chemical Manufacturing
Company, he held several positions in production and product development,
regulatory affairs, and quality assurance. Before joining Wockhardt, Mr. Berry
was corporate vice president for technical affairs at Banner Pharmacaps Inc.
Mr. Berry's professional experience covers pharmaceuticals, nutritional
supplements, diagnostic products, medical devices, and cosmetics. He is cred-
ited for patents in antacid formulation, controlled release, foaming bath oil,
and chewable gelatin shell capsules. He is a member of the Regulatory Affairs
Professionals Society, the Pharmaceutical Quality Control Association, the
American Academy of Pharmaceutical Sciences and the National Association
of Pharmaceutical Manufacturers (on the Board of Directors). Mr. Berry has
published more than 25 papers on GMP, softgels, validation, and nutritional
supplements. He is coeditor for a second edition of Pharmaceutical Process Val-
idation and coeditor of Validation of Bulk Pharmaceutical Chemicals.
xix
xx Validation of Active Pharmaceutical Ingredients
Daniel Harpaz
Daniel Harpaz is president of Harpaz Consulting Services, a firm that provides
global regulatory and technical advice to FDA regulated industries. He holds
a BS and MS in chemical engineering, an MBA, and a PhD in industrial
pharmacy.
With over 30 years of experience in the pharmaceutical industry, Dr.
Harpaz has held senior positions in research and development, quality con-
trol, and engineering and has handled diversified programs for his employees
and clients, domestically and internationally. He presents and publishes on
GMP and validation issues, is on the editorial board for the Journal of Valida-
tion Technology, and is a member of many professional and trade associations.
CONTRIBUTING AUTHORS
Stephen R. Byrn
Stephen R. Byrn is the Charles B. jordan Professor at Purdue University's
School of Pharmacy and Pharmacal Sciences. He is also head of the Depart-
ment of Industrial and Physical Pharmacy and director of the Center for AIDS
Research at Purdue University. He received his BA from DePauw University
and his PhD in chemistry from the University of Illinois at Champaign-
Urbana. He was a postdoctoral fellow at UCLA. Dr. Byrn's research focuses on
the solid-state chemistry of drugs and has emphasized the application of X-
ray crystallography and solid-state nuclear magnetic resonance spectroscopy
to pharmaceutical problems. He is committed to educating scientists to bring
a wide range of analytical techniques to bear on solid-state problems. Dr.
Byrn has extensive experience as a consultant in the pharmaceutical indus-
try, currently serves on the Chemistry III, Dissolution, and Excipients sub-
committees of the U.S. Pharmacopeia, and is the chair of the Drug Substance
Technical Committee for PQRI.
Eric Duffy
Eric Duffy holds a PhD in synthetic organic chemistry from Tufts University.
He has a decade of experience in drug discovery and development, regulatory
affairs, and specialty chemicals manufacturing. This experience led to posi-
tions within the U.S. Food and Drug Administration in the Office of Generic
Drugs (reviewing antibiotics, anti-infectives, and antifungals), the Office of
New Drug Chemistry (team leader), and the Division of Oncology Drug Prod-
ucts. Dr. Duffy has served on many committees and working groups, includ-
ing BACPAC I, BACPAC II, the Drug Substance Committee (chairperson), the
Author Biographies xxi
rONA Metabolites Working Group, the New Drug Substance Source Working
Group, and International Conference on Harmonisation Q3A/Q6A Working
Groups.
Barbara J. Evanoff
Barbara J. Evanoff is a regulatory affairs analyst for Bristol-Myers Squibb Co.
She has a BA in chemistry. Ms. Evanoff has 10 years of experience in manu-
facturing process development and analysis and 10 years of experience in
drug regulatory affairs, primarily in the area of bulk pharmaceuticals and in-
termediates. She is a member of the American Chemical Society.
Frank J. Golden
Frank J. Golden is the manager of supplier quality assurance and internal au-
dits at Glaxo Wellcome Inc. He has an AAS in biological technology, a BS in
biology, and an MBA. Mr. Golden was an FDA investigator and compliance
officer for 13 years and for the last 10 years has served in quality assurance
and compliance groups in the pharmaceutical industry. As a Certified Qual-
ity Auditor from the American Society for Quality, he routinely provides GMP
and audit training to Glaxo Wellcome staff, contractors, and other industry
personnel. Mr. Golden is a member of the Parenteral Drug Association, ASQ,
and the North Carolina Regulatory Affairs Forum.
Robert A. Hahn
Robert Hahn is an associate attorney at Olsson, Frank, and Weeda, P.C. He has
a BA magna cum laude, Phi Beta Kappa, from Brown University, a law degree
from Columbia University Law School; and an MA in public health from the
Harvard School of Public Health. Mr. Hahn was admitted to the New York
State Bar in 1985. Previously, he was director of legal affairs at Public Voice
for Food and Health Policy (now merged with the Consumer Federation of
America); vice president and counsel at Manufacturers Hanover Trust Com-
pany; and an associate in the Guangzhou, China, office of Lewis, D' Amato,
Brisbois, Bisgaard, Buxbaum & Choy.
William E. Hall
Dr. William E. Hall is an international expert on cleaning validation in the
pharmaceutical industry. He holds a BS from the University of Arkansas and
an MS and a PhD from the University of Wisconsin. With more than 40 years'
xxii Validation of Active Pharmaceutical Ingredients
Karl L. Hofmann
Karl L. Hofmann, Jr., is director of quality assurance at Bristol-Myers Squibb
Co. He holds a BS and an MS. Mr. Hofmann has over 25 years of experience
in pharmaceutical manufacturing and quality assurance. He is a member of
the Parenteral Drug Association, the Pharmaceutical Research and Manufac-
turers of America Bulk QC Work Group, and the International Society for
Pharmaceutical Engineering. He is the author of several papers and text chap-
ters dealing with the manufacture of sterile pharmaceuticals and GMP for the
manufacture of bulk pharmaceuticals. Mr. Hofmann has also lectured at the
Center for Professional Advancement on the topic of sterile filtration.
Robert V. Kasubick
Robert V. Kasubick is vice president of operations and regulatory affairs at
Oakwood Laboratories. He has a BS from Pennsylvania State University, an
MS from Connecticut College, and a PhD from Purdue University. Dr. Ka-
subick's experience includes a variety of positions in research, quality control,
pilot plant operations, manufacturing, and regulatory affairs at Pfizer, Bristol-
Myers Squibb, Wyeth Ayerst, and Ben Venue Laboratories. He has a strong
background in the formulation and manufacturing of tablets, capsules, and
sterile injectables.
Nirmal K. Khanna
Nirmal K. Khanna is a full-time consultant to the director of chemical opera-
tions at Hoffmann-La Roche. He holds a BChE from liT (Delhi), an MChE
from New York University, and an MS in industrial and management engi-
neering from Columbia University. Mr. Khanna has more than 25 years of
experience in development, manufacturing, and engineering related to fine
chemicals, APis, and biotechnology products. As a consultant, he has executed
Author Biographies xxiii
Max Lazar
Max S. Lazar is Vice President of FDA and DEA Compliance at Hoffmann-La
Roche. His undergraduate degree is from Brooklyn College of the City Uni-
versity of New York. During his 34 years' professional working experience
with Hoffmann-La Roche, Mr. Lazar has held positions as laboratory analyst,
quality control laboratory supervisor, quality control manager, and quality
control director. At the company's largest bulk manufacturing site in the
United States, he has been director of process development and director of
engineering. Mr. Lazar was the founder of the Pharmaceutical Research and
Manufacturers of America's Quality Control Committee Work Group on APis.
He is vice chairman of the USP Expert Committee and a topic leader for the
International Conference on Harmonisation Q7 Expert Working Group for
the development of an international guideline for Good Manufacturing Prac-
tice for APis. He has published numerous papers and addressed many orga-
nizations on the subjects of API and FDA compliance issues.
Rob Murphy
Rob Murphy is a senior manager in quality assurance at Amgen Inc. He re-
ceived a BS in biochemistry from the University of Missouri. He has six years
of experience in validation and has worked on the licensure of three manu-
facturing facilities and four different products. He has made numerous pre-
sentations concerning validation and preapproval inspections to the
Parenteral Drug Association, the Pharmaceutical Research and Manufacturers
of America, and the U.S. Food and Drug Administration.
Robert A. Nash
Robert A. Nash is a consultant and adjunct professor of industrial pharmacy
and cosmetic science at St. John's University. He was formerly director of
pharmaceutical development of the Purdue Frederick company as well as
manager of pharmaceutical product development at Lederle Laboratories and
a research associate of Merck, Sharp, and Dohme Research Labs. Mr. Nash has
published widely in the fields of pharmaceuticals and cosmetic science and
holds nine U.S. patents. He is also coeditor of Pharmaceutical Process Valida-
tion and a member of the editorial advisory board of the Journal of Validation
Technology. He is an active member of International Sodety for Pharmaceuti-
cal Engineering, the Academy of Pharmaceutical Research and Science, the
American Chemical Society, and the American Association of Pharmaceutical
Scientists.
Author Biographies xxv
Neil F. O'Raherty
Neil F. O'Flaherty is a principal at Olsson, Frank, and Weeda, P.C. He received
a BA from the University of Notre Dame and a JD from Loyola University of
Chicago School of Law. He was admitted to the Illinois Bar in 1990 and the
District of Columbia Bar in 1991. Mr. O'Flaherty concentrates his practice in
the area of FDA regulation of medical devices. He has spoken and written ex-
tensively on device-related topics, including FDA regulation of in vitro diag-
nostics and blood bank software and FDA device inspection and enforcement
authority. Over the years, Mr. O'Flaherty's device work has included assis-
tance to the Advanced Medical Technology Association, the largest trade as-
sociation for the medical device industry in the United States, including
assistance on device tracking, medical software, and device reclassification
matters. His practice also includes legal matters relating to other FDA-regu-
lated products.
Fred C. Radford
Fred C. Radford is the president of Alert Consultants, Inc., a firm specializing
in human and veterinary drug and medical device submissions and the es-
tablishment and auditing of quality assurance systems. He has a BA in Eng-
lish from Western Michigan University, a BS with high honors in chemistry
from Grand Valley State University, plus graduate studies in business. Mr.
Radford is a Regulatory Affairs Certified professional. Prior to the formation
of Alert Consultants, Mr. Radford held various supervisory positions at Per-
rigo Company (Allegan, Mich.) as it grew from a dozen products to over 800
products and 20,000 product configurations, including quality control su-
pervisor, R&D supervisor, compliance manager, quality assurance director,
business development director, and export and international director. He has
developed a variety of manual and electronic systems that are still being used
today. Mr. Radford is a corporate representative for the the Nonprescription
Drug Manufacturer's Association, the Council for Responsible Nutrition, the
National Association of Pharmaceutical Manufacturers, and other organiza-
tions. He is also a member of many professional organizations, including the
Regulatory Affairs Professional Society, the Food and Drug Law Institute, the
American Association of Pharmaceutical Scientists, the Parenteral Drug Asso-
ciation, the Drug Information Association, and the American Society for
Quality.
Robert J. Seely
Robert Seely specializes in downstream processing, scale-up, troubleshooting,
and validation of recombinant therapeutic protein processes at Amgen. He
has a BS from Oregon State University, an MS in biochemistry from the
xxvi Validation of Active Pharmaceutical Ingredients
Arthur B. Shaw
Arthur B. Shaw serves as an expert in Drug Master Files. He has a BS from the
City College of New York and a PhD in biochemistry from Cornell University.
After postdoctoral work, he joined Revlon Health Care Group's Protein
Chemistry Research and Development Group. He began work at the FDA in
the Division of Gastrointestinal and Coagulation Drug Products in 1990. Af-
ter serving as chair of the Drug Master File Technical Committee, he was rec-
ognized as the FDA's Expert in DMFs in 2000.
Eric B. Sheinin
Eric Sheinin is vice president for general policies and requirements at the
United States Pharmacopeia. Formerly he was the deputy director of the Of-
fice of Pharmaceutical Science of the Center for Drug Evaluation and Re-
search of the Food and Drug Administration. He has a BS in zoology from the
University of Illinois at Champaign-Urbana and a PhD in chemistry from the
University of Illinois at Chicago Medical Center. Previously he held leader-
ship positions in the Office of New Drug Chemistry in the Office of Pharma-
ceutical Science; the Division of New Drug Chemistry III in the Office of New
Drug Chemistry; the Division of Medical Imaging, Surgical and Dental Drug
Products; and the Division of Oncology and Radiopharmaceutical Drug Prod-
ucts. He was also chief of the Drug Standards Research Branch and a research
chemist in the Division of Drug Chemistry of the Center for Drugs and Bio-
logics. Author or coauthor of over 30 publications, he has presented papers
at over 75 scientific conferences. He is a member of the American Association
of Pharmaceutical Scientists, the American Chemical Society, and the USP
Committee of Revision. He is currently a member of the AAPS/APQ Com-
pendia! and Regulatory Affairs Committee.
John Shirtz
john Shirtz is manager of quality control microbiology at Catalytica Pharma-
ceuticals. He has a BS in biology from the State University of New York at Al-
bany and an MS in molecular biology/biotechnology from East Carolina
Author Biographies xxvii
Irwin Silverstein
Irwin Silverstein is a quality assurance specialist at International Specialty
Products, supporting cGMP compliance for the pharmaceutical products
manufactured by the firm, primarily excipients. He has a PhD in chemistry
from New York University. He led the effort that achieved ISO 9002 certifica-
tion in 1991 and assisted in the development of the cGMP compliance pro-
gram. He is a Certified Quality Auditor and Certified Lead Auditor for ISO
9000.
Dr. Silverstein was a founding member of the International Pharmaceu-
tical Excipients Council GMP Committee and was instrumental in the devel-
opment of their Good Manufacturing Practices Guide for Bulk Pharmaceutical
Excipients. He chaired the IPEC committee that developed significant change
and impurity profile guides and helped to develop the recently completed
manufacturer and distributor audit guides.
John Smith
John Smith is a review chemist for the U.S. Food and Drug Administration.
He holds a BA in chemistry from Rutgers University and a PhD in chemistry
from the University of Minnesota. Prior to joining the FDA Office of Generic
Drugs and the Office of New Drug Chemistry, he was a process research and
development chemist with Merck & Co., Inc., and a technical service chemist
in the enhanced oil recovery group at OXY USA, Inc. Dr. Smith has served on
numerous technical committees within the Center for Drug Evaluation and
Research, including the Chemistry, Manufacturing, and Controls Coordinat-
ing Committee; the Packaging Committee; and the Drug Substance Techni-
cal Committee. He is presently the chairman of the Drug Substance Technical
Committee and the BACPAC II Working Group.
Peter D. Smith
Peter D. Smith is director of international compliance services at KMI/Parexel
LLC. He has a BS in biology from Roger Williams College (Bristol, Rhode
xxviii Validation of Active Pharmaceutical Ingredients
Island). Early in his career, Mr. Smith was an investigator for the Food and
Drug Administration, specializing in GMP inspections at drug production fa-
cilities, at API manufacturers, and medical device manufacturers, along with
GLP and clinical study audits. From 1986 to 1984, he was associate director
of the FDA's International and Technical Operations Branch within the Office
of Regulatory Affairs, where he was responsible for foreign field inspections
in human and veterinary pharmaceutical plants. In 1994, Mr. Smith joined
Kemper-Masterson, Inc. (now called KMI/Parexel LLC), where he specializes
in GMP compliance issues. His primary expertise is in the fields of API man-
ufacture, preapproval inspections, nonsterile dosage forms, GMP quality sys-
tems, and FDA regulatory issues. He is a member of the International Society
for Pharmaceutical Engineering and the Parenteral Drug Association.
Kasturi Srinivasachar
Kasturi Srinivasachar is a chemistry team leader in the Division of Cardio-Re-
nal Drug Products of the Center for Drug Evaluation and Research. He has a
PhD in organic chemistry from the University of Chicago. After postdoctoral
appointments at the Swiss Federal Institute of Technology (Zurich), the Uni-
versity of California (Irvine), and the University of Kansas (Lawrence), Dr.
Srinivasachar joined the National Institutes of Health in 1986 to work in the
area of immunotoxins. He was involved in the development of targeted drug
delivery systems using new acid cleavable cross-linking agents for conjugat-
ing toxins like ricin and diptheria toxin to monoclonal antibodies. Dr. Srini-
vasachar joined FDA in 1993 prior to becoming a chemistry team leader. In
addition to his regulatory activities at the Center for Drug Evaluation andRe-
search, he has been engaged in research on antisense oligonucleotides at the
Center for Biologics Evaluation and Research.
Joseph G. Stowell
joseph G. Stowell is director of laboratories for the School of Pharmacy and
Pharmacal Sciences at Purdue University. He has an AB in chemistry from the
University of California at Irvine and a PhD in organic chemistry from the
University of California at Davis, specializing in natural-product synthesis.
Dr. Stowell joined the staff of Purdue University's School of Pharmacy and
Pharmacal Sciences after two years in technical services at Eli Lilly and Com-
pany. Dr. Stowell's research interests encompass the chemistry of pharmaceu-
tical solids, computational chemistry, and pharmaceutical manufacturing.
Author Biographies xxix
Arthur Y. Tsien
Arthur Y. Tsien is a principal at Olsson, Frank, and Weeda, P.C. He has a BS
magna cum laude from Tufts University and a JD from the University of
Washington. He was admitted to the Washington Bar in 1978 and the Dis-
trict of Columbia Bar in 1987. Currently he is a member of the District of Co-
lumbia Bar and the Washington State and American Bar Associations. Mr.
Tsien served as law clerk to Chief Judge Frank D. James of the Washington
Court of Appeals from 1978 to 1980 and as associate chief counsel for veteri-
nary medicine and enforcement at the FDA from 1980 to 1985. He concen-
trates his practice in FDA regulatory issues and litigation.
David F. Weeda
David F. Weeda is a principal of Olsson, Frank, and Weeda, P.C. He has a BA
cum laude from St. Thomas University, Miami, and a JD from the Loyola Uni-
versity of New Orleans School of Law. Mr. Weeda served as associate chief
counsel for biologics and enforcement at the FDA from 1976 to 1981. He
served as adjunct law professor at the Columbus School of Law at Catholic
University of America from 1985 to 1989. He applies his expertise primarily
to assist manufacturers of pharmaceutical and biological products in ap-
proval, regulatory, compliance, and legal matters. He has also defended com-
panies and individuals charged with violating the Federal Food, Drug, and
Cosmetic Act, the Controlled Substances Act, and related federal criminal
laws. He is a frequent lecturer before trade and professional groups and is gen-
eral counsel to the National Association of Pharmaceutical Manufacturers.
Irving L. Wiesen
Irving L. Wiesen is a food and drug law attorney specializing in all areas of law
affecting the pharmaceutical industry, including all areas of FDA regulation-
drug approvals, drug research, Good Manufacturing Practices, FDA proceed-
ings, and promotion and marketing regulations. In addition, his law practice
includes licensing, research, sales and manufacturing agreements, general
commercial and marketing issues, antitrust, personnel, and litigation. Mr.
Wiesen is a graduate of the New York University School of Law, where he was
was also an editor of the Journal of International Law and Politics. Mr. Wiesen is
employed by Ullman, Shapiro, and Ullman, was formerly a partner at Bass and
Ullman, and served for many years as division counsel for Boehringer Ingel-
heim Pharmaceuticals, Inc. Mr. Wiesen has also lectured before all the major
professional organizations serving the pharmaceutical industry and has pub-
lished in periodicals and books on topics relating to FDA regulation.
1
INTRODUCTION
Daniel Harpaz
Harpaz Consulting Services
Suffern, New York
The subjects of Good Manufacturing Practice (GMP) and validation are not
new to the pharmaceutical industry (Berry and Nash 1993; Tetzlaff et al.
1993; Berry 1988; Reisman 1995; Agalloco 1995; FDA 1987, 1994a, 1993a;
Tetzlaff 1992a, 1992b; Tetzlaff 1993; Harpaz 1996; Amer 2000). There have
been discussions on the subject and controversies have arisen and been re-
solved since the 1960s (Gold 1996; Nash 1993; Sharp 1995; Simmons 1997;
Selby 1999; Chapman et al. 2000). For years these issues have been directed
toward the dosage form sector of the pharmaceutical industry. Since 1991, fo-
cus has also been directed toward the manufacturers of active pharmaceutical
ingredients (APis) as evidenced by the U.S. Food and Drug Administration's
(FDA's) increased effort in inspections of domestic and foreign API manufac-
turing facilities and their agents (FDA 1991, 1994b, 1998a; Gold Sheet 1993;
Falcone 1999). In the mid-1990s, the term active pharmaceutical ingredient was
introduced by the FDA instead of bulk pharmaceutical chemical (BPC).
In its Guideline to Inspection, the FDA set the following criteria to identify
an industrial chemical as a BPC (FDA 1991):
1
2 Validation of Active Pharmaceutical Ingredients
Active chemical ingredients and excipients used in drug products may, there-
fore, be considered as BPCs. These materials can be made by chemical synthe-
sis, fermentation, enzymatic reactions, recombinant DNA, recovery from
natural materials, or a combination of the above.
One basic problem that has evolved is that the FDA has not issued GMP
regulations for BPCs as it did for drug products (21 CFR Parts 210 and 211), for
medical devices (21 CFR Part 820), and for foods (21 CFR Part 110). After issu-
ing a revised Guideline to Inspection of Bulk Pharmaceutical Chemicals in 1991,
FDA spokespersons assured the bulk chemical industry that GMP regulations
were to follow. However, with the change in the political environment in
Congress in 1994, the FDA changed its direction and decided to issue a guide
to industry, spelling out specific GMP requirements and clarifying the con-
cepts of process validation for APis, instead of specific GMP regulations. The
first such document was issued in August 1996, where the FDA introduced the
term active pharmaceutical ingredient, or API, instead of BPC. Since the majority
of the APis for U.S. consumption were produced in Europe, the European
Pharmaceutical Inspection Conference (PIC) introduced its own version of
GMP regulations as a guidance document (PIC 1997). In response, the FDA re-
vised its guidance to industry and agreed to develop internationally harmo-
nized GMP regulations (FDA 1998b). The International Conference on
Harmonisation (ICH) API guidance document, known as Q7a, was issued for
public comments at presstime. There are no significant differences between
Q7a and the FDA's 1998 guidance (Rivera Martinez 2000). Details about the
development of GMP regulations for APis are covered in Edwin Rivera-
Martinez's chapter, "The FDA's Perspectives on Active Pharmaceutical Ingredi-
ent Manufacturing, cGMP Controls, and Validation."
As part of the ongoing harmonization for new drugs, the FDA issued nu-
merous guidance documents related to API quality, i.e., specifications, impu-
rities, and stability (FDA 1996, 1997, 1999a; FR 1997, 2000).
The purpose of this book is to provide some food for thought in estab-
lishing guiding principles, and a number of concepts will be developed in this
regard, for example, process validation, cleaning validation, quality assur-
ance, technology transfer, microbial controls, biotechnology, and so on.
GMP CONCEPTS
GMPs, in most simplistic terms, are the minimum requirements that a manu-
facturer must satisfy in producing drugs. The legal ramifications of not com-
plying with GMP and the extension of the GMP regulations for finished
pharmaceuticals to APis are described in the chapter by David Weeda, Arthur
Tsien, Neil O'Flaherty, and Robert Hahn, "The Legal Framework for the Regu-
lation of Active Pharmaceutical Ingredients." Validation is a concept that is
part of the GMP regulations that involves documentation as evidence that a
manufacturing process is in control. Irving Wiesen's chapter, titled "The Legal
Introduction 3
Basis for Validation," explains the relations between GMP and validation. To
clarify its position on validation, the FDA issued a revision to the GMP regu-
lations in May 1996 (FR 1996c) and expanded it in its latest API Guidance
(FDA 1998a, 1998c). The concepts of process validation for nonsterile drug
products are still open to interpretation and are not implemented alike by the
industry (Amer 2000; Chapman and Harpaz 2000). A number of chapters ad-
dress in detail how to validate properly.
Additional terms have been incorporated into the everyday language of
people in the dosage form industry and are significant to those involved with
the API industry. Robert Nash's chapter, API Terminology and Documenta-
11
REGULATORY
APis are considered components of drug products, and therefore are subjected
to FDA regulations (Harpaz 1996). These are numerous and cannot all be cov-
ered in this book. However, those regulations that are related to GMP are
worth mentioning.
Site Registration is a filing process notifying the FDA that a site is being
used for manufacturing, packaging, labeling, and distributing drug. This reg-
istration process applies to domestic and foreign sites, yet distributors of for-
eign-made drugs must register the site of manufacturing and name a U.S.
agent. The U.S. agent will assist the FDA in communication with the foreign
establishment (FR 1999). In addition to informing the FDA about the site,
the drugs must be listed. Drug Listing is a process of submitting appropriate
forms describing the drug product and drug substance that are distributed
(21 CFR Part 207). The distribution of drugs in the United States requires
FDA approval; new drug products and new drug substances (new molecular
entities) are subject to the filing and approval of New Drug Applications
(NDAs). Generic drug products are subject to the filing and approval of
Abbreviated New Drug Applications (ANDAs). Antibiotics are subject to Ab-
breviated Antibiotic Drug Applications (AADAs) (21 CFR Part 314). Drug sub-
stance, intermediate, and excipient manufacturers are expected to submit to
the FDA Drug Master Files (DMFs) (21 CFR Part 314.420). A DMF is a compi-
lation of technical data describing the manufacturing, quality, and controls
of the material. A DMF is not reviewed by the FDA upon application, and it
does not undergo a formal approval process. This confidential and extensive
document is designed to create an open file for review by the FDA only when
an NDA or ANDA is filed by a dosage form manufacturer making reference to
the material described in the DMF (FDA 1989). It is very important that a
DMF holder maintains the currency of the DMF, because it will be examined
for its relevancy during a site inspection by the FDA investigator. In his
chapter, Dr. Arthur Shaw describes in detail the FDA review process for
DMFs.
4 Validation of Active Pharmaceutical Ingredients
For economic or other reasons, frequent changes do occur in the API in-
dustry. In recognition, the FDA issued guidance documents regarding changes
made postfiling (FR 1997b; FDA 1998d, 1999). These are covered in the chap-
ter by Eric Sheinin, Eric Duffy, Kasturi Stinivasachar, and John Smith, "Postap-
proval Changes to Bulk Drug Substances."
practices described in their current DMFs. Fred Radford's chapter, "Quality As-
surance Systems," and Ira Berry's chapter, "Vendor Qualification and Certifi-
cation," describe some of the systems that are required to conform to GMP
regulations. Peter Smith describes his observations in the chapter "Domestic
and Foreign API Manufacturing Facility Audits and Findings." An area of con-
cern to the FDA is a poor change control program and a lack of adequate in-
vestigations. Frank Golden's chapter, "Investigating Process Deviations,"
addresses these issues.
In 1992, the FDA implemented a new policy for the approval of NDAs
and ANDAs. This policy calls for a preapproval inspection (PAl) of the dosage
form manufacturing site to assure compliance with GMP and verification of
the accuracy and completeness of the data presented to the FDA (FDA 1992).
The PAl policy was extended to cover API manufacturers. This event triggered
a large number of inspections of foreign manufacturers (Gold Sheet 1993).
During an inspection of an API manufacturing site, the FDA investigator re-
views compliance with GMP with emphasis on the following areas (21 CFR
Part 314; Avallone 1992a; Anisfeld 1997; FDA 1998a; Falcone 1999)
• Impurity Profile
• Solvent Recovery
• Polymorphism
• Reprocessing
• Change Control
• Cleaning Validation
• Process Validation
• Stability (determination of degradation products and establishing
retest dates)
• Development Reports
Excipient Council (IPEC) issued a proposed GMP for Excipient BPCs in 1995,
and a guide on "Significant Change for Bulk Pharmaceutical Excipients in
2000" (IPEC 1995; IPEC-Americas 2000). Irwin Silverstein describes how to
manage changes in manufacturing in his chapter, "Excipients: Facility, Equip-
ment, and Process Equipment Changes."
This introduction chapter was written to acquaint the reader with the
regulatory requirements for APis. The chapters to follow were written by ex-
perts in their fields and provide more detailed information about the manu-
facturing and control processes of APis.
REFERENCES
Agalloco, J. 1995. Validation: An unconventional review and reinvention. PDA f.
Phann. Sci. & Tech. (July).
Amer, G. 2000. Process validation issues: A discussion with C. Coleman, USFDA. f. Val-
idation Tech. (May).
Anisfeld, M. 1997. Implementation of U.S. GMPs in the manufacture of active ingredi-
ents: A case study of implantation, costs and benefits. Phann. Tech. (April).
Avallone, H. L. 1992a. GMP Inspections of drug-substance manufacturers. Phann. Tech.
(June).
Avallone, H. L. 1992b. Drug substance purity. Phann. Tech. (December).
Barr, D. B., W. C. Crabbs, and D. Cooper. 1993. FDA regulation of bulk pharmaceutical
production. Phann. Tech. (September).
Berry, I. R. 1988. Process validation: Practical applications for pharmaceutical prod-
ucts. Drug Dev. Ind. Phann. 14 (2 and 3).
Berry, I. R., and R. A. Nash, eds. 1993. Phannaceutical process validation. New York: Mar-
cel Dekker, Inc.
Boehlert, J.P. 1997, Impurities-where are we now. Phann. Tech. (June).
Brocklenbank, M.P., and P. V. Deo. 1996. GMP issues for bulk pharmaceutical chemi-
cal plants. Phann. Eng. (January/February): 8-26.
Byrn, S., and R. Pfeiffer. 1995. Pharmaceutical solids: A strategic approach to regulatory
considerations. Phann. Res. (July).
Chapman, K. G., and D. Harpaz. 2000. Proposed validation standard VS-1: Nonaseptic
pharmaceutical processes, introduction and preamble. f. Validation Tech. (February).
Chowhan, Z. 1994. Drug substance physical properties and their relations to the per-
formance of solid dosage forms. Phann. Tech. (March).
DeCamp, W. H. 1999. The impact of polymorphism on drug development: A regulator's
viewpoint. Presented at the Congress of the International Union of Crystallogra-
phy in Glasgow, UK (August).
8 Validation of Active Pharmaceutical Ingredients
EMEA. 1999. Note for guidance on process validation. London: European Agency for the
Evaluation of Medicinal Products.
Falcone, M. 1999, Drug preapproval inspection program 1998 results. Presented at the
Twenty-Third International Good Manufacturing Practices Conference in Athens,
Ga. (March).
FDA. 1987. Guideline on general principles ofprocess validation. Rockville, Md., USA: Food
and Drug Administration, Center for Drugs and Biologics.
FDA. 1989. Guideline for Dmg Master Files. Rockville, Md., USA: Food and Drug Admin-
istration, Center for Drug Evaluation and Research.
FDA. 1991. Guide to inspection of bulk pharmaceutical chemicals: Reference materials and
training aids for investigators. Rockville, Md., USA: Food and Drug Administration,
Center for Drug Evaluation and Research.
FDA. 1992. Pre-approval inspection/investigation. Compliance Policy 7346.832.
Rockville, Md., USA: Food and Drug Administration.
FDA. 1993a. Recommendations for submitting documentation for sterilization process vali-
dation in application for human and veterinary dmg products. Rockville, Md., USA:
Food and Drug Administration, Center for Drug Evaluation and Research.
FDA. 1993b. Guide to inspection of validation of cleaning processes. Rockville, Md., USA:
Food and Drug Administration, Division of Field Investigation.
FDA. 1994a. Guide to inspection of oral solid dosage form pre/post approval issues for devel-
opment and validation. Rockville, Md., USA: Food and Drug Administration, Divi-
sion of Field Investigation.
FDA. 1994b. Guide to inspection of sterile dmg substance manufacturers. Rockville, Md.,
USA: Food and Drug Administration.
FDA. 1996. Guidance to industry, QlB: Photostability testing of new drug substances and
products. Rockville, Md., USA: Food and Drug Administration.
FDA. 1997. Guidance to industry, Q3B: Impurities in new dmg products. Rockville, Md.,
USA: Food and Drug Administration.
FDA. 1998a. Active pharmaceutical ingredients. Compliance Program Guide 7556.002F.
Rockville, Md., USA: Food and Drug Administration.
FDA. 1998b. Guidance for industry-manufacturing, processing or holding active pharma-
ceutical ingredients. Rockville, Md., USA: Food and Drug Administration.
FDA. 1998c. Global harmonization task force study group #3-draft process validation guid-
ance. Rockville, Md., USA: Center for Devices and Radiological Health.
FDA. 1998d. BACPAC I: Intermediates in dmg substances synthesis/bulk active postapproval
changes: Chemistry, manufacturing, and controls documentation. Rockville, Md., USA:
Food and Drug Administration.
FDA. 1998e. Guidance for industry ANDAs: Impurities in dmg substances. Rockville, Md.,
USA: Food and Drug Administration, Center for Drug Evaluation and Research.
FDA. 1999. Guidance for industry, changes to an approved NDA or ANDA. Rockville, Md.,
USA: Food and Drug Administration.
Introduction 9
PhRMA. 1996. PhRMA guideline for the production, packaging, repackaging, or hold-
ing of drug substances, part II. Pharm. Tech. Uanuary).
Reisman, H. B. 1995. Eight rules to live by for successful validations. f. Validation Tech.
(August).
Ressler, R. 1999. Batch crystallization-a good solid solution to tough solids problems.
Pharm. Eng. (September).
Rivera-Martinez, E. 1994. An FDA perspective on bulk pharmaceutical chemical GMPs,
control, and validation. Pharm. Tech. (May).
Rivera-Martinez, E. 1996. Update on international inspections/latest guidance on
GMPs. Paper presented at NAPM BPC Workshop in New York (March).
Rivera-Martinez, E. 2000. FDA's international API inspections-update on ICH Q7 A.
Paper presented at the Synthetic Organic Chemical Manufacturers Association's
Annual Conference in Washington, D.C. (May).
Selby, D. 1999. Can validation improve the bottom line? Pharm. Eng. (November-
December).
Seely, R. ]., et al. 1999. Defining critical variables in well-characterized biotechnology
process. Biopharm (April).
Sharp,]. 1995. Validation-how much is required? PDA f. Pharm. Sci. & Tech. (May).
Simmons, S. ]. 1997. GIPA's bulk audit template. Pharm. Tech. (October).
Tetzlaff, R. F. 1992a. Validation issues for new drug development: Part I. Pharm. Tech.
(September).
Tetzlaff, R. F. 1992b. Validation issues for new drug development: Part II. Pharm. Tech.
(October).
Tetzlaff, R. F. 1993. Validation issues for new drug development: Part III. Pharm. Tech.
Uanuary).
Tetzlaff, R. F., R. E. Shepard, and A.]. LeBlanc. 1993. The validation story: Perspectives
on the GMP inspection approach and validation development. Pharm. Tech.
(March).
21 CFR Part 207. Registration of producers of drugs and listing of drugs in commercial
distribution.
21 CFR Parts 210 and 211. Current Good Manufacturing Practice in manufacturing, pro-
cessing, or holding of drugs: General.
21 CFR Part 314. Application for FDA approval to market a new drug or an antibiotic drug.
21 CFR Part 314.420. Drug Master Files.
2
David F. Weeda
Arthur Y. Tsien
Neil F. O'Fiaherty
Robert A. Hahn
Olsson, Frank and Weeda, P.C.
Washington, D.C.
This chapter provides a broad overview of and perspective on the legal frame-
work by which the U.S. Food and Drug Administration (FDA) regulates active
pharmaceutical ingredients (APis). While validation of APis has recently be-
come a very important FDA regulatory requirement, it is only one of many
API manufacturer obligations under the much broader statutory concept of
current Good Manufacturing Practices (cGMPs). Moreover, while cGMPs are a
very important aspect of the FDA's regulatory control over APis and their
manufacturers, they do not represent the full scope of FDA legal authority
over such products and the companies that make them. While a detailed ex-
position of all of the legal aspects of FDA regulation of APis is beyond the
scope of this brief chapter, we attempt to provide the reader with useful in~
sight into how APis fit into the statutory scheme of the Federal Food, Drug,
and Cosmetic (FD&C) Act, as amended, 21 U.S.C. § 301 et seq., and how the
FDA typically regulates APis in the normal course. We highlight many of the
11
12 Validation of Active Pharmaceutical Ingredients
when a processed chemical substance becomes an API. The FDA has acknowl-
edged that "[t]he question of when an industrial chemical becomes an [API]
can be complex, and there is no satisfactory answer" (FDA 1994, 2). Despite
this uncertainty, the FDA has enumerated three criteria that can be used to
identify when a chemical has become an API:
While these criteria may seem straightforward at first blush, they can
prove most difficult to apply in specific cases. Chemical manufacturers should
consider developing reasonable, "good faith" rationales as to when or if cer-
tain of their products become APis. This may be especially prudent for prod-
ucts for which the manufacturer and the FDA may disagree as to whether the
products are APis or as to when they become APis. Persuasive positions
against treating a particular product as an API (or as an API too soon) may
help to properly minimize the scope and scrutiny of FDA oversight of a chem-
ical manufacturer's operations. API firms may wish to enlist the help of legal
counsel with expertise in FDA regulatory issues in developing such positions.
APis as "Drugs"
Under the FD&C Act, the FDA has authority to regulate, among other articles,
"drugs." The FD&C Act, in relevant part, defines a "drug" as an article
items as "drug products" (i.e., products in a finished dosage form) [21 CFR
§ 210.3(b)(4)]. Consistent with the FD&C Act, the FDA considers APis to be
components of drug products (FDA 1994, 2-BPC Guide). As such, APis meet
the definition of a "drug" under the FD&C Act. They are "articles intended for
use as a component of" a drug product [21 U.S.C. § 321(g)(1)(D)].
API ADULTERATION
Among other things, the FD&C Act is intended to protect the public against
unsafe, ineffective, and/or otherwise violative drug products. There are two
main categories of violative products under the FD&C Act: "adulterated" and
"misbranded" products. Under the FD&C Act, among other things, it is illegal
to introduce, or deliver for introduction, into interstate commerce any drug
that is adulterated or misbranded [21 U.S.C. § 331(a)]. Generally, a drug is
adulterated if there is or may be a compositional defect that makes it unsafe
and/or ineffective or potentially unsafe and/or ineffective. As this book gener-
ally deals with the topic of API validation, we primarily limit our discussion of
violative product categories to circumstances in which an API, as a drug, is
rendered adulterated (e.g., through lack of cGMP compliance generally or
The Legal Framework for the Regulation of APis 15
cGMP Noncompliance
There are several ways an API, as a drug, can become adulterated. Probably the
most common means of adulteration is through noncompliance with the
cGMPs. Under the FD&C Act, a drug is deemed to be adulterated if
[T]he methods used in, or the facilities or controls used for, its
manufacture, processing, packing, or holding do not conform
to or are not operated or administered in conformity with cur-
rent good manufacturing practices to assure that such drug
meets the requirements of this Act as to safety and has the
identity and strength, and meets the quality and purity char-
acteristics, which it purports or is represented to possess
[21 U.S.C. § 351(a)(2)(B)].
The FDA has promulgated regulations enumerating cGMPs for the com-
mercial manufacture of finished dosage form drug products at 21 CFR Parts
210 and 211. The cGMP regulations describe the FDA's expectations regarding
all aspects of pharmaceutical manufacturing. These include organization and
personnel, buildings and facilities, equipment, components (raw materials),
production and process controls, packaging and labeling controls, storage and
distribution controls, laboratory and testing controls, record keeping and re-
porting, and controls for returned and salvaged product. The cGMP regula-
tions require that product complaints be expeditiously investigated and that
appropriate corrective action be taken quickly when warranted. The cGMP
regulations also contemplate that company management will adopt and pre-
serve a corporate philosophy of quality assurance and control that extends to
all FDA-regulated activities of the firm. In short, the cGMP regulations require
pharmaceutical manufacturers to establish and maintain policies and proce-
dures that give reasonable assurances that every commercially manufactured
product batch shipped for human or animal use meets its predetermined
specifications (e.g., strength, purity, quality, stability, etc.).
Legally speaking, APis are not subject to the FDA cGMP regulations be-
cause these regulations technically apply only to finished dosage form drug
products [21 CFR § 211.1(a)]. However, because of the statutory provision
against cGMP noncompliance [21 U.S.C. § 351(a)(2)(B)], API manufacturers
still have a legal obligation to implement and follow some form of cGMPs. As
the FDA has noted, "there are many cases where GMPs for dosage form drugs
and [APis] are parallel" (FDA 1994, 3). As such, the FDA looks to many of the
requirements of 21 CFR Parts 210 and 211 as guidelines for the inspection of
16 Validation of Active Pharmaceutical Ingredients
API manufacturers' cGMP operations. The BPC Guide identifies and interprets
for FDA investigators those portions of Parts 210 and 211 that should be used
as a "regulatory yardstick" in measuring the acceptability of an API manufac-
turer's cGMP operations:
This document [BPC Guide] does not supersede the GMP regu-
lations, rather it provides general guidance to inspectional
personnel as to the extent and point of application of some of
the concepts of Parts 210 and 211 to [API] production (FDA
1994, 3).3
the need for such validation in the context of API manufacturing operations.
In June 1992 the FDA summarized its general views on API process validation
in its Compliance Program No. 7346.832 (Preapproval Inspections):
This language clearly demonstrates the FDA's position that process valida-
tion becomes increasingly important as the API manufacturing process pro-
gresses. It also shows the FDA's realization that the stringency and type of
process validation appropriate to fulfill cGMP obligations is a function of many
factors, including the complexity and intended use of the API in question.
The FDA also appears to realize that process validation is a fairly new con-
cept and a rather significant undertaking for many API manufacturers. There-
fore, it has tailored its expectations and related regulatory actions accordingly:
Yet, the FDA will not hesitate to withhold drug product marketing application
approval for those referencing an API where its manufacturer has an inade-
quate validation plan or repeated failures. The FDA enunciated this policy as
follows:
These FDA statements unmistakably manifest the high priority the FDA
places on API process validation and the FDA's increasing expectation that
API manufacturers fully meet the FDA's validation policies or face adverse ac-
tion for themselves and their finished drug product customers. The FDA's ex-
pectation can already be seen in the string of Warning Letters that have been
issued to API manufacturers over process validation deficiencies since 1992.
(See "Warning Letter," pp. 32-33, and Note 10 for more details.) However,
these statements also manifest the FDA's intent to give the API industry time
to digest and implement its expectations regarding process validation.
Process validation does not end with the FDA's approval of a new drug or
new animal drug. Postapproval manufacturing changes must be validated to
the extent that their effect on the identity, strength, quality, purity, and po-
tency of the drug may affect the drug's safety and effectiveness. Depending on
the nature of the change, the dosage form manufacturer may be required to
obtain FDA prior approval before implementing the change. If a change is
deemed by the FDA to be a "major manufacturing change" (i.e., a change de-
termined by the FDA to have "substantial potential" to adversely affect the
identity, strength, quality, purity, or potency of the drug as these relate to the
drug's safety or effectiveness), the holder of the approved application must
submit, and the FDA must approve, a supplemental application for the
change. For nonmajor changes, the FDA may require a supplemental applica-
tion or merely a report, but the change may be implemented without prior
approval. The supplemental application or report must include information
on the validation of the change and such other information as the FDA may
require [21 U.S.C. § 356a].
In addition, the FDA has issued a draft guidance document recommend-
ing that certain postapproval changes in APis relevant to the performance of
the finished dosage form should be documented, reported to the FDA, and
subjected to chemical, manufacturing, and control tests. 4
Finally, it is worth noting that validation, as a cGMP concept, should not
stop with and be applied only to API production processes. Consistent with
FDA expectations, it also should be applied in other cGMP areas, such as
equipment cleaning and analytical methods. In the BPC Guide, the FDA
opines that cleaning of multiuse equipment is an area where validation must
be carried out. The FDA recommends that the API manufacturer determine
the degree of effectiveness of its cleaning procedure for each API or interme-
diate used on a particular piece of equipment (FDA 1994, 9). According to the
The Legal Framework for the Regulation of APis 19
FDA, validation data should verify that the cleaning process will remove
residues to an acceptable level:
The residue limits established for each piece of apparatus
should be practical, achievable, and verifiable. When review-
ing these limits, ascertain the rationale for establishment of
that level. The manufacturer should be able to document, by
means of data, that the residual level permitted is scientifi-
cally sound (FDA 1994, 10).
Additionally, in discussing laboratory controls to be employed by API manu-
facturers, the FDA comments that "analytical methods should be validated."
The FDA considers this necessary with respect to analytical methods used to
determine an API's conformance to specifications as well as for analytical
methods used to determine levels of remaining residues on equipment (FDA
1994, 23).
API MISBRANDING
A drug, including an API, is generally misbranded if there is something wrong
with its label or labeling that will or could lead to unsafe or ineffective use. For
instance, an API is misbranded if its label or labeling is false or misleading in
any particular (e.g., an untrue representation as to its quality, strength, or pu-
rity) [21 U.S.C. § 352(a)]. In addition, an API is misbranded if its labeling does
not bear adequate directions for use [21 U.S.C. § 352(£)(1)]. Generally, an API
is exempt from bearing adequate directions for use (and thus is not mis-
branded on this basis) if its label bears the statement Caution: For manufactur-
ing, processing, or repacking [21 CFR § 201.122]. However, generally speaking,
this exemption does not apply if the substance is intended for use in manu-
facturing, processing, or repacking operations that cause the finished article to
be a "new drug" or a "new animal drug" unless there is an approved or pend-
ing premarket approval application in effect [21 CFR § 201.122(a)]. An API
also can be exempt from bearing adequate directions for use if it is approved
for investigational use and its label bears the following statement: Caution: For
manufacturing, processing, or repacking in the preparation of a new drug or new an-
imal drug limited by federal law to investigational use [21 CFR § 201.122(b)].
An API also can be misbranded due to circumstances not directly linked
to its label or labeling. An API that purports to be a drug, the name of which
is recognized in an official compendium, is misbranded unless it is packaged
and labeled as prescribed therein (unless the FDA has consented to some
modification) [21 U.S.C. § 352(g)]. In addition, if an API is a bulk drug sub-
stance and its manufacturer is not registered as a manufacturer and/or has not
listed the product with the FDA, the API is considered misbranded [21 U.S.C.
§ 352(o)].
The Legal Framework for the Regulation of APis 21
API INSPECTIONS
Starting in the late 1980s (and primarily resulting from the generic drug
scandal that forced the FDA to rethink its regulatory philosophy related to the
approval of new brand name and generic drugs), the FDA tightened its con-
trols applicable to the manufacture of all drugs, including APis. At approxi-
mately the same time, the FDA was recording less than satisfactory
inspectional results in overseas cGMP audits of API manufacturers exporting
products to the United States. During 1989, the FDA found cGMP deviations,
resulting in adverse inspectional observations, in about 60 percent of all for-
eign bulk firms inspected. One in five (20 percent) of those inspected were
judged by the FDA to have violations of such a magnitude as to make them
unacceptable as suppliers to the U.S. pharmaceutical market.
The FDA's concerns were also heightened by FDA reviewer findings of re-
current problems with drug product applications in the raw materials area. In
a study completed in 1990, the FDA found inadequate information on raw
materials to be the most common problem cited in "not-approvable" letters
issued to ANDA sponsors. The intensive application auditing conducted
by FDA field offices as part of the generic industry investigations and the
22 Validation of Active Pharmaceutical Ingredients
For preapproval drug products, the FDA may inspect and copy R&D docu-
ments that support process validation; these documents often are known in
the trade as technology transfer documents or development reports. As is evi-
denced by the BPC Guide, the FDA appears fairly intent on conducting, as it
deems appropriate, a review of certain product records as part of an API facil-
ity inspection.
API firms must remember that FDA investigators may ask to review
records that they have no legal authority to inspect, such as R&D records not
related to an IND or INAD. However, legal authority or not, once a firm con-
sents to disclosure of records, the investigator's review and inspection of them
is legitimate under the law. API firms need to know the scope of the FDA's in-
spectional authority over product records so they can make informed deci-
sions about disclosure on an FDA investigator's request. When in doubt, a
firm may wish to contact legal counsel with FDA regulatory expertise to dis-
cuss the risks and benefits of disclosing any record.
This program circular applies only to those BPCs which are in-
tended for use as active components of drug products, and the
manufacture of which requires registration under§ 510 of the
Act [21 U.S.C. § 360].
As a general rule, the FDA does not regularly inspect the operations of estab-
lishments that produce BPCs for use as excipients in finished drug products. 7
According to the FDA, inspections of inactive ingredient operations are gener-
ally discretionary. However, such firms can always be inspected "for cause"
(FDA 1994, 3).
An API company's regulatory history and circumstances can greatly af-
fect the level of scrutiny with which the FDA will approach an establishment
inspection. Depending on the perceived status of a particular bulk active
drug substance, the FDA may choose to conduct an abbreviated or full in-
spection of the manufacturer's operations. As an initial matter, the first in-
spection of any API firm is deemed to require a full inspection under FDA
policy (Compliance Policy No. 7356.002F). A full inspection consists of a
complete inspection of all systems and processes of the firm, including the
following:
26 Validation of Active Pharmaceutical Ingredients
Other than these four agreements, however, little progress has been made in
harmonizing regulatory requirements with other countries or reaching agree-
ments for mutual recognition of product approvals or cGMP inspections.
The FDA has taken the position that it cannot rely on a given foreign
regulatory authority unless and until it is satisfied that the regulatory scheme
in that particular country is equivalent to the regulatory scheme enforced by
the FDA. These concerns were reinforced by a 1995 report by FDA's Foreign
Inspection Working Group, which found that a higher percentage of signifi-
cant cGMP problems had been observed at foreign facilities in comparison
with domestic facilities.
Because of these concerns, the FDA's policy statements on harmoniza-
tion endorse the concept of mutual recognition in theory but stress that such
recognition can come only when it is assured that regulatory systems abroad
are equivalent to its own system. As the Foreign Inspection Working Group
explained, "FDA's most important criterion for such agreements must be de-
termining the equivalence of foreign regulatory programs to FDA's programs"
(FDA 1998c). Consistent with this philosophy, the FDA's 1995 Compliance
Policy Guide on International Memoranda of Understanding (MOU), which
sets forth the FDA's overall policy for developing, initiating, and monitoring
MOUs with agencies of foreign governments or international organizations,
stated that before accepting the procedures and activities, including enforce-
ment methods, of foreign governments as equivalent to its own, the FDA will
seek assurance that such activities provide the same level of product quality,
safety, and effectiveness that is provided under the FD&C Act, the Fair Pack-
aging and Labeling Act, the Public Health Service Act, and any other relevant
law of the United States. The FDA may find it necessary to confirm by on-site
review or other appropriate means that the foreign government agency has
the necessary authorities, product standards, capabilities, and infrastructure
to successfully achieve the proposed terms of the MOU and, therefore, that a
determination of equivalence can be made.
The FDAMA included specific provisions directing the FDA to proceed
with efforts to achieve harmonization with Europe. The FD&C Act, as
amended by FDAMA, now requires the FDA to "support the Office of the
United States Trade Representative, in consultation with the Secretary of
Commerce, in efforts to move toward the acceptance of mutual recognition
agreements relating to the regulation of drugs, biological products, devices,
foods, food additives, and color additives, and the regulation of good manu-
facturing practices, between the European Union and the United States"
[21 U.S.C. § 383(c)(2)]. The FDAMA also required the FDA to "participate
through appropriate processes with representatives of other countries to re-
duce the burden of regulation, harmonize regulatory requirements, and
achieve appropriate reciprocal arrangements" and to "make public a plan that
establishes a framework for achieving mutual recognition of good manufac-
turing practices inspections" no later than 180 days after the date of the law's
enactment [21 U.S.C. §§ 383(c)(4), 903(b)(3)].
The Legal Framework for the Regulation of APis 29
equivalent. The annex provides, however, that "under specific and delineated
circumstances" including "serious concern in relation to product quality or
consumer safety," the regulatory authority of the importing party may seek
more information regarding an inspection report and, if not satisfied, carry
out its own inspection.
APis would be covered by the annex on pharmaceutical cGMPs to the
extent that they are regulated by the authorities of both the United States and
the country in which the facility is located. Where the manufacture of APis is
not regulated by the country in which an API manufacturer is located, the
FDA will continue to require that the FDA itself inspect and pass the facility,
as a precondition for permitting importation of either the APis or a finished
product made from those APis.
Other than the individual agreements with Sweden, Switzerland, Can-
ada, and Australia, and the new MRA with the EC, there are no other signifi-
cant efforts underway to harmonize inspection systems for drugs, including
APis. APis manufactured domestically for use in other countries will likely
have to conform to the requirements of the country of destination, unless
that country unilaterally recognizes the U.S. regulatory scheme. Manufactur-
ers of APis in such countries who wish to import their products into the
United States (or sell their products to finished dosage form manufacturers for
importation into the United States) will have to comply with U.S. cGMPs and
will have to permit FDA inspection.
Administrative Tools
Form FDA 483
At the end of an establishment inspection, if the FDA investigator has ob-
served what he or she regards as significant violations, the investigator will
generally issue to the inspected firm a list of inspectional observations,
known as a "Form FDA 483." 9 While not required, it is considered extremely
prudent to respond to a Form FDA 483 in writing. The response should ad-
dress any factual inaccuracies in the observations and explain what the firm
intends to do to address each legitimate observation, including a description
of any relevant corrective action plan. Inspected companies receiving a Form
FDA 483 should respond to the FDA promptly. While there is no required
time frame for a response, we suggest attempting to respond within 10 work-
ing days (or 2 weeks) of receiving the inspectional observations. If more time
is needed to respond adequately, we suggest contacting the relevant FDA of-
fice or district to acknowledge that the firm takes the Form FDA 483 seriously
and is working on a response to fully address FDA observations, giving an es-
timate as to when a response will be submitted. There have been several in-
stances in which a firm has not responded to a Form FDA 483 within 30 to
45 days and the firm's response has crossed in the mail with an FDA Warning
Letter, as discussed below.
Warning Letter
Oftentimes, if a firm neglects to or is late in responding to a Form FDA 483, or
the FDA is not satisfied with the company's response, the FDA will issue a
Warning Letter to the firm. A Warning Letter constitutes an FDA communica-
tion notifying an individual or firm that the FDA considers one or more prod-
ucts, practices, processes, or other activities to be in violation of the FD&C
Act, or other acts, and that failure of the responsible party to take appropriate
and prompt action to correct and prevent any future repeat of the violation
The Legal Framework for the Regulation of APis 33
Recall
Besides issuing Forms FDA 483 and Warning Letters, the FDA can also,
through publicity or otherwise, attempt to pressure a firm to conduct a vol-
untary recall. While the FDA has no legal authority to require the recall of
drugs, such pressure is often effective given that the FDA could alternatively
seek seizure and condemnation, an injunction, and/or criminal prosecution
to address the existence of violative distributed product. The FDA has issued
guidelines for conducting voluntary recalls in 21 CFR Part 7. A "recall" is de-
fined as a firm's removal or correction of a marketed product that the FDA
considers to be in violation of the laws that it administers and against which
the FDA would initiate legal action (e.g., seizure) [21 CFR § 7.3(g)]. A "correc-
tion" means a repair, modification, adjustment, relabeling, destruction, or in-
spection (including patient monitoring) of a product without its physical
removal to some other location [21 CFR § 7.3(h)]. In short, a company's con-
duct of a voluntary recall is often viewed as the "nonlegal" alternative to the
FDA's seeking to institute a legal proceeding to address distributed product
that is in violation of the FD&C Act.
Judicial Tools
The FD&C Act gives the FDA authority to take more serious actions against
adulterated or misbranded drugs in U.S. commerce and their companies and of-
fidals, beyond Forms FDA 483 and Warning Letters. 11 Through recommenda-
tion to the U.S. Attorney, the FDA can seek to have certain legal actions initiated
in federal district court. The actions are brought by the U.S. Attorney because
the FD&C Act provides the FDA with no independent litigation authority. Due
to the serious nature and possible ramifications of FDA legal actions, it is essen-
tial for defendants to retain legal counsel to represent their rights.
defendant in the case (i.e., it is an in rem legal action). In such an in rem ac-
tion, the federal government seeks to condemn the FDA-regulated article and
declare its forfeiture due to a violation of the FD&C Act. Any interested party,
owner, or agent may appear to claim the article by filing a verified claim stat-
ing the nature of his/her/its interest in the article. The interested company or
individual can then defend the article against condemnation and forfeiture in
court.
Usually, a seizure will be preceded by prior notice by the FDA to respon-
sible company officials that their product(s) is in violation of the laws en-
forced by the FDA. For instance, the FDA might issue a Warning Letter prior to
commencing a seizure action. However, the FDA does at times proceed with-
out prior notice if it perceives the violation is intentional or flagrant, involves
willful fraud, or presents a reasonable possibility that someone might be in-
jured or die (RPM, ch. 4, pp. 79 and 174).
Injunction
Through the U.S. Attorney, the FDA can also initiate a legal action in federal
district court to enjoin a drug firm and its responsible officials from violating
the FD&C Act (e.g., promoting and distributing allegedly violative drugs, in-
cluding APis) [21 U.S.C. § 332]. The purpose of an injunction is to halt the
flow of violative products in interstate commerce and to correct conditions
that caused the violation to occur. It is not mandatory to demonstrate that
the law has been violated to seek an injunction. It is only necessary to show
that there is a likelihood that it may be violated if an injunction is not
entered. According to the FDA, an injunction should be considered for
any significant "out-of-compliance" circumstance, but particularly when a
health hazard related to the violation has been identified (RPM, ch. 6, p. 187).
The FDA may consider an injunction to be appropriate when violations
are pervasive and affect many different products (e.g., significant cGMP viola-
tions).
Criminal Prosecution
The FDA, through the U.S. Attorney, can also initiate criminal proceedings in
federal district court against a drug company and/or its officers and employ-
ees as individuals for violating the FD&C Act. To be convicted of a misde-
meanor violation of the FD&C Act, criminal intent (mens rea) is not required
[21 U.S.C. § 333(a)(1)]. Misdemeanors are punishable by a maximum of one
year incarceration, a maximum fine of $100,000 for individuals (and
$200,000 for corporations) per offense, or both [21 U.S.C. § 333(a)(1);
18 U.S.C. § 3571(b) and (c)].l 2 To be convicted of a felony violation of the
FD&C Act, the activity must involve an "intent to defraud or mislead" or be a
repeat FD&C Act offense. Felony violations are punishable by a maximum of
36 Validation of Active Pharmaceutical Ingredients
Before a violation of the FD&C Act is reported by the FDA to any U.S. At-
torney for institution of a criminal proceeding, the prospective defendant
must be given appropriate notice and an opportunity to present his or her
views, either orally or in writing, with regard to such recommendation for
prosecution [21 U.S.C. § 335]. Therefore, companies that and individuals
whom FDA is considering for prosecution have an opportunity to persuade
the FDA not to proceed further with a criminal action. Representation by legal
counsel is essential at this preprosecution stage.
It is important to remember that corporations can be held accountable
for the actions of their employees and agents acting within the scope of their
employment or agency, even if the wrongful acts are committed by lower-
level employees or representatives. Moreover, company officers can be held
personally responsible for FD&C Act violations in criminal proceedings. The
standard of liability for corporate officers under the FD&C Act was construed
in United States v Park, 421 US 658 (1975). Under the Park case, a corporate of-
ficer may be convicted of a misdemeanor under the FD&C Act if the prosecu-
tion demonstrates that the officer "had, by reason of his position in the
corporation, responsibility and authority either to prevent in the first in-
stance, or promptly to correct, the violation complained of, and that he failed
to do so." Criminal liability is not based merely upon actual "awareness of
some wrongdoing" or "conscious fraud" (United States v Park [421 US at
The Legal Framework for the Regulation of APis 37
673-674]). This is because "the [FD&C] Act imposes not only a positive duty to
seek out and remedy violations when they occur but also, and primarily, a
duty to implement measures that will insure that violations will not occur."
Although the U.S. Supreme Court in Park recognized such a standard created a
great burden on corporate officers, it explained that such a standard is "no
more stringent than the public has a right to expect of those who voluntarily
assume positions of authority in business enterprises whose services and prod-
ucts affect the health and well-being of the public that supports them" (United
States v Park [421 US at 672]).
A corporate officer's guilt may not, however, be based solely on his or
her corporate position. A corporate officer may defend himself/herself on the
basis that he/she was "powerless" (i.e., lacked authority) to prevent or correct
the violation. In making such a claim, the officer has the burden of producing
evidence, but the ultimate burden still lies with the government, which must
prove the officer's guilt beyond a reasonable doubt, "including his power, in
light of the duty imposed by the [FD&C] Act, to prevent or correct the pro-
hibited condition" (United States v Park (421 US at 672-673]).
Sampling and Related Procedures. Under its§ 381 authority, the FDA can
sample FDA-regulated articles, including APis, offered for import. Upon sam-
pling product for testing, the FDA will issue a "Notice of Sampling" (Form
38 Validation of Active Pharmaceutical Ingredients
FDA 712) to the owner or consignee of the product. If the shipment is found
to be in compliance after examination, the FDA will issue a "Release Notice"
(Form FDA 717) to the owner or consignee. If sample examination indicates
the article appears to be in violation, the FDA will issue a "Notice of Detention
and Hearing" (Form FDA 718). In that notice, the FDA will specify the nature
of the violation and set a place at which the owner or consignee can provide
oral or written testimony as to the admissibility of the article into U.S. com-
merce. Generally, the notice allots a time period of 10 working days during
which testimony may be offered. Extensions can be granted when reasonable
(RPM, ch. 9, p. 41). After the hearing, the FDA will issue either a Release No-
tice or a "Notice of Refusal of Admission" (Form FDA 772). If a refusal notice
issues, the notice will provide that the prodl!ct must be destroyed or exported
under the U.S. Customs Service's supervision within 90 days of the notice
(RPM, ch. 9, p. 41). The owner or consignee can also attempt to bring an arti-
cle into compliance with the FD&C Act or to remove it from the FDA's juris-
diction by timely submitting a "Request for Authorization to Relabel or
Perform Other Acts" (Form FDA 766). Such reconditioning (e.g., converting
product from drug use to another use) can avoid the need for product de-
struction or reexportation.
Automatic Detention/Import Alert. The FDA also has the authority to auto-
matically detain imported product (i.e., to place the product on "Import
Alert"). Under FDA policy, automatic detention should be recommended
whenever there is information that indicates that future shipments of a prod-
uct or products offered for entry into the United States appear violative
within the meaning of 21 U.S.C. § 381(a). An Import Alert may cover a spe-
cific manufacturer, or geographic area or country, if information supports
such a broad Import Alert (RPM, ch. 9, p. 347).
There are many circumstances and situations that could lead the FDA to
institute automatic detention through issuance of an Import Alert. An API
could be placed on automatic detention based upon one violative sample
where use of the product may lead to adverse health consequences, or where
the product is violative in a way that is likely to continue because of the prod-
uct's ingredients or formulations (e.g., due to unapproved color additives or
because the API's composition does not meet an applicable standard of iden-
tity) (RPM, ch. 9, pp. 347-348). Automatic detention recommendations also
can be based on multiple violative samples. In relevant part, under FDA policy
the FDA considers recommendations for automatic detention to be appropri-
ate for the following:
reinspection, establishing that the appearance of the violation(s) has been re-
moved, is usually required before the Import Alert will be canceled for that
firm (RPM, ch. 9, p. 350).
The provisions of§ 381(e)(1) apply to the export of unapproved new animal
drugs unless banned in the United States [21 U.S.C. § 381(e)(3)J.
Drugs exportable under§ 381(e) may be labeled in accordance with the
requirements of the country of destination if also labeled in accordance with
FDA requirements. However, the labeling must state that any conditions of
use unapproved in the United States have not been approved by the FDA
[21 u.s.c. § 381(f)J.
Section 381(e) does not govern the export of unapproved new drugs for
human use and unlicensed biological products. These products are governed by
21 U.S.C. § 382.15 Section 382 provides three alternative mechanisms for
exporting unapproved new drugs and unlicensed biologicals for foreign
The Legal Framework for the Regulation of APis 41
commercial use. First and most importantly, any unapproved product may be
exported to any country without FDA export approval, if the product is lawful
in the country of destination and has been approved for marketing in one of
the following 25 listed countries: Australia, Canada, Israel, Japan, New Zealand,
Switzerland, South Africa, and countries in the European Union or the Euro-
pean Economic Area. 16 Second, any unapproved product may be exported,
without FDA export approval, to a country not listed above, if the product is
lawful in the country of destination and the FDA determines that the destina-
tion country has adequate requirements concerning drug product safety and
effectiveness, GMPs, adverse reaction reporting, and drug labeling and promo-
tion. Third, a petition process is available for persons seeking to export a prod-
uct under conditions that do not comply with either the first or second
criterion set forth above [21 U.S.C. § 382(b)]. Exporters of unapproved new drugs
and unlicensed biologicals under§ 382(b) must provide the FDA with a "simple
notification" at the time of first export, identifying the drug (and the country, if
not one of the 25 listed countries). Exporters must also maintain records of the
products being exported and the destination countries [21 U.S.C. § 382(g)].
Certain other provisions of § 382 govern the export of unapproved new
drugs and unlicensed biologicals for investigational and manufacturing uses.
Such new drugs and biologicals may be exported for investigational use to any
of the 25 listed countries in accordance with the laws of the relevant foreign
country and without FDA export approval or compliance with the FDA's IND
requirements [21 U.S.C § 382(c)]. Although notification to the FDA is not tech-
nically required for such exports, an FDA draft guidance advises that "firms
that export a product in anticipation of market authorization ... notify the
FDA when they export the product" (FDA 1998a). An unapproved new drug or
unlicensed biological intended for formulation, filling, packaging, labeling, or
further processing in anticipation of marketing approval in any of the 25 listed
countries may be exported pursuant to the relevant foreign country's laws,
without FDA export approval or notification to the FDA [21 U.S.C. § 382(d)].
If an API is an unapproved new drug for human use or an unapproved
new animal drug for animal use, it is subject to the requirements of§ 382 for
purposes of export. Other BPCs (e.g., inactive ingredients or excipients,
FDA-approved APis, and APis for use in OTC drug products subject to FDA
promulgated monographs) can be exported pursuant to 21 U.S.C. § 381 if
they do not comply with the FDA requirements (i.e., they are adulterated,
misbranded, or otherwise violative).
The export provisions of§§ 381 and 382 were revised in April and Au-
gust 1996, and it is unclear how certain provisions apply to APis. For example,
the bulk active ingredient for an unapproved new drug is treated as an unap-
proved new drug by the FDA. However, in applying this concept to the export
of such a bulk active ingredient for further processing in a listed country un-
der§ 382, the result appears to be that the FDA must be given export notifica-
tion if the unapproved finished dosage new drug is approved in the foreign
country [21 U.S.C. § 382(b) and (g)], while notification is recommended but
42 Validation of Active Pharmaceutical Ingredients
not required if approval is anticipated [21 U.S.C. § 382(d)]. In June 1998 the
FDA issued a draft guidance document titled Draft Guidance for Industry on Ex-
ports and Imports Under the FDA Export Reform and Enhancement Act of 1996,
setting forth its interpretations of the export provisions of§§ 381 and 382 and
addressing certain inconsistencies in the provisions (FDA 1998a).
DMFTypes
There currently are five types of DMFs:18
CONCLUSION
APis are actively regulated articles under the FD&C Act. Increasingly, the FDA
has used its authority over "drugs," as given in the FD&C Act, to monitor, reg-
ulate, and enforce the quality, strength, and purity of APis for use in human
and animal drug products, as well as biologics. The FDA views APis as having
a significant and direct impact upon the safety and effectiveness of the fin-
ished drug products and biologics in which they are used. Currently, the FDA
appears to be heavily focused on the cGMP compliance status of both foreign
and domestic API manufacturers as a means of asserting tighter control over
the quality of the finished drug products and biologics in which they are
used. The FDA is conducting more frequent and more in-depth establishment
inspections of API manufacturers, both domestically and overseas, as a means
of more closely overseeing API cGMP compliance. The FDA's attention is
especially directed at issues concerning API validation. Increasingly, the FDA
is using Warning Letters to enforce cGMP compliance by API firms; but it
must be remembered that the FDA also has the ability to act more harshly
against noncompliant API manufacturers by seeking seizure and condemna-
tion of products, injunctions against manufacture and/or distribution, and
criminal prosecution of firms and their officers and employees. The FDA's
ability to regulate the import of APis into the United States for use in the
manufacture of finished drug products and biologics also gives the FDA a
strong enforcement tool against noncompliant foreign API manufacturers.
The FDA can use its import sampling, detention, and "refusal of admission"
authority to regulate the influx of foreign APis or to bar their entry when the
FDA has concerns regarding their quality or safety.
Finally, the FDA has established the DMF system by which API firms can
submit information regarding their products to the FDA, in support of drug
product and study applications, without having to divulge formulation, man-
ufacturing process, or other proprietary information to its applicant cus-
tomers. The quality of information and data submitted in an API
manufacturer's DMF, as well as the API manufacturer's ultimate conformance
to representations made in its DMF, can greatly impact on the fortunes of its
customers' drug product and/or study applications, often greatly contributing
to their approval or nonapproval.
NOTES
1. A company that makes BPCs that are not APis (i.e., excipients or in-
termediates) is not subject to the registration requirement and
therefore is not subject to mandatory biennial inspection [21 U.S.C.
§ 360(g); 21 CFR § 207.10; See 21 CFR § 207.3(a)(4)].
46 Validation of Active Pharmaceutical Ingredients
REFERENCES
Code of Federal Regulations, 21 CFR Parts 7, 20, 201, 207, 210, 211, 312, 314, and 511.
Compliance policy guides§ 490.100 (Process validation requirements for drug products
subject to pre-market approval). CPC no. 7132c.08; 30 August 1993. Rockville,
Md., USA: Food and Drug Administration.
Compliance program guide manual, Compliance program nos. 7346.832 (Pre-approval
inspections) and 7356.002F (Bulk pharmaceutical chemicals). Rockville, Md., USA:
Food and Drug Administration.
FDA. 198 7. Guideline on general principles ofprocess validation. Rockville, Md., USA: Food
and Drug Administration.
FDA. 1989. Guideline for drug master files. Rockville, Md., USA: Food and Drug Admin-
istration.
FDA. 1994. Guide to inspection of bulk pharmaceutical chemicals: Reference materials and
training aids for investigators. Rockville, Md., USA: Food and Drug Administration,
Center for Drug Evaluation and Research.
FDA. 1998a. Draft guidance for industry on exports and imports under the FDA export reform
and enhancement Act of 1996. Rockville, Md., USA: Food and Drug Administration.
FDA. 1998b. Draft guidance for industry on bulk actives postapproval changes: Chemistry,
manufacturing, and controls documentation (BACPAC I: Intermediates in drug substance
synthesis). Rockville, Md., USA: Food and Drug Administration.
The Legal Framework for the Regulation of APis 53
FDA. 1999. Guidance for industry: ANDAs: Impurities in drug substances. Rockville, Md.,
USA; Food and Drug Administration.
FDA Regulatory Procedures Manual: August 1997: Chapters 4 (Advisory Actions), 6 Oudi-
cial Actions), and 9 (Import Operations/Actions).
Federal Food, Drug, and Cosmetic Act, 21 U.S.C. § 301 et seq.
Federal Rules of Criminal Procedure Nos. 17 and 41.
FR. 1985. New drug and antibiotic regulations. Federal Register 50:7452, 7489 (Feb. 22,
1985).
FR. 1991. New drug and abbreviated new drug applications; proposed preapproval in-
spection requirements. Federal Register 56:3180 Oan. 28, 1991).
FR. 1993. New drug and abbreviated new drug applications; preapproval inspection re-
quirements. Federal Register 58:47340 (Sept. 8, 1993).
FR. 1995. New drug applications; Drug Master Files. Federal Register 60:34486 Ouly
3, 1995).
FR. 1998a. Mutual recognition of the FDA and European Community Member State
conformity assessment procedures; pharmaceutical GMP inspection reports. Fed-
eral Register 63:17744 (April10, 1998).
FR. 1998b. Removal of regulations regarding certification of antibiotic drugs. Federal
Register 63:26066 (May 12, 1998).
FR. 1998c. Draft guidance for industry; exports and imports under the FDA Export Re-
form and Enhancement Act of 1996. Federal Register 63:32219 Oune 12, 1998).
FR. 1998d. Mutual recognition of pharmaceutical good manufacturing practice inspec-
tion reports ... between the United States and the European Community. Federal
Register 63:60122 (Nov. 6, 1998).
FR. 1999a. List of bulk drug substances that may be used in pharmacy compounding.
Federal Register 64:996 Oan. 7, 1999).
FR. 1999b. Foreign establishment registration and listing. Federal Register 64:26330
(May 14, 1999).
FR. 2000a. International Conference on Harmonisation; draft revised gudiance on im-
purities in new drug substances. Federal Register 65:45085 Ouly 20, 2000).
FR. 2000b. International Conference on Harmonisation; draft guidance on Good Man-
ufacturing Practice for active pharmaceutical ingredients; availability. Federal Reg-
ister 65:46936 (Aug. 1, 2000).
House Committee on Commerce, Subcommittee on Oversight and Investigations,
Oversight hearing regarding: U.S.-EU (European Union) mutual recognition agreement on
drug inspections, 105th Congress, 2nd session, 1998, p. 4.
In re Grand Jury Subpoenas, 803 F2d 493 (9th Cir 1986).
In re Medtronic, Inc., 500 F Supp 536, 540-541 (D Minn 1980).
54 Validation of Active Pharmaceutical Ingredients
Irving L. Wiesen
Attorney at Law
Stamford, Connecticut
The U.S. Food and Drug Administration's (FDA) emphasis on the validation
of the drug and device manufacturing process represents the continuation of
a lengthy progression of increasingly strict scrutiny over the process and con-
text of drug manufacture that has emerged in the regulatory, judicial, and
legislative realms. This progression, driven by a widely perceived need for the
strictest public protection, has been facilitated by the very flexibility and
open-endedness of the FDA's regulatory scheme, which has allowed its evo-
lution on the basis of providing a dynamic and progressive standard for drug
quality. This has resulted in a legal and regulatory framework far different
from that envisioned in the early food and drug statutes; it represents a con-
ceptual shift in the nature of the drug manufacturing process and its rela-
tionship to government and the consumer.
55
56 Validation of Active Pharmaceutical Ingredients
rather than of its method of manufacture. Thus, the quality of a drug prod-
uct was historically determined on the basis of the conformity of the final
product with standards of drug quality, purity, and strength established for
each drug product. The first legislative initiative involving drugs, for exam-
ple, the Pure Food and Drugs Act of 1906, mandated merely that drugs listed
in an official compendium were required to meet the standards of quality, pu-
rity, and strength contained in that compendium, unless otherwise indicated
on the drug label. Similarly, standards of quality applied to the newly emer-
gent field of antibiotic drugs in the 1940s required testing of each batch of
manufactured product prior to its release for marketing.
The flaw in these approaches to drug quality was that standards applica-
ble only to the physical, final drug product could be satisfied only by testing
the final product to determine that it met the relevant quality standards.
Such a methodology, to be effective, necessarily required a large sampling of
final product in order to yield results sufficiently valid to be extrapolatable to
the batch or product run as a whole. Thus, the typical sampling sizes were not
statistically reliable as an indicator of the quality of the batch as a whole.
Moreover, it was difficult, if not impossible, to determine what percentage of
finished product defects would render the entire batch unacceptable. It even-
tually became apparent that no adequate statistical model for finished prod-
uct testing could be constructed that would not be economically prohibitive
but that could also provide an adequate measure of drug quality for the batch
as a whole. A new approach was needed to ensure product quality. 1
Congress was quite concerned about the uneven and sometimes un-
acceptable quality of drug products from some portions of the phar-
maceutical industry. The purpose of section S01(a)(2)(B) of the act is
to provide assurance that the drug product quality would not fall be-
low that which was feasible and available under contemporary tech-
nology (FR 1978).
The cGMP standards enacted into law in the 1962 statute that are ap-
plicable to drugs are described in Section 501(a)(2)(B) [21 U.S.C. 351(a)(2)(B)]
as relating to "[t]he methods used in, or the facilities or controls used for, its
manufacture, processing, packing, or holding." These methods, facilities, and
controls used in manufacturing, packing, or holding, the statute continued,
were to be
The statute determined that failure to meet this standard would cause the
drug product itself to be considered "adulterated" and subject to legal seizure
and sanction. Thus, in an important departure from the previous statutory
scheme, the 1962 Amendments determined the quality status of the final
product on the basis of the method of manufacture and storage, rather than
on the content and quality of the final drug product itself.
The reason for the shift in scrutiny back into the production process was
the perceived need to enact stricter controls over drug quality. As one semi-
nal court opinion noted,
[T]he GMP provision stems from congressional concern over the dan-
ger that dangerously impure drugs might escape detection under a
system predicated only on seizure of drugs shown to be in fact adul-
terated. In order to insure public safety, Congress determined in 1962
that it was necessary to regulate the means of production themselves
(United States v. An article of drug . . . George N. Bell Manufacturing
Chemists [484 F.2d 748, 749 (7th Cir. 1973)].2
58 Validation of Active Pharmaceutical Ingredients
As other courts have found, echoing the legislative history behind the 1962
Amendments,
(T]he 1962 amendments were intended to strengthen and broaden
the Act by effecting better, safer medicine and a more effective system
of enforcement (United States v. Bel-Mar Laboratories, Inc. [284 F.Supp.
875, 880-01 (E.D.N.Y. 1968], citing 1962 U.S. Code Cong. & Admin.
News, p. 2884).
More specifically, the court noted,
[t]he purpose of Section 3Sl(a)(2)(B) was to attack commerce in un-
safe and unreliable drugs in its incipiency by giving the Food and
Drug Administration (FDA) " ... additional authority to require that
sound methods, facilities, and controls be used in all phases of drug
manufacturing and distribution" (1962 U.S. Code Cong. & Admin.
News, p. 881).3
Advancing the quality control standards into the manufacturing process
was thus perceived as a better preventive quality measure that would better
prevent the marketing of unsafe products. As one court noted,
[T]he GMP provisions of the statute for devices and human drugs and
their implementing regulations, are prophylactic measures designed
to prevent the distribution of poorly manufactured drugs and devices .
. . . Simply put, the GMP regulations are intended to be preventive,
by requiring manufacturers to build quality into their devices, rather
than permit a defective device to be distributed and used to treat pa-
tients. (United States v. 789 Cases [799 F.Supp. 1275, 1285 (D. Puerto
Rico 1992)]). 4
An important feature of the cGMP standard embodied in Section SOl is
that it leaves open the question of what specific standards must be employed
in the manufacturing process, leaving that determination to the FDA and to
the evolution of industry standards, as these are developed and applied within
the industry. The FDA, taking the initiative from its Congressional mandate,
developed an extensive set of standards, which it codified in the Code of Fed-
eral Regulations (CFR), Title 21, Parts 210 and 211, containing its views of
those areas of a manufacturer's operations that must conform to the cGMPs.
These areas include facilities, personnel, production, process and package op-
erations, and controls as well as labeling, containers and closures, laboratory
procedures, and handling and control of records and documentation. 5
As noted, the statute was fashioned by Congress to be deliberately vague
on the precise standards that constitute the cGMPs, having determined that
the statutory purposes of quality assurance were best met by a flexible, chang-
ing, and FDA-determined set of standards. It is this very indeterminacy,
however, that laid the statute open to challenge as unconstitutional because
The Legal Basis for Validation 59
time there is enforcement action" (FR 1978), thus further buttressing the
FDA's position that binding rules were intended by Congress. Moreover, the
FDA showed, Congress looked to a streamlined procedure for the adoption of
the FDA's regulations, to avoid a lengthy and wasteful period of rule-making
before the new standards could be adopted. The FDA concluded,
[T]o the extent that a stronger Congressional mandate can be gleaned
from the various reports, amendments, and debates, it appears that
binding standards were to be issued by FDA and issued through ...
less cumbersome notice-and-comment rule making procedures.
(FR 1978).
In addition to its analysis of the legislative history, the FDA further ana-
lyzed the judicial precedent that established its authority to issue binding reg-
ulations under Section 701(a) of the Act. 6 Comparing its cGMP regulations
with other rule-making involving prescription drugs, in particular the FDA's
new drug" review procedures applied to over-the-counter (OTC) drugs, the
11
FDA found the same considerations at work as were cited by the courts in
support of the FDA's rule-making powers. 7 The binding nature of the FDA's
regulations, these courts observed, were based on the strong policy of public
protection that demanded strong standards, subject to reasonable, but not
paralyzing, judicial review. The FDA, summarizing the policy expressed in
these judicial opinions, noted,
[t]he statutory standard of current good manufacturing regulations"
11
In the case of United States v. An article of drug ... George N. Bell Manufac-
turing Chemists [484 F.2d 748-750 (7th Cir. 1973)], the defendant, charged
with violations of the cGMPs, attacked the statute as void for vagueness due
to the imprecision in the terms current and good. The court, rejecting this ar-
gument, noted that these terms presented no unconstitutional vagueness.
Defining the term current, the court held that it fulfilled a sufficiently precise
and definable purpose by differentiating obligations based on the time they
emerge into general acceptance as industry standards:
[t]he term current fixes the point in time when the acceptability of the
relevant production practices must be determined. Thus, the statute
does not permit prosecution for failure to follow safety practices which
were not recognized prior to the production of the subject drugs.
The term good, the court went on to say, was also meaningful, notwith-
standing the fact that many dictionary meanings could be found for the
word. Conceding, however, that the word was not precise, the court noted
that "[t]he Constitution requires only a reasonable degree of certainty in
statutory language." Quoting previous opinions of the U.S. Supreme Court
on this issue, the court declared that a certain degree of imprecision is not
only inevitable, but desirable as well:
[F]ew words possess the precision of mathematical symbols, most
statutes must deal with untold and unforeseen variations in factual
situations, and the practical necessities of discharging the business of
government inevitably limit the specificity with which legislators can
spell out prohibitions. Consequently, no more than a reasonable de-
gree of certainty can be demanded. Nor is it unfair to require that one
who deliberately goes perilously close to an area of proscribed con-
duct shall take the risk that he may cross ... the line (Boyce Motor
Lines, Inc. v. United States [342 U.S. 337, 340]). 11
Moreover, the Bell court noted, the statute could not be viewed separately
from the FDA's regulations that were specifically authorized and mandated by
the statute. Congressional intent in drafting the legislation contemplated
that the regulations would operate in tandem with the statute.
"[T]he Secretary's interpretative regulations as to good manufacturing
practice for purposes of judging the adequacy of the methods, facili-
ties, and controls," the court stated, quoting Congress, "would be
prima facie evidence of what constitutes current good manufacturing
practice in any proceeding involving 351(a)(2) of the Federal Food,
Drug, and Cosmetic (FD&C) Act as amended by the bill" (1962 U.S.
Cong. & Admin. News, p. 2890).
The court concluded the FDA's regulations themselves, in providing stan-
dards under the cGMPs, "considerably illuminate the statutory language"
The Legal Basis for Validation 63
and served, in effect, as the legal definition of the terms (United States v. An
article of drug . .. George N. Bell Manufacturing Chemists [484 p. 2d 750]).12
Other courts addressing the issue of the vagueness of the cGMPs have
pointed to the all-encompassing regulatory scheme that was a product of col-
laboration between the FDA and the drug industry, and that, accordingly,
provides substance and meaning to the term cGMPs. In United States v. Bel-
Mar Laboratories, Inc. [284 F.Supp. 875, 883 (E.D.N.Y. 1968)], the court noted
the term "is not strange to those in the trade to whom the subject section is
directed." Citing practices reaching back to 1948, the court traced early enun-
ciations of the cGMPs to a cooperative effort between the FDA and industry
in which a series of inspections of drug manufacturers was combined with ed-
ucational conferences to establish the more progressive industry practices as
"good manufacturing practices." This program was extended and institu-
tionalized by the 1962 Amendments as minimum requirements. Accordingly,
the court in Bel-Mar noted,
[t]his is not a case where there is no meaningful referent in business
practice or usage ... or where there are no regulations in point avail-
able for guidance.... Indeed, the drug industry has actively partici-
pated in the regulatory process, and the regulations emerging
therefrom have been carefully considered.n
Finally, the courts have noted, it was Congress' purpose in enacting the
cGMP standard that it be flexible and able to encompass the changing stan-
dards of ever-changing and improving product manufacturing. Thus, the
court noted in United States v. Morton Norwich Products, Inc. [1975-1977 Jud.
Rec. 169 (N.D.N.Y.)] that
[t]he term good manufacturing practice is and of necessity must be flex-
ible in its application to the manufacture of particular drugs. Fur-
thermore, considering the end to be accomplished (i.e., the identity,
strength, quality, and purity of the drugs being introduced into com-
merce for the purpose of use by human beings, improvements and
consequent change in what is cGMP is always to be anticipated as
well as a desired end.
Thus, for the foregoing reasons, the courts have consistently rejected the
"void for vagueness" constitutional attack on the cGMPs. 14
and the participation of industry, provided, these courts held, the requisite
particularity and specificity and also provided adequate notice and guidance
to the affected parties as to be constitutionally sound. In doing so, however,
a lacuna remained open and unremarked-that the cGMP scheme, even in-
cluding the degree of specificity embodied in the FDA regulations, must be
inherently open-ended if it is-as Congress intended-to embody a dynamic,
progressive, and "current" standard of manufacture for the drug industry.
Thus, irrespective of the greater specificity of the regulations in comparison
with the underlying statute, even the regulations must be sufficiently general
as not to ossify a manufacturing standard needing constant revision through
lengthy and contentious rule-making by the FDA.
This degree of open-endedness, though smaller than that of the statute,
provided an opening for further constitutional attack, in the case of the Na-
tional Association of Pharmaceutical Manufacturers (''NAPM") v. Department of
Health and Human Services [586 F.Supp. 740 (S.D.N.Y. 1984)], in which a
generic pharmaceutical trade association attacked the FDA's regulations as,
inter alia, insufficiently precise under the constitutional standard, not com-
portive with the statutory mandate, and not applicable to new drugs. This
case represents the last major judicial analysis of the constitutionality and ap-
plicability of the FDA's cGMP scheme and contains important pronounce-
ments on the legal basis for the cGMPs.
In NAPM, the plaintiffs argued that the cGMP statute applies only to
"old" drugs, not to "new" drugs, which require FDA approval via a New Drug
Application (NDA). So-called "old" drugs are drugs that can be marketed
without advance FDA approval because they were marketed prior to enact-
ment of the statute. Because these old drugs could be marketed without FDA
approval, their method of manufacture would otherwise be unregulated ab-
sent the application of the cGMP statute. In contrast, the NAPM argued,
"new" drugs require FDA approval prior to marketing of, inter alia, the man-
ufacturing methods used in production, and that also have their own en-
forcement mechanisms by which such approval could be withdrawn if the
manufacturing methods were later found to be inadequate, were therefore
not intended to be subject to the cGMP statute. The court soundly rejected
this argument on the basis of the legislative intent, judicial precedent, and
statutory construction. All of these, the court determined, supported-either
explicitly or implicitly-that the cGMP statute was intended to apply to new
drugs with equal force as to old drugs.lS The adulteration provisions of the
Act, the court noted, provide a significantly broader range of enforcement
mechanisms, such as seizure, as well as applicability to individual lots of a
given product. Thus, if a particular lot of product was found to be adulter-
ated, regulatory action could be limited to the particular lot at issue. In con-
trast, the new drug provisions permit or prohibit marketing of a drug product
per se by rendering the application valid or invalid. Action that is more lim-
ited than product-wide invalidation is thus not possible under the new drug
provisions of the Act, which provides a rationale for the application of the
The Legal Basis for Validation 65
[t]he government has not contended that any of the articles of drug
already manufactured and presently on hand are in fact dangerous to
the health and well-being of potential users. Nor has the government
shown that the safety, identity, quality, and purity of inventory drugs
could not be assured by appropriate sample testing and assay proce-
dures.l6
The action of the court in Medwick became the basis for the new legal
framework applied to the cGMPs. A subsequent case, United States v. Undeter-
mined Quantities ... Larson Laboratories, Inc. [1978-80 FDLI ]ud. Rec. 109
(W.O. Penna. 1979)], applied this principle to a condemnation proceeding
66 Validation of Active Pharmaceutical Ingredients
brought by the government to seize and destroy various drug products that
were not manufactured and tested in accordance with the cGMPs. Failure to
meet the cGMPs, the court stated, caused the drugs to be "adulterated" under
the Food and Drug Statute, 21 U.S.C. 351(a)(2)(B). The regulations, the court
noted,
These court rulings have been embodied in the FDA's policy, as contained
in the FDA's "Standard Drug GMP Paragraph," standard language that the
FDA utilizes in its regulatory letters to manufacturers found deficient in
cGMPs during the course of an FDA inspection. "A drug," the FDA states in
its standard language, "is adulterated regardless of whether it is physically de-
ficient in some respect. The purpose of the good manufacturing practice pro-
vision of the Act is to control the process of drug manufacturing and to attack
the production of unreliable drugs in its incipiency, not after the fact."
Since the 1962 Amendments, the FDA has continued to shift its focus in
drug quality toward manufacturing operations. If the 1962 Amendments es-
tablished, as it were, endpoints relating to aspects of the process of manufac-
turing itself, the FDA extended this to mandating specific segments of the
manufacturing process 19 and, further, establishing controls to determine that
those processes are operating as expected. In fact, so extensively has the FDA
shifted its attention to the manufacturing process side, that the idea has been
raised as to whether, in view of the degree of control and testing over the
manufacturing process, endproduct testing might even be eliminated (Davis
1994).
It is worth noting, however, that the FDA's cGMP regulations apply to "drug
products," which are defined in the regulations as a "finished dosage form"
(i.e., a capsule, tablet, solution, etc., which is the final manufactured form of
The Legal Basis for Validation 67
VALIDATION
Concomitant with the new focus on the quality of drug manufacturing as a
guarantor of product quality came concepts of controls to verify the consis-
tency of the manufacturing process itself. The idea of finished product test-
ing as a check on product quality was similarly extended backward into the
manufacturing process in the form of testing the manufacturing process itself
at various critical points to determine that it was performing as expected.
In the mid-1970s, roughly contemporaneous with the FDA's rule-making
regarding cGMPs, the issue was raised within the FDA whether finished prod-
uct testing of sterile products was adequate to determine the sterility profile
of an entire batch of product. Out of this concern was born the idea that
68 Validation of Active Pharmaceutical Ingredients
manufacturing be made only on the basis of a full and in-depth review of the
validation documentation from beginning to end (i.e., from equipment vali-
dation, process performance qualification, to product and package testing).
The FDA's guideline also described the kinds of validation that were ac-
ceptable and the parameters for their use. Validation, the FDA noted, could
be prospective as well as retrospective. Prospective validation is a study of the
manner in which the manufacturing process conforms with a predetermined
set of criteria and specifications developed on the basis of R&D on the prod-
uct, prior to the beginning of commercial manufacturing. This is the
standard means of validation now required of all products. Nevertheless, the
FDA recognized circumstances in which so-called "retrospective" validation
might be appropriate and might yield valuable data, on the basis of the in-
spection of data available for a product after the manufacturing process has
been under way for a substantial period of time. 21 Detailed finished product
test results, the guideline noted, could be statistically analyzed in terms of the
degree of variance observed, in comparison with the degree of variance that
might be expected from the process. This form of validation permitted cer-
tain conclusions regarding the manufacturing process to be reached on the
basis of finished product specifications and, therefore, represented a throw-
back to pre-cGMP conceptions of product quality.
The court in Barr also addressed one of the more vexing problems in-
volved in validation (i.e., the number of batches required to perform a proper
retrospective validation study). In contrast to the government's contention
that a series of 10 batches would be appropriate, Barr argued that by means
of statistical analysis, a smaller number of batches might be appropriate. The
court, reviewing the various figures provided by the experts, ranging from
somewhere above 5, and up to 20 or 30, declined to settle on a precise num-
ber of studies applicable in all cases. Rather, the court determined that, in the
absence of definitive guidance from the FDA's regulations, the "general rule"
in retrospective validation should be to test 20-30 batches in a retrospective
validation study, but a firm can depart from this number provided it can sup-
port any such departure with statistical or other evidence that supports vali-
dation. The court noted, however, that because a 10 percent failure rate is
unacceptable, if one batch fails, a minimum of 10 batches would be required
to support a retrospective validation study.
The court's decision-making with respect to the number of batches re-
quired for validation reveals an attempt to comport with the deeper, under-
lying goals and purposes of validation, while simultaneously attempting to
provide the definitive decision-making sought by the adversaries before it.
The court, having been importuned by the litigants to determine whether the
Barr practices comported with the cGMPs and, hence, whether Barr's prod-
ucts could be marketed, was required to make definitive determinations even
as the issues before it stemmed from a statute and regulations cast in vague
terms precisely to permit the flexible and subtle scientific distinctions that
courts are typically ill-suited to make. Accordingly, the court wisely chose in
a number of critical areas to preserve the open-endedness of the cGMP
scheme by providing guidance based on the expert testimony before it, while
allowing flexibility to a company to act otherwise, provided it could show ad-
equate justification for doing so.
The court adopted such a flexible approach in other areas of validation,
by suggesting appropriate standards and methods as a "general rule," while
leaving a case-by-case determination to the company and to its ability to jus-
tify its decision-making. For example, on the issue of sampling during the
manufacturing process, the court was called upon to adjudicate Barr's prac-
tice of sampling from drums of blended product, as opposed to sampling
from the mixer itself during the blending step, as urged by the FDA. Deter-
mining content uniformity, the court rightly observed, was appropriate for
the blending stage, where uniformity problems in the manufacturing process
will likely be discovered. In contrast, sampling from drums of blended prod-
uct is not qualitatively different from sampling of the final product, which is
no longer within the realm of testing for process validation. Accordingly, the
court determined that the mixer was the most appropriate point for sampling
as a general matter, but if Barr wished to sample from the drum, it must
demonstrate the appropriateness of the technique.
The Legal Basis for Validation 73
[W]ith regard to past violations, there can be no dispute that Barr has
violated the Act by failing to follow manufacturing practices that
comply with cGMP as required under section 351(a)(2)(B) and, there-
fore, has introduced adulterated drugs into commerce in violation of
section 331(a).
Although yet incomplete, in light of these efforts, the court determined that
a general shutdown was inappropriate and unnecessary.
The question of noncompliance with product validation requirements,
however, was viewed as of greater concern:
[T]o the extent that Barr relied upon investigations which do not sat-
isfy section 211.192, as construed by the Court, to release batches or
to complete retrospective and prospective validation studies, these
actions and studies are invalid. Reliance on faulty methods cannot be
cured by subsequent compliance.
Moreover, the court noted, the many failures of Barr's batches itself demon-
strated that Barr's manufacturing procedures were not properly validated,
notwithstanding that the procedures may have been contained in Barr's
ANDAs and followed by the company. In such instances, failures in practice
were of greater importance than merely adhering to the ANDA procedure, be-
cause the ANDA procedure, the court observed, as often the result of testing
on smaller batches, may not evidence problems that might occur or be re-
vealed in scaled-up production. Accordingly, the court found that "[i]n order
to comply with cGMP, firms must correct any process that demonstrates its
own inadequacies in practice," and further validation studies were necessary
notwithstanding reliance on the procedures contained in the ANDAs. Barr,
the court held, was required to cease distribution of certain products that
were of particular concern to the government based on the degree of failures.
Other products, the court held, could be distributed only if concurrent or
prospective validation studies were performed, and the products tested in ac-
cordance with proper procedures. 27
Following issuance of the Barr decision and the ending of its judicial se-
quellae28, the FDA issued a lengthy analysis of the issues in Barr in which it
elaborated on the evidence in the case, and the basis for its decision-making
in light of the decision of the court (FR 1993b). In its analysis, the FDA
pointed to Barr's repeated exclusion of failing results and batches from its ex-
amination of its manufacturing processes as key to the FDA's view that its val-
idation program, such as it was, was fatally flawed. The exclusions included,
the FDA noted, out-of-specification test results from commercial batches,
out-of-specification results from in-process blend uniformity testing, finished
product assay testing, content uniformity testing, dissolution testing, and
stability testing. These exclusions, the FDA noted, which occurred both with
respect to Barr's prospective and retrospective validation studies, distorted
the results of the studies to the extent that no guidance could be extracted
with respect to the performance characteristics of the manufacturing
processes under examination.
In addition to the above, Barr's validation notebooks, which were sub-
mitted by Barr to validate its products retrospectively, were inadequate to
establish proper validation due to imprecision in testing data. Insufficient
76 Validation of Active Pharmaceutical Ingredients
data, averaged data, and missing data that characterized the documentation
rendered the notebooks insufficient to establish retrospective validation of
the manufacturing processes for Barr's products. Moreover, the FDA analyzed
a number of Barr's supplemental applications that contained changes that,
the FDA stated, could cause variability in the characteristics of the in-process
materials as well as in the finished products. These, the FDA found, required
validation prior to implementation.
Based on the foregoing, the FDA found Barr violative of a number of pro-
visions of the FD&C Act, specifically 21 U.S.C. 35S(j)(3)(A) [methods, facili-
ties, and controls inadequate to assure identity, strength, quality, and purity],
21 U.S.C. 357(a) [applicable to ANDAs], and accordingly determined to refuse
to approve applications of Barr under 21 U.S.C. 357(a), 355(c)(1)(B), (d)(3),
(j)(3)(A), and (j)(4)(C).z9
CONCLUSION
The history and progression of the FDA's legal basis for validation evidences
a steadily increasing reaching back into the process of drug manufacture, an
evolution fostered by the flexibility and open-endedness embedded in the
regulatory framework to provide the FDA with a dynamic, progressive stan-
dard for assessing product quality. This progression, deriving its impetus from
the particular exigencies of pharmaceuticals and their intimate relation to
human health and well-being, has as its endpoint the delivery of safe and ef-
fective drug products to a vulnerable consumer. There has thus emerged an
ever-widening fencing-in process, taking greater and greater areas of drug
manufacture into its ambit, subject to ever-greater scrutiny and control. It is
for this reason that the concern of drug and device legislation and regulation
has increasingly been with the context of drug manufacture, as opposed to
merely the product of that manufacture. 3D
NOTES
1. FDA officials conceded the inadequacy of finished product testing as a
means of assuring drug product quality as a reason for moving toward
process validation. A former FDA official who was at one time in charge
of the FDA's postmarketing sampling program, described the problems
as follows:
"Several attempts by my predecessor and by me were made to
have our statisticians design the program to give better reliabil-
ity of batch characteristics. All failed. The statisticians would
The Legal Basis for Validation 77
aff'g Toilet Goods Ass'n v. Gardner [360 F.2d 677 (2d Cir. 1966)]; and
Weinberger v. Hynson, Westcott & Dunning, Inc., [412 U.S. 609 (1973)];
CIBA Corp. v. Weinberger (412 U.S. 655 (1973)].
10. See also United States v. Articles of Drug ... Colchidne (442 F.Supp. 1236
(S.D.N.Y. 1978)], aff'd sub nom, United States v. Consolidated Midland
Corp. [630 F.2d 215 (2d Cir. 1979)]: "The Secretary's interpretive regula-
tions as to what constitutes good manufacturing practice concretize the
statutory language of 21 U.S.C. 351(a)(2)(B), eliminated the possibility
of vagueness, ... and have the binding force of law."
11. See also United States v. Bel-Mar Laboratories, Inc., (284 F.Supp. 875, 883
(E.D.N.Y. 1968)], wherein the court noted that "there are responsible
segments of opinion within the industry itself which oppose a greater
degree of specificity in this area."
12. Lest it be supposed that the defendant was merely churlish in its argu-
ments concerning these terms, the defendant in Bell actually cited pre-
vious U.S. Supreme Court decisions that held the terms current and good
to be unconstitutionally vague. The court in Bell differentiated those de-
cisions as specific to their factual contexts and inapplicable to the case
at bar.
13. See also United States v. Morton Norwich Products, Inc. (1975-1977 Jud.
Rec. 169 (N.D.N.Y.)] and United States v. Kendall Co. [324 F.Supp. 628)
D.Mass. 1971)].
14. See, e.g., United States v. Kendall Co. [324 F.Supp. 628 (D.Mass. 1971)],
which rejected the argument in the context of a criminal prosecution
for the introduction into interstate commerce of adulterated drug prod-
uct.
15. For example, in addition to finding explicit support in the legislative
history to support application of the statute to new drugs, the court also
endorsed the government's view that inclusion of new drugs should be
implied in the absence of any explicit exemption for new drugs. Such
an exemption should be read into the statute only if it is necessary "to
prevent absurd results or consequences obviously at variance with the
policy of the enactment as a whole" {National Assodation of Pharmaceu-
tical Manufacturers ("NAPM") v. Department of Health and Human Services
[586 F.Supp. at 750 (S.D.N.Y. 1984)]}.
16. That Congress intended legal sanction to apply to the drug manufac-
turing phase per se is evident from the legislative history underlying the
statute that deems adulterated any product not produced in conformity
with the cGMPs, irrespective of whether the drug product actually was
deficient in some respect. See 1962 U.S. Code Cong. & Admin. News,
p. 2890; United States v. Bel-Mar Laboratories, Inc. [284 F.Supp. at 881
(E.D.N.Y. 1968)].
The Legal Basis for Validation 79
17. See, e.g., United States v. Dianovin Pharmaceuticals, Inc., et al. [342 F.Supp.
724 (Puerto Rico 1972)].
18. See United States v. Undetermined Quantities of Various Articles [800 F.Supp.
499, 502 (S.D. Tex. 1992)]: "In order to prove a claim of adulteration of
a device based upon non-compliance with GMP regulations, the Gov-
ernment need not establish that the device is actually deficient as a result
of the GMP violation"; United States v. Lit Drug Company [333 F.Supp.
990, 998 (D.N.J. 1971)]: "Thus a drug may be pharmaceutically perfect
in content but still be regarded as adulterated under the law"; United
States v. 789 Cases [799 F.Supp. 1275 (D. Puerto Rico 1992)], which ap-
plies to the device context the above case law construing the effect of
the cGMPs and Section SOl in the area of drugs. Thus, the court, citing
the case law, held in the case of medical gloves kept under unsanitary
conditions that "the government is not required to prove any actual
contamination of the product to establish adulteration. . .. The gov-
ernment need only prove that there is a reasonable expectation that the
articles could become contaminated with filth" {United States v. Bronx
Drug Co .. .. Isaac Zonana [1969-74 FDLI Jud. Rec. 267 (S.D.N.Y. 1971)]}.
19. The requirement that nonanalytical methods be stability-indicating is
an example of increasingly specific forms of manufacturing processes
being mandated by the FDA.
20. Notably, the FDA suggests that any changes to the product specifica-
tions be made only in accordance with documented change control pro-
cedures.
21. This type of validation was allowed by the FDA on a limited basis for
products that had been marketed for a long time when it began to de-
velop its detailed validation program in the late 1980s. A continued role
for retrospective validation is viewed as primarily augmentative to
prospective validation (i.e., providing additional data to supplement
and support prospective validation data) and also to either build confi-
dence in a particular manufacturing process or impugn it as test results
are received.
22. The Guidance, which is detailed in its validation requirements for APis,
codifies many of the requirements previously enunciated by the FDA
and enforced in inspections. The Guidance, however, firmly establishes
the validation requirement for APis, noting, inter alia, that "[m]anufac-
turers should be actively engaged in a validation program for all
distibuted APis," and that "[v]alidation should extend to those steps de-
termined to be critical for the quality and purity of the final API."
23. Assay testing measures the potency (i.e., concentration of the active in-
gredients in the drug product). Content uniformity is a measurement of
the consistency and variability in potencies among different samples
80 Validation of Active Pharmaceutical Ingredients
and dosages of the drug product. Dissolution testing measures the rate at
which the drug will dissolve and thereby release its active ingredients
into the body.
24. Testing at the "blend" state, which is an intermediate manufacturing
process stage at which the various drug product ingredients are blended,
is a hallmark of validation testing, because it is performed on an inter-
mediate sample, prior to the finished product stage. It is designed to de-
termine that the blending of ingredients results in uniformity and
appropriate dispersion and integrity in the active ingredients at a criti-
cal step in the manufacturing product.
25. See 21 CFR Section 211.165(e); 211.194(a)(2). The regulation itself refers
to the requirement for the validation of testing methods and notes, par-
enthetically, that if the method of testing is contained in the USP or
other reference, or is contained in the NDA, a statement referencing this
method is sufficient [21 CFR 211.194(a)(2)]. ·
26. The government had sought an injunction from the court to shut down
the operations of Barr pending its correction of the problems found.
27. In addition to injunctive relief, the court ordered recalls of products that
were released on the basis of inadequate, or inconsistent, testing prior
to release.
29. The series of the FDA enforcement and court actions culminating in
John D. Copanos et al. v. Food and Drug Administration et al. [854 F.2d 510
(D.C. Cir. 1988)] represent yet a further extension of the cGMP rubric,
by applying a company's history of compliance to negate the validity of
the drug application itself and not merely the process of its manufac-
turing. In this case, the FDA seized and condemned product, and ulti-
mately withdrew the company's NDAs, on the basis of serious and
repeated failure to manufacture the products in conformity with ap-
plicable cGMPs.
30. Counterparts to this concern for context may be found (e.g., in the
FDA's debarment authority, which debars persons and companies con-
victed of wrongdoing from being associated with the submission of drug
applications to the FDA).
The Legal Basis for Validation 81
REFERENCES
Compliance Policy Guide (Process Validation Requirements for Drug Products Subject to
Pre-Market Approval). CPG 7132c.08; August 30, 1993. Rockville, Md., USA: Food
and Drug Administration.
Davis, J. S. 1994. Retesting and laboratory investigations. Journal of Pharmaceutical Sci-
ence & Technology 48:107.
FDA. 1990. Guidelines on general principles of process validation. Rockville, Md., USA:
Food and Drug Administration.
FDA. 1991. Guide to inspection of bulk pharmaceutical chemicals: Reference materials and
training aids for investigators. Rockville, Md., USA: Food and Drug Administration,
Center for Drug Evaluation and Research.
FR. 1963. Federal Register 28:6385.
FR. 1978. Federal Register 48:45014-45024.
FR. 1993a. Current good manufacturing practices in manufacturing, processing, pack-
ing or holding of drugs; revision of certain labeling controls. Federal Register
58:41348.
FR. 1993b. Barr Laboratories, Inc., refusal to approve certain abbreviated applications,
opportunity for a hearing. Federal Register 58:31035.
4
Arthur B. Shaw
Division of Gastrointestinal and Coagulation Drug Products
Food and Drug Administration
The Food and Drug Administration (FDA) is charged with ensuring that safe
and effective drugs are available to the American public. In order for the FDA
to adequately review an application to market a drug, the application must
contain details on chemistry, manufacturing, and controls (CMC) as required
by 21 CFR 314.50. In addition, submissions to the FDA to ship unapproved
drugs for investigational use (Investigational New Drug Applications [INDs]),
covered under 21 CFR 312, must also contain CMC information [21 CFR
312.23 (a) (7)]. A number of years ago, the FDA recognized that it was desir-
able to provide a mechanism whereby manufacturers of bulk drug sub-
stances, excipients, and packaging materials could provide information for
review by the FDA without filing a formal application. This Drug Master File
(DMF) system was established so that companies submitting New Drug Ap-
plications (NDAs), INDs, and Abbreviated New Drug Applications (ANDAs)
could incorporate information in the DMFs by reference. This means that a
DMF holder does not have to submit the same information in each applica-
tion. (In the following discussion an "application" refers to an NDA, an IND,
an ANDA, an Export Application, or another DMF, while an "applicant" refers
to the individual or company that submits an application. A "holder" is an
individual or company that submits a DMF.) If an active pharmaceutical in-
gredient (API) manufacturer chooses to provide the details of its manufactur-
ing process in each application that uses the API, it may do so. However, most
firms prefer to keep the information in a DMF.
83
84 Validation of Active Pharmaceutical Ingredients
Guideline
Detailed information on the submission of a DMF may be found in the Guide-
line for Drug Master Files (DMF Guideline) published by the FDA in September
of 1989. Even though the guideline is in the process of being revised, most of
the basic features are not expected to change. This guideline, as well as other
guidelines and guidances mentioned in this chapter, may be obtained from
the Drug Information Branch using any of the following resources:
Telephone: 301-827-4573
Fax-on-Demand 800-342-2722 or 301-827-0577 (the DMF Guide-
(FOD): line is document 4001)
E-mail: druginfo@cder.fda.gov
Internet: http:/ /www.fda.govI cder I guidance/index.htm
The DMF Guideline contains information on how to organize and sub-
mit a DMF, but the details on the technical content of the DMF are found in
the guidelines for that particular technical area (drug substance, drug product,
etc.). For APis, the appropriate document is the Guideline for Submitting Sup-
porting Documentation in Drug Applications for the Manufacture of Drug Sub-
stances, also known as the "Drug Substance Guideline" (DSG). It should be
noted that guidelines were issued under 21 CFR 10.90(b), which provides for
the use of guidelines to state procedures or standards of general applicability
that are not legal requirements but that are acceptable to the FDA. Note that
new guidelines are called "Guidances." Guidance documents represent the
FDA's current thinking on a particular subject. They do not create or confer
any rights for or on any person and do not operate to bind the FDA or the
public. An alternative approach may be used if such approach satisfies the re-
quirements of the applicable statutes, regulations, or both.
DMF returned
to Holder
DMF assigned
number and
placed In file
No
Yes
DMF
Reviewed
Drug Master Files 87
REVIEW OF A DMF
The FDA reviews a DMF only when it is referenced in an application (Figure
4.2). Some of the reasons for this policy are as follows:
No Application
remains AE/NA
No review of DMF
amendment, application
remains AEINA
reviewed
88 Validation of Active Pharmaceutical Ingredients
After a DMF is reviewed, the review is filed with the DMF jacket. If there
are deficiencies, the DMF holder is informed of the deficiencies in a letter. The
applicant whose DMF is supported by the DMF is informed that there are de-
ficiencies, but the details are not provided to the applicant.
In general, an "Action Letter" (i.e., an approvable [AE], not approvable
[NA], or approval [AP] letter) is sent to an applicant when all the reviews (in-
cluding reviews of supporting DMFs) for that application are complete. How-
ever, depending on the timing of the review of the DMF relative to the "due
date" of the application and the progress of other reviews, the applicant may
be sent an "Information Request" (IR) or a discipline review (DR) letter, which
are not classified as an "action letters." This situation occurs more frequently
with NDAs than with ANDAs.
If there are no deficiencies in a DMF, neither the holder nor the appli-
cant is informed of this fact (see below).
When a DMF holder amends a DMF to correct the deficiencies, it should
notify the applicant whose application is supported by the DMF. The appli-
cant should then amend its application, informing the FDA that the DMF has
been amended. The DMF amendment will not be reviewed unless the appli-
cation that it supports is amended. The reason for this has to do with the de-
tails of the "review clock" for review of NDAs and ANDAs. The clock is
stopped by the issuance of the action letter (AE or NA) by the FDA and can be
restarted only by a complete response to the letter by the applicant. (In the
case where the applicant was notified of the DMF deficiencies in an IR or DR
letter, which are not classified as an agency "actions," the clock was not
stopped. However, the timing of the response to the IR or DR letter may effect
an extension of the review clock.) There are often situations in which an ap-
plicant receives an action letter and chooses to withdraw or otherwise sus-
pend activity on the application. In this case, any DMF amendment in
response to a DMF deficiency letter would not need to be reviewed. Therefore,
the review of a DMF amendment can occur only if the application that the
DMF supports is amended.
The difference in .the handling and storage of DMFs and applications
dictates that an added step should be followed when a DMF is amended.
When the review of a DMF is complete, the DMF jacket is returned to the
CDR. However, when the review of an application is finished, the application
Drug Master Files 89
APPROVAL OF DMFs
The FDA neither approves nor disapproves DMFs. These would be agency "ac-
tions." In addition, the FDA believes that it is important to retain the flexibil-
ity to review DMFs for drug substances that may be used in different drug
products having different characteristics (e.g., dosage form, route of adminis-
tration). Therefore, the FDA only issues a letter listing deficiencies in a DMF.
In order to avoid any inference that the DMF has been "approved," the FDA
does not inform the holder when there are no longer any deficiencies. This
aspect of the DMF review process as it applies to APis will be discussed more
fully below.
TYPES OF DMFs
Several types of DMFs are provided for in 21 CFR 314.420. These distinctions
originally were made mainly for administrative purposes. However, as the
FDA has developed guidelines and policies concerning the submission and re-
view of DMFs, the types of information submitted in the different types of
DMFs are more clearly defined.
Many API manufacturers are told by their customers or consultants that
they need to file a Type I DMF, which covers "manufacturing site, facilities,
operating procedures, and personnel" [21 CFR 314.420 (a) (1)]. Under an
amendment to the CFR (65 FR 1776, January 12, 2000), the FDA no longer
accepts Type I DMFs for either foreign or domestic sites. Since many API
90 Validation of Active Pharmaceutical Ingredients
manufacturers with foreign plants have been filing Type I DMFs for their sites,
they are affected by this change. It is also unnecessary to update or reference
existing Type I DMFs.
Since the Center for Drug Evaluation and Research (CDER) reviews in-
formation about sterile manufacturing facilities, both foreign and domestic, it
is still necessary to have that information available for review. Therefore, in-
formation about sterile manufacturing facilities (usually for finished drug
products) can be maintained as Type V DMFs, which are defined as contain-
ing "FDA-accepted reference information."
The type of DMF that is of primary concern to API manufacturers is the
Type II DMF, which covers the "drug substance, drug substance intermediate,
and materials used in their preparation, or drug product" [21 CFR 314.420 (a)
(2)]. Detailed guidance on what should be included in a Type II DMF for drug
substances and intermediates may be found in the DSG.
There are a number of aspects of the DMF system that have given rise to
some misunderstanding by DMF holders:
• A Type II DMF should cover only one topic. For instance, separate
DMFs should be submitted for different drug substances, even if
they appear to be closely related. If there are a number of APis in an
existing DMF, the holder should consider resubmitting each API in
order to facilitate review of the individual APis.
• An API and a drug product manufactured from the API should be
submitted in separate DMFs.
• All DMF holders should submit an annual report, specifying any
changes that have taken place since the last update and a list of all
companies authorized to refer to the DMF (authorized applicants).
The list of authorized applicants should contain a specific reference
to the portion of the DMF to which the company may make refer-
ence. If there have been no changes since the last update, the
holder may simply submit a letter stating that fact, along with the
list of authorized applicants.
• In the DMF Guideline, Section V.A., there is a list of items that
should be included in an LOA. Item 8 states that the LOA should
contain a "statement of commitment that the DMF is current and
that the DMF holder will comply with the statements made in it."
This statement is not a substitute for the submission of an annual
update.
• When an amendment or annual report is submitted, a transmittal
letter containing the following information should accompany it:
A statement identifying the submission as an amendment
The DMF number and subject
Drug Master Rles 91
TypeofDMF
Type of amendment
• Annual update
• Response to agency letter
• New information or revision (not in response to FDA
letter)
• Administrative changes
• Other (specify)
A list of the specific changes or information in the amend-
ment, including the affected section and/or page numbers of
the DMF
The name and address of all applicants authorized to reference
a portion of the DMF being amended
The number of each application that relies on the subject of
the amendment for support, if known
Signature of the holder or the authorized representative
Typewritten name and title of the signer
(Note: This list is slightly expanded from the list found in Section
IV.A.2 of the DMF Guideline.)
In addition, the holder should issue new LOAs identifying the date
of the amendment or annual report, which may be incorporated by
reference.
• Each page of each copy of the DMF should be dated and consecu-
tively numbered. An updated table of contents should be included
with each submission.
MANUFACTURING PERFORMED AT
MORE THAN ONE SITE
In some cases a firm may have all or part of the manufacturing procedure per-
formed at more than one plant, either at another plant owned by the firm or
using an outside contractor.
If a firm uses its own plants and/or processes to manufacture the same
material, a separate DMF for the manufacturing process at each location may
be submitted or one DMF can cover the manufacturing at all sites. Table 4.1
provides recommendations on how this information should be filed.
92 Validation of Active Pharmaceutical Ingredients
Same Site One DMF-Identify any differences One DMF-Identify any differences
*Example: Differences in climate at different sites may require different controls on moisture and
temperature during manufacturing.
INTERMEDIATES
There has been a good deal of confusion about whether a DMF is required
for the preparation of an intermediate or a starting material. This is not
strictly a DMF issue, since the policy concerning the information about in-
termediates and starting materials is covered in the DSG and is the concern
of the Drug Substance Committee at CDER. Any questions about this matter
should be directed to this committee. If it is determined that a particular
chemical is an intermediate whose preparation should be fully described, as
outlined in the DSG, then a DMF may be filed for that intermediate. An LOA
from the DMF holder for the preparation of the intermediate should be sub-
mitted in the application that uses the active drug substance prepared from
the intermediate, if possible. This will permit the reviewer to know which
DMFs need to be reviewed in support of a particular application. If the API
manufacturer believes that the nature of the intermediate is a trade secret
that it would prefer not to reveal to the applicant, it is not necessary for the
intermediate manufacturer to submit an LOA permitting the applicant to in-
corporate the information by reference. However, the intermediate manufac-
turer should submit an LOA to the DMF for the API. The plant where the
intermediate is prepared may be subject to inspection, depending on the na-
ture of the intermediate.
Yes
No
of the drug substance in the DMF may be necessary. On the other hand, a
rereview is performed when there is a reason to reassess information that was
previously evaluated by a reviewer. For instance, if the only previous review
was done to determine whether there was a safety concern in an IND, a
rereview may be necessary. Many times a DMF for a new drug substance is
referenced in an IND and the initial review is done only to determine if the
Drug Master Files 95
preparation of the drug substance meets the minimal requirements for the
initiation of safety studies in a Phase I clinical trial. This review often is not
done in as great a depth as is required for a DMF in support of an NDA. For
more details on the CMC requirements for an IND see Guidance for Industry:
Content and Format of Investigational New Drug Applications (INDs) for Phase 1
Studies of Drugs, Including Well-Characterized, Therapeutic, Biotechnology-Derived
Products, published in November 1995 (FOD number 0804).
If a reviewer determines that a rereview should be conducted and the
conditions listed above do not apply, the reviewer must document the reason
for the rereview and obtain supervisory concurrence.
It is felt that adoption of the above policy should eliminate or minimize
the number of rereviews for the same DMF.
SUMMARY
DMFs provide a convenient process by which API manufacturers can submit
confidential information for review by the FDA in support of a number of ap-
plications. Changes in the FDA's review procedures should streamline the re-
view process so that the American public can continue to have access to safe
and effective drugs at reasonable prices.
5
This chapter discusses the U.S. Food and Drug Administration's (FDA's) cur-
rent expectations regarding the manufacturing, control, and validation of ac-
tive pharmaceutical ingredient (API) processes. It provides a broad overview
of the FDA's draft Guidance for Industry Manufacturing, Processing, Holding Ac-
tive Pharmaceutical Ingredients-its development, scope, and factors the FDA
considered in determining how much specificity to include in the guidance.
In addition, the spectrum of Good Manufacturing Practice (GMP) controls in
API production and how manufacturers should apply validation concepts to
API processes is discussed. The chapter also examines several controversial ar-
eas in API manufacturing for which the FDA received extensive comments
and how the FDA addressed these in its March 1998 draft API guidance.
Finally, the author includes a brief update on the International Confer-
ence on Harmonisation's (ICH's) Q7 A initiative to develop a GMP guidance
for APis. However, this chapter does not address the consensus achieved to
date in the ICH Q7 A API negotiations. Once the guidance reaches Step II of
the ICH process, the Q7 A Expert Working Group (EWG) will most likely re-
vise it based on worldwide comments received on the latter.
97
98 Validation of Active Pharmaceutical Ingredients
draft even included extensive preamble language that would have been pub-
lished with the new regulation.
However, reality eventually set in. On 7 July 1995, FDA senior manage-
ment recognized the difficulty of developing and issuing a new API regulation
because of the prevailing deregulatory climate. Thus, the FDA decided to
cease efforts to develop an API regulation and to draft an industry guidance
instead. This important task was assigned to the Division of Manufacturing
and Product Quality in COER's Office of Compliance.
The Office of Compliance circulated the first draft of the API GMP guid-
ance for comments within the FDA in March 1996. On September 20, 1996
the FDA unveiled an August 1996 discussion draft of the industry guidance at
an international API conference in Canberra, Australia, sponsored by the
Pharmaceutical Inspection Convention and Pharmaceutical Inspection Co-
operation Scheme (PIC and PIC/S). The draft was reviewed along with other
API GMP documents prepared by the European Chemical Industry Council/
European Federation of Pharmaceutical Industries' Association (CEFIC/
EFPIA), PhRMA, PIC and PIC/S, and other organizations.
On 1 October 1996, the FDA distributed the discussion draft at the Par-
enteral Drug Association's (PDA's) annual PDA/FDA conference in Bethesda,
Maryland. On 8 November 1996 COER's Office of Compliance distributed the
discussion draft to pharmaceutical trade associations for comment. Subse-
quently, the FDA posted the draft on COER's Web site with a request for com-
ments by 10 December 1996. The FDA later extended the deadline for
submitting comments on the draft guidance to 31 January 1997.
The FDA received more than 2,000 comments on the August 1996 API
draft guidance from 17 manufacturers, 2 consulting firms, and 1 FDA re-
viewer. Comments were also submitted by 7 pharmaceutical associations, in-
cluding the National Association of Pharmaceutical Manufacturers, the
National Pharmaceutical Alliance, the Generic Products Industrial Associa-
tion, the PDA, the PhRMA, the German Association of Research Based Phar-
maceutical Companies, and the CEFIC/EFPIA.
From March to July 1997 a working group convened in COER's Office of
Compliance classified and summarized the comments received on the draft
guidance. From August to October the group reviewed the comments and
made appropriate changes to the guidance.
COER's Office of Compliance recirculated the revised guidance for inter-
nal FDA comments on 25 November 1997. On 15 January 1998 COER sub-
mitted for FDA clearance a draft Federal Register Notice of Availability and
revised guidance incorporating final comments from COER, CBER, and ORA.
However, at a 5 February 1998 meeting of the ICH at Tyson's Corner, Vir-
ginia, the FDA supported the decision to develop an internationally harmo-
nized GMP guidance for APis. At this meeting, the FDA also announced the
decision to issue its API GMP document as draft guidance.
The FDA released its revised draft API guidance (dated March 1998) for
public distribution on 17 April 1998, by publishing a Notice of Availability in
100 Validation of Active Pharmaceutical Ingredients
the Federal Register. The FDA has received 881 comments from 28 organiza-
tions on the March 1998 draft. COER's Office of Compliance has entered the
comments into a database and is currently reviewing the comments.
The FDA's March 1998 Guidance for Industry Manufacture, Processing or
Holding Active Pharmaceutical Ingredients can be viewed and downloaded from
the COER guidance Web site at http://www.fda.gov/cder/guidance/index.htm.
After connecting to the Web site, look for the document under "Compliance
(Draft)." The API guidance is the third document listed under this category.
Although this guidance is identified as "Draft-Not for Implementation," it
represents current FDA thinking and expectations on the manufacture and
control of APis.
oversees. The FDA foresees that the guidance will be beneficial to API manu-
facturers in developing countries that currently market or intend to market
APis in the United States. In these countries, the API industry has long wanted
and expects inclusion of more "how to elements."
Third, the draft API guidance also addresses the manufacture and control of
APis for drug products not covered by applications. Although the FDA does not
routinely inspect manufacturers of APis intended solely for over-the-counter
(OTC) drug products, the FDA expects the cGMP concepts and expectations em-
bodied in this industry guidance to apply to these API manufacturing operations.
Fourth, but just as important, is the FDA's desire and need to provide ad-
ditional guidance in problem areas or deviations most cited during inspec-
tions of API facilities.
Figure 5.1. depicts the countries that were hosts to the largest number of
API inspections during fiscal years 1995 through 1999. During this period the
FDA conducted 128 inspections of API manufacturers in Japan, followed by
91 inspections in Italy, 57 in France, 47 in China, and 42 in the United King-
dom. Inspections of API manufacturers in these 5 countries accounted for
52 percent of the FDA's API inspections worldwide during the 5 years. There-
maining 48 percent of the FDA's API inspections abroad were conducted in
Ireland, Germany, India, Spain, and Switzerland.
Figure 5.2 shows the types of API processes the FDA inspected overseas
during fiscal years 1995 through 1999. Inspections of nonsterile APis derived
l!'ennentation
Nonsterile
12%
Plant/Animal
Extra(' lion
4%
Sterile
2%
Others_//
2% Fermentation
Control Testing Lab
Sterile
1%
1%
The FDA's Perspectives on API . .. Validation 103
from chemical synthesis processes accounted for 72 percent of all API inspec-
tions, followed by nonsterile APis derived from fermentation processes
(12 percent), crude bulk not elsewhere classified (NEC; 6 percent), and APis
produced from plant/animal extraction processes (4 percent). Sterile APis pro-
duced from chemical synthesis and fermentation pr9cesses accounted for
2 percent and 1 percent, respectively, of the inspections in the 5-year period.
Crude bulk NEC includes inspections of bulk intermediates and API microniz-
ers. Plant/animal extraction APis includes manufacturers of human
menopausal gonadotropins, follicle simulating hormone, and human chori-
onic gonadotropins.
Figure 5.3 shows the most common cGMP deficiencies cited during the
FDA's inspections of API manufacturers abroad in fiscal years 1995 through
1999. Notice that laboratory controls accounted for the largest percentage of
GMP deficiencies (16 percent), followed by records/reports (14 percent),
process controls (12 percent), equipment cleaning (9 percent), process valida-
tion (7 percent), water systems (7 percent), and API stability programs (7 per-
cent). Deficiencies in written procedures, control of raw materials and
intermediates, reprocessing/reworking of APis, and building/facilities ac-
counted for 13 percent of the deficiencies cited during the five-year period.
The large percentage of deficiencies in the laboratory may be attributed
to the FDA's intensified inspectional focus in this area in the last several years.
Laboratory controls are important at API facilities since inadequate testing by
the API manufacturer can result in production of dosage products with impu-
rities or other contaminants that the dosage manufacturer may not detect.
Figure 5.3 Most Common cGMP Deficiencies Cited During Inspections of API Man-
ufacturers, Fiscal Years 1995-1999
Others
-----14%
Lab Controls
16%
Process
Validation
7% Records/Reports
Equipment 14%
Process Controls
Cleaning
12%
9%
104 Validation of Active Pharmaceutical Ingredients
The most frequently cited deficiencies in the laboratory included use of un-
validated test methods, failure to perform equipment suitability tests, failure
to investigate abnormal or missing analytical data, retesting without appro-
priate investigations, and laboratory data not reviewed for accuracy by a sec-
ond person. FDA inspectors also identified use of secondary reference
standards without comparing against official standards as a significant prob-
lem in developing countries where USP primary standards are expensive or
difficult to obtain.
The most prevalent documentation problems found during the FDA's in-
spections abroad were incomplete batch records or records that did not reflect
actual operations; activities often documented before actual completion; re-
lease of API batches before completing the review of production records; and
lack of equipment use, cleaning, and maintenance records. In addition,
changes to API processes beyond preestablished limits without approval by
the quality unit or without addressing these through the firm's change con-
trol system were frequent problems at API manufacturers.
The most common Form FDA 483 citations regarding equipment clean-
ing included inadequate equipment cleaning and validation protocols, inade-
quate sampling and testing of equipment surfaces, failure to establish the
specificity and sensitivity of analytical methods, and failure to establish
residue limits. In addition, FDA inspections uncovered many instances in
which manufacturers were not testing for residues of solvents (i.e., organic
volatile impurities) used in API production.
Deviations noted with respect to process controls included failure to
identify and monitor critical process parameters, failure to set expected yields
for critical process steps, inadequate in-process testing and batch testing of in-
termediates and APis, and blending of out-of-specification API batches with
batches that have passed specifications. Inadequate facilities, utilities,
and controls to prevent cross-contamination was also frequently cited at API
facilities and API contract micronizers. Occasionally, FDA inspections uncov-
ered common micronizing equipment used to process pharmaceuticals of
varying therapeutic significance, toxic non pharmaceutical materials, and pes-
ticides.
Despite all the articles and chapters published regarding water systems,
problems with process water are quite prevalent at API manufacturers. The
most common deficiencies noted included process water not shown to be suit-
able for its intended use, specifications not established for chemical/microbial
quality, inadequate investigations and corrective actions following recurring
abnormal microbiological test results, and reliance on point-of-use filters to
clean up water while ignoring the production and distribution system. FDA
inspections also found that water used in the final isolation and purification
steps of APis intended for use in formulating sterile drug products was
not routinely tested for bioburden or endotoxins. This is significant, since
the sterilization and subsequent processing steps in sterile drug production
will not remove endotoxins that may be present in the API or other raw
materials.
The FDA's Perspectives on API . .. Validation 105
The FDA's draft API guidance applies to the production and control of drug
and biologic APis for use in human and veterinary drug products. Based on
recommendations received from industry during the initial comment period,
the FDA clarified the scope in the March 1998 draft by adding the following
sentence: "The guidance applies to the later chemical isolation and purifica-
tion steps of APis derived from biological or fermentation processes" (FDA
1998). Fermentation and biological processes usually include measures to pre-
vent or minimize contamination when pure cultures are inoculated in the
laboratory onto selected agar media and with each subsequent transfer of the
stock culture. Inclusion of this statement in the scope does not imply that
cGMPs do not apply to fermentation or biotech processes. The statement sim-
ply recognizes that these processes are unique and may require more compre-
hensive guidance than that provided in the draft API guidance.
In addition, the FDA clarified that the guidance applies to the synthesis
stages of a sterile API up to the point where the API is rendered sterile. In the
United States, sterilization of the API and subsequent aseptic processing steps
are subject to the cGMP regulations for finished pharmaceuticals (21 CFR
211). Why? Sterile APis are usually aseptically filled into the final dispensing
container without additional purification steps.
In response to many recommendations from industry, the FDA also in-
cluded a new section that identifies cGMPs for the manufacture of APis used
to produce drug products for clinical trials. This includes language similar to
that found in the PhRMA Guidelines for the Production, Packing, Repacking, or
Holding of Drug Substances.
The FDA also received several comments from industry inquiring
whether the draft API guidance applied to the manufacture and control of ex-
cipients. Recognizing there are many similarities between the manufacture of
APis and excipients, the FDA added a statement to the scope stating, "Al-
though this document focuses on the manufacture of APis, much of the guid-
ance provided may be useful for the manufacture of excipients." However, the
FDA may have to revise this statement based on the most recent comments
received on the March 1998 draft.
The draft API Guidance does not apply to medical gases, bulk-packaged
drug products, and radiopharmaceuticals.
106 Validation of Active Pharmaceutical Ingredients
Since April 1984, with the first publication of the Guide to Inspection of Bulk
Pharmaceutical Chemical Manufacturing, the FDA has acknowledged that there
are "basic differences" between the processes used for the production of BPCs
and those used for finished drug products. BPCs, both actives and inactives,
usually are produced by chemical synthesis, recombinant DNA technology,
fermentation, enzymatic reactions, recovery from natural materials, or com-
binations of these processes. The production of BPCs typically involves signif-
icant changes of starting materials or intermediates by chemical, biological, or
physical processing steps. Purification is the ultimate objective.
In contrast, finished drug products are formulated from bulk raw materi-
als the quality of which can be measured against established specifications by
dosage manufacturers. Most important, the manufacturing processes for fin-
ished pharmaceuticals typically do not involve purification steps.
The FDA has long recognized that the "GMP concepts" embraced in the
cGMP regulations for finished pharmaceuticals are valid and can be applied to
API processes. These concepts include control of raw materials; building, not
testing, quality into a product; in-process testing and controls; process valida-
tion; and others. In fact, such concepts can be applied in any manufacturing
process, whether it involves constructing an automobile or airplane, or man-
ufacturing a computer chip or a medical device. Notwithstanding, API manu-
facturers frequently ask, "At what processing step and to what extent should
GMP controls be applied in an API process?"
In the April 1984 BPC inspection guide the FDA acknowledged that in
many bulk processes "it is neither feasible nor required to apply rigid controls
during the early processing steps." Page 4 of the guide explains that GMPs
"should be increasingly tightened according to some reasonable rationale," as
processing proceeds from early intermediate steps to final isolation and pu-
rification steps. Beginning "at some logical processing step, usually well be-
fore the final finishing operation," manufacturers should impose appropriate
GMP controls and maintain these throughout the remainder of the process.
At what processing step should GMPs begin to apply? Since 1984, the FDA has
maintained that GMP controls become applicable at that point where a "start-
ing material" is introduced into the process. Page 3 of the FDA's April 1984
BPC guide states the following:
This statement was revised slightly in the September 1991 version of the
BPC inspection guide by deleting "ludicrous" from the second sentence and
rewording the third sentence to read as follows: "As a general rule, however, it
is reasonable to expect GMP concepts to start to become applicable at that
point where a starting material enters a biological or chemical synthesis or se-
ries of processing steps, where it is known that the end product will be a BPC."
The FDA's March 1998 API guidance embodies this important concept. The
third paragraph in the introduction of the guidance explains that the "FDA
expects appropriate cGMPs to be applied to all steps in the manufacturing
process, beginning with the use of starting materials."
Figure 5.4 shows the spectrum of GMP controls in a typical API process.
Once the starting material is introduced into the API process, manufacturers
should increase GMP controls according to some reasonable and scientifically
sound rationale as processing proceeds from early process steps to final syn-
thesis, isolation, and purification steps. Of course, how much control depends
on the process and manufacturing stage.
However, the definitions section was deleted in the September 1991 revision
of the BPC inspection guide and this early definition of "starting material" re-
ceived little attention from the API or pharmaceutical industry.
The FDA's March 1998 API guidance includes a definition for a starting
material that is almost identical to the definition found in the ICH Harmo-
nized Tripartite Q3A Guideline, Impurities in New Drug Substances. It simply
substitutes API for the term drug substance as shown below:
Although this harmonized definition for a starting material has been rec-
ognized among the ICH parties since the Q3A guidance was recommended for
adoption at Step 4 of the ICH process in March 1995, the term remains con-
troversial and is still the subject of much debate today. In the European Union
(EU), for example, the term starting material has raised concerns because it is
widely used in Europe to refer to raw materials, both actives and excipients,
for manufacturing drug products. Beyond the EU, many industry officials
claim that the FDA and ICH Q3A definitions are too restrictive, since both
definitions limit starting materials to those that are "normally commercially
available." Some API manufacturers maintain that the definition is too vague
and is not applicable to all API processes, such as APis derived from fermenta-
tion and biotechnology processes. Other manufacturers maintain that identi-
fying the starting material in API processes may be arduous, and that
additional criteria should be incorporated into the definition to help in the
identification process.
The FDA's February 1987 Guideline for Submitting Supporting Documenta-
tion in Drug Applications for the Manufacture of Drug Substances attempted to ad-
dress these concerns by including the following criteria for identifying a
starting material:
The drug substance guidance explains that the starting materials will fre-
quently meet several of these criteria. If it does not meet any of the above cri-
teria, "it is probably not the starting material." It further explains that if the
starting material is not commercially available, it should meet the third crite-
rion. While helpful, the above criteria still did not address all situations,
prompting occasional meetings between FDA chemists and NDA applicants
to mediate the designation of the starting material in a new process. For some
API processes, such as semisynthetic antibiotics, the starting material itself is
often an active ingredient. In other instances, manufacturers subject an inter-
mediate produced in-house or received from a supplier to a final synthesis
and purification step to obtain the API and designate the intermediate as the
starting material.
One approach that may help identify the starting material involves
evaluating the actual or intended use of a material and where it is introduced
into the process. For example, does a material have both industrial and phar-
maceutical uses or is it sold or intended for use only in API production? Fig-
ure 5.5 shows how this approach can be applied in a multistep API process.
In this example, the first and second steps result in the production of mater-
ial "C" that has both industrial and pharmaceutical uses. A percentage of
material "C" is introduced into step three of the process and is further syn-
thesized and purified, resulting in the production of the API in step six. In
this example, the starting material is "C" and the API process begins with
step three where "C" is introduced into the chemical synthesis process that
results in production of the API. Steps one and two would not be considered
part of the API process, and would not be subjected to cGMP controls since
INDUSTRIAL
Major Intermediate Extensive
•
USES
J Tests J In-process
I + + /Tests
= API USES
A - B - c •••• . . . n - E - F - API
I
API Starting Material
I
Minor
In-process
Final Intermediate
Key Intermediate
Tests
> API process begins with the use of Starting Material C to produce Intermediate D
> Level of control increases throughout synthesis of Intermediates E-F and API
> Control needed is highly dependent on the manufacturing process
110 Validation of Active Pharmaceutical Ingredients
these steps result in the production of a substance that has both industrial
and pharmaceutical uses. Like the original definition of starting material in
the FDA's April1984 BPC inspection guide, this approach removes from con-
sideration those materials not destined for use in API production. This
approach, however, may not be practical for all API processes, and manufac-
turers may need to develop additional criteria to help identify the starting
material.
The FDA recognizes that the "starting material" concept may not ade-
quately address all API processes, and that specific language may be needed to
address APis derived from fermentation, biotechnology, and other unique
processes. Whatever the outcome, one thing is certain. API manufacturers
should thoroughly understand their processes, exercise good judgment, and
adequately document the rationale used to determine the processing step
where cGMP controls begin to apply.
termediate steps to final synthesis, isolation, and purification steps. Early pro-
cessing steps may only require elementary in-process monitoring, tests, and
documentation. However, critical process steps in subsequent synthesis, isola-
tion, and purification steps would require more sophisticated in-process con-
trols, tests, documentation, and, of course, validation. In addition, the group
agreed this approach would embrace critical steps before the final intermedi-
ate that result in important molecular structural changes or the introduction
and removal of impurities.
The "control and validate the final API step or steps" would provide the
minimum burden to industry and the lowest quality assurance for APis.
Although validation of the later synthesis and purification steps is the ap-
proach emphasized in the FDA's September 1991 BPC inspection guide, the
task force concluded this approach was not scientifically justified. It mini-
mizes control of earlier manufacturing steps that may be critical to API qual-
ity and is not consistent with the fundamental cGMP concept of assuring
quality by adequately controlling each step of the manufacturing process. In
addition, the group felt that this approach may actually promote the use of
dedicated "GMP" facilities that receive an intermediate from an outside
source and perform the final synthesis and purification steps.
After considerable discussion, members of the FDA GMP task force con-
cluded that the "control all steps, validate critical process steps" approach was
the most rational validation approach. Shown below are 10 reasons for sup-
porting this approach:
The PMA concept paper also suggests that API manufacturers consider the fol-
lowing when determining which process steps should be validated:
approach should not be viewed as a viable alternative when the number and
frequency of API production runs permit timely completion of validation
prior to API distribution." Although not mentioned in the API guidance,
manufacturers should consult with the FDA before attempting concurrent
validation for an API process.
The draft API guidance also clarifies FDA expectations regarding retro-
spective validation of established API processes. In the United States this ap-
proach is often considered when a manufacturer located abroad is referenced
for the first time in a drug application for an API it has manufactured for the
last 5 to 10 years for non-U.S. markets. Before attempting this approach, how-
ever, manufacturers should assure that the API process has not changed signif-
icantly and that there is sufficient production, testing, and control data on
past batches to show the process consistently produces acceptable API
batches. Inspections by the FDA have uncovered many instances in which
manufacturers have attempted retrospective validation of existing API
processes despite significant changes to the process, repeated batch failures
caused by process variability, or lack of impurity profile data. Retrospective
validation should be attempted only when
The FDA's August 1996 API draft guidance did not include advice on the
number of production lots to include in process validation studies. The FDA
received many comments regarding this omission and corrected it in the
March 1998 version. For prospective validation the FDA recommends three
consecutive successful production lots as a guide, but cautions that additional
process runs may be warranted in some instances to show consistency of the
process. For retrospective validation the FDA recommends reviewing data on
10 to 30 consecutive batches to assess process consistency. However, fewer
batches may be examined if justified.
The equipment cleaning validation section of the FDA's August 1996 API
discussion draft implied that all equipment cleaning methods should be vali-
dated. This drew many comments from industry and prompted the FDA to
rewrite the entire section. The March 1998 draft guidance states: "Equipment
cleaning methods should be validated, where appropriate." Overall, "cleaning
validation efforts should be directed to situations or process steps where cont-
amination or incidental carryover of degradants poses the greatest risk to API
quality and safety." If residues are removed by subsequent purification steps,
"it may be unnecessary to validate cleaning methods" in early synthesis steps.
Although not mentioned in the guidance, this approach may not be appropri-
ate for all API processes or cleaning procedures (e.g., cytotoxic API facilities).
In addition, the March 1998 draft guidance explains that cleaning valida-
tion should reflect actual equipment use patterns. If a family of APis (i.e.,
group of APis with similar toxicological and pharmacological properties) is
produced in the same equipment and the equipment is cleaned by the same
process, a worst case or "most difficult to remove" API may be selected to rep-
resent all APis processed in this manner. The API selected for this cleaning val-
idation study should be based on evaluating various characteristics of the API
family, such as potency, toxicity, solubility, stability, and difficulty of cleaning.
In response to industry recommendations, the March 1998 API guidance
also emphasizes the importance of routinely monitoring equipment cleaning
activities after cleaning validation. Section IV.E states: "Cleaning procedures
should be checked by appropriate methods after validation to ensure these
procedures remain effective when used during routine production."
What about cleaning validation for APis intended for clinical trials? Sec-
tion X.V. of the March 1998 API industry guidance does not specifically ad-
dress this issue. Typically, APis for clinical trials are produced in laboratory
facilities or pilot scale equipment that are often easier to clean than equip-
ment found in commercial production facilities. In addition, APis for clinical
trials often consist of a single or limited number of batches, which makes
cleaning validation difficult or inexact.
However, Section XV. C. of the API guidance states: "During all phases of
clinical development including the use of small-scale facilities or laboratories
to manufacture clinical API batches, procedures should be in place to ensure
that equipment is calibrated, clean, and suitable for its intended use." Proce-
dures for the use of facilities "should ensure that materials are handled in a
manner that prevents contamination and cross-contamination."
Although this language is quite general, the important point is that
manufacturers of APis for clinical trial drugs should ensure that equipment is
clean and suitable for its intended use. This may be accomplished by effective
cleaning and verification procedures that fall short of a cleaning validation
program that the FDA would expect to see in a nondedicated commercial
scale API facility.
120 Validation of Active Pharmaceutical Ingredients
PROCESS WATER
The quality and GMP expectations for process water also differ for dosage
forms and APis. USP 23 (Section 1231, Page 1984) prohibits the use of potable
water for manufacturing pharmaceuticals but allows its use in the production
of USP drug substances. Potable water generally has been recognized by both
industry and the FDA as the minimum quality water for the production of
APis, provided the water complies with established regulatory requirements
for source drinking water and data from periodic testing show compliance
with chemical and microbiological standards, including freedom from patho-
genic organisms.
Page 12 of the FDA's September 1991 BPC guide explains that "water
used in the production of BPCs in many instances (e.g., fermentation of an-
tibiotics) may be potable water obtained from wells or surface sources." The
FDA's August 1996 draft API guidance states: "Water for any API process
should, at a minimum, meet the standards for potable water, as stated in the
United States Environmental Protection Agency's (EPA) National Primary
Drinking Water Regulations (NPRDWR) set forth in 40 Code of Federal Regu-
lations, Part 141." This language was revised in the March 1998 draft (Section
V.F) to allow the use of drinking water meeting EPA standards "or comparable
standards of other authorities such as the European Union, Japan, or the
World Health Organization."
However, several organizations commented that if water not meeting
potable water standards is shown to be suitable for its intended use, this
should not be objectionable. They maintain that in many instances, water
used in early process steps need not be of drinking water quality, as the ag-
gressive nature of the process may destroy trace quantities of impurities lim-
ited in drinking water. In addition, they contend that starting materials
themselves often contain chemicals or impurities that are often limited in
drinking water.
From the FDA's perspective, a manufacturer would have to provide a
substantial amount of data to justify the use of water in API processing that
does not meet drinking water standards. This should include data to show
that the water supply is not contaminated by insoluble organic chemicals or
by compounds leaked into water sources from underground seepage or runoff
during increment weather. Furthermore, use of a lesser quality of water for
API processing would be difficult to justify when the International Pharma-
ceutical Excipients Council has adopted the use of potable water as the mini-
mum quality water for production of pharmaceutical excipients (IPEC 1995).
The quality of process water used during later isolation and purification
stages, particularly its microbial attributes, has generated even more discus-
sion and continues to be debated today. Review of technical literature, refer-
ences, and comments submitted to the FDA's August 1996 and March 1998
draft API guidance disclosed several opinions on this issue. Officials at some
API manufacturers contend that the microbial quality of water is irrelevant
The FDA's Perspectives on API . .. Validation 121
because the manufacture of most synthetic APis involves use of strong acids
and/or bases, high temperatures and/or pressures, or reagents that themselves
are bacteriostats. These factors may preclude the buildup of microorganisms
in the API. Others maintain that potable water can be used in later isolation
and purification steps if the API manufacturer proves the water is suitable for
its intended use and shows that residual chlorine and other ions present in
potable water do not adversely alter API quality. Many API manufacturers re-
portedly prefer this latter approach rather than dealing with the potential
problems of microbial growth in deionizer, ultrafiltration, and reverse osmo-
sis systems used to produce purified water. Yet others, including FDA spokes-
persons in the early 1990s, advocated that the quality of water used in final
isolation and purification steps should be similar to that used for manufactur-
ing the dosage form incorporating the API (Avallone 1992).
Publications from the FDA, industry, and other sources have not ade-
quately addressed this issue. For example, the FDA's September 1991 BPC in-
spection guide states: "if the water is used in later processing steps such as for
a final wash of the filter cake, or if the BPC is crystallized from an aqueous sys-
tem, the water quality standards should be higher than normally specified for
purified water." However, as pointed out by the German BPC industry (Dem-
mer et al. 1994), "If purified water can be used routinely to manufacture oral
or topical drug products, it is difficult to justify a higher quality for the 1500 or
2000 L of water used just to wash the final crystals of a nonsterile BPC on a
centrifuge (presuming that the BPC will not be used in parenteral drug manu-
facture)."
Most recently, the Water for Pharmaceutical Purposes section of USP 24, of-
ficial as of 2 january 2000, states that "drinking water may be used in the
early stages of chemical synthesis and in the early stages of the cleaning of
pharmaceutical manufacturing equipment." This language could lead one to
conclude that drinking water should not be used in final isolation and purifi-
cation stages of a chemical synthesis process. However, USP 24 does not ad-
dress this in its discussion of the uses of purified water. It only states that
"Purified Water is used as an excipient in the production of official prepara-
tions; in pharmaceutical applications, such as cleaning of certain equipment;
and in the preparation of some bulk pharmaceutical chemicals."
The FDA's August 1996 draft API guidance included the following lan-
guage addressing the quality of water used in final isolation and purification
steps:
Many organizations, however, commented that the examples given (e.g., final
crystallization and isolation) may not be critical for all API processes and that
only the manufacturer could determine this. Thus, the language was revised
in the March 1998 draft by substituting "critical manufacturing steps" with
"certain process steps" and rewording the section to read as follows:
meets compendia! specifications for WFI. This approach emphasizes the water
quality that should be met, not the method used to produce process water.
Obviously, when process water is treated to achieve an established qual-
ity (i.e., purified water, WFI), the treatment process and associated distribu-
tion systems should be qualified, validated, properly maintained, and
routinely tested following established procedures to ensure water of the de-
sired quality.
API production, and recent FDA and industry guidance documents clearly dis-
tinguish the two terms.
The FDA's August 1996 discussion draft defined both reprocessing and
reworking as deviations from a "validated process." Based on many industry
comments, the FDA revised both definitions in the March 1998 draft by sub-
stituting "validated process" with "established process." This change is con-
sistent with PhRMA's definitions and would provide for reprocessing or
reworking of intermediates produced by noncritical process steps that may
not be validated.
The March 1998 draft API guidance defines reprocessing as "introducing
an intermediate or API that does not conform to standards or specifications,
back into the process and repeating one or more steps that are part of the es-
tablished manufacturing process." Recrystallizing using the same solvent is
the most common example of reprocessing, although other physical manipu-
lations, such as dissolution, filtration, and milling, are often employed.
Reprocessing is considered a frequent and commonly accepted practice
in the API industry. It is conducted primarily to increase yields, to obtain a
purer material, or to bring important attributes such as particle size distribu-
tion, bulk density, and tap density into conformance with established specifi-
cations. In contrast, reprocessing of a drug product is atypical and rarely
results in improving drug purity.
Reworking as defined in the FDA's March 1998 draft API guidance, in-
volves "subjecting an intermediate or API that does not conform to standards
or specifications, to one or more processing steps that are different from the
established manufacturing process." Recrystallizing using a different solvent
is a clear example of reworking. Reworking often alters the chemical structure
of the material and would include taking the molecular salt of the API back to
its base, although the subsequent step of converting the base into the salt is
part of the established process. Reworked batches should be subjected to ap-
propriate evaluation to show that the reworked API or intermediate is of
equivalent quality to that produced by the original process.
Again, the true difference between reprocessing and reworking is
whether the actions taken with the nonconforming batch deviate from the
established process. Reprocessing involves subjecting an intermediate or API
batch to a step or steps of the same process, whereas reworking involves sub-
jecting a nonconforming batch to a different process.
Assuring the purity of APis and testing for impurities has been and continues
to be a major concern of the FDA. In the last four decades, several incidents
have occurred in which the presence of precursors, by-products, or other im-
purities in APis used in dosage manufacturing resulted in serious patient side
The FDA's Perspectives on API . .. Validation 125
effects and deaths. A classic example of this was the thalidomide tragedy in
the mid-1960s, when a change in the API manufacturing process, imple-
mented to improve yields, reportedly introduced a new impurity, the d-
isomer of the active. This d-isomer was not detected by routine in-process or
final testing and had not been previously consumed by humans. It apparently
caused fetal abnormalities and prompted the famous 1960-1962 U.S. Senate
Kefauver hearings and significant changes in U.S. Food and Drug Law.
In 1988 and 1989, changes in one manufacturer's bacterial fermentation
and purification steps for producing the amino acid L-tryptophan inad-
vertently introduced a trace contaminant, at a concentration of less than
0.1 percent. This contaminant was correlated with the outbreak of
eosinophilia-myalgia syndrome (EMS) in persons who repeatedly consumed
the amino acid as a dietary supplement. At least 27 people died of EMS di-
rectly or indirectly and more than 1,500 reported becoming ill before re-
searchers established a clear link between EMS and 13 tainted lots of
L-tryptophan produced by the modified process (Newton 1991). These inci-
dents clearly emphasize the importance of identifying and quantifying impu-
rities in APis and determining how the impurity profile is affected by changes
in the manufacturing process.
Establishing and maintaining impurity profiles is both a filing and a
cGMP issue. For a new active ingredient, establishing an impurity profile is an
important element of drug testing and development. API manufacturers are
expected to submit data on initial impurities identified along with toxicity
data in a drug master file or drug application. However, once the API process
is scaled up and commercial batches are produced, monitoring of impurities
becomes a significant cGMP issue because changes in the API's impurity pro-
file usually signal a change in equipment operating parameters, materials, or
processes. Most important, the appearance of an impurity in commercial size
API batches that was not present during the clinical stages presents serious
concerns regarding the stability, safety, and efficacy of the finished product
incorporating the API.
API manufacturers routinely conduct tests for ordinary impurities, re-
lated compounds, and organic volatile impurities if these are specified in the
USP monograph for the active ingredient. These tests are batch release specifi-
cations that must be met to comply with the USP monograph. Such testing,
however, does not substitute for impurity profile testing of APis nor do these
tests sufficiently characterize the purity of APis. The USP acknowledges that
compendia} methods may not be specific and are frequently inadequate, par-
ticularly for active ingredients obtained from multiple sources when each
source may use a different manufacturing process, resulting in distinct impu-
rity profiles. Page 7 of the General Notices and Requirements section of
USP 24 states:
The FDA's September 1991 revision of the BPC inspection guide discusses
the importance of characterizing and controlling impurities and outlines the
FDA's approach to evaluating API impurity testing during cGMP inspections.
Page 21 of the guide states: "It is important that manufacturers identify and
set appropriate limits for impurities and adequately control manufacturing
processes so that the impurities consistently meet established specifications."
Appendix A of the guide references the USP definition of an impurity profile
and clarifies that the FDA expects "the manufacturer to establish an appropri-
ate impurity profile for each BPC based on adequate consideration of the
process and test results." Most important, the guide directs investigators to
compare the impurity profile for the pilot batch material with that of the
commercial size BPC batches to determine if the profile has changed signifi-
cantly. Investigators should specifically ask "for current complete purity pro-
files, and these profiles should include the levels of solvents normally found
in the purified drug substance along with acceptable specifications."
The FDA's Perspectives on API . .. Validation 127
Section IX.B. of the March 1998 draft API guidance states, "Impurity pro-
files should be established and maintained for each API that identify or quan-
tify each impurity observed." Impurity profiles are an important part of a
historic analysis and the FDA expects API manufacturers to establish appropri-
ate impurity profiles for each API as part of the process validation effort. This
should be "based on adequate consideration of the process and test results"
and include collecting data on (1) actual and potential organic impurities that
may arise during synthesis, purification, and storage of the API; (2) inorganic
impurities that may arise from the manufacturing process; and (3) organic and
inorganic solvents used during the manufacturing process known to carry
over to the API.
For new drug substances produced by chemical synthesis, ICH Q3A rec-
ommends the identification of all recurring impurities at or above 0.1 per-
cent. For established APis, the FDA's November 1999 Guidance for Industry
ANDAs: Impurities in Drug Substances recommends identification of all recur-
ring impurities at or above an apparent level of 0.1 percent in batches manu-
factured by the commercial process.
In summary, API manufacturers should ensure that appropriate and vali-
dated analytical methods are in place to detect and quantify recurring impuri-
ties in APis. Such testing, if conducted on a routine or batch-by-batch basis,
allows manufacturers to detect unanticipated changes by continuously com-
paring the impurity profile against the profile submitted in a Drug Master File
or drug application, or that shown by historical analysis. As voiced by
Boehlert (1987), apart from the primary concern of safety, few in industry
would argue that there are also very sound business reasons for knowing
the impurity profile of a drug substance or the degradation profile of a drug
product.
During the April 1998 meeting, the ICH EWG reviewed the revised PIC
and PIC/S guidance along with the following API guidance documents:
Thus, the ICH EWG initially had at their disposition two API documents pre-
pared by industry, two prepared by regulatory bodies that had gone through a
comment phase, and the WHO document. These documents provided excel-
lent building blocks from which to craft an ICH harmonized guide.
The EWG examined all five documents but could not achieve a consen-
sus on using one API document as a basis for the ICH initial draft. Thus, the
Rapporteurs agreed to draft the initial ICH guidance and drculate this to the
EWG by July 1998 for comments.
Comments on the initial draft were discussed by the EWG at the 31 Au-
gust to 3 September 1998 ICH meeting in Tokyo, Japan. To date, the Q7A
EWG has met on five other occasions. These include a meeting in London in
February 1999, Brussels in March 1999, Los Angeles in June 1999, and Wash-
ington, D.C., in October 1999. The last meeting was held 28 February to
3 March 2000 in Tokyo.
Since its inception in April 1998, the ICH EWG has produced seven
drafts, a substantial achievement considering this is the first time ICH has
been involved in developing a harmonized API GMP guidance. It is a long, de-
tailed process, and the EWG still has much ground to cover, but in the end,
the ICH harmonization process should result in an API guidance document
that will satisfy the needs of both industry and regulators.
CONCLUSIONS
This chapter has focused mainly on the FDA's current expectations regarding
the manufacturing, cGMP controls, and validation of API processes as embodied
in the FDA's draft Guidance for Industry Manufacture, Processing or Holding Active
Pharmaceutical Ingredients. Now that the FDA is involved in developing an inter-
nationally harmonized guidance on cGMPs through the ICH process, many
130 Validation of Active Pharmaceutical Ingredients
have asked why the FDA continues to discuss its draft API guidance at industry
seminars and forums and how the current draft is used by FDA investigators.
Clearly, the FDA is committed to the ICH Q7 A initiative and will do its
best to expedite the development of a harmonized GMP guidance that can be
implemented globally and that will provide greater assurance of the quality of
APis used to manufacture drug products. However, even if the ICH guidance
reaches Step II by the middle of the year 2000, it may take several months for
the EWG to review worldwide comments received on the document, revise it,
and resubmit it to the ICH Steering Committee for their approval and adop-
tion by the regulatory bodies. Thus, there may not be a final version of the
ICH harmonized guidance until late 2000 or early 2001.
Meanwhile, the FDA's inspections of API manufacturers, both domestic
and international, continue. The FDA is expected to clearly communicate its
cGMP expectations to the regulated industry. For manufacturers of APis,
these expectations are articulated in the FDA's March 1998 Guidance for Indus-
try Manufacture, Processing or Holding Active Pharmaceutical Ingredients. Al-
though identified as a draft, the industry guidance represents the FDA's
current thinking on the manufacturing and control of APis. Thus, it is usually
reviewed by FDA investigators when preparing for inspections of API facili-
ties. API manufacturers should also review the draft guidance and understand
the cGMP and validation concepts embodied in the document when prepar-
ing for FDA inspections.
REFERENCES
Avallone, H. L. 1992. GMP Inspections of Drug-Substance Manufacturers. Phann. Tech.
16 (6):46-55.
Boehlert, J.P. 1997. Impurities-Where Are We Now? Phann. Tech. Gune): 56, 58, and 60.
CEFIC/EFPIA. 1996. Good Manufacturing Practices for Active Ingredient Manufacturers.
Brussels, Belgium: European Chemical Industry Council/European Federation of
Pharmaceutical Industries' Associations.
CFR. 1978. Title 21, Part 211, Current Good Manufacturing Practice For Finished Phar-
maceuticals. Code of Federal Regulations. 43(190)
Curtis, E. A. 1996. Parameters and quality attributes. Paper presented at the Pharma-
ceutical Education & Research Institute, Inc. Bulk Pharmaceutical Chemical
Process Validation Course, September Wilmington, Del., USA.
Demmer, F., N. C. Franklin, S. Geussenhainer, H. Hausler, R. Kirrstetter, C. Rufer,
E. Walter, and F. Zimmermann. 1994. FDA regulation of bulk pharmaceutical
chemicals-an industrial commentary: part II. Phann. Tech. 18 (12):36-43.
FDA. 1994. Guide to inspection of bulk phannaceutical chemical manufacturing: Reference
materials and training aids for investigators. Rockville, Md., USA: Food and Drug Ad-
ministration, Office of Regulatory Affairs and Center for Drugs and Biologics.
The FDA's Perspectives on API ... Validation 131
FDA. 1987. Guideline for submitting supporting documentation in drug applications for the
manufacture of drug substances. Rockville, Md., USA: Food and Drug Administra-
tion, Center for Drugs and Biologics.
FDA. 1987. Guideline on general principles of process validation. Rockville, Md., USA:
Food and Drug Administration, Center for Drug Evaluation and Research, Center
for Biologics Evaluation and Research, and Center for Devices and Radiological
Health.
FDA. 1991. Guide to inspection of bulk pharmaceutical chemicals: Reference materials and
training aids for investigators. Rockville, Md., USA: Food and Drug Administration,
Office of Regulatory Affairs and Center for Drug Evaluation and Research.
FDA. 1994. Bulk GMP's for drug substances-position paper on GMP control and validation.
Rockville, Md., USA: Food and Drug Administration, Center for Drug Evaluation
and Research.
FDA. 1996. Draft guidance for industry: Manufacture, processing, or holding of active phar-
maceutical ingredients. Rockville, Md., USA: Food and Drug Administration, Center
for Drug Evaluation and Research, Center for Biologics Evaluation and Research,
and Center for Veterinary Medicine.
FDA. 1997. Good guidance practices (GGP's). Rockville, Md., USA: Food and Drug Ad-
ministration, 62 FR 8961.
FDA. 1998. Draft guidance for industry: manufacturing, processing, or holding active phar-
maceutical ingredients. Rockville, Md., USA: Food and Drug Administration, Center
for Drug Evaluation and Research, Center for Biologics Evaluation and Research,
and Center for Veterinary Medicine.
FDA. 1998. Active pharmaceutical ingredients (APis). Compliance Program Guide
7556.002F. Rockville, Md., USA: Food and Drug Administration.
FDA. 1999. Guidance for industry ANDAs: Impurities in drug substances. Rockville, Md.,
USA: Food and Drug Administration, Center for Drug Evaluation and Research.
Hall, W. E. 1997. Cleaning for bulk pharmaceutical chemicals (BPCs): Validation of bulk
pharmaceutical chemicals. Buffalo Grove, Ill., USA: lnterpharm Press, Inc.
IPEC. 1995. Good manufacturing practices guide for bulk pharmaceutical excipients. Arling-
ton, Va., USA: International Pharmaceutical Excipients Council.
ISPE/FDA. 1996. Baseline pharmaceutical engineering guides for new and renovated facili-
ties, Vol. I, Bulk pharmaceutical chemicals. Tampa, Fla., USA: International Society
of Pharmaceutical Engineering and the Food and Drug Administration.
Nash, R. A. 1997. BPC Terminology and Documentation. In Validation of Bulk Pharma-
ceutical Chemicals, edited by I. R. Berry and D. Harpaz. Buffalo Grove, Ill., USA: In-
terpharm Press, Inc.
Newton, P. 1991. High performance liquid chromatography and the mystery of L-
tryptophan. LC-GC 9(3):208-213.
PhRMA. 1995. PhRMA guidelines for the production, packaging, repacking, or holding
of drug substances, part I. Pharm. Tech. 19 (11):22-32.
132 Validation of Active Pharmaceutical Ingredients
PhRMA. 1996. PhRMA guidelines for the production, packaging, repacking, or holding
of drug substances, part II. Pharm. Tech. 20 (1):50-63.
PhRMA. 1997. PhRMA guidelines for the validation of cleaning procedures for bulk
pharmaceutical chemicals. Pharm. Tech. 21 (9):56-73.
PMA Validation Advisory Committee. 1985. Process validation concepts for drug prod-
ucts. Pharm. Tech. 9 (9):78-82.
PMA Bulk Pharmaceuticals Committee. 1993. Concepts for the process validation of
bulk pharmaceutical chemicals. Pharm. Tech. 17 (12):32-40.
PDA. 1995. Technical Report No. 18: Validation of Computer-Related Systems. Bethesda,
Md., USA: Parenteral Drug Association.
Rivera Martinez, E. 1999. FDA's guidance for industry manufacturing, processing,
holding active pharmaceutical ingredients-Update on ICH Q7 A. Paper presented
at the Synthetic Organic Chemical Manufacturers Association's Annual Confer-
ence, May, Washington, D.C.
Rivera-Martinez, E. 1999. Fiscal year 98 update-FDA's international inspections. Paper
presented at PhRMA's 1999 Technical Symposium, june, Braselton, Ga., USA.
USP. 1995. Water for pharmaceutical purposes. In United States pharmacopeia 23, chap-
ter 1231. Rockville, Md., USA: United States Pharmacopeia! Convention, Inc.
USP. 1999. Water for pharmaceutical purposes. In United States Pharmacopeia 24, chap-
ter 1231. Rockville, Md., USA: United States Pharmacopeia! Convention, Inc.
6
DOMESTIC AND FOREIGN
API MANUFACTURING FACILITY
AUDITS AND FINDINGS
Peter D. Smith
KMI/PAREXEL
Rockville, Maryland
133
134 Validation of Active Pharmaceutical Ingredients
must be structured. For the purpose of this chapter, however, the distinction
between QC and QA will be used as it is common industry practice.
Many GMP deficiencies encountered during FDA inspections and serious
regulatory problems experienced by the API industry could be reduced by a
strong and effective QA unit. Very often, especially in foreign API manufactur-
ing plants, the QA unit is limited in scope of responsibility and authority, and
sometimes the "QA unit" is a single person. Sometimes the QA director is a fig-
urehead, with no authority to halt the shipment of noncompliant products
and unable to influence GMP compliance and effect corrective actions. This
situation is a recipe for inspectional problems. Since many FDA inspection
techniques are based heavily on investigating from the QA perspective (such as
tracing a document trail, challenging systems, auditing documentation for
completeness), a competent QA group can provide a constant "FDA" direction,
preventing or recognizing and acting on compliance problems as they emerge.
Generally, FDA Investigators find that most systems operate well under
normal conditions and situations. For this reason, the FDA is always looking
for the exceptions and nonroutine events, assessing how these events are
handled and resolved. QA can play a large role in assuring these incidents are
dealt with correctly and consistently.
The FDA expects QA to be involved, and influential, in all operational
areas that effect product quality. This applies to the review and approval of
many documents and procedures, including validation protocols and reports,
material and product release, master/batch production records, Standard Oper-
ating Procedures (SOPs), change control, deviations and failure investigations,
and product quality reviews. The GMPs require written procedures describing
the authority, definition, organization, and responsibilities of the quality unit.
In a typical structure that is acceptable to the FDA, the QC manager (an-
alytical lab) answers to the QA director, who is equivalent in position and au-
thority to other department managers, such as the production director, and
answers to top management. In Europe, where there is a requirement to have
the position of Qualified Person (QP), the FDA does not automatically equate
the QP and QA. Even though the QP, by European requirements, releases
product, this may not be sufficient for the FDA, since the release procedure
must include additional activities that the QP may not always perform, such
as production record review and ensuring deviations are investigated.
The following briefly addresses QA-related areas where problems are
commonly found.
It is clear that the FDA considers SOPs to be very important. The cur-
rent GMP regulation (21 CFR Parts 210/211, September 1978) contains 33
references to "written procedures/programs," that is, SOPs. SOPs are the only
way the FDA can receive assurance that operations that affect the quality of
the final product will be done according to the same approved process each
time. As such, every activity required by the GMPs and/or that affects prod-
uct quality should be covered in some SOP. The SOP system should be clearly
articulated, and most important, ensure that all procedures reflect actual
practices.
The FDA considers an incomplete SOP to be a problem and lack of an
SOP for an activity a bigger problem. But the worst offense is not following
an SOP. This is why SOPs must reflect actual practice. Therefore, a "good-
looking" SOP that is not followed can be a serious problem. From the audi-
tor's perspective, once one SOP is found not to be followed, doubt is cast on a
company's compliance with all written procedures. The inspector will then
begin to look for similar circumstances. lf other examples of SOPs not being
followed are discovered, a serious regulatory situation can develop.
To ensure that procedures are followed, the responsibilities for each ele-
ment required by SOPs must be clearly defined. Human nature dictates that
generally, if one understands his or her duties and tasks, there is a high prob-
ability that the duties and tasks will be completed. The reverse is that if re-
sponsibilities are not clearly defined and understood, there is a potential that
required tasks may not be completed. Many procedures require the input
from multiple individuals or groups. A "Responsibilities" section in each pro-
cedure should identify the responsible individuals or groups, and their duties
should be listed, preferably in bullet fashion, beginning wi~h a verb (for ex-
ample, ensure, review, approve, create).
A comprehensive SOP system should include or consider the following:
• SOP #1, the SOP for SOPs, is a very important cornerstone for the
entire system. It should describe all aspects of the system, including
generation, format, approval, distribution/retrieval, and revision.
• Establish a standard format for all SOPs such that each includes
headings for purpose, scope, responsibilities, definitions, related
SOPs, and the actual step-by-step procedure.
• Combine SOPs of the same subject or system. (This reduces redun-
dancies and contradictions and makes the SOP system easier to
manage.)
• Be sure all SOPs include clear step-by-step instructions and can be
followed easily, reflecting actual practices.
• Flowcharts should be made part of many SOPs. These are very use-
ful training tools and assist management and inspectors in seeing
the whole picture.
136 Validation of Active Pharmaceutical Ingredients
• Do not use words such as adequate or necessary unless the SOP de-
fines what is adequate or when something is necessary and the cri-
teria for making these decisions.
• There should be an SOP describing the meaning of review and ap-
proval signatures, that is, a description of what each person signing
a document actually did or reviewed.
• For foreign companies, an English translation of the SOP index that
describes by title the SOPs' content is very helpful to demonstrate
the scope and breadth of the SOP system.
• Production processes
• Production equipment
• Facilities
• Utilities
• Raw materials
• Specifications
• Analytical methods
• Analytical instruments
• SOPs
• Computer-related systems
QUALIFICATION
The accomplishment of the equipment and utility qualification activities and
process and cleaning validations are vitally important. The FDA expects all
processes for marketed products to be validated, and those products that are
not validated are at regulatory risk. Any process qualification (PQ) accom-
plished using equipment that is not verified and documented as qualified, is
not sound. Qualification is a basic part of and prerequisite for validation.
Staffing to accomplish the validation work may need to be temporarily
increased, especially in a new facility. A possible solution would be to reas-
sign personnel from other areas, such as production, to work as part of the
validation team. The dual functions of personnel such as the maintenance
engineers, to accomplish qualification work and keep up with routine main-
tenance, hamper efficient completion of validation activities. Staff attached
to the validation team would provide dedicated individuals to accomplish
equipment qualifications in coordination with other validation work. The
separation would also allow routine maintenance to be conducted by a staff
dedicated to that purpose.
Common problem areas observed with regard to API equipment and fa-
cility qualification are as follows:
EQUIPMENT CLEANING
The FDA's concern regarding minimizing the potential for contamination is
largely derived from experience with improperly cleaned equipment and con-
tainers. Several years ago, recalls in the United States resulted from use of im-
properly cleaned intermediate containers, which contaminated an API. The
API then contaminated milling equipment at a contract milling facility,
which in turn contaminated additional materials.
Cleaning is also a huge task for API manufacturers, who report that
equipment is often down for cleaning more time than it is operating to pro-
duce product. Well-designed and validated cleaning procedures can make this
task easier and eliminate potential regulatory problems. One almost certain
reason for inspection failure is inadequate, unvalidated cleaning procedures
in multiuse equipment.
Cleaning Validation
The FDA expects that there are cleaning procedures for all product contact
surfaces. Validation must apply to all procedures for all products in all equip-
ment that are used for multiple products. It must include the "worst-case" sit-
uation, which is the most difficult to clean material with the greatest
potential for adversely effecting the final API. All validations must include
surface sampling (swabs). A validation totally based on analysis of rinse sam-
ples provides information regarding the material that has been removed, but
provides no information regarding residual material remaining on equipment
surfaces following the cleaning process. Validation must include a rational
limit for residues based on scientifically sound tests and reasoning.
The following cleaning validation failure is commonly seen during
preapproval inspections (PAis). The FDA performs a product specific preap-
proval inspection for product A in a multipurpose plant. The FDA inquires
about cleaning and cleaning validation. The company presents a complete,
well-reasoned and well-documented cleaning validation package for product
A. The FDA Investigator pushes the package aside. Why? At this moment, the
FDA is not concerned about how well product A can be cleaned but is con-
cerned about how well product B, product C, and so on can be cleaned. These
are the products that can precede product A in the equipment stream and
could potentially contaminate product A, the API of concern for this inspec-
tion. However, the cleaning of product A may be important to the FDA re-
garding the contamination potential for other products. That is why a
company should have a comprehensive cleaning validation program incorpo-
rating all products.
EQUIPMENT CALIBRATION
Often critical instrumentation is not identified and labeled to show that it is
properly calibrated, and measuring equipment, such as balances and scales,
are not checked for reliability using an actual weight between formal calibra-
tion checks.
Domestic ... API Manufacturing Facility Audits and Findings 149
LABELING CONTROLS
Control of labels in API production is not difficult but is largely ignored in the
industry. The FDA expects all labels and labeling operations to be controlled.
Labels should be stored in a secure, limited access location. Preparation and
issuance of labels should be controlled, and there should be a reconciliation
of labels issued, used, destroyed, and returned. API operations often use labels
that are preprinted, except for variable information (batch number, gross and
net weights, expiration date), which is completed by hand at the time labels
are applied. Storage of these labels and their preparation should be controlled
by an SOP and documented. Labels that are generated in-house by computer
must be controlled and documented in a similar manner.
RECOVERED SOLVENTS
Recovery of solvents in API production is a common and necessary industry
practice. The important issue with recovered solvents is the potential
150 Validation of Active Pharmaceutical Ingredients
Recovery in the first situation has the least potential for harm, if impu-
rity carryover occurs. Recovery from the second situation does have the po-
tential for depositing impurities downstream of the step in which removal of
the impurity is accomplished. The last situation has the greatest potential for
carryover of impurities, perhaps many different residues from a number of
different process streams.
Solvent recovery processes must be shown to be effective and validated.
There must be specifications for recovered solvents. These specifications may
be different from those for the virgin solvent, but must be equivalent in terms
of the activity in the chemical process and must be shown to contain accept-
able levels for all potential impurities. There must be identification of con-
tainers of recovered solvent vs. virgin solvent.
• In-process sampling
document control group. The log would then show a second batch record was
issued for a particular batch.
The following are typical problems or omissions with regard to API batch
records:
The GMPs require all staff who perform duties that may effect the qual-
ity of the final product to be adequately trained to do their jobs. The FDA
leaves the exact training requirements up to the individual companies. Com-
monly, the FDA expects three levels of training:
PROCESS VALIDATION
Since the majority of this book is devoted to API process validation, only brief
details from the FDA perspective will be mentioned here.
Process validation has been in our vocabulary since 1978, but there is
still not a clear understanding throughout the API industry. Today, the FDA
expects all APis to be validated, even though the agency has not actively at-
tempted to seek compliance regarding "old" APis. Many of these old APis
have been manufactured for many years but have not been validated to in-
clude satisfactory support documentation. Although there are attempts to
validate most new APis, many fail to be accomplished properly. These inade-
quacies include lack of
• process justification,
• scale-up/biobatch vs. commercial size batch comparison,
• identification of critical parameters,
• special tests designed to demonstrate that critical parameters can be
achieved,
• acceptance criteria for these tests, and
• validation of blending processes.
Often the API production process is not completely defined and "frozen"
when material is produced for Phase III clinical trials. Validation cannot be
performed until the process is fixed. Development work must cease when val-
idation begins. Also, the FDA will find it objectionable if the API process for
Phase III studies differs from the commercial process filed in an Abbreviated
New Drug Application or New Drug Application.
The FDA encourages prospective validation, which may be conducted on
R&D or commercial size batches. If R&D-scale batches are used for process
validation, the process then can be scaled up (without changes) and trans-
ferred to commercial production, in which confirmatory testing would be
done. The FDA expects each process parameter to be justified (that is, to have
a development history that demonstrates the necessity and purpose of all
steps and parameters). All critical steps must be validated. It is the responsibil-
ity of the company to identify the critical steps or parameters. The criteria for
criticality should be based on the effect the step or parameter has on the final
API quality. In other words, a critical step is one that should it fail, may
have an adverse effect on the quality of the final API. Although the latter
162 Validation of Active Pharmaceutical Ingredients
production steps are generally more critical, early steps can be critical as well.
For example, if in an API process step 1 produces a toxic impurity that is in-
tended to be removed in step 2, and there is no subsequent step designed to
remove this impurity, then step 2 would be a critical step. Should step 2 fail,
the final API impurity profile could be adversely affected.
Retrospective validation is allowed, but discouraged, by the FDA because
of the limitations of this validation method. A minimum of 20 (preferably 30)
batches is necessary in a retrospective validation. All batches included must
have been produced by an identical process. If there were any changes, the
retrospective method cannot be used. Another limitation is that routine test-
ing on these batches may not have included tests that demonstrate critical pa-
rameters can be achieved.
REFERENCE
FDA. 1998. Guidance for industry, manufacturing, processing, or holding active pharmaceu-
tical ingredients [Draft]. Rockville, Md., USA: Food and Drug Administration.
7
VALIDATION OF APis:
A CASE STUDY
Nirmal Khanna
Consultant to Hoffman-LaRoche
Nutley, New Jersey
During the last five years, the industry has come a long way in understanding
and adapting validation in the manufacture of active pharmaceutical ingredi-
ents (APis). I believe the previous misgivings and confusion are now largely
behind us, and, generally speaking, validation has gained respect, at least
among all progressive manufacturers.
Technical literature has blossomed on this subject thanks to the Food
and Drug Administration (FDA), the International Society for Pharmaceutical
Engineering (ISPE), and the technical community, which have taken the chal-
lenge head-on by publishing on numerous validation topics, conducting sem-
inars, and developing key reference documents such as the Baseline
Pharmaceutical Engineering Guides. These documents now adequately sup-
port validation studies in the API manufacturing arena.
In this chapter, I present process validation as a case study for an API
manufacturer. The approach presented in the previous edition is updated to
accommodate the current regulatory environment. The objective is to illus-
trate the methodology for developing and executing a successful validation
program. In addition, this review includes examples of computer validation
and relocation of an API to another equipment train.
Today, a successful validation program must carry out either prospective
validation for a new drug substance or concurrent validation for an existing
drug substance (see Appendix 7.1). In the early 1990s, the FDA accepted ret-
rospective validation as a regulatory tool for a short period, but now this
163
164 Validation of Active Pharmaceutical Ingredients
approach should be used only for reviewing the manufacture of existing drug
substances and learning from it. Knowledge gained from retrospective reviews
can substantially benefit the company's concurrent validation program.
The ultimate company goal should be to minimize variability in manu-
facturing operations and consistently produce a quality drug substance. A suc-
cessful validation program must demonstrate that variability among the critical
parameters in production is under control. The validation program must use
common sense and technical sense at every step to accomplish that goal.
WHAT IS VALIDATION?
Process validation is defined in the FDA guidelines (FDA 1987) as "Establish-
ing documented evidence that provides a high degree of assurance that a spe-
cific process will consistently produce a product meeting its pre-determined
specifications and quality attributes." The chosen process must consistently
produce a product to predetermined specifications and quality attributes
within each batch and between the batches. The end product must consis-
tently meet specifications and must be reliable, safe, and effective. Docu-
mented evidence means quantitative assessment, measurement, and conduct
of processes. A high degree of assurance is achieved through sufficient prod-
uct and in-process controls, verification procedures, personnel training,
Validation of AP/s: A Case Study 165
MANUFACTURING OPERATIONS
The API manufacturer has been producing several bulk actives since 1980 in a
few multiproduct equipment trains. These facilities are maintained and oper-
ated according to cGMP. A master validation program has been developed and
reviewed with the FDA district office for their blessings, and the validation
manager has been busy validating each product since 1996.
The typical bulk active is produced in four chemical synthesis steps. The
first two steps produce a prime intermediate from purchased materials, whose
quality is monitored. This prime intermediate is inventoried on-site and is re-
leased by Quality Control for production campaigns. In the third step, the
prime intermediate is reacted with another purchased material to produce the
basic chemical structure of the drug product. In the last step, another additive
that often modifies the chemical moiety slightly is added to produce the final
product.
A typical equipment train consists of several batch equipment modules
to complete the chemical synthesis and purification steps of the process. Also,
Validation of AP/s: A Case Study 167
a few dedicated modules are provided, which meet the needs of a specific API.
The equipment train under validation was installed during 1980-1985. Re-
cently, two reactors were replaced. Dryer, cooling/heating system, and puri-
fied water units were installed. A Honeywell control system was added for
monitoring and controlling critical process parameters. Also, a rotary sifter
and a blender were installed in the packaging line to improve blend unifor-
mity. In addition, the drum filling room was rebuilt to Class 100 specifica-
tions for handling a parenteral product.
follow this example to the letter; however, the critical SOPs or Guidelines
must be adopted by a progressive manufacturing organization.
Good production batch records are extremely critical to the success of a
validation program. This API manufacturer has been improving its master batch
records since 1993. After completing a successful retrospective review and per-
formance history of the API, each critical parameter and specification has been
assigned an operating range. The batch records are written in clear and concise
format for the operating staff. Prior to initiating the validation effort, the vali-
dation manager or quality assurance personnel reviewed the master batch
records with the production manager to remedy any remaining inconsistency.
A validation viewpoint on this subject is included in Appendix 7.4.
In addition, as a minimum, as-built PFDs must be available to the operat-
ing staff and the validation team to facilitate the validation effort. The batch
records, PFDs, and P&IDs were updated by IDEAL Corp. with top priority to
support the validation effort. The company hired an outside contractor to up-
date its PFDs and as-built P&IDs. This work was completed during 1995-1996
for all production trains. Master batch records revision was completed in 1996.
VALIDATION PROGRAM
Following the FDA doctrine (FDA 1987), a validation program was developed
for the New Jersey manufacturing site. In addition, the company launched a
formal retrospective review program on all existing APis to identify opportu-
nities for improving production operations.
A validation manager was assigned to the job, who developed the work
teams and assigned responsibilities. Master plans were developed, meetings
were held weekly, and a schedule was developed for execution of all major
validation activities (see Table 7.1).
Retrospective Reviews:
Master Plan, Old APis (12) JM 8 weeks
Concurrent Validations:
Master Plan, Train A NK 8weeks
Master Plan, Train B NK 4 weeks
Master Plan, Train C JS 8 weeks
Master Plan, Train D JS 6 weeks
Prospective Validations:
Master Plan-New Dedicated Train E NK 8weeks
Master Plan-Old API moved to new site NK 6 weeks
Validation of APis: A Case Study 169
RETROSPECTIVE REVIEWS
Master Plan
IDEAL Corp. adopted a master plan for retrospective reviews to examine its older
API processes thoroughly. The purpose of this program was to demonstrate that
the production of each API at the New jersey facility has taken place in a satis-
factory and consistent manner according to the documented manufacturing
procedures. This review effort will document whether each process has consis-
tently met predetermined specifications regarding process parameters, in-process
control testing, and process yields. It will document that a product has met pre-
determined quality control specifications. It will establish that process documen-
tation is complete and accurate, each variance was satisfactorily investigated,
and findings were implemented. A typical master plan addressed the following:
• Scope ofprogram: This section included a list of candidates to be val-
idated and indicated priority, if any. The list identified processes
that will be prospectively validated or reasons for their exclusion.
• Time frame: This section indicated when preparation of the formal
reports will begin and included a realistic schedule.
• Personnel resources: This section listed the names of personnel who will
participate in writing the reports and the team of personnel who will
meet on a regular basis to review progress and manage the project. It
listed the experts from other departments who may be consulted.
• Scope of retrospective report: This section indicated the time frame of
the data that will be reviewed for each report. Typically, 20-30 con-
secutive lots of the most recent production were reviewed. When
fewer lots were available, such circumstances were clearly ad-
dressed. The scope described at what stage of the process retrospec-
tive validation will begin.
In general, the review began from the process step involving
the final chemical transformation forming the structural elements
of the API and continued downstream through subsequent isola-
tion/purification steps. However, if significant impurities were be-
ing introduced or removed at an earlier step, then the review team
often decided to initiate validation from that point in the process.
170 Validation of Active Pharmaceutical Ingredients
CONCURRENT/PROSPECTIVE VALIDATIONS
The concurrent/prospective validation studies had a much larger scope (see
Appendix 7.1). Besides monitoring the process and the cleaning, these valida-
tions documented a review of critical utilities, process equipment, and con-
trolled environment facilities.
Two validation engineers were hired to write, execute, and prepare sum-
mary reports for the various protocols. These chemical engineers were com-
puter literate, possessed good analytical and writing skills, and had
pharmaceutical industry experience. The core team members for this effort
also were derived from Validation, Production, and Quality Assurance func-
tions. And personnel from the Process Development, Quality Control, and
Maintenance groups assisted the core team on need basis.
To create validation documents, the validation engineer developed a
good working knowledge of the process by reviewing the batch records, PFDs,
and P&IDs, reading all technical, development, and annual product reviews
on the product. The work team participated in the review, execution, and ap-
proval of the various validation documents.
A typical concurrent or prospective validation review covered the fol-
lowing:
• Controlled environments facilities, such as dryer rooms, packaging
rooms, milling rooms (installation qualifications [IQs], operational
qualifications [OQs])
• All critical utilities, such as nitrogen, compressed air, and clean
steam (IQs, OQs)
• Deionized (DI) and purified water systems (IQs, OQs, performance
qualifications [PQs])
• Process equipment (IQs, OQs)
• Computer control systems (IQs, OQs)
• Process operations/steps (PQs)
• Equipment cleaning (PQs)
IQs documented that the equipment has been installed in accordance
with approved design and specifications, regulatory codes, and manufactur-
ers' recommendations. A typical IQ checklist included the equipment list, reg-
ular filter list, the HEPA filter list, the critical instrument list, noncritical
construction completion verification forms, the list of applicable SOPs/
Manufacturing Procedures (MFPs), materials of construction (product contact
surfaces), and the lubricant list.
OQs documented that the new equipment can operate as designed and
intended and is capable of operation over the entire range of process vari-
ables. The OQs were a testing process that evaluated the equipment/system
Validation of AP/s: A Case Study 173
After the validation team declared an equipment train under validation, any
modification or change pertaining to the process or equipment thereafter was
documented under the change control policy of the organization. Each
174 Validation of Active Pharmaceutical Ingredients
Master Plan
As a first step, master plans were prepared for all production trains. The key el-
ements of a typical prospective validation master plan for a multiproduct
train were as follows.
1. Introduction/scope: A brief overview of the project and scope of the
validation activities, which identified the validation team and spec-
ified individual and departmental project responsibilities.
2. Process/facilities description: A brief description of the manufacturing
process, the facilities, and equipment, including:
• Process synthesis description, in-process controls, and com-
puter controls;
• Utilities and support systems;
• PFDs, overall facility layout; and
• Packaging area, controlled environments, material/people
flow, and so on.
3. List of systems to be validated including purified water system, sol-
vent recovery, equipment cleaning, and so on; where necessary, ref-
erence was made to guidelines or SOPs on change control,
equipment maintenance, and calibration.
4. Validation approach: This section described an outline of the general
requirements and/or conditions for execution and acceptance. All
assumptions made, the sequence of activities, and the extent of val-
idation runs for PQs were covered. It stated that a minimum of
three consecutive successful API lots must be manufactured to
demonstrate that the process is validated (PQs). These lots must be
produced in the equipment train used for the manufacture of the
marketed product. The point in the process after which process val-
idation should apply was determined for each product and the val-
idation criteria for determining which steps must be validated was
documented in this section.
In general, only the process steps involving the final chemical
transformation forming the structural elements of the API and its
subsequent isolation/purification steps were included in the valida-
tion study. However, if significant impurities were being introduced
or removed at an earlier step, then the validation team often de-
cided to initiate validation from that point in the process.
Validation of AP/s: A Case Study 175
Validation Protocols
Protocols were written for each train to qualify process, controlled environ-
ment facilities, process equipment, utilities, water systems, computer control
systems, equipment cleaning, and so on. Templates were created particularly
for the attachments. When solvent was recycled in the process, a solvent re-
covery protocol was added. These protocols were typically approved by the val-
idation team members (validation engineer, process manager, plant engineer,
and lastly by a quality assurance coordinator). An outline and a few concurrent
and prospective protocol briefs are presented in Appendices 7.4 and 7. 7.
Summary Report
After execution, a formal summary report was prepared for each validation
protocol. It provided an analysis of the data gathered and summarized the
findings. The summary report accurately documented the expected and
176 Validation of Active Pharmaceutical Ingredients
actual results. Discrepancies, if any, were appropriately discussed, and any fol-
low-up actions were included. An outline of a summary report is presented in
Appendix 7.9G.
CLEANING OPERATIONS
Two APis were often campaigned in the same equipment train. Each produc-
tion campaign often lasted about three months. At the conclusion of the
product run, an end-of-campaign cleaning was performed. Use of hot potable
water and 2 to S percent sodium hydroxide as cleaning agents, and occasional
use of detergents, was quite common. The rinse operations employed potable
water, DI water, or purified water and occasionally used solvents. For par-
enteral APis, the final rinse operations often used purified water and followed
up with solvent rinse.
A general master plan on cleaning, "Guidelines for Cleaning of Equip-
ment and Facilities," was issued to all production supervisors. Other support
documents included cleaning procedures/guidelines for key equipment such
as dryers, reactors, filters, centrifuges, mills, and dust collection equipment.
Each production supervisor used the guidelines for developing the manual
cleaning procedures for equipment systems in each train.
Each production supervisor was responsible for postproduction and pre-
production cleaning. Preproduction cleaning was enforced if (1) mainte-
nance had been performed between campaigns, (2) equipment remained
sealed for an extended period, (3) equipment was not adequately covered or
sealed and dusty/dirty operations had been performed since the last cleaning,
or (4) the next product to be manufactured was not known at the time of the
original cleaning and toxicological impact demanded more stringent clean-
ing requirements.
All cleaning procedures were reviewed and approved by Quality Assur-
ance. All cleaning procedures, like batch records, were written with sufficient
detail. These procedures defined which parts of the equipment train were to
be disassembled, and directed operator attention to "dead legs" in transfer
lines and so on during cleaning operations.
This facility had a generic SOP that required each cleaning procedure to
include (1) cleaning and sanitizing agents, amounts, volumes, and solvents;
(2) temperature and times; (3) conditions for disassembly of equipment and
piping; (4) rinses and final rinse volumes; (S) sampling and swabbing as re-
quired; and (6) inspection and testing. Other issues such as acceptance criteria
and intervals between cleaning were also addressed.
Written procedures were issued for cleaning and general housekeeping
of production facilities. These procedures included the methods, equipment,
and materials used for removal of residual product from floors, walls, and so
Validation of AP/s: A Case Study 177
on. These procedures described how to sanitize general areas, maintain con-
trolled environments, and decontaminate pure packaging rooms. These pro-
cedures included monitoring for microbial control.
Cleaning guidelines enforced "how clean is clean" by recommending
the level of bulk active residue left in the process equipment that can be tol-
erated in the first production batch after cleaning. The maximum residue al-
lowed in the process equipment after cleaning was determined according to
the hierarchy in Table 7.2.
Since finished APis possessed varying degrees of toxicity, a multiproduct
train in this service was assigned the highest criticality in cleaning. Here, toxi-
cological and pharmacological properties of each API were taken into account
to determine the maximum allowable bulk active residue in each case. A family
of APis was defined as a group of products that possessed similar toxicological
and pharmacological properties based on their use, solubility, and toxicity.
The 25-ppm criteria was arbitrarily chosen. It was considered safe
enough and it helped in quantifying the "visually clean" criteria for the clean-
ing validation programs. Allowable residue, R, for finished APis with varying
toxicity/pharmacological properties was calculated using the following steps:
1. For API being cleaned, the lowest daily dose administered to SO-kg
adult was extracted from the Physician's Desk Reference (PDR) (A).
2. The next API batch to be processed was converted into total num-
ber of daily dosages using maximum daily dose from the PDR (B).
3. Safety factor (S): used 1/1000 for carcinogens, otherwise used 1/100
to determine acceptable exposure.
4. R =A X B X S.
1. Multiproduct train for finished APis, from point at which 25 ppm orR*, whichever
moiety first formed is smaller
2. Multiproduct train for family of APis, from point at which 25 ppm
moiety first formed
3. Multiproduct train for API intermediate 25 ppm
4. Dedicated equipment for intermediates and API product 25 ppm
5. Multiproduct trains for GRAS substances** 25ppm
Where
n n
MAR = L MARi = L TRi -::; xx.xx grams
1 1
MARi = Wi X MAR
MAR = maximum allowable residue on contact surfaces for train AA
MARi = maximum allowable residue on contact surfaces for operation i
TRi = total residue (mg) on contact surfaces for operation i
Ci = residue concentrations (mg/L or J.Lg/mL)
Vi= volume of rinse (gallons)
i = 1 through n, cleaning suboperations
Wi = weight factor for operation i
SRi = swab residue per inch 2 of contact surface for operation i
Ai = contact surface area (ft2) of equipment for operation i
Concurrent Validation
One of the equipment trains at the facility was operated with a distributed
control system (DCS). This system was installed in 1990 with selected Honey-
well TDC 3000 components and was dedicated to the operation and control
of a few critical unit operations in the equipment train. The DCS provided
centralized control and monitoring capabilities utilizing operator consoles
with a touch screen display. This DCS had an excellent performance history.
The validation for this existing system was based on retrospective review
of the current state of the technical documentation relating to system specifi-
cations and testing, procedural documentation, and records relating to opera-
tional environment (e.g., change management, user SOPs, security, user
180 Validation of Active Pharmaceutical Ingredients
Validation File
All original validation documents were kept at the manufacturing site under
supervision of the documentation manager, and these were made available on
demand to interested personnel prior to any anticipated Inspection from the
regulatory agency.
After a system was validated, the system was maintained in the "validated
state" through implementation of calibration and enforcement of change
control policy by the organization.
To ensure the accuracy of the generated data, the calibration of manu-
facturing instruments was completed before the prospective or concurrent
validation testing began. In addition, regular calibration was conducted at
scheduled intervals throughout the life of the equipment.
Each equipment train had both critical and noncritical instruments.
Critical instruments had a direct effect on product quality, efficacy and yield,
operator safety, and the environment. Calibration of the critical instruments
was scheduled based on manufacturers' recommendations or the organiza-
tion's experience. Calibration procedures were traceable to U.S. National In-
stitute of Standards and Technology standards.
Readings from noncritical instruments (i.e., referenced instruments)
were generally not recorded in batch records. Typically, such instruments
were calibrated at the time of installation or on need basis at the production
manager's request.
IDEAL Corp. enforced a modification/change control and revalidation
policy at this manufacturing facility, which prevented unauthorized modifica-
tions to a validated system or a system under validation. It dictated how to im-
plement the proposed modification to a validated process. Such a change
control program addressed changes to processes, equipment, and raw materi-
als. This policy dictated that an assessment must be made before implementing
any modification or change to the validated systems to determine if revalida-
tion is needed. The modification/change control team reviewed the reason and
justification for the change and decided if revalidation was required.
Under the change control policy, emergency changes were allowed
when it was necessary to save product in process or protect operators and the
environment. Such changes can occur during unusual and/or unexpected cir-
cumstances. After the situation had stabilized, the normal change approval
process was initiated to ensure that all concerned parties were aware of the
measures taken to correct the situation, and the issue of validation testing and
documentation was appropriately addressed.
182 Validation of Active Pharmaceutical Ingredients
After the initial validation study was completed, if an API was not sub-
jected to any major change related to process or equipment or raw material,
then only one concurrent revalidation (process PQs only) was executed for
each batch size once every three years. Each API was supported by both a
sound change control and annual product review program, which provided
assurance that inherent minor raw material/process variability did not ad-
versely impact the validated state prior to the scheduled triennial revalidation.
If a critical piece of manufacturing equipment was replaced that was not
similar (i.e., this was not a like-for-like change), then three prospective valida-
tion batches were executed for each batch size. This revalidation covered IQs
and OQs for the new equipment and process PQs of the API. If the change was
not identical and not critical, then the rationale for doing less than the afore-
mentioned was concluded by the modification/change control team.
If no significant modifications to the process or related equipment had
been recorded, and the product continued to meet consistently the in-process
and QC specifications, then only one concurrent revalidation (process PQs
only) was executed for each batch size once every three years. In addition,
critical utilities such as compressed gases were retested for purity at least once
a year.
If there were frequent deviations in critical process parameters, in-process
tests, and product quality, the problems were resolved, and the API was immedi-
ately targeted for revalidation. If multiple minor changes were executed, a peri-
odic review of all change control forms may also indicate the need to revalidate.
IDEAL Corp. qualified suppliers of raw materials and excipients. Out-of-
specification raw materials were rejected and returned to the supplier. Change
of a supplier required that each raw material must meet the release and or U.S.
Pharmacopeia (USP) specifications. In addition, samples from three different
vendor lots were characterized, physically and chemically, and where neces-
sary tested microbiologically to determine the new raw material equivalency.
Any deviation from original specification in the new raw material was
considered a change and required a review and senior management approval
prior to use. If necessary, three qualification batches of API were produced and
placed on routine stability. The API was released for subsequent use only after
meeting all specifications.
Production (the process manager and his day-shift supervisor), one from En-
gineering, and one from Quality Assurance. Other personnel from the Pro-
duction, Engineering, and Maintenance groups assisted the core team on
need basis. The responsibilities and functions of this validation team were as
follows:
• The validation engineer developed the necessary documents
(master plans, protocols, and summary reports) and shared leader-
ship of the validation team with the process manager. The valida-
tion engineer provided training to execute the protocols,
monitored the validation effort to ensure completion on sched-
ule, and prepared summary reports for final management ap-
proval. The validation team verified and approved all validation
documents.
184 Validation of Active Pharmaceutical Ingredients
CONCLUSIONS
Overall, the validation effort at IDEAL Corp. helped to build employee quality
awareness and significantly reduced process and procedural deviations. This
effort helped to establish and maintain control over production processes and
provided management with validation documentation to meet the regulatory
requirements.
Validation is a team effort. The validation team must be familiar with
the process and validation principles, and all should be willing participants
for implementing a successful program.
A validation manager must be a good team player to accomplish the
task. He or she should possess team-building skills or should be given the ap-
propriate training to develop those skills. Prior to initiating the process vali-
dation effort, the validation manager must develop a good working
knowledge of the process. He or she should read technical documentation on
the facility and equipment and development reports, investigation reports,
and annual product reviews on the product. The knowledge gained from a
study of these reports is essential for developing validation protocols and di-
recting the overall validation effort.
The validation manager should be prepared to work against the bias and
attitudes of process and production personnel in the company. He or she
should be ready to face comments such as:
• Why are we doing this?
• What have we done wrong?
• We have made this product for the last 10 years.
Validation of AP/s: A Case Study 185
REFERENCE
FDA. 1987. Guideline on general principles ofprocess validation. Rockville, Md., USA: Food
and Drug Administration.
186 Validation of Active Pharmaceutical Ingredients
ADDITIONAL READING
FDA. 1993. Guide to inspections of validation of cleaning processes. Rockville, Md., USA:
Food and Drug Administration.
FDA. 1998. Guidance for industry, manufacturing, processing, or holding active phar-
maceutical ingredients. Rockville, Md., USA: Food and Drug Administration.
ISPE/FDA. 1996. Pharmaceutical engineering guides for new facilities. In Bulk pharma-
ceutical Chemicals, vol. 1. Tampa, Fla., USA: International Society for Pharmaceuti-
cal Engineering; Rockville, Md., USA: Food and Drug Administration.
Lazar, M. S. 1993. Concepts of process validation of bulk pharmaceutical chemicals.
Pharmacetical Technology 17:32-40.
Lazar, M. S. 1995. Sterile bulk pharmaceutical chemicals, a PhRMA position paper.
Pharmacetical Technology 19:38-42.
ACKNOWLEDGMENTS
I wish to acknowledge A. Seminerio, former Director of Validation and Tech-
nical Operations, and Leo Chambers, current Director of Chemical Opera-
tions at Hoffmann-La Roche, Nutley, for their support and encouragement in
the preparation of this chapter. I have been executing validation studies un-
der their leadership since 1993. I also wish to acknowledge other colleagues
for their contributions.
Validation of AP/s: A Case Study 187
APPENDIX 7.1
What Is Concurrent/Validation?
What Is Prospective Validation?
To meet the FDA regulatory requirements, the API manufacturer under cGMP
must execute either a concurrent validation program or a prospective valida-
tion program.
Concurrent Validation Program
• API is routinely manufactured in an existing facility and re-
leased to markets.
• API is routinely manufactured in an existing facility, and a few
like-for-like changes are executed.
Prospective Validation* Program
• New API manufacture in a new train-New Drug Application
(NDA) filed
• Existing API manufacture is moving to a new site.
• API is routinely manufactured in a facility where new equip-
ment was installed recently and a few process changes are be-
ing implemented under CBE (Changes Being Effected).
*Under prospective validation, the drug substance (API) and the drug product are not released until all
validation activities are successfully completed.
188 Validation of Active Pharmaceutical Ingredients
APPENDIX 7.2
Events and U.S. Regulations
APPENDIX 7.3
SOPs-Operations, IDEAL Corp.
APPENDIX 7.4
Batch Records-A Validation Viewpoint
To implement a successful validation program, the production manager must
eliminate point values from batch records and assign ranges to the key
process parameters and in-process control test values.
Process parameter ranges and in-process control test ranges are an im-
portant issue in all production operations. With existing operations, these
ranges must be established by reviewing the batch records. For newer
processes, these ranges can be adequately addressed during the process devel-
opment phase. In addition, batch records should clearly dictate the basis for
expected yields, and the rationale employed should be well understood and
used by the operating staff.
Batch records must avoid the use of such words as approximately, ca. 80
and lack of key process data or critical process data. Whenever feasible, a
range should be used rather than an approximation (i.e., 75-80, rather than
approximately 78). If, however, "approximately" is used, it implies being near
or close to the number specified (i.e., approximately 15 minutes does not
mean 10 minutes). Care should also be exercised when deciding the number
of significant figures to be used. For example, "Heat at 70-80°C for 10 min-
utes" would mean that a recorded temperature of 80.2°C could be rounded to
80.0 and would not be considered out of range.
If the operator needs more than one attempt to meet a specification,
batch records format should incorporate loops to meet that specification.
All batch records including cleaning records should be formally adopted
by the organization with approval signatures. All batch records at IDEAL
Corp. were reviewed and approved by Quality Assurance.
192 Validation of Active Pharmaceutical Ingredients
APPENDIX 7.5A
Miscellaneous Activities-
Prospective Validation
Support Systems:
TypicaiiQsjOQs-New Facilities
APPENDIX 7.58
Miscellaneous Activities-
Prospective Validation
Process Equipment:
TypicaiiQs, OQs-New Facilities
APPENDIX 7.5C
Miscellaneous Activities-
Prospective Validation
Boldface data: for existing facilities with satisfactory history. Audit critical loops for 1/0 check, point-to-
point.
1.98 Validation of Active Pharmaceutical Ingredients
APPENDIX 7.6
Outline of a Typical Retrospective Protocol
Introduction
Purpose
Scope
Summary and Recommendations
Synthesis Flowchart
General Description of the Process
Process Parameters
List of Key Process Parameters with Ranges
Compilation of Results (Including Statistical Review/Control Charts)
Discussion of Out-of-Range Results (Variance Reports)
In-Process Controls (IPCs)
List of IPC Tests (Typically all IPCs Described in the MFPs)
Analytical Methodologies
Compilation of Results
Discussion of IPC Trends and Failures (investigation reports)
Quality Control Testing
List of Quality Control Tests
Analytical Methodologies
Compilation of Results for Batches Under Review
Discussion of Impurities
Discussion of Quality Control Rejections/Reprocessing (investigation
reports)
Yield Data
Process/Equipment Changes
List of Approvals for Process Change (APCs)
Rationale/justification
Description/Location of Production Equipment and Facilities
Size, Material of Construction, Function
List of PFDs and P&IDs
Maintenance/Instrumentation/Calibration/History
Plant Utilities
Equipment Cleaning
Procedures and Analytics
Attachment
Annual Product Review Report from Quality Assurance
Validation of AP/s: A Case Study 199
APPENDIX 7.7
Outline of a Typical Concurrent
or Prospective Validation Protocol
This protocol describes the qualification requirements and acceptance criteria
for the equipment system, facility, or process to be validated. It includes data
needed for execution. The main elements of a validation protocol are as fol-
lows:
Objective
Description
Responsibilities
Installation Qualification: A list of the check sheets and engineering draw-
ings and specifications that are needed to document that the system(s) is in-
stalled according to design. There should be certified drawings for new
projects and "as-built" engineering drawings for existing projects. Identify all
critical instruments and confirm these are calibrated. Calibration records
should be maintained by the department.
Operational Qualification: An outline of the operational qualification test-
ing procedures and requirements for the system(s). The prospective validation
will include all hydro testing of process equipment and other equipment per-
formance tests for the new train. Heating, cooling, turning, pressure, and vac-
uum limits for the process equipment are reviewed.
Process Performance Qualification: A detailed description of tests and test-
ing procedures and validation approach is discussed.
Acceptance Criteria: All criteria are clearly documented.
Approval: How the document will be approved and reviewed, summary
report format, and approval signatures.
Attachments: As necessary.
200 Validation of Active Pharmaceutical Ingredients
APPENDIX 7.8
Key Instruments Used in OQ Activities
The following instruments were used at IDEAL Corp. to execute OQ activities:
1. Air Data Multimeter, Shortbridge Instrument Inc.
This instrument was used for pressure balancing and static pressure
measurement for HVAC systems.
2. Draeger Aeroset Apparatus
This apparatus was used to verify and confirm specifications re-
garding the dew point and hydrocarbon content of compressed
gases at use points in the process (e.g., compressed air, compressed
nitrogen).
3. Met One Laser Particle Counter
This instrument was used to confirm the specified environmental
quality in the product packaging areas (clean rooms) or to check
the quality of compressed gases used in the process.
4. Alnor Balometer
This instrument was used for monitoring velocity measurements
for supply ducts to confirm specified air changes.
5. Pioneer Porta-Strobe
This tachometer was used for measuring rpm.
Validation of AP/s: A Case Study 201
APPENDIX 7 .9A
Retrospective Example
1.0 Introduction
The purpose of this retrospective validation report is to provide detailed doc-
umentation demonstrating that the production of Supreme hydrochloride
drug substance has performed satisfactorily and consistently during the
1989-1994 campaigns. This assessment determines whether the process has
consistently met predetermined specifications regarding process parameters,
in-process control testing, quality control testing, and expected process
yields. The time period, 1989 through 1994, represents the most recent pro-
duction experience in which a significant number of lots (19) was produced.
Supreme is marketed under the trade name Sure®, a therapeutic agent
used in the treatment of a disease. Supreme manufacturing con-
sists of six steps.
2.0 Summary/Recommendations
The data compiled in this report demonstrate that all six process steps in the
manufacture of Supreme from the purchased material, , have per-
formed consistently and in an overall satisfactory manner from 1989 to the
present.
Nineteen lots of Supreme, Lots 203 thru 221, were produced by convert-
ing 94 crude batches into 60 pure batches. All Supreme lots passed quality
control testing and were subsequently released. No unusual impurities were
detected, and the annual product records contain no bulk product com-
plaints.
Overall, the batches produced were reasonably consistent in batch
weights. Among the 94 batches, only 1 crude and 1 pure had low batch
weights. These deviations were examined satisfactorily.
Among the 60 pure batches, 58 had process yields within the specified
MFP range. One batch exceeded the specification range, and the second batch
had low yield.
Specification ranges of the operating parameters were refined and noted.
No major process equipment revision or process change was observed during
this review period.
A few equipment- and instrument-related failures were reported. These
were minor in nature, and none had any impact on the quality of Supreme
product.
The master plan for the retrospective validation of APls lists four accep-
tance criteria. Based on the data compiled for this report, the Supreme process
would meet three of the four criteria.
202 Validation of Active Pharmaceutical Ingredients
All lots passed QC testing. Each key process parameter has been within
specified ranges at least 90 percent of the time for batches reviewed (exclud-
ing variances caused by equipment malfunction or operator error). In a few
instances, where deviations did occur, these were minor in nature, and none
had an adverse effect on product quality. In-process control test results were
within specifications at least 90 percent of the time for batches reviewed (ex-
cluding test failures caused by equipment malfunction or operator error).
Most variances and test failures were satisfactorily investigated and doc-
umented. A few minor variances were not documented and investigated dur-
ing the 1989-1990 period. Therefore, this criterion is not attained. However,
product quality was not adversely affected by any of the variances. This situa-
tion has now been corrected. Batch records and all variance documents are
now being reviewed by Quality Assurance to ensure compliance with IDEAL
policy (SOP-IDEAL-031).
Based on the batch data reviewed, the following recommendations are
made:
Process In-Process
Step Operation Control Test Method Specification
Step 1 formation unreacted TLC < 1%
Step 2 base unreacted TLC <2%
formation
If a batch fails any of the in-process tests outlined above (except mois-
ture determination), purification steps 4 and 5 must be repeated. Thus, the
204 Validation of Active Pharmaceutical Ingredients
Batch No.
Test 001 002 003 004 005 006 007
5 % Solution in Water c&c c&c c&c c&c c&c c&c c&c
Color ms ms ms ms ms ms ms
Abbreviations: ms = meets specification; c&c = complete and clear
Validation of AP/s: A Case Study 205
lot Numbers
Test 203 204 205 206 207
Appearance ms ms ms ms ms
Color ms ms ms ms ms
ms =meets specification
Moving range control charts were prepared for both steps (see Attach-
ments). Control chart for step 5 highlights a variability in the yield data for
the 1989-1990 batches and signals a consistent improvement trend starting
with batch 037. It also suggests that the current specification limits should be
modified. Ideally, the process specification limits should fall outside the indi-
cated upper and lower control limits.
Steps 1,2,3
AUC-7 Autoclave, 150 gal., temperature recorder controller,
600 psigj600°C rating, level alarm, temperature alarm
316L SS
11.0 Cleaning
The process equipment trains are shared on a campaign basis with
_ _ _ _ production. In a few instances, process equipment modules are ei-
ther dedicated or shared among the pure or the methanol pure processing
steps.
208 Validation of Active Pharmaceutical Ingredients
For the precleaning and the postcleaning needs, the following table
summarizes the solvent wash and limits of detection for the various APis un-
der discussion.
12.0 Attachments
Moving Range Control Charts
Percentage of Expected Yield, _ _ _ _ from----
Percentage Yield, Sifting Operation
Product Review: Test Data, Trend Analysis, Variance Reports, and Investi-
gation Reports
210 Validation of Active Pharmaceutical Ingredients
APPENDIX 7.98
Prospective Example:
Process Equipment, Train B (IQs, OQs)
I. Objective
Production of drug substance is being moved from building 60 to
train Bin building 125. The objective of this protocol is to assure that the ex-
isting equipment in building 125 can handle the production of the new drug
substance. This protocol will define requirements and acceptance criteria for
the process vessels and equipment that will be utilized for produc-
tion. Successful completion of these qualification requirements will provide
assurance that the vessels and equipment will perform as required. This pro-
tocol has been prepared under the guidelines established under the Validation
Master Plan, Revision 0, dated Feb. 15, 1999.
II. Description
Process equipment covered under this protocol will handle production of
_ _ _ _ from the starting material
Only one process step, with will be carried out in
the former facility in building . This facility was satisfac-
torily validated for the production of in 1998.
All other processing operations will be conducted in train B,
building 125. This four-story facility was built in 1987 and has satisfactory op-
erational history. This facility has state-of-the-art multipurpose reactor sys-
tems and utility support systems.
In addition, the following filtration equipment, which is small and still
available, will be moved from building and installed in building
125: single plate filter ( ) and two 18-inch glass filters. These filters
were previously used in the process in building _ _ __
All process equipment is covered under regular preventive maintenance
programs. Maintenance frequency varies from monthly to yearly and
depends equally on the equipment manufacturer's recommendations and
IDEAL's experience.
Instrumentation calibration is regularly performed by the Maintenance
Department. A record of such calibrations is kept by that department. Critical
instruments are calibrated either semiannually or annually. Weigh scales are
calibrated once every six months. Any new scales moved to 125 from other
buildings will be recalibrated prior to use.
The following key process equipment will be utilized in the various
_ _ _ _ production steps.
Validation of AP/s: A Case Study 211
Building 125A
Building 125B
Ill. Responsibilities
This protocol has been developed by the validation team. The responsibilities
of the team and various departments are detailed in SOP . This doc-
ument will be a guide in the execution of this protocol.
V. Operational Qualification
OQ is a testing process that evaluates the equipment. Controls are adjusted
during this phase of testing, and performance trials are conducted to verify
that the process equipment operates in accordance with design spedfications.
The OQ serves as a final operational audit prior to conducting performance
214 Validation of Active Pharmaceutical Ingredients
Building 125A
This facility was previously qualified and documented under Protocol
----·Recently, the cold brine (0 to -10°C) was routed to R-7400, R-7410,
and E-7416 to meet FUDR process requirements and to control emissions.
Therefore, only heating/cooling operations in R-7400 and R-7410 with either
water or the step solvent and tray dryer operation will be verified
as follows:
Building 1258
Where applicable, heating, cooling, vacuum, and mixing performance will be
verified with either water or step solvent for the following process
equipment: R-0020, R-0030, R-0040, S-0050, and X-0070.
VII. Documentation
All required documentation (approved protocol, completed data sheets, etc.)
will be filed in the validation project file. Any discrepancies or variations ob-
served during the execution of this protocol must be documented in the sum-
mary report. During execution, documents will be forwarded to the
validation manager in building _ _ __
Upon completion of protocol execution, a summary report will be pre-
pared. The summary report will be reviewed and approved by the validation
team and by the management of the Chemical Operations, Plant Engineering
and Maintenance, and Quality Assurance Departments. Approval will be doc-
umented on the summary report approval page, which is included as Attach-
ment 21 in this protocol.
APPENDIX 7.9C
Concurrent Example:
Controlled Environment ( IQ, OQ)
I. Objective
The objective of this protocol is to define the qualification requirements and
acceptance criteria for the controlled environments system. Successful com-
pletion of these qualification requirements will provide assurance that the
controlled environments system will perform as required.
II. Description
The controlled environments system has been designed to provide a clean
processing environment. The system services the air lock, the milling/staging
room, and the sifting/packaging room.
Outside air is prefiltered through 30 percent efficiency filters, 95 percent
efficiency cartridge filters, and finally passed through terminal HEPA filters
(99.99 percent removal of particles 0.3 J.Lm and greater) for each room. The
rooms are maintained at a positive pressure; any room pressure differential of
±0.02 in. WC will activate a local alarm. These alarms have a 20 sec delay.
The air-handling unit controls the facility temperature by modulating a
steam preheat coil and a direct expansion cooling coil. A temperature varia-
tion outside of 72°F ± 6°F will activate a local alarm. The air handler is also fit-
ted with a steam grid humidifier, which maintains the relative humidity. A
value outside of 30 to percent range will activate a local alarm.
A dust collection system (DC-10) provides local collection of any prod-
uct dust. There is a central vacuum system for cleaning the rooms. Normally
the exhaust fan, dust collection unit, and air handler operate constantly. A
failure of any of these units will activate a local alarm.
The new floors are constructed using poured concrete with an epoxy
quartz coating. Drains have proper pitch to ensure that no puddling occurs.
New walls have been constructed and are covered with cocooning. The new
ceiling panels are gasketed aluminum. These are suspended and are secured in
place. Windows, lighting fixtures, and utilities are flush mounted to minimize
dust accumulation. All equipment located in the area has external surfaces of
polished stainless steel or appropriately coated carbon steel, to ensure a
smooth rust-free surface that is easy to clean and maintain.
Ill. Responsibilities
See other examples for text.
Validation of AP/s: A Case Study 221
V. Operational Qualification
OQ is a testing process that evaluates the system. Controls are adjusted during
this phase of testing, and performance trials are conducted to verify that the
equipment operates in accordance with design specifications under static
conditions. During the OQ, data are collected to establish a performance base-
line to provide assurance that the system can operate as intended, and for fu-
ture troubleshooting. Prior to the OQ testing, the controlled areas will be
cleaned and/or sanitized according to approved procedures.
The OQ testing procedures and requirements for the controlled environ-
ments system for the pure area are as follows:
B. Operational Qualification
All monitoring and functional testing of the systems will be completed and
approved; all discrepancies must be resolved and documented in the sum-
mary report. The OQ will document that the system is capable of operating
within specified parameters.
224 Validation of Active Pharmaceutical Ingredients
VII. Documentation
See other examples for text.
Temperature Temperature
Room in room (°F) outside (°F) Time Performed by
Rm. 110 Date: OF OF
Date: OF OF
Date: OF OF
Relative Humidity (Design Specification: _____ to _ _ _ _% RH)
Room Relative humidity Time Performed by
226 Validation of Active Pharmaceutical Ingredients
APPENDIX 7.90
Concurrent or Prospective Example:
Supreme Process {PQ)
I. Objective
The objective of this protocol is to define the process qualification require-
ments and acceptance criteria for the manufacture of in building
10. Successful completion of these validation requirements will provide assur-
ance that the manufacturing process meets all in-process tests and QC specifi-
cations. This protocol has been prepared under the guidelines established by
the master plan.
II. Description
_ _ _ _, tech grade, is reacted with in acetone in a dedicated
equipment train to produce . About 160 kg of is pro-
duced in a typical batch. The following is a complete listing of all manufac-
turing operations documented in the MFPs:
Ill. Responsibilities
This protocol has been developed by the IDEAL validation team. The respon-
sibilities of the validation team and various departments involved with this
project are listed below.
V. Performance Qualifications
During the process validation, all in-process tests will be performed as de-
scribed in the MFPs. QC release testing on the final product will be performed
by the QC labs. A minimum of three successive successful production runs
will be monitored during this testing period. If a successive batch should fail
for a reason unrelated to process performance (e.g., power failure or equip-
Validation of AP/s: A Case Study 229
ment breakdown), that batch will be removed from consideration and an-
other batch will replace it.
The process qualification testing procedures and miscellaneous require-
ments are as follows:
1. MFPsjSOPs
All MFPs and SOPs associated with the process must be listed on Attachment
2. The process will be run using approved MFPs.
2. Raw Materials
The intermediate, must meet all in-process "finished lot" tests. List
all raw materials utilized for each validation batch, their IDEAL lot/batch
numbers and expiration dates, and QC release date, if any, on Attachment 3.
4. Sampling/Testing
The in-process sampling/testing will monitor the development of the product
at individual steps. This sampling/testing will be in accordance with the SOP
VII. Documentation
VIII. Modification/Change Control and Revalidation
7. QC Test Summary
8. Performance Qualification Summary
9. Summary Report Approval Page
Compiled b y : - - - - - - - - - - - - - - - Date: _ _ __
Reviewed b y : - - - - - - - - - - - - - - - Date: _ _ __
MONITORING OF
Attachment 4 PROCESS PARAMETERS Pg. _ _ of _ _
Finished Lot
Attachment 6 IN-PROCESS TESTS Pg. _ _ of _ _
Protocol: A-SUP-01 Supreme Process Validation Rev. 0
Validation Run 1 Batch/Lot No.: _ _ __
PERFORMANCE QUALIFICATION
Attachment 8 SUMMARY Pg. _ _ of _ _
Protocol: A-SUP-01 Supreme Process Validation Rev. 0
APPENDIX 7 .9E
Concurrent or Prospective Example: Cleaning
I. Objective
Two products, and , are routinely campaigned through
the process train AA. The objective of this protocol is to define the qualifica-
tion requirements and acceptance criteria for the various equipment cleaning
procedures utilized in this operation. This protocol pertains to the end-of-
campaign cleaning performed for this facility.
Successful completion of the qualification requirements will provide as-
surance that execution of these cleaning procedures consistently results in
product contact surfaces at acceptable levels of cleanliness. The equipment
will be considered clean if the next batch to be manufactured will not be con-
taminated with more than 12.5 g of the cleaned product residue. This value
is based on the 25 ppm limit and the smallest final batch size of 500 kg. The
25 ppm criterion is chosen for this dedicated train.
II. Description
This protocol will specifically address all end-of-campaign equipment clean-
ing operations that offer contact surfaces to the acetyl product being pro-
duced.
During end-of-campaign cleaning, all key vessels, reactors, and transfer
pipes are treated with = 2-3 percent sodium hydroxide solution. Where feasi-
ble, difficult to clean equipment components and piping are dismantled and
immersed in a portable cleaning tank containing = 2-3 percent sodium hy-
droxide solution. Equipment is adequately rinsed with potable water, and to
confirm cleanliness, final rinse samples are analyzed using an HPLC test pro-
cedure with 0.2 J,Lg detection limit. If the cleaning specification is met, equip-
ment is considered clean and ready for use in the next production campaign.
Key process equipment is routinely sanitized with either acetone rinse or
sanitized with regular steam and finally rinsed with purified/DI water.
During a long production campaign, once every three months, all end-
of-campaign cleaning operations are scheduled and performed on the entire
equipment train.
Following is a complete listing of the end-of-campaign cleaning opera-
tions documented in the MFPs:
234 Validation of Active Pharmaceutical Ingredients
Ill. Responsibilities
Where
11 11
MAR= LMARi = LTRi ~ 12.5 g
1 1
MARi = Wi X MAR
MAR = maximum allowable residue on contact surfaces for the acetyl
train
MARi = maximum allowable residue on contact surfaces for operation i
TRi = total residue (mg) on contact surfaces for operation i
Ci = residue concentrations (mg/L or f.Lg/mL)
Vi= volume of rinse (gallons)
i = 1 through n, cleaning suboperations
Wi = weight factor for operation i
SRi = swab residue per inch 2 of contact surface for operation i
Ai = contact surface area (ft2) of equipment for operation i
The weight factors, Wi, for each suboperation, are calculated by dividing
the product contact surface area of the cleaned equipment in the subopera-
tion by the total product contact surface area of the train.
The following table shows the estimated value for Wi and the corre-
sponding maximum allowable product residue on equipment.
Product Cleaned
V. Acceptance Criteria
The following acceptance criteria are required for this cleaning validation:
1. All equipment must be inspected and verified as visually clean.
2. The total residue (TRi) found in the final rinse/swab of any subop-
eration must not exceed the maximum allowable residue (MARi).
3. After the rinse sample meets the acceptance criteria, a swab sample
will be tested for verification. If confirming swab test results exceed
105 percent of the rinse sample results, then the cleaning operation
will be repeated.
4. If swabbing is not feasible, a second final rinse sample will be tested
to confirm cleanliness. The second rinse sample must show a
downward trend in TRi residue or confirm a "none detected" result.
5. If process equipment being cleaned cannot retain the rinse water,
then its cleanliness will be verified by two swab samples.
6. The summation of total residue (ITRi) found in the final
rinse/swab of all contact areas in suboperations must not exceed
the MAR (i.e., 12.5 g).
7. The completed cleaning batch records must be approved by the
Quality Assurance Record Release group.
8. After cleaning, the first batch campaigned must meet
Quality Control chemical and microbial testing specifications.
238 Validation of Active Pharmaceutical Ingredients
VI. Documentation
See other appendices for text.
Appendices:
A. Swabbing Procedure
Bl-B7 Diagrams Showing Swabbing Locations
C. Maximum Allowable Residue, Acceptance Limit
Attachments:
1. Monitoring of Cleaning Results
lA. Swab Test Results
lB. Total Residue Values
2. MFP/SOP Review
3. Operator Training Checkout
4. Validation Test Instruments and Calibrations List
5. Performance Qualification Review
6. Summary Report Approval Page
Validation of APis: A Case Study 239
Each piece of equipment will be swabbed in at least three areas: that is,
one random (4 in.Z) head of tank, one random head gasket area, one random
(4 in. 2 ) side of tank. Average each pair of swabs to get the average quantity of
residue for each piece of equipment. Record individual swab values, swabbing
area used, and the average residue per square inch on Attachments IA and lB.
240 Validation of Active Pharmaceutical Ingredients
Description
Operation CLN Vac-u-Max System Results
CLN-01, Step 4 wand & hoses, visual Acceptable (Y/N):
check (loop no.)
CLN-01, Step 5 vacuum filter replacement Acceptable (Y /N):
CLN-03, Step 5 R-2101, visual & HPLC pH water rinse _ _ __
check (loop no.)
Residue _ _ _ _ mg
Compiled b y / D a t e - - - - - - - - - - - - - - - - - - - - - -
Reviewed b y / D a t e - - - - - - - - - - - - - - - - - - - - - -
Compiled b y / D a t e : - - - - - - - - - - - - - - - - - - - - - -
Reviewed b y / D a t e : - - - - - - - - - - - - - - - - - - - - - -
242 Validation of Active Pharmaceutical Ingredients
APPENDIX 7.9F
Concurrent or Prospective Example:
Micronization
I. Objective
The objective of this protocol is to demonstrate that the micropulverization
equipment in cell , of building , will perform as required
and that the micronized product will meet its predetermined specifications.
II. Description
Supreme is micropulverized in approximately 100 kg batches. The primary
pieces of equipment employed in this service are the Fitzmill and the Micron-
Master Jet Pulverizer. This facility is also used for conducting , pro-
duction campaigns.
Supreme is pulverized in a 10 HP Fitzmill fitted with fixed s/s impact
edge blades and 60 mesh s/s screen. The dry crystalline powder is hand fed
and milling temperature is controlled by circulating a coolant through the
grinding chamber jacket. The mill is operated at -5000 rpm and at lowest
feed screw setting. The pulverized powder pushes through a 60 mesh screen
and collects in the hopper.
Next, the pulverized material is continuously micronized through a 4"
Teflon lined Orbital Micron-Master Jet Pulverizer. This micronizer is operated
with SO CFM of 105 psig filtered nitrogen (.01 f.Lm filter) and the feed rate is
controlled between 8 to 10 kg/hr. This feed rate minimizes blow back and has
historically produced Supreme with 90th percentile below 10 f.Lm particle size.
The entrained particles from the Micron-Master enter a cyclone from
which most of the product exits into a fiberpack. The balance of the product
is carried with nitrogen into a bag collector where fines accumulate. The bag
collector is intermittently pulsed with nitrogen to allow fines to drop into a
second fiberpack. Nitrogen exits through a HEPA filter located on the roof.
The micronization facility exhaust exits through a terminal HEPA filter
located on the roof. The production area is maintained under negative pres-
sure (.04 to .08 inches of water).
The operator walks through an air lock; dons a proctective cap, gown,
gloves, and shoe covers; and then walks through a water shower to enter the
cell area. Once in the cell, the operator wears a protective breathing apparatus
hooked to the fresh air supply port.
Validation of AP/s: A Case Study 243
111. Responsibilities
V. Operational Qualification
OQ is a testing process that evaluates the control system. Controls are ad-
justed during this phase of testing, and performance trials are conducted to
verify that the system operates in accordance with design specifications.
The OQ also serves as a final major component and systems operational
audit prior to use. During the OQ, data are collected concerning critical pro-
cessing parameters that could affect operation. The operational data collected
during OQ will serve as the baseline for PQ (for new facilities).
The OQ testing procedures and requirements for the existing micropul-
verization system are as follows:
244 Validation of Active Pharmaceutical Ingredients
V. Performance Qualification
PQ is performed on the process to ensure the consistency and/or effectiveness
of the process. Critical operating parameters are defined and will be moni-
tored. A minimum of three successive batches will be monitored during this
protocol execution. If a batch should fail for a reason unrelated to process per-
formance (e.g., power failure or equipment breakdown), that batch will be re-
moved from consideration and an additional batch will be made.
The PQ requirements for the Supreme micropulverization process are as
follows:
A. Validation Batches
The validation batches must be run using approved manufacturing proce-
dures. Include copies of the batch records for the validation batches as At-
tachment 10.
B. Feed Materials
All feed materials utilized for validation batches must be released by Quality
Control, and these should be identified with lot numbers. Include a copy of
QC test results on Attachment 15.
B. OQ Acceptance Criteria
All monitoring and functional testing of the system will be completed and ap-
proved. OQ will document that the system is capable of operating within
specified parameters and is ready for use.
C. PQ Acceptance Criteria
All monitoring and testing of the micropulverization step will be completed
and approved. PQ is performed on the processing step to ensure and docu-
ment the consistency and/or effectiveness of the operation.
1. All feed material must meet "finished lot" or QC specifications.
2. All critical process parameters must be within the ranges specified
in this protocol and MFPs.
3. The final yield obtained must be within the ranges specified in the
MFPs.
4. All in-process tests must meet spedfications as per MFPs.
5. Final product must meet IDEAL Quality Control specifications.
VII. Documentation
VIII. Modification/Change Control and Revalidation
IX. Index of Attachments
A. IQ Attachments
1. Engineering Documentation
2. Engineering Drawings
3. Equipment/Filter List
4. Materials in Product Contact
5. Utilities
6. Spare Parts List
7. Instrument List
8. Lubricant List
9. Installation Qualification Summary
B. OQ Attachments
10. SOPs/MFPs Review List
11. Operators Training Record
12. Set Up and Verification
13. Alarm and Safety Switch Verification
14. Operational Qualification Summary
Validation of AP/s: A Case Study 24 7
C. PQ Attachments
15. Feed Materials
16. Micronizer Operational Data
17. Particle Size Analysis
18. QC Test Summary-Certificate of Analysis
19. PQSummary Report
20. Summary Report Approval Page
Alarm Checkout
Alarm Description/Test Test Result
Expected Actual
Hopper Cover on Rtzmill
Performed by/date:
MICROPULVERIZATION
Attachment 16 OPERATIONAL DATA Pg. _ _ of _ _
Fitzmill Pulverizer
Glycol Coolant
Feed Screw Setting rpm Temp. (°F) Amperage
250 Validation of Active Pharmaceutical Ingredients
Sample
Location Uniform Nonuniform Performed By Date
Drum1
Drum2
VALIDATION RUN: _ _ __
Drum 1
Drum 2
Fines Drum
Compiled b y - - - - - - - - - Date-------------
Or attach QC certificate of analysis for particle size.
Validation of AP/s: A Case Study 251
Reviewed b y : - - - - - - - - - - - - - - - - Date: _ _ _ __
252 Validation of Active Pharmaceutical Ingredients
APPENDIX 7.9G
Concurrent Example: DCS Summary Report
Table of Contents
I. Summary ..............................................000
II. Objective .............................................. 000
III. Description .............................................000
IV. Results ................................................ 000
V. Conclusions ............................................000
Appendix 1-Copy of Approved Protocol without Attachments ........000
Appendix 2-All Executed Protocol Attachments and Supporting Data ... 000
I. Summary
Protocol 125- -DCS-01, Computerized Process Control System for
_ _ _ _ Production, was approved in May 1999 and was concurrently exe-
cuted during July/August 1999.
The process in building is controlled by the dis-
tributed control system (DCS) that was assembled with selected Honeywell
TDC3000 components. In this fadlity, the DCS controls the and
_ _ _ _ steps and the wastewater stripping.
All monitoring and testing spedfied by the protocol were adequately ad-
dressed, documented, and reviewed, and were acceptable. The satisfactory ex-
ecution of the protocol has confirmed that all modules of the DCS will
continue to perform as expected and, therefore, are qualified. Thus far, the
DCS has an excellent performance record for the process in build-
ing _ _ _ _ ,
Protocol 125-----'-DCS-01 is a part of the validation effort being
undertaken for production at Nutley. The overall validation plan is
presented in the Validation Master Plan, Rev. 1, dated 26 January
1999.
II. Objective
The objective of Protocol 125- -ACS-01, Rev. 0, was to demonstrate
concurrently that the existing DCS servidng the production facil-
ity in building will operate reliably and repeatedly over time.
Validation of AP/s: A Case Study 253
The validation plan defines the activities, which will be carried out to as-
sess the state of the system against current practices, identify any deficiencies,
and ensure their correction. The results of these activities will provide the
documentation needed to support the validation of the system.
This validation plan has been prepared under the guidelines established
by the Process Validation Master Plan and to comply with the fol-
lowing IDEAL computerized systems validation (CSV) documents: (1) CSV
Policy, (2) CSV Planning and Reporting Guideline, and (3) IDEAL Pharma
Computerized Systems Validation Guidelines, SOP-·_ _ __
Ill. Description
The DCS is associated with the following two key steps of the _ _ __
process in building : (1) , and (2) . This system
controls and monitors (a) slurry transfer, (b) delivery
and addition, (c) generation, (d) reaction, (e) _ _ __
neutralization, (f) step, and (g) wastewater stripping. In the
_ _ _ _ step, the DCS automatically makes the necessary prechecks before
batches are begun and carries out process operations according to the batch
sequence program.
This system was installed in several phases between 1990 and 1994. First,
the two reactors, R100 and R101, were converted from board-
mounted single loop controllers and on/off switches into the DCS. Next, a
third reactor, R102, and the HCL feed unit were added. And finally
the step was converted into the DCS in 1994.
The DCS is assembled with selected Honeywell TDC3000 components. It
provides centralized control and monitoring capabilities utilizing operator
consoles with a touch screen display. The system links to the process through
the Data Hiway, which is a proprietary network that uses a command/
response message-exchange technique. A detailed general description of the
DCS is available in the protocol.
Based on inputs from Production as well as hazard and operability study
(HAZOP) analysis, several improvements have been incorporated successfully
into this system during the last few years. The DCS controls the process in a
reliable and consistent manner. To date, this system commands an excellent
performance history.
IV. Results
The following IQs were executed:
254 Validation of Active Pharmaceutical Ingredients
In the event of the above listed failures, the following titles describe the
appropriate response: (1) Honeywell Emergency Procedures, (2) Interlocks
and Other Safety Features, and (3) Bernoulli Boot-up Procedure for TDC 3000.
These procedures are listed in the attachment.
V. Conclusions
The IQs and OQs of Protocol were satisfactory. All items referenced
in the protocol were adequately addressed. The successful execution has
demonstrated that all modules of the DCS will perform as expected.
Auditing of critical loops was postponed in the current review, because
such an evaluation would have required a complete shutdown of the system.
Such an audit will be scheduled during the intended shutdown in July 2000,
and a separate report will be issued.
8
ACTIVE PHARMACEUTICAL
INGREDIENT VALIDATION:
AN OVERVIEW AND
COMPARATIVE ANALYSIS
Max S. Lazar
Hoffmann-La Roche Inc.
Nutley, New Jersey
261
262 Validation of Active Pharmaceutical Ingredients
stated that 21 CFR Part 211 would be considered the guideline for application
to bulk pharmaceutical chemicals.
The FDA began to identify specific areas of focus. Two notable initial fo-
cal points were water systems, including endotoxin monitoring, and valida-
tion of the bulk manufacturing process.
FDA FOCUS
The FDA began to move rather quickly by using industry and FDA meetings
to bring their new message to the forefront. The FDA also increased the fre-
quency and number of overseas inspections of API facilities. It continued to
say that nothing was new in its position; however, this increased level of at-
tention from the FDA sent shock waves through the API industry.
The industry knew the FDA commissioner's position from the 1978
CGMP Preamble. However, the FDA's past public positions, lack of action,
and no public guidelines establishing which sections of the current drug
product GMP regulations applied to this industry all added to the confusion.
Suddenly, the industry was faced with a regulatory position that demanded
validation or shut down! While the industry had recognized the need for the
basic documentation and control requirements of the GMPs, it did not gen-
erally believe that full validation was a formal requirement. Ultimately, the
FDA agreed that if firms had active validation plans in effect, and were actu-
ally implementing them, no major regulatory action would be taken.
INDUSTRY REACTION
While the industry tried to determine what was happening on the regulatory
front, the FDA continued to state that nothing was new. The FDA's stated po-
sition was that they thought that industry was doing validation as part of
normal operations.
Of major concern to API producers was the fact that there existed a per-
ception within the FDA that dosage form and API validation were the same.
The industry decided to develop a validation document that would illustrate
the actual practices (CGMP) and provide the industry position on this matter.
Bulk producers were concerned that, without such information, the regula-
tory authorities would overreact and force the industry into practices that
were inappropriate and not germane.
API Validation: An Overview and Comparative Analysis 263
1993). The paper identified key elements needed during the validation steps
and focused on important differences between galenics and bulk chemicals
(Table 8.2).
One key difference between galenic and bulk chemical (API) manufac-
turing is the dynamic nature of chemical processing. Due to the complexity of
the chemistry normally involved, it takes years of experience and real-time
development to fine-tune a chemical process.
Flexibility is a basic requirement of bulk chemical processing, so that
yields and subtle variations in chemical by-products can be controlled and ad-
dressed using the defined process. It is much more difficult to lock in a chem-
ical process than a galenic operation. Normal regulatory rigidity could be
disastrous and potentially hindering to modern chemical processing.
Flexibility applied to operating conditions allows chemists to address
chemical variations that may, from time to time, result in the formation or in-
troduction of new impurities or concentrations of known impurities that are
unexpected. A well-designed and well-developed process can adequately cope
with such occurrences. Therefore, the development phase of a chemical syn-
thesis becomes one of the most important phases in the life cycle of an API.
Unlike galenic validation, where prospective protocols form the foundation
of validation, the development report for bulk chemicals is the building block
critical to its validation.
DEVELOPMENT DOCUMENTS
Any new bulk chemical or API process validation should contain the key ele-
ments identified in Table 8.2. Probably the most important element is the de-
velopment document. It is during the development phase that the chemistry
is identified, side reactions described, by-products examined, and critical op-
erating conditions established. The purification steps are established that are
capable of producing a final compound that is of sufficient purity and that
possesses the physical characteristics to generate reliable dosage forms that
are reliable and consistent in their medical benefits.
TECHNOLOGY TRANSFER
The next critical element in the validation process is the technology transfer
program and documentation. This is the step where laboratory-scale or pilot
plant-scale technology is transferred to full-scale operation. Using information
from the development phase:
CHANGE CONTROL
Another key element in any validated process is the use of an effective change
control system. Without such as system, any process will go out of control over
time. Although such changes may result in acceptable product, it may be slowly
migrating toward an "out-of-control" state. A disaster is waiting to happen!
Proper change control procedures help assure that minor changes over
time do not add up to an unexpected quality event. A sound change control
system will review and contain some key elements. A number of important
fundamentals are included in Table 8.3.
The work done during the development phase results in the identification
and documentation of steps critical to the successful synthesis and purifica-
tion of the API. However, due to the complexity and dynamic nature of most
chemical syntheses, running experience will add additional important infor-
mation that can further identify critical steps or processing conditions.
A great deal of new information is gained during the start-up and initial
years of full-scale operations. Important information is usually identified dur-
ing the investigation of deviations encountered by the process. When prop-
erly documented, these data form the basis for the identification of additional
or revised critical operating parameters.
WELL-DEFINED PURIFICATION
One of the most significant differences between dosage forms and APis is the
fact that API chemicals have purification as part of their normal processing.
Unlike galenics, the process has the ability to improve the purity of the active
268 Validation of Active Pharmaceutical Ingredients
ingredient and reduce impurity levels. This one attribute of API allows
chemists to control variations by improving the purity profile of the final API
substance. This makes bulk or API manufacturing far more robust in its ability
to deal with variation than galenic production.
The purification process established during the development phase must
be monitored and enhanced as experience is gained by manufacturing
chemists running full-scale production. Again, a good change control system
together with an investigation system that carefully reviews deviations will
provide for enhancement of the originally developed purification steps.
TYPES OF VALIDATION
As with dosage form manufacturing, APis can undergo various forms of vali-
dation, such as the following classical types currently in use by industry:
• Retrospective
• Prospective
• Concurrent
Each of these validation approaches has its strengths and weaknesses. It is im-
portant to note that FDA personnel have generally taken a negative position
on the use of retrospective validation.
Retrospective Validation
While the FDA is not receptive to the use of retrospective validation, in the
case of "old," long-running bulk processes, it has had its place. Retrospective
data can be very helpful in identifying processes that are in control and can
be reliable in producing reproducible materials.
Retrospective data should be used to determine if a process needs further
development. The greatest problem in using retrospective data is to determine
whether any significant changes occurred during the life cycle of the process.
While such changes are the primary reason for regulatory resistance to the use
of retrospective validation, this alone should not invalidate its use. A process
that has reliable product history, showing no quality failures over a long period
of time, should be able to be retrospectively validated. The robust nature of
many processes, together with sound change control and investigation sys-
tems, should be able to undergo changes without reducing the assurance that
the process is reliable in consistently producing a quality product. After all,
isn't this what validation is all about? It is important to note that current
changes need to be prospectively or concurrently validated. Using retrospective
validation for such justification is inappropriate under current requirements.
API Validation: An Overview and Comparative Analysis 269
Prospective Validation
Prospective validation is the process of choice by regulators. Under this ap-
proach, a predefined set of criteria is established, acceptance criteria are set,
and the process is run to assure that at least three consecutive lots will meet
these established limits. When this occurs, the process is said to be validated.
Concurrent Validation
Concurrent validation is essentially the same as prospective validation. How-
ever, as material is produced and each lot's performance against established
protocols is determined, product is not withheld until three consecutive lots
are produced. Validation is ongoing while production and distribution takes
place.
For new APis, the use of concurrent validation makes the greatest sense.
While an initial lot should always be produced under prospective validation
conditions, the rest of validation should be conducted within the scope of
concurrent validation. The primary reason for this position is that, as stated
earlier in this chapter, bulk chemical (API) manufacturing is more dynamic
and robust than most dosage form processes. Its chemistry has purification
that can address variations better than those found in galenic production,
and the actual development process is ongoing for years under full-scale pro-
duction. To expect a full-scale bulk chemical process to be fixed and locked in
is unrealistic and simplistic. The best approach is to apply concurrent valida-
tion techniques to such processes, so that improvements can be made and re-
alized, while improving economic and quality attributes.
Concurrent validation provides the manufacturer with flexibility for im-
provement while giving the regulatory authorities a chance to see that proper
CONTROL and change systems are established. This approach provides the
best of all worlds.
REFERENCES
FDA. 1991. Guide to inspection of bulk phannaceutical chemicals. Rockville, Md., USA:
Food and Drug Administration.
FDA. 1993. Guide to the inspection of bulk phannaceutical chemicals. Rockville, Md., USA:
Food and Drug Administration.
FR. 1978. Part 211-Current good manufacturing practice for finished pharmaceuti-
cals. Federal Register 43 (190), Book 2.
ICH. 2000. Draft guidance ICH Q7a Expert Work Group. Geneva, Switzerland. Interna-
tional Conference on Harmonisation.
Pharmaceutical Manufacturer's Association. 1993. Concepts for the process validation
of bulk pharmaceutical chemicals. Phann. Technol. (December): 32-40.
9
IMPURITIES IN DRUG
SUBSTANCES AND
DRUG PRODUCTS
Stephen R. Byrn
Joseph G. Stowell
Purdue University
West Lafayette, Indiana
Impurities in drug substances and drug products are reviewed in this chapter.
Impurities are among the most important quality issues in pharmaceuticals.
Obviously, the presence of impurities or contaminants can be a major safety
issue. It is the dear goal of the industry to minimize impurities whenever
possible.
Impurities are defined and described in a wide range of documents, in-
cluding the United States Pharmacopeia (USP) (USP 1999a), several guidances
and amended regulations from the Food and Drug Administration (FDA)
(Federal Register, january 12, 1999; June 28, 1999; November 23, 1999; De-
cember 3, 1999; FDA 1999a, 1999b), and several draft guidances (Federal Reg-
ister, january 5, 1999; january 21, 1999; June 28, 1999; October 1, 1999; FDA
1999b, 1999d, 1999e). The discussions in these various documents regarding
impurities are reviewed and defined in this chapter. The use and validation of
assays for impurities also are reviewed. Following this, an example of an im-
purity study is presented. This chapter provides an overview of the various is-
sues related to impurities.
As the science of analytical chemistry advances, driven by scientific
curiosity, the concepts of purity change. For example, high performance
liquid chromatography (HPLC) has greatly advanced our ability to detect
271
272 Validation of Active Pharmaceutical Ingredients
QUALITY
Quality is the totality of features and characteristics that bear on the ability of
a drug substance or drug product to satisfy fitness for use, which includes
safety, efficacy, and performance. Quality requires a strong system of controls
and specifications that serve to define in measurable ways the excellence of a
product. Quality cannot be tested into a product, but rather, it is a system that
controls everything that affects the product.
For USP substances, the USP monographs ensure quality. A USP monograph is
a highly abbreviated Drug Master File (DMF) and defines the specifications
and tests needed to list a substance as being USP compliant. In recent years,
the gap between the specifications required by the USP and those required
by the FDA in New Drug Applications (NDAs) has widened considerably.
Thus, the USP specifications should be viewed as a minimum requirement.
The USP monograph for digoxin drug substance active pharmaceutical ingre-
dient (API) involves the following methods and procedures for analysis of im-
purities (USP 1999e):
• USP gitoxin impurity standard
• Dissolve in chloroform:methanol (2:1) at 0.30 mg/mL
• Spot digoxin standard solution, gitoxin standard solution, and
the test solution on a reverse-phase (C18) thin layer chromatogra-
phy plate
• Develop using methanol:water (7:3)
Impurities in Drug Substances and Drug Products 273
Foreign Substances
It is impossible to include in each monograph tests for every possible impu-
rity, contaminant, or adulterant that might be present. Examples of foreign
substances are pesticides in plant-derived products or cyanide adulteration
by malicious intent. Thus, tests for cyanide are not included in every article
even though cyanide adulteration of pharmaceutical products was a major
problem a few years ago. Instead, current Good Manufacturing Practices
(cGMPs) are relied on to ensure that contamination or adulteration does not
occur.
Toxic Impurities
Toxic impurities have significant undesirable biological activity. Such impuri-
ties require individual identification and quantification. All impurities that
are toxic need to be identified.
Ordinary Impurities
Tests for ordinary impurities are defined in each monograph. Ordinary impu-
rities, according to the USP definition, can arise either from the synthetic
process or from degradation. Monographs generally contain a chromato-
graphic purity test coupled with a nonspecific assay for percentage purity, or a
chromatographic purity-indicating assay that serves as an assay for percent-
age purity. HPLC methods are becoming widely used for determining ordi-
nary impurities. Thin layer chromatography is another good method for
detecting ordinary impurities. However, this method does not generally have
the precision, accuracy, or limit of detection of HPLC. In some cases, specific
274 Validation of Active Pharmaceutical Ingredients
tests for a given impurity are included. Analytical methods for ordinary im-
purities must be validated as described in the USP.
Ordinary impurities, at the levels allowed, are not considered toxic and
are considered to be qualified based on clinical trials of the drug product.
However, as our knowledge of toxicology advances, it is important to realize
that materials previously considered safe might be redefined as toxic.
Purity of drug products is an important issue since degradation of the
drug substance when mixed with excipients often accelerates, in part because
of processing. If possible, an analytical method that detects impurities while
measuring percentage purity is most desirable. However, two different meth-
ods are used in many cases. These methods are made difficult by the need to
separate excipients from the drug substance. In some cases, the USP contains
specific limit tests for certain impurities.
Other Impurities
USP materials may be manufactured by a variety of routes and thus may con-
tain impurities that were not considered during validation of the monograph
tests or assay for impurities. Excluding organic volatile impurities (OVIs) and
solvents, the amount and identity of the new impurity is stated and labeled
under the heading "Other Impurities" in the certificate of analysis. Of course,
the other impurities must not be toxic. The presence of an unlabeled impurity
at 0.1 percent or greater is a variance from the USP standard. In addition, the
sum of other impurities combined with the monograph-listed impurities can-
not exceed 2.0 percent unless otherwise stated in the monograph.
Signal Impurities
Signal impurities are distinct from ordinary impurities in that they require in-
dividual identification and quantification using specific tests. For example,
diazotizable substances in thiazides are considered signal impurities.
Concomitant Components
Concomitant components are components such as optical and geometrical
isomers and mixtures (e.g., conjugated estrogens). Concomitant components
are not considered impurities in the ordinary sense. However, the FDA has
raised considerable eoncern about optical isomers. In addition, major con-
cerns have arisen over polymorphs and solvates in the last few years, espe-
cially since these materials have different physical properties and can have
different dissolution rates.
• starting materials;
• by-products;
• intermediates;
• degradation products; and
• reagents, ligands, and catalysts.
Specifications
If toxic impurities are present, the specifications and the method to detect
them should be below their toxic limit. For organic impurities, the specifica-
tions should include
• each specified identified impurity,
• each specified unidentified impurity at or above 0.1 o/o,
• any unspecific impurity with a limit of not more than 0.1 o/o, and
• total impurities.
Specifications should also include limits for residual solvents (Federal
Register 1997a) and inorganic impurities.
Qualification of Impurities
Qualification is the process of "acquiring and evaluating data which estab-
lishes the biological safety of an individual impurity or a given impurity pro-
file at the level(s) specified" (ICH 1996b). The level of the impurity that has
been tested in safety studies and/or clinical studies is considered qualified. Im-
purities that are metabolites do not need further qualification. Qualification is
particularly important if there is evidence of adverse reactions in patients.
New impurities above the threshold level should be qualified in the same way
as existing impurities.
Impurities in Drug Substances and Drug Products 277
Figure 9.1 shows a decision tree from the ICH guidelines section Q6A
that guides the establishment of acceptance criteria for a specific impurity in
a new drug substance (Federal Register 1997b). This decision tree directs the de-
termination of the impurity level plus upper confidence level in relevant
batche~. It also directs determination of the upper limit after shelf life has ex-
pired. If either of these levels is greater than the qualified level, then a new
level needs to be set.
Figure 9.2 from the ICH guidelines section Q6A describes a procedure to
establish acceptance criteria for a degradation product (Federal Register 1997b).
As in Q6A Decision Tree 1, if the total level of impurities exceeds the qualified
level, then a new qualification level must be set.
Figure 9.1 Q6A Decision Tree 1 for Establishing Acceptance Criteria for a Specified
Impurity in a New Drug Substance (Federal Register 1997b)
Estimate maximum
Determine mean + upper increase in impurity at
confidence limit for the retest using data from
impurity (let this = Al relevant accelerated and
long-term stability studies.
Acceptance criterion =
qualified level OR establish
new qualified level2
1 Relevant batches are those from development, pilot, and scale-up studies.
Definition: uper confidence limit= three times the standard deviation of batch analysis data
278 Validation of Active Pharmaceutical Ingredients
Figure 9.2 Q6A Decision Tree 2 for Establishing Acceptance Criteria for a Degrada-
tion Product in a New Drug Product (Federal Register 1997b)
Acceptance criterion = NO
maximum likely level
YES
1 Relevant batches are those from development, pilot, and scale-up studies.
VALIDATION
The suitability of each validated method for its intended purpose must be
demonstrated (Federal Register 1995, 1997b, 1997d; ICH 1995; 1996a). Valida-
tion applies to the four most common types of analytical procedures:
1. identification tests,
2. quantitative test for content of impurities,
3. limit tests for control of impurities, and
4. quantitative tests of the active moiety in samples of drug sub-
stance or drug product (or other selected components in the drug
product).
Identification tests must ensure the identity of the analyte. These tests
are usually performed by comparison of the sample properties with a refer-
ence standard. The most common method involves infrared spectroscopy, but
chromatographic behavior and chemical reactivity also are used sometimes.
The USP allows dissolution and recrystallization as a means to eliminate
polymorphism from identification. This procedure sometimes produces
amorphous material that contains broad, featureless X-ray diffraction pat-
terns that may not ensure the absence of foreign substances. In addition, the
creation of impurities during this procedure cannot be ruled out. Finally, the
polymorph initially present may be crucial for stability or drug performance.
For all of these reasons, use of this method is discouraged. It is much better to
show identity between the drug substance and the reference standard directly.
Impurity tests can be either quantitative or limit. They must accurately re-
flect the purity of the sample. Of course, more extensive validation is required
for a quantitative test than for a limit test. Assay tests determine the level of the
analyte in a given sample. These tests provide quantitative measurement of the
major component. Assay tests for a drug product, a drug substance, other com-
ponents, and for dissolution tests must be performed in the same manner.
Validation of a method requires specificity, accuracy, precision, repeata-
bility, intermediate precision, reproducibility, limit of detection (LOD), limit
of quantitation (LOQ), linearity, and range where:
Impurities in Drug Substances and Drug Products 281
Figure 9.3 Decision Tree for the Qualification of Degradation Products (Generic
Products) (Federal Register 1999g; FDA 1999b)
Decrease DP level
below threshold Qualified
YES YES
Decrease below
threshold
~NO Qualified
• Is the DP observed in the
RLD and at a similar level?
~NO
NO
•If at a higher level, or a new
YES
DP is detected ... is it
qualified from the scientific
literature?
YES
Acceptable
Justification•
Qualified
Qualified
but not 505(iJ
1Best effort; not possible; 2 RT, peak heights/area spectral similarity; 3 Genetic Drug Pathway; 4 e.g., qualified by
QSAR
DP = drug product; RLD = reference listed drug; QSAR = quantitative structure activity relationship
282 Validation of Active Pharmaceutical Ingredients
1999 (Reynolds 1999). Impurity measurements are critical for release tests,
raw materials, and possible in-process tests. It is very important to show that
the validated process is robust and unlikely to result in excessive impurities.
Development research is a critical component in process validation. De-
velopment research will identify the mechanism and rate of degradation and
predict degradation levels at expiration. Ultimately, development research
will allow the establishment of specifications. Stability of the drug substance
is evaluated during validation. Of course, understanding stability is critical to
the development of a validated process. Figure 9.5 summarizes the compo-
nents of stability testing during validation (Reynolds 1999).
The control of impurities during changes is critical to maintaining qual-
ity. Changes to improve yields should be evaluated carefully to determine
whether these result in increased impurity levels. The resulting impurity pro-
file should be comparable with the impurity profile of the API batches used in
drug safety and for clinical trials. Process changes should also be evaluated to
ensure they do not have an adverse impact on analytical methods because of
increased interference caused by new or higher levels of impurities or by-
products. If these methods are affected, then they should be modified as nec-
essary. Dosage-form manufacturers should be notified of any changes in the
manufacturing process.
Drug substance batches that have excessive impurities must be re-
processed or discarded. Any reprocessing must follow established methods and
procedures. Appropriate tests should be conducted to make sure the reprocess-
ing does not affect other critical quality attributes of the drug substance.
ENANTIOMERS AS IMPURITIES
Enantiomers, or optical isomers of the drug substance (API), have the same el-
emental analysis as the drug substance. However, the ICH guidelines section
Q6A point out that for chiral drug substance developed as a single enan-
tiomer, the other enantiomer "should be considered in the same manner as
for other impurities" (Federal Register 1997b). Furthermore, the ICH guidelines
section Q6A also points out that technical limitations may prevent the appli-
cation of the 0.1 percent limit. Nevertheless, the ICH guidelines section Q6A
requires assurance of control and appropriate testing with suitable justifica-
tion. A chiral HPLC assay is preferred to an achiral assay and methods such as
optical rotation.
Polymorphs, like enantiomers, have the same elemental analysis as the drug
substance. Solvates and hydrates have different elemental analyses because of
the incorporation of solvent or water. The solvent will be detected as an or-
ganic volatile impurity. Water will be detected as part of the water test. How-
ever, polymorph solvates and hydrates are sometimes unwanted components
of the drug substance. In particular, these alternative solid forms can have dif-
ferent dissolution rates and stability from the parent drug substance. In such
cases, these solid forms need to be controlled.
The need for control is most clearly outlined in the ICH Q6A docu-
ment, which describes methods to set specifications for new drug substances.
Figures 9.6 and 9.7 show the decision trees in ICH Q6A related to setting
specifications for polymorphs. It requires acceptance criteria if the poly-
morph affects safety, efficacy, or performance. In fact, many major compa-
nies are setting acceptance criteria for polymorphs because of the difficulty
of proving that the solid form does not affect safety, efficacy, or perfor-
mance. In many cases, it is easier and faster to set criteria than it is to prove
a lack of effect.
Although the USP contains a procedure to negate the influence of poly-
morphs or solvates on an identity test, some monographs contain controls on
polymorphs. In particular, the carbamazepine USP monograph contains the
following tests for drug substance (USP 1999b):
• Packaging and storage
• USP reference standards <11>
• Identification, Infrared Absorption <197M>
• X-ray diffraction <941>
• Acidity
286 Validation of Active Pharmaceutical Ingredients
• Alkalinity
• Loss on drying <731>
• Residue on ignition <281>
• Chloride <221>
• Heavy metals, Method II <231>
Figure 9.6 Q6A Decision Tree 4 for Investigating the Need to Set Acceptance Crite-
ria for Polymorphism in Drug Substances and Drug Products (Federal Register
1997b)
Drug Substance
r-:l
U Conduct polyroorphism screen
on drug substance NO FURTHER ACTION
YES
NO
NO FURTHER TEST OR
ACCEPTANCE CRITERION
FOR DRUG SUBSTANCE
NO
Figure 9. 7 Q6A Decision Tree 4 for Investigating the Need to Set Acceptance Cri-
teria for Polymorphism in Drug Substances and Drug Products (Federal Register
1997b)
Continued from Figure 9.6 Drug Product - Solid Dosage Form or Liquid Containing
on previous page. Undissolved Drug Substance
N.B.: Undertake the following process only if technically possible
to measure polymorph content in the drug product.
• Chromatographic purity
• Organic volatile impurities, Method V <467>
• Assay
The X-ray diffraction test ensures the polymorph purity of the carbamazepine
drug substance.
BACPAC
BACPAC (Bulk Active Chemical Postapproval Changes) is an initiative aimed
at developing guidances that allow postapproval changes in drug substance
synthesis for site, scale, and equipment changes. BACPAC is divided into two
288 Validation of Active Pharmaceutical Ingredients
parts. BACPAC I deals with changes in the final intermediate and steps lead-
ing up to the final intermediate, whereas BACPAC II (not yet finalized) will
deal with changes in the API. The final intermediate is defined as the last
compound synthesized before the reaction that produces the drug substance
(Federal Register 1998b; FDJ\_1998). The final step forming the new drug sub-
stance must involve covalent bond formation; ionic bond formation (i.e.,
making the salt of a compound) does not qualify. Consequently, when the
drug substance is a salt, the precursors of the organic moiety used to make the
salt should be considered the final intermediate rather than the organic moi-
ety itself. A central tenet for the guidance is that any change can be assessed
by comparing pre- and postchange material. The prechange material is de-
fined by 10 historical lots (the average plus 3 times the standard deviation);
the postchange material is defined by 3 lots (the average plus 3 times the stan-
dard deviation). Three criteria determine equivalence of the impurity profiles
of the pre- and postchange material:
1. If the postchange material shows no new impurity at or above
0.1 percent
2. If the existing impurities and residual solvents are at or below the
upper statistical limit of the historical data
3. If the total impurities are at or below the upper statistical limit
If all three of these criteria are met, the postchange material is equivalent to
the prechange material and the appropriate relaxed reporting requirements
apply. The physical properties of the API are generally unaffected by the phys-
ical properties of the final intermediate. The particle-size distribution profile
and the solid form of the API are considered critical and other physical prop-
erties may also be important in some cases. However, physical properties of
the API need not be evaluated if equivalency in the impurity profile can be
demonstrated for the final intermediate.
For a BACPAC I example, consider a case involving the simultaneous im-
plementation of a site change, a scale change, and a process change of an in-
termediate produced in a four-step process (Moss 1999). The site change was
from one building to another on the same campus. The scale change was an
increase from 300 to 500 gal. The process change involved eliminating water
washes in the Stage 3 intermediate. In this example, the most stringent re-
quirements apply, which is the filing of a Changes Being Effected (CBE) sup-
plement. The combined data package needs to contain a description of the
changes (i.e., the site, scale, and process changes) along with a comparison of
impurity profiles before and after the changes for the final intermediate that
is produced in Stage 4 of the process (see Tables 9.1 and 9.2).
Table 9.1 describes the impurity profile comparisons for the Stage 3 ma-
terial. It is clear that the postchange material contains more impurities than
prechange material. For this reason the purity of the intermediate at Stage 4,
the final step, was assessed to determine whether these impurities were carried
Impurities in Drug Substances and Drug Products 289
Table 9.1 Comparison of Impurities at Stage 3 of the Process for Prechange and
Postchange Materials
Impurity Specification Upper Statistical Limit Maximum Result
in an Existing Building in a New Building
Table 9.2 Comparison of Impurities at Stage 4 of the Process for Prechange and
Postchange Materials
Impurity Specification Upper Statistical Limit Maximum Result
in an Existing Building in a New Building
through. Table 9.2 shows the results of this comparison. It is clear that at
Stage 4 the materials of the two processes are equivalent. Thus, the change
was filed using the CBE filing mechanism. The physical properties of the drug
substance pre- and postchange were also compared and shown to be equiva-
lent, although the analysis was not necessary since the impurity profiles of the
pre- and postchange Stage 4 material (the final intermediate) are equivalent.
REFERENCES
FDA. 1998. Guidance for industry. BACPAC I: Intermediates in drug substance synthesis.
Bulk active postapproval changes: Chemistry, manufacturing, and controls documenta-
tion. Draft guidance. Rockville, Md., USA: Center for Veterinary Medidne.
FDA. 1999a. Guidance for industry. Changes to an approved NDA or ANDA. Rockville, Md.,
USA: Center for Drug Evaluation and Research.
FDA. 1999b. Guidance for industry. ANDAs: Impurities in drug substances. Rockville, Md.,
USA: Center for Drug Evaluation and Research.
FDA. 1999c. Guidance for industry. ANDAs: Impurities in drug products. Draft guidance.
Rockville, Md., USA: Center for Drug Evaluation and Research.
FDA. 1999d. Guidance for industry. NDAs: Impurities in drug substances. Draft guidance.
Rockville, Md., USA: Center for Drug Evaluation and Research.
FDA. 1999e. Guidance for industry. Chemistry, manufacturing and controls changes to an
approved NADA or ANADA. Draft guidance. Rockville, Md., USA: Center for Veteri-
nary Medicine.
Federal Register. 1995. Guideline on validation of analytical procedures: definitions and ter-
minology. Federal Register 60 (40, 1 March 1995):11259-11262.
Federal Register. 1996. Guidelines on impurities in new drug substances. Federal Register 61
(3, 4 January 1996):371-376.
Federal Register. 1997a. Draft guideline on impurities: Residual solvents. Federal Register 62
(85, 2 May 1997):24301-24309.
Federal Register. 1997b. Draft guidance on specifications: Test procedures and acceptance cri-
teria for new drug substances and new drug products: Chemical substances. Federal Reg-
ister 62 (227, 25 November 1997):62889-62910.
Federal Register. 1997c. Guidelines on impurities in new drug products. Federal Register 62
(96, 19 May 1997):27453-27461.
Federal Register. 1997d. Guideline on the validation of analytical procedures: Methodology.
Federal Register 62 (96, 19 May 1997):27463-27467.
Federal Register. 1998a. Draft guidance for industry on manufacturing, processing, or
holding active pharmaceutical ingredients. Federal Register 63 (74, 17 April 1998):
19267-19268.
Federal Register. 1998b. Draft guidance for industry on PACPAC I: Intermediates in drug syn-
thesis; bulk actives postapproval changes: Chemistry, manufacturing, and controls docu-
mentation. Federal Register 63 (229, 30 November 1998):65793-65794.
Impurities in Drug Substances and Drug Products 291
Federal Register. 1999a. Draft guidance for industry on ANDAs: Impurities in drug products.
Federal Register 64 (2, 5 january 1999):516.
Federal Register. 1999b. 21 CFR Parts 172, 173, and 184: Foods and drugs, technical
amendments. Federal Register 64 (7, 12 january 1999):1758-1761.
Federal Register. 1999c. Draft guidance for industry on NDAs: Impurities in drug substances.
Federal Register 64 (13, 21 january 1999):3303.
Federal Register. 1999d. 21 CFR Parts 5, 206, 250, 314, 600, and 601: Supplements and
other changes to an approved application. Federal Register 64 (123, 28 june
1999):34608-34625.
Federal Register. 1999e. Draft guidance for industry on changes in an approved NDA or
ANDA. Federal Register 64 (123, 28 june 1999):34660-34661.
Federal Register. 1999f. Guidance for industry on changes to an approved NDA or ANDA.
Federal Register 64 (225, 23 November 1999):65716-65717.
Federal Register. 1999g. Guidance for industry on ANDAs: Impurities in drug substances.
Federal Register 64 (232, 3 December 1999):67917-67918.
ICH 1995. Guideline for industry. Q2A: Text of validation of analytical procedures.
Rockville, Md., USA: Center for Drug Evaluation and Research.
ICH 1996a. Guideline for industry. Q2B: Validation of analytical procedures: Methodology.
Rockville, Md., USA: Center for Drug Evaluation and Research.
ICH 1996b. Guideline for industry. Q3A: Impurities in new drug substances. Rockville, Md.,
USA: Center for Drug Evaluation and Research.
ICH 1997. Guideline for industry. Q3B: Impurities in new drug products. Rockville, Md.,
USA: Center for Drug Evaluation and Research.
Moss, A. 1999. Unpublished results. Research Triangle Park, N.C., USA: Glaxo Wellcome.
Reynolds, S. 1999. Presented at the Advisory Committee for Pharmaceutical Science
Site-Specific Stability Subcommittee. Rockville, Md., USA: Center for Drug Evalua-
tion and Research.
United States Pharmacopeia, 24th ed. 1999a. Rockville, Md., USA: U.S. Pharmacopeial
Convention.
USP. 1999b. Carbamezapine. In United States Pharmacopeia, 24th ed. Rockville, Md.,
USA: U.S. Pharmacopeial Convention.
USP. 1999c. Chemical tests <466>. In United States Pharmacopeia, 24th ed. Rockville,
Md., USA: U.S. Pharmacopeial Convention.
USP. 1999d. Chemical tests <467> Organic volatile impurities. In United States Phar-
macopeia, 24th ed. Rockville, Md., USA: U.S. Pharmacopeial Convention.
USP. 1999e. Digoxin. In United States Pharmacopeia, 24th ed. Rockville, Md., USA: U.S.
Pharmacopeial Convention.
USP. 1999f. General information <1086> Impurities in official articles. In United States
Pharmacopeia, 24th ed. Rockville, Md., USA: U.S. Pharmacopeial Convention.
292 Validation of Active Pharmaceutical Ingredients
USP. 1999g. General notices: Foreign substances and impurities. In United States Phar-
macopeia, 24th ed. Rockville, Md., USA: U.S. Pharmacopeia! Convention.
USP. 1999h. Preface: Impurities. In United States Pharmacopeia, 24th ed. Rockville, Md.,
USA: U.S. Pharmacopeia! Convention.
10
INVESTIGATING
PROCESS DEVIATIONS
Frank J. Golden
Glaxo Wellcome, Inc.
Zebulon, North Carolina
293
294 Validation of Active Pharmaceutical Ingredients
the extent to which the FDA considers the cGMPs to apply to APis. It also
includes an explanation of various methods for conducting investigations
into process deviations. At the conclusion of the chapter, examples of process
deviation investigations are provided.
PROCESS DEVIATIONS
Process deviations are defined as any operational nonconformity. This differs
from out-of-specification (OOS) situations, in which a nonconformance
event is noted by the result of a physical, chemical, or biological test in
which the sample did not meet the expected results. OOS situations (dis-
cussed in another chapter) already provide the focus when analytical results
do not meet predetermined limits or expectations. The FDA has made its
opinion known relative to OOS situations by court cases (U.S. v. Barr), pro-
posed GMP revision, and guidance documents. Many of the concepts ex-
pressed in these publications can be used when investigating process
deviations.
Process deviations, also called departures or excursions from approved
conditions or procedures, include product contamination when someone no-
tices the contamination in the course of an operation (e.g., leaking pipe) or
any operational issues in which a measured parameter such as temperature,
time, pressure, vacuum, pH, etc. does not meet its previously approved limits.
A process deviation is any excursion from the previously approved manufac-
turing step. Therefore, if a temperature is exceeded, a mixing time is abbrevi-
ated, an ingredient is added in the wrong manner, or a yield limit is exceeded,
then a process deviation exists.
Process deviations can occur during any step in the manufacture of APis.
Following the FDA's guidance, any process deviations, regardless of whether
they occur in a validated step, need to be investigated. This is in contrast to
the guidance provided in the FDA's Manufacture, Processing or Holding of Active
Phannaceutical Ingredients which states that only "critical" steps need be vali-
dated (FDA March 1998). However, this qualification does not apply to
process deviations, and as such all process deviations require investigation.
The depth of the investigation may be impacted by the level of the step in the
API process.
The challenge for process deviations is to determine the cause, extent,
and impact of the deviation. The way one detects a deviation is by comparing
the preapproved methods or steps with what was actually done. Unlike OOS
cases, there may not be a test result that indicates the deviation.
Investigating Process Deviations 295
REGULATORY CONSIDERATIONS
To further illustrate the point that the FDA considers APis to be drugs and that
APis need to be manufactured under GMPs, a number of excerpted FDA warning
letters are listed below. A warning letter is correspondence from the FDA advis-
ing a company that its actions are in violation of the FD&C Act. The following
citations were found through a search of the FDA warning letter Web page.
• No distinction is made between bulk drug substances and fin-
ished pharmaceuticals, and failure of either to comply with
cGMP constitutes a failure to comply with the requirements of
the Act
• Although the GMP regulations under Title 21 ... , Parts 210 and
211, are used as guidelines in the API industry, Section 501(a)(2)(B)
of the Act requires that all drugs be manufactured ... in accordance
with cGMPs. Failure to comply with cGMPs constitutes failure to
comply with ... the Act.
• No formal system existed to assure that changes in manufacturing
processes were drafted, reviewed and approved by appropriate orga-
nizational units and reviewed and approved by the Quality unit.
• The Quality Control Unit failed to:
Problem Description
There must be a clearly stated problem so the investigation can be organized.
For example, if a temperature in a particular step was exceeded then the sub-
sequent investigation can concentrate on the effects of that excursion. If the
problem is not clearly stated then resources might be expended on issues that
do not impact the problem.
Classification of Deviation
At this point it is worthwhile to classify the deviation. Only a few general
categories would be used, such as process, equipment, component, or em-
ployee. These classifications will be useful for trend analysis to determine if
there is a need for a more serious fix. Keeping the classification types to a
small number will allow an easier review in a later trend analysis. Remember
that any computer system used for a cGMP compliance purpose requires
validation.
298 Validation of Active Pharmaceutical Ingredients
Materials Used
Are the materials used the ones designed for this stage of the process? Different
materials might yield different results. Most companies require raw materials
to go through an acceptance by QA, but what about other production materi-
als like filters or filter aids (e.g., charcoal)? Is there an opportunity for an em-
ployee to choose what is needed? What kind of documentation or traceability
system is there to show exactly what material was used? If reused materials
such as solvents are used, is there a way to ensure that they are of a particular
quality, or a way to determine how long they have been used? If a material re-
quires some preparation before its use, are there records that document this?
Suitability of Facilities
Some API manufacturing processes can be done outside, in open nonwalled
buildings, or in very controlled environments. The nature of the facilities
needed depends on the step involved in the process and what contaminants
Investigating Process Deviations 299
Suitability of Equipment
What is the calibration and/or preventive maintenance (PM) history for a par-
ticular piece of equipment involved in an investigation? The equipment log-
books required by the cGMPs can serve as fast methods of determining that
history. Missed calibration schedules or out-of-calibration reports associated
with a piece of equipment could cause performance issues. Is the PM adequate
for the equipment?
Compare the PM with the equipment manufacturer's manual and de-
termine if they are equivalent. If not, the API manufacturer should have a
way to ensure that the equipment is being maintained adequately. Some-
times equipment is old or was bought through other agents and may no
longer have an operations manual. Then one can compare the equipment
used with similar equipment for which a manual is available or contact the
equipment manufacturer for guidance. Is the equipment in suitable condi-
tion? Look for evidence of tape or wire or any other informal mechanism of
keeping equipment running. If such evidence is present, the manner in
which the equipment operates could be affected. The cGMPs require equip-
ment to be suitable for intended use. Ensure that the correct equipment is
used both in size and makeup. A larger reactor may have an effect on a
process designed for a smaller vessel. Some processes require glass-lined reac-
tors and can be affected if not processed that way. The batch record should
document the equipment used in the process, so this determination should
be fairly simple.
Employee Training
When a deviation occurs in which an operator failed to follow the prescribed
parameters, it is necessary to determine if that employee's training was ade-
quate. Many companies use these deviations and do trend analysis to deter-
mine where they need to focus the training. The manufacture of APis takes
some very unique skills, which can involve the handling of very toxic materi-
als and require significant controls of the operation. Employees may need
more than just Standard Operating Procedures (SOPs) or cGMP training to do
their jobs. Adequacy of training is somewhat subjective in an environment
where there are few constants and employees must improvise to do their jobs.
Therefore, the adequacy of training does not focus just on the employee but
300 Validation of Active Pharmaceutical Ingredients
on the training system as a whole. Even in the best situation there can be em-
ployees who are either unwilling or unable to do the job correctly. This situa-
tion could require the API manufacturer to take some disciplinary action.
Extent of Deviation
The event that is being investigated was probably found during the manufac-
turing of one batch. However, most APis are made in groups of batches (cam-
paigns}, and companies use similar equipment. So how does this deviation
affect other batches? Expand your review to other products or manufacturing
trains. You may also want to know how often a particular deviation has oc-
curred. This may affect your judgment regarding what action to take. A devi-
ation database is helpful here so you can search for similar problems.
Validation Impact
According to the current API draft guidance all critical steps in the manufac-
ture of an API need to be validated. Therefore, the API manufacturer has pre-
viously determined that the process employed will yield a product of
consistent quality. However, the deviation has changed the process. An evalu-
ation needs to be performed to determine if the deviant process is equivalent
to the validated process. For noncritical processes and other nonvalidated
processes the deviant batch can be compared with historical production.
Equivalency
The tool best suited to determine variation in different populations is statis-
tics. The deviation lot is different from the validation lot in that something
was changed in the deviation lot. This difference could lead to variability in
the product, which may not be of the same quality as the validation or his-
torical batches. Techniques such as process capability and relative standard
deviation are available for determining the equivalency.
Testing Required
Depending on the deviation encountered, the testing to show adequacy will
vary. Safety testing may be needed if low levels of a particulate are found. In
most cases full assay tests will be required to determine that the deviation
batch meets the specifications. These tests are basically experiments designed
to prove the hypothesis that the deviation had no impact on the product.
Therefore, appropriate acceptance criteria need to be established and the null
Investigating Process Deviations 301
Regulatory Impact
Since most APis are involved with some regulatory submission, the process
deviation must be evaluated before any action is taken. Reprocessing is gener-
ally permissible, but reworking a product may require a regulatory filing. As
regulatory agencies harmonize it is important that all submissions are
checked to ensure compliance in the various markets. However, even an ap-
proved rework procedure can pose questions for a validated process if used
too often.
Results of Investigation
After the investigation is concluded, the results need to be documented in an
objective format. Reference needs to be given to information sources. Some-
times the sources can be included with the results; however, for large amounts
of information it may be easier just to reference it, as long as the information
can be found at a later date. Report what is known and what the impact of the
results mean. Summarize results for easy review.
Corrective Action
The action taken to correct the deviation needs to be listed. Corrective action
corrects the deviation and is focused on the deviant batch. When followed,
the action will cause the batch to be acceptable.
Preventive Actions
Preventive action is taken to prevent the deviation from recurring. This often
requires some future activity such as training, new equipment purchase, or
change to operations. A follow-up system needs to be established to ensure
that future actions are completed. The use of a tracking database can help to
ensure actions are taken.
302 Validation of Active Pharmaceutical Ingredients
Conclusions
The conclusion is generally a short statement indicating what the deviation
was, a summary of the results of the investigation, the impact on other lots,
and whether the deviant batch can be accepted or rejected.
Documentation
In a regulated environment such as API manufacture, the documentation is
very important. Its purpose is to collect all the available information that
shows the deviant lot is acceptable. It also allows for a later review to deter-
mine if there are adverse trends. Documentation needs to be properly filed so
that it can be found quickly in the event of a regulatory inspection.
Periodic Review
Documentation on deviant lots needs to be reviewed periodically to identify
adverse trends. Pareto-type analysis can be performed to determine if particular
problems, products, or systems have recurring issues. Changes made to a
process need to be documented and reviewed for cumulative validation impact.
The following steps can be used as a checklist to aid in performing devi-
ation inventions: define problem, identify probable cause, prioritize and in-
vestigate causes, analyze information obtained, determine extent, verify
solutions, document investigation, complete investigation in a timely fashion
(circa 30 days), get approval signatures, track for future reference, and follow-
up on commitments.
Juran and Gryna (1980) also discuss the following techniques for per-
forming problem analysis and improving the level of quality:
Example 1
Description of the Deviation
During the manufacture of API lot 45 the temperature in the reaction vessel
exceeded the limits of the process by 10°F. The master formula requires a tem-
perature between 120 to l40°F. An automatic vent on the vessel failed to open
during the process.
manually to relieve the pressure. It was determined that the plant compressed
air system had gone down for about 1 hour, which prevented the automatic
valve from working. The other instances of temperature excursion noted dur-
ing the database review were attributed to operator error and therefore are ir-
relevant to this deviation.
The API was sampled in triplicate and the assay results were 95.6, 96.3,
and 96.2 percent. The relative standard deviation of the values was within the
RSD found during the validation of the API. An impurity profile was also per-
formed and the results were consistent with the validation batches. Reference
QC notebook 1122, page 30.
Follow-up Action
Production needs to investigate a system of notifying the operator when plant
utilities such as compressed air go down. Responsible person: Fred Lee. Target
date: March 1, 2000.
Conclusion
The API exceeded the temperature for 10 minutes during the process. The fail-
ure of the plant compressed air system caused an automatic valve not to
open. Tests of the deviant lot showed there was no adverse impact on the
API's quality attributes or the validated process. API lot 45 is acceptable and
can be approved and released.
Example 2
Description of the Deviation
During the manufacture of API lot 100 an operator used an unapproved raw
material. The raw material used was the correct type but had been supplied by
an unapproved supplier.
Follow-up Action
QA needs to counsel the staff to ensure that all material received are from ap-
proved sources. Responsible person: Joe Smith. Target Date: Completed. QA
needs to perform an audit of this supplier to determine if they can be added to
the approved supplier list. Responsible person Frank Gordon. Target date: Jan-
uary 2000.
Conclusion
API lot 100 will remain on hold until QA has audited the supplier and deter-
mined if they are acceptable.
Investigating Process Deviations 307
Postscript
It has been determined that the cost of auditing this supplier is greater than
the cost of losing this one batch. Therefore, API lot 100 will be rejected and
destroyed.
Example 3
Description of the Deviation
After the manufacture of API batch BB it was discovered that the cleaning
documentation from the previous lot (batch AA) was lost. Batch AA was a dif-
ferent API and a complete cleaning was required before the equipment could
be used to manufacture lot BB. The cleaning documentation is held in a sepa-
rate system from the batch records.
Follow-up Action
Production will now file the cleaning records with the batch documentation
so QA can review them at batch release. Responsible person: Judy Jones. Tar-
get date: Completed.
Conclusion
The documentation for the cleaning of equipment after the manufacture of
API lot AA was lost. Lot BB was manufactured after lot AA. Interviews with op-
erators confirmed the cleaning was done. The cleaning is documented in the
equipment log book. An in-process lab test shows that samples for the clean-
ing solvent passed the IR test. Additional tests of lot BB showed no residue
from lot AA. This lot can be approved and released.
REFERENCES
Code of Federal Regulation, Title 21, Parts 210 and 211: Current good manufacturing
practices for finished pharmaceuticals.
FDA. November 1998. Bulk active postapproval Changes: Chemistry, manufacturing, and
controls (Draft guidance). Rockville, Md., USA: Food and Drug Administration.
FDA. 1984. Bulk pharmaceutical chemical guide. Rockville, Md., USA: Food and Drug
Administration.
FDA. 1996. 211.192 Proposed amendments. Federal Register (3 May 1996).
FDA. 1998. Good manufacturing practices for finished pharmaceutical. Code of Federal
Regulations, Title 21, Part 211.
FDA. March 1998. Manufacturing, processing, or holding active pharmaceutical ingredients
(Draft guidance). Rockville, Md., USA: Food and Drug Administration.
Food Drug and Cosmetic Act as amended, 1985.
ICH. 1999. Good manufacturing practice guides for active pharmaceutical ingredients (Draft
No. 4), Geneva, Switzerland: International Conference on Harmonisation.
Juran, and Gryna. 1980. Quality planning and analysis, 2nd ed. New York: McGraw Hill.
www.fda.gov/cder/drug.htm.
11
TECHNOLOGY TRANSFER:
ACTIVE PHARMACEUTICAL
INGREDIENTS
309
310 Validation of Active Pharmaceutical Ingredients
PRELIMINARY CONSIDERATIONS
Often, due to project timing, these two events may actually occur simultane-
ously.
Another very useful section in the process transfer document is the process
status table usually found in the process detail section. An example is seen in
Table 11.2.
Knowledge of the identity, quality, and quantity of starting materials, in-
termediates, solvents, and reactants is critical to a thorough understanding of
the process and the ability to carry out a successful scale-up. An example of a
typical report format is shown in Table 11.3.
Technology Transfer: Active Pharmaceutical Ingredients 315
RXN-4414414 - - - - - - - - ,
.----2____ SM 1212
RCOOH
50%Me0H:50%/IPA
4
TN 31
Coupling Reaction
Aqueous
' - - - - - - - - - - - • Hazardous Waste
Toluene
316 Validation of Active Pharmaceutical Ingredients
Intracompany Project
Nearing the end of the research involvement, when the need for additional
quantities of drug substance for expanded clinical trials is established (i.e., the
company makes a "go" decision about the continuation of the clinical candi-
date), technology transfer becomes important. In anticipation of this deci-
sion, preliminary meetings of interdivisional teams may be held to plan for
the project, well in advance of any actual technology transfer activity. It is im-
portant to begin information exchange early to facilitate the planning
process.
When technology transfer from pilot scale to full commercial scale be-
gins, the process should be well defined and sufficiently rugged. The manu-
facturing facility selected for the API manufacture should have been evaluated
and deemed adequate to perform the intended operations. In addition to con-
sidering the business issues, such as tax advantages, this evaluation should
obviously include equipment size and design, facility layout, availability of
waste handling systems, and utilities. Additionally, the GMP support systems,
including adequate laboratory facilities, documentation systems, training,
Technology Transfer: Active Pharmaceutical Ingredients 319
the same material of construction as those in the commerctal facility, with the
exception of size. Although all processes are different and have different re-
quirements, as a guideline the pilot scale equipment should be nominally at
least 10 percent of the capacity of that found in the commercial plant.
Another reason for pilot plant scale-up is to ensure the API impurity pro-
file is well characterized. Since the reactions in large-scale equipment often
are subject to variations caused by interphase reactions, localized reactions,
and so forth, it is not unusual to encounter reaction by-products not foreseen
from the laboratory-scale experience. These can be dimers of the desired com-
pound, sterioisomers, different polymorphs, enantiomorphs, or a variety of
by-products from the reaction mixture. Often the scale-up experience reveals
the need for additional downstream purification steps to purge the unwanted
moieties to acceptable levels.
Raw Materials
Starting materials for the synthesis should be evaluated. Typically, the prelim-
inary quality specifications were established from the early research synthesis,
and further refined based on manufacturing experience. It is likely that com-
pendia grade materials were utilized in the prescale-up batches. Potential
commercial suppliers of all materials need to be investigated. If a business
partner is the source for any intermediates, the product specifications should
be set forth in the contractual documents prior to the initiation of any work.
These specifications are intended primarily to provide assurance that the in-
termediate will be of the requisite quality to perform consistently in the sub-
sequent synthetic steps. The impact on product quality of using grades of raw
materials and/or solvents that are different from those identified in the devel-
opment work must be evaluated and justified.
could have been avoided. The importance of careful and accurate definition
of critical process parameters is probably the most important consideration in
the success of a technology transfer.
Process Equipment
As stated earlier, the goal of the technology transfer project is to duplicate the
existing validated process at another location. For this reason, any variation
from the specified process equipment must be carefully controlled to mini-
mize adverse impact on the process.
Analysis of the existing equipment, considering the requirements of the
particular chemistry, is essential to predict and eliminate problems prior to
initiating scale-up runs. An example of a typical process analysis listing po-
tential problems and recommendations for resolution is given in Table 11.4.
The open-ring analogue had not been detected previously, although this
was a well-characterized synthesis and hundreds of batches had been manufac-
tured, albeit at the originating site. Fortunately, in this particular case, the down-
stream processing was demonstrated to purge the impurity to below acceptable
levels. Had this not been the case, however, it might have been necessary to de-
velop and validate (and possibly file a regulatory petition) to recover this batch.
Cleaning Validation
Unless-and even if-the technology transfer is done in a new facility, the issue
of equipment cleaning must be addressed. A treatise on cleaning validation is
not in the scope of this chapter, but cleaning validation is an important re-
quirement for successful completion of the project. For most chemical opera-
tions, the cleaning agent is typically a solvent. For aqueous process streams
where the reagents are water soluble, the task may be straightforward. When
reactions are carried out in organic solvents, the task becomes more formidable
and may prompt safety and environmental concerns. In any case, a formal pro-
tocol such as those outlined in various papers on the topic (see, e.g., Mc-
Cormick and Cullen 1993, pp. 329, 330) and study to verify the equipment is
suitable for use in carrying out the process is a GMP requirement. Although the
goal of any cleaning process is complete removal of the previous product, the
capabilities of modern analytical techniques, detecting residual compounds at
the parts-per-billion level, reveal the need to establish acceptable residual levels
following the cleaning procedure. Such levels are determined after considering
a number of factors including toxicity of the original compound, minimum
therapeutic effect levels, equipment surface area, and minimum batch size for
the subsequent manufacturing. Once the levels are established, a plan is set
forth in a protocol to study the effectiveness of the selected cleaning procedure.
Prior to initiating the formal study, it is appropriate to determine the rel-
ative effectiveness of the cleaning process at small scale using coupons or
swab/ rinses. This also requires validation of the swab recovery technique
(e.g., percentage recovery of a known charge), rinse technique if used, and, of
course, the analytical method.
Note: Many in the field would claim only an automated cleaning process
(i.e., clean-in-place) can be validated, hinting that human intervention can-
not be deemed reliably consistent. In any case, cleaning effectiveness must be
demonstrated.
Process Validation
No discussion of technology transfer would be complete without the mention
of process validation. In a pure sense, the project may not be considered com-
plete until the process validation at commercial scale has been successfully
324 Validation of Active Pharmaceutical Ingredients
completed. It is not the purpose of this chapter to delve into the detail of
process validation for APis; however, this part of the project is critical because
it demonstrates the link between the process development activity and the
commercial scale production and verifies the critical parameters identified in
the earlier work. In the course of the study, the critical process parameters will
be controlled to ensure the process remains within established ranges.
The study report should provide a comparison between the ranges or
limits established at development scale and those demonstrated by the three
successive validation lots or batches. Verification that these parameters are
indeed within limits and reproducible is one of the acceptance criteria for
the study. A summary table of typical in-process parameters is provided in
Table 11.5.
Analytical Methods
Simultaneous with the evolution of the chemical process are the development
and refinement of the analytical procedures necessary to properly character-
ize the drug substance and any necessary intermediates and starting materials.
* Note: Temperature excursion less than one minute. See deviation investigation sec. VII. B.
Technology Transfer: Active Pharmaceutical Ingredients 325
The medicinal chemist in the research organization is not concerned with an-
alytical methods development that will be used to ultimately monitor the
quality of the drug substance. Although monitoring methods are developed
in the research organization while the drug is in the clinic, it is unlikely that
these are the final methods that will be used for monitoring the quality of the
drug substance once it is in production.
For drug substance purity determination, usually a specific analytical
method such as high performance liquid chromatography (HPLC) or gas
chromatography will be used for purity determination in small molecules.
Since the impurities that are discovered will probably change as the synthetic
pathway changes, there will be a continuing need for support and interaction
with the analytical methods development members of the team. In develop-
ing the methods, the identity and structure of impurities likely to result form
the proposed synthesis should be determined, and "pure" samples of each
should be synthesized to use as markers to determine at which point in the
chromatogram each will elute. When the retention time for each impurity in
a particular system is established, this information can be used to identify the
presence of a particular impurity in a batch sample. An example of an in-
process isocratic HPLC system with retention times established for the known
reaction impurities is given in Table 11.6.
Additionally, the methods development members of the team may be
called on to provide support for developing in-process methods that may be
used to monitor critical process parameters once the synthetic process is set
and is ready to be performed in a pilot or production facility. A key objective
for the process development chemist is early identification of the key process
parameters, which are amenable to either on-line monitoring or to monitor-
ing by obtaining a sample and waiting for an analysis to be performed.
In addition to chemical characterization, physical characterization of
the molecule must also be performed. Once the API is synthesized in the new
ANCILLARY ISSUES
API Container/Closure
Along with the properties of the drug substance, characteristics regarding the
stability of the drug substance will have been generated throughout the clinical
development. The manner in which the drug substance and any synthesis in-
termediates have been stored is known and should be communicated in the de-
velopment report. A stability study will have been performed that shows the
drug substance stability to heat, light, acid, base, and humidity in a given con-
tainer system-for a drug substance, generally a polyethylene bag of some type,
or for a sterile drug substance, an aluminum can, glass bottle, or sterile plastic
bag. Ideally, a package should be chosen for the API that has no chemical inter-
actions with the molecule and minimizes the chances for any external chemi-
cal interactions by outside ingress. The storage conditions should be
communicated so that commercial shipping containers that contact the prod-
uct will be of the same chemical composition so that the stability testing for in-
tegrity and compatibility do not have to be repeated. Also, the need for the use
of desiccant of some type for controlled temperature storage, or for sensitivity
to light, should be established and communicated so that any unusual storage
requirements may be accommodated. This can be a problem in the event that
refrigerated storage is required for a large quantity of raw material, and the pro-
posed manufacturing facility has no refrigerated warehousing capability.
Technology Transfer: Active Pharmaceutical Ingredients 327
Stability
An important part of the medicinal chemist's early work is elucidation of the
drug candidate's chemical stability. The tendency of a drug substance to form
degradation products under normal storage and handling conditions is an in-
dication of difficulties for the formulation chemist and may ultimately
threaten the commercial viability of the drug candidate.
The medicinal chemist will perform acid, base, temperature, light, and
humidity stressed studies on the drug substance to elucidate its decomposi-
tion profile. This information should be communicated in the development
report, which may facilitate the process development chemist's efforts to
identify the optimum synthetic process.
Any changes made to the process after the original scale-up must
demonstrate a drug substance with the same stability characteristics as de-
fined in the original regulatory submissions for the molecule. This evaluation
can be made either under "accelerated" conditions or by direct comparison of
the long-term stability profiles of the molecule. Tests must be chosen that can
adequately indicate the true stability of the molecule, and when the testing is
performed at the appropriate testing intervals, a retest period can be estab-
lished for the API. This combination of tests, storage time, and temperature
results in the generation of a stability protocol that will be followed fairly
closely throughout the API life to evaluate any changes made.
Regulatory Issues
This chapter is not intended to describe the strategies associated with regula-
tory filings (e.g., NDA), but it often makes good sense to conduct manufactur-
ing trials for the process at or close to commercial scale prior to submission of
the final technical process description to the regulatory agency. As stated
above, the commercial scale process rarely, if ever, performs identically to the
laboratory scale. For this reason, subtle or substantial changes to process para-
meters may be necessary to achieve the desired product quality, yield, or op-
erating efficiencies required at commercial scale. If the parameters are too
closely defined in the regulatory documents, based only on laboratory-scale
experience, significant project delays will result from the need to modify the
regulatory filings and await approval.
SUMMARY
Successful technology transfer of drug substance manufacturing requires care-
ful planning, effective communication, and flawless execution. If any of these
elements is missing, the probability of an efficient, timely, and cost-effective
328 Validation of Active Pharmaceutical Ingredients
REFERENCES
Allen, T. ]. 1985. Managing the flow of technology. Cambridge, Mass., USA: MIT Press.
Feigenbaum, A. V. 1991. Management strategies for quality. In Total quality control, 3rd
ed. New York: McGraw Hill.
McCormick, P. Y. and L. F. Cullen. 1993. Cleaning validation. In Pharmaceutical process
validation, 2d ed., vol. 57, ed. by I. R. Berry and R. A. Nash, New York: Marcel
Dekker, Inc.
Neiss, E. S. and T. A. Boyd. 1984. Pharmogenology: The industrial new drug develop-
ment process. In The clinical research process in the pharmaceutical industry, vol. 19,
ed. by G. M. Matoren. New York: Marcel Dekker, Inc.
Repic, 0. 1998. Principles of process research and chemical development in the pharmaceuti-
cal industry. New York: John Wiley & Sons.
12
POSTAPPROVAL CHANGES TO
BULK DRUG SUBSTANCES
Eric Sheinin
United States Pharmacopeia
Rockville, Maryland
Kasturi Srinivasachar
Eric Duffy John Smith
Food and Drug Administration,
Center for Drug Evaluation and Research
Rockville, Maryland
In recent years, the Food and Drug Administration (FDA) has undertaken an
initiative to develop guidance for postapproval drug manufacturing changes.
Several guidances for drug product manufacturing changes, the Scale-Up and
Postapproval Changes (SUPAC) guidances, have provided recommendations
for demonstrating equivalence of products following manufacturing changes.
Analytical testing and in vivo testing recommendations were provided for the
following classes of drug products: immediate release and modified release
solid oral drug products and nonsterile semisolid drug products. Guidance is
now being developed for drug substance manufacturing changes under the
Bulk Actives Postapproval Changes (BACPAC) initiative. This brief chapter de-
scribes this initiative from its inception and development to its present form.
The objective of this initiative is to develop recommendations for sound
scientific approaches to assess the potential for drug substance manufacturing
changes to adversely affect the identity, strength, quality, purity, and potency
of drug substances as they may relate to the safety and effectiveness of drug
329
330 Validation of Active Pharmaceutical Ingredients
The discussions provided the FDA with invaluable input for the develop-
ment of guidance for drug substance manufacturing change, and many of the
concepts considered at the workshop are to be found in the guidances that
were crafted. Since it was made clear that industry would find the greatest
value in guidance on the manufacture of intermediates, this is where the
initial efforts were focused. It was decided that two guidances would be cre-
ated-one for intermediates, BACPAC I, and one for drug substances, BACPAC
II. It was also decided to limit the guidances to chemical synthetic processes
only.
This chapter should not be used in lieu of these guidances, since neither
BACPAC I nor BACPAC II has been finalized.
BACPAC I
A draft BACPAC I guidance was released for public comments, and the com-
ments have been evaluated. When this chapter was written, the draft guid-
ance was being revised based on the comments received.
Scope
BACPAC I is a guidance for industry concerning postapproval changes to in-
termediates in the synthesis of drug substances used in both human and vet-
erinary drug products. It defines the FDA's recommendations regarding the
filing mechanism and data that should be submitted in support of these
changes. Since most of the modifications to intermediates involve an evalua-
tion of the impurity profile, it was considered appropriate to use the threshold
levels for identification and qualification of impurities in the International
Conference on Harmonisation of Technical Requirements for the Registration
of Pharmaceuticals for Human Use (ICH) guideline Impurities in New Drug Sub-
stances, Q3A. Consequently, BACPAC I does not apply to the categories of drug
substance excluded by ICH Q3A, namely, natural products, biotechnology-de-
rived drug substances, synthetic oligonucleotides and peptides, and radio-
pharmaceuticals. These classes of drug substances have been excluded from
consideration primarily because many of them are structurally complex mate-
rials for which monitoring of impurities at low levels may not be feasible. It
can be argued that short synthetic peptides and oligonucleotides are well-char-
acterized small molecules and should be covered by BACPAC I, but in practice
it is difficult to determine at what point these would be better classified as
complex molecules. Furthermore, because each coupling of an amino acid/nu-
cleotide is equally important, dividing BACPAC recommendations between fi-
nal intermediate and final bulk (BACPAC I vs. BACPAC II) is not as logical for
these complex materials as it is for conventional organic molecules. In solid
332 Validation of Active Pharmaceutical Ingredients
phase synthesis of such materials, hardly any intermediate is isolated at all. For
these reasons, it was decided to exclude the entire category. Additional guid-
ances will be developed that will address postapproval changes to these sub-
stances. The synthetic steps involved in the preparation of semisynthetic
conventional molecule drug substances do, however, fall within the scope of
this document even though such drug substances are excluded by Q3A.
BACPAC I covers changes up to and including the final intermediate
with some restrictions as noted below. These early modifications should, in
general, have a low probability of having an adverse impact on the identity,
strength, quality, purity, or potency of the drug substance. Additionally, these
modifications would not be expected to affect the physical properties of the
drug substance. Changes in manufacturing site, manufacturing scale, equip-
ment, specification, and process are addressed for all intermediates; however,
changes that result in a structurally different final intermediate or changes to
the specification for the final intermediate are beyond the scope of BACPAC I.
Changes to bona fide starting materials, except for specification changes, are
also excluded. Such changes are not usually reported to the FDA, except for
those starting materials derived from natural sources.
Filing Mechanism
The regulations at 21 CFR 314.70(a) requires that all changes to an approved
application be reported to the FDA. Changes can be documented in a supple-
ment to the application or in an annual report. BACPAC I provides guidance
on the appropriate filing mechanism for a given change to intermediates in a
drug substance synthesis. There are three categories of supplements-prior
approval, when the change may not be implemented before approval by the
FDA; Changes Being Effected in 30 days, which should be submitted at least
30 days prior to distribution of product made using the change; and Changes
Being Effected when the change can be implemented at the time of submis-
sion. It is important to note that Changes Being Effected supplements still re-
quire FDA approval even though material manufactured using the change
may be distributed and used prior to formal approval. As allowed by regula-
tion 314.70(a), BACPAC I provides for less burdensome filing of some postap-
proval changes. It should be emphasized that the only implication of this is
that some changes may be implemented without waiting for FDA approval;
that is, there is no reduction in the type or amount of data needed to support
the change. BACPAC I also suggests that certain minor changes need not be
formally filed with the FDA, and data generated to qualify these changes can
be kept on-site and made available to FDA investigators.
The supplemental New Drug Application/Abbreviated New Drug Appli-
cation (NDA/ANDA) filings referred to in the preceding paragraph are the re-
sponsibility of the holders of the applications. When information on drug
substance synthesis is provided in Drug or Veterinary Master Files, a BACPAC
Postapproval Changes to Bulk Drug Substances 333
Assessment of Change
BACPAC I advocates a data-driven strategy for the assessment of change that
is considered to be scientifically superior to an arbitrary classification of
changes as major or minor. The diversity of drug substance structures and the
plethora of synthetic routes that can be employed to arrive at a given struc-
ture make it difficult, if not impossible, to make a priori generalizations about
the risk associated with a particular modification. In the BACPAC I approach,
change is assessed by comparing pre- and postmodification material and es-
tablishing equivalence between the two. If equivalence cannot be demon-
strated, the provisions of BACPAC I do not apply and the effects of the
change on the dosage form may need to be evaluated. Under these circum-
stances, it is recommended that the appropriate chemistry review team be
contacted.
Two major factors for determining equivalence in the drug substance are
the impurity profile and physical properties. Equivalence of the impurity pro-
file can be established at an intermediate downstream from the change or on
the drug substance itself. NDA and ANDA holders that follow the former
route will derive the maximum benefit from BACPAC, since the physical
properties of the drug substance are not likely to be impacted. No further an-
alytical testing is needed for these materials. However, this approach repre-
sents a radical change in the way intermediates are characterized and
analyzed. Assessment of change is best carried out at the intermediate imme-
diately following the change, as this provides the most useful information
concerning on potential impurities based on the reactants and reagents used,
the reaction conditions, and the reaction mechanism. Analysis of later inter-
mediates or the drug substance is complicated by the fact that any impurities
initially present can undergo secondary transformations in subsequent steps.
Demonstrating equivalence early in a synthetic process provides greater assur-
ance that a manufacturing modification will not affect the identity, strength,
quality, or purity of the drug substance. For this reason, the guidance some-
times recommends less burdensome filing than the regulation when the im-
purity profile is shown to be equivalent for an intermediate prior to the final
intermediate.
BACPAC I recognizes that establishing equivalence at downstream inter-
mediates may not always be feasible. Intermediates may not have been well
characterized for a number of older synthetic drug substances, and it may not
be economically viable to develop suitable analytical methodologies for these.
334 Validation of Active Pharmaceutical Ingredients
changes are contemplated. NDA and ANDA holders should use their judg-
ment and previous experience to determine which changes are "major"; for
example, if it is known from scale-up studies of pilot scale batches that a cer-
tain step is scale sensitive, then increasing the scale of commercial batches
should be justified by equivalence testing.
Specification Changes
Tightening of acceptance criteria and certain changes to comply with com-
pendia! requirements are of no major concern. However, relaxing acceptance
criteria, replacing an analytical method with one that does not qualify as an
improvement, deleting tests, or revising specifications because of a change in
grade/supplier of a solvent, reagent, or starting material may have the poten-
tial for an adverse effect on the identity, strength, quality, or purity of the drug
substance. In many of these cases, the effect of the change on the impurity
profile of a subsequent intermediate or the drug substance needs to be evalu-
ated and the data submitted in a supplement. There are some exceptions
when the quality of downstream intermediates or the drug substance would
clearly not be affected by the change, such as, elimination of redundant test-
ing; equivalence testing is not called for in these instances, and the change
may be filed in an annual report.
Process Changes
Changes to the manufacturing process account for more supplements than
any of the other types of changes covered by BACPAC I, although there often
is overlap with these and other types of changes. For example, it is likely that
a change in the route of synthesis will involve the use of different equipment
and perhaps different starting materials, and different intermediates may be
formed. These new starting materials and intermediates will have specifica-
tions different from the previous starting materials and intermediates. It is
convenient to divide process changes into three basic categories:
1. Same starting materials and intermediates.
2. Synthesis route changes involving different starting materials
and/or intermediates, excluding the final intermediate.
3. Redefinition of an intermediate as a starting material.
The first section covers changes within a step or steps of the synthetic
scheme and includes, among others, process parameter or solvent changes.
Such changes generally should be supported by equivalence testing. It is de-
sirable to establish equivalence as close to the change as possible and a less
restrictive filing mechanism is suggested if equivalence is demonstrated prior
to the final intermediate.
Postapproval Changes to Bulk Drug Substances 337
BACPAC II
The BACPAC II guidance was at a much more preliminary stage in the draft-
ing process than the BACPAC I guidance at the time of this writing; thus,
there was some uncertainty concerning what information the guidance
would convey and what topics it would cover. Nevertheless, some remarks
can be made with a reasonable expectation that they will bear some resem-
blance to the details contained in the final guidance.
338 Validation of Active Pharmaceutical Ingredients
Scope
The classes of compounds covered by BACPAC II will almost certainly be the
same as those covered by BACPAC I, since equivalence in the impurity profile
of pre- and postchange materials will probably be a key factor in determining
filing mechanisms in BACPAC II, as it is in BACPAC I. Therefore, BACPAC II
also will likely be limited to conventional, synthetic drug substances for
which impurities can be quantitated at levels comparable to the ICH Q3A
threshold levels. The excluded categories of compounds are the same as those
listed in the BACPAC I guidance.
BACPAC II, by definition, will cover changes in the manufacturing
processes for drug substances that take place after the final intermediate. The
covered changes also will include changes in specifications for final interme-
diates, which were not covered in BACPAC I. Whereas BACPAC I covered site
changes for intermediates only (including changes in the manufacturers of
intermediates), BACPAC II will cover site changes that involve or include
changes in location of the manufacturing operations after the final interme-
diate. BACPAC II may also cover changes in the source of a drug substance.
Principles of Equivalence
It is expected that BACPAC II will embrace the general principles of equiva-
lence described in BACPAC I. Given that BACPAC II covers changes made after
the final intermediate, a few modifications may be needed to the practical ap-
plication of these principles. For example, equivalence testing on intermedi-
ates likely will be eliminated, since by definition few intermediates can exist
after the final intermediate. On the other hand, BACPAC II may need to take
into account the fact that some drug substances can exist in a variety of forms,
for example, the racemate of a single-enantiomer drug substance, or crude ma-
terials that require further purification to attain the purity required by the
drug substance specification, or the premilled or premicronized forms of a
drug substance. There may also be a different emphasis on changes to sol-
vents. Whereas a new solvent introduced early in a synthetic process is un-
likely to remain in the drug substance, a new solvent used in the final
synthetic step, or later, is much more likely to be present.
The principles of equivalence of physical properties likely will receive
greater emphasis in BACPAC II. In BACPAC I, demonstration that physical
properties were equivalent was appropriate only in a few circumstances. In
BACPAC II, there will be a larger number of changes for which equivalence of
physical properties should be demonstrated. Preliminary drafts of BACPAC II
have considered more closely the question of what conditions should prompt
a comparison of pre- and postchange physical properties.
Postapproval Changes to Bulk Drug Substances 339
Filing Mechanisms
As in BACPAC I, different types of changes likely will be described in terms of
what information or documentation should be provided to support a pro-
posed change, and what kind of submission(s) should be made to the FDA to
report the change and to provide the supporting documentation. For drug ap-
plications, the choice of submissions will be annual reports, Changes Being
Effected supplements (changes effected immediately or in 30 days), or prior
approval supplements. Although preliminary discussions of BACPAC II have
indicated that there will still be many changes for which an annual report
submission will be sufficient, it is anticipated that a greater proportion of
changes will recommend supplements than was the case for BACPAC I. This is
because changes made late in the manufacturing process (i.e., those covered
by BACPAC II) are usually expected to have a greater potential to adversely af-
fect the identity, strength, quality, or purity of drug substances than those
changes made earlier (i.e., BACPAC I changes).
Types of Changes
In the BACPAC I guidance, the section on types of changes contains the most
specific guidance on the kind of information that should be provided to
support a BACPAC I change and the manner (type of submission) in which it
should be reported to the FDA. There will be a similar section in BACPAC II to
serve the same purpose. Since this part of BACPAC II is the one most likelyto
undergo revision and editing as the draft is developed, it is very difficult
to make accurate predictions about its content. However, it is very likely that
the section will be subdivided, as was this section in BACPAC I, into discus-
sions of (1) manufacturing site, manufacturing scale, and equipment changes;
(2) specification changes; and (3) manufacturing process changes.
Summary
It is expected that BACPAC II will follow the same general form and principles
of equivalence as found in BACPAC I. The primary differences will most likely
be due to the fact that BACPAC II will deal with changes made toward the end
of the manufacturing process of a drug substance, when the potential for ad-
verse effect on the identity, strength, quality, or purity of the drug substance
is significant. It is also likely that there will be a greater emphasis on changes
to the physical properties of the drug substance, and consideration of how
such changes may affect drug products made from those drug substances.
BACPAC II will likely cover the same classes of drug substances as BACPAC I,
and many of the same types of changes.
340 Validation of Active Pharmaceutical Ingredients
CONCLUSION
The BACPAC concept follows naturally from the development of the SUPAC
guidances by the Center for Drug Evaluation and Research (COER). The
SUPACs provided a reduction in the regulatory burden faced by the pharma-
ceutical industry when making certain types of changes to certain types of
dosage forms. In a similar manner, these documents provide a faster mecha-
nism for the introduction of a change that can lead to the realization of im-
proved quality of the drug substance and economic benefits for the drug
substance manufacturers as well as for the drug product manufacturers. In
general, the amount of testing that is necessary to support the change will be
the same as it is today, but the filing mechanisms will be less burdensome. For
example, a change that currently requires a prior approval supplement under
the regulations may possibly be reported in a Changes Being Effected supple-
ment or even in an annual report, depending on the change and the intended
use of the drug substance. In some situations, the amount of recommended
testing may actually represent an increase over that expected today but would
be compensated for by the more rapid introduction of the change as the result
of the reduction in the filing burden. The amount of information that should
accompany the submission, whether a supplement or an annual report,
should be the same regardless of how the change is reported.
BACPAC I will lead to regulatory relief for certain types of changes made
prior to the final intermediate. However, although the SUPACs were based on
scientific data gathered at several universities during research sponsored by
CDER, the philosophy of the BACPACs is based more on concepts developed
at the March 1997 workshop as well as on concepts developed by COER's
Drug Substance Technical Committee and the BACPAC I and II working
groups. A further reduction in the regulatory burden, both in terms of recom-
mended filing mechanisms and the amount and type of data that should be
included with any BACPAC submission, may be possible in the future based
on the results of research sponsored by the PQRI. The PQRI Drug Substance
Technical Committee has proposed two projects that will test the hypothesis
that a specification (tests, procedures, and acceptance criteria) can be devel-
oped that will allow certain changes to be made during the synthesis or man-
ufacture of the drug substance with a reduced filing mechanism over those
recommended in BACPAC I and II. The underlying principle in both BACPAC
I and BACPAC II is the assumption that it should be possible to make certain
changes that will not have an adverse impact on the identity, strength, qual-
ity, or purity of the drug substance or the quality of the drug product. This
principle involves the demonstration of the "sameness" of the pre- and
postchange material. The BACPAC I guidance presents a detailed discussion of
how and when the sameness of the impurity profile should be demonstrated.
Ideally, this should be shown at the earliest opportunity in the manufacturing
process. The second critical criterion is the demonstration that the physical
Postapproval Changes to Bulk Drug Substances 341
properties of the drug substance have not changed as a result of the change.
Again, the guidance provides a detailed discussion of how and when the
sameness of the physical properties should be demonstrated. It is possible that
the chemical structure should be recharacterized for certain process changes.
The BACPAC working groups accepted the recommendation of the
March 1997 workshop that the reduction of regulatory burden for early steps
in the synthesis would be the most beneficial to the drug substance manufac-
turers. This is why BACPAC I covers changes up to and including the final in-
termediate. Based on the comments received to the draft BACPAC I guidance,
the working groups decided to finalize BACPAC I before announcing the avail-
ability of BACPAC II for public comment. A draft BACPAC II had been pre-
pared and was in the initial stages of the clearance process within COER when
it became obvious that many of the comments received on BACPAC I were
germane to BACPAC II, as well. Further, based on the workshop conclusions, it
seemed appropriate to finalize the first BACPAC before expending additional
resources on the second one.
Once BACPAC I is finalized, work on BACPAC II will proceed. It is ex-
pected that the same concepts that are included in the first guidance will be
part of this latter guidance. At some point in the future, these guidances may
be combined into a single document covering all changes to drug substance
manufacturing.
13
VENDOR QUALIFICATION
AND CERTIFICATION
Ira R. Berry
Wockhardt Americas Inc.
East Hanover, New Jersey
The concepts and practice of "validation" have been applied in the pharma-
ceutical industry for many years. Validation has been discussed by the regu-
latory authorities and has been promulgated in Good Manufacturing Practice
(GMP) regulations since the mid-1970s (Berry 1981, 1988, 1993; Madan and
Komotar 1979; 21 CFR; FDA 1987; Berry and Nash 1993). These practices and
regulations have focused on finished dosage forms, traditionally tablets, cap-
sules, softgels, solutions, suppositories, creams, and other such pharmaceuti-
cal products. Little attention has been given to the validation of active
pharmaceutical ingredients (APis). This particular chapter will focus on the
activities performed by the manufacturer of a finished dosage form, in quali-
fying and certifying a vendor (manufacturer) of an API used to produce a fin-
ished pharmaceutical product. These APis can also be referred to as the drug
substances used in the manufacture of a drug product.
Considerable effort-in the allocation of resources, time, and expense-
is devoted to process validation by a manufacturer of pharmaceutical finished
dosage forms. Plant facilities, equipment, personnel, materials, and manufac-
turing and control procedures are factors that are included in a validation pro-
tocol and study. Requirements have been developing in recent years to extend
the validation process to include the manufacture of APis (Martinez 1994;
IQA 1992; PMA 1994; ISPE/FDA 1995; FDA 1998b; ICH 1998). This program
certainly makes good sense, as we can consider that process validation of a
pharmaceutical product would be invalid if the manufacture included the use
343
344 Validation of Active Pharmaceuticals Ingredients
of an API that may not have been produced following the intent of GMP or
that may have been produced by a manufacturing process that was out of
control.
DEFINITION OF TERMS
There are publications that describe process validation of pharmaceutical fin-
ished dosage forms, which enumerate and define the many terms used in de-
scribing that program (FDA 1987; Berry and Nash 1993). It is important here
to note and define some terms that are specific to APis. These terms already
have taken on different meanings to different people and must be standard-
ized for a discussion of their application to provide clarity and uniformity.
Vendor, supplier, distributor, and manufacturer are not terms that can be in-
terchanged in all cases. In simplistic terms, the "vendor" or "supplier" of an
API is the seller to a manufacturer of finished dosage forms. The "manufac-
turer" of an API may sell its product directly to finished dosage form manu-
facturers, in which case there would be direct contact between both
organizations, and the "manufacturer" would also be the "vendor" or "sup-
plier" as specified in the terms indicated above. Alternatively, the "manufac-
turer" of an API may sell its product to another company that sells to the
manufacturers of finished dosage forms. In fact, that API "manufacturer" may
sell its product to many "distributors" who supply finished dosage form man-
ufacturers. Also, each "distributor" may conceivably purchase the same API
from several"manufacturers." These scenarios have described the "manufac-
turer" of the API as a "vendor" to another company ("distributor") who is a
"vendor" to finished dosage form manufacturers. The term vendor is synony-
mous with the terms supplier and distributor. Thus, it is very possible that a
"manufacturer" of an API may not be the "vendor" or "supplier" to a finished
dosage form manufacturer.
Furthermore, it should also be kept in mind that a "manufacturer" of
APis purchases raw materials from organizations that can also be "manufac-
turers" or "distributors." In either case, again, the "supplier" is the firm from
whom the API manufacturer purchases raw materials. In this regard, it is
very important-when considering validation of an API-to establish the API
manufacturer-vendor relationship. It would be wasteful to qualify and certify a
vendor who may not be the manufacturer of an API and who may sell the
"same" API manufactured by several sources and when some of the API lots
may not meet all the established specifications. When certifying and qualifying
a "vendor," the process must be for a specific "manufacturer" of a specific API.
Agent is a term that is usually used to define a representative of a foreign
API manufacturer and who sells the API in the United States.
Qualification of an API vendor is the process whereby the vendor is ap-
proved by the finished dosage form manufacturer for a given API that will be
Vendor Qualification and Certification 345
QUALIFICATION/CERTIFICATION
PROCEDURE OVERVIEW
Every finished pharmaceutical manufacturer should have a written proce-
dure by which to qualify and certify an API vendor. If the vendor is not a
manufacturer, then the vendor should be qualified and certified for each
specific manufacturer. It is imperative that this procedure include all aspects
of the current regulatory requirements. It is not sufficient to simply pur-
chase an API for the first time and use it in a product lot for commercial dis-
tribution without a qualification/certification program, even though that
API may meet all of the raw material specifications and even though the API
may be compendia!.
Written specifications and test methods should be established for every
API that is used to manufacture a product. These specifications must be based
on the testing of material from a specific manufacturer(s) and not necessarily
a vendor-who may be a supplier and distributor for several manufacturers.
An example of a prototype API (raw material) specification document is
shown in Figure 13.1, to be used as a guide.
Qualification of the vendor from whom a finished pharmaceutical man-
ufacturer will purchase an API should be performed following a written pro-
cedure for that manufacturer. This Standard Operating Procedure (SOP)
should describe the various steps to be performed in qualifying vendors. The
procedure also should include a provision to certify a vendor, after it is qual-
ified, by categorizing each vendor based on credibility and history and by ex-
plaining the level of testing required by the finished pharmaceutical
manufacturer on an API lot sampling plan or time schedule basis.
Vendor Qualification and Certification 34 7
CERTIFYING A VENDOR
There are several reasons to qualify a vendor (i.e., manufacturer of API), and
these have been discussed in detail above. One of the benefits of this process
is that subsequent to vendor qualification, it may not be necessary to perform
full specification testing on every lot of a raw material on receipt; the process
then creates the need to certify a vendor.
A pharmaceutical manufacturer of finished dosage forms should have a
written procedure to certify and classify vendors, which can be used to de-
scribe abbreviated testing for APis that are vendor qualified. Attention should
certainly be given to the need for differences between actives and excipients,
and compendia! and noncompendial ingredients. The bases for abbreviated
testing are the level of agreement on test results between the vendor and
dosage form quality control laboratories and the degree of process control and
352 Validation of Active Pharmaceuticals Ingredients
MONITORING A VENDOR
At this point, vendor qualification has been completed and the vendor has
been certified and classified-in conformance to written SOPs. The next step
is to establish a documented program to monitor subsequent deliveries of the
subject material from the vendor. This operation should also be described in
a written SOP.
In monitoring a vendor, a program and schedule should be established
regarding abbreviated testing of the material. If every lot is fully tested against
the material specifications by the dosage form manufacturer, then there is no
Vendor Qualification and Certification 353
issue; however, there may be some tests that will not be performed on every
lot and that will be reported in the vendor's CofA. It is the decision of the
manufacturer to perform full testing "periodically," and this schedule should
be established in a written program. Special attention is focused on APis, non-
compendia! excipients, and excipients that are especially sensitive or critical
to the success of the manufacturing process to establish sound databases be-
fore abbreviating the testing requirements.
In the monitoring program, as well as in a routine testing program, it is
expected that all the dosage form manufacturer's material specifications will
be satisfied in the vendor's CofAs and by the manufacturer's quality control
laboratory. If any out-of-specification or failing result should be reported,
then an investigation should be conducted and a report written. If the out-of-
specification/failure result is confirmed, then consideration should be given
to requalifying the vendor. All of these procedures should be described in
written SOPs. It should be noted also that a written SOP for change control
should be in place so that written documentation, such as laboratory meth-
ods and specifications, cannot be changed without following a defined ap-
proval procedure. Furthermore, if initial material draft or tentative
specifications require change, and such change is supported by scientific data,
then consideration should be given to implementing the change through an
appropriate program.
VENDOR AUDITS
One critical step in vendor qualification is verification that the vendor should
be in compliance with the intent of GMP. This has been indicated above. One
of the problems faced by industry and the FDA is that currently there is no
cGMP regulation for drug substances or excipients. There are several move-
ments underway to develop guidelines; however, there is no official regula-
tory document at this time by which to measure cGMP compliance for a
manufacturer or a "vendor" as described.
There are many elements in an audit that is conducted by a dosage form
manufacturer (or regulatory agency) of the facility that manufactures an API
(i.e., elements that the API manufacturer should have in place in that opera-
tion). The person conducting the audit may want to use a checklist developed
for this purpose for two main reasons. (1) The checklist will include all areas
of the audit to be covered so that nothing will be forgotten. (2) Boxes on the
checklist can be marked, with brief comments that can be added by the audi-
tor, obviating the need for much time spent writing, and allowing for more
time to be spent observing the facility and asking plant personnel questions
in a dialogue. An example of the framework for such a checklist is shown in
Figure 13.3. Remember that this is only a recommendation of a few criteria
that are provided as food for thought.
354 Validation of Active Pharmaceuticals Ingredients
Documentation
QC/QA program
SOP manual
Personnel training
Master records
Rework procedure
Documentation
An organization that follows quality principles must rely on its systems of
documentation in order to maintain regulatory compliance. An API manu-
facturing operation must utilize written procedures that are followed to de-
scribe the manufacturing and control operation.
Vendor Qualification and Certification 355
Personnel Training
"People" are one of the major elements in a manufacturing operation. It is
very important that personnel be trained in the duties and responsibilities
that they are expected to perform. If personnel training is not conducted, fol-
lowing an explicit procedure, then there will not be assurance that a manu-
facturing and control process will be performed properly and consistently.
Detailed and complete process validation will not substitute for poorly
trained people who cannot perform a given operation in the same manner,
consistently, and who are not familiar with the procedures that they are
expected to follow. In fact, people may not even be aware that procedures ex-
ist for the functions that they are responsible to perform. Further, these pro-
cedures may not be clear or in sufficient detail and this may not be discovered
unless people are trained properly.
material and consider issues such as retesting and resampling. Also, there is a
need to investigate a failure and provide a written report to explain the devi-
ation-how it occurred and how to prevent it from recurring-and also jus-
tify the disposition of the batch in question. The FDA has issued a draft
guidance (FDA 1998a) to deal with this issue.
Cleaning Validation
One of the important elements of a validation program is cleaning validation.
The objective is to provide cleaning procedures (and agents) for equipment
and facilities to prevent cross-contamination of API products and the intro-
duction of foreign materials. This program is especially important for a man-
ufacturing operation that does not utilize dedicated equipment.
Stability Program
An API manufacturer should have an ongoing stability program in place by
which to establish expiration dating/retest date for bulk products. There
should be an SOP that describes this program. The program itself should be
based on the use of stability-indicating assay methods that are validated
and that consider degradants, process impurities, and residual solvents (FR
1996). The bulk product samples that are placed into stability testing must
be in the same design bulk container/closure system with the same mate-
rials of construction as those used for production quantities, but may be
of smaller size. Guides are available on this subject (FDA 1998d, 1998e,
1998f).
Control of Suppliers
Attention should be given to those critical raw materials used in the manu-
facture of APis and especially to any intermediates that are purchased. Just
as a dosage form manufacturer must pay attention to their suppliers of APis,
as part of their quality assurance (and validation) programs, so the API man-
ufacturer must turn to their suppliers of critical materials. Validation and sta-
bility efforts are expensive and time-consuming projects, and must indicate
control throughout the entire manufacturing cycle, from the production of
basic raw materials through the production of APis through production of
the dosage form.
Vendor Qualification and Certification 359
Distribution Records
An API manufacturer's documentation system must extend to distribution
records so that each shipment of each lot of each API product can be traced
to every customer shipped that lot. This documentation is especially impor-
tant in the event that a lot of API product is identified as being defective af-
ter it is quality control approved and shipped to a customer so that the lot can
be retrieved by the API manufacturer. An API lot can be found to be defective
if it should fail to meet its predetermined specifications or if any component
used to manufacture the lot is found to be defective to the extent that it im-
pacts on the quality of the API.
Safety Program
Just as for any manufacturing operation, an API manufacturer has invested a
good amount of capital in a facility, equipment, and personnel and has a need
to protect that investment. In addition, a manufacturer has a moral need
to protect its workforce. One important means to provide this protection is
that the API manufacturer should establish, implement, and monitor an in-
tensive safety program. This program should consist of SOPs, personnel train-
ing, and a committee to monitor the program. Sometimes overlooked as
being secondary to the operation of a plant to manufacture and sell product,
the prevention of workplace safety hazards that can result in disasters, such
as fire and flood, certainly demands as much attention. Also, the prevention
of absenteeism by providing personnel with safety equipment, a safe working
environment, and detailed training is a meaningful objective.
Calibration Program
It is very important for an API manufacturer to have a calibration program for
measuring devices used in production and laboratory instruments. This is yet
another example of a program that should be defined in the SOP system. A
manufacturing operation cannot be considered to be in control if the devices
used in production are not calibrated. For example, balances and scales, pres-
sure and vacuum gauges, thermometers, recorders, conveyors, refrigeration
systems, and water meters cannot be used in a manufacturing process, and es-
pecially in a validated manufacturing process, unless they are demonstrated
to be accurate in a program for routine calibration. Furthermore, we cannot
support the accuracy of laboratory test results unless the laboratory instru-
ments are shown to provide accurate results; an ongoing calibration program
is necessary in this case also.
THE AUDITORS
The discussions above have included the need for SOPs to cover many areas
of a manufacturing operation, including internal and external audits. There is
more than one type of audit of an API manufacturing facility, and this issue
will be addressed here. SOPs should enumerate "what" is to be audited and al-
lowed to be audited, "who" does the audit, and "how often" the audit is done.
This relates to audits done in-house by a department of the API manufacturer
that does not have direct responsibility for producing and testing/releasing
product (internal audits). Such audits can also be performed by a third party,
as an external function. In either case, responsibilities should be defined.
Written reports should be issued on the completion of an audit, deficiencies
should be taken seriously and followed-up and corrected. It is most important
that specific problems not be addressed but rather the systems that encom-
pass these problems be evaluated. These systems should be corrected, rewrit-
ten, or written as necessary to prevent problems. Individual problems are only
symptoms of more serious systems failures.
There are other audits that are performed, two of major importance be-
ing done by customers (i.e., dosage form manufacturers or agents) and by reg-
ulatory authorities. There should also be SOPs for these types of audits,
Vendor Qualification and Certification 363
explaining the system of areas that are permitted to be audited and other ar-
eas that may be proprietary and the responsibilities of API personnel in lead-
ing the audit team. It is especially important in this case, and also for
internal/ external audits, that API personnel be adequately trained in the
SOPs and their responsibilities. Poorly trained and unknowledgeable API per-
sonnel can cause a lot of damage in not providing correct information and
not representing the API manufacturer properly, in addition to the poor im-
pression created.
BE PREPARED
The best advice to be given in advance of an audit is to be prepared. An API
manufacturer should perform their daily operations as though an audit will
be conducted every day. The best preparation for no surprise in an audit is to
keep the operation under tight control and to train all personnel in their re-
sponsibilities. A manufacturer that does otherwise, and has loose control over
the plant, will encounter difficulty at some point in time (GMP Trends 1998a,
1999a-f; The Gold Sheet 1994, 1995, 1997, March 1999, April1999). The issue
will not be "if" an audit discloses a problem but rather "when" a problem will
be disclosed.
acceptable provided that the entire process has been described in the
master batch records and validated. It is unacceptable to perform
operations that are not described (in sequence) in the master batch
records for a validated process without first performing revalidation.
• The manufacturing procedure included in a DMF should be the same as
for the master and executed batch records. As above, the manufactur-
ing procedure used in routine production should be the same as the
one in the DMF and that has been validated. This includes the se-
quence of steps and the flow scheme for the final purification step.
• There should be written reports of investigation into product failures. It
is important to investigate a product failure to meet specifications
and to document that investigation-both as a corrective action
and to prevent recurrence. Investigation includes a review of batch
records for the out-of-specification batch and successful batches
and also a discussion with manufacturing, laboratory, and other ap-
propriate personnel.
• The lack of a formal procedure to track product complaints is observed
in many organizations. A written procedure is needed, with a cor-
responding log record and assigned personnel responsibilities.
• Adequate cleaning procedures are oftentimes not in place and validated.
This is especially important for nondedicated equipment and will
help prevent cross-contamination of different products.
• There must be a sufficient number of quality unit personnel in order to
establish and implement a quality assurance program. This obser-
vation is self-explanatory.
• Equipment calibration programs are sometimes not written and imple-
mented. Measuring equipment and instruments that are used in
production and laboratory operations should be calibrated rou-
tinely in a defined, written program to assure that they are func-
tioning properly. This includes devices such as thermometers,
gauges, speed of movement mixers and conveyors, and laboratory
instruments.
• No stated retest date or shelf life and no stability data are observations
that appear frequently in audits. Just as for finished dosage forms,
it is important to define a date after which laboratory testing
should be repeated to assure that an API has not undergone a
change, based on stability data.
• Poor labeling control is often an understated deficiency. Packaging with
the proper labeling is one of the most controllable phases of a man-
ufacturing operation, yet it is also an operation that results in a
Vendor Qualification and Certification 365
PREPARATION AIDS
There are many documents that are available and procedures and practices
that can be used to help provide the philosophy and framework for GMP to
an API manufacturer. Some of these have been discussed earlier in this chap-
ter, but a list is provided here for ready reference:
366 Validation of Active Pharmaceuticals Ingredients
REFERENCES
Berry, I. R. 1981. Process validation of raw materials. Pharm. Tech. 5 (2):38.
Berry, I. R. 1988. Process validation: Practical applications for pharmaceutical prod-
ucts. Drug Dev. Ind. Pharm. 14 (2 and 3): 377.
Berry, I. R. 1993. Process validation of raw materials. In Pharmaceutical process valida-
tion, 2nd ed. New York: Marcel Dekker, Inc.; p. 203.
Berry, I. R., and R. A. Nash, eds. 1993. Pharmaceutical process validation, 2nd ed. New
York: Marcel Dekker, Inc.
21 CFR. Code of Federal Regulations, Title 21, Parts 210, 211, and 314. Washington,
D.C., USA: U.S. Government Printing Office.
FDA. 1987. Guideline on general principles ofprocess validation. Rockville, Md., USA: Food
and Drug Administration.
FDA. 1990. Sterile drug process inspections. Program #7356.002A, FDA Compliance Pro-
gram Guidance Manual. Rockville, Md., USA: Food and Drug Administration.
Vendor Qualification and Certification 367
Fred C. Radford
Alert Consultants, Inc.
Byron Center, Michigan
From the time of ancient China's bureaucratic and centralized state control,
to today's open and empowering fourth or fifth wave of discipline, and from
simple tools and handicrafts to complex drugs produced with biotechnology,
the assurance of quality has always been a part of government, industry, and
society (Qiupeng et al. 1995).
As is true today, many innovative quality programs resulted from infor-
mal and voluntary efforts to create and meet competitive pressures. As is also
true today, an ever-growing government bureaucracy issued formal and im-
plicit regulations based on societal and government-mandated laws or de-
crees. Most people feel it is the role of government and industry with their
many supporting "quality assurance" or compliance systems to minimize the
likelihood of undesirable situations. We would like a risk-free environment so
we can live in tranquility and the pursuit of happiness.
But ... the problem ... is us. We have the primary inputs to
processes and also the propensity for error.
369
370 Validation of Active Pharmaceutical Ingredients
bring all into compliance, order, and tranquility. But as glimpses of insight
surface, so does the idea that we have found the problem, and it is us. We
have the primary inputs to processes and also the propensity for error.
Look at the U.S. quality during its beginnings. The early settlers in Amer-
ica carried on basic manufacturing techniques largely based on those devel-
oped over many centuries in Europe. After gaining independence, the
colonies gradually moved from agriculture production to implement and im-
prove on these manufacturing capabilities. Along with the skill itself, the mas-
ter craftsman passed on to an apprentice his or her particular method of
quality control, usually some form of inspection Ouran 1995).
Taylor's system of "scientific management" gave rise to the
use of independent inspection departments early the last
[1900-2000] century Ouran 1995).
With seemingly unlimited natural resources and a strong entrepreneur-
ial spirit, these new Americans soon entered the Industrial Revolution that
had also begun in Europe. We saw the simultaneous introduction of the cot-
ton gin, interchangeable parts, and new firearms. American innovation
through Frederick Taylor's system of "scientific management" (he did not call
it scientific) gave rise to the use of independent inspection departments early
in the last century Ouran 1995). Taylor's unconventional system of mass pro-
duction played a major part in U.S. productivity leadership, especially as
adopted by Henry Ford.
Today where quality assurance or control is still perceived as a
force or entity distinctly outside the production pathway, we still
find an obvious or sometimes subtle adversarial relationship.
But this system also had a long-term negative effect that we feel to this
day. It separated designers and engineers, in development and planning, from
those supervisors and workers who were responsible for the execution of
manufacturing. A rivalry developed between the inspector and the inspected.
This adversarial relationship continues to have significant negative effects in
product development and manufacturing as well as overall product quality.
Today, where quality assurance or control is still perceived as a force or entity
distinctly outside the production pathway, we still find an obvious or some-
times subtle adversarial relationship.
Inspection will undoubtedly always be with us in some form
or other, by manual and high-tech approaches.
For the past decade, attempts to eliminate this inspector-inspected sepa-
ration and the sometimes bitter opposition it fostered have been the goal of
professional management, regulatory agencies, such as U.S. the Food and
Drug Administration (FDA), and the regulations and policies they promul-
gate. Inspection will undoubtedly always be with us in some form or other,
Quality Assurance Systems 37:1.
both by manual and high-tech approaches. But inspection has taken a sec-
ondary position to the recent emphasis on building quality into processes and
end products. We see transition into a worldwide movement toward total
quality management (TQM), a process and systems approach, and continuous
improvement.
In the 1960s, the United States was initially shocked into a refocus on
quality. After the WWII production experience, it seemed that nothing could
stop us. We were "the only game in town." But at the same time a new concept
of total quality and continuous improvement was being taught to the recover-
ing Japanese by American statisticians W. Edwards Deming and Joseph M. Ju-
ran. Several decades later, U.S. markets were flooded by Japanese products, and
major companies began to ask, "If Japan can do it, why can't we (NBC 1980)?"
Deming and others led the quality march through their speaking, writ-
ing, seminars, and hands-on guidance of industry clients. Many industry
leaders surged toward this new direction. Philosophies, definitions, and tech-
niques were developed with a myriad of acronyms-JIT (just in time), TQM,
TPM (total process management), CIS (continuous improvement systems).
Many U.S. industries were quick to adopt and improve on TQM. The concepts
of verification of true quality gradually shifted from inspection data to the
validation of processes and the use of statistical process control (SPC). Simi-
larly, the bearer or owner of the responsibility for quality throughout the pro-
duction cycle changed. According to Juran,
(PIA) first published voluntary GMP guidelines in 1968. The World Health Or-
ganization (WHO) published its GMP guidelines in 1969. These were followed
worldwide outside the United States. The Pharmaceutical Inspection Conven-
tion (PIC) was established in 1970 by the European Free Trade Association
(EFTA) and followed the WHO text in its GMP guide. The most recent WHO
guidelines are a mix of guides from the European Economic Community
(EEC) and the ISO 9000 quality system guidelines of the International Orga-
nization for Standardization (Heir 1994).
The various international GMP requirements, objectives, and foci are
similar but differ considerably in their legal status. Some are legally binding,
and some are in the form of guidelines. Comparison is difficult, however, be-
cause of the varying rigor of implementation by industry and unlike relation-
ships between companies and the government agency inspectors. However,
for the U.S. domestic products and foreign products for import, it is still the
FDA that sets the standards. Manufacturers of active pharmaceutical ingredi-
ents (APis) must keep current with the FDA's inspection program and the strict
enforcement of GMP as linked with their New Drug Application (NDA) and
Abbreviated New Drug Application (ANDA) preapproval inspection. The FDA
has made GMP the major issue for the pharmaceutical industry (Heir 1994).
The FDA's drug GMPs, as currently applied to APis, along with
their much more specific 1998 draft guidance on APis, place
most of the emphasis on the critical parts of the process for
producing a quality product.
But the difference in this long list of rapidly developing regulatory con-
trols is more than status or expected level of enforcement. A key distinction
that must be kept in mind is the compliance approach, or the point of appli-
cation of the varying quality systems and standards. ISO 9000, for example, is
primarily applied to the product produced, with only a minimal emphasis on
how this is done. The ISO has not required a new corporate philosophy or cul-
ture change. If your process is very good at a certain point, you can set a spec-
ification and measure or test for compliance. This may meet the customer's
delivered product specification. You may appear to have a good process that is
under control, even though a significant quantity of end product is rejected
through some form of inspection. Certification may be achieved even though
competence is lacking. Once certified, a company can forget about continu-
ous improvement (Hawkins 1996). In contrast, the FDA's GMPs as currently
applied to APis place most of the emphasis on the critical parts of the process
for producing a quality product. Required quality control and auditing prac-
tices should result in improvement of formulations and processes. The FDA
places less weight on inspection criteria.
In the last two decades, new combinations of social, economic, regula-
tory, and competitive pressures have become major challenges for the phar-
maceutical industry. With the growing additional emphasis on reducing
healthcare costs and the expiration of many patents, both the industry and
374 Validation of Active Pharmaceutical Ingredients
organization have the same needs; and (5) the FDA's recent initiatives are
based on the quality management and validation of processes and only sec-
ondarily on in-process and endproduct inspection.
... ...
The new way is:
concerning practically all aspects of the business (Heir 1994). This supports
the need for TQM.
And now in the past several decades, customers have taken the quality
issue to a new level beyond the availability, safety, and efficacy of the end
product. They want companies they can trust. Customers want agreements
and long-term relationships infused with trust and dependability (Popcorn
1991). They want to see Dr. Stephen Covey's "7 habits" in action.
For most companies that hold compliance and change as a high priority,
the interpretation of GMP in the strictest sense is secondary to the way in
which these requirements are currently applied by the FDA. In fact, even
when the FDA seemingly incorrectly interprets GMP, or as with the recent
Quality Assurance Systems 381
Barr decision bases its application on a judge's ruling, the reasonable thing to
do as a company is go along with it. When most companies follow an inter-
pretation, even a questionable one, the FDA considers it state of the art or cur-
rent GMP. The new requirement will hold until clearly shown in a data-based
approach as no longer necessary, or when a more effective alternative is pre-
sented and scientifically defended.
Many companies still try to "just get by." Others have been over-
whelmed by the rapid pace of change over the last decade and have or will
382 Validation of Active Pharmaceutical Ingredients
remain in a catch-up mode for some time. It seems unfortunate that some will
never catch up. And that fact raises the potential of more incidents of failure
and further damage to an otherwise healthy industry.
The international inconsistency of regulations and enforcement men-
tioned above only adds to the difficulty. Regulatory inspections of manufac-
turing facilities may last hours or months, may be announced or
unannounced, may be formal or relatively informal, may be by qualified or
unqualified inspectors, or they may not take place at all in some countries.
The penalties for noncompliance may include the following:
• Practically none
• Withdrawal of manufacturing licenses
• Withholding of registration approvals
• Prosecution of the company or individuals often under criminal
rather than civil law (Deleers 1994)
In the United States, the FDA's enforcement powers were significantly
increased by the introduction of the PAl program, linking the NDA or ANDA
approval to GMP compliance. Withholding an approval is a very severe
penalty and can be very damaging to a company. The FDA has tied this au-
thority and priority to the API manufacturer as a key player in this drug li-
cense approval.
The key objectives of the FDA's PAl program were stated as follows:
• Evaluation of the establishment's compliance with cGMP require-
ments, including coverage of the specific batches used to demon-
strate bioequivalence
• Evaluation as to whether the establishment has adequate facilities,
equipment, procedures, and controls to manufacture the product
in conformance with application commitments
• Audit of the accuracy of the biobatch manufacturing and testing
information submitted with the application
• Collection of a sample of the biobatch from the bioequivalence test
laboratory (Heir 1994)
PAis are rigorous. The FDA's expectations are high. This can be seen by a
thorough review of the "bulk inspection guide" and the new draft guidance
(FDA 1998) and by the number of companies receiving a refusal to approve.
These inspections are specific to the NDA and challenge the integrity andre-
producibility of the API specifications in the NDA or ANDA. The FDA also ver-
ifies that the API process is as described in the Drug Master File (DMF)
submitted to the Center for Drug Evaluation and Research (CDER) in
Rockville, Md. If the data do not satisfy the FDA, then the investigator will
send a recommendation to CDER that the application for a specific API be
Quality Assurance Systems 383
withheld from approval. Corrective action may be taken, but the time lost to
turn this type of situation around can have enormous economic conse-
quences (Heir 1994).
In conclusion, (1) quality must be defined in terms of corporate philoso-
phy, the specific standards the company decides to apply, and the needs of
the customer; (2) a TQM emphasis from top management makes implementa-
tion easier and the whole organization a more enthusiastic and effective
team; (3) a strategy of minimal meeting of requirements is of high risk and
leaves the company vulnerable to an outside auditor's strong criticism, which
is untenable even with a limited customer demand base; and (4) a new level
of ethical expectation within a company, and by numerous customers, ex-
ceeds a mere focus on expected quality characteristics.
VP Quality Assurance
Compliance Manager
VP for Quality
mean broad responsibility over the entire quality function, as defined on page
S1 of the FDA's guidance (FDA 1998). In other companies, the term quality as-
surance is used in a narrower sense to designate the specialized activities of
conducting audits and preparing summary reports for managers (Plettenberg
1994). There is also a sense in which the term total quality is preferred to total
quality management, as the latter may imply that only management has con-
cern for quality.
Consider TQM as just one of many variously defined quality terms that a
company needs to consider. Terms vary and so do philosophical approaches
and checklists for methods and tools. For example, under TQM, on which
philosophy will a company base its actions? Which criteria will they plan to
satisfy? Deming's 14 points? Juran's list of criteria? Others? What about ISO
9000? Lastly, do we "reengineer" for new processes or new facilities? As
we move closer to U.S. fundamental practices and requirements, should we
also look at the ICH requirements and the European Community (EC), the
Quality Assurance Systems 385
Japanese, and other GMP programs? What about Far Eastern or Oriental pro-
grams? A clear mission and a broadly based team effort will be necessary what-
ever the selected criteria.
The application of existing regulations to APis is enigmatic as well. The
interpretative extensions and variety of enforcement emphases are still a
moving target. Most FDA field managers and investigators have been quite
clear recently in stating their position that current GMP regulations for fin-
ished dosage forms found in 21 CFR Parts 210 and 211 are applicable to APis
since the FD&C Act states that all"drugs" are covered by cGMP. Other FDA'ers
have agreed with the GMP preamble text itself, which refers to bulk drug
GMPs being developed in another time and place or published as a Guidance
for Industry (FDA 1998). And finally, about 60-80 percent of our drug sub-
stances are imported, adding to the definitional problem the differences in
language and cross-cultural exchanges.
Whatever the interpretation inside or outside the FDA, the finished
dosage form GMPs and this new very specific guidance, as well as guidances
covering inspections and validation, are being applied vigorously to API man-
ufacturing today by the FDA. As mentioned above, the FDA's leverage is huge,
as this enforcement is tied directly to the ANDA/NDA PAl program and covers
APis, excipients, contract labs and facilities, and any other facilities listed in
an NDA.
In summary, top company management must first bring into focus its
overall purpose and strategy for the long term. This begins with its intended
market and available resources. For example, if a company intends to market
APis in the United States, the requirements are currently fairly well defined. If
the market also includes the EC or Japan, the differences and additional re-
quirements, even if only in documentation formatting, must be determined
and made part of the implementation plan. Adding compliance programs
later can be very difficult.
TANGENT CONSIDERATIONS
If the APis under consideration include those where contamination or innate
toxicity is of much greater concern, this presents an even greater challenge
(e.g., antibiotics, cytotoxics, steroids, biologicals, pesticides, herbicides [Gins-
bury and Bismuth 1994]). Likewise, if the current product line includes excip-
ients or inactive ingredients, this must be factored into the overall equation.
Secondly, if customers are requesting ISO certification, for example,
other terminology, documentation, or systems must be part of the implemen-
tation plan. These are considerations beyond our scope. However, it should be
noted that most of these approaches prescribe a leadership philosophy and
the type of culture that is desirable from the standpoint of the primary cus-
tomer, the FDA, and the particular country's culture from which employees
will be drawn.
386 Validation of Active Pharmaceutical Ingredients
And lastly, the Quality Assurance unit, however organized with respect
to product testing or compliance activities, is assigned authority not only to
assure that all of the actions required under cGMP are being taken, but that
the quality assurance and control departments are performing in compliance
with their organizational responsibilities.
Change is the primary context and goal of all quality programs. The
FDA's new guidance devotes several pages to its scope (FDA 1998). It must be
given a top priority in the corporation. Change, whether reactive or proactive,
should be oriented toward continuous improvement in products and
processes in the context of a continuous monitoring of regulatory and cus-
tomer requirements. Change is the greatest challenge in our environment,
and we need to give it appropriate priority. Organizations with management
systems engineered for a quality outcome must have change as their primary
goal as an extension of continuous improvement. Leadership and an appro-
priate corporate quality philosophy are key elements in the implementation
of such a TQM system. As noted above, there are many different definitions of
TQM. Variations in the detailed formulations occur from year to year. One
author (Cohen 1995) lists the following definitions of the seven major aspects
ofTQM:
1. Leadership
2. Information and Analysis
3. Strategic Quality Planning
Quality Assurance Systems 387
full text information is available. Add to this the challenge of keeping it cur-
rent and identifying the changes, for example, when the FDA "posts" an up-
dated version on its Web page.
A second and critical part of the information element of a quality pro-
gram is membership in trade associations and, minimally, the attendance by
regulatory. and quality people at periodic updates and technical committee
meetings. The general updates on industry changes are critical for planning
and continuing compliance. Involvement in scientific committees is for in-
formation, but, more importantly, for the making of contributions to the so-
lutions of shared problems. Such contributions can be extended or slanted for
maximum benefit to each individual company.
Trade associations are also helping companies by developing their own
specialized CO-ROMs and Internet Web sites for the purpose of listing key
documents, schedules, and announcements. These systems usually include
message boards or "listservs" for all members to browse, interact, and solve
problems. You list your question, and then wait usually a short time to read
one or more replies from your peers. The American Society for Quality (ASQ),
for example, maintains an Internet Web site and a CD-ROM containing the
full text of previous years of their Progress magazine. The Nonprescription
Drug Manufacturer's Association (NOMA) has placed all of the historical over-
the-counter (OTC) drug review documents and numerous other FDA and in-
dustry publications on CD-ROM. Other organizations will likely follow suit
with back issues of newsletters, press releases and other relevant, though
presently archived, documents. Full text commercial services such as News-
page.com allow keyword or phrase searching of key pharmaceutical trade
journals, such as "the Pink Sheet" for as little as $29.95 a month. For added
convenience, Newspage lets you set up a keyword profile that will automati-
cally search each day's new articles and send headlines or full text to your E-
mail account.
Regulatory and technical seminars and meetings covering general or
very specialized regulatory, quality, and related technical topics occur
throughout the year. Networking at these gatherings of industry colleagues
can be extremely beneficial to quality staff. No person or company is an is-
land-these meetings are a must for either personal representative attendance
for the larger API producers, or by a link to customers, suppliers, consultants,
or trade associations. Another option is to buy tapes or proceedings from such
meetings. This information and material should be reported on by a reviewer
in as much detail as possible. Responsible managers should study, analyze,
communicate, and implement relevant changes. For complex issues, copies of
reports and proceedings may be indexed, archived, or scanned into databases
for future use as needed. As you perhaps suspected, most of these conferences
are now listed on the Internet by category, date, and location.
An aggressive company will maintain a library of these materials that is
easily accessed. Doing this up front can save money in the long run that may
Quality Assurance Systems 391
be spent not only in finding answers but in knowing the questions. Money
saved in consulting and legal fees can quickly and greatly exceed the cost of a
highly organized professional secretary, documents clerk, or even a profes-
sional librarian.
Depending on the product line and company size, it may be wise to de-
velop a working relationship with a reputable and experienced law firm. Over
time, teach them all the ins and outs of how you do things. When a situation
gets "sticky," an experienced regulatory lawyer can be of great help in prob-
lem solving and decision making. We pay them well to know the subtle con-
nections among the legislation and case law, regulations, and cGMPs. In that
same situation, an outside attorney can perform an audit of your company's
systems, and his or her findings are protected under attorney-client privilege.
A good firm is usually found by word of mouth, by attending a regulatory
conference or training program, or perhaps by "surfing the Internet."
Another important information source is your customers. Part of there-
lationship with customers is to know their exact needs. Sharing regulatory
and quality expectations from the product end is an important role for cus-
tomers. It is critical to put in writing in as detailed manner as possible the in-
formation you will both need, monitor, and share. This is fundamental to
TQM. It is just a part of a corporate information system which in today's
world is almost limitless in what support it can provide.
Many of the companies producing APis on a contract basis would be
considered "small businesses" by U.S. standards. In the last few years, they,
along with the rest of the pharmaceutical industry, have been in a continuous
catch-up mode as the FDA radically changed its posture, expectations, and
methods of inspection. As stated above, the most critical factor in this agency
change was the PAl tied directly to the approval of an NDA or ANDA. During
these crucial inspections, the currency and accuracy of DMFs and the ability
of the plant described to produce finished materials are the key reasons for
FDA acceptance.
To other sectors, it seems that such broad changes have decreased in fre-
quency, with issues and changes occurring now only in peripheral or highly
specialized areas of products. At a recent manufacturing controls industry
meeting, it was observed by many that this was the first meeting in half a
dozen years that focused almost entirely on the future and improvement
possibilities and new technologies as opposed to sorting through a "large
bag" of compliance and technical problems. Now there is an opportunity for
each company to take both a futuristic, an environmental, and an inward
look. And with that begin to plan for improved quality through marginal im-
provements, for the installation of a total quality system, and, in some cases,
a total reengineering of old and archaic processes. The goal is to have a sys-
tem in place that will satisfy the FDA when they come in on a preapproval
inspection. Reasons for the FDA to recommend withholding of approval are
listed below:
392 Validation of Active Pharmaceutical Ingredients
~ API ~
~ Q ~
u
~ A ~
~ L ~
I
~ I
~
~ T ~
y
~
~ s ~
y ~
s
~ T
~
~ E ~
~ M
Quality Assurance Systems 395
REFERENCES
Adamson,]. R. 1992. An approach to validation. Pharmaceutical Engineering (Septem-
ber/October): 16-22.
Bajaria, H.]., and R. P. Copp. 1991. Statistical problem solving: A team process for iden-
tifying and resolving problems. Garden City, Mich., USA: Multiface Publishing
Company.
Barr, D. B. et al. 1993. FDA regulation of bulk pharmaceutical chemicals production.
Pharmaceutical Technology (September): 54-70.
Bongiovanni, ]. ]. 1994. Continuous improvement: A strategy for implementation.
Drug Information Journal 28 (4):943-948.
Cohen, L. 1995. Quality function deployment. Reading, Mass., USA: Addison-Wessley
Publishing Company.
Covey, S. R. 1993. The seven habits of highly effective people (audiotape). Provo, Utah,
USA: Covey Leadership Center, Inc.
Deleers, M. 1994. From quality control to total quality management: A logical evolu-
tion. Drug Information foumal28 (4):917-920.
FDA. 1991. Guide to inspection of bulk pharmaceutical chemicals: Materials and Training
Aids for investigators. Rockville, Md., USA: Food and Drug Administration, Center
for Drug Evaluation and Research.
FDA. 1998. Guidance for industry: Manufacturing, processing, or Holding active pharmaceu-
tical ingredients. Rockville, Md., USA: Food and Drug Administration.
Ginsbury, K., and G. Bismuth. 1994. Compliance auditing for pharmaceutical manufactur-
ers. Buffalo Grove, Ill., USA: Interpharm Press, Inc.
Hawkins, P. 1996. Is ISO 9000 diminishing the Baldridge Award? Quality Management
1904:2.
396 Validation of Active Pharmaceutical Ingredients
Heir, R. S. 1994. Good manufacturing practice: An historical overview and actual sta-
tus. Drug Infonnation Journal28 (4):957-963.
NBC. 1980. If Japan can ... why can't we? Executive director, Reuven Frank (videocas-
sette, 80 min.). New York: National Broadcasting Company, Inc.
ICH. 1997. Internationally hannonised guide for active phannaceutical ingredients: Good manu-
facturing practice. Geneva, Switzerland: International Conference on Harmonisation.
Juran, J. M. 1995. A history of managing for quality in the United States of America. In
A history of managing for quality, edited by]. M. Juran. Milwaukee, Wis., USA: Qual-
ity Press.
Latzko, W. ]., and D. M. Saunders. 1995. Four days with Dr. Deming: A strategy for mod-
ern methods of management. Reading, Mass., USA: Addison-Wesley Publishing
Company.
Meyer, P., and M. Korteweg. 1994. Introduction: Quality management in pharmaceuti-
cal development: From molecular design to drug approval. Drug Infonnation Jour-
na/28 (4):915-916.
Plettenberg, H. D. 1994. Quality-related terminology in "good practice" regulations
and ISO standards. Drug Infonnation Journal28 (4):921-929.
Popcorn, F. 1991. The Popcorn Report (audiotape). New York: Simon & Schuster, Inc.
Qiupeng, ]., C. Meidong, and L. Wenzhao. 1995. Ancient China's history of managing
for quality. In A history of managing for quality, edited by]. M. Juran. Milwaukee,
Wis., USA: Quality Press.
Weissinger, J. 1994. A systems approach to quality auditing. Drug Infonnation Journal
28 (4):1085-1087.
15
CLEANING FOR ACTIVE
PHARMACEUTICAL INGREDIENT
MANUFACTURING FACILITIES
William E. Hall
Hall and Associates
Winterville, North Carolina
REGULATORY REQUIREMENTS
An important aspect of cleaning in API facilities is the regulatory expectations.
These regulations drive cleaning programs in the entire pharmaceutical indus-
try, including API facilities. Regulatory requirements are very dynamic and
may change considerably from year to year. The current Good Manufacturing
Practices (cGMP) Regulations continue to change as various guidelines,
397
398 Validation of Active Pharmaceutical Ingredients
guidance documents, and amendments are issued by the Food and Drug Ad-
ministration (FDA). Since pharmaceutical products are shipped internation-
ally, there is a desire that global regulations be developed. To this end, the
International Conference on Harmonisation (ICH) is addressing global require-
ments for the manufacturing, packaging, and holding of APis. Undoubtedly,
the subject of cleaning will be addressed in these forthcoming regulations.
However, many differences currently exist both in the regulatory requirements
of different countries and cultural differences. These differences will require
years of negotiations before a single set of standards will be finalized.
In the interim, the FDA has published a guideline document (Guide to In-
spection of Bulk Phannaceutical Chemicals, 1991) that, along with the cGMP
Regulations, is used as the official basis for current inspections. In this con-
text, the term bulk phannaceutical chemicals (BPCs) applies to APis. This docu-
ment specifically states, "There are basic differences between the processes
used for production of BPCs and the processes used for the production of fin-
ished products." These differences will be apparent in the cleaning processes
as well as the manufacturing process. However, many inspectors continue to
note in their presentations that the present cGMP regulations do not distin-
guish between dosage forms and BPCs.
Other sections of this document instruct the FDA inspector to evaluate a
BPC facility for the potential for cross-contamination from any source as well
as the relative ease and thoroughness of cleanup.
The BPC guideline also addresses the need for detailed cleaning proce-
dures, sampling plans, analytical methods, and cleaning limits, and the
reader is referred to this document for the specific statements on these issues.
However, these concepts and requirements will be incorporated throughout
this chapter.
One of the most significant sections of the BPC guideline is the section
dealing with limits. The guideline states that residue limits should be "practi-
cal, achievable, and verifiable." This is very encouraging as opposed to requir-
ing that a level of zero residue be achieved, which is impossible to achieve in
actual practice because of the tremendous sensitivity of modern analytical
methods. This concept will be expanded in a later section of this chapter.
Another document that addresses cleaning in an active ingredient facil-
ity is The Manufacturing, Packaging, and Holding of Active Phannaceutical Ingre-
dients. This document was issued by the FDA in 1998 and was issued as a
"discussion document" not for implementation. Although not official, this
document embodies the current thinking of the FDA regarding the expecta-
tions for controls for the production of APis as well as the cleaning processes
associated with them. This document includes sections on equipment clean-
ing and maintenance procedures, equipment cleaning methods, and clean-
in-place (CIP) methods. The most significant section of the document in
regard to cleaning is titled "Validation of Equipment Cleaning Methods."
This section states "equipment cleaning methods should be validated, where
appropriate." The document recognizes that the various purification and
Cleaning for API Manufacturing Facilities 399
a process, whereas in other parts of the facility, equipment may be used for
multiple products. This is important to the FDA and will be an early "up-front"
question of the inspector. It is also important for the manufacturer of actives
to give some thought to this concept in order to develop an appropriate clean-
ing program that addresses areas where cross-contamination can occur.
It is an FDA requirement that separate facilities be used for the manufac-
ture of penicillin and cephalosporins. It is also encouraged that separate facil-
ities and air handling systems be used for the production of certain steroids,
alkaloids, certain hazardous or toxic drugs, pesticides, chemicals, and/or start-
ing materials.
In this context, it is desirable at an early stage of developing a cleaning
program to develop a matrix of equipment that demonstrates what products
may potentially be run in the equipment. Table 15.1 demonstrates a simple
matrix for a given manufacturing module. These matrices are valuable for giv-
ing an overall preliminary review of a facility prior to creation of a master
plan. Much valuable information can be gained from a matrix. It allows the
viewer to easily identify the most likely points of cross-contamination. For ex-
ample, by review of the matrix in Table 15.1, it can be seen easily that the
filler is used only for a single product, Product C, and is thus a dedicated piece
of equipment. As dedicated equipment, the cleaning program for this product
would be minimal or at least much less stringent than for the reaction vessel,
since the latter is involved in four products and represents a major potential
source of cross-contamination.
Another valuable use of the matrix is to determine quickly if any piece of
equipment is being overlooked in establishing the cleaning program. A later
section of the chapter discusses the "worst case" approach, whereby a single
product is selected to represent a group of products. This approach allows the
viewer to determine if, by choosing a single product, any piece of equipment
is overlooked, and thus there might be no data developed to indicate the
equipment could be cleaned. It is highly desirable to have at least some data
Reaction Vessel X X X X
Holding Tank X X X
Crystallizer X X X
Grinding/Screening X X
Filler X
Cleaning for API Manufacturing Facilities 401
on all the equipment in a facility. Thus, if the worst case product did not con-
tact an infrequently used piece of equipment, it would be desirable to choose
an additional product that was actually run in the equipment not covered by
the primary worst case product. Samples could be taken and assayed for the
secondary worst case product after cleaning to verify that the equipment was
suitably cleaned by the cleaning procedure. Using this approach would guar-
antee that there was actual cleaning data for all equipment and that no equip-
ment was missed by the primary worst case approach.
An earlier section noted that manufacturing processes for APis differ signifi-
cantly from those for dosage forms, i.e., finished pharmaceutical products.
This section will expand on and explain these differences in more detail.
Table 15.2 shows a comparison of the manufacturing processes for APis and
dosage forms.
The differences between APis and dosage forms illustrated in Table 15.2
have a major influence on cleaning programs and procedures developed for
APis. Since the manufacture of APis involves chemical synthesis, the potential
cleaning residues may contain precursors and by-products, in addition to ac-
tives and residual solvents. Since any cleaning program must first identify
what potential contaminants are present, there are generally more potential
contaminants in API processes than for dosage form manufacturing. In addi-
tion, the precursors and by-products often have medical or toxicological activ-
ity in the human body and, thus, their presence as a contaminant is more
serious than an excipient residue from a dosage-form manufacturing situation.
Table 15.2 also indicates that purification is an important part of the
manufacturing process for APis. Typically, chemical reactions occur in the early
steps, and the final steps are a combination of recrystallizations, filtrations,
and other purification steps. Since residues from early steps may be subse-
quently removed by the purification in the later steps of the process, cleaning
requirements should be more flexible in the early stages of the manufacturing
process and less flexible (i.e., more stringent) in the final stages of the process.
Level 1 Cleaning
Level 1 cleaning is used only between steps in the same manufacturing process.
For example, in the manufacture of pseudoephedrine, there may be five steps,
and the overall process could be represented as a simple flow diagram.
Step A ~ Step B ~ Step C ~ Step D ~ Step E
If, for a given piece of equipment, on a specific occasion, step A of the
first batch in a campaign was to be followed by manufacturing a second batch
(i.e., a repeat of step A for a second identical batch of the same product), then
a level 1 cleaning would be required.
Level 2 Cleaning
Level 2 cleaning is used when cleaning between steps in the same manufactur-
ing process. In the above example, a level 2 cleaning would be used if step B
was to be performed immediately after step A for the same product line (pseu-
doephedrine in this case). The same would be true if step D for pseudo-
ephedrine was carried out after step C for pseudoephedrine, step E after step D,
and so forth. In all these cases a level 2 cleaning would be used if no other
product were manufactured in the equipment between the two steps involved.
Level 3 Cleaning
A level 3 cleaning would be performed when cleaning after an intermediate or
final product step of one product in preparation for production of an inter-
mediate step of another product. As an example, consider the manufacturing
Cleaning for API Manufacturing Facilities 403
Level 4 Cleaning
A level 4 cleaning would be used when cleaning after any intermediate or fi-
nal product step of one product in preparation for production of a final prod-
uct step of another product. In the example above for the level 3 cleaning, if
step C for pseudoephedrine was followed by step D for guaifenesin, a level 4
cleaning would be required. The important difference between the level 3 and
level 4 cleaning is that in the latter case, the next production will be for a fi-
nal product step.
Philosophy of Cleaning
The four levels of cleaning would differ in the thoroughness of the cleaning
process, the cleaning conditions, the level of verification of cleaning, and the
level of risk associated with a potential contamination in the order:
NATURE OF CONTAMINANTS
It is very important to know the nature of the potential contaminants in-
volved in the manufacturing of APis. Many of the potential contaminants are
highly reactive chemical compounds that were chosen as starting materials
largely because of their highly reactive chemistry. It is important to remember
that the same properties that make a chemical highly reactive in the process
reactor also make the chemical highly active from the biological standpoint
in the human or animal body. It is generally true that the more chemically ac-
tive materials will also be more toxic to the patient. It is also important to
note that potential contaminants may be either starting materials (precursors)
or they may be by-products of the various chemical synthesis reactions, ac-
cording to the general scheme:
CLEANING TECHNIQUES
There are three types of cleaning used in API facilities: clean-in-place (CIP),
clean-out-of-place (COP), and manual.
CIP can be either controlled by automated programs or manually con-
trolled. CIP tends to be very reproducible and consistent and is readily vali-
dated. Even though a CIP system may be used, cleaning validation is still a
requirement. Samples must be taken, analyzed, and results documented.
After validation of the CIP cleaning process, suitable documentation
must be maintained that demonstrates that critical parameters, such as tem-
perature and rinse cycles, are still being achieved on a daily basis. These latter
records are typically incorporated into the batch record documentation. The
hardware and software controlling the cleaning process must also be vali-
dated.
COP is the term used when equipment is disassembled and taken to a
central washing machine. The washing equipment also requires validation to
Cleaning for API Manufacturing Facilities 407
demonstrate that the machine achieves the proper temperatures and cycle
times and that detergent is dispensed in the proper amounts. An inherent ad-
vantage to this type of cleaning is that the equipment is disassembled during
each cleaning event and, thus, can be visually inspected during the reassem-
bly process. However, the loading pattern of equipment into the washing ma-
chine should be taken into account in the development of protocols for this
type of equipment since larger pieces of equipment can "shield" other pieces
and prevent adequate exposure to the cleaning solutions.
Almost all API facilities have at least some manual cleaning processes.
While some may argue that manual cleaning processes are not validatable,
the consensus opinion of experts is that manual cleaning processes are capa-
ble of and must be validated. The key issue for manual cleaning is the level of
detail in the cleaning procedures themselves and the quality of the training
program. Most difficulties for manual cleaning processes can be traced back
eventually to inadequate training.
As with all validated processes, it is important that the processes not be
changed once they are validated. A subtle change in a wash temperature, cy-
cle time, detergent, or drying condition can undermine the validated clean-
ing process. Any change in any of these parameters should be subjected to a
change control process for evaluation of validation impact and possible
revalidation.
SAMPLING
There are many different types of sampling for cleaning purposes. There are
swab sampling, solvent rinse sampling, rinse water sampling, placebo sam-
pling, sampling of following products, direct surface monitoring, coupon sam-
pling and other methods that are combinations of these types. Even within a
given category of sampling, there are subtypes of sampling. For example, there
are dry swabs and wet swabs that are moistened with water or other solvent.
However, the list of sampling methods acceptable to the FDA appears to
have been reduced to swab sampling, rinse sampling, and solvent rinse sam-
pling (since these terms are referred to in the various inspection guides uti-
lized by FDA inspectors).
The FDA has a strong preference for swab sampling because it believes
that some residues need a mechanical or physical action to remove the
residue and that rinse samples might give a false indication that the equip-
ment was clean. When product contact surfaces lend themselves to easy ac-
cess by the sampler, swab sampling is easily accomplished. However, there
are product contact surfaces that do not lend themselves to easy access, such
as the inner surfaces of hoses, transfer pipes, filters, condensers, and small in-
tricate equipment such as micronizers, microfluidizers, brushes, and numer-
ous other examples. Also, tanks and other "closed" systems may not have
408 Validation of Active Pharmaceutical Ingredients
ports large enough for entry for sampling purposes. In the cases of wire
screens or sieves or brushes, swabbing simply is not appropriate because of
the nature of the material. In these cases, it is reasonable and acceptable to
use either solvent rinses or rinse water sampling. Because residue tends to be
trapped in the overlapping areas of metal screens, a better sampling program
would involve soaking the screen in the solvent for which the residue is
known to be soluble.
The main concern of the FDA regarding the use of rinse sampling is that
if large volumes of rinses are used, the residue can be diluted to the extent
that it will not be detected by the analytical method. To overcome this poten-
tial difficulty, the volume of the rinsate should be kept as low as possible. If
large volumes of rinses were used, then the rinse samples may be concen-
trated by evaporation of some or all of the solvent after sampling. The evapo-
ration would have the effect of increasing the sensitivity of the analytical
testing. In some cases, a sufficiently sensitive analytical method is available so
that evaporation is not required.
Regardless of the sampling methodology, a sampling protocol should be
developed that demonstrates the locations from which samples will be taken.
Normally, a schematic diagram of the equipment is prepared, and the sam-
pling locations may be marked directly on the diagram.
The sampling locations should include all areas that are known to be dif-
ficult to clean. It is also a good idea to include some of the "easier to clean" ar-
eas for calculation purposes. The sampling protocol should indicate what type
of samples (rinse, swabs, etc.) will be used and should include the details of
exactly how the samples will be obtained and processed. For example, the
protocol should address such items as
• the volume of rinses (if rinse sampling is used);
• the specific areas sampled;
• the specific type and size of swab to be used;
• the number of strokes of the swabs;
• the direction of swabbing (i.e., either horizontal or vertical or
both); and
• how the samples should be labeled and transported to the analyti-
cal facility.
For CIP systems, it is advisable to disassemble the equipment during the
cleaning validation for sampling purposes, even though the equipment is not
normally disassembled during use. The disassembly not only facilitates sam-
pling but also allows the sampler to visually examine the inner product con-
tact surfaces to determine if there is gross contamination that remains
undetected by the sampling and analytical technique.
Cleaning for API Manufacturing Facilities 409
ANALYTICAL METHODS
Analytical methods used for cleaning samples must be carefully chosen ac-
cording to the specific residue, type of sample, and cleaning situation. The
most common error is in choosing a method that is not sensitive enough. The
sensitivity required depends upon the acceptable limit, which, in turn, de-
pends on the potency or toxicity of the potential residues. A common error
associated with the sensitivity is the assumption that "none detected" is equal
to zero. It is important to remember that "none detected" is not equal to zero
but instead is equal to the sensitivity of the analytical method as reflected in
either the limit of detection (LOD) or the limit of quantitation (LOQ).
Another factor to remember is that the analytical method used for testing of
cleaning samples must be validated itself, a concept often referred to as meth-
ods validation.
Because of their codependency, it is often highly desirable to develop an-
alytical and sampling methodology concurrently. If the sampling will be done
by swabbing, then one of the first activities for the analytical department
should be to determine the recovery from the surface of the equipment. This
is usually done by spiking known amounts of the expected residue on surfaces
of the same material (e.g., stainless steel, glass, plastics) as the equipment to
be sampled. The recovery would be simply defined as:
amount detectedxlOO
percent recovery=-----------
amount spiked onto surface
rubber "policeman" and also allowed to stay in contact for several minutes.
This method offers a combination of the physical action of swabbing plus the
solvation action of the solvent and may give good recoveries in some situa-
tions. A list of analytical methods typically used for cleaning validation sam-
ples is shown in Table 15.3.
Table 15.3 also illustrates whether the method is specific or nonspecific
in nature. This is significant since several of the regulatory guidelines refer to
the use of specific analytical methods. While many of the simpler methods
such as visual, pH, conductivity, and total organic carbon (TOC) are nonspe-
cific in nature, they still render valuable information relative to the level of
cleaning and the presence of any possible contaminant. The trade-off is that
many of the nonspecific methods are extremely sensitive and rapid. Due to
these properties, they can often be very effective to evaluate cleaning as well
as offer a valuable monitoring application, since they lend themselves to in-
line or on-line application. For several years, heat distillation stills have been
equipped with conductivity monitors that automatically either shuts down
the still or dumps water to drain that does not meet the standard pro-
grammed into memory. Extension of this concept to include on-line
* Indicates the most commonly used analytical methods for cleaning validation
Cleaning for API Manufacturing Facilities 411
Visual Examination
Although a nonspecific method, visual examination is probably the most pop-
ular and easy to use analytical method of all. Some companies have carried out
studies to make this technique quantitative for their particular application. In
contrast to the other analytical methods, this method gives the observer the
most complete and immediate indication of the condition of cleanliness in
the equipment. For situations where the entire product contact surface can be
observed (e.g., a large manufacturing tank), the entire surface can be evaluated
visually. If the manufacturing equipment is a transparent S L glass flask
(biotechnology manufacturing), the visual examination of the equipment un-
der good lighting is a valuable means of determining whether the equipment
is clean. This simple method thus bypasses the difficulties of taking a finite
sample from a limited location or series of locations. It also does not suffer
from recovery difficulties as do swab sampling or rinse sampling.
412 Validation of Active Pharmaceutical Ingredients
research compounds, because little is known about the toxicity of the mater-
ial or the effect on the body in the diseased state. Therefore, a greater safety
factor is applied (i.e., a smaller fraction is allowed to carryover), and the limit
will be lower for these cases. At the other end of the continuum is the dosage
form of lowest risk (i.e., the topical dosage form). Since there is far less risk for
contamination to cause medical problems for this dosage form, the safety fac-
tor is appropriately less (i.e., a larger number). Of course, the majority of the
dosage forms will fall somewhere in between these two extremes, as indicated
in Table 15.4.
If it is known, for example, that the following product B will have a max-
imum daily dose of 1000 mg (for example, 10 tablets each containing 100 mg
of active) and a batch size of 300 kg, then it is possible to calculate the limit
using a simple proportion as follows:
0.1 mg = ___x_m--""g_ _
1000 mg 300,000,000 mg
0.1 mg xmg
1500 mg 100,000,000 mg
x = 6,667 mg
method is based on the concepts of acceptable daily intake (ADI) and no ob-
served effect level (NOEL) developed by various scientists in the U.S. Environ-
mental Protection Agency (Dourson and Stara 1983), the U.S. Army Medical
Bioengineering Research and Development Laboratory (Layton et al. 1987),
and the Toxicology Department at Abbott Laboratories (Conine et al. 1992).
Basically, these workers were attempting to determine the amounts of
chemicals that the human body could ingest on a daily basis without undue
risk and toxicity. In the process, they found that this level of ADI could be cal-
culated from the toxicity of the materials expressed as an LD 50 . These data are
widely available on Material Safety Data Sheets and other references in which
toxicity data can be found.
The NOEL is calculated from the LD 50 by the mathematical relationship
as follows:
NOEL= LD 50 X 0.0005
where the 0.0005 is a constant derived from a large toxicology database. Once
the NOEL is known, then the ADI can be calculated by the relationship:
ADI =NOEL/SF
where B is defined as the smallest batch size of any other product made in the
same equipment and R is the largest normal daily dosage of any product made
in the same equipment.
As an example, consider a fictitious chemical substance, X. If it is as-
sumed that the following toxicity, batch size, and dosage information is
known, then the MACO can be calculated as follows:
Table 15.5 Dividing a Total Residue Limit Among Various Pieces of Equipment
Name of Equipment Surface Area (Sq.Ft.) %of Total Limit (Oral) Umit(IV)
area of the equipment was 23 ft2). The total allowable residue for all
6 swabs (summed together) is as follows:
Protocols
The protocol is the experimental plan that will be followed to demonstrate
the capability of the cleaning process. This experimental plan usually con-
tains some or all of the following elements.
422 Validation of Active Pharmaceutical Ingredients
Scope
The scope is a verbal description of the products and processes to be covered
by the experiments outlined in the protocol.
Objective
The objective is a statement of what is to be accomplished by the experi-
ments. It is typically a short general statement expressing the purpose of the
study-to demonstrate that the cleaning procedure will successfully and con-
sistently reduce the levels of residue to a predetermined level of acceptability.
Description of Process
A brief description of the manufacturing process naming the equipment used
in manufacturing the product is often included in this section as well as a de-
tailed description of the cleaning process or a reference to the number of the
Standard Operating Procedure (SOP) or other procedure. This would be an ap-
propriate section in which to list the equipment used in the manufacturing
process and any special auxiliary cleaning equipment such as high pressure
rinsing equipment, cleaning agents, and washing machines. It is also appro-
priate to distinguish whether the cleaning process is CIP, COP, or manual in
nature.
Test Functions
After the critical parameters are determined, the next step is to develop the ac-
tual tests that will be used to validate the cleaning process and determine if
the cleaning procedure is adequate and validatable. An example of test func-
tions is the visual examination of the equipment to verify that the equipment
Cleaning for API Manufacturing Facilities 423
it be based on medical dosage levels, medical effect levels, or the toxicity lev-
els for the particular residue substance. The rationale should also define what
the basic approach is (i.e., whether a total residue [the so-called train concept]
approach will be the basis for pass or fail or whether there will be separate, in-
dividual limits for each piece of equipment).
There may be multiple requirements for acceptability. For example, it
may be a requirement that the total residue not exceed a certain level, as well
as that the concentration of contaminant not exceed a prescribed concentra-
tion (usually expressed as parts per million, ppm). There are usually addi-
tional requirements such as requiring that the equipment be visibly clean
when examined with a "black" light (ultraviolet).
A good rationale will also address assumptions or conditions that may be
present that can affect the risk of contamination. For example, if the equip-
ment is dedicated completely or in part to the production of a single product
or intermediate, the risk is much less than for a multiproduct situation, and
this should be stated in the rationale. Many companies assume that if a
residue were to occur in a particular piece of equipment, such as a mixer, that
it would be uniformly distributed in the following product. Assumptions of
this nature should be stated in the rationale.
If there are calculations or equations used in determining quantitative
limits, they should be described in detail, and each term and step in the cal-
culation should be fully explained in detail. In many cases, it is appropriate to
include a sample calculation.
Documentation
The documentation section of the protocol indicates exactly what documen-
tation must be a part of the final validation report. This would include items
such as original analytical records, charts, reports,· signed statements by man-
agement ·of the analytical department that the analytical methods are vali-
dated, and signed statements by production supervision that personnel were
properly trained in the cleaning procedures.
Approval
The protocol should be formally approved by appropriate signees represent-
ing appropriate expertise qualified to determine if the experimental plan will
test the process as desired. One of the signatures should be a representative of
the Quality Assurance/Quality Control unit.
cleaning procedure was used for all products in a given facility or all products
manufactured in a certain piece of equipment). As cleaning has become more
scientific, there has been a realization that the cleaning technique used must
be directed toward the specific equipment and the products made in that
equipment.
Some companies have modified their use of cleaning agents. Particularly
for manufacturers of active ingredients, there has been a recent trend away
from the use of organic solvents for cleaning purposes, especially in the final
stages of the manufacturing process because of the toxicity of the organic sol-
vents. Some companies have found that aqueous-based cleaning is safer than
organic solvent cleaning in terms of potential carryover of the toxic organic
solvent residuals into the next product. Since organic solvents must be recov-
ered or disposed of, they also present an environmental impact.
Some companies have moved to the use of more product-specific clean-
ing agents, while others have moved away from cleaning agents in an attempt
to simplify their cleaning methodology. Many of the older cleaning methods
that were developed many years ago were quite arbitrary but became en-
trenched in our procedures. A commonly heard comment was, "That is the
way we have always done it." Some companies are finding that hot water is as
effective as any other cleaning method for their products.
Still other companies are experimenting with high pressure water clean-
ing. These devices function in a similar manner to those used in the "do-it-
yourself" car washes, except that they may involve considerably higher
pressure. These devices may be particularly appropriate for hard to remove
residues such as proteins. Any user of this technique should be aware of the
safety factors that these devices present; fingers and limbs have been lost by
careless use of these high pressure devices.
Another emerging trend is in the indirect visualization of hard to access
areas such as pipes, transfer hoses, or small intricate pieces of manufacturing
equipment. The fiber optic probe allows the viewing of surfaces that cannot
be accessed in any other manner.
Some companies are experimenting with the use of video cameras to ex-
amine equipment after cleaning. The cameras come equipped with a light
source and can be placed on a central post inside the tank. The device is in-
dexed and covers the entire inside surfaces of large tanks and may actually
prove to be superior to having a worker climb inside the tank. It is also safer
(no fumes) and less likely to lead to further contamination from the entry
process. The tapes can provide visual documentation should problems arise
later on.
An analytical trend in companies is the use of TOC for evaluation of
cleaning samples. This technique will undoubtedly have a major impact on
pharmaceutical analysis in general, and water and cleaning validation in par-
ticular. Newer analytical technology will continue to develop. Also, there is
ongoing research to develop newer and faster techniques to evaluate biobur-
den and endotoxin.
Cleaning for API Manufacturing Facilities 427
REFERENCES
Baffi, R. 1991. A total organic carbon analysis method for validating between products
in biopharmaceutical manufacturing. f. Parenteral Sd. Technol. 45:13.
Code of Federal Regulations, Title 21, Part 211, Current Good Manufacturing Practices for
finished phannaceuticals. Washington, D.C.: U.S. Government Printing Office.
Conine, D. L., B. D. Naumann, and L. H. Hecker. 1992. Setting health-based residue
limits for contaminents in pharmaceuticals and medical devices. Quality Assur-
ance; Good Practice, Regulation, and Law 1:171.
Dourson, M. L. and]. F. Stara. 1983. Regulatory history and experimental support of
uncertainty (safety) factors. Reg. Toxicol. Phannacol. 3:224.
FDA. 1991a. Guide to inspection of bulk phannaceutical chemicals. Reference materials
and training aids for investigators. Rockville, Md., USA: Food and Drug Adminis-
tration, Center for Drug Evaluation and Research.
FDA. 1991b. Biotechnology inspection guide, Washington D.C.: U.S. Government Print-
ing Office.
FDA. 1998. Guidance for Industry, Manufacturing, Processing, or Holding Active Phannaceu-
tical Ingredients. Rockville, Md., USA: Food and Drug Administration.
Jenkins, K. M., A.]. Vanderwielen, J. A. Armstrong, L. M. Leonard, G. P. Murphy, and
N. A. Piros. 1996. Application of total organic carbon analysis to clearing valida-
tion. PDA f. Phann. Sci. Technol. 50:6.
Layton, D. W., B.]. Mallon, D. H. Rosenblatt, and M. ]. Small. 1987. Deriving allowable
daily intakes for systemic toxicants lacking chronic toxicity data. Reg. Toxicol.
Phannacol. 7:96.
United States v Barr Laboratories, Civil Action No. 92-1744, United States District Court
for the District of New Jersey.
16
VALIDATION OF STERILE APis
Robert V. Kasubick
Oakwood Laboratories
Oakwood, Ohio
The manufacture of drug substances and drug products has been regulated
since the enactment of the federal Food, Drug and Cosmetic (FD&C) Act in
1906. The FD&C Act was expanded, most notably, in 1938, and again in
1962. The 1962 amendment included requirements for current Good Manu-
facturing Practices (cGMPs). The procedures for the control of cleanroom op-
erations and aseptic processing stem from the requirements posed by cGMPs.
The requirement for the validation of a microbiological control process
is embedded in 21 CFR 211.113(b), Control of Microbiological Contamina-
tion, which states,
429
430 Validation of Active Pharmaceutical Ingredients
REGULATORY ASPECTS
Aseptic processing has been defined in several documents. Among these doc-
uments are the 21 CFR Part 211 cGMP regulations (1993), Federal Standard
209E (1992), and the FDA Guideline on Sterile Drug Products Produced by Aseptic
Processing (1987a). The basics for validation are set forth by the FDA Guideline
on General Principles of Process Validation (1987b). These documents have es-
tablished the conditions that must be met and validated for aseptic process-
ing. A summary of these conditions is given below.
• Microbial limits should be statistically established for environmen-
tal monitoring.
• Environmental control limits should include maximum levels for
viable and nonviable organisms.
• All equipment must be sterilized before each use.
• All personnel must be monitored for microbial contamination. The
monitoring must be done each day for all operating shifts.
• Particulate monitoring must be done on each operating shift.
• Sampling locations should represent conditions throughout the
controlled areas.
• Media fills must simulate production operations, especially regard-
ing number of personnel, equipment used, and the process followed.
• The aseptic process must be validated on a periodic basis.
The demonstration and documentation that these conditions are being met
by the manufacturing process controls is the intent of validation.
FACILITY
Now that the process has been defined in general terms, the specifics must be
addressed. The general process described above must be evaluated in terms of
the following parameters:
• Room classifications
• Airflow patterns
Validation of Sterile APis 433
Figure 16.1 General Process for The Production of Sterile Bulk Drug Substances
Area 1
Dissolution
Area 2
~-·····-····--------·-···- -------·-·····-----------------------------------------------------··-----·---------·--·-·-···-------------------------···-·----1
Sterilization Precipitation
Isolation
"" Crystallization
,.
~-----····----------------
Area 3
---------------------------------------------------·-·-··················--···············-·-···-···----·-·····-----------------i
Area 4
··-·-···-·····-···-···-···, ··-·······-·····-········ ····-·········-·····-···-·-·········-···-·····-···-·-
Sampling Packaging
434 Validation of Active Pharmaceutical Ingredients
• Pressure differentials
• Personnel flow patterns
• Material flow patterns
Room Classification
Room classifications are assigned according to Federal Standard 209E (1992).
This standard establishes room classification according to the number of par-
ticles less than 0.5 ll-m found in a cubic foot of sampled air. Thus a Class 100
area is one that has ~100 particles, a Class 10,000 area has ~10,000 parti-
cles, and a Class 100,000 area has ~100,000 particles per cubic foot that are
~0.5 ll-m in size. The status of the room when the particle count is established
is not specified by the federal standard. However, Section 5 1.2.1 of 209E states
that the status of the clean room during collection of the samples shall be re-
ported as one of the following conditions: "as-built," "at-rest," "operational,"
or as otherwise specified. Generally, the validation data are reported as taken
under the "at-rest" condition, since the introduction of people and operating
equipment quickly introduces nonreproducible quantities of particles. The
"at-rest" condition provides the best opportunity to develop trend data on
the operational capabilities of the area under consideration. Federal Standard
209E provides in-depth details for collecting samples, evaluating results, and
so on; therefore, these actions will not be discussed.
Figure 16.2 is a simplified representation of a typical aseptic suite. The
Class 100 areas are the areas directly over the portions of the operation where
the product has the potential of exposure to the environment. A Class 100
condition is required by the cGMPs for any area where the product has the
potential of exposure to the environment. Surrounding these Class 100 areas
are areas that are generally put into a Class 10,000. Frequently these areas ex-
ceed the Class 10,000 requirement and are actually closer to a Class 1000 area.
This is the segment of the suite where autoclaves are unloaded, materials are
staged, sterilized items are transported, and so on. Class 10,000 areas are those
from which the critical or Class 100 areas are reached. Next to the Class
10,000 areas are the Class 100,000 areas where items are cleaned and prepared
for sterilization, and materials are weighed, formulated, and so on. The Class
100,000 also includes the site for personnel to have initial entry into the asep-
tic processing suite.
The validation protocol for the air system should include details of how
the air samples will be taken and tested to verify each classification. As indi-
cated above, most of the data will be generated under the "at-rest" condition,
but situations will occur where "operational" data, i.e., when personnel or
equipment are in motion, may be required. In areas where dry powders are
being processed, "operational" particle data will not be of value because the
particles introduced to the environment will be inherent to the process and
will not represent the capabilities of the environmental control system.
Validation of Sterile AP/s 435
Corridor 2
Area 3 Area 4
Gowning3 Corridor 1
Class 100,000
0
Class 10,000 Class 100
must be outward from the Class 100 area where the sterile drug substance is
or may be exposed to the environment. The pressure differential between
adjacent classification areas is required by the cGMPs to be a minimum of
0.05 inches of water. The above criteria dictate that the airflow will be from
each of the processing areas into the access corridors and gowning/degown-
ing areas before exiting to the uncontrolled areas.
For most manufacturers of sterile drug substances, the flow pattern de-
scribed in the previous paragraph must be modified. Since most drugs exist in
a powder or crystalline form they are easily introduced into the environment.
Therefore, the portions of the aseptic suite not directly involved in manipu-
lating the dry drug substance must be protected from potential contamina-
tion by the drug substance. The potential contamination of areas where the
dry powder is not manipulated can be achieved by having the airflow toward
the powder processing.
Figure 16.3 is a representation of validation criteria for the airflow direc-
tion and pressure differentials in a typical aseptic suite used for filling a pow-
der product. The values displayed are pressure differentials in inches of water
pressure relative to the uncontrolled areas, which are considered to be at zero
inches of water. The arrows show the direction of airflow.
The cGMPs dictate that the airflow must be outward from the Class 100
area where the sterile drug substance is, or may be, exposed to the environment.
Therefore, the direct packaging (filling) site in Area 4 should be under
laminar flow and have a static rating of Class 100. The actual airflow will be
from the Class 100 area into Area 4 to control exposure for the sterile drug
substance. However, the overall airflow will be from the corridor into Area 4
p =0.05 p = 0.07
p = 0.10
t t
Area 1 Area 2 Area 3 Area4
I I
I
I
-o
II
0
0
-
-o
II
0
0
' -o
II
0
0
- .
lr
-o
II
0
0
l
(11 CX> CX> CX>
I
' ll
= 0.10
GovJning Gowning 2
, Gowning 3 p
Personnel Flow
For personnel entering the aseptic suite, the entry is in Gowning Area 1
(Figure 16.4). From here they go to Gowning Area 2 to don a gown (jumpsuit)
to minimize the ingress of potential contaminants into Area 1. For those
personnel going into other areas, additional gowning is required and
438 Validation of Active Pharmaceutical Ingredients
ll I' ~
t • ~
Material Flow
Material flow will follow the same pattern as indicated for personnel. Con-
tainers going into Area 1 must be clean to assure minimum potential for the
introduction of microorganisms. For materials transferred from Area 1 to Ar-
eas 2, 3, or 4, the controls must be more extensive. Procedures must be in
place to assure that no possibility for the introduction of contamination has
been overlooked.
Materials will enter the aseptic core by either using the same air lock
system as personnel, or entry through sterilizing ovens or sterilizing fil-
ters. For equipment or materials entering through the air lock system,
sufficient contact plate testing must be conducted to assure that all possible
areas for contamination have been disinfected. Corners and joints are the
most difficult spots to clean and are the most likely places to harbor micro-
organisms.
If materials enter through sterilizing ovens, the ovens must be validated
to show that all configurations will be exposed to minimum sterilization con-
ditions. An excellent review of the points that must be considered for oven
validation is presented by the FDA document entitled Sterilization Process Val-
idation (1993a). Since the materials will be in sterile storage for some time, val-
idating the ability of the materials to remain in an aseptic condition for the
maximum anticipated storage time will be necessary.
The ability of the filter to sterilize the drug substance solution, and any
other liquid or solution passed through the filter, must be validated. The man-
ufacturers of the filters will certify that filters rated at 0.2 Jl.m will remove 10 7
organisms per centimeter squared. Using only the manufacturer's certification
that the filter will remove this quantity of organisms is no longer sufficient.
Each filter must be validated for the specific solution being filtered. The major
filter manufacturers have developed programs for validating filters with spe-
cific solutions.
SUPPORT SYSTEMS
Water Systems
Foremost among the support systems are the water and air systems. The water
system has received considerable attention. A good overview of what may be
expected from an FDA inspector can be found in the Guide to Inspections of
High Purity Water Systems (1993b). This guide does not specifically address val-
idation but does provide background and guidance for items that must be
addressed.
The objective of water system validation is to provide assurance that the
system eliminates endotoxins from the incoming water and prohibits the
440 Validation of Active Pharmaceutical Ingredients
The concepts for the these five steps were published in 1983 (Carleton et al.).
This section will focus only on the actions necessary to accomplish Step 4. A
simplified WFI system is shown in Figure 16.5. In the system depicted, the
validation protocol should require testing at the six points shown as A, B, C,
D, E, and F.
The purpose of testing and establishing action limits or levels is to assure
that the water system is under control. The major consideration in the valida-
tion of high purity water systems is the acceptance criteria. Consistent results
throughout the system over a period of time form the primary element.
Any action limit established will depend on the overall system and fur-
ther processing of the finished product and its use. In general, the FDA prefers
100-300 mL for water samples. Sample volumes less than 100 mL are unac-
ceptable. The major concern in a water system is endotoxins. Because water
can pass the Limulus Amebocyte Lysate endotoxin test and still fail the mi-
crobial action limit, it is important to monitor water systems for both endo-
toxins and microorganisms.
To assure that the system is not stressed, the quality of the incoming
water must be monitored (Point A). The quality of water introduced into
most facilities varies considerably. The acceptance criteria for incoming
water must, at a minimum, meet the U.S. Environmental Protection
Agency regulations for drinking water. The variation allowed in the para-
meters can be defined only after the system has been operated for a period
of time and determining the effect of the test parameters on the overall
ability of the system to produce WFI that consistently meets U.S. Pharma-
copoeia (USP) specifications. If the feedwater is from a municipal water
system, reports from the municipality testing can be used in lieu of in-
house testing.
The ability of multimedia filters, softeners, and the reverse osmosis sys-
tem to remove most of the contaminants to a consistent level must be docu-
mented. This documentation will be achieved by showing that the
pretreatment system provides constant quality water to the stills (Point B) de-
spite the fluctuations in incoming water quality.
The ability of the distillation system to produce WFI, as defined by the
USP, must be documented. The testing at Point C should be conducted over a
Validation of Sterile AP/s 441
Multimedia Softener
City Water Filters System
Reverse
Osmosis
System
still No.2
Still No.1
Storage Tank
Air Systems
The second area of concern is the air system. The air supplied to the aseptic core
is usually filtered through 0.2 1-Lm HEPA filters to remove particles from the in-
coming air. Therefore, incoming air, if the filters are working properly, is seldom
the source of contamination. Two other possible sources of contamination are
As indicated above, the air filtration system must provide particle reduction.
The acceptance criterion for the validation of the HEPA filter system is a mini-
mum of a 99.99 percent reduction of incoming particles. The degree of reduc-
tion can be determined and validated by introducing a dioctyl phthalate
(DOP) aerosol into the duct system a short distance upstream from the filter.
The concentration of the DOP should be in the neighborhood of 80 to 100 1-Lg
per liter of air at the filter's designed airflow rating. The scanning probe on the
downstream side of the filter should be capable of a sampling rate of at least
1 ft 3 of air per minute. The downstream probe should be positioned 1 to 2 in.
from the filter face. The validation protocol should, besides validating the ca-
pability of the filter to remove the appropriate amount of particles, provide a
method to show that the frame holding the filter in place will not pass any air.
This phase of filter validation testing is generally conducted with no activity
in the area.
The air introduced into the area under consideration is intended to min-
imize the exposure of the sterile material to contamination from the environ-
ment. These Critical or Class 100 areas should be supplied with a HEPA-
filtered laminar or unidirectional flow of air having sufficient velocity to
sweep particulate matter away from the filling/dosing operation. The velocity
of the air exiting a filter intended to provide a Class 100 condition is specified
Validation of Sterile AP/s 443
Equipment Sterilization
Equipment used in the processing of sterile bulk substances presents special
problems. This equipment, which includes items such as crystallizing tanks,
centrifuges, and dryers, is intended to be sterile before use. Sanitation, usually,
is not acceptable to the FDA. However, the FDA does recognize that some
equipment is not amenable to sterilization. In those cases, the validation of
the sanitation process is extremely critical. The acceptance criteria for the san-
itation process must be narrow, and the support data must be well docu-
mented. The validation program should show the effectiveness of the
disinfecting program for this and all subsequent processing areas. If a se-
quence or rotation of disinfecting agents is used, the validation program
should be sufficiently long to cover the use of all agents.
The method of choice for sterilizing large equipment and associated
transfer lines is saturated clean steam under pressure. The validation process
must prove that the steam being delivered meets the USP criteria for WFI, py-
rogens, and bioload. The validation must also prove that the steam is steriliz-
ing all surfaces. When validating the ability to sterilize equipment, heat
distribution studies in the autoclaves must be done to determine the cold
spots where condensate could accumulate. The point of steam injection and
discharge must be part of the testing pattern, including any low spots. As with
the WFI system, the validation effort should be over a period sufficiently long
to allow the system to go through several cycles. It is necessary to show that
the steam-in-place (SIP) cycle is reproducible and capable of achieving ade-
quate sterility at the extremes of the operating conditions.
The validation of the sterilization or depyrogenation of equipment out-
side the aseptic core is essentially the same for both drug substance and drug
product. This validation procedure has been thoroughly covered by an FDA
guideline (FR 1993). Standard items, such as load mapping at a minimum of
10 points showing a uniform and stable heat distribution throughout the
chamber demonstrating that the coolest position remains above the mini-
mum temperature for the minimum run time and biological challenges with
a minimum of 1,000 endotoxin units per measured site with a reduction ac-
ceptance criteria of not less than three logs, must be covered. In addition to
these items, the hot air ovens must be validated for particles introduced dur-
ing the sterilization operation. The number of particles should be determined
by sampling after the oven has reached the set depyrogenation temperature.
The validation of any sterilizer or depyrogenation oven is not considered
Validation of Sterile AP/s 445
acceptable unless three consecutive runs that have met all acceptance criteria
have been completed. There should be three consecutive runs at both the
maximum and minimum load configurations.
Another area that must be included in the validation protocol is equip-
ment cleaning. Procedures must be developed to remove any previously used
chemicals or materials from the equipment. The cleaning procedures must be
validated to demonstrate that the level of residual materials present after
cleaning is acceptable. The criteria applied to the cleaning procedure to deter-
mine acceptable residual levels is as follows:
Filtration Systems
All process gases entering the aseptic core must be validated as sterile and par-
ticle and pyrogen free. Therefore, validating the ability of the in-line filters to
remove microorganisms will be necessary. An adequate sample is required to
evaluate the pyrogen potential. The pyroburden should have a sample size of
30-40 L of gas. Additionally, the nonviable particle count should be done on
a sample of not less than 1 ft3 of gas. There are no set limits for nonviable par-
ticles in a gas stream. The specification will be set based on the data generated
during the OQ and IQ operations. The validation of the process gases must be
run separately from any media trials conducted, to show the ability of the sys-
tem to provide aseptic media. Bioburden data on the incoming gas stream will
446 Validation of Active Pharmaceutical Ingredients
be necessary to show control of the incoming material and to show that the
in-line filters will not be stressed beyond their capabilities to remove organ-
isms. The validation process must also include the sterilization of the filters to
be used in the gas lines.
There are two types of filters to be considered when establishing the val-
idation protocol: gas and fluid. Gas filters will be required on all incoming
process gases and on all system vents. The validation procedure will need to
cover the sterilization of the filters and their installation. Since the potential
exists that a filter may have to be changed during the processing of a drug
substance, the validation should also cover the procedure of removing and in-
stalling a filter while maintaining aseptic conditions.
The validation of the filters used to sterilize incoming solutions and sol-
vents is considerably more involved. The protocol for these filters must con-
sider not only the effect of the bioburden of the incoming solutions but also
the effect of viscosity, pH, ionic strength, osmolarity, flow rates, temperature,
and pressure on the ability of the filter to remove microorganisms. If organic
solvents are to be employed in the process, their effect on the filter's ability to
function must also be documented. Filter validation must be conducted in
the manufacturing facility. The testing can be contracted to an outside labo-
ratory. Several filter manufacturers have programs to validate filters. However,
care must be taken that the protocol meets FDA criteria. One criterion is that
the actual manufacturing conditions must be simulated. The FDA has noted
(1994b) that the potential for the drug product to cause a reduction in mi-
croorganism size must be considered. Therefore, conducting the filter valida-
tion with the actual drug substance solution presents a situation that is in line
with the FDA's views. The FDA further states that in the cases where a preser-
vative has been added, conducting the validation with the preservative ex-
cluded from the formulation is acceptable.
Filter manufacturers have developed what they call a matrix approach to
validation. However, the FDA has gone on record to say that the matrix
system proposed by filter manufacturers may not be adequate (Ben Venue
Laboratories 1994). The FDA's major concern with the matrix approach, as
proposed by filter manufacturers, is that the approach does not take into con-
sideration any interactions between variables that would decrease the ability
of the filter to retain microorganisms. Again, this concern of the FDA is elim-
inated if the actual drug substance solution is used in the filter validation.
Other items that must be included in the validation study are the
bioburden of the drug substances, procedures for determining the integrity of
the filters before and after use, and several changes of the filters to cover the
potential for filter failure and appropriate replacement.
Validation of Sterile AP/s 447
Heat Exchangers
Certain portions of processing will require heating or cooling, which is the
function of a heat exchanger. The quality of the heating or cooling media is
generally less than the quality of the process.stream. Controlling the heat ex-
change system to assure no passage of the heating or cooling media into the
process stream is critical. This control is generally accomplished by having the
heating or cooling media at a lower pressure than the process stream. The val-
idation protocol must include a section to document that the pressure moni-
tors are functioning as designed.
Vacuum Systems
The primary concern with vacuum systems is that nonsterile gas is not drawn
into the system, either during the application of the vacuum or after the com-
pletion of the vacuum cycle and the subsequent adjustment to atmospheric
pressure. The validation procedure must document that the system does not
leak under the operating conditions. The procedure also must verify that all
system vents prevent the ingress of nonsterile gases.
drug substance particles into the environment, is almost impossible. The vali-
dation of this phase of the process will show that the manufacturing facility
system controls the environment reproducibly and minimizes the number of
particles in the atmosphere, while maintaining the inward airflow to prevent
the contamination of other areas of the aseptic suite. Because of the drug sub-
stance particles being introduced into the atmosphere, and subsequently
being deposited on room surfaces, validating the procedures for removing
the drug substance from the walls, floors, and equipment will be especially
critical.
In the area dedicated to packaging the drug substance in containers for
shipment, the validation will be directed toward environmental control, as
was done in the milling area and other areas. The validation should also show
that if an equipment failure occurs, the procedures in place are adequate to
have the equipment removed, repaired, resterilized, and reintroduced into
the aseptic areas without compromising the sterility of the environment or
the drug substance.
VALIDATION MAINTENANCE
Once all aspects of the aseptic process, facility, and operations have been val-
idated, any changes proposed for these areas must be reviewed to determine if
the changes will affect any of the parameters covered during the validation. If
the changes will affect a parameter, that parameter must be revalidated once
the change has been made. The implementation of minor changes in the field
without prior review and approval has caused severe problems when the FDA
has inspected the facility. A validation program can only guarantee the effec-
tiveness and quality of a process when that process is operating according to
the procedures and acceptance criteria in the initial validation effort.
REFERENCES
Ben Venue Laboratories. 1994. Private communication.
Carleton, F.]., D. Conrad, R. Myers, S. Chrai, and R. Kieffer. 1983. Design concepts for the
validation of a water for Injection system. Technical Report No. 4. Bethesda, Md.,
USA: Parenteral Drug Association
CFR. 1993. Current Good Manufacturing Practices for finished pharmaceuticals. Code
of Federal Regulations Title 21, Part 211, pp. 81-100.
EC. 1993. Rules and guidance for pharmaceutical manufacturers. London: HMSO.
FDA. 198 7a. Guideline on sterile drug products produced by aseptic processing. Rockville, Md.,
USA: Food and Drug Administration, Center for Drug Evaluation and Research.
450 Validation of Active Pharmaceutical Ingredients
FDA. 1987b. Guideline on general principles of process validation. Rockville, Md., USA:
Food and Drug Administration, Center for Drugs and Biologics and Center for De-
vices and Radiological Health.
FDA. 1991. Guide to inspection of bulk pharmaceutical chemicals: Reference materials and
training aids for investigators. Rockville, Md., USA: Food and Drug Administration,
Center for Drug Evaluation and Research.
FDA. 1993a. Sterilization process validation. Rockville, Md., USA: Food and Drug Ad-
ministration, Center for Veterinary Medicine and Center for Drug Evaluation and
Research.
FDA. 1993b. Guide to inspections of high purity water systems. Rockville, Md., USA: Food
and Drug Administration, Division of Field Investigations.
FDA. 1994a. Guide to inspections of sterile drug substance manufacturers. Rockville, Md.,
USA: Food and Drug Administration.
FDA. 1994b. Human drug CGMP notes. Rockville, Md., USA: Food and Drug Adminis-
tration.
Federal Standard 209E. 1992. Airborne particulate cleanliness classes in clean rooms and
clean zones. Washington, D.C.: U.S. General Services Administration.
FR. 1993. Guideline for submitting documentation for sterilization process. Federal
Register 58:63996.
Lazar, M. S. 1993. Concepts for the process validation of bulk pharmaceutical chemi-
cals. Pharm. Techno!. 17 (12):32-40.
Lazar, M. S. 1995. Sterile bulk pharmaceutical chemicals: A position paper. Pharm.
Techno!. 19 (8):38-42.
Ljungqvist, B., and B. Reinmtiller. 1997. Clean room design; minimizing contamina-
tion through proper design. Buffalo Grove, Ill., USA: Interpharm Press, Inc.
17
VALIDATION OF BIOTECHNOLOGY
ACTIVE PHARMACEUTICAL
INGREDIENTS
451
452 Validation of Active Pharmaceutical Ingredients
MASTER PLANNING
The Master Plan is the first document to be written, the first one to be referred
to in carrying out a validation program, and is commonly the first one to be
requested during a regulatory inspection. This document gives an overview of
what is to be validated and can include information on how specific systems
will be tested, when these activities will take place, and who will perform the
various validation studies. It can contain the specific variables of a given
process or it can be generic and apply to any protein and any site. In the lat-
ter case, the nature and scope of the process validation approach are de-
scribed. A second document, the Validation Protocol, will be required when
validating a specific product. The protocol usually includes a detailed process
description, the testing strategy, and acceptance criteria.
The generic approach provides a governing document that helps the val-
idation team (or an inspector) initially visualize the general scope. And, as
each process is different, the Validation Protocol will list defined variables and
scales. This document is written and signed by those responsible for doing the
work.
The Master Plan should state areas of responsibility-who, by depart-
ment, will be charged with the responsibility of completing the validation ac-
tivity. The team that actually performs most of the process validation is an ad
hoc team that initially begins in the process development area. Members from
clinical manufacturing, Quality Control (QC), and Quality Assurance (QA) are
included for broader input and because validation activities impact these
other areas. Process Development and Manufacturing provide the bulk of the
scientific guidance, and are assigned, as system owners, one or more unit op-
erations for which they are directly charged to monitor and evaluate the data.
QC is included so that they have an early warning system for sample load
and timing, and also to provide assurance that the most appropriate assays are
being chosen by the process members. A goal of the team is to generate well-
defined protocols, with a minimum numbe-r of the most relevant samples. We
wish to avoid obtaining data from the QC group only to realize later that the
wrong polyacrylamide gel electrophoresis procedure, for example, was used,
or the specified high performance liquid chromatography (HPLC) procedure
was developed specifically for final bulk product and upstream samples show
interference.
QA is included to assure compliance with applicable regulations and
guidelines. Their role is to review the protocols for completeness, and to
review the reports to ensure the protocol was followed as written and the con-
clusions are supported by the data obtained, and to make sure the documen-
tation meets the applicable regulatory requirements. They are free to suggest
alternative or more extensive analyses, and their comments are to be ad-
dressed by the validation team.
Validation of Biotechnology Active Pharmaceutical Ingredients 453
EQUIPMENT QUALIFICATION
Equipment qualification documentation helps ensure quality because it
serves to provide evidence that engineering specifications were followed and
that these specifications meet the demands of the manufacturing process. In
simpler terms, the documentation should provide evidence that what you
bought was installed and operates correctly. The principles are that simple.
The effect of not having this information is obvious; less consistency, less con-
trol. The methods of collecting this information are just as simple. Most of the
information contained in the qualification documentation probably exists
anyway.
When a piece of equipment, a software program, or a manufacturing
process is used, it serves a function. Prior to the design of the equipment, the
program, or the process, the function must be defined. If not, how would one
know they purchased the correct equipment, wrote software correctly, or cre-
ated a process that is effective? In order to define the function, certain re-
quirements are necessary. In this chapter, these requirements are called
functional requirements. Functional requirements are the cornerstone of the
equipment qualification process. The requirements dictate how equipment or
systems need to operate to produce the desired output. The output may be
Water for Injection (WFI) or a database, but the principles remain constant.
Basing the installation qualification (IQ) and operational qualification (OQ)
on the functional requirements of the system gives an absolute base from
which to work. The requirements are usually documented and given to the
vendor or design engineer when a project begins. If specific functional re-
quirements are not documented, check any design documents or purchase
specifications. These documents should outline what the equipment is de-
signed to do. They may not be clearly illustrated but the requirements of the
system were most likely considered before the purchase specification was writ-
ten. A design qualification (DQ) can be a significant portion of the IQJOQ and
is done up-front before the actual purchase is made. This phase of the qualifi-
cation documents the exact requirements of the system.
Once the functional requirements are written, a traditional validation
approach can be applied. An IQ document can be used to provide informa-
tion that equipment is installed per the requirements and design documenta-
tion. An OQ document can be used to illustrate that equipment operates as
defined in its functional requirements and design documentation. Further-
more, a performance qualification (PQ) document can assess the performance
of an equipment or system as defined in its functional requirements.
Installation Qualification
Like other manufacturing processes, biopharmaceutical processes need equip-
ment that is installed properly to assure proper operation. Biopharmaceutical
manufacturers use IQ documentation to help prove their processes are in a
454 Validation of Active Pharmaceutical Ingredients
state of control, to keep track of things like change parts and spare parts, to
know what utilities are used, to know what process instrumentation needs to
be calibrated, to make sure current drawings are on file, and, most important,
to assure equipment is installed according to its requirements. Table 17.1 il-
lustrates the information that may be included in an IQ document.
Operational Qualification
Biopharmaceutical manufacturers need equipment that operates per require-
ments to ensure consistency and quality. OQ documentation is the means to
capture such information. Many of the requirements outlined in the design
documentation can be tested to prove adequate op~ration. Procedures used to
operate the equipment can also be checked during the OQprocess. Table 17.2
is an example of what can be included in an OQ document.
Performance Qualification
If the performance of equipment or systems can be measured, the results can
be documented. This is called a PQ document. The difference between OQ
and PQ lies in the testing strategy. The OQ shows that equipment/systems op-
erate as intended by design. The PQ shows the equipment/systems can per-
form (i.e., clean, sterilize) as intended using a challenge representative of the
process in which it will be used. Performance testing can be combined with
operational testing documentation.
CLEANING VALIDATION
Cleaning processes used in the manufacture of biopharmaceuticals can be val-
idated using simple sampling techniques and a combination of analytical
techniques used to detect specific and nonspecific contaminants (Murphy
1996). The key to understanding what sampling and analytical methods to
use lies in an understanding of how the specific unit operations react to
potential contaminants and how the quality of the product may be affected if
these residues are not removed to appropriate levels.
Upstream processing steps, such as fermentation or cell culture opera-
tions, contain many different compounds that may be left behind following
processing. Adequate cleaning of these residues helps assure batch-to-batch
consistency and can aid in preparing process equipment for sterilization.
Most of the potential contaminants found in biotechnology are carbon based
making a nonspecific test method, such as total organic carbon (TOC), a
valuable tool in assessing the cleanliness of equipment. Other nonspecific test
methods, such as pH and conductivity, can also be used to detect the
Validation of Biotechnology Active Pharmaceutical Ingredients 455
Utility Hook-Up Description The utility requirements of the system can be traced
Pressure Requirements back to the design requirements of the equipment.
Temperature Requirements can be used to The IQ check that the proper
Estimated Usage connections were made_
Type and Size of Connection
Drawing Reference Number
Electrical Requirements
System Manual Reference Manuals that are included with equipment or systems
can be referenced to show manufacturer
recommendations were considered during installation.
EQUIPMENT STERILIZATION
PROCESS VALIDATION
Unlike the IQ/OQ of equipment validation, process validation is usually
much less defined. Cleaning validation, also, is relatively straightforward in
that the physical/chemical principles are easy to comprehend, and once the
appropriate protocols are executed, the program is finished. The same proto-
cols essentially apply to any piece of equipment, any system, at any site. By
contrast, process validation deals with the microbiology and biochemistry of
a dynamic process. As such, it is a long-term program that begins in the labo-
ratory and continues through commercial manufacturing.
Basically, the main focus of the purification process validation program
is to demonstrate and document (1) removal of host cell contaminants, (2) re-
moval of process additives, (3) consistent product purity and identity, and
(4) consistent process yields.
The ultimate goal is to establish, and document, a well-understood
process that consistently performs to expectations, and produces a product of
consistent quality. Adequate in-process controls are essential in producing a
product of consistent quality. Final bulk purity assays are used to verify this
and further ensure quality.
During the evolution of a process a number of well-known procedures
are followed and landmarks reached (Martin-Moe et al. 2000). First, a process
is developed to be cost-effective, scaleable, and robust. This is done to ensure
adequate amounts of material with minimal batch failures. The key to achiev-
ing this is process understanding, or process characterization. Experiments are
run to make improvements or troubleshoot upsets. Thorough process devel-
opment increases process understanding. Second, the process is often scaled
several times to meet increased production demands for clinical trials and
eventually to meet market needs. During scaling and campaigning, more data
on process performance are gained. If these activities are well documented,
the process is largely validated already. There are a few additional protocols
that should be performed to extend process understanding, but basically the
validation program is well underway.
Full process characterization is of enormous value to manufacturing, in
terms of maintaining a smooth-running plant and minimizing lost batches. It
is also of great value to Quality Assurance in providing supporting informa-
tion to justify lot release for batches that have drifted slightly at some point
during manufacturing. In actuality, full process characterization is a more en-
compassing program than process validation. When the former is completed,
458 Validation of Active Pharmaceutical Ingredients
Timing
At minimum, the critical components of facilities validation need to be essen-
tially complete by the manufacture of product for Phase I clinical trials. This
is necessitated by the requirement that the product be manufactured in com-
pliance with current Good Manufacturing Practices (cGMP). Process valida-
tion should be underway at that point, with any critical issues identified and
addressed. There should be a minimal program in place to (i) show process
consistency from batch to batch and (ii) prevent unauthorized changes in the
process. For Center for Biologics Evaluation and Research (CBER) filings, the
process validation needs to be completed prior to the license submission. At
that time, all aspects of process validation should be finalized and docu-
mented, with the obvious exceptions of (and specific references to) ongoing
validation and revalidation.
In recombinant protein production, process validation frequently is ne-
glected until late in clinical development. This is understandable due to a va-
riety of reasons. The drug may not show favorable clinical results in late stage
trials, so why invest the time or money before it is a proven product candi-
date? Process validation is often seen as a perfunctory activity solely per-
formed for regulatory agencies. Finally, there may be a fear that the process
will change dramatically and early validation will be negated. As a result of
these misunderstandings, the process validation activity can be diagrammed
as in curve A of Figure 17.1; very little effort until Phase 3 clinical testing,
when a mad dash is made to gather data to support the Biologics Licensing
Application (BLA).
We hope to demonstrate here that the above perceptions are ill-founded
and early process validation is of great value to manufacturing, not just in sat-
isfying Food and Drug Administration (FDA) requirements. Curve B (Figure
17.1) illustrates a more reasonable approach to validation. There is a higher
amount of effort during process development and initial scaling activities. It
will be seen later that this effort is in effect already going on by the develop-
mental scientists and engineers. These activities are not necessarily dedicated
to establishing process validation data, but one should merely capture and
document data as they are generated when establishing a workable process.
Validation of Biotechnology Active Pharmaceutical Ingredients 459
~ 30
/
/
20
/
10
0
Lab Tox II Ill Mkt
Phase of Development
Note also in curve B the level of activity is spread out over time, lessen-
ing the painful dash at the end, and more importantly, early process under-
standing will actually assist in process development and help prevent batch
failures in subsequent clinical material manufacturing. Further, the area un-
der curve B is greater than that of A, meaning a more complete characteriza-
tion package, a more substantial database to assist plant troubleshooting and
to support proposed process improvements; in sum, a more thorough under-
standing of the process.
Process Variables
Every bulk protein process contains several unit operations and a host of vari-
ables, or parameters. It is convenient, and meaningful, to divide them into
two distinct groups. The set of parameters that can be preset and are used to
run the process can be thought of as operational, or input parameters. These
are commonly found in the manufacturing procedures or associated Standard
Operating Procedures (SOPs). These parameters, such as flow rate, tempera-
ture, pressure, time, mixing speed, and raw material weights, define the
process and, when followed as prescribed, should result in a consistent
process and consistent final product quality. These parameters are usually
very controllable, often within very narrow ranges.
460 Validation of Active Pharmaceutical Ingredients
Another class of variables, the performance variables, are the output pa-
rameters. These are not directly controllable and the resulting values depend
on how closely the operational variables are maintained and interact. Exam-
ples of these parameters are step yields, purity at each step, and other step
characteristics that the process development biochemist or engineer feels are
useful in describing the performance of a given unit operation.
Each of these classifications will be described further, in detail, with spe-
cific examples for some typical unit operations in a recombinant protein pro-
duction process.
Operational Parameters
Operational parameters, or input variables, are usually controllable, and often
merely require demonstration of consistency, within some prescribed range.
The list of these input variables, however, can become quite large. Therefore,
the number should be limited to only those that can be reasonably expected
to affect the operations of a given step. The mixing rate during a refold step
might have a dramatic bearing on the outcome of that step. This variable,
then, should be addressed for process validation purposes. During develop-
ment of that operation, the development scientists will have altered the rate,
perhaps in conjunction with varying other parameters, and settled on a speed
that gives an acceptable yield and purity. This mixing rate can then be speci-
fied and controlled, within a reasonable range, during the manufacturing
process.
The ranges at the time of beginning manufacturing may be considered
provisional, as they may have been established by limited development stud-
ies, past experience, and general scientific judgment. During the course of
manufacturing for early to midphase clinical trials, monitoring these parame-
ters begins the validation process and substantiates that the chosen ranges are
acceptable or need to be shifted.
A given process may involve hundreds of operational variables. Al-
though all the variables are important, not all are critical. We reserve the use
of the term critical to apply to variables that either are difficult to control or
are near an edge of failure (Seely et al. 1999). Most operational parameters are
easy to control within narrow ranges and are not near a failing point. With
thorough process characterization and robustness, there should be only a few
critical variables in a process.
Returning to the example of refolding tank mixing speed, the first level
of validation, and frequently the only level that needs to be covered for vali-
dating the operational parameters, is to document that when mixing is main-
tained within a defined range, the expected yield and purity result, within
some range. If either side of that range is near a limit of failure, further vali-
dation may be required. Additional studies might include running the
process at lab scale at that limit and determining what happens to the prod-
Validation of Biotechnology Active Pharmaceutical Ingredients 461.
uct. One may wish to examine the interaction of multiple variables. This ap-
proach is often very informative when based on statistical experimental
design (Kelley 2000). The number of possible interactions in a protein pro-
duction process can become astronomical and only those that are expected to
have significant interactions and consequences should be so thoroughly
investigated.
Chromatography is most certainly affected by pH, temperature, and
ionic strength, and all three will show interactions. However, it is reiatively
uncommon for minor fluctuations in any one, or in all three, to lead to major
process upsets. A common approach here is to record the exact data for these
variables and analyze by trend charts or maximum/minimum values after
multiple runs are done for a variety of other reasons such as in the production
of product for toxicology or stability tests. Often the extremes of the specified
ranges will be reached at some time, and the yield and purity data from those
runs can be reviewed for acceptability.
We maintain that each extreme need not be specifically tested for the
sake of demonstrating acceptability. The ranges were originally set by a com-
bination of sdentific judgment and previous experimental results. The final
justification comes after many, many runs, at full scale, and will combine
other variables not previously envisioned. Recall the concept that process val-
idation is an ongoing process of a growing body of data. This requires an on-
going in-process sampling and data monitoring program to be in place. The
program need not be cumbersome, but should encompass recording discrete
data points for each of the operational variables, and at least a yield calcula-
tion and purity assay at each step in the process. Here again it can be seen that
capturing process data during development and early clinical manufacturing
can provide significant validation data.
Performance Parameters
Performance parameters are a set of select output variables, such as step yields
and purity, that while they are not directly controllable, are a measure that
the unit operation did indeed perform as expected. These are individually
chosen by the unit operation owner to be the most useful, from a multitude
of possibilities that exist for any given step.
These performance, or output, parameters take many runs to define sta-
tistically. Data gathered in the early stages of development and technology
transfer can serve to set preliminary or provisional control limits. Once the
process is at the commercial manufacturing scale, operational and perfor-
mance values can be recorded for as few as three consecutive runs to show
consistency. These are commonly referred to as the conformance, or qualifi-
cation, lots. Process data from these runs can be compiled into a final process
validation package. Additional studies, such as plasmid stability and process
pool stability are required and will be discussed later.
462 Validation of Active Pharmaceutical Ingredients
Impurity Profile
An important element of demonstrating process consistency is tracking the
product-related impurities. For proteins, these are trace amounts of species
that are oxidized, acetylated, dimerized, cleaved, and so on. The relative
amounts of these species should be consistent from batch to batch. Rarely are
they fully identified before process validation is performed, but they can
merely be numbered and the levels (in area percentage of the total chro-
matogram) can be tabulated or graphed.
Although consistency of the main peak is important to monitor, the
trace impurities provide a very sensitive tool for monitoring unit operation
Additional Studies
Thus far, we have stressed validation data that are gleaned directly from ob-
serving the process. This is where the majority of the validation package will
be derived. We have also seen that significant process data are generated dur-
ing development, scale-up, and manufacturing for various phases of clinical
trials. If these data are adequately captured and documented, they automati-
cally contribute to the process validation program. There are a number of side
issues, however, that need to be explored and incorporated. A typical list of
protocols for validating a recombinant protein process is given in Table 17.4.
In this example, Protocol 01 for monitoring the process at large scale is
described above. The others provide validation information that either is in-
cluded in the final package submitted as part of a BLA or provides additional
data to justify that the process is sound. These will not be further discussed
here. An example of a protocol is given in Appendix 17.1 to show an accept-
able format and degree of detail required.
Table 17.4 Example List of Protocols Needed for a Typical Recombinant Protein
Process
Number Title
Process Monitoring
In a well-designed process, sufficient data can be gained from the above pro-
tocols, and from at least three production plant runs, to allow assemblage of a
complete process validation package. However, continued monitoring is re-
quired to accumulate adequate data on the performance parameters. At least
12 data points, preferably 30, are needed to calculate the upper and lower
control limits (UCL and LCL). These data are then plotted as control charts,
and the UCL and LCL are projected for upcoming production runs. The new
data, as they are received, are plotted directly on these plots so the manufac-
turing personnel can immediately see if they are in control or if an excursion
or trend is occurring. An example of a control chart for the yield on a chro-
matography step is shown in Figure 17 .2.
If the control limit values cannot be specified at the time of BLA filing, it
should be clearly stated in the process validation section which parameters
will be control charted, how many data points will be required, and how the
limits will be calculated.
The control limits are commonly calculated as ±3 standard deviations of
the population (Trubinski and Majeed 1984). Calculation based on the aver-
age moving range is reported to provide more discrimination between normal
Validation of Biotechnology Active Pharmaceutical Ingredients 465
process variation and that caused by special factors, for which an assignable
cause can usually be found (Gershon 1991; Greer and Halteman 1991). This
calculation is
X ± (2.66)(mR)
where, X is the mean of the first 12-24 data points, mR is the average moving
range with a running window of 2, and 2.66 is a factor that brings the control
limits to approximately ±3 standard deviations.
Once the control charts are in place for each identified performance pa-
rameter, the ongoing monitoring consists of plotting the new data points for
every subsequent batch. Recalculation of the control limits should not be nec-
essary unless there is process drift that cannot be otherwise explained or, of
course, if there is an implemented process change. An example is given in the
Revalidation section.
Every excursion outside of a control limit requires an investigation at
that step in the process, and perhaps at previous and subsequent steps, a for-
mal report as to the nature of the cause and any actions taken to correct it.
The batch is not necessarily discarded; rather, disposition is based on the
cause found and is evaluated on a case-by-case basis. We would become
90
UCL
i. •
()
85
• •
Gl
e:. • • •
c
...J
w 80 • •
s::
•
75 LCL
70 +----+----+----+----+----+----+----+----+----+----+---~
2 3 4 5 6 7 8 9 10 11 12
BATCH NUMBER
466 Validation of Active Pharmaceutical Ingredients
concerned with the development of a definite trend in the data, within the
control limits, although we have not formally implemented trend definitions,
such as the Western Electric (1956) control rules.
Change Control
An important component to validation that is often overlooked is an ade-
quate change control program. Clearly, once a process is validated, there
needs to be a strong program in place to ensure the process is not changed,
even in minor ways, without prior authorization by the appropriate individu-
als. The program needs to be well documented so changes can be clearly
traced, but it need not be overly cumbersome.
Even in the early stages of development, process changes need to be
recorded. Good documentation can be very useful later in development and
scale-up. Written descriptions as to what is being changed and why adds to
process understanding. Knowing things that do not work well is often as in-
formative as knowing those that do.
A particular filter membrane material may be replaced by one that hap-
pens to bind some level of DNA. If this information were to become lost dur-
ing process transfer, the plant might revert to the previous material for cost
reasons and the process would be different, with unknown effects down-
stream.
At some stage of development, the process becomes basically fixed. Re-
finements have been made to provide a robust and cost-effective process. This
usually occurs by the time of pivotal Phase 3 clinical trials for biotechnology
products. Thus, the process is known, describable, and the operational para-
meters such as flow rate, temperatures, and pressures are clearly defined. The
performance parameters, such as step yields, are necessarily specified within
wide limits until extensive production data are accumulated.
Further changes are expected to be required as the process is scaled up
for Phase 2 and 3 manufacturing. Most are based on necessities of scale, but
some will be based on further refinements for increased purity, ease of
production, and increased robustness. Indeed, such changes can be imple-
mented well after licensure, and with proper documentation and authoriza-
tion should not be automatically avoided.
The required documentation is basically a justification, based on solid
data, that the proposed change does not significantly alter the manufacturing
process and results in product of the same bioequivalancy. By not altering the
manufacturing process, we mean the same basic physical and chemical princi-
ples are involved. Changing a type of cation exchanger is clearly less of a sub-
stantive change than switching to an anion exchanger, or, more drastically,
using an entirely different separation mechanism such as liquid-liquid extrac-
tion. With the latter, severe changes can certainly be made, but more data and
documentation would be required, and the process might be considered
Validation of Biotechnology Active Pharmaceutical Ingredients 467
Revalidation
Revalidation of a process need not follow the concept of revalidation of a fa-
cility and equipment or cleaning validation. That is, once it is validated, there
is no need for revalidation unless there is a change. In the absence of changes,
there is normally a low level of equipment and cleaning revalidation rou-
tinely performed on an annual or biennial basis. Process revalidation can
merely be a formal review of the performance parameters, the nature and fre-
quency of excursions of these parameters, and operational variables. Such a
review could be included as part of the annual product review.
When a change is proposed, it may or may not have a significant impact
on the process or product quality. The proposed change does, however, need
to be reviewed by a process scientist or process engineer in order for that de-
termination to be made. Many changes, such as like-for-like filters, might
have no effect on the process, but the final call should be from a process bio-
chemist or engineer and not just QA.
If the change affects the process or quality, some degree of revalidation
will need to be performed. The specifics will vary with the process and the
change, but the Master Plan can give some guidance on this issue. That docu-
ment might state that the unit operation owner is to review the original
process validation report and draft a protocol to readdress all or pertinent
variables of the step in question, and set the number of runs to be monitored.
A decrease in wash buffer volume at a chromatography step might be
proposed to decrease process waste volumes and decrease process time. This
change holds a reasonable chance of affecting quality, and some preevalua-
tion would be required to justify acceptability (see "Change Control," above).
Beyond that, the process owner should issue a protocol to monitor the vol-
umes used, to sample for in-process purity assays, and to track the process per-
formance parameters already in place. At the end of the monitoring program,
Validation of Biotechnology Active Pharmaceutical Ingredients 469
an addendum to the process validation report is written and signed by the rel-
evant persons. It is important to keep the revalidation reports associated with,
but distinct from, the originals. Previous data are not superseded; rather,
process validation documents are freestanding, nonevolving documents that
can be added to, but not changed. Another way of stating this is that all
process validation documents have unique numbers with no provision for re-
visions.
Making a change that is expected to shift the value of a performance pa-
rameter requires more extensive revalidation. One that decreases the purity at
a specific step is most troublesome, and substantial data showing recovery of
purity downstream, and certainly demonstrating biochemical equivalency at
the final bulk stage, is absolutely necessary.
On a particular Escherichia coli process, we defined the performance of a
seed flask growth step in terms of the time it took to reach the transfer optical
density of 2.0 at 660 nm. This growth time was useful in describing that step
as it verified proper nutrient composition, temperature, aeration, and am-
poule inoculation volume. When the time came to begin using a new seed
lot, it was known the initial cell density was slightly lower and that the LCL
would be frequently violated.
A protocol was issued to implement the new seed lot, suspend the for-
mal enforcement of control limit excursion, and monitor the new growth
times to allow recalculation of the control limits (both upper and lower). This
required 12 runs to complete the protocol, and the step was considered reval-
idated, with new control limits.
REFERENCES
FR. 1996. Current Good Manufacturing Practice: Amendment of certain requirements
for finished pharmaceuticals; proposed rule. Federal Register 61 (87):20103-20115
(3 May 1996).
Gershon, M. 1991. Statistical process control for the pharmaceutical industry.]. Parent.
Sci. Techno/. 45: 41-50.
Greer, D. A., and E.]. Halteman. 1991. The Swiss army knife of control charts. In Proc.
Joint Statistical Meeting. San Francisco, pp. 1-5.
Kelley, B. D. 2000. Establishing process robustness using designed experiments. In Bio-
phannaceutical process validation, edited by G. Sofer and D. W. Zabriske. Marcel
Dekker: New York, pp. 29-59.
Martin-Moe, S., W. H. Kelsey, ]. Ellis, and M. E. Kamarck. 2000. Process Validation in
Biopharmaceutical Manufacturing. In Biophannaceutical process validation, edited
by G. Sofer, and D. W. Zabriskie. New York: Dekker, pp. 287-298.
Murphy, R. 1996. In Cleaning and cleaning validation: A biotechnology perspective, edited
by]. Voss. Bethesda, Md., USA: PDA, pp. 91-106.
4 70 Validation of Active Pharmaceutical Ingredients
Seely, R.J., H. V. Hutchins, M.P. Luscher, K. S. Sniff, and R. Hassler. 1999. Definining crit-
ical variables in well-characterized biotechnology processes. BioPharm 12 (4): 33-36.
Trubinski, C.]., and M. Majeed. 1984. Retrospective process validation. In Pharmaceu-
tical process validation, edited by B. Loftus and R. Nash. New York: Marcel Dekker,
pp. 149-179.
AT&T. 1956. Statistical quality control handbook. (This handbook is no longer available
through commercial sales. Inquiries may be addressed to AT&T Technologies,
code 700-444, Indianapolis, In 46219.)
Validation of Biotechnology Active Pharmaceutical Ingredients 4 71
APPENDIX 17.1
Introduction
Validating the stability of each buffer held for an extended period is an im-
portant part of process validation. This will be done by purposely holding
each buffer in its respective hold tank and testing for maintenance of the
chemistries given in the appropriate manufacturing SOP for each buffer, and
for presence of bioburden and endotoxin.
Purpose
This protocol will define the procedures to perform the extended hold testing,
with data sheets to be completed for each buffer. The protocol will demon-
strate that the buffers are stable for up to 18 days.
Scope
This protocol is general in nature, to be used for all buffers expected to be held
for greater than 24 hours. Individual data sheets will be completed for each
test, with data entry slightly different for each buffer. The stability program
applies to the process as run in building _ __
Stock solutions, such as 6 N HCl, are not addressed here; the expiration
dates arrived at in Amgen Center are used.
The solubilization buffer is also not examined. This solution is prepared
over a relatively long time period (9 h), tested, but then is used within the
next 24 hours.
The monitoring of stability will be performed for the three time periods
given below, and for two consecutive batches.
Responsibilities
1. Process Development
1.1 Write initial protocol.
1.2 Ensure that every buffer identified in the Scope section is
tested.
472 Validation of Active Pharmaceutical Ingredients
1.3 Obtain most of the required samples and complete the in-
formation on the data sheets and work closely with oper-
ators to obtain some samples.
1.4 Perform the pH and conductivity tests, using the same in-
struments used in manufacturing at point of use.
1.5 Compile and report the results.
1.6 Control the finalized documents.
2. Manufacturing
2.1 Prepare the buffers at full scale.
2.2 Assist Process Development in obtaining some of the
samples.
2.3 Perform the initial tests outlined in the buffer specific
SOP for buffer release.
3. Analytical Resources
3.1 Log in and route the samples submitted.
3.2 Perform the endotoxin assay.
3.3 Perform the bioburden assay.
3.4 Supply the results to the protocol originator.
4. Quality Assurance
4.1 Review and sign protocol and report.
4.2 Control a scanned copy of the documents and raw data.
Procedure
Buffer tanks will be labeled with the date of preparation and the date for the
10-, 14-, and 18-day elapse times. This will be done by Process Development.
1. For each buffer and time point, enable buffer transfer and flush at
least 4 L of buffer through the sample valve at the point of use and
remove 40 mL in a polypropylene tube. Label"PV Chern." and in-
clude date, initials, time point, and name of buffer. This sample is
for pH and conductivity.
2. Also collect a 10 mL sample into a polystyrene tube. Label "PV
LAL" and include date, initials, time point, and name of buffer.
This sample is for endotoxin.
3. Also collect 100 mL in a polypropylene container. Label "PV BB"
and include date, initials, time point, and buffer name. This sample
is for bioburden.
Validation of Biotechnology Active Pharmaceutical Ingredients 4 73
Acceptance Criteria
Each buffer will be validated for stability up to 18 days if all the buffer chem-
istry, endotoxin, and bioburden criteria in Table A are met.
8. Table B. Buffer Stability Data Report Table
Buffer N a m e - - - - - - - - - - - - - - - - - - - - - - - -
Buffer C o m p o s i t i o n - - - - - - - - - - - - - - - - - - - - -
Procedure N o . - - - - - - - - - - - - - - - - - - - - - - -
Lot No. (Date of P r e p . ) - - - - - - - - - - - - - - - - - - -
Date _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ __
Initials - - - - - - - - - - - - - - - - - - - - - - - - - -
474 Validation of Active Pharmaceutical Ingredients
Zero (Transfer)
10 days
14 days
18 days
Other
18
MICROBIOLOGICAL ATTRIBUTES
OF ACTIVE PHARMACEUTICAL
INGREDIENTS
475
4 76 Validation of Active Pharmaceutical Ingredients
In March 1998, the FDA issued a document titled, Guidance for Industry:
Manufacturing, Processing, or Holding Active Phannaceutical Ingredients (U.S.
DHHS 1998). Though this document was issued as a draft for comment pur-
poses only, it begins to provide guidance to industry by expanding on Mo-
tise's earlier comments, and by clearly outlining the FDA's philosophy
regarding the relationship between API manufacture and the application of
relevant GMPs. Broadly speaking, the FDA views validation and documenta-
tion of processes and test methods as key to assuring quality and purity of
APis. More specifically, the FDA expects that applicable GMPs will be applied
more stringently as API production proceeds from synthesis through purifi-
cation and (where applicable) sterilization. 21 CFR, 211.113, "Control of mi-
crobiological contamination" (1998), states,
adaptations of the established methods for finished drug products. Since there
is no set of rules that specifically governs the API industry, the benchmarks,
testing standards, methods, and data interpretations used in the microbiolog-
ical analyses of the bulk material are not uniformly applied throughout the
industry. Unfortunately, the microbiological quality of APis between and
even within manufacturing environments may vary significantly.
PRELIMINARY ISSUES
appropriate temperature (22 ::±:: 2.5°C or 32 ::t 2.5°C) for not less than 14 days
and examining test specimens for the presence of growth. No observed
growth indicates that the lot of medium is sterile and suitable for use.
In the growth promotion portion of the test, each lot of medium is in-
oculated with fewer than 100 colony forming units (CFU) of each of a general
panel of microorganisms described in the USP Sterility Test (USP 1999b), or
indicator organisms appropriate to the particular selective medium under test
(e.g., Salmonella used to test Brilliant Green Agar, Escherichia coli used to test
MacConkey agar, etc.). After incubation, plates are examined for evidence of
growth on general-purpose media and proper reactions on selective media.
Documented recovery and appropriate biochemical reactions of all test or-
ganisms coupled with the lack of growth on the sterility portion of the test al-
lows for the release of the medium for use in the laboratory.
Note: A CFU is a colony forming unit, or a bacterial colony that arises from one bacterial cell.
482 Validation of Active Pharmaceutical Ingredients
BIOBURDEN
methods and data interpretation are consistent with industry and (where ap-
plicable) compendia! standards. Validation of a supplier's test methods and
the lot-specific documentation of test data should be requested. A vendor au-
dit is a prudent measure even if the API manufacturer performs its own con-
firmatory testing of the data presented on the CofA. When performing a
vendor audit, including contract manufacturers and contract testing labora-
tories, assume that the laboratory providing the CofA is an extension of the
API manufacturer's own laboratory. Contract laboratories and suppliers
should be held to the same standards (training, methods validation, SOPs,
documentation, investigation of OOS results, etc.) to which an in-house lab-
oratory would be held.
Because they are generally unblended, microbial contamination of in-
coming raw materials or process intermediates is rarely consistent across the
batch or lot of product but rather is very often found in "pockets" within the
batch. Since microorganisms are ubiquitous in the nonsterile manufacturing
environment, these pockets of microorganisms can be formed by exposure of
the API or intermediate to operators and/or the environment. Frequently,
however, pockets are formed as the result of improperly cleaned and dried pro-
cessing equipment. Improper cleaning can result in contamination of the first
portion of a batch with a bolus of microorganisms. As the process continues
and the system is purged, later stages of the batch will contain fewer microor-
ganisms. Likewise, a mechanical intervention due to equipment failure or a
system shut down could result in an intermediate portion of the batch being
contaminated. Testing of large samples taken as composites across the batch
are suggested to increase the probability that any large pockets of contamina-
tion will be sampled and detected.
API PROCESSING
point during manufacture where the process evolves from a series of chemi-
cal reactions to a recognizable API is the point at which strict adherence to
cGMPs becomes an issue for the API manufacturer (FDA 1991b; Brocklebank
and Deo 1996; PhRMA 1995a-c, 1997).
It is important for the API manufacturer to recognize that once a sterile
powder is made, there is no further processing to remove contaminants or im-
purities such as particulates, endotoxins, or degradants. Therefore, it is very
important to understand those practices and processes that may affect the mi-
crobial profile of the sterile bulk powder during its manufacture.
Nonsterile liquid APis are often rendered sterile by filtration through a
sterilizing filter. Powdered APis are reconstituted, filtered, and dried again
downstream of the sterilizing filter. FDA expectations for filtration efficiency
and validation are clearly defined, and have remained virtually unchanged
for many years (FDA 1987b).
Routine processing of sterile APis usually involves the transfer of the
nonsterile liquid material from a manufacturing vessel into a sterilized hold-
ing vessel through one or several sterilizing filters. Many companies utilize the
concept of redundant filtration on the premise that filter failure is usually a
highly unusual event, so a failed filter would generally be supported by an ac-
ceptable filter and therefore minimize the risk of microbial contamination.
The filtration process must be capable of removing at least 107 microorgan-
isms per cm2 of filter area. Several major filter manufacturers have described
the mode of filtration as a "sieving" process, and this concept has been con-
firmed through the use of scanning electron microscopy to examine filter sur-
faces. This microscopy demonstrated that after filtration of a liquid
containing bacteria, the membrane surface is not covered by a monolayer of
cells, but rather consists of a multiple layer sieve effect with some layers of
cells on the surface of the filter acting as a sieve to exclude other bacterial cells
and large particulates, some of which penetrated as deep as 30 J..t.m into the
membrane (Osumi et al. 1996).
All filters must pass a bubble point (or pressure hold) test, which is a
means to demonstrate integrity of the filter. The purpose of this is twofold:
(1) to provide the API manufacturer assurance that the filter used for steril-
ization is devoid of flaws before being used in the process, and (2) to provide
demonstration of the integrity of the filter after it was used for processing.
Testing is performed by pressurizing the upstream side of the filter and ob-
serving for bubbles in water out of the downstream side. If no bubbles are
seen when pressure is applied up to the manufacturer's recommended bubble
point value (usually in terms of pounds per square inch), the filter is consid-
ered acceptable for use. Filter manufacturers usually have technical experts
who are willing to assist in the selection of the appropriate filter medium de-
pending on the composition of the API (e.g., materials with high solvent con-
tent, extreme pH, etc.) to provide a filter medium and configuration with
construction materials that will not be attacked or damaged by the material
being filtered.
488 Validation of Active Pharmaceutical Ingredients
as wooden pallets, pads of paper, cardboard, and any other materials that can-
not be adequately sanitized.
Equipment coming in contact with the API product must be rugged, eas-
ily cleanable, and inert to the product. Equipment should have smooth sur-
faces with curved corners and no seams to facilitate cleaning. Any sterile
holding vessels should be equipped with microporous hydrophobic vent fil-
ters to prevent the inadvertent introduction of microbial contamination
through the vent. Manufacturing equipment may be used for several prod-
ucts, or it may be dedicated to a single product. If used for more than one
product, careful attention should be given to cleaning between campaigns to
prevent "crossover" of dissimilar products. Validation of cleaning agents and
cleaning procedures is an important part of any API process to assure not only
that there is no residual product remaining after cleaning, but also to assure
that the cleaning process is effective against any bacteria that might be part of
the normal bioburden.
Depending on the process, equipment used in the production of APis
may require sterilization after cleaning. The method of choice for the steril-
ization of equipment and transfer lines is saturated clean steam under pres-
sure (FDA 1994). Appropriate sterilization cycles for all items used in the
manufacture of the product must be developed as part of the validation of the
process. For the sterilization cycle to be valid, the bioburden (both numbers
and types of microorganisms) of the product should be determined and eval-
uated for its resistance to the proposed sterilization cycle. The development
and validation of steam sterilization revolves around the use of F0 values, D-
values, and z-values to describe the efficiency of the sterilization process
(Pflug 1980). The term F0 is defined as the actual time of sterilization in terms
of its equivalence to 121.1 oc, the D-value is the time it takes to reduce the chal-
lenge microorganism population by one log (90 percent), and the z-value is
the number of degrees of temperature necessary to cause the D-value to
change by a factor of 10. These three parameters are used routinely in the
evaluation and validation of steam sterilization processes.
Thermocouples and resistance thermal devices (RTDs) are routinely
used to monitor the temperature at various locations within the sterilization
chamber in order to demonstrate the uniformity of heat distribution and
penetration in the empty chamber and throughout the load being sterilized.
Some of the more sophisticated sterilizers can be programmed to monitor the
level of sterilization at various points within the chamber by means of imbed-
ded RTDs, and they can be programmed to terminate the cycle at the moment
the coldest part of the chamber reaches the appropriate combination of tem-
perature and exposure time.
Biological Indicators (Bis) are carriers that usually contain large popula-
tions of bacterial spores known to be resistant to the effects of the sterilant,
which in this case is moist heat. Bls are used to support the physical monitor-
ing (F0 , D, and z-values) of the sterilization process and provide a biological
demonstration that the sterilization cycle is effective against even the most
490 Validation of Active Pharmaceutical Ingredients
is 0.5 minutes, and the desired SAL is at least 10-6 (no more than 1 CFU in
1,000,000 g) the Fa determination is 4.0 minutes:
This means the process must deliver the equivalent of 4.0 Fa (minutes of ster-
ilization at temperatures equivalent to 12l.l C) to assure a 6-log SAL due to
0
exceed that of the filter sterilization validation. All other forms of sterile
product (ointments, creams, suspensions, etc.) need to follow these same
considerations.
Containment
In general, the production of multiple APis in the same facility is not an ob-
jectionable practice. However, for certain APis such as penicillin, some
steroids, and other drug or toxic substances that could cause adverse or even
fatal reactions in some patients, there must be separate facilities and com-
pletely separate air-handling systems to isolate these materials from each
other. Documented regulatory guidance on this issue is uncharacteristically
limited, however, with the only known published citation being in the FDA
Guide to Inspections of Sterile Drug Substance Manufacturers (1994).
Isolation of two manufacturing processes does not necessarily mean that
production must take place in two separate buildings or in areas separated by
some significant distance. Separation may be achieved within a building (or
a plant) by effectively isolating and sealing off from one another these two
types of operations. Although many different methods of segregating pro-
duction activities have been used to effectively isolate them from others
494 Validation of Active Pharmaceutical Ingredients
within the same facility, some production activities (e.g., fermentation and
purification of penicillins) can only be isolated through the use of separate
air-handling systems (Brocklebank and Deo 1996).
immediate and adjacent areas in which the product or containers into which
the product is being transferred are handled.
The air in critical areas should be supplied as high efficiency particulate
air (HEPA)-filtered laminar flow air (FDA 1987b). HEPA filters must be certi-
fied prior to use and should be recertified at least semiannually for critical ar-
eas. The dioctyl phthalate (DOP) aerosol test is the method of choice for
challenging and certifying HEPA filters. A DOP aerosol is introduced up-
stream of the filter, and a probe is positioned downstream of the filter to de-
tect any particles that get through the filter medium. Readings equivalent to
a 0.01 percent penetration of the challenge particles indicate a significant
leak.
There are two ways to sample the air and test it for the presence of mi-
croorganisms. The preferred method is described as "active" sampling, which
involves the intake of a specified volume of air into an instrument, and ex-
posing it to a plate or plastic strip containing sterile microbiological growth
medium. The number of microorganisms that are observed on the growth
medium after incubation is indicative of the number of microorganisms pre-
sent in the sampled volume of air. Popular instruments used for active air
sampling are the slit to agar sampler, sieve-type samplers, and the centrifugal
air sampler. Generally speaking, slit to agar instruments sample a larger vol-
ume of air than centrifugal air samplers. The use of slit to agar samplers in
nonsterile areas can result in a grossly overgrown plate due to exposure to a
large volume of nonsterile air. In these areas, the use of a carefully directed
and carefully timed centrifugal air sampler can provide enumeration of mi-
crobial counts in a specific volume of air without overgrowth.
In passive sampling, settling plates, which are petri dishes filled with ster-
ile microbiological growth medium, are placed in areas on the floor and equip-
ment in the controlled area, and are allowed to sit open for some specified
period of time, usually one hour. Longer exposure times are possible or even
desirable depending on the manufacturing conditions. It should be noted that
in any air sampling technique, care must be taken not to overexpose the
growth medium to too much air, as desiccation of the medium can affect re-
covery of microorganisms. Since there is no active intake of a specified volume
of air, the microorganisms that fall onto the surface of the plate find their way
there through the forces of gravity and air movement in the room. This
method is less well defined than active sampling procedures in that counts
cannot be correlated with a specific volume of air, and is subject to inadver-
tent contamination by spills, operator error, etc. However, settling plates,
when properly distributed and analyzed, can provide a general picture of the
microbiological quality of the air in both classified and unclassified areas.
In any air sampling method, the firm can utilize either a general pur-
pose growth medium such as soybean casein digest (SCD) medium to get a
broad picture of the quality of the air or various selective growth media to
look for specific types of microorganisms such as the utilization of Sabouraud
dextrose agar (SDA) or potato dextrose agar to select specifically for fungi.
Microbiological Attributes of Active Pharmaceutical Ingredients 499
No matter what method is used to sample the air, the firm must set a
limit for the number of allowable CFU per cubic foot, cubic meter, or (in the
case of settling plates) per hour of air in the controlled area. The limits are
usually linked to the classification of the room (Class 100 rooms have the
lowest limit) and the specific activity that takes place in the room. In the
General Information Chapter <1116>, Microbiological Evaluation of Clean
Rooms and Other Controlled Environments, the USP has proposed limits
for active air sampling in classified areas of 0.1 CFU per cubic foot of air for
Class 100 rooms, 0.5 CFU per cubic foot of air for Class 10,000 rooms, and
2.5 CFU per cubic foot of air for Class 100,000 rooms (USP 1999h). Al-
though no official limits have yet been established for unclassified areas, a
survey conducted by PhRMA suggests that many companies involved in
monitoring these areas set action and alert limits for total counts based on
the history of the area and the intended use of the product (PhRMA
1995a-c, 1997).
After incubation of exposed growth media, colonies are counted and the
total number of CFU per cubic meter, cubic foot, or hour of exposure is
recorded. Representative colonies are screened for the presence of objection-
able microorganisms. In Class 100 and some Class 10,000 areas, representa-
tive colonies are generally identified to the species level because of the
criticality of potential product exposure to the environment. For Class
100,000 areas and unclassified areas, representative colonies are identified by
at least a Gram stain and may be identified at least to the genus or even
species level depending on the criticality of the process and the eventual
route of administration of the product. Identification of representative
colonies serves a number of purposes.
• It provides a profile of normal flora present in the manufacturing
area (baseline).
• It provides a mechanism for screening for objectionable organisms.
• It provides a benchmark when investigating batches that have
failed microbial limits or sterility testing.
• When trended, it serves to alert QC/QA/manufacturing to drifts
away from the normal operating condition and prevent product
failures by early intervention to correct potential problems.
walls and floors and also large flat surfaces on equipment. Swabs are used to
sample small irregular surfaces such as nooks and hard-to-clean areas of
equipment, grates, and corners where walls or walls and floors meet.
Contact plates are small petri dishes (25-30 cm 2) filled with sterile mi-
crobiological growth medium. The plates are slightly overfilled so that the
surface of the medium rises above the rim of the plate. The exposed agar is
pressed against the surface in question, picking up resident microorganisms.
After sampling, care must be taken to wipe the area clean to remove any resid-
ual growth medium from the surface.
As with media used for the microbiological analysis of air, contact
plates can contain either general growth media or selective growth media.
Contact plates usually contain neutralizing agents such as lecithin and
polysorbate 80 to counteract the bactericidal or bacteriostatic effects of resid-
ual disinfecting or sanitizing agents that may remain on equipment, walls,
or floors after cleaning. Contact plates are considered to be quantitative, as
colonies that are recovered from surfaces can be easily enumerated after in-
cubation. As with air sampling plates, representative colonies are chosen for
identification to establish a baseline of normal flora and screen for objec-
tionable microorganisms.
Alternatively, two different incubation techniques using only SCD
agar supplemented with lecithin and polysorbate 80 have been described
as giving equivalent or better recoveries of yeast and mold than using the
selective SDA agar (Marshall et al. 1998). In the first technique, SCD
medium supplemented with lecithin and polysorbate 80 is incubated
first at 30-35°C for 70-72 hours and shifted to 20-25°C for an additional
70-72 hours. In the second technique, supplemented SCD medium is in-
cubated only at 30-35°C for 72 hours. It must be remembered that growth
promotion testing must mimic the particular incubating technique that is
routinely used by the laboratory. For example, if a lab chooses to monitor
using SCD and shift incubation temperatures after 72 hours, each lot of
medium must be "growth promoted" using bacteria, yeast (Candida albi-
cans), and mold (Aspergillus niger) and shifting the temperature as in rou-
tine use.
Not all surfaces are amenable to sampling using contact plates. For ir-
regular or hard-to-sample surfaces, a sterile swab is moistened with sterile wa-
ter and is rubbed over an area of the surface or crevice that is roughly equal
to the area of a contact plate (25-30 cm 2). Swabs may be incubated directly
in liquid bacteriological growth medium containing neutralizers, in which
case the result is recorded as "growth" or "no growth." Alternatively, the
swab may be temporarily placed in a measured volume of sterile transport
medium containing neutralizers, and once returned to the lab, the transport
medium can be plated so that the number of CFUs that are picked up by the
swab may be enumerated. As with contact plates, swabs may be transported,
plated, and incubated in selective media to encourage the growth of particu-
lar microorganisms.
Microbiological Attributes of Active Pharmaceutical Ingredients 501
Sterility Testing
Sterile API batches are usually tested for the presence of microorganisms us-
ing a composite sample taken from several containers across the batch. The
Sterility Test consists of reconstituting powdered API or pooling a liquid ma-
terial in a suitable diluting fluid and filtering the resulting solution through
one or more 0.45 J.Lm filters. The filter(s) are then incubated in two different
bacterial growth media, and are examined periodically for growth, which is
evidence of microbial contamination of the material (Shirtz 1987; USP
1999b). For those products that are insoluble, the USP allows for a "direct
test" where the product is introduced directly into tubes containing the
growth medium. As with the membrane filtration test, tubes are examined pe-
riodically for evidence of growth.
Validation of the Sterility Test requires that the specimen be proven in
preliminary testing not to interfere with the sterility test process. In this pre-
liminary testing, called "bacteriostasis and fungistasis" (B/F), the sample
quantity is diluted and, if necessary, inactivated in such a manner to render
it ineffective against potential contaminating microorganisms. The effective-
ness of this inactivation must be demonstrated by suitable growth of several
strains of indicator microorganism in the final test media vessels.
The USP and most international compendia require the use of two dif-
ferent culture media for the Sterility Test, one for the detection of aerobic mi-
croorganisms and the other for anaerobic microorganisms, each with its own
incubation requirements. The media vessels are visually examined periodi-
cally after testing for evidence of contamination, which is usually shown by
the development of turbidity or by the development of fungal structures. If
none is present, the batch from which the sample is taken is considered as
having met the requirements of the sterility test. However, if the media ap-
pears turbid or if there appears to be evidence of fungi, the sample is consid-
ered to have failed. Extenuating circumstances may, under specific conditions
where analyst or other testing error can be proved, allow for a repeat test. It is
incumbent on the manufacturer to provide convincing documentation via a
well-documented investigation to allow this retesting (USP 1999b). Such doc-
umentation may consist of evidence the test procedure was flawed in some
way so as to influence the outcome of the test, and that the positive result was
more likely to have occurred through analyst error than via the product itself.
Sterility testing is usually performed under a laminar flow hood in a
Sterility Test suite, which is a classified/controlled area. This area should be
cleaned, monitored, and held to the same specifications and requirements as
classified areas used in production. Since the Sterility Test is a very labor in-
tensive task that is prone to contamination by inadvertent analyst error, many
parenteral manufacturers and contract laboratories are electing to use isolator
systems for sterility testing. The isolator system is regarded as the current state
Microbiological Attributes of Active Pharmaceutical Ingredients 503
of the art in the microbiology laboratory, as its use nearly eliminates potential
contamination of the test by operator error (Shirtz 1995; Wood 1995). The
driv- ing force for the movement to isolators for sterility testing is the restric-
tive nature of the FDA's stance on retests as defined in their 1987 Aseptic Pro-
cessing Guideline (FDA 1987b) and reference to current USP procedures (USP
1999b).
Few tests in the compendia have the limitations of the sterility test.
cGMP requirements demand an extremely low contamination rate for aseptic
processing, which is proven through careful process validation and strict en-
vironmental control. Examination of data on the probability of a sterility re-
jection suggests that the sterility test does not, in fact, assure sterility in a
batch. Data published for the probability of detecting sterility failures in fin-
ished vials provides an excellent source of guidance when interpreting steril-
ity test results from APis (Table 18.3).
Table 18.3 indicates that while the current USP sterility test has difficulty
detecting low-level contamination, it will usually detect grossly contaminated
product (Shirtz 1987; Wood 1995). Thus, the USP Sterility Test is not really a
check on the sterility of a batch of product or drug substance but rather is a
monitor for gross manufacturing breakdowns.
Table 18.3 Probability of Lot Rejection Based on Contamination Level and Sample
Size
% Contamination
and ultimately into finished dosage parenteral preparations primarily via wa-
ter systems. The presence of endotoxins in oral dosage forms is not consid-
ered to be a problem, because endotoxins do not pass from the intestinal tract
to the blood system.
Endotoxins are quite stable molecules. They can survive autoclaving and
can pass through sterilizing filters. Thus, a preparation may be sterile, but if
it was once exposed to Gram-negative bacteria, it may still contain endotox-
ins. Conversely, since endotoxins are unique components of Gram-negative
cell walls, a preparation may be nonsterile (i.e., contain numbers of viable
Gram-positive bacteria) but may be free of detectable endotoxins.
guide specifically written for the validation and use of quantitative LAL test
methodologies (FDA 1991a).
Of the two tests (the rabbit pyrogen test or the LAL test), the LAL test is
the preferred method for the detection of endotoxin in APis, intermediates,
raw materials, water, and finished pharmaceutical dosage forms. Characteris-
tics of the LAL test that make it the pyrogen test method of choice over the
rabbit test include the following:
• The LAL test is specific for endotoxins, the primary pyrogenic con-
taminant in pharmaceutical preparations.
• The LAL test is considerably more sensitive and certainly more con-
sistent in the detection of endotoxin than the rabbit pyrogen test.
• Endotoxin levels in products under test can be quantitated using
LAL, which facilitates trend analyses to monitor the quality of any
process over time.
• LAL testing is less time and labor intensive than rabbit pyrogen
test, meaning that associated costs of LAL testing are lower than is
the USP rabbit pyrogen test.
Endotoxin Limits
The concept of the endotoxin limit defines a maximum allowable level of en-
dotoxin in the product. The endotoxin limit for a dose of a parenteral prod-
uct is 5 EU/kg (FDA 1987a; USP 1995a). This 5 EU/kg limit or the "threshold
pyrogenic dose" was determined experimentally in rabbits and defines a level
of endotoxin above which is likely to cause a fever (Tsuji et al. 1980; Dabbah
et al. 1980). Endotoxin levels below the threshold pyrogenic dose are clini-
cally insignificant, as they are too low to cause a fever in an animal. There is
no way to measure for the absence of endotoxin in a drug product; the sensi-
tivity of the test method provides a minimum detection level.
The endotoxin limit for any drug product and/or compendia! drug sub-
stance is dependent on the maximum human dose of the drug product or
substance, and is calculated using the formula,
K
M
where K = the threshold pyrogenic dose of 5 EU /kg, 0.2 EU /mL
for intrathecals, and M = the maximum human dose in units/kg.
Those substances with high dosages have relatively low endotoxin lim-
its; those substances with low dosages have relatively high endotoxin limits.
The FDA has calculated endotoxin limits for most compendia! drug products
and drug substances, and has listed these limits in the "Appendix E" to its
1987 Guideline (FDA 1987a). USP monographs for most parenteral drugs and
some APis also specify endotoxin limits.
Microbiological Attributes of Active Pharmaceutical Ingredients 507
might need to be tested for total microbial count and for the presence of ob-
jectionable microorganisms, but it does not need to be tested for endotoxin.
Recognizing that dextrose is a natural product that may contain some level of
endotoxin, customers for parenteral grade may have in-house specifications
that are passed on to the supplier requiring low bioburden and low endotoxin
in the lot of material to be purchased. Purchasers may ask for preshipment
samples to confirm the manufacturer's certification and assure themselves
that the lot of material to be shipped is acceptable for the intended purpose.
Endotoxin specifications for noncompendial articles may be set by the
user based on a "back calculation" from the endotoxin limit that has been es-
tablished for the final product (McCullough 1988). For example, assume a
mythical formulation consisting of four general components: an active ingre-
dient that is derived from recombinant technology, an organic stabilizer, and
a preservative, all in a buffer solvent. Each of these components is a potential
contributor of endotoxin to the final formulation: the active ingredient is a
product of a recombinant process and is considered a natural product; the sta-
bilizer may be extracted from a plant or animal source and is a natural prod-
uct; the preservatives are probably synthetics; the chemicals that are used in
the buffer solution are inorganics; and the water is a very important raw ma-
terial used in the production of this or any product. Since the active ingredi-
ent and stabilizer are derived from natural sources, they should each be
considered as a significant potential source of endotoxin, and should be given
a priority for validation and endotoxin testing. Microorganisms generally do
not grow in or on purified inorganic chemicals, and so the salts used in the
preparation of the buffer should be given a lower priority in the testing hier-
archy since these materials will likely contribute little or no endotoxin to the
final formulation. Water is a major raw material and must be monitored for
endotoxin levels, particularly if the water has been given the label of WFI or
other categories of water with established compendia! endotoxin limits.
The easiest way to assign endotoxin limits to the four fractions (active
ingredient, stabilizer, preservative, and buffer) is to take the limit for the final
formulation and divide it by four. Using this method, the amount of active
ingredient in 1 mL of the formulation could contribute up to 25 percent of
the total allowable endotoxin (endotoxin limit); the stabilizer could con-
tribute up to 25 percent; the preservative could contribute up to 25 percent;
and the chemicals used to prepare the buffer could contribute up to 25 per-
cent. If WFI is used in the formulation, its contribution should be less than
the compendia! 0.25 EU/mL limit. If water other than WFI is used, its poten-
tial contribution may be significant and needs to be taken into account. For
this example:
• The final formulation is allowed 4 EU /mL.
• Each component is allowed to contribute 25 percent of the allow-
able load, or 1 EU/mL.
Microbiological Attributes of Active Pharmaceuticallngredients 509
Yet another way to look at the problem, particularly if the active ingre-
dient is produced in a Gram-negative host, is to assign virtually all of the en-
dotoxin load to the active ingredient, regardless of its concentration in the
final formulation, because it is the fraction that is most likely to contribute
endotoxin to the final product. There is no one "right way" to assign endo-
toxin limits to noncompendial materials. However, no matter which method
is ultimately chosen for the assignment of endotoxin limits to formulation
components, specifications and alert/action limits should be assigned based
on a solid logic stream, sound scientific principles, and where possible, on
historical data and the origin of the component in question.
SUMMARY
For many years, the FDA has recognized the significance and importance of
stringent requirements for the manufacture of pharmaceutical dosage forms.
These requirements, or cGMPs, were originally designed to be applied to fin-
ished products only. In recent years, however, the FDA has stated frequently
the intention to extend these requirements to drug components, including
APis. This extension of the requirements is pushing the cGMP concepts fur-
ther back in the process, forcing API manufacturers to consider many of the
same current microbiological concerns involved with finished product pro-
cessing, holding, and distribution.
Many of these issues have applied for years in the sterile API area, espe-
cially with those for which no further sterilization processing is required.
These considerations, however, may be somewhat new to nonsterile API man-
ufacturers. Primary among these are the water systems used for API process-
ing. Since water is an integral part of most processes including the
formulation, processing solutions, and equipment washing, every effort
should be made to assure its continual microbiological quality. Likewise, the
quality of incoming materials should be assessed for their potential to add
Microbiological Attributes of Active Pharmaceutical Ingredients 511
GLOSSARY
Active Pharmaceutical Ingredient The active ingredient in the final dose
form product (Brocklebank and Deo 1996).
Aer~bicMicroorganism A microorganism capable of growing in the presence
of atmospheric oxygen (Prescott et al. 1993).
Airborne Particulate Cleanliness Class The level of cleanliness specified by
the maximum allowable number of particles per cubic meter (or cubic foot)
of air (Federal Standard 209E 1992).
Anaerobic Microorganism A microorganism capable of growing in the ab-
sence of atmospheric oxygen (Prescott et al. 1993).
Bacteriostatic A substance or environment capable of inhibiting the growth
and reproduction of bacteria (Prescott et al. 1993).
Barrier A device that prevents contact between operators and the aseptic
field enclosed within the barrier (Wagner 1995).
Bioburden A term used to describe the microbial content of a material, in-
cluding both the types and numbers of microorganisms present (Leahy 1986).
Biological Indicator (BI) A carrier containing a specific species of heat resis-
tant microorganism used to test the effectiveness of a sterilization process
(Leahy 1986).
Bubble Point Test A test to predict or verify the performance and integrity of
a filter (HIMA 1982).
CFU A colony forming unit is a macroscopically visible growth or cluster of
microorganisms on a solid medium (Prescott et al., 1993).
512 Validation of Active Pharmaceutical Ingredients
Containment The separation of the work area from the outside environment
to protect the people and the environment from potent or undesirable sub-
stances, or the execution of a process in a manner that prevents the discharge
of contamination to the outside environment (Wagner 1995).
Controlled Areas Areas of a facility that are designed and maintained to min-
imize the amount of airborne particulates (Federal Standard 209E 1992).
DOP Testing A method used to test the integrity of HEPA filters in a con-
trolled environment (FDA 1987b).
HEPA Filter High efficiency particulate air filter, used to filter out at least
99.998 percent of the particles 0.3 JJ..m or larger from the air entering a clean
zone (Wagner 1995).
Isolator A barrier system that exchanges air with the outside environment
only through HEPA or equivalent filters, completely separating the process
from the operator of environment (Wagner 1995).
LAL Limulus Amebocyte Lysate, an extract from the circulating blood cells
of the North American horseshoe crab, Limulus polyphemus, used in the de-
tection of endotoxin in drug substances and drug products.
Laminar Airflow Airflow in which a whole body of air moves in the same di-
rection with uniform velocity in parallel flow lines (Wagner 1995).
Objectionable Microorganism Any microorganism that can cause infections
when the drug product is used as directed ("pathogenic") or any microorgan-
ism found in a sterile drug product. Sometimes, high numbers of less harm-
ful microorganisms may be considered as "objectionable" (FDA 1993).
Particulates Objects of solid or liquid composition, or both, generally be-
tween 0.001 J.Lm and 1000 J.Lm in size (Federal Standard 209E 1992).
Pretreatment Systems used to remove chlorine and other impurities from
source water prior to its introduction into a still, RO unit, or UF unit. Pre-
treatment systems usually consist of a carbon bed, sand filter, and bed of
mixed ionic material.
Pyrogens Any substance capable of causing a fever in a human or other
mammal.
Raw Material The starting materials used in the manufacture of an API.
Recombinant DNA Technology The techniques used in carrying out genetic
engineering (Prescott et al. 1993).
Reverse Osmosis A water treatment process in which the natural process of
selective permeation of molecules through a semipermeable membrane sepa-
rating two aqueous solutions of different concentrations is reversed. Pressure
is applied to overcome osmotic pressure and force pure water through the
membrane (Gennaro 1985).
Sterile The complete absence of viable microorganisms (Gennaro 1985;
Leahy 1986).
Sterilization A process by which all forms of viable microorganism, includ-
ing bacterial spores, are removed or destroyed based on a probability function
(Gennaro 1985; Wagner 1995).
514 Validation of Active Pharmaceutical Ingredients
REFERENCES
Brocklebank, M.P. and P. V. Deo. 1996. GMP issues for bulk pharmaceutical chemical
plants. Pharm. Engin. Oanuary/February): 8-26.
Carroll, M. 1995. Microbiological monitoring and control in isolation systems. In Isola-
tion technology: Applications in the pharmaceutical and biotechnology industries, edited
by C. M. Wagner and J. E. Akers. Buffalo Grove, lll., USA: Interpharm Press, Inc.
Code of Federal Regulations. 1998. Title 21, parts 210 and 211. Current good manufac-
turing practices.
Cooper, James F. 1990. Resolving LAL testinterferences. f. Parent. Sd. Technol. 44(1):13-15.
Dabbah, R., E. Ferry, and D. A. Gunther. 1980. Pyrogenicity of E. coli 055:B5 endotoxin
by the USP rabbit test-a HIMA collaborative study. f. Parent. Drug Assoc. 34:212.
Federal Standard 209E. 1992. Airborne particulate cleanliness classes in cleanrooms and
clean zones. Washington, D.C.: General Services Administration.
FDA. 1987a. Guideline on validation of the limulus amebocyte lysate test as an end product
endotoxin test for human and animal parenteral drugs, biological products and medical
devices. Rockville, Md., USA: Food and Drug Administration.
FDA. 1987b. Guideline of sterile drug products produced by aseptic processing. Rockville,
Md., USA: Food and Drug Administration.
FDA. 1990. Compliance program guidance manual for bulk pharmaceutical chemicals.
Rockville, Md., USA: Food and Drug Administration.
Microbiologica/Attributes of Active Pharmaceutical Ingredients 515
FDA. 1991a. Kinetic LAL testing: interim guidance for human veterinary dmg products and
biologicals. Rockville, Md., USA: Food and Drug Administration.
FDA. 1991b. Guideline to the inspection of bulk pharmaceutical chemicals. Rockville, Md.,
USA: Food and Drug Administration.
FDA. 1993. Guide to inspections of high purity water systems. Rockville, Md., USA: Food
and Drug Administration.
FDA. 1994. Guide to inspections of sterile dmg substance manufacturers. Rockville, Md.,
USA: Food and Drug Administration.
FDA. 1995. Human Dmg CGMP Notes 3(2):6.
FR. 1976. Current good manufacturing practice in the manufacture, processing, pack-
ing, or holding of large volume parenterals for human use. Federal Register 41
(1 June 1976), 212. 49.
Gennaro, A. R., ed. 1985. Remington's pharmaceutical sciences. Easton, Penn., USA: Mack
Publishing Co.
Greenberg, A. E., L. S. Clesceri, and A. B. Eaton, eds. 1992. Standard methods for the
examination of water and wastewater. Washington, D.C.: American Public Health
Association.
HIMA. 1982. Microbial evaluation of filters for sterilizing liquids, document #3, volume 4.
Washington, D.C.: Health Industry Manufacturers Association.
Hyde, W. A. 1998. Origin of bacteria in the clean room and their growth requirements.
PDA f. Pharm. Sci. Technol. 52(4):154-158.
ISO. 1998. ISO 13408-1, Aseptic processing of health care products-Part 1: General re-
quirements. Geneva, Switzerland: International Organization for Standardization.
Leahy, T. ]. 1986. Microbiology of sterilization processes. In Validation of aseptic phar-
maceutical processes, edited by F.]. Carlton and]. P. Agalloco. New York: Marcel
Dekker.
Marshall, V., S. Paulson-Cook, and]. Moldenhauer. 1998. Comparative mold and yeast
recovery analysis (the effect of differing incubation temperature ranges and
growth media). PDA J. Pharm. Sci. Technol. 52(4):165-169.
McCullough, K. Z. 1988. Process control: in process and raw material testing using
LAL. Pharm. Technol. 40.
Motise, P. ]. 1995. Human Dmg cGMP Notes, vol. 2, no. 3. Rockville, Md., USA: Food
and Drug Administration.
Osumi, M., N. Yanada, and M. Toya. 1996. Bacterial retention mechanisms of mem-
brane filters. f. Parent. Sci. Technol. 50(1):30-34.
PDA. 1990. Technical Report# 13: Fundamentals of a microbiological environmental mon-
itoring program. Bethesda, Md., USA: Parenteral Drug Association, Inc.
Pearson, F. C. 1985a. Endotoxin. In Pyrogens: endotoxins, LAL testing, and depyrogena-
tion. New York: Marcel Dekker.
516 Validation of Active Pharmaceutical Ingredients
Pearson, F. C. 1985b. LAL assay. In Pyrogens: endotoxins, LAL testing, and depyrogenation.
New York: Marcel Dekker.
Pflug, I. j. 1980. Syllabus for an Introductory Course in the Microbiology and Engi-
neering of Sterilization Processes. St. Paul, Minn.: Environmental Sterilization Ser-
vices, p. 22.
PhRMA Quality Control Bulk Pharmaceuticals Work Group, Quality Steering Com-
mittee, PhRMA Science and Regulatory Section. 1995a. PhRMA guidelines for the
production, packing, repacking or holding of drug substances: part I. Pharm. Technol.
19(12):22-32.
PhRMA QC Section Bulk Pharmaceuticals Committee and Sterile Bulk Pharmaceutical
Chemicals Subcommittee, Sterile Bulk Pharmaceutical Chemicals. 1995c. A
PhRMA position paper. Pharm. Technol. 19(8):38-42.
PhRMA Quality Control Bulk Pharmaceuticals Work Group, Quality Steering Commit-
tee, PhRMA Science and Regulatory Section. 1995b. PhRMA guidelines for the pro-
duction, packing, repacking or holding of drug substances: part II. Pharm. Technol.
20 (1):50.
PhRMA Environmental Monitoring Work Group. 1997. Microbiological monitoring of
environmental conditions for nonsterile pharmaceutical manufacturing. Pharm.
Technol. 21(3):58.
Poole, S., P. Dawson, and R. G. Das. 1997. Second international standard for endo-
toxin: calibration in an international collaborative study. J. Endotoxin Res.
4:221-231.
Prescott, L. M.,j. P. Harley, and D. A. Klein. 1993. Microbiology, 2nd ed. Dubuque, Iowa:
Wm. C. Brown Publishers.
Schmitz, A. J., M. X. Cooper, T. E. Munson, and R. Dabbah. 1995. Microbiological test-
ing of nonsterile pharmaceutical articles-a review. Pharm. Forum 14(4):4163.
Shirtz, j. 1987. Sterility testing. Pharm. Engin. 7(6):35-37.
Shirtz, j. 1995. Isolation technology for sterility testing at Burroughs Wellcome Co.,
Greenville, NC. In Isolator technology, edited by C. M. Wagner and j. E. Akers. Buf-
falo Grove, Ill., USA: Interpharm Press, Inc.
Tsuji, K., A. Steindler, and S. Harrison. 1980. Limulus amebocyte assay for detection
and quantitation of endotoxin in a small volume parenteral product. Appl. Envi-
ron. Microbiol. 40:533.
United States Department of Health and Human Services (U.S. DHHS). 1998. Guidance
for industry: manufacturing, processing, or holding active pharmaceutical ingre-
dients. http://www.fda.gov/cder/guidance/index.htm.
United States Pharmacopeia! Convention, Inc. 1999a. The United States pharmacopeia
24. Chapter 85, Bacterial endotoxins test. Rockville, Md., USA: United States Phar-
macopeia! Convention, Inc.
United States Pharmacopeia! Convention, Inc. 1999b. The United States pharma-
copeia 24, Chapter 71, Sterility Tests. Rockville, Md., USA: United States Pharma-
copeia! Convention, Inc.
Microbiological Attributes of Active Pharmaceutical Ingredients 517
United States Pharmacopeia! Convention, Inc. 1999c. The United States pharmacopeia
24, Chapter 1231, Water for pharmaceutical purposes. Rockville, Md., USA: United
States Pharmacopeia! Convention, Inc.
United States Pharmacopeia! Convention, Inc. 1999d. The United States pharma-
copeia 24, Chapter 85, Pyrogen test. Rockville, Md., USA: United States Pharma-
copeia! Convention, Inc.
United States Pharmacopeia! Convention, Inc. 1999e. The United States pharmacopeia
24, Chapter 61, Microbial limits test. Rockville, Md., USA: United States Pharma-
copeia! Convention, Inc.
United States Pharmacopeia! Convention, Inc. 1999f. The United States pharmacopeia
24, Chapter < 1111 >, Microbiological attributes of nonsterile pharmaceutical
products. Rockville, Md., USA: United States Pharmacopeia} Convention, Inc.
United States Pharmacopeia! Convention, Inc. 1999g. The United States pharmacopeia
24, Chapter <1078>, Good manufacturing practices for bulk pharmaceutical ex-
cipients. Rockville, Md., USA: United States Pharmacopeia! Convention, Inc.
United States Pharmacopeia! Convention, Inc. 1999h. The United States pharma-
copeia 23, Chapter <1116>, Microbiological evaluation of clean rooms and other
controlled environments. Rockville, Md., USA: United States Pharmacopeia! Con-
vention, Inc.
Wagner, C. M., and J. E. Akers (eds). 1995. Isolator technology. Buffalo Grove, Ill., USA:
lnterpharm Press, Inc.
Weitnauer, A. C., and L. F. Comb. 1996. Reverse osmosis: two-pass RO for
pharmaceutical-grade purified water. Ultrapure Water. (March): 42-45.
Wood, R. T. 1995. Points to consider in the use of sterility testing isolators. In Isolator
technology, edited by C. M. Wagner and j. E. Akers. Buffalo Grove, Ill., USA: Inter-
pharm Press, Inc.
19
EXCIPIENTS: FACILITY,
EQUIPMENT, AND
PROCESSING CHANGES
Irwin Silverstein
International Specialty Products
Wayne, New Jersey
The term process change is used here to reflect changes made in facility,
equipment, or processing. (Note that terms appearing in bold are defined in
the glossary.) Change as it relates to the facility includes new locations or im-
provements to existing locations, while equipment change encompasses all
production hardware, such as vessels, agitators, and instrumentation. The
term processing covers all operating steps and parameters, set points, on-line
and off-line process controls, raw materials, and testing.
The issue of process change has significant importance to the customer,
whether or not the product is used in a pharmaceutical application. Manufac-
turers often claim that changes made in the facility, equipment, process, ma-
terials, or even test methods have resulted in a product that is "improved,"
even if the improvement is a reduction in manufacturing cost. However, expe-
rience has shown that such "improvements" or changes can have a deleterious
impact on product performance. This impact, in the pharmaceutical industry,
can range from subtle changes (e.g., a shortening of shelf life) to the dramatic
(e.g., the failure of a dosage form mixture to process properly or have the in-
tended therapeutic effect). Either effect can lead to a product recall.
The U.S. Food and Drug Administration (FDA) requires validation of the
facility, equipment, and process so that the impact of any such change will
not alter the consistency of the products supplied to the pharmaceutical
519
520 Validation of Active Pharmaceutical Ingredients
ramifications of such a regulatory change are now being considered and a fi-
nal guidance is not expected for some time.
The FDA has proposed revisions to the Current Good Manufacturing
Practice 21 CFR Parts 210 and 211 (FDA 1996) that include the requirement
for a "quality assurance system" for change. The system would ensure revali-
dation whenever a change is made that might affect the safety or efficacy of
the dosage form. The quality control unit would have responsibility for "re-
viewing changes in product, process, equipment, or personnel, and for deter-
mining if and when revalidation is required." The quality unit would thus
implement the proposed FDA guidance (FDA 1999).
The FDA has specified that the bulk manufacturer should notify them
when a process change is "significant" and there is a DMF for the product.
Otherwise, companies holding DMFs are only required to provide an annual
update to reflect changes. However, in its guideline (FDA 1989) the FDA does
not attempt to define process change, let alone "significant," or to indicate
the need for updates beyond the statement to notify affected applicants of
pertinent changes (FDA 1989). In its draft guidance, BACPAC I (FDA 1998),
the FDA has proposed criteria for evaluating the significance of changes in the
manufacture of API intermediates. The International Pharmaceutical Excipi-
ents Council-Americas has prepared a guidance (IPEC-Americas 2000) for the
evaluation of change in BPE manufacture.
The FDA attempts to define changes in the manufacture of the dosage
form that require revalidation (FDA 1987). It states in the Guideline on General
Prindples of Process Validation that revalidation is required whenever a process
change "could impact on product effectiveness or product characteristics, and
whenever there are changes in product characteristics" (FDA 1987). The FDA
also specifies revalidation whenever there are adverse differences in raw mate-
rial characteristics. The document goes on to state that "tests and methods of
analysis which are capable of measuring characteristics" should be used to de-
termine "whether a process is slipping out of control" (FDA 1987).
The FDA also discusses the issue of change in its Guidance for Industry:
Manufacturing, Processing, or Holding Active Pharmaceutical Ingredients (FDA
March 1998) in the section titled Change Control/Revalidation. This guidance
recommends that the manufacturer evaluate the impact of the change on the
chemical and physical properties of the API such as the chemical purity, im-
purity profile, and physical characteristics such as particle size and density,
moisture content, and susceptibility to microbial contamination. It further
suggests that the manufacturer classify the potential impact of the change on
the API as major or minor. A major change has a likely impact on the above
noted API attributes, whereas a minor change is unlikely to affect an attribute.
It is apparent that the FDA has been actively addressing the issue of
change in recent years. It is also evident that the guidance from the FDA in
this matter is addressed to API manufacture but is less appropriate to the ex-
cipient. Therefore, the IPEC guide (IPEC-Americas 2000) will be used to dis-
cuss the matter of process change in this chapter.
522 Validation of Active Pharmaceutical Ingredients
70
60
50
40
30
20
10
0
Process Site Raw Material Specification Formulation Unspecified tabei/Pkg
Definition
pH
5.6
5.4
5.2
5
4.8
4.6
4.2
Lot Number
Figure 19.3 Solution pH process capability before process change, February, 1995
Frequency
Average
Upper Spec Limit
Normal
Curve
0
4.5 4.6 4. 7 4.8 4.9 5.0 5.1 5.2 5.3 5.4 5.5
pH
variation before and after the change. Finally, the average and standard devi-
ations of each process are determined. Figure 19.3 shows the process capabil-
ity for solution pH prior to a process change. The normal curve, also called
the Gaussian distribution, illustrates good process capability since it falls en-
tirely within the lower and upper specification or process limits.
Figure 19.4 is a process capability histogram after the process was
changed. Examination of the graph shows the normal curve is narrower than
before and continues to fall within the specification limits. However, the
process average has shifted downward from a pH of 5.0 to 4.8, so that it is no
longer centered within the limits. Therefore, this change appears to be signif-
icant, and validation is needed along with customer notification.
The effect of the final process change is illustrated in Figure 19.5. The
process is again centered at a pH of 5.0, and the normal curve falls comfort-
ably within the specification limits. Since the distribution is narrower than it
was for the original process, the only effect on the solution pH is a reduction
in its variation. Such a change is considered not significant, and neither vali-
dation nor customer notification is indicated.
In the series of changes reflected in Figures 19.3-19.5, visual examina-
tion was sufficient to determine objectively when the change was significant.
An even more objective evaluation can be made using statistical techniques.
The confidence level needed for this determination should be at least 95 per-
cent. Conducting at-test of the means using Student t distribution allows the
528 Validation of Active Pharmaceutical Ingredients
Figure 19.4 Solution pH process capability after process change, February, 1995
Frequency
1 Average
Upper Spec Limit
4~5 4.6 4.7 4.8 4.9 5.0 5.1 5.2 5.3 5.4 5.5
test of the null hypothesis that the averages are statistically different. Per-
forming an analysis of variance (ANOVA) of the distributions for the two
process results will identify whether the process variation is statistically sig-
nificant. If either statistical test for a critical characteristic or operating para-
meter indicates a statistically significant difference, there has been a
significant process change. As discussed, a reduction in variation requires no
validation. Computer software simplifies this evaluation. Quality Progress, the
magazine of the ASQ, prints a listing of statistical software each year in the
March issue.
While the use of statistical techniques provides an objective method for
evaluating process consistency and change, it has one serious shortcoming:
the analysis relies on production data alone to determine significance. As
noted, the FDA requires evaluation of the impact on the physical properties
and impurity profile (FDA 1998), whereas IPEC suggests considering the im-
pact of the change on the excipient chemical and physical properties, impu-
rity profile, moisture level, microbial contamination, and performance, as
reflected in functionality testing (IPEC-Americas 2000).
IPEC recommends measuring the effect of the change on the chemical
and physical properties that are specified for the product. The evaluation
Exdpients: Facility, Equipment, and Processing Changes 529
Figure 19.5 Solution pH process capability after process is centered, June, 1995
Frequency
10 Average
Lower Spec Upper Spec
8 Limit Limit
6
Normal
Curve
4
4.5 4.6 4.7 4.8 4.9 5.0 5.1 5.2 5.3 5.4 5.5
pH
should also take into consideration unspecified properties that may be altered
by the process changes such as the particle shape, surface area, or bulk density
of powders or the pH and viscosity of liquid products. The molecular distribu-
tion of polymer products should also be considered.
Both the FDA and IPEC require comparing the impurity profiles before
and after the process change to identify if there are significant differences in
the presence or level of impurities as a consequence of the process change.
IPEC goes further to suggest that the moisture levels should be examined,
since moisture is ubiquitous and often has an effect on the performance of
the product. Microbial contamination or susceptibility can be altered by
process change, and IPEC recommends that challenge testing of the product
after the process change be considered. Finally, the performance of an excipi-
ent can be affected by the process change. Therefore, it is recommended by
IPEC that the excipient be tested in model formulations to determine the im-
pact of the process change.
Since much work is required to thoroughly evaluate a process change,
the IPEC significant change guide (IPEC-Americas 2000) suggests risk levels
for consideration. A level 1 change reflects a minor risk that the new process
530 Validation of Active Pharmaceutical Ingredients
will result in a significant change in the excipient. As a result, the guide only
calls for the manufacturer to document the change and update the DMF, if
there is one, at the annual update, but customer notification is necessary.
A level 2 change might have a significant impact on the BPE perfor-
mance or properties. The manufacturer should evaluate the impact of the
change on the chemical and physical properties of the product as well as on
the impurity profile. If there are any changes in the postchange product, then
the manufacturer should notify the customers. However, preapproval of the
process change is not required.
Level 3 changes are always significant. Customers should always be in-
formed of the change as early as possible so that they can begin evaluating the
potential impact on their use of the ingredient. The manufacturer should
plan to build inventory of the prechange product since the customer will
probably need to evaluate the postchange product in its formulation.
The IPEC guide discusses the level of change that results from changes in
the site or scale of manufacture, equipment, process, packaging, and specifi-
cations. There are many examples used to help clarify the decision-making
process in reaching a determination of the level of change.
It is recommended that objective data be used wherever possible to mea-
sure the impact of a process change. The tests performed should provide vari-
able results and not attributes. The preferred data is that derived at the
production unit, but the batches should not be released until the statistics
have demonstrated that the change is not significant. Usually this will in-
volve making three production-scale batches using the changed process. At
least a comparable number of batches made prior to the process change
should be used for comparison.
The manufacturer must decide whether to keep the three production
batches under evaluation in quarantine or to release the lots upon quality
control approval. Holding the lots in quarantine is practical when demand for
the product is high and batches are made frequently. However, many API and
some BPE products are manufactured infrequently. Even so, the prudent man-
ufacturer will make every effort to manufacture three batches for evaluation
even though it means raising inventory levels and associated costs. When this
approach is not feasible, the only option left is to rely on the evaluation of
small-scale production or scientific judgment in considering the significance
of the change.
An alternative is to evaluate the change in a pilot unit that has a demon-
strable correlation to the production unit. If the statistical evaluation of pilot
scale data shows no statistical change, then full-scale production can proceed
without revalidation. However, the prudent manufacturer will confirm the
lack of impact on the product through statistical techniques.
Another approach is to rely on an understanding of the process chemistry
for evaluating the likelihood of a significant process change. A technical report
should document the reason why no significant impact on the product is an-
ticipated. Again, the judicious manufacturer will confirm this expectation.
Excipients: Facility, Equipment, and Processing Changes 531
The decision tree is a useful quality tool for visualizing the relationship be-
tween process change and validation. A decision tree developed by IPEC (IPEC-
Americas 2000) is shown in Figure 19.6. The major categories of change-site,
scale, equipment, process, packaging, and specification-are arrayed across the
top. Decision points are illustrated with a diamond shape. The response to the
question contained therein is used to determine the risk level of the change.
Processing change is divided into major change categories of process,
equipment, and specification. Changes in process control can be evaluated us-
ing the six criteria of IPEC (IPEC-Americas 2000) to compare the product
equivalency or by using statistical comparison of the process output to demon-
strate equivalence. If equivalent, validation would not be necessary. Equip-
ment changes are either replacement in kind or their impact should be
determined using the IPEC change criteria. Specification changes such as a raw
material from a new source or an improved test method should be evaluated
for their impact on the product. If a new raw material is to be used, a signifi-
cant change must have occurred because the process chemistry is now differ-
ent. If a revised specification or improved test method results in a product of
different quality, then the change to the product will be reflected in the pres-
ence of either new impurities or existing impurities at a new concentration.
FACILITY
Relocating production from one site to another, either in the same plant or to
another one, would seem to be an obvious example of a process change re-
quiring process validation and customer notification. Validation is required
because the new manufacturing location will probably use different equip-
ment, at least some different raw material sources, and different personnel.
The FDA suggests (FDA 1998) that site changes probably won't alter the API
intermediate since it will be purified to produce the drug substance. There-
fore, it suggests that installation qualification (IQ) and operational qualifi-
cation (OQ) be performed along with a comparison of the impurity profile
and physical properties. For excipient site changes, IPEC suggests (IPEC-Amer-
icas 2000) that a new site of manufacture will likely affect the BPE and thus it
is a level 3 change.
It is possible to use the same raw material sources as at the other site if
they are delivered to the site via rail or road, but any materials delivered by
pipeline will likely be from a new source. Clearly, process water falls into the
latter category, as do industrial gases. The IPEC-Americas guide (IPEC-Ameri-
cas 2000) classifies material changes as level 2 unless the new raw material is
bought to the same specification and is produced by the same manufacturing
process, wherein it is a level 1 change. The change in raw material source to a
new facility, even using the identical process, indicates the need for validation
and customer notification.
Figure 19.6 Quality Tool Decision Tree (page 1)
~
N
-~
~
......
a·
::J
0
.......
~
Manufacture Quality Control Intermediate Excipient
!:::!".
or Packaging Lab Spec Spec 05
Yes ~
Q.l
~
3
Q.l
8c:::
......
£"
..,
No ~
-
~
c-L~e12) Materials Equipment Manufacturing Q..
Process Yes (ii•
::J
Gb (ij
~·~
~No Yes
Figure 19.6 Quality Tool Decision Tree (page 2)
-o·(b"~
Materials Manufacturing
Process
;::,
1i!
Supplier Type Specification Process Process Steps Reprocessing ~
C")
Control
:::.:
'St
~
~-
•
Yes (!)
No ;::,
~ ( Level1 )
Scale
.:->
§
Q..
~
0
Level3
~
~)eves (J)
(J)
~-
9
~No Q)
;::,
Yes ~
(J)
"'
(Levell)
U1
w
w
534 Validation of Active Pharmaceutical Ingredients
EQUIPMENT
Changes to the equipment involve modification or replacement of the pro-
duction or test equipment and control devices. Production equipment in-
cludes items such as reactors, agitators, and pumps, whereas control devices
Excipients: Facility, Equipment, and Processing Changes 535
component used to make the filter, such as the fabric. It is unlikely for the
bulk pharmaceutical manufacturer to validate the variation of filter porosity,
but filtration performance should be monitored for conformance to process-
ing requirements.
Mechanical changes can also be sudden in nature, such as the collapsing
of the plates in a distillation column or the failure of a reactor seal. The col-
lapse of the plates in a column reduces the number of theoretical plates and,
thus, the efficiency of the separation during distillation. This can result in a
change in the purity profile of the distillate. As the purity profile changes, the
manufacturer will often adjust distillation conditions to maintain the desired
purity profile. This is sometimes done without even knowing that the deteri-
oration in separation is due to equipment failure. Even when known, the op-
erating conditions might be adjusted because of the inability to shut the unit
down for repairs. Equipment failure may become apparent only when main-
tenance is done on the column. Since the manufacturer cannot easily identify
when the collapse took place, it would be very difficult to know which lots of
product are affected and then to alert those customers. It is difficult to envi-
sion validating the process with this eventuality in mind.
Changes in the chemicals used in excipient manufacture can involve
catalysts, initiators, deionizer resins, carbon beds, and so on. This type of
change is almost always gradual.
Catalysts are often used in continuous reactors for reactions such as hy-
drogenation. These catalysts have a finite longevity during which their activ-
ity changes, often going through a maximum efficiency before gradual
decline. The manufacturer will compensate for this decline by gradually ad-
justing processing conditions such as reaction temperature and flow rate. The
effect of these changes in operating conditions is often reflected in a subtle
change to the impurity profile of the product. Since the catalyst life is often
measured in months, it must be recognized that gradual, but subtle, product
variation will occur. Finally, the processing conditions required may vary
somewhat from batch to batch of catalyst. Thus, the replacement of the cata-
lyst could also result in a subtle change in the purity profile. While it is possi-
ble to revalidate the process and notify the pharmaceutical customer of such
change, it is not possible to produce material matching the purity profile of
earlier material, since that catalyst has already been consumed. It is also an
unreasonable burden to expect the manufacturer to revalidate the process
every time the catalyst is replaced.
Carbon beds are used to adsorb chemicals, usually impurities from the
product stream. Virgin carbon is more efficient in adsorption, which can de-
cline with usage. When carbon beds are used in a continuous process, subtle
changes in trace levels of impurities can result in an unhomogeneous prod-
uct. The manufacturer must remain alert to lot-to-lot changes in the adsorp-
tion characteristics of the carbon and ensure the impurity levels remain
within established limits.
Excipients: Facility, Equipment, and Processing Changes 537
PROCESSING
Both the FDA and IPEC consider the use of a new raw material in the
production process significant, as indicated by the FDA requirement for fil-
ing a prior approval supplement (FDA 1998) and IPEC assigning the
change a level 3 (IPEC-Americas 2000). IPEC considers a raw material from
a new manufacturer or plant as possibly significant and thus level 2, re-
quiring the evaluation of its impact on the quality of the product. Statisti-
cally significant changes to the product require validation and customer
notification.
However, sometimes the bulk manufacturer may find it difficult to iden-
tify when a raw material is being provided from a new supplier. API and BPE
products are often manufactured in quantities that are small by chemical in-
dustry standards. This may lead the manufacturer to purchase relatively small
quantities of raw materials, making it necessary to go to a distributor. Distrib-
utors usually purchase their chemicals from one source but will often switch
to another supplier when economics or availability dictates. A manufacturer
purchasing from a distributor is unlikely to be notified of a switch in source,
nor would the manufacturer necessarily notice a change, unless it became ob-
vious from use of SPC. If the bulk manufacturer is notified, there may not be
sufficient time to validate the change or to alert customers for their approval
prior to the switch over to the new supplier.
A similar scenario involving raw material sources concerns commodity
chemicals, those materials sold in large quantities for which there are indus-
try standard specifications. Chemical companies are known to conduct
exchanges where large volume commodity chemicals are involved. An ex-
change may occur between companies A and B for methanol, where company
B will agree to provide its methanol for the customer of company A in ex-
change for similar consideration by company A. The customer of company B
will probably not receive notification of the change in advance, if at all. Since
the manufacturer of the API is probably a small customer of the commodity
chemical, it cannot exert enough economic leverage with the supplier to pre-
vent exchanges. One final comment involving commodity chemicals is that
exchanges may involve product made overseas for domestically produced ma-
terial, again unknown to the bulk manufacturer. Under this circumstance,
neither revalidation nor customer notification is possible.
Manufacturers often list several approved suppliers wherever possible
but typically use one almost exclusively. The use of another approved source
of raw material in a validated process should not require revalidation if the
raw material continues to meet specifications and the raw material quality is
essentially identical to the source covered in the validation. As noted above,
the criteria for concluding the raw material sources are equivalent are the
demonstration that the mean and ::!::3 standard deviations for each supplier's
material is statistically the same.
Changes to process control should also be evaluated for their impact on
the product quality attributes. Such changes may include improvements to
Excipients: Facility, Equipment, and Processing Changes 539
CONCLUSION
Process change validation and notification is a difficult issue for both the man-
ufacturer and the customer. The pharmaceutical industry must balance the
need for consistency of the product with the processing industry need for con-
tinuous improvement. It is evident that the bulk manufacturer needs clear, ob-
jective criteria to justify the effort involved in validation and customer
notification. While both the FDA and IPEC have begun to add clarity to the is-
sue of change, an attempt has been made to provide practical guidance to the
manufacturer and an understanding of the issue to both the maker and user.
As mentioned previously, statistical techniques, including SPC, can be a
useful tool in determining whether or not there has been a significant change
to the equipment or processing. The validation and customer approval result-
ing from process change places constraints on continuous improvement for the
bulk manufacturer. Variation in bulk chemical quality requires the drug formu-
lators to monitor their raw material quality, design more robust processes, and
monitor their finished dosage form quality more carefully. Reducing API and
BPE quality variability saves the pharmaceutical manufacturer these costs.
Therefore, process improvements by the bulk manufacturer should be encour-
aged where they can be shown to have a beneficial reduction in lot variation.
Excipients: Facility, Equipment, and Processing Changes 541
GLOSSARY
Active Pharmaceutical Ingredients (API): The active ingredient that is in-
tended to furnish pharmacological activity or other direct effect in the treat-
ment of illness.
Batch Process: A manufacturing process that produces the excipient from a
discrete supply of raw materials that are present before the reaction is com-
pleted.
Bulk Pharmaceutical Excipient (BPE): Any substance other than the active
ingredient that is included in the drug delivery system.
Continuous Process: A manufacturing process that continually produces the
excipient from a continuous supply of raw material.
Critical Operating Parameter: An operating condition that can impact a
product quality attribute, either a specification parameter or performance
characteristic.
Drug Master File (DMF): A compilation of technical data filed with the FDA
describing the manufacture, quality, and control of a product.
Drug Product: A finished dosage form.
Drug Substance: An active ingredient that is intended to furnish pharmaco-
logical activity or other direct effect in the treatment of illness.
Impurity Profile: A description of all of the impurities present in the product.
Installation Qualification (IQ): The documented verification that equip-
ment was installed according to an approved design.
Operation Qualification (OQ): The documented verification that equipment
performs as intended.
Physical Property: A quality parameter that can be measured solely with me-
chanical equipment.
Process Change: Changes made in facility, equipment, or processing of a
product.
Processing: All operating steps and parameters, set points, on-line and off-
line process controls, raw materials, and testing used in the manufacture of a
product.
Significant Process Change: A processing change that alters a product's
physical or chemical property or that is likely to alter the product perfor-
mance in the dosage form.
Statistical Process Control (SPC): The application of statistical graphical
techniques for monitoring process variation.
542 Validation of Active Pharmaceutical Ingredients
REFERENCES
ASQ. 1996. Specifications for the chemical and process industries. Milwaukee, Wis., USA:
ASQ Quality Press, pp. 127-128.
FDA. 1987. Guideline on general principles ofprocess validation. Rockville, Md., USA: Food
and Drug Administration, p. 12.
FDA. 1989. Guidelines for Drug Master Files. Rockville, Md., USA: Food and Drug Ad-
ministration Center for Drug Evaluation and Research, Dept. of Health and Hu-
man Services.
FDA. 1996. Current good manufacturing practice: Amendment of certain requirements for
finished pharmaceuticals; Proposed rule. Federal Register (May 3).
FDA. 1994. Guide to inspections of bulk pharmaceutical chemicals. Rockville, Md., USA:
Food and Drug Administration, Div. of Field Investigations (HFC-130), Division of
Manufacturing and Product Quality (HFD-320), p. 3.
FDA. 1998. BACPAC I: Intermediates in drug substance synthesis. Rockville, Md., USA:
Food and Drug Administration, Drug Information Branch (HFD-210), Center for
Drug Evaluation and Research.
FDA, March 1998. Manufacturing, processing, or holding active pharmaceutical ingredients
(Guidance for Industry). Rockville, Md., USA: Food and Drug Administration,
Center for Drug Evaluation and Research, Center for Biologics Evaluation and Re-
search, Center for Veterinary Medicine.
FDA. 1999. Changes to an approved NDA or ANDA (Guidance for Industry). Rockville,
Md., USA: Food and Drug Administration, Drug Information Branch (HFD-210),
Center for Drug Evaluation and Research.
The Gold Sheet-Quality Control Reports. 1985. The Gold Sheet 29 (4):2.
IPEC. 1995. Good manufacturing practices guide for bulk pharmaceutical excipients. Arling-
ton, Va., USA: International Pharmaceutical Excipients Council.
IPEC-Americas. 2000. Significant change guide for bulk pharmaceutical excipients. Arling-
ton, Va., USA: International Pharmaceutical Excipients Council.
ISO. 1994. Quality systems-Model for quality assurance in production, installation, and ser-
vicing (ISO 9002:1994, ANSI/ASQC Q9002-1994). Geneva: International Organiza-
tion for Standardization.
Juran, J. M., and F. M. Gryna. 1988. Juran's quality control handbook, 4th ed. New York:
McGraw Hill, pp. 28.5, 28.22-23.
Lazar, M.S. 1995. PhRMA guidelines for the production, packing, repacking, or hold-
ing of drug substances: Part 1. Pharm. Techno!. (December): 30.
20
Robert A. Nash
St. John's University
Jamaica, New York
According to the federal Food, Drug, and Cosmetic Act in the United States
Code of Federal Regulations under Title 21, the term drug means articles recog-
nized in the official United States Pharmacopeia (USP), the official Homeo-
pathic Pharmacopeia of the United States, or the official National Formulary
(NF) and their official supplements. This includes articles intended for use in
the diagnosis, cure, mitigation, treatment, or prevention of disease in man or
other animals; articles, other than food, intended to affect the structure or
any function of the body of man or other animals; and finally, articles in-
tended for use as components in the drug but not including devices and their
components.
According to the official definition of drugs, no such distinction is made
among auxiliary terms, such as drug product (pharmaceutical dosage form), ac-
tive pharmaceutical ingredients (API), inactive ingredient (excipient, inert compo-
nent of the drug product), and in-process material (mixtures of active and
inactive ingredients prior to the creation of the finished dosage form). All
four meet the definition of the term drug. Since by definition a pharmaceuti-
cal is a medicine or drug product, then Part 211 of the Code of Federal Regula-
tions-which covers current Good Manufacturing Practice for Finished
Pharmaceuticals (cGMP) applies to the drug in all its forms: drug product, ac-
tive ingredient, inactive ingredient, and in-process material. Furthermore,
since the basic concept of validation is incorporated within the meaning
of section 211.110 (a) and (b) and proposed section 211.220 of the cGMP
543
544 Validation of Active Pharmaceutical Ingredients
regulation, it follows that the legal basis for requiring validation documenta-
tion for both active and inactive ingredients has been properly established.
The former term, bulk pharmaceutical chemical (BPC), first used by the
Pharmaceutical Manufacturers Association (PMA, now called PhRMA) in their
December 1978 Guideline for the Production, Packing, Repacking, or Holding
of Bulk Pharmaceutical Chemicals, has no legal basis in the regulations
(Tuthill 1979). API has been defined as the ingredients or components (both
active and inactive) used in the manufacture of dosage form drug products.
According to Tuthill, such chemicals are usually made by chemical synthesis,
by processes involving fermentation, or by recovery (isolation, extraction, or
purification) from natural materials. In his article, Tuthill spelled out the re-
quirements of cGMPs for APis, including validation. The term bulk is most
likely derived from the term sterile bulk antibiotics, which are repacked from
their "bulk form" into dispensing containers without further processing. Ac-
cording to Fry (1984), such products, even in bulk form, are finished pharma-
ceuticals and, therefore, subject to cGMP regulations. However, sterile APis are
handled under a separate set of Food and Drug Administration (FDA) guide-
lines (7356.002A). Prior to 1978, APis were referred to as raw materials and
bulk chemicals (Byers 1966).
The regulatory priority of APis over inactive ingredients (especially key
excipients) is clearly established in the following FDA publications: Compli-
ance Program Guidance Manual for APis (7356.002F), Guide to Inspection of API
Manufacturing (revised September 1991), and Guidance for Industry-Manufac-
turing, Processing, or Holding Active Pharmaceutical Ingredients (draft document
issued March 1998).
The table of contents of the draft document issued March 1998 is as follows:
1. Introduction
2. Organization and personnel
3. Buildings and facilities
4. Process equipment
5. Control of raw materials
6. Production and process controls
7. Packaging and labeling controls
8. Holding and distributing of APis and intermediates
9. Laboratory controls
10. Records and reports
11. Validation
12. Change control/revalidation
13. R~processing/reworking of APis and intermediates
API Terminology and Documentation 545
The past resistance to the validation of APis is that much of the required
information and documentation should be contained within the scope and
requirements of a successfully completed DMF. However, a DMF document
does not have the legal weight of the cGMP regulations, which provide the
basis for requiring API validation documentation.
546 Validation of Active Pharmaceutical Ingredients
The FDA principle "You are what you claim you are" applies to APis as
well as to foods, drugs, and cosmetics.
Take, for example, dextrose. When dextrose is used as a sweetener in
baked goods, it is a food ingredient and subject to the requirements of food
products. When dextrose is used as an excipient in drug tablets or in liquid
preparations as a sweetener, it is an API. When it is used in the manufacture of
sterile dextrose injection, it is an active drug substance and an API but now
subject to assay and testing for bacterial endotoxins and 5-hydroxymethyl
furfural content.
Pharmaceutical excipients (inactive ingredients) are substances, other
than the active drug substance or the drug product, that have been evaluated
for safety and are included in the pharmaceutical dosage form (drug delivery
system) for one or more of the following functions:
1. Aid in the processing of the drug product during manufacture
(i.e., binder, disintegrant, lubricant, suspending agent, filtering
aid, etc.)
2. Protect, support, or enhance, stability, bioavailability, or patient ac-
ceptability (i.e., chelant, surfactant, sweetener, etc.)
3. Assist in product identification (i.e., colorant, flavor, film former, etc.)
4. Enhance any other attribute of the overall safety and effectiveness
of the drug during storage or use (i.e., inert gas, preservative, sun-
screen, etc.)
Like APis, pharmaceutical excipients are made by chemical synthesis,
fermentation, recovery from natural materials, etc. Often in the manufacture
of pharmaceutical excipients, such as clays, celluloses, starches, and natural
gums, purification procedures may not be employed. In addition, the physical
and chemical change of certain excipients during processing is not uncom-
mon. Unlike APis, many excipients have complicated chemical and physical
structures that do not yield easily to modern analytical and chromatographic
methods.
More than 200 monographs of pharmaceutical excipients appear in the
third edition of the Handbook of Pharmaceutical Excipients, published jointly
by the American Pharmaceutical Association (APhA) and the Pharmaceutical
Press (2000). In addition, more than 200 of the same pharmaceutical ingredi-
ents (excipients) are listed in NF 19 and cover more than 40 different exdpi-
ent categories, from acidulants to wetting agents. It has been estimated that
there are more than 1,000 different pharmaceutical excipients in use world-
wide at the present time.
The International Pharmaceutical Excipient Council in the United States
(L. Blecher, Chairman, 1361 Alps Road, Wayne, NJ 07470) has issued a GMP
guideline for excipient bulk pharmaceutical chemicals. The Council, in con-
junction with both the European and Japanese Pharmaceutical Excipient
API Terminology and Documentation 54 7
Weak acids & RM+ Weak acid neutralized 8-11 moderate acid: pylorus;
their salts (30%) with strong base to weak acids: small intestine
make water soluble salt
Weak bases RNH 2+x- Weak base neutralized 3-6 weak bases: pylorus;
& their salts RNWx- with strong acid to moderate base: small intestine
(45%) RWX- make water soluble salt
Neutral molecules R Requires cosolvency 5-8 stomach to rectum
(nonelectrolytes) to make water soluble
(15%)
Quaternary R4 wx- Soluble in water 5-8 active transport
compounds (10%)
API Terminology and Documentation 549
Weak acids and weak bases and their salts account for about 75 percent
of the APis currently used in drug products.
Prodrugs are drug substances that are biotransformed in the body to ac-
tive metabolites and chemotherapeutic agents. Examples include sulfa-
salazine to sulfapyridine, phenylbutazone to oxy-phenbutazone, aspirin to
salicylate, and hetacillin to ampicillin. In some cases, like aspirin (ester) and
hetacillin (amide), hydrolysis in water releases the active drug moiety con-
tained within the basic structure of the prodrug.
The FDA often considers such simple, uncomplicated amides, lactams,
esters, and lactones as derivatives of the active drug substance in the same
way as it treats salts (electrolytes) and ion-pair complexes (nonelectrolytes) of
the same basic chemical structure.
COMPENDIAL STANDARDS
CHIRAL APis
According to the FDA's guideline for marketing chiral drugs (APis), issued in
May 1995, drug companies have the choice of whether to develop chiral drugs
as racemates (50 percent mixture of the D and L forms or enantiomers) or as
individual single enantiomers. Enantiomers have opposite rotational optical
activity in solution.
Most companies today have decided to move toward the development
of the pharmaceutically active, single enantiomer. If the racemate had been
approved alone or in pharmaceutical dosage forms, the development program
for the single active enantiomer can be shortened.
API Terminology and Documentation 551
The following approved, first line, active drug racemates are candidates
for single enantiomer research at the present time:
The advantage of the active enantiomer is that it has twice the activity of
the racemate and at least one-half of the toxic potential. The potency stability
of the active API enantiomer in both the solid state and solution is an impor-
tant concern to be addressed during the validation program.
the activity. The PMN program is mandated by the Toxic Substances Control
Act (TSCA). Any substance that is not listed in the TSCA Inventory of Chemi-
cal Substances is classified as a new chemical substance. The significant new
use rule (SNUR) applies to new uses for an existing substance.
The following new chemical substances are not subject to the PMN re-
porting mechanism:
The only situation in which the manufacturer of an API would be affected (i.e., must
prepare and submit a PMN) is when the manufacturer imports the new chemical
substance or makes it in the plant in quantities greater than 1,000 kg per year as a
reactant in the chemical synthesis of either an intermediate or the active drug sub-
stance itself.
The API manufacturer must complete on a specified PMN form all avail-
able data on the chemical identity, amounts to be produced, by-products and
impurities, intended use, environmental release potential, disposal particles
to the environment, human exposure potential, and available data on toxic-
ity and safety. Under the TSCA, the EPA is required to protect from disclosure
all confidential business information (CBI) submitted on properly identified
documents.
The EPA will send a letter by return mail and include a PMN number as-
signed to the submission and the expiration date of the PMN review period.
API Terminology and Documentation 553
PROCESS DESCRIPTION
There are four primary options used in the manufacture of APis. They are
chemical synthesis, fermentation, extraction from natural products, and purifica-
tion from crude materials. A flow diagram and a description of the chemistry
involved are used in defining the manufacturing process.
I have chosen Dow's process (Midland, Mich) for the manufacture of as-
pirin and salicylic acid to illustrate a typical API flow diagram (Figure 20.1).
The GMP-designed aspirin plant, which is capable of producing 12 million
lb/yr, is state of the art with advanced process control systems, stainless steel
tanks, glass-lined reactors, metal detection, and fully automated and comput-
erized to provide for production flexibility and process control.
According to the flow diagram logic, five reagents are used (i.e., liquid
phenol, sodium hydroxide, carbon dioxide under pressure, hydrochloric acid,
and acetic anhydride). Two forms of aspirin are produced. They are aspirin
USP crystals (not less than 99.5 percent pure and containing not more than
0.1 percent salicylic acid).and aspirin with starch granulation for tableting ap-
plications. The process also yields salicylic acid USP crystals (melting point
158-161 oc and purity not less than 99.5 percent) as a by-product of the basic
aspirin process.
The chemistry is relatively simple and consists of four reaction steps:
Figure 20.1 Flow Diagram of Dow's Process for the Manufacture of Aspirin and
Salicylic Acid
Intermediate
L-------~r=========~------~~P~a~ck~a~g~in~g API&
Intermediate
Acetic Acetic Acid By-Product
Anhydride
A Pis
j
.
Weighed
.. Premix
Reaction Precipitation
Filtration/
Ingredients
. Blender Centrifugation
)::.
Additional Ingredients Organic Solvent ::2
_t_ I (bi
3:s·
Milling and
Blender ""-
Dryer 0
Sizing
~
tll
;::,
Q.
~
C')
~
To Warehouse
~ Labeling
_.. Packaging
§
Qj
.....
Source: Pharm. Engineering 13(4), 1993 g·
en
....en
en
m
Figure 20.3 Typical Fermentation API Process
~
Organic Solvent or Water-----, ~
~
o·
::::s
Weighed 0.....,
Ingredients Sterilization Fermentation Cell Separation Inactivation ~
Q.
~-
§
Q)
- Final Product
Purification -- Product
Purification Product Recovery ~I Solvent Extraction 2t:
I -~2
OrganJSolvent ~
Q..
~-
~ Bulk Preparation Preservation --
To Warehouse
or
plant (lOx stage), with a view toward increasing yield and reducing residual
impurities. Fractional factorial designs, constraint, and "worst-case" analysis
are used to establish control of the manufacturing process.
IMPURITY PROFILE
The USP permits up to 2 percent of ordinary nontoxic impurities in the API.
Individual impurities greater than 0.1 percent should be fully characterized
and quantified by validated analytical methods. Impurities include residual
intermediates, reagents, by-products, degradation products, catalysts, heavy
metals, electrolytes, filtering aids, and residual solvents.
Known toxic impurities, however, should be held to a tighter standard
below 0.1 percent. One of the objectives of the prospective validation pro-
gram for APis is to maintain control over the impurity profile and to hold
contaminants and impurities to an achievable minimum standard.
RETROSPECTIVE VALIDATION
Retrospective validation of APis consists of a review and analysis, using statis-
tical process control methods, the physical process parameters, and analytical
test data for immediate past batches (at least the last 10-30 consecutive lots),
and should include numerical data for starting materials, key intermediates,
and the finished API. Impurity profiles are an important part of such historic
560 Validation of Active Pharmaceutical Ingredients
REVALIDATION
The revalidation of an API process may be initiated at periodic intervals (an-
nually) or whenever significant changes are made to equipment, systems, or
processes. The revalidation effort will depend on the nature and extent of the
changes made. The evaluation and decisions regarding the need for revalida-
tion should be documented.
Any indication of failure (more than 10 percent of the batches) should
result in an investigation to identify the cause and to take necessary corrective
action, and an assessment should be made regarding the need for additional
formal process validation. In the absence of changes or process failure, peri-
odic review of data covering manufactured lots should be made to assess the
need for more formal revalidation.
CHANGE CONTROL
Process validation of an API should include a Standard Operating Procedure
(SOP) to reassess a process whenever there are significant changes in process,
equipment, facilities, reactants, process materials, systems, etc., that may af-
fect the critical quality attributes and specifications of the API. Such changes
should be documented and approved in accordance with the scope of the
change control SOP. The change control SOP should consist of the following
elements:
The FDA recently instituted a new program to speed the procedure of approv-
ing changes for both APis and drug products. With respect to APis, it is called
bulk actives post/approval changes, or BACPAC. The types of changes being con-
sidered under the BACPAC area are as follows:
REPROCESSING
One of the major areas of difference between APis and drug products is repro-
cessing. The reprocessing of an API is done primarily to increase yield, to ob-
tain a purer material, or to bring important parameters (i.e., particle shape,
size distribution, etc.) into conformity with their specification limits. In con-
trast, reprocessing of a drug product rarely results in improved drug purity.
The use, for example, of recrystallization procedures and secondary re-
covery from mother liquors is not contrary to the spirit and intent of the
cGMPs. Reprocessing of APis, if carried out by procedures already used to
manufacture the original batch, in other words, recycling through one or more
consecutive unit operations, is an acceptable practice as long as
CLEANING VALIDATION
According to section 211.67 of the CFR, equipment cleaning and mainte-
nance of the cGMP regulations,
PHARMACEUTICAL DISCOVERY
DRUG
API PRODUCT
DRUG PRODUCT
API MANUFACTURE
MANUFACTURE
VALIDATION DOCUMENTATION
Plans, protocols, and reports with respect to validation documentation of
APis are covered by most of the following elements. The formatting, content,
and specifics are left to the discretion of the reader.
• Introduction: Purpose, scope, corporate quality policy, organiza-
tional structure, and responsibilities
• Process Description: Flow diagram; chemistry; manufacturing in-
structions; equipment IQ OQ, and performance qualification (PQ);
facilities and equipment maintenance; process conditions; critical
process variables and specifications; in-process checks; mother
API Terminology and Documentation 567
In addition, two other outlines are presented in Tables 20.4 and 20.5
on formatting validation documentation for APis. A summary of the essen-
tials of the FDA's Guide to the Inspection of API Manufacturing is presented in
Table 20.6.
3. Corporate Policy: develop basic operational SOP documentation with respect to validation poli-
cies and procedures
6. Basis of Design: develop qualification requirements, definitions, and specifications, for pro-
posed system or process
9. Environmental Program: provide SOP documentation and procedures for personnel training,
system or process security, and environmental concerns including cleaning validation and main-
tenance of equipment and facilities
10. Change Control and Revalidation: establish the basis for initiating
568 Validation of Active Pharmaceutical Ingredients
Table 20.6 Summary of the FDA Guide to Inspection of API Manufacturing, Re-
vised March 1998
1. Prevent contamination/cross-contamination (need separate air handling system)
2. Water systems/air quality (potable water acceptable for nonsterile operations)
3. Aseptic/sterile processing (EtO is acceptable)
4. Multipurpose equipment/cleaning/closed systems-acceptable for outdoors
5. Protect environment against waste
6. Cleaning of product contact surfaces (cleaning procedure/sampling plan; analytical method)
Limits: practical, achievable, and verifiable
7. Raw materials (storage inside and outside is acceptable)
8. Containers, closures, and packaging components
9. Mother liquors (secondary recovery is acceptable)
10. In-process blending/mixing (blending off out-of-spec material is not acceptable)
11. Reprocessing (investigation and reason for failure)
12. Validation (variations that affect chemical/physical/microbial characteristics-establish rei·
evance and reproducibility)
13. Process change control system in place
14. Control productjprocess impurities
15. In-process testing
16. Packaging and labeling
17. Expiry dating and stability data
18. Laboratory controls and analytical methods validation
RECOMMENDED READING
Anisfeld, M. H., and F. Shaviv. 1997 Implementation of U.S. GMPs in the manufactur-
ing of active ingredients. Phann. Techno!. 21 (4):40-54.
Armstrong, M., E. Duckworth, J. Linder, A. Meisch, and D. Yoakam. 1994. API pilot
plants-bridges to the future. Phann. Engineering 14 (4):8-14.
Barr, D. B., and W. C. Crabbs, and D. Cooper. 1993. FDA regulation of API production.
Phann. Techno[. 17 (9):54-70.
Baseline phannaceutical engineering guide, Vol. 1, APis. 1995. Tampa, Fla., USAISPE.
REFERENCES
APhA. 1994. Handbook of phannaceutical excipients, 2nd ed. Washington D.C.: Ameri-
can Pharmaceutical Association, and London: Pharmaceutical Press.
APhA. 2000. Handbook ofphannaceutical excipients, 3rd ed. Washington D.C.: American
Pharmaceutical Association, and London: Pharmaceutical Press.
FDA. 1998. Guidance for industry, manufacturing, processing, or holding active phar-
maceutical ingredients. Rockville, Md., USA: Food and Drug Administration.
FDA. 1998. Guidance for industry, BACPAC 1: Intermediates in drug substances syn-
thesis, chemistry, manufacturing, and controls documentation. Rockville, Md.,
USA: Food and Drug Administration.
Fry, E. M. 1984. An FDA perspective on APis. Phann. Techno/. 8 (2):49-52.
PIC. 1999. Recommendations on validation master plans, IQ/OQ, non-sterile process
validation, cleaning validation. Geneva Switzerland: Pharmaceutical Inspection
Convention.
API Terminology and Documentation 571
PIC. 1997. Internationally Harmonised Guide for APis, GMPs. Geneva Switzerland;
Pharmaceutical Inspection Convention.
Tuthill, S.M. 1979. APis: GMP. Pharm. Techno!. 3 (2):48-52.
Wintner, B. 1993. Environment emissions control in the pharmaceutical industry.
Pharm. Engineering 13 (4):8-22.
Index
573
574 Validation of Active Pharmaceutical Ingredients
Guidance for Industry: Content and Format history, 188, 372, 429
of Investigational New Drug Applications on imports, 40
(INDs) for Phase I Studies of Drugs, In- judicial analysis, 61, 77
cluding Well-Characterized, Therapeutic, Kefauver-Harris amendment to, 372
Biotechnology-Derived Products, 95 site inspections, 4-7, 23
Guidance for Industry: Manufacturing, Pro- violation punishment, 51
cessing, or Holding Active Pharmaceuti- fermentation, 551, 558
callngredients, 98-101, 105, 114, 115, FIFO (first-in/first-out), 142
116-117, 118-119, 120, 124, 127, 137, filters
293,294,296,476,521,544 in airflow patterns, 437, 442
Guideline for Drug Master Files, 42-43, 84 blinding of, 535-536
Guideline for Submitting Supporting documentation, 440
Documentation in Drug Applications for in microbiological control, 487-488,
the Manufacture of Drug Substances, 84, 492-493,502,504
108, 126 validating, 439
Guideline for Validation of the Limulus filtration systems, 445-446, 448, 479. See
Amebocyte Lysate Test as an End Product also water systems
Endotoxin Test for Human and Animal final intermediates, 556
Parenteral Drugs, Biological Products and finished drug products, 106. See also dosage
Medical Devices, 505, 506, 507, 510 form manufacturing
Guideline on Sterile Drug Products Produced first-in/first-out (FIFO), 142
by Aseptic Processing, 431, 496 Food and Drug Administration. See FDA
Guidelines on General Principles of Process Food and Drug Amendments of 1962, 55,
Validation, 431, 521, 553, 554 56-59
Guide to Inspection of API Manufacturing, Food, Drug, and Cosmetic Act. See FD&C Act
544,567,569 foreign API facilities. See also international
Guide to Inspection of Bulk Pharmaceutical manufacturing
Chemicals, l, 2, 17, 98, 106, 113, 376, agents for, 344
380,398 FDA guidance affecting, 100-101
Guide to Inspection of Validation of inspections, 26-30, 37, 101-105, 345-346
Cleaning Processes, 6 vendor qualification considerations, 349
Guide to Inspections of High Purity Water foreign substances. See impurities
Systems, 439 Form FDA 483
Guide to Inspections of Sterile Drug on cleaning process, 104, 406
Substance Manufacturers, 493 legal effect of, 51
Kinetic LAL Testing: Interim Guidance for as part of EIR, 48
Human Veterinary Drug Products and responding to, 32
Biologicals, 505, 507, 510 on SOPs, 134
"Manufacture, Processing or Holding of Form FDA 712, 37-38
Active Pharmaceutical Ingredients," Form FDA 717, 38
70, 79 Form FDA 718, 38
The Manufacturing, Packaging, and Form FDA 766, 38
Holding of Active Pharmaceutical Form FDA 772, 38
Ingredients, 398 Fourier transform infrared (FTIR), 410
Sterilization Process Validation, 43 9 F0 value, 489, 512
FDAMA (FDA Modernization Act) fractional crystallization, 551
amendments, 46 fractional factorial design, 554, 559
on foreign manufacturing, 27, 28 Fry, Edmund M., 21
on OTC drugs, 47 FTIR (Fourier transform infrared), 410
in vendor qualification, 351 fungistasis, 512. See also B/F (bacteriostasis
FD&C (Federal Food, Drug, and and fungistasis) testing
Cosmetic) Act
adulteration protection, 14, 15 galenic validation, 263-264, 267
applying to bulk and finished drugs, 67, Gantt chart, 563, 564
385,388,543 Gardner v. Toilet Goods Ass'n, 77
enforcement tools, 34-37 (see also GC (gas chromatography), 265, 274, 549
Warning Letters) generic drug scandal, 21, 24, 374
and foreign manufacturers, 28 Generic Pharmaceutical Association, 330
580 Validation of Active Pharmaceutical Ingredients
microbiological control. See also sterility New Chemical Entities (NCEs), 24, 312,
validation 375,406
affecting processing, 486-488 New Drug Applications. See NDAs
bioburden, 484-486 new drugs, 14
endotoxin testing, S03-S06, S06-S10 applying cGMP to, 64-6S
environmental monitoring, 494-501 exporting, 40-42
facilities and equipment, 488-493 preapproval inspections, 23-24
as governed by GMPs, 47S-478 NF (National Formulary), 13, 19, S43
isolator systems, 493-494 NIR (near infrared), 410
and process change, S29 NOEL (no observed effect level), 418-419
SOPs, 478-479 Nonprescription Drug Manufacturer's
sterility testing, S02-S03 Association (NDMA), 390
water quality, 479-484 no observed effect level (NOEL), 418-419
microcrystalline cellulose, S47
micronization, 242-2S 1 objectionable microorganism, S13
microscopy, 410 Office of Generic Drugs, 93
misbranding Office of New Drug Chemistry, 93
and exporting, 40 Office of Regulatory Affairs (ORA), 98, 99
FD&C protecting against, 14, IS, 20 Office of the General Council, 98
and importing, 39 on stability programs, 1S9
mobile phases, labeling of, 1S8 on starting material, 108
Motise, Paul, 47S OOS (out-of-specification) results
MSDS (Material Safety Data Sheets), batch release procedure, 136
313,418 CofA validation, ISS
MVD (maximum valid dilution) factor, SOS guidelines for handling, 1S8, 296
microbiological control, 484
NADA (New Animal Drug Application), 14. versus process deviations, 294
See also new animal drugs vendor audits, 356-357
National Association of Pharmaceutical open isolator, 494
Manufacturers (NAPM), 99, 330 operational parameters, 459, 460-461,
National Association of Pharmaceutical S24-S2S
Manufacturers ("NAPM") v. Department Operational Qualification. See OQ
of Health and Human Services, 64, 78 optical isomers, 27S. See also enantiomers
National Association of Pharmaceutical optical microscopy, S49
Manufacturers ("NAPM") v. FDA, 61 OQ (Operational Qualification), S41
National Center for Drugs and Biologics, 21 equipment, 453, 4S4, 456, 535
National Drug Manufacturers microbiological control, 482
Association, 330 site changes, S31
National Formulary (NF), 13, 19, S43 site inspections, 143, 145, 158
National Nutritional Foods Ass'n v. validating sterile APis, 430, 445
Weinberger, 77 validation case study, 172-173, 180,
National Pharmaceutical Alliance, 99, 330 192-197,200
NCEs (New Chemical Entities), 24, 312, validation master plan, 563
37S,406 ORA (Office of Regulatory Affairs), 98, 99
NDAs (New Drug Applications) oral administration, 485
DMF supporting, 42, S4S (see also DMFs) organic impurities, 27S,.276
and drug listings, 3 organic nonelectrolytes, 548
interstate commerce requirement, 14 organic volatile impurities (OVIs), 274
PAl policy, S (see also PAl) OTC (over-the-counter) drugs, 47, 101, 390
postapproval changes, 332-333, 337, S34 out-of-specification results. See OOS
in quality assurance, 373 output variables. See performance
using Process Development Report, 311 parameters
versus USP monograph, 272 over-the-counter (OTC) drugs, 47, 101, 390
NDMA (Nonprescription Drug OVIs (organic volatile impurities), 274
Manufacturer's Association), 390
near infrared (NIR), 410 packaging, 28, 326, S23. See also labeling
New Animal Drug Application (NADA), 14 PAl (preapproval inspection) policy
new animal drugs, 14, 23-24, 40 developmental reports for, 6
Index 583
preventative maintenance (PM), 299. See also case study, 168, 169, 172-176, 182-184
equipment cleaning process, 233-241
process capability study, 526-527, 528, 529 computer systems, 197
process change, 519, 541. See also BACPAC I; guidelines, 161, 163, 187, 554
BACPAC II; change control; micronization, 242-251
postapproval manufacturing changes process equipment, 195-196, 210-219
equipment, 534-537 protocol, 199, 560
facility, 531, 534 support systems, 192-194
identifying significant, 522, 524-531, supreme process, 227-232
532-533 providone, 54 7
regulations, 519-524 pseudoephedrine, 402-403
technology (see technology transfer) Pseudomonas aeruginosa, 485
Process Development Report, 311, 313-316 Public Health Service Act, 28, 51
process flow diagrams. See PFDs Pure Food and Drugs Act of 1906, 56,
processing, 519, 541 164, 188
process pool stability testing, 461 purification. See impurities
process qualification. See PQ purification stage testing, 550
process status table, 316 purity profiles, 536, 539-540
process transfer document, 313-316 pyrogens, 503, 504-506, 513
process validation
activity timing, 458-459 "Q" documents. See under ICH
analytical methods, 409 QA (quality assurance)
Barr Laboratories decision, 70-76 annual reviews, 139
case study, 166-185, 187-259 batch release procedure, 136
change control, 266-267, 466-468 change control system, 138-139
cleaning (see cleaning process) compliance inspections, 381-383
critical parameters in, 115_-116, 161, deviation and failure investigations,
165,422,460 136-137, 296
critical steps in, 112-115, 161-162, emphasizing GMPs in, 380-381
267,554 evolution of, 369-375
definition, 16, 69, 164, 430, 553 installing system of, 383-38 7
documenting (see documentation) management philosophy, 375-380
dosage form versus APis, 263-264 in Master Plan, 452
explosive suppression, 566 Medical Products Quality Assurance Staff,
goal of, 457 23-24
guideline application for APis, 110-113 in microbiological control, 484
history, 67-68, 164 PDSA cycle, 388-393, 395
impurity testing (see impurities; impurity quality system diagram, 394
profiles) reworking and reprocessing, 137-138
master planning, 452 standard operating procedures, 134-136
microbiological control, 477, 482- structure, 133-134
484,495 technology transfer, 318
modular approach to, 165-166 validation case study, 167-168
monitoring, 464-466 in vendor qualification, 350, 355,
as part of GMP, 2-3 364,365
protocols (see validation protocols) QC (quality control)
revalidation, 467, 468-469 definition of quality, 272
sterility (see sterility validation) laboratory operations, 154-160
technology transfer, 266, 323-324 in Master Plan, 452
types of, 71, 72, 116-118, 268-269 quality control unit, 133, 295, 386
of unit operations, 554 technology transfer, 318
variables, 459-462 in vendor qualification, 350
in vendor audits, 357 QFD (quality function deployment), 387
prodrugs, 549 QP (Qualified Person), 134, 136
production equipment, 145-146 QS 9000 standard, 379
product validation, 430 Qualified Person (QP), 134, 136
prospective validation, 117, 269 quality assurance. See QA
in Barr Laboratories decision, 71 quality control. See QC
Index 585
quality function deployment (QFD), 387 room classifications, 434-435, 497, 499. See
Quality System Program, 4 also airborne particulate cleanliness
quarantine control, 141, 143 class
quaternary compounds, 548 RTDs (resistance thermal devices), 489
rabbit pyrogen test, 504, 506 Sabouraud dextrose agar (SDA), 498
racemates, 550-551 safety factor (SF), 418
raw data handling, 156 safety programs, 318, 360
raw materials, 513. See also starting salicylic acid, 554-556
materials Salmonella, 485
changes in, 522,523,531,534,538 sampling. See also swab sampling
handling, 140-143,347 air, 498-499
in technology transfer, 314, 316, 320 Barr Laboratories decision, 72
R&D (research and development), 160- cleaning validation, 178, 407-409,
161,318 423,456
rDNA technology, 12 facility for, 142
reaction stage testing, 550, 559 before import, 37-38
reagents, labeling of, 158 RODAC™, 438, 499
recalls, 34, 349, 359 stability programs, 159-160
recombinant DNA technology, 513 surface, 499-501
rectal administration, 485 trending data from, 501
refractive index, 326 vendor qualification, 349, 350
replicate organism detection and counting scale changes, 562
(RODAC™) samples, 438, 499. See also Scale-Up and Postapproval Changes
contact plate sampling (SUPAC), 329, 520
reprocessing scale-up process. See technology transfer
in APis versus drug products, 562 scanning electron microscopy, 549
in deviation investigation, 301 SCD (soybean casein digest) medium,
in FDA BPC guidelines, 296 498,500
and preapproval inspections, 5 SDA (Sabouraud dextrose agar), 498
versus reworking, 123-124, 137-138 SDS-PAGE (sodium dodecyl sulfate-
in vendor qualification, 357, 363-364 polyacrylamide gel electrophoresis)
research and development (R&D), 160- analysis, 410, 412
161,318 search warrants, 22, 31
residue limits. See also cleaning process seizure action, 34-35, 57
calculating, 414-420 SF (safety factor), 418
regulatory requirements, 398, 399 signal impurities, 27 4
residue on ignition testing, 550 significant new use rule (SNUR), 552
resistance thermal devices (RTDs), 489 significant process change, 522, 524-531,
retrospective validation, 117, 118, 268 541,560
in Barr Laboratories decision, 71, 72 significant process steps, 113. See also
case study, 168, 169-171, 179-180, 198, process validation
201-209 site changes, 531, 534, 561-562. See also
FDA accepting, 163-164 change control; technology transfer
guidelines, 162, 554, 559-560 site inspections
revalidation, 468-469, 554, 560. See also common carrier authority, 30
change control; process change EIRs, 48
reverse osmosis, 4 79, 513 equipment and facility qualification,
reworking 143-146, 361
in deviation investigation, 301 equipment calibration, 148-149, 361
in FDA BPC guidelines, 296 equipment cleaning, 146-148, 358, 400
versus reprocessing, 123-124, 137-138 FDA guidelines, 4-7, 22-23
in vendor qualification, 357, 363-364 foreign, 26-30, 37, 101-105, 345-346
rinse sampling, 407, 408, 411, 419 grand jury subpoenas, 31-32
risk, 415-416, 529-530 history, 21-22
RODAC™ (replicate organism detection and labeling controls, 149, 362, 365
counting) samples, 438, 499. See also for OTC drugs, 47
contact plate sampling priorities, 25-26
586 Validation of Active Pharmaceutical Ingredients
process validation, 161-162 starting materials, 93, 107-110, 332. See also
QC laboratory operations, 154-160 raw materials
and quality assurance, 133-139, 379 State Pharmaceutical Administration
raw materials handling and controls, (China), 128
140-143 statistical process control. See SPC
record keeping, 150-152 steam cleaning, 444-445
recovering solvents, 149-150 stearic acid, 54 7
research and development, 160-161 sterile, definition, 513
scope of authority, 23-25 sterile bulk antibiotics, 544
. and search warrants, 22, 31 sterility validation. See also cleaning process;
training, 153-154 environment monitoring;
in vendor qualification, 350, 353-366 microbiological control
site registration, 3 facilities, 432, 434-439, 456-457
smallest therapeutic dose method, maintenance, 449
416-417 manufacturing process, 432, 433,
SNUR (significant new use rule), 552 447-449
sodium chloride, 547 microbiological control, 489-493
sodium dodecyl sulfate-polyacrylamide gel protocol format, 431-432
electrophoresis (SDS-PAGE) analysis, regulatory documents, 431
410,412 support systems, 439-447
sodium hydroxide, 547 sterilization, definition, 513
sodium saccharin, 547 sterilizing filter, 514. See also filters
sodium starch glycolate, 547 steroids, 400, 493
solvents. See also cleaning process sucrose, 547
as impurities, 274, 275, 276 sulfanilamide, 3 72
recovery of, 5, 149-150 SUPAC (Scale-Up and Postapproval
rinse sampling, 407, 408 Changes), 329, 520
SOPs (Standard Operating Procedures). See suppliers, 344. See also vendors
also documentation swab sampling. See also sampling
change control, 467, 468, 560-561 analytical methods, 409
compliance, 4 FDA preference for, 407-408
endotoxin testing, 5 10 limit calculation, 419-420
equipment cleaning, 146 microbiological monitoring, 499, 500
FDA guidelines, 134-136 versus visual examination, 411
microbiological control, 478-479, Swiss Intercantonal Office for the Control of
482-483 Medicines, 128
operational parameters in, 459
in validation case study, 167-168, talc, 547
189-190 Taylor, Frederick, 3 70
vendor audits, 355, 362 technology transfer. See also change control;
vendor qualification, 346, 347, 352, 353 site changes
warehouse operations, 140-143 API container/closure, 326
soybean casein digest (SCD) medium, categories, 312-313
498,500 marketing role, 310-311
SPC (statistical process control), 541 organization, 317-319
in determining significant change, in PAl compliance, 392
525-526 process definition, 311
in improving manufacturing process, 523 Process Development Report, 313-316
in processing changes, 538, 539 regulations, 327
stability, 5, 326, 327, 461 scale-up process, 319-326
stability programs stability, 327
in facility audits, 159-160 validating, 266
and impurities, 284 technology transfer team, 317-318
in vendor qualification, 358, 364 temperature conditions, 437
Standard Operating Procedures. See SOPs testing methods, 549-550. See also specific
standard solutions, labeling, 158 method
Staphylococcus aureus, 485 TGA (Therapeutic Goods Administration),
starch, 547 127, 128
Index 587
recombinant protocol requirements, 463 water systems. See also filtration systems; WFI
sample, 471-474 in cleaning process, 426
validation summary report, 175-176, deficiencies, 104
252-259, 463 FDA guidelines, 120--123
vendor certification impurities, 283
ISO 9000, 3 73 microbiological control, 479-484
procedure overview, 346-347 site changes, 531
purpose, 345-346 sterility validation, 439-442
system, 351-352 validation case study, 172, 173, 17 6,
vendor qualification 178-179
definition of terms, 344-345 weak acids and their salts, 548-549
in microbiological control, 485--486 weak bases and their salts, 548-549
monitoring program, 352-353 Weinberger v. Bentex Pharmaceuticals, Inc., 77
procedure overview, 346-347 Weinberger v. Hynson, Westcott & Dunning,
purpose, 345-346 Inc., 78
site inspections, 353-366 WFI (Water for Injection). See also water
steps, 347-351 systems
vendors, 344, 352 FDA guidelines, 122
Veterinary Master Files (VMFs), 51 in microbiological control, 480, 481,
visual examination 483,508
of cleaning samples, 410, 411-412, in steam cleaning, 444, 445
422-423, 426 system diagram, 441
in determining significant change, 527 WHO (World Health Organization), 128, 373
VMFs (Veterinary Master Files), 51 worst-case approach ·
cleaning validation, 400--401, 405-
warehouse operations, 140-143 406,456
Warning Letters, 32-34 limit calculation, 417
on cleaning process, 406 process qualification, 554, 559
deficiencies sited in, 48-51, 363-365
excerpts from, 295-296 x-ray diffraction, 549
for foreign firms, 27
on process validation, 18 zvalue, 489, 514
Water for Injection. See WFI