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Conducting Audits, Gap Assessments &

Corrective Actions Volume II

Table of Contents
Implementing an Effective Provider Qualification Program 3
at the Contract Laboratory
Richard C. Wedlich, Agata E. Libera, Joseph M. Fransen,
Eric Sadosky, Matthew T. Therrien, and Kevin J. Webb

The Changing Face of FDA Inspections for Sterile Products 9

Jeanne Moldenhauer

Laboratory Self Audits 17

Paul L. Pluta

Internal Audit Preparation-A Key Element 29

of an Effective GXP Training Process
David Markovitz

First Impressions—The Plant Tour 32

Paul L. Pluta

Implementing Quality Agreements at the Contract Laboratory 38

Richard C. Wedlich and Kevin J. Webb

Preparation, Preparation, and More Preparation 43

Ballard Graham, Richard Poska, Robert Ertmann, and Paul L. Pluta

Analysis of Recent Drug GMP Inspections by FDA and AIFA: 52

Different Approaches and Significant Trends
Sofia Cerioni, Ph.D., Raffaele Lasala and Enrica Lombardini

When Quality Needs an Audit 60

James Kaar and Pat Klemens

Quality is Audited 66
James Kaar and Pat Klemens
Conducting Audits, Gap Assessments &
Corrective Actions Volume II
Table of Contents (continued)
Quality Responds to the Audit 73
James Kaar and Pat Klemens

The ‘Physics’ of Changing of a Supplier Quality Program 81

James Kaar and Pat Klemens

The Business of Auditing and Auditing the Business: Part V 88

James Kaar and Pat Klemens

The Business of Auditing and Auditing the Business: Part VI 95

James Kaar and Pat Klemens

The Business of Auditing and Auditing the Business: Part VII 101
James Kaar and Pat Klemens

FDA 483 Responses—Compliance Considerations 106

Richard Poska and Ballard Graham

An Introduction to Cold Chain Management 116

Ernest Castiaux

Conducting Valuable Preliminary Investigations 120

Peter Weichel

Technical Problem Solving 125

David Ingram

Compliance Case Study #7—Broken Punches in Tablet Compressing 133

Paul L. Pluta
Implementing an Effective Provider
Qualification Program at the
Contract Laboratory
Richard C. Wedlich , Agata E. Libera, Joseph M. Fransen, Eric Sadosky, Matthew T. Therrien,
and Kevin J. Webb

ABSTRACT to show the regulatory agency that we take responsi-

This paper is intended to provide useful hands-on guid- bility for the provider’s service or product (i.e., “work”
ance  regarding the process of provider qualification. contracted or purchased) is to perform and document
What we have learned of this comes mostly from being a qualification of the provider. Our approach typically
employed in smaller contract research organizations includes an audit (facility-based on-site assessment)
(CROs) that have been focused on providing good followed by a periodic quality review of their work and
manufacturing practices (GMP) and good laboratory requalification. The qualification audit might focus on
practices (GLP) support to major pharmaceutical and the quality systems that are in place at the provider’s
medical device manufacturers in the form of special- facility to ensure the provider can meet regulatory re-
ized contract analytical testing services. While this quirements. It might include verification that the CRO
niche is small in comparison to manufacturing, it is can perform the requested testing by asking them to
clearly within the purview of the US Food and Drug complete “qualification trials” performed on standards
Administration that monitors and holds it to standards or “knowns” before considering them qualified to per-
in common with manufacturing. The objective for the form testing to support a GMP or GLP study. Manu-
lab is to design and implement a program that meets facturers of drug products and medical devices have,
all applicable regulatory requirements, not demand too over many years, developed vendor and supplier qual-
many company resources and correctly place the pro- ification programs intended to ensure that products
viders. The approach taken is risk-based. The program and services they purchase are “fit for intended use or
design must integrate well with the laboratory’s other purpose.” Even so, with economic globalization come
quality systems. We cannot claim to be the originators challenges that even the world’s most reputable compa-
of these ideas; rather, this paper takes from many sug- nies must face anew. As they outsource to smaller com-
gestions made by many quality assurance (QA) auditors panies (i.e., providers), they recognize that the chain
over many years having the task of qualifying our lab- is only as strong as the weakest link (2). FDA Warning
oratory. Letters abound containing observations such as “Your
firm failed to properly evaluate a contract laboratory
to ensure GMP compliance of operations occurring at
INTRODUCTION the contract site……Although you have agreements
The provider selected to support a GMP or GLP pro- with other firms that may delineate specific responsi-
grams is, from a regulatory viewpoint, “part-and-par- bilities to each party, you are ultimately responsible for
cel” to the operation (1). Those GMP and GLP require- the quality of your products and the reliability of test
ments imposed upon an organization in order to ensure results.”(3). Most quality agreements (QAG) between
the quality, integrity, identity, purity, and/or strength of the contract-giver and contract-receiver will contain a
the product pass through to the provider. The only way

3 Conducting Audits, Gap Assessments & Corrective Actions Volume II

“right to audit” section. This section details the orga- our case is the adulteration or loss of the GMP and/or
nization’s expectations allowance to enforce the terms GLP data that we report to our clients.
of the agreement and perform regular (on-site) audits Domains are also convenient for sorting out the
(4). Vendor and supplier, or more generally, “provid- methods potentially used for qualification. For exam-
er” qualification is, and will continue to be, a hot topic ple, the mail audit questionnaire used to qualify a GMP
appearing frequently in FDA inspections of contract contract lab is typically inappropriate for qualifying a
laboratories. provider of metrology services, so it makes sense to
place these providers into different domains. While
SCOPE AND METHODS qualification procedures and risk assignments may vary
All CROs, regardless of size, rely upon a large number from domain to domain, the provider qualification
of providers. All of these should be considered as falling program will recognize the similarities among domains
under the scope of the provider qualification program. and treat them all the same way. We do this by develop-
At first, this may appear a daunting task owing to the ing and implementing a master plan standard operating
number and diversity of providers: pest control, jani- procedure (SOP) while simultaneously developing and
torial services, chemical reagents, reference standards implementing domain-specific, specialized SOPs. For
suppliers, instrument service providers, calibration ser- example, procedures for program administration, qual-
vices, archival services, facility services (e.g., electrical ity monitoring, and record keeping are in the master
and HVAC), stability storage, computer software sup- plan that, for conducting a mail audit of a contract lab,
pliers, third party auditors, consultants, and providers is in the appropriate domain-specific SOP.
of data to support GMP and or GLP studies to name
a few. While our focus tends to be on laboratories, the
concepts presented here apply to the qualification of all PROCESS MAPS
contract service providers. Provider qualification is a process or collection of pro-
It is convenient to group providers and develop a cesses that interface with a number of quality systems
qualification strategy that works for each group (i.e., in the organization. It therefore relies upon a diverse
domain). This eliminates the need to write a general work pool and “extends into the white spaces of the
procedure to fit all, which is nearly impossible to do. The organization chart” (5). For example, any disqualifica-
defining properties of each domain, once identified, will tion procedure should be based on the provider’s failure
lead to an understanding of 1) the proper procedures to to respond appropriately to a corrective action report
qualify members of the domain and 2) the proper “risk” issued by your QA group and documented using your
(defined later) to assign to the provider in the domain. corrective and preventive action (CAPA) quality sys-
Accepting “very low risk” as one possible assignment tem. It will necessitate a decision from management to
allows the program to be comprehensive and flexible seek out another source and require the requestor of the
without overburdening it. service/material to do so. It might also necessitate an
A list of domains we use is provided in Table I. As investigation involving the principal investigator, ana-
a rule of thumb, providers are lumped by considering lysts, client, and others. 
how “close to the data” they are. This is clarified with an It is useful to map out the process. Typical map de-
example: contract labs providing GLP/GMP data such signs include using a train of boxcars where the process
as the results from an analysis on a test article or client is the train and each boxcar is a major activity and use of
sample are as “close to the data” as one can get and define a flowchart. The process map is a good way of showing
a domain into which we also place those that “manipu- key roles and responsibilities. Also, key documentation
late” or handle data, including providers of data archival and approvals needed along the process as well as start,
services and providers of software intended to handle end, and in-process benchmarks can be mapped. Pro-
data. The boundaries between domains are admittedly cess controls such as documentation and approvals are
rather arbitrary. Still, the domains chosen should be in- typically inserted at the links between critical activities
dicative what “you are trying to guard against,” which in and may represent specifications to be met, points for

4 Conducting Audits, Gap Assessments & Corrective Actions Volume II

Table I: Domains for the Contract Lab to Consider in Organizing a Provider Qualification Program.

Domain Examples Risk

Providers of GMP and/or GLP experimental (test) data
Direct Data archival services
Impact Computer software for manipulation/storage of data
Stability storage providers
Indirect Providers of metrology-based services such as those who install, qualify, and perform PM and repair
Impact instrumentation or equipment
Providers of computer software not specific to data analysis and storage and IT services Moderate
Indirect Providers of materials such as reference standards, chemical reagents, and solvents and purified
Impact gases used in the GMP and/or GLP lab
Little Providers of facility-based services such as pest control, waste management, HVAC, janitorial,
Impact laundry, electrical, plumbing, etc.
Providers of experimental (test) data generated intentionally under non-regulated (non-GMP and
non-GLP) laboratory conditions (e.g., analytical method optimization data prior to GMP method
No Impact Very Low
Providers of materials not used to support GMP and/or GLP work

(Note: The list is not meant to be all-inclusive but rather suggestive. By “impact,” it is meant “impact on the quality and
integrity of the experimental GMP and/or GLP data”)

monitoring and self-improvement, bottlenecks, delays, RISK MANAGEMENT

and expenses. A rough example of a process map in the In assigning a risk level to a provider, we assess both the
form of a flowchart is given in the Figure for the quali- likelihood and severity of a non-compliance or other
fication of a provider.  quality issue (e.g., complaint) stemming from the use
The qualification process does not end once the pro- of that provider for the particular service and/or type of
vider has been qualified and placed onto the approved material we are asking them to provide. The risk matrix
provider list. QA will assign a requalification date. For (likelihood vs. severity) is therefore pre-defined before
some domains, it is a good idea to work out a QAG with any steps to qualify the provider are taken and certainly
the provider prior to the qualification audit. During the before any outcome is determined as to whether or not
audit, the auditor can verify that the provider has the the provider should be deemed “qualified.” The risk as-
means to meet the terms of the QAG. Often, however, signment determines the extent of the qualification (i.e.,
the client will not make the effort to initiate the QAG how much time and money will be spent on it, how long
without first ensuring that the provider is qualified. Also, it will take to complete, and what procedures will be fol-
the QAG details how specific aspects of the work are to lowed to perform it). A provider is deemed “qualified”
be done, and since the provider must first be qualified when we have determined and documented that they
to do the work, QAG checks are made after the work is are “fit for our intended use.” A variety of methods that
in progress. QA must monitor the services performed/ employed to qualify providers are listed in Table II.
materials provided throughout the qualification period. Risk levels used are very low, low, moderate, and
The program must provide the means for 1) following high. As an example, a very low risk assignment might
up on complaints received about the provider’s goods be given to the laundry service that cleans lab-coats.
or services, 2) assuring CAPAs are taken by the provid- Providers may provide multiple services or types of
er and reported by QA, 3) rejection and quarantine of materials, and a risk assignment is made for each. For
materials deemed adulterated, and 4) disqualification of example, under one contract, the contract lab may be
the provider. providing research and development (R&D) data that
are not intended to be generated following strict adher-
ence to GMP lab conditions while under another they

5 Conducting Audits, Gap Assessments & Corrective Actions Volume II

Figure: Example Flowchart (QA for Quality Assurance and DCU for Document Control Unit) Showing One
Time Through the Loop for Qualification of a Provider.
(Note: There is actually no end to this process, since periodic requalification is required)

are providing GMP data. The risk assignment can be

adjusted. For example, a pest-control service provider
may be considered low-risk because there is no inher-
ent problem with pests at the facility but be raised to
a higher risk level should the pest concern grow. The
pest risk depends upon many factors, including geo-
graphical location, climate, and type of operation (e.g.,
production vs. laboratory), which may all impact upon
the likelihood of having pests and your tolerance level,
which impacts upon the severity of the problem.
A provider that falls into the high-risk category will
typically be qualified by conducting a mail audit (a
copy of the most recent FDA Establishment Inspection
Report [EIR], if applicable, should be attached) pur-
suant to conducting a facility audit using either NSF
Pharmalytica auditors, a third party auditor, or a com-
bination of both. A provider of a chemical reagent that
falls into a low risk category may be qualified based on
past direct personal experience using the provider and
the provider’s reputation in the industry. One outcome
of the qualification process is the assignment of one of
the following classifications to the provider: Approved,
Conditional, or Not Approved. The classification does
not extend beyond the qualification meaning that it is
limited to what is being deemed as “fit for use.”
Risk should be lowered/managed by 1) careful selec-
tion of the provider, 2) proper qualification, 3) diligent
monitoring of the product or service over the lifecycle,
4) implementing change control procedures via the
QAG, 5) writing good in-house standard operating
procedures (SOPs) for conducting the provider qual-
ification and managing and administering the quali-
fication program, 6) providing training internally on
the written procedures, 7) establishing good quality
systems in your own lab that interface well with the
qualification program, 8) using “common wisdom”
such as  expecting a lot from yourself if you are going
to expect a lot from others, and 10) developing good
relationships with your providers.
Consider the following as an example of cost-effec-
tively lowering the risk of outsourcing by leveraging
your own lab’s strong GMP/GLP program. A lab that

6 Conducting Audits, Gap Assessments & Corrective Actions Volume II

Table II: Common Considerations Used by the Qualification Team to Evaluate Provider Qualifications.

1 Past direct or personal experience using the provider

2 Provider’s reputation in the industry
3 Provider’s website and capabilities and expertise claims
4 Professional references submitted by the provider
5 Relevant certifications (e.g., International Organization for Standardization (ISO) certifications, lab accreditations), licenses, etc.
6 Dunn & Bradstreet financial review of the firm to assess the provider’s commercial viability; this may be a critical concern; for
example, if the provider is to be relied on to provide stability storage for extended times (e.g., years).
7 Information available through the Freedom of Information Act helping to establish the quality history of the firm, such as the FDA
EIR and debarment history
8 The provider’s quality manual

9 A mail audit using a well-designed quality questionnaire

10 A facility (on-site) audit or a qualified third party audit or assistance in the audit preparation and conduct.

has a strong program will have quality systems and on strong cause-and-effect relationships (e.g., testing).
practices in place serving to lower the risk of using a SOPs work well when the “process elements” are peo-
provider of material (e.g., reagent, solvent, standard) ple and the compliance world thinks in terms of SOPs.
that ships with a lot-specific certificate-of-analysis that Having the correct set of SOPs in place, a management
is generated by the provider. These include 1) proper team to enforce them, and using the QA group to check
use of experimental “blanks,” 2) use of analytical sys- that they are being followed establishes the required
tem suitability testing/requirements, 3) having a strong control. SOPs are an excellent vehicle for training em-
out-of-specification (OOS) investigation program in ployees using the provider qualification program and
place, 4) employing point-of-use checks, 5) document- play a large role in the continuous improvement of the
ing in the experimental record the lot number used, and program. Each organization must write its own quali-
6) making routine checks on materials receipt and stor- fication program SOPs. They will match well with key
age. Combined, these may eliminate the need to spend roles and responsibilities and with the process maps.
a lot of time and money qualifying the material so that They must form a clear path to the goal of the qualifica-
the focus is on qualifying the provider in order to estab- tion program.
lish “quality at the source” (6). Any materials identified
as OOS or otherwise deemed adulterated are removed ADMINISTERING THE PROGRAM
to quarantine storage, and the provider, depending on “Strategies do not fail when they are being analyzed
corrective action taken, may ultimately be disqualified. or when the objectives are being set. They fail during
As another example, consider equipment and instru- implementation and, more particularly, due to the lack
mentation installed and qualified by a metrology-based of proper project management.” (7). Once in place, the
provider and intended to provide GMP/GLP data. Al- biggest challenge posed by the provider qualification
though you would qualify such a provider, the risk is program at the small CRO is its administration, and this
further lowered by requiring regularly-scheduled (e.g., becomes even more apparent within a large CRO. How
“day of use”) performance checks be conducted on the a CRO handles this challenge is a test of how well the
equipment or instrumentation. company is vertically integrated. A non-exhaustive list
of things to consider follows:
WRITTEN PROCEDURES (SOPS) • Give careful consideration when identifying po-
Use of SOPs is one important way to control and reduce tential providers for qualification (8).
• Keep the number of qualified providers to an op-
risk. There are, of course, other, non-procedural ways timal minimum.
such as so-called “engineering controls” that are based • Put enough controls into place and in the right

7 Conducting Audits, Gap Assessments & Corrective Actions Volume II

places. other quality systems in the organization and thereby
• Consider using a process control spreadsheet. reduces the cost of maintaining the program while in-
• Train personnel on written procedures, including creasing its chance for success.
the quality agreement.
• Review and revise: “If processes are not continual-
ly and incrementally adjusted and improved, they REFERENCES
naturally deteriorate to a point where they stop 1. B. Frey, “Supplier Management,” published on  IVT Net-
functioning.”(9). work.
• Take a risk-based approach, and use risk man- 2. R.E. Cole, “What Really Happened to Toyota?”, MIT Sloan
agement tools including a strong change-control Management Review 52 (4), 29-35, 2011.
program. 3. FDA Warning Letter WL 11-09 dated Jan. 20, 2011.
• Understand that having more details in the process 4. R.C. Wedlich and K.J. Webb, “Implementing Quality
map allows for more control but also makes for a Agreements at the Contract Laboratory,” Journal of GXP
more labor-intensive/expensive program to ad- Compliance 16 (4), 54-58, 2012.
minister. It can also increase the risk of non-com- 5. G. Rummler and A. Brache,  Improving Performance:
pliance by “promising too much.” It is necessary to How to Manage the White Space on the Organisation
establish an optimal program and this may require Chart, Jossey-Bass, San Francisco, CA, 1995. 
a couple of iterations.  6. D.M. Stephon, “Establishing a Supplier Qualification Pro-
• Understand that provider qualification is not a gram,” Journal of GXP Compliance 6, 2002.
task; it’s a program. 7. A.P. Van Der Merwe, “Project management and business
• Do not forget your client or your provider when development:   integrating strategy, structure, processes
you stand in between them. Establish a good qual- and projects,” International Journal of Project Manage-
ity history with both. ment 20, 401-411, 2002.
8. D. Jenke, “Insights Gained into the Identification, Qualifi-
As an example of the third item (a control measure), cation and Utilization of CRO Laboratories in Extractables
consider at the purchasing level to include a drop-down and Leachables Studies,”  Pharmaceutical Outsourcing:
The Journal of Pharmaceutical and Biopharmaceutical
menu of approved suppliers on your electronic purchase Contract Services, posted March 27, 2013, available at:
order from which to select the provider. Should the re- http://www.pharmaoutsourcing.com/Featured-Articles).
questor prompt purchasing to buy materials from a sup- 9. Ibid (7).
plier not on the approved provider list, the request would
be returned and the requestor would either ask QA to
Originally published in Journal of GXP Compliance Volume 17
initiate a provider qualification or would seek another Number 3
provider. Considering the fourth bullet (process control
spreadsheet), this may be a simple electronic spreadsheet
that mates with the process map and be used to track/ About the Authors
monitor key process parameters such as the provider
qualification status and requalification due date. An ex- Mr. Richard C. Wedlich is Director of Quality Assur-
ample of the seventh bullet (a risk management tool) is ance. He may be reached by email at rwedlich@nsf.org.
the quality QAG. Another is the process map. Ms. Agata E. Libera is Quality Assurance Auditor. She
may be reached by email at alibera@nsf.org. Mr. Joseph
M. Fransen is Quality Assurance Auditor. He may be
SUMMARY reached by email at jfransen@nsf.org. Mr. Eric Sadosky
The goal is ultimately to gain competitive advantage is Metrologist. He may be reached by email at esado-
through the management of the supply chain thus reduc- sky@nsf.org. Mr. Matthew T. Therrien is Operations
ing the risk (cost) of a non-compliance with, for exam- Manager. He may be reached by email at mtherrien@
ple, GLP/GMP regulations, quality specifications, client nsf.org. Mr. Kevin J. Webb is Program Manager. He may
expectations, or some combination of these. In order be reached by email at kwebb@nsf.org. All authors are
to do this, provider qualifications must be meaningful, from NSF Pharmalytica, a part of NSF Health Sciences.
timely, well-documented, and risk-based. Having a well
thought-out plan for the qualification program from the
start helps ensure that the program integrates with the

8 Conducting Audits, Gap Assessments & Corrective Actions Volume II

Jeanne Moldenhauer

The Changing Face of FDA Inspections

for Sterile Products
Jeanne Moldenhauer

ABSTRACT • Copy of the discrepancy SOP

• Listing of all discrepancies from the last two
Since the advent of the US Food and Drug Admin- years
istration’s Systems-based Inspections Pilot Program • Copy of the laboratory out-of-specification
in 2000, and its subsequent issuance (1), as well (OOS) procedure
as the FDA’s Current Good Manufacturing Prac- • Listing of all OOS occurrences from the last
tices (GMPs) for the 21st Century (2), industry has two years
• SOP for rework/reprocessing
been advised that there would be a change in how • Listing of all reworks/reprocessing from the
FDA inspections of pharmaceutical manufacturers last two years
would be conducted. It has been several years since • Listing of all products, components, and ma-
these documents have been issued. This paper dis- terials rejected for the last two years, includ-
cusses some recent FDA inspections of facilities that ing reason for discard
• Listing of all sterility failures from the last two
manufacture aseptically processed sterile drugs and years (or worded as listing of sterility false
how the inspections were conducted. positives for the last two years).

INITIATING THE INSPECTION Depending upon the time allotted for the FDA
A typical inspection has a minimum of two inves- inspection, investigators may require more or fewer
tigators, typically someone that understands qual- documents. In general, more information is re-
ity and the manufacturing process while the other quired in advance for international inspections that
investigator is qualified for evaluation of labora- have a specified time period for completion.
tory activities. The inspections have typically been
planned, with a notice provided to the plant prior FACILITY TOUR
to initiation of the inspection. Especially for foreign It is typical for the investigators to request a quick
inspections, documents were provided identifying tour of the entire facility. This initial tour gives them
various documents that the investigators would like a snapshot of the operations at the facility. This tour
to see as part of the inspections. Some typical inclu- may lead to a detailed set of activities that the inves-
sions for these documents are: tigator will want to observe during the inspection.
• Listing of site standard operating procedures Most companies are prepared with a brief (30-60
• Copy of the site organizational structure minute) PowerPoint presentation that gives a brief
• Copy of the complaint SOP overview of the company’s history, manufacturing
• Listing of all complaints for the last two years capabilities, and organization. This presentation is
• Copy of the SOP for stability failures usually a precursor to the actual inspection process.
• Listing of all stability failures from the last two One of the first things conducted is the detailed
• Copy of the change control SOP (and possibly prolonged) observation process.
• Listing of all change controls from the last two
• Listing of all qualified equipment with the
dates of the most recent qualifications

9 Conducting Audits, Gap Assessments & Corrective Actions Volume II

Jeanne Moldenhauer

CONDUCTING THE INSPECTION–THE example, if the cleaning is documented in logbooks,

OBSERVATION PROCESS when it is reviewed by the quality organization?
During the various presentations given when FDA Another concern might be, if the logbook has a
changed to the systems-based inspection process, it secondary reviewer signature and one sees errors or
was indicated that FDA investigators would spend incomplete information in the logbook, what does
more time on the actual production floor during the secondary reviewer signature mean?
their inspections. This has been evidenced in the Operators performing cleaning will be queried
reviewed inspections where the investigators spent regarding how they perform the cleaning. When
about 70% of the inspection observing the manu- answering, they might specify activities and pro-
facturing and/or laboratory environment. It is com- cedures. One of the concerns during this process
mon for the investigator to choose to spend a large is whether all the steps they conduct are included
amount of time watching the actual production or in the documentation, so that their “claims” can be
laboratory process (depending upon the expertise verified have been completed.
of the investigator). For aseptically filled products, Later, in the documentation review process, the
this includes gowning up and observing the entire inspectors may also look to verify that all of the
production run of at least one lot of product for each steps required in the procedure can be verified. This
different facility and/or type of operation (e.g., vials, includes documentation of the required times for
syringes, bags). The observation process includes use of cleaning agents and other timing required
all aspects of manufacturing, including release of steps. The investigators also may look to see that the
equipment, the set-up process, manufacturing, and cleaning was performed at the correct frequencies.
EVALUATION OF THE EFFECTIVENESS Observation can assess the ability of equipment to
properly wash vials. Should a company indicate that
OF THE CLEANING PROCESS multiple air flushes are used as part of the process,
Watching the cleaning process used for equipment
the investigator may notice vials proceeding in the
can provide many opportunities for further obser-
process that have moisture in the vials. This leads
vation and evaluation. For example, how do the site
to questions about the maintenance of the nozzles
personnel verify the effectiveness of cleaning? Are
used in the air flush process, such as questions about
they just basing this upon the review of the signed
what is conducted during the preventative mainte-
logbooks or forms? Recent inspections have shown
nance procedures and when those procedures were
a need for an actual physical review of the equip-
last conducted.
ment to assess the appropriateness of the cleaning
Some of the observations may include assessing
conducted. It might be useful to use simple instru-
whether samples across a series of nozzles are all
ments, like flashlights, to see if all of the particulate
processed in the same way and in a consistent man-
is removed, whether fibers from the cleaning pro-
ner. The investigators may also look at the quality
cess are left behind, and to determine if the cleaning
of the vial cleaning process. Is there evidence of re-
process was properly conducted.
sidual detergent? Is water for injection used as the
Should an observation be made that some type
final rinse? Do the vials appear to be clean?
of cleaning is not effective, this would typically re-
In the documentation review process, the inves-
sult in a more detailed review of other equipment
tigators may look to assess how the validation was
to determine if the observation is an isolated event,
conducted, including an assessment of the func-
or whether it is representative of a pattern of poor
tioning of the air flush system. They may also review
cleaning practices. This may also lead to questions
the various processes for maintenance and ongoing
on how the quality department is involved in the
qualification of the system.
acceptance or review of the cleaning process. For
Observation of the compounding area frequently

10 Conducting Audits, Gap Assessments & Corrective Actions Volume II

Jeanne Moldenhauer

involves looking at the equipment used in the com- PERSONNEL BEHAVIOR, TRAINING,
pounding process. For example, is it dedicated or AND GOWNING
shared? If it is shared, how does one know what When site personnel are used to escort the investiga-
product is currently being made using the equip- tors through the manufacturing process, it is critical
ment? What is the process for tubing? Is it re-used that these employees be meticulous to ensure that
or single use? If it is cleaned, how is this performed? they are properly gowned when entering the aseptic
Investigators also look for status forms or placards viewing areas (or any other area requiring special
on the equipment. For example, how does one know gowning). Starting out with incorrect gownin or be-
it is cleaned or dirty, sterilized or not sterilized? For coming inappropriately gowned during the process
equipment requiring calibration, how can one de- (like having hair outside of the bonnet) can become
termine whether the calibration is current? A com- official observations on the inspection report. This
mon concern is how tubing is stored and used in can also trigger a subsequent review of the training
these areas. What types of documentation are used record for those quality personnel (that typically
in this area for cleaning and disinfection? If clean- are the escorts) to assess how they are trained and
ing and disinfection are documented in logbooks, evaluated and their ability to enter these areas.
where are the logbooks stored? Investigators look closely at how the operators
If clean-in-place (CIP) systems are used, the in- intervene in the production process. During the
vestigators might review the start and end times to actual production process, they look for whether
assess whether the cleaning cycles used are consis- product is segregated or discarded as part of the in-
tent. Another concern they might have is whether tervention. They may also assess whether additional
some of the ingredients used in the area are “worst- sampling should have been conducted as part of the
case” from a cleaning perspective. If so, does one process.
have cleaning validation data using this worst-case All of these reviews also provide information on
ingredient? the effectiveness of the training programs being
Drying in place (DIP) systems are also reviewed. used for aseptic behavior and gowning. When poor
Is there a validated system for drying? How is dry- behavior is observed, it is common to follow up
ing assessed? If visual checks are used, can one easily with a detailed review of the training conducted for
see all the areas to make the determination? Once a individuals working in the aseptic area, including
system is dried, how is the status documented? the requirements for qualification to work in these
The investigators typically look at the procedures There is a heightened observational focus on how
used to bring items into the aseptic area (note: ad- the operators perform during the aseptic manufac-
ditionally, this is a good time to look closely at how turing process. Some of the types of considerations
the operators intervene into the aseptic process to included during this part of the observation include:
set up the equipment). What type of “heroics” is • Do the interventions conducted reflect good
involved in the equipment set-up? If the operator aseptic technique? For example, are operators
comes into contact with aseptic or sterile surfaces, observed leaning over the aseptic manufac-
turing area? Are they only using sterile tools
do they utilize additional sampling to ensure that the to handle sterile containers? Do different op-
area is not contaminated? Was the system designed erators conduct interventions in the same way
for easy set-up and minimal risk of contamination? for the same type of occurrence? How are the
interventions documented?
• How are the environmental monitoring
samples collected? Are the sampling sites in
locations that truly assess the process? For

11 Conducting Audits, Gap Assessments & Corrective Actions Volume II

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example, are they at the work height and lo- minute or more?
cation where they are measuring worst case It is also important to carefully review the defect
conditions? samples. One recurring concern was whether the
• Are extra environmental samples taken when
operators come into contact with surfaces in quality assurance department reviewed and ap-
the aseptic area? proved the sample set. Part of this would include
• Are the sampling methods and locations ap- an “approved” labeling of some sort on the sample
propriate for the types of interventions con- defect set. It is also important to assess the appro-
ducted during the process? priateness of the sample defect set to the types of
• What is the duration of time the operator
is present in the aseptic area? Since they get sample defects in the site procedures. For the vari-
tired over time, is this time duration reflected ous defects, one must also be able to distinguish be-
in media fills? tween critical and non-critical defects. Additionally,
• Are the gowning and other apparatuses worn does the inspection include the use of both black
appropriate for the types of tasks conducted and white backgrounds? If both clear and colored
by the operator? For example, if they have
extensive safety equipment, does the garment vials are utilized, are there sample sets that include
still have the needed flexibility to do the re- the various defects in the colored vials manufac-
quired tasks? tured?
• Is the aseptic behavior consistent throughout The training of inspectors is also investigated.
the manufacturing process? Some of the issues relative to the training include
• How fast do operators move in the aseptic
area? This is based upon the expectation that the following:
slow, deliberate movements should be made. • Whether both clear (colorless) and colored
• Some investigators have asked for maps of the vials are used in the training and certification
area that included the location for each type of • The number of individuals qualified to per-
sampling with identification of what sampling form inspections
was at each map point (e.g., settling plate, ac- • The frequency of qualification
tive air, or surface). • Whether the qualification reflects the total
• When and how do the operators sanitize their time an inspector would work in a typical
hands? Is it after each and every time they shift (including breaks and the stresses of lon-
touch something? ger work periods)
• What are the materials of construction used • The relationship between the number of de-
in this area (data was later compared to clean- fects in the lot inspected and the whole lot
ing and disinfection studies)? • Whether all defects are included in the sample
• There have been many comments on the need set used for qualification
for quality oversight during the production • How the operator looks at the vial (e.g., bot-
process to ensure the aseptic behavior was ap- tom and sides, swirled, upside down)
propriate, to identify the need for additional • Any changes in the qualification process
samples during interventions, and so forth. across years (e.g., who determines whether
new defects that have been found should be
updated into the sample set).
In most cases, this type of observation is conduct-
ed for the entire production of a batch of product. It is also important to verify that all of the inspec-
tors are currently qualified for inspection.
For manual visual inspection systems, one of the The review of environmental monitoring data and
key concerns during inspections is consistency of practices in sterile drug manufacturing sites con-
the inspection by different operators. For example, tinues to be an important part of the inspection. In
if they are looking at three vials at a time, do all op- addition to the regular practices of looking at media
erators spend about a minute to look at the vials, or being qualified for use, growth promotion testing,
do some spend a few seconds while others spend a whether environmental isolates are used, qualifi-

12 Conducting Audits, Gap Assessments & Corrective Actions Volume II

Jeanne Moldenhauer

cation of methods, and trending of data, there are tation that shows it was reviewed and deemed ac-
some other types of considerations being posed. ceptable for use.
Some of the current issues include:
• Does one have a written program that defines
what to do, when to do it, why do it, and how LABORATORY PRACTICES
it is scientifically justified? The investigator typically covering the laboratories
• Did one use a risk-based approach to deter- (microbiology and chemistry) is also responsible
mine sampling locations? for the review of practices and procedures relative
• Did one use a risk-based approach to select to the stability program. As might be expected, a
appropriate methods and frequencies of mon-
itoring? significant amount of time was spent reviewing
• Are particulate monitoring probes appropri- records from batches with deviations and investiga-
ately placed in relationship to the work area? tions. Some of the common types of issues in this
• Does one have maps available showing all of type of review include the following:
the sampling sites, and are they color coded Requesting data to show the reliability of methods
(or otherwise identified) to show each type of
sample collected? (e.g., was relative standard deviation calculated in
• Does one have smoke study data to justify residual solvents test?). Have the methods been ap-
the sampling locations used? Specifically, for propriately qualified or validated?
settling plates, investigators want to see the • System suitability was not being evaluated as
correct airflow pattern to show that organ- part of the failure investigation.
isms would “fall out” onto the media in the • Are all provisions for chromatography tests
selected sampling location (air sweeping over in the general information section applicable
the sample would push the counts away from to all tests (including gas chromatography)
the plate while air swirling over the sample being implemented? For example, is system
would allow for fall out). suitability being testing?
• Does one have a system to ensure that extra • Insufficient information is documented in
samples are collected during batch production investigations (e.g., what was the corrective
of places where an operator may have touched action taken?).
a surface (this implies some type of oversight • In an investigation where samples are taken
of production to identify these areas)? from several different containers, but only one
• Is the right type of sample for each sample site container failed, did one review the sample re-
being used (e.g., using a settling plate when sults for all of the containers? Did one deter-
an active air sampler should have been used)? mine whether the material was hygroscopic?
• For automated systems, is an appropriate vali- If so, did one complete a test for water first?
dation of the software used? • In a failure investigation, once one has con-
firmed that the data is valid (it is an OOS),
does the investigation fall under the purview
SMOKE STUDIES of quality assurance?
Investigators today are looking for comprehensive • Are all the periodic calibration dates entered
smoke studies that show the airflow in the area. onto all the applicable laboratory records?
They have recommended not using the simple • Does one have a working system to ensure
that the time period from finding an OOS to
smoke stick and moving around the room. There generating a field alert, if necessary, is met?
is a preference for the systems that generate several • In the validation of automated systems in the
parallel streams of smoke at a time to show the air- laboratory, are challenges conducted to ensure
flow in an area. There is also an increased interest in that all of the workstations are included in the
having smoke study data that shows the impact of validation? Is stress testing performed?
• Are requirements for data integrity assessed
how and when interventions are performed. Smoke in qualification and requalification activities?
study data are also requested to support the use of • Are reference libraries used for identification
environmental monitoring sampling locations. in chemistry tests rather than using the actual
The filed smoke study should be readily available reference standard? The reference standard
for review. Additionally, there should be documen- should be used.
• Is testing performed to identify all unknown

13 Conducting Audits, Gap Assessments & Corrective Actions Volume II

Jeanne Moldenhauer

peaks? Hopefully that “best behavior” is carried through

• For stability studies, is the laboratory ap- into routine production practices.
propriately staffed to ensure that all tests are Ensuring that the interventions conducted in me-
performed as required and on time?
• Do procedures clearly indicate how many dia fills and in production are representative of both
samples should be tested for each type of test? the number and types of interventions performed
• If products have allowances for reconstitu- is important. It is also important to ensure that the
tion, is the reconstituted product tested at affected product is treated the same way in produc-
release, during stability at the initial time of tion as it is during the media fill.
reconstitution, and at the end of the maxi-
mum allowable time? There is an increasing focus on the sterilization
• Is a statistically valid sample size of reserve of media used in the media fill (with European
samples reviewed on an annual basis to en- investigators questioning this more often). Media
sure that they have not deteriorated? manufacturers typically state on the label that the
• Are the probes in stability chambers located media should be steam sterilized at a specific set of
at “worst-case” conditions?
• Are microbial methods performed using sci- parameters. Today, some companies have chosen to
entifically appropriate methods? aseptically fill media for sterilization during its use
• Is particulate monitoring conducted at the in a media fill. The issue starts with the fact that the
exit of the tunnel? manufacturer does not recommend this steriliza-
• Are touch plates (fingertip impression plates) tion cycle. Some investigators have asked for com-
required after contacting a sterile surface?
• Are sampling locations scientifically justified panies to only sterile-filter media that is made to be
and appropriate? sterile-filtered (as claimed by the manufacturer).
• Is a system for trending of microbiology data Companies performing the aseptic sterilization
used? process typically use the growth promotion test
to show that the media is acceptable for use. De-
All of these types of issues go hand-in-hand with pending upon the company, they may or may not
whether the individuals working in the laboratory use stressed organisms or environmental isolates as
have been appropriately trained and qualified for part of this process. Some regulatory investigators
the operations they conduct. are also concerned that the media post-sterilization
will work effectively with low levels of bioburden.
DELINEATING THE ROLES OF QUALITY Once, an investigator wanted longer incubation
ASSURANCE AND QUALITY CONTROL times for media fill units, asking for a minimum of
Throughout inspections there appears to be a sig- 28 days with 14 days at each temperature range. No
nificant distinction between the roles of the quality information was provided on the rationale for this.
assurance group versus the quality control group. The company in question had no history of slow-
This distinction appears to supersede the good growing microorganisms present nor had they had
manufacturing practices (GMP) wording of the any issues with contamination recently (more than
“quality unit.” As such, procedures were requested five years).
that showed the roles and responsibilities for indi-
viduals filling these roles in the company. STERILIZATION CYCLES
The Parenteral Drug Association’s (PDA) Techni-
MEDIA FILLS cal Report Number 1: (revised 2007) Validation of
It is well understood that the media fill is a signifi- Moist Heat Sterilization Processes, Cycle Design,
cant part of the aseptic processing program. How- Development, Qualification, and Ongoing Control
ever, the role of the media fill documentation may (3) has had a significant impact on the understand-
be lesser than observing the actual aseptic process. ing of steam sterilization for many investigators. It
During the media fill, personnel are typically at has become more common for investigators to ask
their “best behavior” to be sure the media fill passes. questions about the biological indicators, includ-

14 Conducting Audits, Gap Assessments & Corrective Actions Volume II

Jeanne Moldenhauer

ing their D and z-values. Additionally, there is an CONCLUSION

increased interest on the controls and procedures Predictions that FDA would spend more time on
used for both overkill and product specific cycles. the manufacturing floor have been evidenced in
various inspections conducted. Investigators are as-
DOCUMENTATION REVIEW sessing the processes to determine whether “good
Compared to the overall inspection process, mini- science” is being used. Additionally, the standards
mal time is typically spent on documentation re- for GMPs continue to evolve, as evidenced by the
view (about 30% of the time). In many cases, this small “c” in [current good manufacturing practices]
includes review of procedures, logbooks, and re- cGMPs. There is also an increased emphasis on con-
cords to determine whether the adverse conditions ducting risk assessments to justify manufacturers’
observed during the observation phase were a result activities.
of not being a requirement in the site procedures or It is also common for the FDA investigators to pro-
whether site procedures were not properly followed. vide some examples of how other companies might
Another portion of the review involves asking the address an issue. For example, they may say, “I have
operator whether they followed the procedure as seen some companies do their validation this way.”
written and then showing them the documentation This type of information is useful in understanding
to determine how to reconcile what was document- potential corrective actions that may be used.
ed versus what they claimed. As such, the promises made by FDA when imple-
menting their new programs for conducting inspec-
tions have become a reality.
Reviewing investigations and deviations involves
an assessment of whether the “whole story” of what REFERENCES
happened was told. Is it possible to clearly identify 1. FDA, “Drug Manufacturing Inspections Program
7356.002” Compliance Program Guidance Manual for
what happened and how it was corrected? Did the FDA Staff (Rockville, MD, 2002) available at: http://
investigation result in a scientifically sound conclu- www.fda.gov/AboutFDA/CentersOffices/OfficeofMed-
sion? Was appropriate follow-up initiated to ensure icalProductsandTobacco/CDER/ucm095598.htm.
that the problem was solved? Was the investigation 2. FDA, Final report for pharmaceutical cGMPs for the
expanded to include all affected batches? Are these 21st Century - A risk-based approach, U.S. Department
of Health and Human Services (Rockville, MD, 2004)
records tracked and reviewed to ensure that they are available at: http://www.fda.gov/downloads/Drugs/
closed out in a timely manner? DevelopmentApprovalProcess/Manufacturing/Ques-
RESPONSIBILITY OF THE QUALITY UNIT 3. PDA, “PDA’s Technical Report Number 1: (revised
Several of the recurring issues or concerns for ad- 2007) Validation of Moist Heat Sterilization Processes,
dressing this topic are: Cycle Design, Development, Qualification, and On-
• Does the manufacturing occur within GMPs? going Control,” PDA Journal of Parental Science and
If not, why isn’t the quality organization doing Technology 61 (S-1). Bethesda, MD, 2007.
something about it?
• Is the quality unit reviewing and approving all
of the required documents (procedures, pro- Originally Published in Journal of Validation Technology
tocols, laboratory investigations, media fills, Volume 18 Number 3
and so forth)?
• Are investigations performed completely
(finding a root cause, correcting the problem,
and closing it in a timely manner)? Is the in-
vestigation based upon good science?
• Is the quality unit sufficiently staffed to do the
work assigned them?

15 Conducting Audits, Gap Assessments & Corrective Actions Volume II

Jeanne Moldenhauer

About the Author

Jeanne Moldenhauer is Vice President of Excellent
Pharma Consulting. She has over 25 years experi-
ence in the pharmaceutical and biotechnology
industries. She chairs the Microbiology/Environ-
mental Monitoring Interest Group of PDA and is a
member of the Science Advisory Board.

16 Conducting Audits, Gap Assessments & Corrective Actions Volume II

Paul L. Pluta and Jerry Lanese

Laboratory Self-Audits
Paul L. Pluta and Jerry Lanese

“Audit 101” provides useful and practical information that addresses various topics associated with audits.
Common-sense suggestions with application to all audits – internal and external, regulatory and non-regu-
latory, domestic and international – are provided. Examples of actual occurrences are described whenever
possible. Audit 101 has previously discussed the following
“First Impressions -- The Plant Tour” (1)
“Preparation, Preparation, and More Preparation” (2).
Reader comments, questions, suggestions for discussion topics, and actual audit experiences are needed to
help us fulfill the column objective. Please send your comments and suggestions to column coordinator Paul
Pluta at paul.pluta@comcast.net.

Every laboratory must become comfortable with be- INTRODUCTION

ing audited. A self-audit conducted internally is an Every organization must become comfortable with
excellent tool for the lab to prepare itself for any au- being audited. Regulatory audits by global agen-
dit, identify problems, test execution, and simulate cies, International Organization for Standardiza-
an actual audit experience. Conducting a rigorous tion (ISO) Registrar certification audits, external
self-audit that simulates an actual audit also helps to customer audits, and internal quality assurance
establish a culture that supports an on-going state of (QA) audits happen frequently. Some may come at
preparedness in the laboratory. Successful laborato- a moment’s notice while others are planned weeks
ries operate in this state at all times. This discussion in advance. The key to a success is to make sure your
provides a guide to the self-audit of a laboratory. area is always prepared for an audit. A functioning
Laboratory systems independent of an actual test laboratory must function in a state of readiness on
result are reviewed beginning with the laboratory a daily basis. However, audits and inspections of
organizational structure through sample collection, the laboratory are often not anticipated. Audits that
analytical testing, and record retention. Areas of start in a distant site’s conference room usually lead
interest are identified including specific function, to the manufacturing floor and ultimately involve
procedures, practices, records, and staff compli- one or more laboratories at the site.
ance with procedures. Topics discussed include the Organizations often have a designated internal
laboratory audit process, relevant audit documents function whose sole purpose is to conduct inter-
and references, laboratory procedure availability, nal audits. These may be very rigorous audits; the
document requests by auditors, and audit training personnel conducting such audits are usually very
for personnel. An approach to gap identification, well experienced. These audits are stressful events
analysis, and prioritization of mitigation projects is for the lab since the results may be communicated
presented. A case study is given describing an ac- to high-level personnel in the organization. To pre-
tual regulatory audit of an analytical quality control pare for these internal audits as well as the afore-
(QC) laboratory and its supporting research and mentioned regulatory, ISO, and other audits, self-
development (R&D) laboratory. audits conducted by the laboratory personnel are
recommended. This is an excellent tool for the lab
to prepare itself for any audit, identify problems, test
execution, and simulate the actual audit experience.
Conducting a rigorous self-audit or that simu-

17 Conducting Audits, Gap Assessments & Corrective Actions Volume II

Paul L. Pluta and Jerry Lanese

lates an actual audit also helps to establish a culture APPROACH TO THE SELF-AUDIT
that supports an ongoing state of preparedness in Areas of interest are identified within each of the
the laboratory. The following discussion provides a elements of the laboratory operation. The auditor
guide to the self-audit of a laboratory. Audits may should investigate the following in each area and
be conducted in different ways. This approach ad- respective activities:
dresses the laboratory systems independent of an • Function of the specific element or activity
actual test result. It begins by identifying the major • Appropriate procedures are in place
elements of a laboratory operation listed according • Procedures accurately reflect the practice
to a typical sequence of activities. It then identifies • Records are complete, accurate, and main-
areas to assess to determine the readiness of the lab- • Staff is compliant with procedures
oratory for an outside audit. The elements of a labo-
ratory operation are listed below beginning with
the laboratory organizational structure through the LABORATORY OVERVIEW
sample collection, testing, and record retention: An overview of the laboratory operation is the first
• Laboratory overview area for review in the self-audit. Areas for review in
• Sample collection this element address the general goals and objec-
• Sample receipt in the lab tives, operations, function, and management of the
• Sample handling and storage in advance be- laboratory. This type of information is requested
fore testing
• Sample testing when the auditor first arrives at the laboratory. In-
• Instrument qualification formation regarding the type of testing conducted,
• Instrument maintenance and calibration qualifications of personnel and management, orga-
• Test method and sampling procedure devel- nizational chart, responsibilities, and other descrip-
opment tive information must be readily available. Docu-
• Test method validation
• Laboratory technical training mentation and records must be provided when
• Data treatment requested. The areas to assess here are:
• Results verification, review and approval • Type of testing conducted in the laboratory
• Results reporting • Areas and units that submit samples to the
• Investigations laboratory
• Record compilation. • Organization of the laboratory, including re-
• Record storage, retention and retrieval sponsibilities and accountabilities
• Qualifications of laboratory personnel
• Qualification of laboratory management
Topics including the laboratory audit process, rel- • Education, training and experience of labora-
evant audit documents and references, laboratory tory management
procedures, document requests by auditors, and • Processes which monitor laboratory perfor-
audit training for personnel are also discussed. mance
When self-audits of laboratory operations are • Laboratory work outsourced to other areas
within the company or outsourced to an out-
completed and gaps are identified, risks are evaluat- side laboratory
ed. The remedial actions required to mitigate these • Prior audit or inspection observations
risks are then prioritized and addressed.
A case study demonstrating an alternate approach
to the laboratory audit is also presented. This case
The areas for review in this element address the
study follows an actual test result “backwards”
source of samples for testing. What areas submit
through the lab, starting with the result. Either of
samples, how are samples collected, required special
these approaches, (incoming sample receipt through
training for sampling personnel, etc. Samples may
final results or final result through incoming sam-
be submitted from various areas in the organization.
ple), may be utilized in a self-audit. A combination
Samples may also be submitted at various stages
of methods, or use of both approaches at different
of manufacturing. Some samples may require im-
times, may serve to best uncover area weaknesses.

18 Conducting Audits, Gap Assessments & Corrective Actions Volume II

Paul L. Pluta and Jerry Lanese

mediate testing, while others may able to be staged SAMPLE HANDLING AND STORAGE IN
within the specific response time for laboratory ef- ADVANCE OF TESTING
ficiency. Each of these considerations may lead to a The areas for review in this element address the han-
specific line of questions including specific require- dling and storage of samples before they are actually
ments, specific handling, and so on. The sampling tested by the laboratory. These areas are:
activity is often not within the control of the labora- • Sample storage while samples are awaiting test-
tory. If the laboratory cannot assure the quality and ing
integrity of the samples received for testing, testing • Provisions for special storage conditions such
results will be suspect because the sampling process as refrigeration, light protection, or other re-
lacks appropriate controls. The specific areas to as- • Qualification of sample storage area
sess are: • Identification and prioritization of samples
• Areas or units that submit samples to the lab that require immediate testing
for testing • Security of storage area
• Qualifications of individuals who actually re- • Specific goals for completion of testing
move the samples from the manufacturing pro- • Procedures for sample handling and storage
cess, stability area, or other source of samples in the laboratory
• Specialized personnel training required for
• Specialized equipment or facilities required SAMPLE TESTING
for sampling The areas for review and assessment in this element
• The qualifications of individuals who deliver address the actual testing of samples:
samples to the laboratory • Reference standard program and controls
• The technical input by the laboratory into • Reagent controls
proper sampling, packaging, and labeling of • Control of chromatographic columns
the samples • Preparation control of stock reagents
• Sample labels • System suitability requirements for test meth-
• Procedures for sampling, packaging, and la- ods
beling, and submission of samples to the labo- • Procedures for handling deviations to analyti-
ratory cal methods or other laboratory procedures
• Procedures for handling changes to test meth-
SAMPLE RECEIPT IN THE LAB ods or other laboratory procedures
• Test procedures
The areas for review in this element address specific • Test-specific work sheets
activities associated with the receipt of samples by • Qualification of analysts to perform tests
the laboratory from the sample delivery person. Are • The performance of required tests
all samples simply dropped into a receipt box or are
there specific receipt procedures under laboratory INSTRUMENT QUALIFICATION
control? Important areas to evaluate are: The areas for review in this element address the ca-
• Sampling receiving area’s security and integ-
rity pability and readiness of laboratory instrumentation
• Sample receiving process for testing. All instruments and equipment must be
• Sample receiving records qualified according to their United States Pharma-
• Storage of samples immediately upon receipt copeia (USP) (or equivalent) instrument categoriza-
and environmental controls tion (3). Laboratory management must be mindful
• Security of receipt area
• Qualification of the sample receiving area of the intended use of the instruments as well as
• Examination and evaluation of samples upon the instrument manufacturer’s recommendations
receipt, including records of the activity regarding the equipment use. Changes to laboratory
• Process for logging samples into a labora- instruments should be evaluated through a change
tory information management system (LIMS) control system:
computer system for tracking • Procedures related to instrument qualification
• Validation of the LIMS system • Responsibility for instrument and equipment

19 Conducting Audits, Gap Assessments & Corrective Actions Volume II

Paul L. Pluta and Jerry Lanese

• Status of laboratory instrument and equip- (GMPs). Changes to validated test methods must
ment qualification be evaluated through a change control system. The
• Change control as it applies to instruments following aspects of the test method validation must
and equipment
be evaluated:
• Responsibilities for test method validation
INSTRUMENT MAINTENANCE AND • The test method validation process
• Status of the validation of all test methods
CALIBRATION • Evidence that test methods perform as in-
The areas for review in this element address main- tended
tenance and calibration activities associated with • The system for changing test methods
instruments and other equipment. Instrument • The involvement of development subject mat-
calibration is significant routine maintenance activ- ter experts in evaluation of changes
• Location and availability of test method vali-
ity for analytical instruments. Instruments must be dation documentation
calibrated or user standardized for actual use. The
following must be assessed:
• Instrument maintenance procedures LABORATORY TECHNICAL TRAINING
• Laboratory instrument calibration program The training of laboratory personnel and associated
• Instrument calibration procedures training records are always requested in an audit.
• Calibration records Areas that should be reviewed include:
• Instrument logbooks • The laboratory technical training program
• Process for determination of appropriate
TEST METHOD AND SAMPLING training for each analyst
• Evidence of analyst qualifications
The areas for review in this element address the • Maintenance of training records and respon-
development of test methods by Analytical research sibility, and current records
and design (R&D) or other technical support func-
• Responsibilities for the development of test
methods, including sampling used in the The areas for review in this element address raw
laboratory data recording, calculations, and other treatment of
• Evidence that specific samples for testing are data to determine test results. The laboratory ana-
representative of the material received lysts who perform the analytical testing record all
• Availability of method development reports data, calculations, and compile instrument docu-
in the lab when needed for problem solving
• Transfer of methods from other labs to this mentation and associated information. Calcula-
laboratory tions may be done with calculators, spreadsheets, or
• Procedures defining test method and sam- other computer software. If computer systems and
pling procedure development software are involved, these must be validated. The
specific areas of data treatment to be reviewed are:
• Procedures for recording data in worksheets
TEST METHOD VALIDATION or notebooks, labeling of instrument print-
The areas for review in this element address test outs, entry into computer systems, calcula-
method validation and associated activities. Test tion, and result reporting
method validation is a key area in the laboratory • Procedures covering averaging and significant
audit. Industry and regulators focus on analytical figures
• Procedures for good recordkeeping practices
method validation. Any type of test method (physi- (good documentation practices)
cal, biological, microbiological, chemical) must • Software and spreadsheets used to perform
have documented evidence that demonstrates the calculations, spreadsheet development stan-
test performs as intended. Test methods must be dards, evidence of validation
appropriately validated if they are used for any test- • Change control
ing required by the good manufacturing practices

20 Conducting Audits, Gap Assessments & Corrective Actions Volume II

Paul L. Pluta and Jerry Lanese

RESULTS VERIFICATION may vary significantly from historical norms. This

AND APPROVAL data requires investigation by the laboratory to
The areas for review in this element address the fi- determine the causes for the aberrant laboratory
nal review and approval of raw data, calculations, results. There should be focus on the reviewing the
data treatment, and other associated activities by following:
• Procedures for handling and investigating
supervision prior to release of results to the appro- out-of-specification or out-of-trend labora-
priate organizations. Laboratory records are signed tory results
and dated by the analyst to affirm performance of • Procedures for laboratory investigations
the testing. They are then reviewed and approved • Evidence of typical laboratory investigations
by laboratory supervision. All records are signed • Retention of laboratory investigation reports
• Corrective and preventive actions resulting
and dated by laboratory supervision affirming from laboratory investigations
performance of the testing, approval of the test re-
sults, and compliance with internal procedures and
regulations. Througout this process, there should be RECORD COMPILATION
heightened emphasis on the assemente of: After testing is completed, data verified, results
• Responsibilities of analysts and reviewers calculated, reviewed, and approved; and results re-
• Procedures covering verification, approval ported to quality or the originator, all records are
and release of raw data, calculations, final re- compiled in a standardized format. Areas for review
ports to appropriate areas, and signature/date in this element include:
requirements for analysts and supervisors • Procedures covering the format for completed
• Responsibilities for approval of all data and laboratory records
calculations prior to reporting results • Procedures for compilation of records
• Evidence of completed records
The areas for review in this element address the RECORD STORAGE AND RETRIEVAL
report of approved results to the sample originator The areas for review in this element address the
or the unit using the data. Sites may have electronic storage and retrieval of laboratory data. Data and
systems into which test results are entered and are test documentation may be stored electronically or
ultimately transferred for final lot disposition. Oth- in hardcopy depending on the organization. Stor-
er sites may have paper systems that accomplish the age must be secure. Access to test records must be
same objective. Sites may also have mixed systems, restricted to qualified personnel. If storage is by
(e.g., electronic systems) for certain samples and electronic systems, these systems must be validated.
paper systems for special samples. Specifically, in Data and test information must be quickly and eas-
results reporting, the following should be reviewed: ily retrievable. Reviewing the following is a neces-
• The process for reporting results to quality or sity:
sample originators • Procedures for record storage, retention and
• Validation of any computerized system used retrieval
in the sample reporting process • Security and environment of the record stor-
• Timeliness of results measured against labora- age areas
tory turnaround goals • Qualifications of individuals responsible for
• Procedures for reporting of results record storage
• Assurance of appropriate testing and com-
plete testing
INVESTIGATIONS Actual laboratory audits may be conducted in vari-
The areas for review in this element address perfor- ous ways. The above elements outline a “start to fin-
mance of investigations when aberrant test results ish” approach to the audit structured according to
are generated. Test data may fail specifications or the business process of the lab. It establishs the labo-
ratory organization infrastructure through the test-

21 Conducting Audits, Gap Assessments & Corrective Actions Volume II

Paul L. Pluta and Jerry Lanese

ing to the storage and maintenance of the records. official reference standards as appropriate
Audits may also be conducted in the reverse order, • System suitability checks on chromatographic
(i.e., following a test result from “finish to start.”). In systems such as gas chromotography or high
performance liquid chromotography
this approach, the audit follows a reported test result • Specifications, standards, and representative
from the laboratory report to data generation. The sampling plans
audit then follows to testing through sample receipt • Adherence to written methods of analysis
and original sampling by the sample originator. The • Validation/verification of analytical methods
attached case study is an example of this latter ap- • Control system for implementing changes in
laboratory operations
proach and represents a realistic audit experience. • Required testing performed on the correct
Use of both approaches at different times will chal- samples
lenge the laboratory system and expose personnel • Documented investigation into any unex-
to a variety of audit circumstances. pected discrepancy
Other documents that may be used as the basis • Complete analytical records from all tests and
summaries of results
for internal audits include the US Food and Drug • Quality and retention of raw data such as
Association Compliance Program Guidance Manual chromatograms and spectra
#7356.002 (4), FDA Compliance Program Guidance • Correlation of result summaries to raw data;
Manual #7345.848 (5), and PIC/S Aide Memoire: In- presence of unused data
spection of Pharmaceutical Quality Control Labora- • Adherence to an adequate out of specifica-
tion (OOS) procedure which includes timely
tories (6) and periodic review of FDA Warning Let- completion of the investigation
ters (7) are also helpful. FDA observations provide • Adequate reserve samples; documentation of
insight into current regulatory emphases and ideas reserve sample examination
for additional areas or questions in a self-audit. • Stability testing program, including demon-
stration of stability indicating capability of
test methods
GUIDANCE MANUAL #7356.002 The guidance also identifies example laboratory
This document was written to provide Center for and control system problems. These include the fol-
Drug Evaluation and Research (CDER) investiga- lowing:
tors an overview of areas to be reviewed during a • Pattern of failure to establish/follow a control
drug manufacturing inspection. It identifies the six system for implementing changes in the labo-
ratory operations
basic systems within a quality system including the • Pattern of failure to document investigation of
laboratory control system. This guidance identifies discrepancies
areas within each system which the investigators • Lack of validation of computerized and/or
should review. It also directs that the firm should automated processes
have written and approved procedures for each of • Pattern of inadequate sampling practices
• Lack of validated analytical methods
the areas and records of these procedure results. The • Pattern of failure to follow approved analytical
investigators are also directed to verify that person- procedures
nel are following the procedures. The areas listed for • Pattern of failure to follow an adequate OOS
the laboratory control system are: procedure
• Training/qualification of personnel • Pattern of failure to retain raw data
• Adequacy of staffing for laboratory operations • Lack of stability-indicating methods
• Adequacy of equipment and facility for in- • Pattern of failure to follow stability programs
tended use
• Calibration and maintenance programs for
analytical instruments and equipment FDA COMPLIANCE PROGRAM
• Validation and security of computerized or GUIDANCE MANUAL #7345.848
automated processes This document provides Center of Biologics Evalu-
• Reference standards source, purity and assay, ation and Research (CBER) investigators an over-
and tests to establish equivalency to current
view of areas to be reviewed during a biological

22 Conducting Audits, Gap Assessments & Corrective Actions Volume II

Paul L. Pluta and Jerry Lanese

manufacturing inspection. It identifies the same six tensive list of very specific questions.
basic systems within a quality system and critical el- The quality assurance system section of this docu-
ements. Standard operating procedures (SOPs) and ment asks the following questions regarding “self
training records are highlighted. It also identifies ar- inspection”:
eas within the laboratory control system that should • How is it, and by whom performed?
be reviewed, as well as observations that could be • How is it reported?
• How are corrective measures implemented?
reported. These are similar to the areas identified in • Is the schedule available and adhered to?
7356.002 and include:
• Written procedures and control system for
laboratory operations OTHER CONSIDERATIONS
• Calibration and maintenance programs for
analytical instruments and equipment Documents Requested by Auditors
• Adherence, validation/verification to the writ-
ten methods of analysis Whenever documentation is requested by an audi-
• Testing and release for distribution tor, it must be quickly retrieved within a reasonable
• Specifications, standards, and representative time (for example, 30 minutes). If R&D reports or
sampling plans other documents or records generated by another
• Stability testing program, including demon- unit are not readily available through an electronic
stration of stability indicating capability of the
test methods report system, hardcopies or relevant reports
• Special testing requirements should be obtained from the originating unit and
• Adequate reserve samples and documenta- stored within the laboratory area to facilitate timely
tion of reserve sample examination retrieval. Excessive time delays in retrieval of docu-
• Required testing is performed on the correct ments are not acceptable.
• Laboratory records
Laboratory Procedures
Auditors always request the approved laboratory
PIC/S AIDE-MEMOIRE procedures and test methods. These are usually
This document provides guidance for GMP inspec- available through an electronic system. In the nor-
tors for training and preparation of inspections. It mal operation of the laboratory, analysts may print
contains nine tables addressing general subjects and a copy for their immediate personal use. This intro-
items to be investigated during GMP inspections. duces the potential for using an outdated procedure
The general subjects addressed in this document when revisions have occurred. Laboratory person-
include the following: nel must be trained to always access the current pro-
• General information cedure when a procedure is needed. There should
• Quality assurance system
• Documentation system be a system that prevents the holding and extended
• Personnel use of printed copies. If printed copies are used in
• Premises and equipment performing testing, they should be destroyed after
• Materials and supplies completion of the activity.
• Sampling and samples
• Testing
• Results and release of test results Audit Training for Personnel
Aside from the technical training for personnel on
An extensive list of specific questions for each of laboratory and testing procedures for the actual
the above sections is listed in PIC/S Aide-Memoire. performance of sample testing, laboratory person-
The above provides a different approach to a labora- nel should also be trained on proper interactions
tory audit with different focus. with auditors. This includes topics such as audit
Supplements addressing GMP inspection of protocol, listening carefully to questions, asking
chemical, physical, and microbiological testing for clarification if requests are unclear, being calm,
laboratories are also provided, also including an ex- and phrases to avoid. Internal audits should include

23 Conducting Audits, Gap Assessments & Corrective Actions Volume II

Paul L. Pluta and Jerry Lanese

analyst interaction to provide practice for handling the process validation. The regulatory audit team,
audits and responding to auditor questions. Labora- compliance officer, and QA manager then departed
tory analysts will be nervous when dealing with ex- for the lab with the process validation report.
ternal auditors. Practice will help to minimize their After arriving at the laboratory and brief intro-
anxiety and fears. ductions of personnel, the lead auditor selected a
single test result reported in the process validation
RISK EVALUATION OF IDENTIFIED GAPS report. The specified result was determined by an
Gaps in procedures, processes, records, and perfor- HPLC test method. He asked to see the following
mance will be identified after conducting a rigorous laboratory documentation associated with the test
self-audit. These gaps must then be evaluated and result:
• The analytical test method procedure associ-
corrective actions initiated. Highest risk gaps must ated with the sample
be prioritized for rapid response. Tables I, II, and • The analytical method validation report
III illustrate the results of a representative self-audit • The analytical method development report
using the activity format discussed. Table I provides
a representative list of audit observations from a After the above review, the auditors then focused
self-audit using the format of the above discussion. on the specific test result. They requested the fol-
Table II demonstrates a risk evaluation of observa- lowing:
tions. Table II provides a prioritized list of project • HPLC chromatogram associated with the
assignments addressing gaps with target dates and sample
• Sample preparatory equipment associated
personnel responsibilities. with the test method
• Actual equipment on which sample was tested
CASE STUDY: LABORATORY AUDIT • Standard used in the test procedure
• Standard storage, handling, and source of
A regulatory auditor team was conducting a new supply
tablet product pre-approval inspection at the prod- • Reagents used in the test procedures
uct manufacturing site. The audit was being con- • Reagent preparation procedures including
ducted in the designated conference room in the expiration dating
manufacturing plant. The regulatory agency audi- • Instrument qualification report
• Calibration procedure
tor, site compliance officer, and QA manager were • Calibration history
present in the conference room. • Name of laboratory analyst
The process validation report for the new product • Resume of laboratory analyst
was requested by the auditors. The process valida- • Training records of laboratory analyst
tion report was retrieved from the validation li- • Name of supervisor who approved data and
brary. The auditors reviewed the report. The auditor • Resume of supervisor
then selected the content uniformity test results in • Training records of supervisor
the validation report. The report provided the sam- • Procedure for sample receipt and storage
pling, test procedure, test lab location, acceptance • Sample receipt area
criteria, table of results, description of data treat- • Sample receipt record
• Sample storage area
ment, and a statement that the data met acceptance • Procedure for data treatment
criteria requirements. • Procedure for data and report storage
The auditors then requested to visit the laboratory • Data and report storage facility
where test data were generated. The testing labora- • Procedure describing report security area
tory was approximately 30 minutes away from the
manufacturing plant. The laboratory supervisor was All laboratory documentation requested was re-
immediately contacted and informed that the audi- trieved and reviewed. Results were consistent with
tors would be visiting his lab in approximately 30 the results reported in the process validation report.
minutes to review content uniformity testing from After looking at the analytical method develop-

24 Conducting Audits, Gap Assessments & Corrective Actions Volume II

Paul L. Pluta and Jerry Lanese

TABLE I: Laboratory self-audit


1 All laboratory equipment not identified in equipment list


2 Sample collection by manufacturing area not well controlled


3 Refrigerated samples transport not controlled

4 Refrigerated sample not immediately stored in lab


No observations


No observations


5 All laboratory equipment not appropriately qualified


6 No maintenance on unidentified equipment


No observations


7 Current procedures not always used for testing


No observations


No observations


No observations


8 Deficiencies in investigation procedure


No observations


No observations


9 Complex procedures do not have sufficient training


10 Audit training needed for new employees

25 Conducting Audits, Gap Assessments & Corrective Actions Volume II

Paul L. Pluta and Jerry Lanese

TABLE II: Risk evaluationof identified gaps




1 All laboratory equipment not identified in equipment list X


Sample collection by manufacturing area not well con-

2 X


3 Refrigerated samples transport not controlled X

4 Refrigerated sample not immediately stored in lab X


5 All laboratory equipment not appropriately validated X

6 No maintenance on unidentified equipment X
7 Current procedures not always used for testing X
8 Deficiencies in investigation procedure X

9 Complex procedures do not have sufficient training X

10 Audit training needed for new employees X

ment report which was written by an analytical laboratory notebook. Consistency between
R&D scientist, the auditors requested to visit the the raw data and the analytical R&D report
R&D lab where analytical method development for representative data was verified.)
• Procedure describing R&D documentation
work was conducted. The R&D area was contacted. practices
The R&D manager was informed that the auditors • Data security and storage policy
would be visiting the laboratory in connection with • Equipment and instrumentation used in the
the content uniformity method development for the development process, including Instrument
new product. After approximately a fifteen minute maintenance and calibration logs
• Standards and reagents used in the develop-
walk between site buildings, the audit team arrived ment process, including expiration dating of
at the analytical R&D lab. The following were then materials.
requested from the R&D lab manager: • Resume and qualifications for R&D scientist
• General overview of R&D laboratory function who developed the test method
• Organizational chart for laboratory • Resume and qualifications for R&D manager
• Analytical R&D report for the content uni-
form test method All auditor questions were successfully answered
• Raw data for testing reported in the analyti- and requested documents provided. No inconsisten-
cal R&D report (This data was recorded in a

26 Conducting Audits, Gap Assessments & Corrective Actions Volume II

Paul L. Pluta and Jerry Lanese

TABLE III: Risk mitigation goals, responsibilites, and target dates

Sample Collection

1. Obtain sampling collection procedures from respective operations areas and from stability area. Review procedures. Note
procedures for refrigerated samples.
Responsibility: __________ Target date: ____________
2. If needed, propose modification of sample collection procedure to responsible area. Follow up to assure training on new pro-
Responsibility: __________ Target date: ____________
3. Review transportation procedures for samples. Note process for refrigerated samples.
Responsibility: __________ Target date: ____________
4. If needed, propose modification of transportation procedures to responsible areas. Follow up to assure training on new pro-
Responsibility: __________ Target date: ____________
5. Review sample receipt procedures for lab. Note process for refrigerated samples.
Responsibility: __________ Target date: ____________
6. If needed, modify sample receipt procedures. Conduct training for laboratory personnel.
Responsibility: __________ Target date: ____________

Laboratory Technical Training

1. Review laboratory procedures. Identify complex procedures. Review training methods associated with complex procedures.
Initiate demonstration training requirements for complex procedures as needed.
Responsibility: __________ Target date: ____________


1. Investigations Procedure. Review Investigations procedure. Modify as needed.

Responsibility: ___________ Target date: _____________
2. Department GMP Meeting. Remind all personnel to destroy printed procedures and use new copies of procedure from elec-
tronic system
Responsibility: ___________ Target date: _____________

Laboratory equipment

1. Verify accuracy of department list of equipment and instrumentation. Add overlooked equipment to list as needed.
Responsibility: __________ Target date: ____________
2. Initiate appropriate validation/qualification of newly identified equipment.
Responsibility: __________ Target date _____________
3. Initiate log book for new identified equipment.
Responsibility: __________ Target date _____________
4. Initiate maintenance program for new identified equipment.
Responsibility: __________ Target date: ____________

Audit Training

1. Conduct audit training for all personnel.

Responsibility: __________ Target date: ____________

27 Conducting Audits, Gap Assessments & Corrective Actions Volume II

Paul L. Pluta and Jerry Lanese

cies between reports and original data was found. REFERENCES

This case describes a typical progression of a regu- 1. Pluta, Paul L., editor. “Audit 101. First Impressions --
latory audit. The audit started with a reported test The Plant Tour.” Journal of GXP Compliance, Volume
result. This result was then tracked to laboratory 15 # 1, Winter, 2011.
2. Graham, Ballard, Richard Poska, Robert Ertmann, and
raw data. Activities associated with the test result
Paul L. Pluta. “Audit 101. Preparation, Preparation, and
were then reviewed. These included laboratory test More Preparation.” Journal of GXP Compliance, Vol-
procedures, supporting equipment and instrument ume 15, #4, Autumn 2011.
information, miscellaneous laboratory systems, 3. USP <1058> Analytical Instrument Qualification.
and review of training of personnel associated with www.usp.org.
4. FDA. Compliance Program Guidance Manual: Pro-
the original test result. The audit then continued
gram, #7456.002. Implementation date 2-1-2002.
to the R&D area the developed the test method of 5. FDA Compliance Program Guidance Manual: Program
interest. R&D reports were reviewed, equipment 7345.848. Implementation date 10-1-2010
was reviewed, calibration records were checked, 6. PIC/S. Aide-Memoire. Inspection of Pharmaceutical
reagent dating was checked, personnel training was Quality Control Laboratories. September 25, 2007.
7. FDA. www.FDA.gov/ICECI/EnforcementActions/
reviewed, etc.
All questions and requests from by the auditor
were successfully answered. All documents were
quickly retrieved. The audit of the quality control Originally published in Journal of GXP Compliance
(QC) and R&D laboratories required one full day Volume 16 Number 3
of review. No deficiencies were cited by the auditor.
The auditors then returned to the manufacturing
area to continue the audit. About the Authors
Paul L. Pluta, PhD, is Column Coordinator and
FINAL THOUGHTS Editor-in-Chief, Journal of GXP Compliance
Successful laboratories operate in a constant state
and Journal of Validation Technology. Contact
of compliance to internal procedures and regula-
Dr. Pluta with comments or questions on this
tions and they are continually prepared for an audit.
discussion at paul.pluta@comcast.net.
There is no “getting ready” for an audit. Successful
laboratories are always ready. In reality, regulatory
Jerry Lanese, PhD, is an independent consul-
auditors may arrive unannounced at a firm at any
tant specializing in quality systems and labora-
time and proceed to initiate an audit. Successful
tory controls. He is a member of the Editorial
laboratories understand this reality and operate ap-
Board of Journal of GXP Compliance. Contact
Dr. Lanese at jerry@lanesegroup.com
Conducting self-audits on a regular basis is a
good way to assess laboratory performance, im-
prove readiness for an audit, and expose personnel
to an audit experience. Using different approaches
and styles as described above and in the case study
is desirable. Knowledge of regulatory requirements,
recommendations, and expectations as described
in official documentation is mandatory. Periodic
review of regulatory FDA Warning Letters is also
Audits are a way of life. A good laboratory and its
personnel are always prepared.

28 Conducting Audits, Gap Assessments & Corrective Actions Volume II

David Markovitz

Internal Audit Preparation: A Key Element

of an Effective GXP Training Process
David Markovitz

Internal audits are a useful tool in maintaining an importance, purpose, and value of audits. The train-
effective quality system. Developing internal audit er should position audits in a positive light. An ef-
checklists makes an internal audit more effective. fective audit collects meaningful data that are used
Developing checklists can be leveraged into a train- to improve and optimize systems and processes.
ing exercise. The exercise trains staff on regulations
as well as directly evaluates site compliance. A GROUP ASSIGNMENT
methodology is presented to train staff and develop Divide the group into small groups of no fewer than
checklists for self-audit. This exercise of developing three people and no more than five people. Assign
audit questions engages the group for training of each group a section or more of the regulation un-
GXP regulations. People are challenged to under- der review to examine. The objective for each group
stand the intent of the regulation and think about is to develop questions and an audit checklist for
how to assess compliance in their organizations. each section of the regulation.


Internal audits are a useful tool in maintaining an The individuals in each group will need some time
effective quality system. Internal GXP audits of- (usually 10 to 15 minutes) to read their assigned
ten reveal gaps and inconsistencies in systems and section of the regulation. Each group should then
processes. Conducting internal audits is a valuable discuss the requirements of their assigned section
training exercise and prepares an organization for and work together to create questions that an au-
audits by an external agency. ditor would ask during an audit. The late Dr. W.
In order to identify any gaps and inconsistencies,Edwards Deming, the famed quality guru who
the internal auditor must know the requirements lived from 1900 to 1993, taught that the questions
and the current regulations. The internal auditor are more important than the answers. Asking good
must know what he or she is looking for. Prepara- questions leads to discovery, and audits are all about
tion is an important aspect in conducting an effec- discovery.
tive internal audit. A method to incorporate audit The real value of this exercise is that the partici-
preparation into the GXP training process is pro- pants of the training session actually study the re-
posed. quirements of the regulation with an eye towards
understanding. This technique can be far more ef-
THE INTERNAL AUDIT fective than sitting through another lecture on the
One method used in maintaining an effective GXP When the small groups begin to discuss their as-
training process is to incorporate GXP audit prepa- signment (after reading the appropriate section of
ration into the training process, as follows. the regulation), they often begin by asking them-
selves the following questions:
• What does this mean?
PRESENTATION • What must one do in order to comply?
Start the training session with a discussion on the • How will we know whether the system or pro-

29 Conducting Audits, Gap Assessments & Corrective Actions Volume II

David Markovitz

cess is in control? product contamination?

• How will we know whether the system or pro-
cess is in compliance? Equipment. The following are example primer
• What questions can we ask of the people work-
ing in the system or process under review? questions for equipment:
• Do we perform routine maintenance on
equipment and do we check to see if any mea-
These questions tend to generate discussion that suring and testing equipment has been prop-
in turn leads to a better understanding of the regula- erly calibrated?
tions and requirements. Groups are then challenged • Do we keep accurate equipment logs and do
to develop questions that can be asked during an we promptly report any maintenance prob-
lems to the right people?
audit. It is useful to provide some primer questions • Do we keep equipment and tools clean and
to help some groups get started. store them in the proper manner?
The following are some primer questions in
clusters relative to certain sections of the good Procedures. The following are example primer
manufacturing practice (GMP) regulations. questions for procedures:
• Are there written procedures that provide a
Materials. The following are example primer “blueprint” or “step-by-step” instructions for
questions for materials: performing our jobs?
• Do we carefully control the components used • Do we know and understand these procedures
in manufacturing? and do we carefully follow them?
• Do we pay close attention to the control num- • Do we regularly check our written procedures
bers assigned to our product components and and make sure they are accurate and up to
to the individual lot numbers assigned to our date?
finished product? • When we see an easier or better way, do we
• Do we know and understand our responsibil- go ahead and deviate from our written pro-
ity to build quality into our products? cedures, or do we discuss the change with
the right people first, and work through our
change control procedure?
Records. The following are example primer ques- • Do we make sure that we’ve received training
tions for records: on each procedure we use? Especially when
• Do we carefully document our work by re- they’ve been changed.
cording all necessary information immedi-
ately on the batch or history record? People. The following are example primer ques-
• When and where a signature is required, do
we sign our names legibly and in non-water- tions for personnel:
soluble ink? • Do we have the necessary education, training,
• When the batch or history record requires it, or on-the-job experience to perform our as-
do we mark down the date and time we started signed functions?
or completed the job? • Have we identified and learned the “must
• Do we confirm our work by checking and knows” for our jobs? For example, do we
double-checking all critical operations to know and understand the safety standards
make sure there are no mix-ups or errors and regulations that apply to our jobs?
• Have we acquired the necessary skills or “must
do” steps that specifically relate to our jobs?
Buildings. The following are example primer For example, do we keep accurate records and
questions for buildings: do we safely operate our equipment?
• Do we have adequate space in our work areas • Do we practice good personal hygiene?
to safely and effectively perform our jobs? • Do we always wear the proper clothing and
• Do we minimize the chance of product con- personal protection equipment in the work-
tamination, mix-ups, and errors by helping place? And do we wear the clothing and
control the internal environment of the work- equipment properly?
• Do we quickly report any conditions in our
workplace that could be a potential source of

30 Conducting Audits, Gap Assessments & Corrective Actions Volume II

David Markovitz

GROUP ACTIVITY Originally Published in Journal of GXP Compliance

Volume 16 Number 1
Groups should come up with 20-30 questions on
their assigned topic. It’s important that each group
write these questions down. This technique pushes
them to seek questions after the obvious handful of About the Author
questions are developed. Most groups don’t reach
20, but most come close. It requires deeper think- David Markovitz is the founder and president of
ing to get beyond the obvious few. Allow approxi- GMP Training Systems, Inc. (www.GMPTrain-
mately 10-15 minutes for the groups to develop ingSystems.com), a provider of GXP training
their questions. This tight timeframe (or deadline) products and services. David may be reached by
helps groups focus on the task and not get sidelined e-mail at David@gmptrainingsystems.com.
talking about anything but the topic at hand.

The next step in the process is to have each group
present their list of questions to the entire training
class. It is not unusual during this process for others
in the class to think of additional questions. Asking
the entire group to contribute additional questions
helps prompt this process. Make sure you capture
and write down these additional questions.

Now that all these questions have been prepared,
it is a great opportunity to collect these and have
someone organize these into an audit checklist.

A logical next step is to organize the participants
into audit teams, where they conduct actual internal
audits within the organization, using the checklist
of questions developed in the training session.

This exercise of developing audit questions breaks
the monotony of lecture and discussion during
training of the GXP regulations. Personnel are chal-
lenged to understand the intent of the regulation
and think about how to assess compliance. This
ultimately leads to a better understanding of the
requirements and thus moves personnel in the or-
ganization further along the journey of maintaining
compliance with GXP requirements.

31 Conducting Audits, Gap Assessments & Corrective Actions Volume II

Paul L. Pluta

First Impressions— The Plant Tour

Paul L. Pluta, Editor

One of the first significant and critical activities conducted in an audit is the plant
tour. The plant tour usually occurs after presentation of credentials and introduc-
tions of site and audit personnel. A short opening meeting describing the specific
objectives of the audit (e.g., good manufacturing practice [GMP], pre-approval
image source getty images

inspection, complaint investigation, etc.), scheduling, and so on then follows. The

plant tour provides a broad overview of the site operations, both in technical manu-
facturing and regulatory compliance. The opening presentation associated with the
tour can be used to help “set the stage” for the audit team. In addition to preparing
them for what they will see on the tour, it can also be used to familiarize the audit
team with the company, the specific manufacturing site, and organizational struc-
There is usually a time and a place that one can pinpoint the exact moment the
regulatory inspection takes a turn for the worse. At any cost, this must not happen
on the opening plant tour. The entire tone of the inspection process is greatly influ-
enced by what the inspector sees while on tour. An experienced auditor will make
important judgments about the site based on the tour experience. If the plant tour
is done well, these judgments will be positive. The plant tour is critical and must be
considered to be of utmost importance. Planning, evaluation, and practice of the
plant tour should be conducted long before a tour is needed in an actual audit.
If bad things happen on the plant tour on day one, what can be expected for the
rest of the audit? The plant tour is definitely not a perfunctory or superficial exercise.


This discussion focuses on the plant tour. It describes potential problems and an
approach to assuring a successful plant tour. However, readers must not infer that
areas in the plant tour are special or should be different than non-tour areas in the
The “audit readiness” mantra is typically lost on the specific tour route. This ap-
proach thoroughly cleans the corridors and room on the tour route, making sure
all of the “sins” are sufficiently hidden away. Only the best and brightest employees
will be working when the tour is conducted. The tour route is freshly painted and
literally “shines.” But what happens when the auditor wants to go into an area that
is not on the planned tour route? Or when he looks in a closet off the tour route?
The plant tour should demonstrate the function and compliance strategy in the
entire plant. The plant must have a culture of audit readiness in all areas at all times.
The following are two axioms that are particularly applicable to the entire phar-
maceutical or medical device plant:
• “A place for everything and everything in its place”
• “Cleanliness is next to godliness.”

32 Conducting Audits, Gap Assessments & Corrective Actions Volume II

Paul L. Pluta

These axioms must be demonstrated not only in PEST CONTROL–FLYING INSECTS

the plant tour but also in all areas of the plant. Do Pest control is always a hot topic. Making sure that
not neglect the readiness of the entire plant–every any bug zappers that kill flying insects have operat-
day and all the time. The plant tour represents the ing bulbs is always a plus. Burned-out bulbs create
entire plant. a terrible impression of the organization and of all
those working in an area. Why didn’t workers in
WHAT CAN GO WRONG? the area report the outage? If they did, why didn’t
There are many often overlooked items on the plant they follow up on the correction? How long have the
tour that can negatively affect the entire audit. Even bulbs been burned out?
when everything is thought to be in order and gen-
erally clean, there are items taken for granted or as- PEST CONTROL–RODENTS
sumed to be of no consequence to auditors. Experi- If there are rodent traps in warehouses and along
ence has shown that seemingly trivial items can lead external walls, make sure they are routinely inspect-
to serious audit consequences and observations. A ed by your staff. Who is supposed to do this and at
sampling of these with unintended consequences what frequency? A trap full of dead mice is not a
suggested by several experienced auditors follows. pretty sight for the inspector.


The floor may be clean and walls painted, but have If you have an aseptic area, make sure there is no
you looked up at the ceiling tiles and the entry operator who is chasing down a fly because, oh wait,
ducts? Fresh stains look different than old stains, the bug zapper wasn’t working. Do you really want
so stain appearance can tell a story—for sure, that to have to show the inspector the last two years of
housekeeping is not doing their job and, perhaps, environmental data because he saw the operator
that the HVAC filters are leaking or are behind their squash that fly? Housekeeping procedures and re-
scheduled replacement. Stains from leaky pipes cords requests can be avoided if the plant presents
are an invitation for piping drawing reviews. Any itself well.
incident that causes review of site drawings is high
risk. Drawing may not be current or not consistent
with recent facility changes. The site engineering TRAINING
department may be well behind, even years behind, Whoever is working in an area is vulnerable to hav-
in updating drawings. How long has it been since ing their training records for what they are doing
piping has been “walked down.” What about dead requested by the auditor. It is not easy trying to
legs in those systems? explain why an operator is not trained on prepar-
ing the cleaning solutions that he has been using
for the last three years. Supervisor training records
SURFACES may be a problem. Supervisors sign-off on opera-
All horizontal surfaces have been cleaned, so we tor performance, but often supervisor training is
should be in good shape, right? International regu- delinquent—not a good example to operators and
lators are known to actually perform the dreaded an obvious embarrassment for the organization.
“white glove” test on the top edge of doors and eas- The operators are trained, but the supervisors are
ily accessed equipment. Also, what about the un- delinquent?
dersides of horizontal surfaces, such as in the drug
dispensing area? What is the dust on the walls in
the drug dispensing area? What about the rust on CROWDED AND SLOPPY ROOMS
the bottoms of the stainless steel chairs in the asep- Avoid excessively crowded conditions (i.e., equip-
tic area? ment, materials, and other miscellaneous supplies).
When hiding the “sins” was previously mentioned,

33 Conducting Audits, Gap Assessments & Corrective Actions Volume II

Paul L. Pluta

it did not suggest shoving them all in a closet to ACCESS TO PROCEDURES

hopefully never be seen. There should not be areas Your operators are all trained on their job functions.
in the plant akin to your attic, basement, or garage. An inspector asks an operator what would seem to
Cleanliness in the plant is not like asking your child be a simple question. The operator does what he was
to clean their room, only to eventually find what trained to do. He replies that he is not sure and will
they did with the mess. have to check the SOP. Just where is the SOP? It is
down two flights of stairs in the department office.
WOOD PALLETS Do you really think the operators will make the trip
Be sure wood pallets are all heat-treated (Pfizer and to the office to consult procedures when questions
J&J learned about this). Better yet, use only plastic pal- arise during processing?
lets in areas where product and packages are exposed
within the manufacturing area. EQUIPMENT IDENTIFICATION
Equipment must be clearly identified. Equipment
CARDBOARD identification numbers must not be painted over so
No cardboard boxes should be in the production that traceability is lost. Equipment identification is
area near open product or where commodities are necessary for linkage to qualification documenta-
prepared. If this is observed by the auditor, the non- tion. If equipment qualification cannot be verified
viable particulate data for the last two years may be by means of documentation, you cannot use the
requested. equipment.


This may sounds easy. If an inspector ever has to ask Equipment calibration status tags are always checked
what the condition of the product tanks are, you have in audits. There must be no equipment with tags that
failed miserably. You show them the equipment use indicate calibration is past due. Further, calibration
log. Why isn’t the equipment use log bound? How are status tags must be readable. Ink must not be faded
the pages tracked? No quality assurance review? No so that calibration status cannot be determined. It
review for the last two weeks? A simple status label is reasonable to conclude that equipment with tags
avoids these questions because they don’t ask to see the that are so badly faded and unreadable is probably
logs. There is nothing worse than an inspector picking out of calibration.
up a bottle of excipient and finding that the material
expired three days ago. A review of the standard op- UNUSABLE EQUIPMENT
erating procedures (SOPs) for material control will be Equipment that is not working, awaiting repair, or
requested. Inventory logs will also be requested. otherwise unusable should be tagged “out-of-ser-
vice.” If portable equipment, it should be removed
PAPER SYSTEMS from the work area. If it is not clearly tagged, how
If your site uses paper copies of procedures in vari- can you be sure it will not be used?
ous locations, all copies of procedures at the various
locations must be current. This is very difficult to “BAND-AIDS” ON EQUIPMENT
control when the facility has multiple locations with Operators do what is needed to keep equipment run-
hardcopy procedures, and even more difficult for ning. This includes taping parts in place, catching
a large facility or for multiple locations. Electronic dripping oil in a bucket, shimming wobbly equip-
systems enable procedures to be immediately up- ment, and so on. When these “Band-Aids” work,
dated and always be current. they become acceptable parts of the equipment—
they become invisible to those working in the area.
However, when fresh eyes (i.e., the auditors) look at

34 Conducting Audits, Gap Assessments & Corrective Actions Volume II

Paul L. Pluta

equipment, they easily see the “Band-Aids,” which, PLANNING THE TOUR
of course, is an obvious failure to properly maintain The route of the plant tour should be carefully
equipment. chosen. The route must not be a haphazard walk-
through the hallways of the plant. The tour should
HOSES be helpful to understand the plant activities. In a
Hoses, tubing, and transfer lines should be hanging typical opening presentation, one of the first ques-
to facilitate drainage. Everyone knows this. Often it tions asked by an inspector is about the process flow.
is the last thing to be done when the room is cleaned. In keeping with the planned agenda, the plant tour
But sometimes it is not done. One auditor reported should start at the beginning of the process flow to
that hoses were stored on the floor in a southwest- best demonstrate the plant function. Start with the
ern US manufacturing plant. A snake crawled into dock where incoming materials are received. There-
the hose. When solution was added through the after, passage of materials to the quarantine storage
hose, the snake was expelled into the product solu- area can be toured. The drug dispensing area can be
tion. The operator was bitten by the snake and was shown at this time. An inspector will most likely
sick for several days. This incident would have been want to see any reject or quality-hold areas during
interesting reading for an auditor. this part of the tour. Be ready to show these often
over-looked areas. Thereafter, the tour should dem-
onstrate all other major plant functions. The tour
SITE INTERCOM SYSTEMS ends with approved product being stored in an area
Be sure to turn off or, even better, disable any inter-
awaiting shipping.
com system that may be used. You would not believe
The tour should demonstrate that “form follows
what can be inadvertently broadcast throughout the
function” (i.e., the plant design and structure is sup-
plant by an unaware employee while the auditor
portive to the logical process flow of activities in the
tour is in progress. Site intercom systems must not
be a vehicle for personal humor.


After designing the planned tour, the route should
Another two axioms are very applicable to the plant
be carefully evaluated. Evaluation should be done
• “You never get a second chance to make a first by a team of people with different attitudes and per-
impression” spectives. High-level evaluation by management is
• “You pass or fail an inspection in the first 30 not usually sufficient. High level people don’t pay
minutes.” attention to details. Personnel who are known for
attention to cleanliness, detail, fastidiousness, and
As mentioned earlier, the plant tour usually oc- other applicable characteristics are valuable partici-
curs on the first day of the audit. How do you think pants in an evaluation. They are able to see things
the rest of the audit is going to go if the plant tour that others do not see, for example:
on day one is poorly conducted or demonstrates • Do hanging mops smell musty?
multiple problems? • Are the undersides of tables dirty with formu-
The plant tour is a critical activity. Like any criti- lation dust?
• Are the tops of doors clean?
cal activity, planning, evaluation, and practice are • Are corners of rooms–floor and ceiling—
necessary to ensure success. These activities should clean?
be done far in advance of an actual audit. The site • Are coveralls, lab coats, booties, and other
should be well prepared for an audit. The plant tour protective clothing available for auditors to
being conducted with the auditors must not be the enter a process room? What training is needed
for proper gowning and entry?
first time it was ever done. • Areas that do not show well (yes, they do exist)
should be avoided if not absolutely necessary.

35 Conducting Audits, Gap Assessments & Corrective Actions Volume II

Paul L. Pluta

• Make sure all stairwells, elevators, etc. are un- OTHER CONSIDERATIONS
cluttered, clean, and safe.
The site should now be ready to conduct a success-
TOUR NARRATIVE. ful tour. The following are additional considerations
After the tour has been finalized, a tour narrative of for the actual tour.
key points should be written. This will be spoken
by the tour leader during the tour with the auditors.
An overview of the tour using the above-mentioned
TOUR PRESENTATION. tour presentation before the actual tour is recom-
A tour presentation (PowerPoint or equivalent) mended. The tour leader should describe the pre-
should be prepared to introduce the audit team to sentation. Tell the auditor what functions the plant
the organization and site. Although usually present- does, and then show that the tour will cover all rele-
ed immediately prior to the tour, it can be provided vant areas. Follow a basic rule of presentation skills.
to the auditor before visiting the site in cases when Tell them what they will see, show them (the actual
advance notice of the audit is given by the agency. tour), and summarize what they have seen (after the
tour is completed).
After the plan has been evaluated and problems COMMUNICATION WITH THE AUDITOR
mitigated, practice runs of the tour route should be The auditor should be asked if he has special interest
conducted. The tour leader is the key person in the in any particular area. For example, the auditor may
tour. Actual walking tours should be practiced with have interest in the prevalence of wood pallets in the
the tour leader and associated personnel as often as plant as result of the recent Tylenol recall. Asking
needed so that there are no unknowns or anxiety the auditor about special interests enables the plant
associated with the actual tour. The narrative of the to openly and prospectively address the auditor’s
tour should be practiced. Sitting in the conference objectives. This also gives the plant the opportunity
room is not the way to practice the tour. The objec- to assemble site experts as needed for the auditor.
tive of multiple practice runs is to assure an excel- This is a subject that should not be taken lightly. If
lent tour when auditors are in the plant–problem you ask, the auditor may show interest in something
free and without anxiety for the tour leader and you are not initially prepared to discuss. It is much
participants. better to ask and get the right people to answer
questions than to struggle with finding information
TOUR LEADER. or people under the time constraints or with the au-
Selection of an appropriate tour leader is important. ditor waiting for an answer.
This person should speak the native language of
the auditor if possible, have good communication CLOTHING REQUIREMENTS
skills, speak clearly, be able to “think on his feet,” Many processing areas have particular clothing
and be knowledgeable of all plant operations. The requirements. Be sure to inform tour participants
plant manager, who may be a financial person with of any site requirements (i.e., no jewelry, make-up,
expertise in finance but minimal GMP knowledge, must have beard covers, hair coverings, booties,
may not be suitable to lead the plant tour. Desig- etc.). Booties don’t work with high heels. This topic
nated people may be selected to lead certain areas should be discussed in the conference room before
to provide the best possible tour. Technical compe- the tour starts. Don’t overlook this topic. It is much
tence is important but is not the sole criterion for more easily discussed in the conference room before
leading the tour. the tour starts. It will be uncomfortable to refuse an
auditor at the point of entry into a restricted area.

36 Conducting Audits, Gap Assessments & Corrective Actions Volume II

Paul L. Pluta

RESTRICTED AREAS want to make their job easy?

The tour leader must be prepared to explain why the The plant tour should represent the condition of
inspector cannot go into a restricted area such as the the entire plant. The plant tour should be well orga-
aseptic processing areas. There is extensive training nized and planned. However, it should not detract
in aseptic technique and gowning that must be com- from efforts for total plant readiness. All areas of the
pleted to enter these areas. On the other hand, do plant should be ready for inspection and be ready all
not attempt to mislead an inspector on the amount the time. Auditors must have a positive impression
of training just to keep him out. If an area can be of the plant when the tour is completed.
seen from windows, suggest this as an alternative.
If the auditor is adamant about entering a restricted FUTURE AUDIT 101 DISCUSSIONS
area, training can be set up, protective clothing pro- Future topics to be addressed in “Audit 101” include
vided, etc., as needed so that the auditor can enter audit preparation, audit room and support room,
the area after all training and clothing requirements responding to auditors, responding to observations,
are met. laboratory audits, and associated topics. Reader
Site procedure must not be violated for the conve- comments, questions, and suggestions for discus-
nience of the auditor. If you violate a procedure to sion topics are needed to help us fulfill the column
allow an auditor to enter a restricted area (for exam- objective. Please send your comments and sug-
ple, safety shoes required and no high heels or san- gestions to column coordinator Paul Pluta at paul.
dals in manufacturing area), you may (and should) pluta@comcast.net.
get an observation for violating the procedure.

Originally Published in Journal of GXP Compliance Volume

The auditor may ask to go to areas that were not planned
in the planned tour. For example, he may ask to see
cold rooms, walk through warehouse aisles, and other
areas not originally planned. As long as these are not About the Author
restricted areas, the tour must be modified to accom-
modate these requests. You should expect this. When The content of this feature was comprised of
things look too good or are too well planned, what is comments from several experienced auditors
being hidden? All areas of the plant must be ready and was compiled by the column coordinator.
for inspection by the auditor at all times—not just the Their examples are actual audit tour occur-
planned plant tour route. rences.

The plant tour is a critical activity. It should be
treated with the utmost importance. It should be
planned and practiced in advance of any actual tour.
Experience with regulators, both domestic and in-
ternational, is that they tend to gloss over areas if
there is nothing that would pique their interest. The
last thing you want is for the dreaded “deep dive”
into records or procedures when something simple
is overlooked or taken for granted. The inspectors
are probably at your plant for some serious reason.
They are looking for deficiencies, and do you really

37 Conducting Audits, Gap Assessments & Corrective Actions Volume II

Richard C. Wedlich and Kevin J. Webb

Implementing Quality Agreements at the

Contract Laboratory
Richard C. Wedlich and Kevin J. Webb

INTRODUCTION A good QAG should be a good fit to the quality

A contract research organization (CRO) provid- program and quality systems at the CRO. The “good-
ing experimental testing services under current ness of fit” can be measured qualitatively and quick-
good manufacturing practices (cGMP) can expect ly by how well the QAG matches the quality manual
to enter into numerous quality agreements (QAG) of the CRO, particularly in the “Responsibilities”
with pharmaceutical industry clients (sponsors). section. This section of the QAG provides details
These agreements, usually initiated by the client, on client requirements to be in compliance with the
are intended to ensure that the CRO addresses cGMPs/good laboratory practice (GLPs) for work
key client concerns according to client require- done at the CRO. For example, the CRO must have
ments. For example, concerns may include issues written job descriptions for positions responsible
such as timely client notification for a confirmed for cGMP-related activities at the CRO. Also, the
out-of-specification (OOS) result. More generally, CRO is responsible for having written procedures
the CRO must support promises made by the cli- and schedules for the calibration and preventative
ent to a regulatory agency. These typically will not maintenance of instruments and equipment at the
appear in the master service (business) agreement CRO used to support the client’s cGMP study.
between the client and CRO, but will appear in the It is common for the client to require notification
QAG. The contract testing lab is, in effect, an exten- of problems in an FDA inspection involving docu-
sion of the sponsor’s internal quality control (QC) mentation or data belonging to the client. Although
lab. The contract lab also has the responsibility to the frequency of occurrence of either of these cases
ensure safety, purity, identity, efficacy, and potency is low, their criticality makes them high risk.
of the product regulated by the US Food and Drug Another high-risk topic is change management.
Administration. Having a good QAG in place, Not all changes are foreseen. Some changes may dra-
though important, is only half the battle. The CRO matically affect the CROs ability to meet the terms
must also have approved procedures and practices of the QAG. Examples are downsizing or relocation
to ensure adequate implementation. Previous pub- of the CRO. The use of third party labs or other
lished papers on this topic relate to QAGs from the contractors creates more risk since these are further
point of view of the “contract giver” or sponsor (1). removed from the client control. Clients must rely
Each CRO (“contract acceptor”) will implement the on the diligence of the CRO to perform an adequate
QAG in a unique way. This paper describes a simple vendor qualification and to continually review work
approach to these agreements from the perspective by the third party as critically as they review their
of the CRO that has been successfully implemented. own work. Often times, the volume, frequency, dol-
lar value, and risk of noncompliance associated with
the work being outsourced by the CRO to the third
CONTENT OF THE party will not justify a second QAG.
QUALITY AGREEMENT There are cases where the QAG can be created
A good QAG must be a suitable agreement and from a template and made effective with only slight
follow the general principles of any suitable agree- modifications. The larger pharmaceutical company
ment. A number of key elements are listed in Table will “think global” in creating such templates (3).
I. These are also detailed elsewhere (2). Doing so can be very cost effective, strategic, and

38 Conducting Audits, Gap Assessments & Corrective Actions Volume II

Richard C. Wedlich and Kevin J. Webb

Table I: Typical QAG content (for a contract testing lab).

Scope: Specifies the products and services to be provided
Other agreements: What to do in the event that other agreements are already in place
Amend/terminate QAG: How to amend or terminate the agreement
Assignment: The CRO shall not assign any or all of its rights or obligations without the client’s written consent, which may be
granted or withheld at the client’s sole discretion
Debarment: No individual or the CRO itself has been debarred or has been convicted of a crime for which it could be debarred
pursuant to the Federal Food, Drug, and Cosmetic Act
Right to audit: Client shall have the right to audit the CRO’s facilities and systems with regard to the products and services being
Responsibilities: Detailed listing of who is responsible to do what and includes both parties
Use of third party labs/contractors: Written consent from client is usually required
Client notifications and approvals: Critical issues that trigger notification of the client and/or the client’s approval
Resolution of quality issues: Protocol for dispute resolution
Investigations: Client-specific and regulatory requirements to be met by the CROs program
Deviations management: Client-specific and regulatory requirements to be met by the CRO
Out-of-specifications (OOS): Client-specific and regulatory requirements to be met by the CRO
Change management: Client-specific and regulatory requirements to be met by the CRO
Analytical methods and standards: Details on how the client and CRO lab will transfer analytical methods, who will approve meth-
ods and who (the client or the CRO) will provide the analytical standards to be used
FDA inspections: The client will typically want to be notified immediately of any FDA inspection of work done at the CRO for the
client. The client will be very specific about how and when notification is required

timely since the basic QAG is created only once and BUSINESS DEVELOPMENT
may be quickly implemented. It will also minimize The QAG has its place in the business development
problems stemming from differences encountered and relationship development process. Achieving a
at regulatory boundaries around the world. good agreement in place with relative ease is a good
indication that other business will develop smoothly.
IMPORTANCE OF Proactive work done in drafting and approving the
THE QUALITY AGREEMENT QAG may save time and money and prevent future
The QAG is a vital document with far reaching im- discontent between organizations. The QAG has its
plications. Meeting the terms of the agreement is a place in the negotiation process to get large projects
responsibility of the quality assurance (QA) func- started and implementing the master service agree-
tion at both the CRO and the sponsor organization. ment for the project. There are costs and timelines
associated with finalizing the QAG that cannot be
In the European Union (EU), having the quality
agreement (also called “technical agreement”) in PROJECT TIMELINE
place prior to contracting the service or process is A typical project timeline sequence is shown in
a regulatory requirement (4). Though not yet regu- Table II. The earlier that a QAG is implemented, the
lated in the United States, QAG are increasing used less the delay it will cause in the project timeline. It is
and expected (5). not uncommon for the review and approval process
to be simultaneous to the qualification audit. Other

39 Conducting Audits, Gap Assessments & Corrective Actions Volume II

Richard C. Wedlich and Kevin J. Webb

Table II: QAG in the early project timeline.

1. Establish a non-disclosure, non-compete agreement between the client and CRO

2. Hold project meetings to discuss the client’s project needs, CRO lab capabilities, CRO capacity and level of expertise

3. Work out pricing and other details of the business agreement

4. Make decision to contract with the CRO for services

5. Complete the qualification of the CRO, including conducting the qualification audit and following-up on any/all audit find-
ings (6)
6. Approve the quality agreement (QAG) (This is often much earlier in the process such as at the time work is anticipated for
the CRO. Timing may vary from client to client. It should be done before steps 7 and 8 below.)
7. Train at the CRO on the QAG

8. Send samples and schedule the laboratory work

sequences are common. For example, some like to ally, all clients will want the right to inspect the fa-
append the QAG to the master service agreement. A cility and audit the work being done in the lab. They
benefit to this approach is that the QAG will almost will require immediate notification from the CRO if
certainly receive a legal review. On the other hand, it any of their projects become part of an FDA inspec-
may delay approval of the master service agreement, tion. Because these requirements are not typically
because the appended QAG will almost certainly re- covered in documents such as protocols, methods,
ceive a legal review! or SOPs, they are inserted in the QAG. The QAG is
tailored to the specific needs of the client.
The quality agreement has its place among impor- QAG AND OTHER DOCUMENT CHANGES
tant controlled documents in the CRO. A partial Controlled documents cannot be changed without
listing of such documents that provide guidance creating a new version and receiving a review and
and detailed written instructions for the conduct approval by either the original approvers or those
of the experimental study/lab work is provided in at the same level of knowledge and authority. Such
Table III. documents typically undergo periodic (often annu-
al or biannual) review, revision, and approval. It is
QUALITY SYSTEMS common to annotate on a “justification for changes”
The QAG typically addresses compliance at the or “history of changes” page the changes that were
quality systems level. Quality systems such as made and the justifications for these changes. Along
change control, investigations, and metrology (in- with being controlled, the QAG is a confidential
strument qualification and calibration) are designed document and must be treated appropriately.
to be comprehensive and address individual client
or project needs. These are applicable to all projects A SIMPLE WAY
in the same way as standard operating procedures TO IMPLEMENT THE QAG
(SOPs) governing day-to-day laboratory operations. Several key elements are critical for the CRO imple-
In this way, a client may have several and diverse mentation of the QAG. Management and QA must
projects ongoing with the CRO all subject to a single have proper respect for the QAG and give it the pri-
QAG. ority it deserves.
The client (sponsor) may have unique require-
ments. For example, they may want approval privi-
lege on certain documents such as analytical test
The QAG must be part of the CRO quality program.
methods and laboratory investigations. Addition-

40 Conducting Audits, Gap Assessments & Corrective Actions Volume II

Richard C. Wedlich and Kevin J. Webb

Table III: Controlled documents in the contract testing lab.


Quality agreement (QAG) Specific to client The QAG requires client and CRO approval and is controlled by
the client (“contract giver”).

Protocol Specific to client and often The protocol typically requires both client and CRO to approve
specific to the project and is controlled by the CRO (“contract acceptor”) or client
depending on authorship. The protocol provides details of the
experimental study (or validation) design and specifications and
may contain detailed instructions for the laboratory to execute,
including how to report data. Protocols often reference analytical
test method and SOP documents.

Test method–Analytical or May be specific to the client The method may or may not require client approval and is con-
­bioanalytical trolled by the CRO or client, depending on who authored it. The
method provides detailed instructions to the analyst in order to
complete the analysis.

Standard operating procedure Not client-specific SOPs do not require client approval and are controlled by the
(SOP) CRO. Laboratory and QA SOPs define the daily activities of the
lab and QA unit to keep the lab in compliance with cGMP and
GLP regulations.

The CRO should have an established SOP of QAG the QAG is achieved via the QAG SOP.
approved by management and QA. A stepwise SOP
describing the implementation of the QAG facili- TRAINING
tates determination of non-compliance. It also fa-Before starting any laboratory project, the principal
cilitates communication to lab personnel and prin-investigator (PI) or study director holds a kick-off
cipal investigators the essential terms of the QAG.
meeting with all participating scientists and at least
These QAG SOPs can form a good basis for training one member of the QA unit. The purpose of the
and can define how the CRO will deal with revisions
meeting is to review the study protocol, analytical
in the QAG. test methods, safety issues, and other aspects to en-
sure project readiness for initiating the project. The
“BUY-IN” PI will review the key elements of the QAG with the
Another key element is “buy-in.” The CRO must project team. The PI uses a checklist to ensure all top-
work through all of its terms and determine how ics have been covered in the meeting. This checklist
each can be accommodated by the quality systems is signed and dated by the PI and all in attendance,
before approving the agreement. If there are weak and maintained by the document control unit with
spots in either the quality program or the QAG, exact copies going into each attendees training file.
these must be remedied. Training on the QAG SOP is completed through the
SOP training program in place at the CRO.
Clear communication of QAG requirements is es- MONITORING
sential. For example, the QAG may be condensed QA will monitor QAG deviations. Any deviation is
to the most essential 10 bullet points in simple lan- addressed through the CROs corrective and pre-
guage. These points are then posted in plain sight ventative action (CAPA) program. Determining the
in training rooms. The owner of the agreement is most likely causes for failure of the CRO lab to ad-
identified only by client code so as to protect client here to the QAG leads to simple preventive actions.
confidentiality. Further detailed communication on CRO QA unit and laboratory management carefully

41 Conducting Audits, Gap Assessments & Corrective Actions Volume II

Richard C. Wedlich and Kevin J. Webb

reviewing the draft QAG should identify potential Week conference, San Diego, CA, June, 2012.
deviations. These will include obstacles such as un- 4. EMA, “Chapter 7,” EU GMP guide.
5. Sayre, SD and Gattoni, TG, “Attention API Suppliers:
clear wording, inconsistencies or contradictions, Quality Agreements are here to stay,” Journal of Ge-
and unrealistic requirements. Any deviation from neric Medicines: The Business Journal for the Generic
the QAG should require an investigation. An inves- Medicines Sector, 5(1), 2007: 39-44.
tigation requires an investigation report and an im- 6. Carter-Hann, B and G. Vinson, “Facilitating Client Au-
pact assessment. QA and management will review dits: The Contract Laboratory Perspective,” BioPharm,
15(7), 2002: 12-16.
the impact assessment and the deviation through
the CAPA program. Ultimately the investigation
report should have a QA follow-up and be approved Originally published in Journal of GXP Compliance Volume
by the CRO QA, management, and the client. Some 16 Number 4
clients may have specific deviation requirements
that are defined in the QAG.
About the Authors
Once the CAPA actions have been approved, QA Mr. Richard C. Wedlich is director of quality As-
will perform an effectiveness check to confirm that surance of the Health Sciences division of NSF
the actions taken have prevented another occur- International. For over the past twenty years,
rence of the deviation. he has held a number of leadership positions in
the pharmaceutical industry, mostly in the ar-
SUMMARY eas of GLP and cGMP laboratory compliance.
A sponsor enters into a QAG with the expectation He is co-founder of Pharmalytica Services,
that the terms will be fully implemented throughout LLC, which was acquired by NSF International
the life of the agreement. The procedure for ensur- in 2011 and is now NSF Pharmalytica. He may
ing that the CRO implements the QAG is based be reached by email at rwedlich@nsf.org.
upon communication and training: specifically, Mr. Kevin J. Webb is Project Manager for the
adequate communication to, and training of, lab Health Sciences division of NSF International.
analysts, principal investigators, lab managers, and He has acted liaison between Pharmaceutical
quality assurance auditors on the critical require- clients and the analytical lab, and successfully
ments imposed on the CRO by the quality agree- coordinated client needs and laboratory per-
ment. Though this is not entirely a novel approach, formance on nearly a hundred projects from
it is straightforward and effective. Having a good small to large. He may be reached by email at
QAG in place does not eliminate the need to audit kwebb@nsf.org.
the CRO. The audit of the CRO should include a
verification check that key personnel are aware of
the terms of the QAG and that the CRO is imple-
menting the agreement.

1. Nims, RW and E Meyers, “Contractee Responsibilities
in Outsourced Pharmaceutical Quality Control Test-
ing,” BioProcess International, 2010: 26-33.
2. Blasini, RP, “Quality Agreements Between Pharmaceu-
tical/Biopharmaceutical Companies and their Con-
tractors,” BioPharm Internationa1 8(4, 2005: 66-70.
3. Hernandez-Diaz, J., “Conduct Vendor Audits and Cre-
ate Quality Agreements,” presented at the IVT GMP

42 Conducting Audits, Gap Assessments & Corrective Actions Volume II

Ballard Graham, Richard Poska,
Robert Ertmann, and Paul L. Pluta

Preparation, Preparation,
and More Preparation
Ballard Graham, Richard Poska, Robert Ertmann, and Paul L. Pluta

INTRODUCTION success in audits will not occur without a “quality

There are three keys to assuring a successful audit: culture” (i.e., a commitment to quality performance
preparation, preparation, and more preparation. as a way of life by all individuals at all times). All
Preparation must be a key component of the ongo- areas of the site must continually function with the
ing audit strategy for all audits. Preparation means potential for audit in mind. Success in audits will
having all things necessary for a successful audit in also not occur without the demonstrated support
place and smoothly functioning ahead of the actual (i.e., actions reflecting words) of senior and func-
audit. Certain audit personnel and systems will es- tional management.
sentially always be part of every audit. These areas
must be addressed well ahead of the audit—“well AUDIT EXAMPLE OVERVIEW
ahead” does not mean the day before agency audi- Audits may be conducted by a variety of groups and
tors are expected to arrive. Certain logistical con- for a variety of reasons. Regulatory agencies, both
siderations are also important and, if done well, may domestic and international, may conduct audits in
“set the tone” for a successful audit. advance of new product approvals, for routine GMP
This discussion addresses the following critical inspections, to investigate patient complaints, to ob-
areas of preparation for a typical audit: tain product samples, and for other reasons. Busi-
• Audit support personnel. Specific audit per- ness customers may conduct audits as part of new
sonnel that will be supporting an audit must
be designated, prepared, competent, and or ongoing vendor qualification.
functioning, literally, at all times. It is impor- Environmental agencies, safety agencies, and oth-
tant that a single lead audit support person be er groups may audit the manufacturing plant at any
identified, usually the site audit coordinator. time. Despite this variety of groups and objectives,
This person should have the final say as to there are functions, activities, and logistics that
how a response is provided and should be the
main conduit of requests from the auditor. are common to essentially all audits. The follow-
• Audit systems. Routine audit activities must ing describes a typical sequence of activities for an
be systematized, functioning, and efficient. unplanned regulatory audit conducted by the local
• Audit logistics. The meeting room, plant government agency:
tour, support room, and other audit logistics • Arrival. Auditors from the agency arrive at
must be well planned. Associated site logistics manufacturing site. Arrival may be unplanned
including the entry function, security consid- (i.e., the site was not notified of the audit), or
erations, and auditor parking should be ad- may have been notified of the audit several
dressed (see Reference). days prior to auditor arrival.
• Notification. Responsible site individuals,
Also discussed are several examples provided by usually quality assurance personnel, are noti-
compliance personnel from multiple companies de- fied by site entry security personnel that audi-
tors are at site.
scribing what may happen when audit preparation • Opening meeting. Auditors and site person-
is insufficient. Comments regarding non-regulatory nel proceed to meeting room in area to be au-
audits (e.g., contract manufacturers or vendors) are dited. Auditors discuss purpose of audit. The
also provided. This discussion addresses consider- site coordinator and leader for the audit are
ations that facilitate a successful audit. However, introduced to the auditors.

43 Conducting Audits, Gap Assessments & Corrective Actions Volume II

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• Area tour. Tour of relevant areas with audi- notice. There is never a time when the designated
tors, site coordinator, tour leader, and appro- site audit personnel should not be ready for an audit.
priate site individuals is conducted. Designated personnel audit functions are dis-
• Auditor requests. Auditors make requests
to site audit coordinator depending on au- cussed. The same individual may perform multiple
dit objectives. Requests may require specific functions. Functions identified are as follows:
documents, procedures, or discussions with • Primary audit contact
area representatives or subject matter experts • Site audit coordinator
(SMEs). • Tour leader
• Site responses. Audit coordinator complies • Support room leaders
with auditor requests through direct respons- • Area representatives
es, through supporting site personnel, or by • Subject matter experts (SMEs).
directly contacting requested personnel. Sup-
porting audit personnel review documents or
facilitate requested personnel meeting with PRIMARY AUDIT CONTACT
auditors. The primary audit contact is the person who is ini-
• Audit support personnel review documents. tially notified by the auditors to initiate the audit.
After review, documents are provided to au- This may occur when the auditors arrive at the site
ditors. Document copies are made for site or may occur several days in advance of the audit.
• Requested personnel meet support person- International audits usually involve advance notifi-
nel to understand auditor questions and then cation. The primary audit contact is often a senior
meet directly with auditors. management person in the quality assurance (QA)
• Activities above are repeated as required department or the site audit coordinator. This per-
throughout the audit. son must be available for contact by the regulatory
• Daily summary. Auditors discuss observa-
tions and concerns at the end of each audit auditors at all times. A backup person should also
day. Auditors describe expected activities be identified for this important function.
planned for the next day and make requests The primary audit contact should be known to the
for next-audit activities. The audit coordina- local regulatory agency. This person should meet lo-
tor initiates site activities as described above. cal agency personnel, describe their facility, provide
The daily summary and subsequent activities
discussion occurs each day of the audit. directions, discuss site parking and entry accom-
• Audit completion. Auditors summarize modations, and so on informally in advance ahead
audit findings to audit coordinator and site of any audit.
management. Official citations (i.e., FDA-483
observations) are presented to site by auditors
if necessary at end of audit. SITE AUDIT COORDINATOR
The site audit coordinator may or may not be the
Each of these activities requires a coordinated same person as the primary audit contact. This per-
preparatory effort by the site (i.e., people, systems, son is the primary site person in the actual audit
and logistics) to efficiently manage the audit. These meeting representing the site and “manages” the au-
preparations include identification of specific audit dit. Questions and requests from the auditors come
personnel for defined audit responsibilities, devel- directly to the audit coordinator, who in turn may
opment of specific audit-related systems to effi- ask the supporting staff (support room leaders) to
ciently perform during the audit, and preparation contact appropriate site personnel or retrieve docu-
of site and associated logistics to support personnel ments as requested by the auditors. The site audit
and systems. coordinator must be knowledgeable of the entire
site operation, know the personnel, know the facili-
ties, be quick-thinking, make good judgments, and
AUDIT SUPPORT PERSONNEL have the interpersonal and communication skills to
Personnel involved in an audit must be designated,
effectively manage the audit. The site audit coordi-
prepared, competent, and ready to function at all
nator requests discussion of potential observations,
times. An audit may be initiated without advance

44 Conducting Audits, Gap Assessments & Corrective Actions Volume II

Ballard Graham, Richard Poska,
Robert Ertmann, and Paul L. Pluta

problems, and other comments from the auditors at individuals, the support room leader will locate the
the end of each audit day. Often immediate remedi- necessary person, work with them to prepare a re-
ation by the site can correct issues expressed by the sponse, and generally prepare them for interaction
auditors and eliminate potential audit observations with the auditor. Regarding documentation, the
or minimize their severity. The site audit coordina- support room leader will locate the necessary docu-
tor ultimately receives the official audit observations ments, thoroughly page through the documents,
from the auditor at the end of the audit. All site au- make copies as necessary, and ultimately deliver the
dit support personnel must recognize this person as requested document to the audit room. Every page
the company lead to ensure that a single consistent of requested documents must be carefully reviewed
message is provided to the auditors. for “Post-It” notes, written comments, and other ex-
traneous information. Multiple support room lead-
TOUR LEADER ers and staff may be necessary if the audit team has
A plant tour is often one of the first activities in the multiple auditors with a great number of requests in
audit. A tour leader must be identified and trained to order to provide responses in a timely manner.
lead this tour. Selection of an appropriate tour leader
is extremely important. This person must be knowl- AREA REPRESENTATIVES
edgeable of plant operations, have good communi- Area representatives are knowledgeable about
cation skills, speak clearly, and be able to “think on specific operations at the site. For example, the
his feet.” The plant manager, who may be a financial engineering representative must be conversant
person with expertise in finance but minimal good with facility drawings, HVAC systems, equipment
manufacturing practice (GMP) knowledge, may calibration, and other engineering functions. A
not be suitable to lead the plant tour. Designated technical support person must be knowledgeable of
people may be selected to lead certain areas within product formulation and process details. Other area
the site to provide the best possible tour. Technical representatives in a large multi-function facility
competence is important but is not the sole crite- might include persons from manufacturing, pack-
rion for leading the tour. The tour leader should aging, aseptic area, analytical laboratory, microbiol-
speak the native language of the auditor if possible. ogy laboratory, and other areas. Area representa-
The importance of the plant tour, planning aspects, tives may also participate in the plant tour when
and associated considerations have been previously their specialized expertise is needed.
discussed (see Reference).
SUPPORT ROOM LEADERS Specialized experts in specific topics related to au-
Support room leaders work with the audit coordi- dits should be identified. For example, research and
nator to provide documents or appropriate people development (R&D) scientists, formulation special-
to respond to auditor requests. The support room ists, bioavailability scientists, stability experts, and
leaders are knowledgeable about all aspects of site other technical experts should be identified for po-
operations, know the people and expertise at the tential contact with auditors. Research scientists are
site, and know how to get answers to auditor ques- likely to be called to discuss the development of a
tions. These leaders will most likely be invisible new product in an US Food and Drug Administra-
during the audit and may never directly speak to tion pre-approval inspection prior to approval of a
the auditor. However, their function is extremely new drug application submission. Regulatory affairs
important. When the auditors request documents personnel may also be consulted for information
or have questions that require the presence of an that has been included in a regulatory dossier.
area head, subject matter expert, or other individu-
als, the audit coordinator will communicate this re- AUDIT SYSTEMS
quest to a support room leader. Regarding specific There are several activities that are essentially al-

45 Conducting Audits, Gap Assessments & Corrective Actions Volume II

Ballard Graham, Richard Poska,
Robert Ertmann, and Paul L. Pluta

ways required for audits. These activities must be circumstances. These areas are usually constructed
well planned. Some should be officially procedural- to provide visual monitoring. Should it be necessary
ized. Execution of these activities must be rapid and for an auditor to enter a sterile area, all gowning re-
efficient. The following activities are discussed: quirments must be strictly followed. Also insist that
• Site visit policy for auditors and other non- they take no unsterile items with them (e.g., note-
employees book, pencils, etc.). If it is necessary for the auditor
• Audit management and recordkeeping
• Internal communication to enter observations in their audit notes, request
• Document retrieval, review, and copying that they do so immediately after leaving the ster-
• Audit comment and observation follow-up ile area. Always insist that auditors practice aseptic
• Audit training techniques including hand sanitizing as required by
• Plant tour. your facility procedures.
Auditors and other visitors must also comply
SITE VISIT POLICY FOR AUDITORS with safety requirements at the site. They must not
AND OTHER NON-EMPLOYEES violate site restrictions on entry to restricted areas.
The site must have a clear policy for dealing with This could include possessing a cell phone in an
auditors and other visitors to the plant. This policy area with solvents. They must also wear appropriate
should be carefully developed and communicated to clothing, protective shoes, safety glasses, and adhere
all. There must be no misunderstanding or violation to other site requirements. There may be jewelry
of the policy by personal friends of site employees and cosmetic make-up restrictions.
or other visitors. Site areas that are completely “off Exceptions to site policy must not be made in the
limits” for visitors must be identified. Appropriate above circumstances. Sites that have violated policy
signage should be posted to clearly designate re- attempting to cooperate with auditors may receive
stricted areas. audit observations for doing so at the end of the
Concern for microbiological and cross-contami- audit.
nation is the primary reason for restricting access
to auditors and other visitors. This is especially AUDIT MANAGEMENT
important in drug firms and high-risk medical AND RECORDKEEPING
device firms. Auditors must adhere to good sanita- Audit management and recordkeeping of audit
tion practices during their audit. Auditors do not activities is the responsibility of the audit coordi-
unknowingly introduce or spread contamination nator. ­Topics discussed, questions answered, and
during their audit. Auditors must adhere to the site documents provided must all be noted for future
sanitation program for employees and wash and reference. Record of the audit should be thorough
sanitize hands, shoes, clothing, and equipment as and complete—it will likely need to be reviewed if
indicated in policy. If possible, minimize auditor’s a FDA warning letter is received in the future. The
unnecessary movement between various areas in audit coordinator should be conscientious in re-
plants. Auditors must wear proper external cloth- cording as much information as possible from the
ing and shoes. If auditors insist on entry into sterile meeting. This record should include auditor ques-
areas, they must undergo appropriate training as tions and comments, document requests, personnel
required by site policy. Attempt to have the auditor requests, discussions, and other occurrences. The
complete activities in one area before moving to the audit coordinator and support personnel should be
next. able to compile a thorough summary of activities
When auditing areas where sterility is maintained and requests.
or sterile rooms are located (especially in pharma-
ceutical or device firms), make sure that auditors
follow the sterile program required in your facility. INTERNAL COMMUNICATION
In general, it is usually not necessary for auditors to The following are several important communica-
enter sterile rooms except in the most extraordinary tion pathways associated with audits:

46 Conducting Audits, Gap Assessments & Corrective Actions Volume II

Ballard Graham, Richard Poska,
Robert Ertmann, and Paul L. Pluta

• Site communication. As soon as the primary should be known so there are no surprises during
audit contact is notified of the audit—either in the auditor review. Copies of retrieved documents
advance of the audit or when auditors arrive are made for site records. Copies should not be
unannounced at the site—all personnel at the
site must be made aware of the ongoing audit. volunteered to the auditors—documents contain
Site personnel must be periodically reminded proprietary information that must be restricted. If
of the ongoing audit when the audit continues copies are requested by the audit, the reason for the
for an extended time. request must be clear. If notice of an inspection is
• Audit daily status. Communication regarding received with identification of the objective of the
the ongoing audit status is the responsibility
of the audit coordinator. The audit coordina- audit, relevant documents should be retrieved and
tor must communicate the daily audit status carefully reviewed prior to the start of the inspec-
to upper management and to associated func- tion.
tional areas who have already participated or
provided information to auditors
• Future audit needs. Auditors are typically AUDIT COMMENT AND
asked about future topics to be reviewed and OBSERVATION ­FOLLOW-UP
other requests at the end of the day. The auditObservations and comments from auditors must
coordinator must quickly notify areas expect-
be quickly addressed and corrected if needed. Sites
ed to participate and the specific issues of in-
terest. Maximum time to retrieve documents, must have a system to record and track commit-
review past events, and prepare responses is ments and follow-up on progress and completion.
valuable. Completion and progress on past commitments
are always reviewed by auditors. Failure to meet
Audit communication must not be haphazard or a previous audit commitment on time is a serious
uncontrolled. The audit coordinator and associated deficiency.
management should be the official and sole sources
of information. Audit coordinators must quickly
and reliably communicate the daily audit status.
Sites should have an audit-training program for
The potential for unintended communication from
personnel who will be dealing with auditors. This
other sources will increase when status updates are
program should include fundamental expectations,
not timely and reliable.
answering questions, other interactions, and other
basic information.
Various documents from a variety of sources will be A plant tour is often one of the first activities in a
requested during the audit. These may include tech- regulatory audit. The importance of the plant tour,
nical reports from R&D or technical support areas, planning aspects, selection of the tour leader, and
policies and procedures, batch records, corrective associated considerations have been previously dis-
action and preventive action (CAPA) investigations cussed (see Reference). Sites may prepare a video of
and reports, validation master plans and specific relevant manufacturing areas to be viewed by audi-
validation reports, and analytical reports and data. tors preliminary to or as a supplement to the actual
These must be retrieved from the appropriate site, tour. The video has the advantage of showing areas
reviewed internally by the audit support staff, and that are not visible without aseptic gowning of visi-
provided to auditors as quickly as possible. Docu- tors. Other areas that are difficult to access for large
ment retrieval must be rapid and efficient. Practic- groups (e.g., HVAC facilities) or that have reduced
ing document retrieval ahead of actual audits is rec- lighting may also be more easily viewed in the video.
ommended. Every page of any requested document Companies must be prepared to address auditor re-
must be reviewed for “Post-It” notes, comments quests to visit areas not planned for the plant tour.
written into the records, and other problems that All areas of the site (except restricted areas) must be

47 Conducting Audits, Gap Assessments & Corrective Actions Volume II

Ballard Graham, Richard Poska,
Robert Ertmann, and Paul L. Pluta

prepared for audit at all times. BUILDING FACILITIES

Consideration for access to other necessary facili-
AUDIT LOGISTICS ties should be addressed in advance of the audit. It
The site must be prepared to accommodate the au- should be established which rest rooms will be used
dit with designated rooms and other considerations. by the auditors. Always have extra housekeeping
planned for any restrooms to be used by auditors.
Routes to the manufacturing areas and the labo-
AUDIT MEETING ROOM ratories should be planned. Planning for lunches
An audit meeting room should be identified in ad-
should be addressed. If there is a site cafeteria, the
vance of an actual audit. This room may also func-
route and best times to go to the cafeteria should be
tion as the auditor’s workroom. The audit meeting
considered. Long lines at the site cafeteria at shift
room should be located in a quiet area of the plant.
breaks should be avoided. If there is no site cafete-
It should have telephone and Internet access. The
ria, ordering food for delivery or other plans should
room should also be reasonably close to restrooms
be discussed with the auditors at the initial meeting.
and other necessary facilities. Auditors should not
walk unescorted through restricted or critical areas
Associated logistical topics such as the location di-
rections, parking, site entry, and security should be
AUDITOR’S WORKROOM addressed as part of audit preparation. Large sites
A separate workroom for auditors should be identi-
should have maps available for visitors. Parking
fied. This room should have a telephone, computer,
areas for auditors in close proximity to the entry
Internet access (not unrestricted site intranet ac-
building should be designated. Auditors should be
cess) for use by the auditors when they need to make
informed that these spaces are available in prior
outside contact or have other privacy requirements.
routine communication. Personnel at the site entry
The audit meeting room may also serve as the au-
building must know whom to contact when an au-
ditor’s workroom by having all site audit personnel
ditor arrives unannounced. A “call list” of respon-
leave the room. Providing communication tools for
sible personnel including the primary audit contact
use by auditors (e.g., phone, Internet access) is not
and site audit coordinator must be readily available
required, but will demonstrate a willingness to co-
for entry personnel. Someone from the plant must
be available at all times to receive auditors. Security
personnel at the site must also be aware of the po-
AUDIT SUPPORT ROOM tential for unannounced visits by auditors.
The audit support room is the room used to review
documents and meet with site personnel prior to in-
teraction with auditors. Document review is an im-
Serious and embarrassing problems may occur
portant task; there must be adequate space and time
when preparation for an audit is not adequate. The
available for document review prior to presentation
following examples were provided by several regu-
to the auditors. Document copies are also assembled
latory, compliance, and validation managers at in-
in this room. This room should be reasonably close
dustry meetings in Philadelphia (2010), Athens, GA
to the audit room. The room should have telephone
(2011), and Amsterdam, The Netherlands (2011).
and computer access. This room will be a busy place
when multiple audit requests are being compiled,
people are assembling prior to entry into the audit CONTACT PERSONS UNAVAILABLE
room, and other associated activities are ongoing. Security procedures at a manufacturing site re-
quired that all visitors to a site be allowed entry only
if a responsible person authorized entry. Because

48 Conducting Audits, Gap Assessments & Corrective Actions Volume II

Ballard Graham, Richard Poska,
Robert Ertmann, and Paul L. Pluta

senior QA management were not available and no some relatively insignificant points. The discussion
one had been designated as responsible for such degenerated into an unpleasant interaction. Person-
activity, the auditors were forced to sit in the entry nel must be trained before interacting with auditors.
area for an extended time period (hours) until the
QA vice president could be contacted. The VP then AUDITOR TRAVEL DIRECTIONS
directed security personnel to escort the auditors to A large pharmaceutical company had multiple fa-
the appropriate location at the manufacturing site. cilities in the area. Auditors arrived unannounced at
Sites must be prepared at all times for the arrival the main site to initiate the audit. After presentation
of auditors. Backup personnel must be designated of credentials, security personnel directed auditors
when primary contact people are unavailable. to another location based on their understanding
of auditor request. Auditors wasted several hours
PLANT TOUR DEFICIENCIES traveling between sites because security personnel
Typical tour deficiencies have included stained ceil- misunderstood the auditor’s request. Security per-
ing tiles, pest control (flying and rodents) issues, sonnel must contact appropriate site personnel to
wood pallets, cardboard boxes in open materials deal with auditors.
or open product areas, equipment status identifi-
cations, calibration, and other areas. All areas of a UNNECESSARY INFORMATION
manufacturing site should always be maintained in
an audit-ready state.
Rather than clarifying what documents the auditor
requested, an entire file was provided. This does two
EMPLOYEE LOUNGE things. First, it provides the perception that you ei-
ADJOINING RESTROOMS ther didn’t understand the reason or nature of the
Auditors were directed to use restrooms that were request, or that you were trying to hide something
in the same general area as the employee lounge. by providing extraneous information. Secondly, it
When auditors were in area, open discussions be- provides the auditor with additional information
tween operators regarding manufacturing problems from which to investigate. Requests must be under-
and management issues were overheard. All person- stood; responses must specifically answer requests.
nel at the site must be aware that an audit is being
DOCUMENT REVIEW PRIOR TO AUDIT This article has focused on regulatory audits; how-
Auditors requested validation reports. Personnel ever, many of the same considerations and recom-
did not review documents before providing them to mendations may be applied to non-regulatory
the auditors. These documents had numerous “Post- audits, visits from business customers, non-audit
It” notes with comment information throughout. visits from local government officials, environmen-
Comments identified problems and questioned tal agency audits, safety agency audits, and other
content of validation reports. Audits must be thor- situations including company internal audits. Se-
oughly and carefully reviewed before presentation curity considerations with proprietary information
to auditors. are a definite concern in business customer audits.


INTERACT WITH THE AUDITOR There are certain topics and documents that are
An alternate SME was called in to discuss technical guaranteed areas for audits. Sites should be familiar
aspects of bioavailability with the auditor. The SME with these areas and prepared to discuss them in
became argumentative during the discussion over detail. For example, key areas in the quality sys-

49 Conducting Audits, Gap Assessments & Corrective Actions Volume II

Ballard Graham, Richard Poska,
Robert Ertmann, and Paul L. Pluta

tems, validation master plan, product complaints, tion oversight throughout the operation.
recent CAPA and investigations, recent environ- • If the audit is being conducted by a regulatory
mental monitoring data, and other “hot topics” agency, familiarize yourself with any informa-
tion that the agency provides in the public
should be ready for review in advance of the actual domain.
audit. Questions on other current areas of interest • A site audit coordinator must be identified.
should also be anticipated. For example, questions All personnel at the site must know the role
on supply chain considerations that result from and responsibilities of this person.
news reports such as materials obtained from ex- • The site audit coordinator should accompany
auditors at all times during the audit.
US sources (i.e., heparin problem), wooden pallet • All requests from auditors must come through
odor control (i.e., J&J problem), and other timely the site audit coordinator.
topics should be expected. • Manage personnel and document flow to the
auditor by means of the support staff.
• Thoroughly review documents internally be-
QUALITY CULTURE AND fore presenting to the auditor.
THE ROLE OF MANAGEMENT • Do not allow persons in your organization
This discussion has addressed fundamental points that have not been properly trained to inter-
face with auditors.
in preparation for regulatory and other audits. • Respond specifically to questions asked by
When addressed properly, these points may con- auditors. Do not volunteer any unsolicited
tribute greatly to a successful audit. However, these information.
points must not overshadow the objective and con- • Be prepared for audit of key areas in the qual-
tent of an audit (i.e., compliance in facility opera- ity system, the validation master plan, prod-
uct complaints, CAPA and investigations, and
tions). Excellent planning in personnel functions, environmental monitoring, and other “hot
systems, and logistics cannot hide substandard topics.”
compliance. Above all else, an organization must • The culture of the organization, as created
live compliance in daily operations. The site must and supported by management, is the guiding
have a quality culture—every person at the site force in ongoing compliance.
must work with quality and compliance in mind
in everything they do. If the entire staff works with REFERENCE
this belief at all times, they will always be ready for 1. Pluta, Paul L., editor, “First Impressions-The Plant
an audit. Management sets the tone for the cul- Tour,” Journal of GXP Compliance, Volume 15 # 1,
Winter 2011.
ture. Employees will give management what they
demand. The actions of management far outweigh
the words of management. Senior management and GENERAL REFERENCES
functional management must demonstrate that 2. FDA, Investigations Operations Manual (IOM). http://
quality and compliance are important. Without
such an attitude, audits will not be successful. As a
vice-president of manufacturing once declared, “I ARTICLE ACRONYM LISTING
look forward to the audit as confirmation that we CAPA Corrective Action and Preventive Action
GMP Good Manufacturing Practice
are doing the right things.”
QA Quality Assurance
R&D Research and Development
CONCLUSIONS SMEs Subject Matter Experts
The following are some basic rules for preparing for
a successful audit: *This article was previously published in the Autumn 2011 is-
• Be prepared at all times for an audit including sue of the Journal of GXP Compliance, Volume 15, Number 4.
people, systems, logistics.
• Know your products and processes.
• Understand the concepts of quality systems.
• Exercise continuous product and documenta-

50 Conducting Audits, Gap Assessments & Corrective Actions Volume II

Ballard Graham, Richard Poska,
Robert Ertmann, and Paul L. Pluta

About the Authors

Ballard Graham is divisional vice president
at Abbott Quality and Regulatory Compli-
ance Oversight, Abbott, Abbott Park, IL, USA.
Richard Poska is director of Regulatory Affairs
Pharmaceutical Product Group Strategic CMC
Initiatives at Abbott, Abbott Park, IL, USA. Rob-
ert Ertmann is a compliance officer at North
Chicago SVP Quality Assurance, Abbott, North
Chicago, IL, USA. Paul L. Pluta, Ph.D., is the
Editor-in-Chief of the Journal of GXP Compli-
ance and Journal of Validation Technology. Con-
tact Dr. Pluta with comments or questions on
this discussion at paul.pluta@comcast.net.

51 Conducting Audits, Gap Assessments & Corrective Actions Volume II

Sofia Cerioni, Ph.D., Raffaele Lasala,
and Enrica Lombardini

Analysis of Recent Drug GMP Inspections

by FDA and AIFA: Different Approaches
Sofia Cerioni, Ph.D., Raffaele Lasala, and Enrica Lombardini

ABSTRACT outcome of the most recent Health Authorities

Companies regulated under good manufacturing inspections on different sites of the company were
practices (GMPs) are routinely inspected by health analyzed.
authorities in order to ensure the quality, safety, and The analysis consists of the collection of the most
efficacy of their products. frequent observations made during these inspec-
Accordingly, the study has two objectives: firstly, tions performed on biopharmaceutical production
to point out where the inspectors’ attentions are fo- processes over the last couple of years (2011/2012).
cused and to highlight the main deficiencies of the The analysis has two aims. Firstly, to identify any
company and, secondly, to highlight the differences trend during the recent site inspections in order
between findings from the Italian Health Authority to bring to light any shortcomings and implement
Agenzia Italiana del Farmaco (AIFA) and the US appropriate corrective action. This insight will also
Food and Drug Administration. help educate readers from any errors made in order
The observations are divided into different cate- to face future inspections more confidently. Second-
gories. In particular, the analysis includes the fol- ly, a comparison was made between the AIFA and
lowing systems: FDA approaches in order to reveal to readers any
• Validation differences and prepare them to face both agencies
• Documentation by knowing where the inspector is likely to concen-
• Deviations trate his attention.
• Quality control (QC) testing In order to perform this second type of analysis, it
• Facility and equipment.
is very important to be aware of the different Health
Authorities inspections aims.
This type of analysis underlines trends, helps firms
The primary mission of FDA is to conduct com-
to improve quality, and prevents recurring observa-
prehensive regulatory coverage of all aspects of pro-
tions in future inspections.
duction and distribution of drugs and drug prod-
The self-inspection plan can take into account the
ucts to assure that such products meet the 501(a)
results of a thorough study of data in order to focus
(2)(B) requirements of the Federal Food, Drug and
the attention of internal auditors and management
Cosmetic Act (FD&C) (1), (2).
on shortcomings.
The goal of FDA inspections is to minimize con-
sumers’ exposure to adulterated drug products.
INTRODUCTION As far as AIFA inspections are concerned, the
Regulatory bodies check that the whole production main objective is to ensure that medicinal products
process is carried out in compliance with current are manufactured with technical and methodol-
regulations in order to ensure the quality, safety, and ogy criteria that guarantee product quality. AIFA
efficacy of drugs. Through inspections on pharma- issues manufacturing authorization and certificate
ceutical manufacturing facilities, they check that the of GMP compliance that must be sent to European
process complies with GMPs. Medicines Agency (EMA) by AIFA as required by
To highlight the main topics/quality systems Directives 2001/83/EC (3) and 2004/27/EC (4).
on which the inspectors focus their attention, the Moreover, AIFA must ensure the equivalence of

52 Conducting Audits, Gap Assessments & Corrective Actions Volume II

Sofia Cerioni, Ph.D., Raffaele Lasala,
and Enrica Lombardini

the Italian inspection approach to the other Europe- the analysis on observations related to the quality
an Union (EU) states and to non-EU countries that system, the facility and equipment system, and the
have signed the GMPs Mutual Recognition Agree- QC system.
ments with EMA. In this frame, the analysis was restricted to a total
of 94 observations, 52 issued by AIFA and 42 by the
The analysis concentrated on findings made by The 94 observations were split into the three
AIFA (adopting the EU-EMA inspection scheme) above-mentioned US guideline categories and were
and FDA taking into account that both these au- then again analyzed and assigned to further subcat-
thorities belong to and apply the Pharmaceutical egories. In this way, it was possible to see in more
Inspections Convention (PIC/S) 5 scheme. detail which parts of the main quality system were
Data from 12 inspections involving six different implicated.
sites of the same company dedicated to biopharma- This further classification can provide the basis
ceutical production were studied. to fill any gaps and be prepared for future Health
Before looking at these data, it should be empha- Authority Inspections.
sized that the sites involved have different charac- As AIFA issues and classifies its observations ac-
teristics: cording to the European Guide to Good Manufactur-
• One is a fully integrated site including both ing Practice (EudraLex Volume 4) (7), the authors
active drug production, fill, finish, and pack- used this guide to identify the subcategories and
aging production activities. consequently also classified the FDA findings with
• Three are involved in some process steps such this scheme.
as upstream and downstream processes or fill
and finish plant with all related support activ- Moreover, the 94 observations split into the sub-
ities located on-site. categories were also divided between those issued
• Two locations are dedicated to QC testing and by AIFA and FDA in order to perform the second
stability studies. part of the analysis.

In the period considered, AIFA performed four

inspections on three Italian sites whilst FDA per-
The graph below shows the number of observations
formed eight inspections on six European sites
divided into the main systems analyzed in this pa-
within a short length of time.
These inspections resulted in a total of 118 obser-
Two points can be made:
vations: 57 were issued by AIFA and 61 by FDA. • A higher percentage of observations can be
For analytical purposes, the observations were seen in the quality system segment.
divided into categories according to FDA Guidance • Each category encompasses a wide area, con-
for industry – Quality Systems Approach to Phar- sisting of many different activities.
maceutical cGMP Regulations (6) and to European
EudraLex (7). In regards to the quality system, findings were
The resulting six categories are the quality sys- divided into subcategories such as Cleaning, De-
tem, the facilities and equipment system, materials viation (nonconformances), Vendor Management,
system, production system, packaging and labeling Personnel, Validation, Audit, Technical Agreement,
system, and the laboratory controls system. and Documentation.
Given that the analysis deals with the biological QC and facility and equipment (F&E) observa-
quality control of biotechnological products, obser- tions were both split into subcategories as shown in
vations related to the materials system, production following graphs.
system, and packaging and labeling system were not The system that was subject to the highest number
taken into consideration. of observations was the quality system; in particu-
In order to have homogeneous data, we focused lar, the subcategories with the highest number of

53 Conducting Audits, Gap Assessments & Corrective Actions Volume II

Sofia Cerioni, Ph.D., Raffaele Lasala,
and Enrica Lombardini

findings being: Figure 1: Observations Analyzed. hav-

• Documentation and procedures
• Validation management
• Deviation management.

When QC and F&E are considered, the subcate-

gories with most observations were:
• Quality control: test method
• Facilities and equipment: environmental con-

Comparing authorities, the graphs below show

the observations divided into the main subcatego-
ries issued by AIFA and FDA.
Comparing authorities, the graphs below show
the observations divided into the main subcatego- ing all activities described with an adequate level
ries issued by AIFA and FDA. of detail; everything has to be written, and even the
From the comparison between the approaches of simplest actions have to be described and document-
the two authorities to the quality system, it can be ed. All the data obtained during an analysis have to
seen that both focused on validation management. be duly recorded and activities, such as the use and
Furthermore, AIFA made many of different ob- cleaning of an instrument, have to be recorded so
servations on documentation, but FDA paid more that what was actually done can be tracked.
attention to deviation management.
In regards to QC, the highest number of findings Validation
for both the regulatory bodies concerned the test Another point implicated in findings is validation:
method. “The validation is not adequate...”
Finally, for F&E, FDA concentrated on environ- A particular point of interest is the validation of
mental controls while AIFA focused on equipment, computerized systems regulated by Code of Federal
maintenance management, and plants (e.g., HVAC Regulations Title 21 Part 11 (8) and by Annex 11 of
management and monitoring and management of the Eudralex (9) that, following the recent revision,
differential pressure between lab rooms of the facil- sets out requirements equivalent to those already
ity). set by the US. The information systems validation
ensures that operations are carried out correctly and
DISCUSSION calculations are accurate.
Examining the observations divided into the main An insufficient validation could generate unreli-
systems, the following considerations can be made. able data due to a system or a method not complete-
ly under control.
Checks must be repeated whenever the software
QUALITY SYSTEMS version is upgraded.

Documentation Deviation
As far as documentation is concerned, several ob-
The third point concerns deviation management;
servations were due to the fact that not all activities
often a poor investigation generates observations
carried out are regulated in detail by procedures.
by regulatory bodies. One example of a finding by
For example, it was commented that “activity X is
the authority is the following: “For the majority of
not governed by procedures, checks to carry out in
the investigations the documentation did not con-
Phase Y are not detailed.”
tain complete information and did not progress to
Therefore, this first point addresses the difficulty of

54 Conducting Audits, Gap Assessments & Corrective Actions Volume II

Sofia Cerioni, Ph.D., Raffaele Lasala,
and Enrica Lombardini

Figure 2: Observations Based on Quality System Subcategories.

Figure 3: Observations Based on Quality Control Subcategories.

Figure 4: Observations Based on Facility and Equipment Subcategories.

55 Conducting Audits, Gap Assessments & Corrective Actions Volume II

Sofia Cerioni, Ph.D., Raffaele Lasala,
and Enrica Lombardini

Figure 5: AIFA vs. FDA Quality System Observations.

Figure 6: AIFA vs. FDA Quality Control System Observations.

Figure 7: AIFA vs. FDA Observations Based on Facility and Equipment System Observations.

56 Conducting Audits, Gap Assessments & Corrective Actions Volume II

Sofia Cerioni, Ph.D., Raffaele Lasala,
and Enrica Lombardini

the actual identification of the true root cause – not like this can also point out both lack of accuracy of
enough ‘whys’ were asked.” the procedure describing each step of the test and
This means that investigations must be carried out weakness of the record-raw data collection process.
thoroughly with the aim of identifying the true root Regarding the first point, procedures must reflect
cause of the deviation. Any unexpected event has to the real activities performed in the laboratory and
be investigated in order to find the real cause of the the equipment and/or part of them involved in the
event. The identification of the deviation root cause process.
allows the implementation of the necessary correc- Moreover, inadequate data collection results in a
tive and preventive actions (CAPAa). The corrective lack of traceability of activities and test outcomes.
action minimizes the cause of a detected non-con- Complete records are essential for demonstrating
formity, and the preventive action reduces the cause that the test has really been performed and the data
of a potential non-conformity. This means that the are of the required quality and reliability.
implementation of an adequate CAPA prevents the
repetition of the unexpected event or result. FACILITY AND EQUIPMENT SYSTEMS
For this reason, it is important to monitor devia- Regarding facility and equipment systems, several
tions to show up any trend and to take action if the observations report “lack of adequate validation of
unexpected event has occurred on other occasions. disinfectants and disinfection process in the various
Another example confirming this insight is, areas.”
“None of the investigations reviewed contained any Cleaning of areas, workbenches, hoods, and in-
trending or ‘look back’ to determine if the current struments was found to be a critical point. Given
event is a repeat.” the need to demonstrate lack of contamination and
Recurrence implies that the previous investiga- cross contaminations, the firm very often lacks data
tions may have failed to find the true root cause or supporting that environmental controls are ade-
may not have identified the most appropriate CA- quate.
PAs. Trend monitoring and analysis allow confir- This kind of observation shows the difficulties in
mation of the pertinence of preventive action taken the correct approach in mapping and monitoring
and, if necessary, allow the implementation of fur- critical points.
ther action to maintain the process under control A confirmation of this can be found in one ob-
with the purpose of continuously improve quality. servation reporting, “critical points to be subjected
Therefore, the firm must ensure that the data ob- to microbiological sampling have not been correctly
tained with the computerized systems are reliable. identified.”
Inappropriate monitoring is applicable both to
QUALITY CONTROL SYSTEMS environment and personnel, as mapping rooms,
As far as the QC system is concerned, several ob- hoods, and personnel gowning is crucial to demon-
servations start with the sentence, “Some analytical strate that the selected sampling points are adequate
methods used for... testing are incomplete or inac- to monitor contamination.
This kind of observation regards the testing meth- AIFA VS. FDA COMPARISONS
od subcategory and reflects two different issues. Examining the observations split between the AIFA
Firstly, there is lack of a rationale for test method- and FDA the following considerations can be made.
ology (i.e., some test steps are executed but are not
supported by a scientific rationale, or, on the con-
trary, not all the required controls are performed).
Quality Systems
Looking at the quality system, validation is a crit-
In this frame, the observation reflects the lack of in-
ical point for both the authorities, although AIFA
depth process knowledge with specific reference to
focuses its attention on documentation and FDA on
the identification of critical steps. Secondly, findings
deviation management.

57 Conducting Audits, Gap Assessments & Corrective Actions Volume II

Sofia Cerioni, Ph.D., Raffaele Lasala,
and Enrica Lombardini

This outcome reflects the different approaches of FDA performs pre-approval inspection (PAI) and
the two agencies in conducting inspections. AIFA routine GMP inspections of all sites that manufac-
looks mainly at process organization through doc- ture products intended for the US market. Accord-
ument/procedure review. On the other hand, FDA ing to the focus of its inspections, FDA concentrates
looks closely at deviations raised during the time- on environmental controls that can have a direct
frame between its inspections in order to check how impact on product quality and safety.
unexpected events have been managed and could
have impacted the quality of product batches sold CONCLUSION
in the US market. The analysis of the principal observations gives an
Considering deviation management, the authors overview, based on the experience of the author’s
observed that the AIFA approach is to review the company, on authorities’ inspection approach to in-
pertinent procedure and then select some examples dustry, identifying trends, and issues on which the
of deviations in order to verify compliance with the inspectors could concentrate.
procedure. The common issue is the difficulty to reach an
adequate level of accuracy at different steps. This
Quality Control Systems is a critical point because the approaches used and
Both health authorities focused their attention on the decision taken should be always supported by a
testing methods, but FDA also looked in great detail scientific rationale. This goal can be achieved with a
at standard and out-of-specification (OOS) man- deeper knowledge of the process.
agement. Methods/processes should be well-known, and
This again reflects the different approaches of the the related criticality should be identified, under-
two authorities in conducting inspections; to guar- stood, and managed correctly. The accurate man-
antee product quality, it is essential to look at the agement of the process allows its control, and so, as
analytical method used, and, in this frame, also at far as biotech products are concerned, this means
standard management. producing safe and efficacious products.
Consequently, the analytical result management is The results of this analysis can be taken into ac-
inspected with particular attention on OOS results; count in defining the self-inspection approach in
this means to put attention on how the OOS inves- order to focus attention on the most critical points
tigation is conducted, documented, and how the and can consequently be used by firms to prevent
retest plan is managed. recurring observations in future inspections.
On the other hand, AIFA observations are distrib- Moreover, this study can support the company
uted among all the different subcategories. management to identify the gaps and implement
the necessary corrective actions. As regards the
Facility and Equipment Systems comparison between AIFA and FDA, the study
The different approach to facility and equipment confirms their different approaches that reflect the
management by the two authorities is in-line with diverse inspection aims.
the objective of their inspections and can be ex- The results can help firms prepare for inspections
plained as follows: knowing where inspectors are most likely to focus
In Europe, the overall facility information is de- their attention.
tailed in the site master file, and controls on facility
changes, GMP status, and manufacturing autho- LESSONS LEARNED
rizations are delegated to the Competent National This analysis demonstrates:
Authorities. EMA does not contemplate any type • Shortcomings are apparent in self-inspections
of change submissions or notifications for facility with some critical points where checks should
changes affecting (centralized) product registra- be intensified.
tions. • In addition, the importance of the quality sys-
tem is highlighted: management should im-

58 Conducting Audits, Gap Assessments & Corrective Actions Volume II

Sofia Cerioni, Ph.D., Raffaele Lasala,
and Enrica Lombardini

plement effective CAPAs in order to prevent

recurring findings.

1. Federal Food, Drug, and Cosmetic Act, 501(a)(2)(B).
2. FDA,  CPGM 7356.002 Compliance program – Drug
Manufacturing Inspections.
3. Directive 2001/83/EC of the European Parliament and
of the council of 6 November 2001 on the community
code relating o medicinal products for human use, Of-
ficial Journal L – 311, 28/11/2004, p. 67 – 128.
4. Directive 2004/27/EC of the European Parliament and
of the council of 31 March 2004 amending Directive
2001/83/EC on the community code relating o medic-
inal products for human use, Official Journal L – 136,
30/04/2004, p. 34 – 57.
5. Pharmaceutical Inspections Convention,  Pharmaceu-
tical inspection co-operation scheme, PIC/S 1/95 (Rev.
About the Author
5), Nov. 7, 2011.
6. FDA,  Guidance for Industry – Quality Systems Ap- Dr. Sofia Cerionia, Raffaele Lasala, and Enrica
proach to Pharmaceutical cGMP Regulations  (Rock- Lombardini are quality assurance professionals
ville, MD September 2006). within the biological quality control of a Merck
7. EudraLex, Volume 4, EU guideline for Good Manufac-
turing Practice for medicinal products for human and
Serono site. They can be reached at sofia.ceri-
veterinary use. oni@external.merckgroup.com, raffaele.lasa-
8. Code of Federal Regulations, Title 21, Food and Drugs la@merckgroup.com, and enrica.lombardini@
(Government Printing Office, Washington, DC), Part merckgroup.com.
9. EudraLex, Volume 4, EU guideline for Good Manufac-
turing Practice for medicinal products for human and
veterinary use, Annex 11: Computerised systems.

Originally published in Journal of GXP Compliance Volume

17 Number 3

59 Conducting Audits, Gap Assessments & Corrective Actions Volume II

Patrick Klemens and James Kaar

When Quality Needs an Audit

Patrick Klemens and James Kaar

Welcome to “Business of Auditing and Auditing the Business.”


This series will discuss a critical activity in compliance—auditing and being au-
dited. We will explore the many dimensions of the audit process, going far beyond
the audit event to underscore the power of this often-misunderstood quality tool.
Our goal for this series is to provide useful and practical information applicable to
everyday situations.
While quality audit is an important tool in the array of methodologies at our dis-
posal, it has the potential to touch many other aspects of the business. For example,
when one verifies the effectiveness of a corrective action, one is performing a nar-
rowly focused audit. However, if the results are not acceptable, this can become an
internal audit of the corrective action process. Audits can be as simple or complex
as we choose to make them, but the strength of the audit comes from the interpreta-
tion of the results and the actions that are driven by those results. This column will
provide ideas on how to conduct audits as the auditor, as well as how to manage the
audit as the auditee—and explain why, even though these two areas are truly “op-
posite sides of the same table,” our actions, reactions, and behaviors do not always
reflect that relationship.
By its very nature, an effective and integrated audit program is difficult to achieve
and maintain. There are inherent challenges to getting the results we want and need
from our various audit programs. For example, the internal audit program should
disclose any gaps in our systems before these gaps are observed by someone outside
the company. And we really want our customer audits to find any gaps before they
are noted by a regulatory body.
Internal audits will have employees auditing other employees. It takes skillful
management to assure that personal relations don’t soften the results and thereby
weaken the program. Even when it is assured that the auditor has no responsibili-
ties for the area being audited, the auditors are part of the company, too—they may
eat lunch with or live next to one of the employees they are auditing. Management
needs to demonstrate a true desire to have these gaps found and to assure that there
are no punitive outcomes, at any level, as a result of internal audit findings.
Likewise supplier audits always have the business relationship in the background.
While we hope professionalism trumps personal pettiness, there can be damage to
the supplier-customer relationship if one side feels abused during an audit. There
are costs associated with maintaining quality systems and with regulatory compli-
ance: how much do you add to the cost of the materials when you ask for a change
in the system?
We hope you find these articles informative and thought provoking. Reader com-
ments, questions, and suggestions are welcome. Please contact Patrick Klemens at
klem123@ameritech.net, James Kaar at kaar54@comcast.net, or journal managing
editor Susan Haigney at shaigney@advanstar.com.

60 Conducting Audits, Gap Assessments & Corrective Actions Volume II

Patrick Klemens and James Kaar

THE PEOPLE First, “Is there a documented procedure for what the
Art. Vice President of Quality for MedicHose, a company is doing?” And the second question is “Do
medical component company. Art is responsible for they follow their procedure?”
the overall compliance of the MedicHose quality In a smaller, family-owned company, information
system. can sometimes fall into the bucket of “Tribal Knowl-
edge”. How does he explain this to the new manage-
Roger. Director of Supplier QA. Roger is respon- ment? A change in management brings many other
sible for the MedicHose supplier quality process, changes with it, including changes in philosophy and
including the approval and monitoring program. changes in the corporate culture. Add to this the ac-
tual culture differences between Europe and America
Joel. Quality Assurance Consultant with expertise and the complexity multiplies.
and credentials including ASQ Certified Quality
Auditor and a Black Belt in Lean Six Sigma. Joel is But the original family was gone now. An old-line
an old personal friend of Art. firm from Europe had purchased MedicHose and it
wasn’t even close to a partnership. While they might
all be on the same team, Art feels he is on the de-
THE COMPANY fense and they are on offense. A group from the new
MedicHose is a family-owned company located in headquarters in Belgium is planning to audit him in
southeastern Minnesota. MedicHose has been in the next month and he simply isn’t ready. He doesn’t
business for 40 years and has a good quality reputa- even know to which standard the Belgian team will
tion. An old-line European company headquartered be auditing. MedicHose doesn’t claim compliance
in Brussels has just purchased MedicHose. Changes to ISO 13485, just ISO 9001, but there have been
have not yet started, but they are sure to come. rumors that the new company wants MedicHose to
get more involved in manufacturing sub-assemblies
THE STORY and some simple medical devices. That would re-
Another audit? quire a rework of the entire quality system. On
Art hangs up the phone. One of his company’s top of that, his last internal audit was more than
more important customers wants to come in for a four months ago, and he is concerned that he isn’t
two-day audit next week. They weren’t due in for meeting his standard operating procedure (SOP)
another six months or more. It seems like ever since requirements to do quarterly self-inspections.
the acquisition, every customer wants to come in At the same time, he is trying to assure that his
to re-audit them. He knows why this is happen- supplier audit program remains on track. Medi-
ing. Anytime a company gets acquired there will be cHose’s two most important suppliers are due to be
questions from both customers and suppliers, and audited this month, too. On top of all of this, he is
the recent emphasis by the FDA on supplier man- trying to draft a new quality policy that MedicHose
agement hasn’t made it easier. But still… would share with its employees and customers.
How did they expect him to run his shop? As VP The phone rings, again. This time Roger, Art’s
of Quality for MedicHose he is responsible for as- director of Supplier Quality, is calling. He tells Art
suring that his company’s products meet the high that they really need to get out to Central PolyCrys.
standards that the original family owners had estab- Two recent shipments of their beads failed incom-
lished almost 40 years ago. He has had to balance ing inspection. Art agrees, and Roger gets his audit
MedicHose’s quality and compliance efforts like team ready to go.
Goldilocks: not too hot and not too cold. As he hangs up the phone, his eyes fall on his new,
half-drafted quality policy. “That’ll need to wait,” he
Art knows MedicHose’s standards, but isn’t sure the tells himself. “I’ve got fires to put out.”
documentation supports them. He knows that the two
big questions during an audit are always the same. Art finds himself in a common predicament. Man-

61 Conducting Audits, Gap Assessments & Corrective Actions Volume II

Patrick Klemens and James Kaar

aging to complete more and more with less and less, o’clock at the little diner down the street from your
he needs to strike the right balance. MedicHose needs office sound? If I remember right, they’ve got Bel-
to have a compliant quality system to maintain its gian Waffles, right?”
certification, but at what cost? They were a small Art saw the irony. “Yeah, I’ll see you there tomor-
company, or at least they had been, and they didn’t row. Thanks…but there will be no Belgium waffling
have all the money and time that a big company around here!”
might have to spend on compliance. He needs to re-
prioritize. He already believes that his current prob- Art wanted to have the meeting, but he wasn’t sure
lems can’t be fixed by his current system, that’s how he he was ready for the meeting. Was he really in need
got here in the first place. of additional resources or was he just feeling the stress
of being acquired. Just how had the MedicHose qual-
Art calls an old friend and asks for some help. Joel ity system gotten so far out of whack? MedicHose had
and Art had worked together earlier in their careers. a great reputation, they were a good company but
Joel had left that company to become a consultant he needed to tell Joel more than that at the meeting
a few years before Art went to work at MedicHose. tomorrow. What information did he need to provide
They have stayed in touch over the years, but Art to his consultant, what was critical for the consultant
has never really considered using Joel as a resource. to know to understand the current situation? Perhaps
He generally doesn’t use consultants at all, figuring the best thing to do (or at least the path of least resis-
it takes too long to get them up to speed and re- tance) would be to hire Joel to review the system and
ally contributing. But this time is different. He really processes from the bottom up. He would have the time
needs someone with a strong quality background to give it a thorough review since he wouldn’t always
who could help him evaluate his situation. Joel has be putting out fires.
all the credentials Art’s looking for: ASQ Certified
Quality Auditor and a Black Belt in Lean Six Sigma. The next day, Joel is already in the booth when Art
And there is the added advantage of knowing Joel comes in almost 20 minutes late.
and having worked with him in the past. “I was starting to think that maybe you forgot
“Hi Joel, Art here. How are you?” After a few about me,” Joel says.
minutes of pleasantries and “how’s the family,” Art “I’m sorry. I didn’t forget. In fact, all I’ve been do-
comes to his point. ing is thinking about your questions. I actually tried
“Joel, I’m really struggling. I’ve got a supplier audit to get out the door three times, but three times I
program that can’t keep up. My internal audit pro- got pulled back for this or that. Things have never
gram has slid badly, and I’ve got corporate folks due been as crazy as they are right now. Everybody is so
here anytime to do a top-to-bottom assessment of nervous about this buy-out.”
my quality program. I’m not sure I know where to “I would imagine so. When did the family start
start…” the business? I’m guessing it has been more than 30
Joel asks the first and perhaps most important years, right?”
question, “Well, Art, what has changed to make you “Yeah, it’s closer to 40 years. I think that’s part of
feel this way? Was your system working for you at my issue, too. The family always set the tone and
this time last year?” direction. We had a strong quality ethic so we never
Art takes a deep breath. “Uh, hmm. I think so. I really had a strong quality system. We did things
can’t say for sure. Why does it matter if it was work- right because the family insisted we never compro-
ing okay last year?” mise. But it’s fair to say that without them, we don’t
“Well, we need to determine what’s going on here. have anything but our culture to fall back on.
I’m thinking that if we go back to last year, we might “It’s ironic,” he continues. “We’ve got good prac-
get some insight into what’s really happening now. tices, but not really good policies or procedures.
I tell you what. You think about it, and I’ll meet I’m finding our SOP system isn’t as descriptive as I
you for breakfast tomorrow morning. How about 8 thought.”

62 Conducting Audits, Gap Assessments & Corrective Actions Volume II

Patrick Klemens and James Kaar

“I’ve seen this with other companies, too,” Joel feel for that than they did for some other aspects of
remarks. “Everybody in the company thinks they the business, based on the visit.”
know what’s expected of them until something “I guess you’re right, it’s more a matter of the un-
changes.” known.”
The waitress interrupts, “Morning, fellas! Are you “Alright,” Joel says, “I think I see a way to begin.
ready to order?” Want to try some of my waffle? You’re going to need
“Sure,” Joel says, “I’ll have the Belgian waffle. I to get very good at everything from Europe real
think my friend here will stick with eggs, bacon, and fast.” He continues, “Again, why is that your biggest
toast. Is that right, Art?” concern?”
“Yeah,” Art mumbles, “and black coffee.” Art explodes, “I already answered that question!”
“So Art, you’ve started to answer my question. “Well, you actually gave me three answers. Now
Things were different last year. What else has I’m trying to get you to prioritize those three,” Joel
changed to make you so nervous?” explains.
Art is ready for the question and he rattles off sev- And so it continues for the rest of the meeting.
eral points in a machine-gun like burst. MedicHose’s VP of Quality trying to distill all the
“First, like I said, we really don’t have a sound qual- concerns that he had into some form of meaning-
ity system. Second, with the acquisition, we really ful information, and his friend (and newly-retained
don’t know the ‘new quality philosophy’ and how we consultant) trying to fit everything into some form
fit in. Third, we aren’t really ready to handle an audit of manageable priority list.
from our new corporate parent. Fourth, we’ve got to Art says, “You know, I feel like I just went through
get our vendor quality into the 21st century. Fifth, I an audit.”
don’t have enough time to do it all. Joel laughs, “You did. It’s not the last one we’ll go
“That’s why I called you. I need someone who can through together, either. We’ll need to continue
help me. I’ve got competing priorities and need to asking questions about how the system works, and
make real progress before the team from headquar- how it worked or didn’t work in the past. We’ll only
ters arrives.” be able to fix the problems by pushing hard on the
“We need to figure out the priority list for what system and evaluating any gaps we discover.”
is in front of you, right now. What is your number Art agrees but wants to know how come his To-
one concern?” Do List has all the action items on it.
Art thought for a moment, then immediately an- Joel laughs again and reminds Art that asking
swers, “The audit by the home office in Belgium.” questions is what he does.
“OK, Joel says, “Why is that your biggest con-
Art replies, “I don’t know what standard they Discussions with Joel enabled Art to prioritize and
will be auditing to, and I don’t know how our SOPs develop a “To-Do List” as follows:
stack up against those of our new company. And • Pending corporate audit
I’m not sure of the intent of the audit. I don’t know • Contact the audit group and ask for them to
if this is a fact-finding mission or a witch hunt.” provide the audit schedule and scope.
Joel smiles, “Now we’re getting somewhere. Is • Conduct an internal review of the quality sys-
tem with an eye towards gaps in the current
there any particular reason why you feel this could system and the impact of not being the whole
be more than an initial audit, a benchmarking of company anymore. If it’s not in a procedure, it
their new acquisition? I mean I would certainly ex- probably isn’t happening.
pect a new owner to come in for an in-depth review • Review the SOP for customer audits and see
of the company that they just bought. There’s only what modifications and inclusions are needed
to allow it to address “Corporate Audits.”
so much one can discover during the due diligence • Supplier audit program
visits. And I think that this applies to the quality • Talk to Roger about scheduling strategies.
system, too, even though they probably had a better What was he trying to accomplish by having

63 Conducting Audits, Gap Assessments & Corrective Actions Volume II

Patrick Klemens and James Kaar

MedicHose’s two most important suppliers ities expect thorough and complete documentation,
scheduled for the same month? the quality organization must define these require-
• Understand the impact of the emergency au- ments for management. The site quality policy is a
dit of Central PolyCrys relative to the delayed
audits of the two top suppliers. key document in defining policies and procedures.
• Do the current auditors have the appropriate Global organizations add cultural complexity to
training for the PolyCrys audit? the workplace. The word “Team” can have many dif-
• Internal audit program ferent definitions and expectations across cultures.
• Review the internal audit SOP for applicabil- Philosophies are likely different, and interpersonal
ity to the current environment.
• Potential problems with the internal audit interactions may be as well.
program may be causing gaps in the informa- Prioritization of activities is key. Prioritization
tion provided to management regarding the will not be effective without carefully defining and
overall quality system. Understand the scope assessing the problems. Asking the right question,
of this issue. Have the “unwritten rules” of the like “What has changed to cause the problem?”,
former owners somehow contributed to the
gaps? helps determine if the cause of new problems is
• Additional administrative issues something recent or a newly discovered situation
• Determine if issues and concerns with the that has existed for a longer time.
supplier program, and the internal audit pro- When you cannot get everything done in the re-
gram, are spilling over into other areas of the quired timeframe, evaluate options (including alter-
quality system (e.g., manufacturing quality
assurance). ing the schedule) and whether you need to get help.
• Is there really a resource problem or some- Decide if there are resources to redeploy on this
thing more systemic? priority and accept that setting the strategic direc-
• Finish development of the new quality policy, tion for the company is not something that can be
assuring that it is aligned with the parent com- delegated.
pany’s quality policy. Facilitate training for the
entire MedicHose organization.
Originally published in Journal of GXP Compliance Volume
The quality function requires a careful balancing to
plan and execute with a primary focus on high-risk
activities. Effective quality organizations are proac-
tive, not reactive. “Fighting fires” detracts resources
from being proactive and attending to the appropri-
ate priorities.
Audits always involve the following key questions:
• Is there a documented procedure for what the
company is dosing?
• Do they follow their procedure?

Smaller or family-owned companies, sometimes

operate based on “tribal knowledge”–that’s “…the
way we do things,”—sometimes without the benefit
of a written procedure. Even stable and longstanding
groups, within a large corporation, may operate in
this same manner. Procedures must be well defined
to allow for consistent training and operational con-
tinuity. Additionally, well-defined procedures help a
company understand the staffing requirements for
their overall operations. Because regulatory author-

64 Conducting Audits, Gap Assessments & Corrective Actions Volume II

Patrick Klemens and James Kaar

About the Authors

Pat Klemens has a comprehensive background in quality manage-
ment and compliance spanning more than 30 years. His experience
ranges from developing complete quality systems for small biotech
firms to managing global quality and compliance programs for a
multi-national corporation. He is currently the director of Busi-
ness Excellence and Training at Abbott where he manages the R&D
deployment of Lean Six Sigma. He is president of Ascend, Inc., a
management-consulting group. He may be reached by e-mail at

Jim Kaar has worked in the quality sciences for more than 30 years.
He was employed by Baxter Healthcare for more than 25 years, be-
ginning in a small manufacturing facility and continuing into Qual-
ity Project Management. Jim left Baxter and formed Quality Focus, a
regulatory compliance and quality consultancy. Quality Focus pro-
vides quality system development, contract auditing as well as other
services to clients ranging from start-ups to Fortune 500 companies.
He may be contacted by e-mail at kaar54@comcast.net.

65 Conducting Audits, Gap Assessments & Corrective Actions Volume II

Patrick Klemens and James Kaar

Part Two: Quality is Audited

Patrick Klemens and James Kaar

Welcome to the second article in the series “The Business of Auditing and

Auditing the Business.” This article continues to explore the elements of the
quality audit (including the emotional components) as we see how an experi-
enced quality professional in a changing business manages an evolving audit
A quality audit is an important tool for any business to employ. When effec-
tively used as an internal audit, the business will gain greater understanding of
its compliance to applicable regulations and internal requirements. Further, the
business can critically evaluate the suitability of its procedures and the health of
the relationships within its functions. This scrutiny can come with a price. As
we see in the story herein, stresses and conflicts during an audit can develop.
Both the management team and the audit team share the responsibility to en-
sure that all audit activities remain professional and focused.
Similarly, conducting audits of external suppliers carries certain responsibili-
ties. Recognizing the fact that all audits are disruptive to the business can be
used by the savvy auditor to develop a more collaborative audit plan that can
serve both parties.
As an audit unfolds, frequently there is the need to make adjustments to the
audit plan. Personnel availability, development of findings, complexity of the
issues, and much more can cause an audit to ebb and flow. These changes, too,
add stress to the auditees. Establishing rapport and good communication are
key to a successful outcome for both parties.
We hope you find these articles informative and thought provoking. Reader
comments, questions, and suggestions are welcome. Please contact Patrick Kl-
emens at pkinfo@ameritech.net or James Kaar at kaar54@comcast.net.

Art. Vice President of Quality for MedicHose, a medical component company.
Art is responsible for the overall compliance of the Medic-Hose quality system.

Roger. Director of Supplier Quality Assurance at MedicHose.

Roger is responsible for the MedicHose supplier qual-
ity process, including the approval and monitoring program.

Michael. Manager of Laboratory Systems at Medic-Hose. His lab is responsible

for incoming materials analysis testing as well as final product testing and re-

66 Conducting Audits, Gap Assessments & Corrective Actions Volume II

Patrick Klemens and James Kaar

Joel. Quality assurance consultant with expertise “Certainly. When would you like to be here?” Art
and credentials including ASQ Certified Quality asked fretfully.
Auditor and a Black Belt in Lean Six Sigma. Joel is a “Perhaps next week, if that would be good for you,”
long-time personal friend of Art. Maxime responded promptly. “We could wait a bit if
necessary,” he added with emphasis.
Maxime Boukent. Corporate Vice President for “Well, yes,” Art began, “it would be better for us if
Quality at Crooneart, Inc. Maxime has global re- we had a bit more time. You see we’re in the middle of
sponsibility for quality and reports to the CEO. a few things here that need our attention at the mo-
THE COMPANIES “Ahh, I’m sure this must be so. Very well. Propose
MedicHose. Family-owned company located in south- an alternate time and direct an email to my attention
eastern Minnesota. MedicHose has been in business later today or tomorrow.”
for 40 years and has a good quality reputation. Art hung up the phone. “Here we go,” he thought.
His first call was to Roger, his director of supplier QA
Crooneart. Old-line European company head- then to Joel, the QA consultant he had hired to help
quartered in Brussels that recently purchased him through the process.
MedicHose. Changes resulting from the acquisition “Roger, I just got a call from Maxime at Crooneart.
have not yet started, but are sure to come. He wants to be here in the next couple of weeks.
What’s the latest on the failed incoming material
from Central PolyCrys?”
BACKGROUND Roger explained that the last two shipments had
In Part 1, we learned that MedicHose had been ac- met incoming inspection specs, but the previous two
quired by Crooneart, a diverse European healthcare had been rejected. Central PolyCrys was investigat-
firm. Art, the VP of Quality for MedicHose, was ing, but they didn’t have anything definitive yet. Art
dealing with a pending audit from Crooneart while reminded Roger that this investigation had to be
also managing internal problems and vendor qual- good for it would certainly be scrutinized by Maxime
ity issues. He asked his old friend, Joel, to come in and his team.
and help him sort things out before the new owners “All right, we’re on it. We’ve re-deployed folks from
began their in-depth audit. Art and Joel developed a other audits and are working closely with the supplier
“to-do” list of top priorities for Art to complete prior to sort this out,” Roger said. “Anything else?”
to the Crooneart audit team’s arrival. “Yes. Let’s go over your audits for the last six months
and the schedule for the next six. And we need to re-
THE STORY—PART TWO view your SOPs and training records for the depart-
Art’s desk phone rang at the same time his cell ment. Got any time mid-afternoon?” Art asked.
phone vibrated. He had just walked in the door and Roger exhaled. “Sure, lots of time. See you at 2 pm.”
was already being pulled in multiple directions. He Art then called Joel. He answered the phone on just
grabbed his cell phone. half of a ring. “Wow, that was fast!”
“Good Morning, Art here,” he said. Joel laughed, “If you’ve got me on speed dial, then
“Good Morning to you,” Art heard. “This is Max- I’ve got you on speed answer!”
ime Boukent.” The caller waited. “That’s good, since the team from Crooneart will
“Ah, yes,” Art replied. “I’ve been expecting your call be here soon.”
(but not necessarily on my cell phone, Art thought). “Hmm,” said Joel, “how are we doing on that to-do
How are you?” list of yours? Can we meet today or tomorrow?”
“I am fine, thank you. I would like to know if we The checklist! Art realized it had been a couple of
could arrange our visit to your facility.” weeks since he had last looked at it. He made a men-
Art noticed this was all business; he was not asked tal note to review it this morning. Then Art suggested
how he was doing. they meet in the afternoon, right after his meeting

67 Conducting Audits, Gap Assessments & Corrective Actions Volume II

Patrick Klemens and James Kaar

with Roger. “Ok, see you about 3:30,” said Joel, and Frequency and scope of vendor audits is not de-
he hung up. fined. There is no requirement to publish or approve
Art was still standing in his office with his coat on. an audit schedule. Audits are done; we just don’t have
He thought, “It’s time to really get going or we’ll never a “real” schedule.
survive the ‘integration process’.” He dug through a
file on his desk that had all of his audit preparation Art started taking notes. No schedule? How many
stuff in it until he found the to-do list buried in the audits do we do each year?
middle. The list read:
• Pending corporate audit No procedure specifically addresses deviations
• Supplier audit program or problem handling. There is no formal system for
• Internal audit program
• Additional administrative issues. documenting corrective actions; however, there is a
log of corrective actions maintained by Quality.
Art breathed a sigh of relief. His team was work-
ing on all the points, more or less, so maybe today No formal system equaled no system at all. Just
wasn’t going to be so bad after all. as it’s true in an audit that “if it isn’t written down,
Art was confident they were making a high qual- it didn’t happen,” Art wrote on his notepad, “if a
ity product despite some compliance gaps. “We procedure isn’t documented, there really isn’t a pro-
have some polishing to do,” he thought to himself. cedure.”
“Hmm, maybe a lot of polishing, but all-in-all, we’re
okay. We’ve been in this business a long time. When Internal audits have historically been sent to the
it comes to high standards, the family owners never company president; however, since the sale of the
wavered. Now it’s in our company DNA…” company was announced almost two months ago, no
He had a small team working on a review of their audit reports have been distributed to management.
quality system. When he checked his e-mail, he saw There is no procedure requiring management review.
their report was waiting for him in his inbox.
He double-clicked the report and began to read. Art wrote “Management Review!!” on his note-
pad. The auditors were talking about a requirement
The quality system at MedicHose was reviewed, for a manager to review the audit reports. A bigger
specifically the standard operating procedures. The question was how to conduct the annual manage-
following were discovered: ment review meeting now that they were part of
We don’t have a good system for training employ- Crooneart. Art noted this was one more item for the
ees. When we asked around informally, most people Merger Quality Plan.
said they were unaware of our operating procedures. Reading the audit report reminded Art that he
Training was an issue, but people on the floor knew still needed to finish the procedure for Quality Plans
their jobs.
and Planning. Joel had provided this tool, and it was
something that MedicHose clearly needed.
Art was pretty sure there weren’t any real issues
here. He stopped himself in mid-thought. This is
Quality planning is generally interpreted as the
exactly what Joel had been talking about. “Don’t ra-
strategic activity companies utilize as part of their
tionalize why an audit finding, or even an employee
management review process. While this may be
suggestion, is not a big deal (or even a little deal),”
seen as the primary application of the tool, there is
Joel had said, “Instead, ask yourself why this item
a second application as well. When a large, perhaps
meant enough to the employee to make a sugges-
systemic, gap is noted within the quality system, a
tion. Why did this item make it into the audit re-
quality plan can be a comprehensive map to how
port when other potential items did not?”
the organization will react. Quality planning is not
Art read on.
intended to take the place of corrective and preven-
tive action (CAPA), but is more of an adjunct to it.

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CAPAs have the requirement of timeliness (open to back down the hall to his office.
various interpretations) that makes them somewhat “I sure am glad to see you,” Art said as he shook
awkward for large projects. A quality plan can parse Joel’s hand. “Sit down and let me fill you in on ev-
out the larger project (into multiple CAPAs if desired) erything that’s been happening. Where do I start?”
and provide an auditable document that shows “yes, Art explained that their primary supplier was still
we know we have a problem here and this is what not sure why there had been two failed lots. At the
we’re doing about it.” As always, the key is to proce- same time, his internal team had highlighted some
duralize the quality planning process. big gaps in their SOPs. Moreover, it seemed that
Roger wasn’t in firm control of their supplier quality
When Roger walked into Art’s office in the after- program. And on top of all that, there was also the
noon, he was shocked. Normally, Art’s office had a fact that he must arrange with Maxime to have the
comfortably cluttered feel, but not this time. Books, audit team there sooner than he thought!
binders, notes, and printouts were everywhere. Joel said, ”Well, let’s set the date for the audit and
“Hi Art. You still want to meet? This place looks a communicate it to Maxime.” Art replied that he had
little chaotic.” a couple of days before he was expected to commu-
“Oh, hi Roger. Yeah, sure. Come on in. I’m just nicate the date.
trying to sort through a lot of things right now. Get- “I know,” said Joel “but you may as well do it soon-
ting ready, you know.” er rather than later. We talked before about the im-
Roger sat down and explained the status of the portance of perceptions. By putting forth a date you
investigation with Central PolyCrys, an important send a signal that you are prepared, and besides, it
component supplier. The problem centered on par- makes scheduling easier if you know the endpoint.”
ticle size distribution issues but it was not yet clear
what was really happening. Central PolyCrys said Perceptions are one of the intangibles of the audit
they had not made any changes to their manufac- process. While the best audits are based on facts (as
turing processes, their suppliers, their raw materi- well as the integrity of the process and individuals
als, or their shipping practices. They were looking involved), we cannot dismiss the role that perceptions
into possible environmental factors as the final sift- play in every audit. The function being audited is as-
ing process was done when it was more humid than sessed by the auditors beginning with the first contact
normal. with the auditee. As these perceptions accumulate,
“When will we have their final report?” Art asked. they can impact the audit’s success and overall out-
“We should have it here soon,” Roger replied. come. Auditees need to be aware of the signals they
Roger went on to explain that they’d gotten behind send and auditors need to honestly deal with their
on their audits in the last few months. He consid- perceptions to ensure that personal bias and possible
ered his audit schedule a plan, not a commitment, misinterpretations don’t influence their findings and
so he hoped to do a bit of shuffling things around management reports.
to get back on track. Plus, some of the upcoming
vendor audits on the list weren’t too important or And so began daily meetings, first with Art and
even “key” suppliers, so he thought he might drop Joel, then adding Roger and finally expanding
some of them. to many of the staff in most of the departments
“OK. Let’s make those changes. But this time, at MedicHose. Art set up several teams to update
email me your list and keep me posted if there are SOPs, conduct training, close investigations, and
any changes,” Art requested. finalize open action items. He maintained close
“Will do,” Roger said. “I’ll make sure of it myself,” contact with each team and pushed them to finalize
then he turned to the door to leave. Joel was stand- their tasks and actions. Art continually quoted Joel’s
ing in the doorway. favorite line, “The best question is the one that never
“Am I too soon?” Joel asked. “No,” Roger replied. gets asked.”
“Your timing is perfect.” Roger turned and strolled On the final evening before the start of the audit,

69 Conducting Audits, Gap Assessments & Corrective Actions Volume II

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Art and Joel met one last time. Joel complimented not a question.
Art on the work that the MedicHose team had ac- Art thought to suggest that they might be more
complished. Then he launched into a review of comfortable if they went to the conference room,
things to remember during the audit. got some coffee, and he could present his overview.
Joel began, “The audit report is just the third most He realized that even as the audit began, he was not
important piece of information that comes out of in control. He wished he had asked for the agenda to
the audit. The conversations that occur contain the be provided prior to the audit, or even created one
second most important piece. And the notes that himself, but it was too late now.
you take capture the most important information to
come out of the audit. Yes, the report is important, Having an audit schedule or agenda is beneficial to
because it is the document that demonstrates com- both the auditor and to the auditee. From the audi-
pliance.” tor’s standpoint, a schedule defines the path of the au-
“Nevertheless,” Joel continued, “you must take dit and prevents this kind of confusion. If the auditee
good notes. You will see your quality system with is expecting an opening meeting and then a tour, they
more clarity during the audit, and you will see many have probably arranged resources that way. If the tour
things that will not be evident to the auditor.” comes first then the auditee’s personnel are confused,
“Remember that these auditors are from Europe and the tour may not be as efficient or informative.
and they may have a different style than what you are For the auditee, a defined schedule helps to organize
used to,” Joel said. He continued with a little laugh, the time of the people who will participate so subject
“Every auditor is different. I remember one guy that matter experts are available when they are needed
was like a ping-pong ball fired out of a cannon...he and can work productively when they are not. The
ricocheted all over during the audit. But when the schedule also helps for planning lunches and arrival
audit was over, I was amazed at the number of docu- and departure times.
ments he had covered. Some auditors stick to their
agenda and are very methodical. They come in all The audit was scheduled for five days. The first
different styles. It’s our job to be ready for whoever three days were straightforward. Maxime and his
walks in the door.” team asked the questions while Art and his team
struggled to provide good answers. Then, each
THE AUDIT night, Art along with his staff and Joel would sit
On the morning of the audit’s first day, Art’s nervous- down and review the day’s events as well as the au-
ness had faded somewhat. He and the rest of the busi- ditor’s likely findings. They’d prepare for the next
ness had worked hard, and he felt they were as ready as day and verify that any requests from Maxime were
they could be for this or any other inspection. If only being promptly addressed. On the first evening, Art
the issue at Central PolyCrys had been resolved. casually mentioned that late in the day they pro-
Maxime Boukent walked into the MedicHose vided two documents that Maxime had requested
lobby with three senior auditors in tow. Most peo- earlier, but had apparently forgotten.
ple, when they met Maxime for the first time, were Joel exclaimed, “That’s great! Remember when
struck by the intensity of his eyes. It was hard to talk we talked about managing perceptions? By provid-
with him, as he seemed to look past you, through ing those documents you sent a clear signal that you
you…into you. wanted to work with the auditors, understand the
“Hello, I’m Art.” He and Maxime shook hands. value of the audit, and that you were not trying to
“It is a pleasure to meet you, Arthur. I am Dr. hide anything.”
Maxime Boukent. Allow me to present the team But during Wednesday night’s session, Michael, the
from Crooneart.” QA lab manager, shared some very bad news.
When he finished, he turned back to Art and said, “I hate to say this,” Michael began, “but we’ve had
“Right, I’d like to begin now with a brief tour.” It was another failed shipment from Central PolyCrys. And,
it might be that those last two shipments that we

70 Conducting Audits, Gap Assessments & Corrective Actions Volume II

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thought had passed are now in question.” got a download from the audit sections that were
Everyone in the room turned to Michael, and it got occurring while he was working with Maxime on
very quiet. He continued, “It seems after the first lots the Central PolyCris problem. Afterwards as he and
failed last month, the guys in the lab modified the Joel talked, Art seemed a little on edge.
test method. Then the next two shipments passed. “Talk to me,” Joel said. “What’s bothering you
But when Verena returned from maternity leave, she about today’s activities?”
used the old method to run the samples from the new “It’s some of the things that Roger mentioned,”
lots, and they failed. At that point, my lab guys de- Art replied. “When we were preparing for the audit,
cided to retest the two ‘passing’ lots using the method we talked about avoiding the term “Key Supplier”
as Verena ran it. Those failed, too. So it looks like because our supplier program doesn’t define such a
multiple shipments have been failing.” relationship. And yet, today Roger said they spent
Everyone sat still, stunned. “What the…have we quite a bit of time on the ‘Key Supplier program.’ I
been making bad product? Which test method is think I should have opened a quality plan around
right?” Art was fuming. our supplier program when we opened the quality
Michael tried to answer, “We haven’t had any fail- plan related to the acquisition. I just didn’t want to
ing product.” overuse the new tool you gave us and have multiple
Art exploded, “How would you know? Your lab is quality plans pending.”
out of control!” Joel thought a moment. “Let’s just wait and see
Joel inserted himself into the conversation. “Folks, what comes out at the wrap-up meeting tomorrow.
it seems like we need to gather our facts and make That will help us figure out our next steps, whatever
some important decisions. Until we know the situa- they are going to be.”
tion, we’re simply guessing. And guessing is not good By the end of the day on Friday, they were ready
anytime. It’s even worse with Maxime in town.” for a closing meeting.
The next morning, Art walked into the audit room Maxime began. “This will be brief. We have our
looking pretty bad. Maxime and the other auditors concerns, which we will share with you once we have
thought he had been drinking. Roger had never seen reviewed our findings with management. For now,
his boss look so bad, but knew that Art didn’t drink. I think we agree there is much to be done. While it
He was immediately concerned and wondered if the is not clear to me how the laboratory test came to
stress of the audit had hurt Art’s health. be modified, I am very much appreciative of your
“Good morning,” Art said quietly. “We have a prob- open and honest approach with my team and your
lem to talk through. I know we’re in an audit, but willingness to work through a very critical problem
we’re also one company now. And together I believe together. My report will also reflect this. We will
we have a situation to handle.” need to be extremely focused to resolve these matters.”
Art outlined what he had learned overnight while With that, Maxime thanked Art and his team for
Maxime and his team furiously scribbled their notes. their hospitality and closed the meeting.
When Art finished, Maxime sat for a moment, look- As he stood and pushed back the chair, he looked
ing hard and directly at Art. at Art. “I will be in contact with you, Arthur. Thank
“I see. This is unfortunate but you are correct that you.”
we are one company. My team is here to collect facts Art briefed Joel on the meeting. “It was over so
and understand your business. However, we are, as quick. Like a shot. Boom. Done.”
you say, colleagues. I propose the following. I will Joel replied, “It’s unfortunate that he didn’t even
work with Arthur and Michael to sort out the lab give you a hint about his report, but we have plenty to
issues, while the audit team continues to work with work on, just from your notes. And we need to find
Roger to complete the audit.” out from Roger what exactly happened during the
And so the next two days flew by. Both teams last two days of the audit. Maxime was certainly right
worked hard to sort out the issues and gather the about one thing. There is a lot to be done.”
facts. Thursday night the team met as usual, and Art “Yeah, I suppose so,” Art shrugged. “But I doubt

71 Conducting Audits, Gap Assessments & Corrective Actions Volume II

Patrick Klemens and James Kaar

that I’ll have much of a role.” report and ask themselves, “What is the actual
current status of our business and our compli-
The following items can be learned from our story: In Part 3 of The Story, we’ll have a chance to see
• A well-defined audit plan or schedule is of
significant value to both the auditor and the how Art and his team deal with the findings, con-
auditee. Failure to share the schedule in ad- clusions, and response to Maxime’s report to man-
vance complicates the audit, diminishes its ef- agement.
ficiency, and adds unnecessary stress to both
• There is significant value in the notes that one Originally published in Journal of GXP Compliance Volume
takes while being audited. There is no time 16 Number 1
that you will look as critically at your own
system as when you are sitting across the table
from an auditor.
• Managing the auditor’s perception of your About the Authors
organization can go a long way to audit suc-
cess. If it takes a long time to retrieve docu-
ments, or answers seem unnecessarily vague, Patrick Klemens is director of Business
the auditor may get the idea that you are not Excellence and Training at Abbott where he
cooperating fully with the audit. For example, manages the R&D deployment of Lean Six
one does not need to audit very long before Sigma. He is president of Ascend, Inc., a man-
encountering an auditee that seems to be agement-consulting group. He may be reached
managing the clock, trying to get through
the audit while producing as little actual in- by e-mail at pkinfo@ameritech.net.
formation as possible. It is incumbent on the
auditees to project an honest image of their James Kaar formed Quality Focus, a regula-
business; similarly, it is critical for the auditors tory compliance and quality consultancy that
to base their work on a fair interpretation of provides quality system development, contract
facts and to minimize the impact of percep-
tions and personal biases. auditing as well as other services to clients
• Auditees should capture their own “lessons ranging from start-up to Fortune 500 compa-
learned” as soon as the auditors are done. As nies. He may be contacted by e-mail at kaar54@
an auditee, you know your business far better comcast.net.
than the auditors will ever know during their
limited contact time. Use your knowledge
and judgment to develop a prioritized action
plan based on what you learned during the
audit as well as what you anticipate will be the
findings from the auditors.
• Every auditor has his own specialties and
preferences. Each has a unique style. Some are
methodical and logical, while others are more
random and chaotic. It’s important to estab-
lish a rapport and understanding early in the
• Quality planning can be a valuable tool for ad-
dressing significant gaps in a quality system.
It can provide a well-defined outline for how
an organization intends to manage the indi-
vidual issues while also allowing for broader
timelines for larger projects.
• The interpretation of the audit results is as im-
portant as the results themselves. By this we
suggest that auditees step back from the final

72 Conducting Audits, Gap Assessments & Corrective Actions Volume II

Patrick Klemens and James Kaar

Part Three: Quality Responds to the Audit

Patrick Klemens and James Kaar

Welcome to the third article in the series “The Business of Auditing and Auditing the

Business.” This article continues to explore the elements of the quality audit (includ-
ing the emotional components) as we see how an experienced quality professional in
a changing business manages an evolving audit situation.
A quality audit is an important tool for any business to employ. When effectively
used as an internal audit, the business will gain greater understanding of its compli-
ance to applicable regulations and internal requirements. Further, the business can
critically evaluate the suitability of its procedures and the health of the relationships
within its functions. This scrutiny can come with a price. As we see in the story
herein, stresses and conflicts during an audit can develop. Both the management
team and the audit team share the responsibility to ensure that all audit activities
remain professional and focused.
Similarly, conducting audits of external suppliers carries certain responsibilities.
Recognizing the fact that all audits are disruptive to the business can be used by the
savvy auditor to develop a more collaborative audit plan that can serve both parties.
While the actual audit is important, we cannot over-emphasize that the real value
is derived as the audit responses are developed, debated, and committed. It is after
the audit that both the auditors and the auditees can take a more holistic view of the
findings. Each team ought to ask if the responses result not only in specific action
items, but also in opportunities to increase the overall quality and compliance profile
of the firm.
We hope you find these articles informative and thought provoking. Reader com-
ments, questions, and suggestions are welcome. Please contact Patrick Klemens at
pkinfo@ameritech.net or James Kaar at kaar54@comcast.net.

Art. Vice President of Quality for MedicHose, a medical component company. Art is
responsible for the overall compliance of the Medic-Hose quality system.

Roger. Director of Supplier Quality Assurance at MedicHose. Roger is responsible

for the MedicHose supplier quality process, including the approval and monitoring

Michael. Manager of Laboratory Systems at Medic-Hose. His lab is responsible for

incoming materials analysis testing as well as final product testing and release.

Joel. Quality assurance consultant with expertise and credentials including ASQ
Certified Quality Auditor and a Black Belt in Lean Six Sigma. Joel is a long-time

73 Conducting Audits, Gap Assessments & Corrective Actions Volume II

Patrick Klemens and James Kaar

personal friend of Art. faxed to him, he had read every word, agonized over
individual phrases, and worried about the sum of
Maxime Boukent. Corporate Vice President for the parts (see Audit Report: Executive Summary).
Quality at Crooneart, Inc. Maxime has global re- It’s one thing to read the observations, but he wanted
sponsibility for quality and reports to the CEO. to know what the report was really telling him about
his operation. He knew that just responding to the
THE COMPANIES observations is never enough. He wanted—no, he
MedicHose. Family-owned company located in south- needed—to respond to the “central message” in the
eastern Minnesota. MedicHose has been in business Crooneart report, too.
for 40 years and has a good quality reputation.
Good audit reports are objective and “stick to the
Crooneart. Old-line European company headquar- facts.
” Citations are based on documented variations
tered in Brussels that recently purchased Medi- from cited standards. When written well, the obser-
cHose. Changes resulting from the acquisition have vation drives the auditee to respond specifically to the
not yet started, but are sure to come. deficiency. And yet, there is also a “central message”
or key take-away message that can be understood by
looking at the observations more holistically. While it
BACKGROUND is not always necessary to respond to the audit team
In Part One, we learned that Crooneart, a diverse with an over-arching response in addition to the in-
European healthcare firm, had acquired Medic- dividual observations, it can be beneficial to consider
Hose. Art, the VP of Quality for MedicHose, was the “central message” and to respond to the audit team
dealing with a pending audit from Crooneart while as well as to the employees within the firm.
also managing internal problems and vendor qual-
ity issues. He asked his old friend, Joel, to come in Art had prepared the final responses himself after
and help him sort things out before the new owners much discussion and debate with his staff. Despite
began their in-depth audit. Art and Joel developed a how he tried to “keep to the facts,” he knew there was
“to-do” list of top priorities for Art to complete prior one area that screamed for action. He faced a major
to the Crooneart audit team’s arrival. personnel decision. It wasn’t going to be pretty.
In Part Two, Maxime Boukent, Corporate VP for
Quality at Crooneart, arrived at MedicHose with There is both an art and science to the development
a full audit team to perform a top-down audit of of audit responses. A good response takes into ac-
the company’s quality system. The audit began well count what was written in the observation, what the
enough, but unexpected events in the Incoming auditors stated during the audit, and what employees
Inspection department caused Roger to turn his noted during the audit. Art knows that his response
attention away from the audit. This combination of must also be doable. Committing to a response that
events led to the exposure of several gaps in opera- cannot be achieved is unwise, if not disingenuous. Fi-
tions at MedicHose. nally, a good response is as concise as possible so that
the meaning and intent are clear.
Art read the audit report again to see if he’d missed Art thought back to the week of the audit. Every-
anything, any subtlety or nuance that would help thing seemed to be going fine until Michael, his lab
him understand what Maxime was really thinking. supervisor, reported the strange test results on the
In reading the report, Art could see that MedicHose incoming samples from Central PolyCrys. Because
had been cited for deficiencies in their internal audit of the urgency of the situation, Art shared the issue
process, CAPA and non-conformances, purchasing with the auditors. Then he and Michael, along with
controls and vendor management, lab controls, and Maxime from Crooneart, worked together to inves-
training. In the three weeks since the report was tigate the problem. Maxime essentially suspended

74 Conducting Audits, Gap Assessments & Corrective Actions Volume II

Patrick Klemens and James Kaar

his part of the audit and turned it over to his sup-

Figure 1.
port team to keep the audit going. Art then assigned
Roger to work with Maxime’s team. In hindsight,
that wasn’t such a good idea.
There were a number of items in the audit report
that were Roger’s responsibility. There were big
problems with Central PolyCrys, one of their critical
suppliers, that hadn’t been resolved. Ever since the
failed lots were identified, there seemed to be more
and more issues that had been discovered as part of
MedicHose’s investigation. Roger couldn’t say when
the last time Central PolyCrys had an on-site ven-
dor audit; he wasn’t aware they had changed some
of their specifications and didn’t know the vendor’s
test methods didn’t match MedicHose’s. MedicHose some 40 years ago, the first rule of qual-
Art pulled out his notebook again to see what it ity was always do the right thing. The second rule,
was that Roger and Michael first said about the fail- and nearly as important, was to never embarrass the
ing incoming receipts. owners. And I think Roger forgot these two rules.”
As Art looked at the initial data (Figure 1), he “Hmm, I see,” Joel replied. “How about I come
was troubled. Every sample tested with Method over and we walk through the response in detail.
PS-1 failed. Following the investigation of this situ- If we can finish by 5 PM, you’ll still make the mid-
ation, Art could see he had enough information to night deadline in Belgium.”
understand what happened. However, now it was
time to either submit his audit responses or ask for Responding to the audit report requires the auditee
an extension. He grabbed the phone and called Joel to address the various pieces of objective evidence that
for a second opinion. support the auditor’s findings. While preparing the
“Hi Joel,” Art began. “Are you available for a few ­response, it is also helpful to review one’s own notes
minutes?” from the audit, as a form of reality check, but also
“Sure...in fact I was just thinking it was time for to help the auditee define the size of the problem. Is
a call. The responses to Crooneart are due today, the finding based on the “auditor’s luck” of finding an
right?” isolated incident, or is there a systemic problem? The
“You’re right,” Art replied. “I’m just not sure I response to the finding needs to reflect the answer to
want to send them as they are. I believe we’ve ad- this pivotal question.
dressed the observations thoroughly. But I’m not
sure if we meet the spirit of the audit findings.” MAKING A PLAN
Joel pressed him, “What are you saying, Art?” When Joel arrived, the first thing he and Art did was
“Well, it’s one thing to answer the specifics. I think to review the MedicHose quality system, both the
I need to go deeper. I need to tell Maxime what I’m structure and the key personnel. Art took copious
going to do to make sure this doesn’t happen again.” notes.
“I agree. The corrective action is always easier, Then Joel read each audit observation and the Medi-
because it is a response. The preventive action is cHose response in a role-playing exercise in which he
a much tougher activity. What are you planning?” took the role of Maxime. Repeatedly, he challenged
Joel asked. Art to explain what he meant in his responses.
“That’s just it. I don’t have a plan, yet.” Art hesi- For example, Observation #4 stated that the pro-
tated, then continued, “But I feel we need to make cess for change management of test methods had
some personnel changes. These problems we had not been followed.
weren’t just procedural. Ever since the family started Art’s written response was: “MedicHose will un-

75 Conducting Audits, Gap Assessments & Corrective Actions Volume II

Patrick Klemens and James Kaar

audit report: Executive Summary

The purpose of the audit was to evaluate the new subsidiary’s level of compliance to the applicable sections
Purpose of relevant regulations and standards referenced below, requirements of commercial agreements, and the
relative alignment of the MedicHose and the Crooneart Quality Systems.

• ISO 9001:2000 Quality Management Systems

References • Appropriate sections 21 CFR 820–Quality System Regulation
• Internal policies and procedures

The relatively short time period since MedicHose became part of Crooneart assures that the two companies
are still working through some of the organizational opportunities created by the merger. However, we have
made it clear that the MedicHose Quality System will remain in force albeit with slight modifications.
Background MedicHose, Inc is located in two buildings (one is a warehouse) at 1285 PVC Valley Drive, containing ap-
proximately 37,000 sq. ft.
There are approximately 85 employees including temporary associates. The facility operates one shift, five
days per week.

Certification & The facility is ISO 9001:2000 certified. The last ISO assessment was June 3, 2011 and resulted in one minor
Registration nonconformance. The resulting corrective action plan was accepted by their notified body.
The facility is not FDA registered.

There were multiple major findings observed during the conduct of this audit.

There were major findings related to Purchasing Controls/Supplier Data, Change Control, Control of Non-
conforming Materials and Methods Validation and Training. Additionally, there are minor findings and open
CONCLUSION questions regarding internal audits as well as corrective and preventive actions (CAPA).

The findings will be communicated to MedicHose management upon acceptance of this report and its rec-
ommendations by Crooneart senior management. I will work directly with the site VP QA to assure complete
remediation of these significant issues.

• During the review of Purchasing Controls, we discussed the approved vendor list (Approx. 104 suppliers)
and how the suppliers are approved and monitored. There is a requirement in the quality manual for sup-
pliers to be monitored and the supplier data to be reported in the monthly operations review. MedicHose
could not provide either data summaries or reports based on such supplier data. Additionally, according to the supplier
quality manager, “Key Suppliers” (term not defined in procedures) require annual audits but audits are
infrequently performed and are usually replaced by a mailed questionnaire. MedicHose was unable to pro-
vide written evidence of any on-site audits performed in the last six months.
Audit Sum-
• While reviewing Nonconforming Material Controls (Sec. 8.3) and Corrective and Preventive Action (Sec.
8.5 and others) it became clear that there were multiple systems for both CAPA and nonconforming mate-
rials. While there is no requirement to have a single system for each of these, we discussed the difficulty
in maintaining the multiple systems and the increased likelihood of errors due to multiple requirements.
However, due to activities outside the normal audit, it became evident that there are significant gaps in the
supplier corrective action process, change control as it affects method validation, as well as the way non-
conforming materials are evaluated and controlled.

76 Conducting Audits, Gap Assessments & Corrective Actions Volume II

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dertake a thorough review of its document change sponse. They role-played “what-if ” scenarios and
management processes, including workflow, review, made changes as needed to the final responses. Art
and approval as well as related computerized sys- felt that he had a good package.
tems used to control documents. This initiative is “All in all, I think this audit has forced us to re-
scheduled to be completed within six (6) months of examine our practices. We’re better for it. But these
the acceptance of this corrective action.” responses don’t tell the whole story.”
Joel tapped the desk, then stared at Art as if he Joel suggested that Art draft his own cover memo
were Maxime Boukent himself. that would describe his intent and timing so that
“Are you saying this is merely a system issue?” he the individual responses had context.
asked. Art agreed. “It’s time I tell ‘the rest of the story.’
With laser-like precision, Art realized that Joel got I’ve also got to act on Roger and share the plan with
to the crux of the issue that had been bothering him. Maxime. Aside from being the lead auditor, he’s
“Yes and no. Our systems can use some tightening, also my boss now.”
but the real issue here was that people went around “Really?” Joel responded. “I guess we both sus-
our systems. No one ever should have been able to pected it. When did you find out?”
use that modified method, at least not without the “Maxime called me last night. He said that after
right approvals and training. I’ve come to the con- Crooneart management had taken the time to un-
clusion that Roger forced the method through the derstand his report, they felt it was time for him
system to help cover up the problem he was having to be ‘more directly responsible.’ I think those were
with Central PolyCrys.” his words. It may be that I only have a short time
“Whew...that’s pretty serious. Why do you think here, too. I can’t say.”
so?” asked Joel. “I see,” said Joel. “Then let’s get this cover memo
Art went on to explain the anomalies in the data, written and show Maxime what kind of leader you
the changes in the specifications, plus he told him are.”
about a conversation that supposedly occurred be-
tween Roger and Michael. THE RESPONSE
“It seems like Roger knew that he messed up Art’s cover memo began with the usual greetings
when he found the specifications and test method and courtesies. But he quickly got to his point. In
had changed at Central PolyCrys. He tried to hide order, he committed to personally:
it by forcing a test method change at MedicHose. A • Release Roger, find a replacement, and tem-
change to the test method that gave results that was porarily handle the duties himself
consistent with those of Central PolyCrys. • Re-vamp supplier audit program to improve
“What now?” Joel asked. vendor relationships (both a compliance need
and a competitive business need)
“Roger has got to go. And I need to explain why I • Establish a culture of compliance based on
shouldn’t go too,” Art answered. CGMP standards and Crooneart’s quality
Art is having a difficult time framing his response • Update MedicHose’s quality policies while
because he knows this was not a failure of the system; linking them into Crooneart’s, publish and
train all staff to the updated version
it was a failure of an individual. It makes it all the • Implement ethics training to help employees
more difficult because the individual is a direct re- understand the importance of personal deci-
port and Art feels responsible, as any good manager sions and actions and how they can impact
would. “Why did this individual perform this way?” the business
“How did the system get altered to allow this situation • Re-vamp the internal audit program to assure
that it is driving improvement within Medic-
to exist?” Art needs to dig deeper to understand the Hose. This will probably include some form
facts around the system failure. of recognition program or (at least) a much
greater visibility within the organization
Joel helped Art review each observation and re- • Provide transparent reporting of findings to

77 Conducting Audits, Gap Assessments & Corrective Actions Volume II

Patrick Klemens and James Kaar

employees and management as issues are sur- their responses in the morning. Besides, he already
faced and are resolved. knew what he must do.

The points described above are useful in this situ-

ation specifically because this was essentially an in-
Roger came to Art’s office at noon. He was unsure
ternal audit. Sharing philosophy and approach is not
what to make of the meeting invitation he received
typically done; however, because the acquired firm
earlier in the day. All it said was ‘General Topics’ so
has not previously been able to share its approach to
that probably wasn’t good.
quality and compliance, these points help frame the
“Hi Art. You wanted to see me?” Roger asked.
“story” that’s told to the new owner.
“Yes, come in. Have a seat. Just a second,” Art said.
Art fumbled with some papers on his desk. As he
Joel read the memo. He was silent for quite some
did, the MedicHose HR Manager, also entered the
time. He had known Art for quite a number of years
office, closed the door, and took a seat next to Roger.
and realized the high level of personal commitment
Art began. “Roger, we need to make some chang-
he was making in this letter to Maxime.
es here. With the acquisition by Crooneart, we’ll be
He looked up from the paper and simply asked,
re-structuring the Quality organization. The way
“Are you up to this?”
MedicHose has handled supplier quality in the past
Art didn’t look away or hesitate. “Absolutely. This
is changing. In the new structure, there is no posi-
is what’s needed. Someone has to do these things...
tion for you.
and I’d prefer it to be me.”
“I’ve asked HR to outline the separation package for
Joel replied “ I don’t disagree with anything that
you. You’ll find it’s fair. After you’ve had a chance to
you have said, I just wonder if there are enough
read it, you’ll need to sign the separation agreement.
hours in your week to do all of these yourself. At
You’ll see we have arranged for some placement help
the risk of making this sound like a sales pitch, I
for you, too.
could help you take on some of these tasks. You and
Right now though, I need you to get your personal
I view the world pretty much the same, and I can
items from your office. I’ll meet you at the main gate in
always keep you well informed of how we’re moving
10 minutes.”
forward. Don’t set yourself up to fail at this by trying
With that, Art stood. Roger looked surprised, but
to keep it all in your own hands.”
it was not his release that surprised him. He knew
his actions were suspect. What surprised him was
While responding to the audit report one needs to
the speed of the action. There was no point protest-
address the various findings and formulate appro-
ing. He turned and left to gather his things and the
priate corrective and preventive actions. It is of key
HR Manager followed.
importance not to “over commit” from the standpoint
of time or sustainability. Although it is necessary to
Author’s note: We debated the pros and cons of in-
provide responses that the auditor will find accept-
cluding the section above that describes the termina-
able, it is much more important for the responses to be
tion of Roger. We chose to include it because termina-
manageable for the organization. If not, the auditee
tions happen like this on a regular basis. Our jobs are
is just setting himself up for another noncompliant
based on our credibility. Furthermore, the essence of
our relationship with regulators also requires credibil-
ity. Once lost, there are consequences. Roger paid for
It was nearly midnight in Belgium when Max-
his credibility loss. It doesn’t matter what a person or
ime’s smartphone beeped. He saw he had received
a firm’s intentions are. The ‘intent to defraud’ or the
the responses to his audit from MedicHose. “Very
‘intent to be honest’ is irrelevant; after reliability and
well,” he thought. “They understand the meaning
trust are missing, there are always consequences.
of a deadline.” He smiled slightly as he shut off his
Likewise an auditor needs to be transparent with no
smartphone and turned out his light. He would read

78 Conducting Audits, Gap Assessments & Corrective Actions Volume II

Patrick Klemens and James Kaar

hidden agendas. If the auditor fails this fundamental duties. I understand your thinking and appreciate
requirement, the integrity of the audit is lost, and so is your commitment. However, you have many more
the auditor’s credibility. things to do, many more strategic things to do, than
run the Vendor Quality group. This is why I have
Art phoned Joel and told him that Roger had been asked Dr. Gaverbos to accompany me here. I have
released. appointed her to this role. While she is here, she
“How did he take it?” Joel asked. will report to you locally and to me globally. She has
“He was almost expressionless. But his lack of considerable experience within Crooneart handling
response suggested to me that he wasn’t surprised difficult situations and began her career in supplier
either. relations.”
“I thought you might also be interested to know “I am very much looking forward to the chal-
that I heard back from Maxime,” Art stated. lenge,” Sophie said. “It will be a real privilege work-
“That was fast,” Joel remarked. “What did he say?” ing here in the US with the MedicHose staff.”
“He said he would be here before the end of the
week,” Art muttered. It’s noteworthy that the critical difference between
strategies and tactics is often over looked. Too often,
CORPORATE REACTION management and employees are overwhelmed by the
When Maxime Boukent arrived again at Medi- day-to-day activities that demand their attention.
cHose, he was much more of a ‘known quantity’ Problem-solving is, of course, critically important;
than he had been the first time. And like the last however, a firm must balance today’s issues against
time, he was not alone. However, instead of leading tomorrow’s demand. In this case, Maxime is saying
a team of auditors, he had just one Crooneart col- that he needs Art to focus on strategy (i.e., focus on
league in tow. the future).
“Hello Arthur,” Maxime began. “I didn’t expect to
be back so soon. I suspect you didn’t expect me so Maxime was only in town two days. He thorough-
soon, either. Allow me to introduce my colleague, ly reviewed each of the responses to the audit and
Dr. Sophie Gaverbos.” signed off on all of them. He told Art that he was
Art said hello and they shook hands. pleased that they were off to such a fine start. And
“Shall we go to your office?” Maxime suggested. then he was gone, leaving Sophie Gaverbos behind.
Art tensed a little, was it going to happen this quick- Art sat back in his chair and glanced down at the
ly for him, too? audit report. The last line of the conclusion caught
Maxime closed the door to Art’s office. He opened his eye. He re-read it. “Guess I was worried for noth-
a folder and Art saw his cover memo and the re- ing,” he mused.
sponses. There were a lot of red ink notes and yellow On Friday evening, Joel called Art. As Art filled
highlights on the pages. him in on all that had happened in the last few days,
Maxime began. “Arthur, I have read your report. Joel exhaled loudly.
I am quite satisfied with the responses. I appreciate “Whew. The good news is you’ve kept your job. It’s
that you take them seriously and have gone beyond clear you’ve offered the right response. But I can see
the specifics to develop a more holistic approach to that Maxime is also hedging his bets, too. He may
the issues here at MedicHose. like what you’ve done so far, but now he’s got his
“Also, I very much agree with your decision to own person in your shop. Keep focused, my friend.
re-organize the Vendor Quality group. And I fully Keep your eye on the ball.”
support the termination of Roger as well.”
He hesitated briefly, then went on. “As you noted WHAT HAVE WE LEARNED?
in your cover memo, you were planning to find a The following items can be learned from this story:
replacement for Roger and temporarily handle his • The audited firm must decide if their audit

79 Conducting Audits, Gap Assessments & Corrective Actions Volume II

Patrick Klemens and James Kaar

responses address the actual findings and

then decide if they indicate a bigger problem.
Taken individually, the observations are just
a collection of findings. It’s incumbent on the
audited organization to assess whether the
findings indicate systemic problems.
• The response actions must be sustainable for
the organization; otherwise a potential (prob-
able) non-conformance is created. Typically,
firms are inclined to over-commit; use cau-
tion here.
• Your firm’s intentions and your own inten-
tions are irrelevant; fraud need not be in-
volved. If your personnel are unreliable or About the Authors
offer unreliable information, there are always
consequences. Patrick Klemens is director of Business Excel-
• It’s necessary to balance strategy and tactics lence and Training at Abbott where he manages
to assure the right balance between business the R&D deployment of Lean Six Sigma. He is
progress and just maintaining status quo.
• Demonstrated personal commitment can president of Ascend, Inc., a management-con-
bolster the confidence of the audited firm and sulting group. He may be reached by e-mail at
well as convince the auditors of the firm’s se- pkinfo@ameritech.net.
• Despite the all-too-common reference to “au- James Kaar formed Quality Focus, a regula-
ditor’s luck,” auditors don’t find every violative
condition during an audit. It’s the obligation tory compliance and quality consultancy that
of the auditee to review what the audit team provides quality system development, contract
found, as well as what they almost found. The auditing as well as other services to clients
auditee may find it useful to ask, “What five ranging from start-up to Fortune 500 compa-
things are we glad they didn’t ask us?” With nies. He may be contacted by e-mail at kaar54@
those answers in mind, a more comprehensive
and meaningful post-audit assessment can be comcast.net.
• Perhaps the real value of the audit is in the op-
portunity to take a step back from one’s day-
to-day work and look with a critical eye, like
an auditor might, at the systems, processes,
and people that make your company go. A
self-assessment, prompted by an audit, can be
the catalyst to real change and improvement.

In Part Four, we’ll see how Art and MedicHose go

about rebuilding a supplier quality system and how
he and Sophie manage to make improvements.

Originally published in Journal of GXP Compliance Volume

16 Number 2

80 Conducting Audits, Gap Assessments & Corrective Actions Volume II

Patrick Klemens and James Kaar

Part Four: The ‘Physics’ of Changing of a

Supplier Quality Program
Patrick Klemens and James Kaar

Welcome to the fourth article in the series “The Klemens at pkinfo@ameritech.net, James Kaar at
Business of Auditing and Auditing the Business.” kaar54@comcast.net, or Cale Rubenstein at cruben-
This article continues to explore the elements of the stein@advanstar.com.
quality audit (including the emotional components)
as we see how an experienced quality professional THE PEOPLE
in a changing business manages an evolving audit Art. Vice President of Quality for MedicHose, a med-
situation. ical component company. Art is responsible for the
In a regulated industry, a quality audit provides overall compliance of the Medic-Hose quality system.
valuable information regarding compliance to regu-
lations and internal requirements. Previously, we Roger. Director of Supplier Quality Assurance at
have discussed the stresses and conflicts that can MedicHose. Roger is responsible for the MedicHose
develop during an audit, even though the auditor supplier quality process, including the approval and
and the auditee both understand the value of the ac- monitoring program.
tivity. This is true even after the audit is completed,
the auditee sometimes feels relief that “…at least Michael. Manager of Laboratory Systems at Medic-
they didn’t find …”. However, those areas that the Hose. His lab is responsible for incoming materials
auditors didn’t find are no less important as targets analysis testing as well as final product testing and
for corrective action than the items in the auditor’s release.
final report.
Conducting internal audits or audits of external Joel. Quality assurance consultant with expertise
suppliers can create certain stresses. Recognizing and credentials including ASQ Certified Quality
the fact that all audits are disruptive to the business Auditor and a Black Belt in Lean Six Sigma. Joel is a
can help the auditor to develop a more collaborative long-time personal friend of Art.
environment for the audit. Establishing rapport and
good communication is key to a successful outcome Maxime Boukent. Corporate Vice President for
for both parties. Quality at Crooneart, Inc. Maxime has global re-
While the actual audit is important, we cannot sponsibility for quality and reports to the CEO.
over-emphasize that the real value is derived as the Sophie Gaverbos. Director of Supplier QA at Medi-
audit responses are developed, debated, and com- cHose. Sophie is on assignment to MedicHose in
mitted. It is after the audit that both the auditors the US from headquarters in Belgium. She reports
and the auditees can take a more holistic view of the locally to Art and globally to Maxime. She has been
findings. In this installment, we see how the audi- tasked with assuring that the MedicHose supplier
tees wrestle with the changes initiated by the audit, quality program is compliant, efficient, and sustain-
how they reconcile their philosophies, and develop able.
an approach to enhance their overall quality system.
We hope you find these articles informative and
thought provoking. Reader comments, questions, THE COMPANIES
and suggestions are welcome. Please contact Patrick MedicHose. Family-owned company located in

81 Conducting Audits, Gap Assessments & Corrective Actions Volume II

Patrick Klemens and James Kaar

southeastern Minnesota. MedicHose has been in satisfaction in dealing with the Crooneart corporate
business for 40 years and has a good quality reputa- audit and managing Roger out of MedicHose, he
tion. knew the sprint was over. Now the marathon was
about to begin.
Crooneart. Old-line European company headquar- Sophie’s rental car was already in the parking lot
tered in Brussels that recently purchased Medi- when Art parked his own car. As he walked past her
cHose. Changes resulting from the acquisition have car, he felt the hood. It was cool to the touch. “Wow,
not yet started, but are sure to come. she’s been here for a while already this morning…”
In the two weeks since Sophie had been at Medi-
BACKGROUND cHose, Art had come to appreciate her abilities.
In Part One, we learned that Crooneart, a diverse While they didn’t always agree, it was good to have
European healthcare firm, had acquired Medic- someone that he could really work along side that
Hose. Art, the VP of Quality for MedicHose, was shared his commitment to continuous improve-
dealing with a pending audit from Crooneart while ment. She was an impressive addition to his staff.
also managing internal problems and vendor qual- Sophie appeared in his office as he plugged in his
ity issues. He asked his old friend, Joel, to come in laptop.
and help him sort things out before the new owners “Good morning,” she said. While her English was
began their in-depth audit. Art and Joel developed a perfect, he could hear an accent that made the words
“to-do” list of top priorities for Art to complete prior sound more like “Gouda Morgan.” He smiled.
to the Crooneart audit team’s arrival. “Good morning, Sophie. How was your week-
In Part Two, Maxime Boukent, Corporate VP for end?”
Quality at Crooneart, arrived at MedicHose with “It was good,” she replied. “I went to a concert in
a full audit team to perform a top-down audit of Minneapolis. It was quite good. In fact, it helped me
the company’s quality system. The audit began well think about a lot of things here we need to do.”
enough, but unexpected events in the Incoming “Oh? You went to a concert and were thinking
Inspection department caused Roger to turn his about work?” Art quizzed.
attention away from the audit. This combination of “Well, yes. Is that odd for an American to do?” she
events led to the exposure of several gaps in opera- asked.
tions at MedicHose. “No, not at all. It’s just that everyone needs some
In Part Three, we saw the value in developing au- downtime. What did you think about?” he asked.
dit responses that go beyond the specific observa- “Well. We have got so much to do. I’d like to talk
tions. Art struggled with his responses to the audit, with you about a new approach.”
knowing that one of his team, Roger, was a poor “Hmm. Okay…what are you thinking?” Art asked
performer and was suspected of failing an integrity cautiously.
challenge. His responses were accepted. However, “Well, it’s quite simple really. I think we start over.
he finds his newest challenge is not just process- Let’s build this supplier quality program from the
related, but people-related, too. In this installment, ground up. The entire existing infrastructure is just
we’ll see how Art and Sophie work to build a mod- slowing us down. We will spend more time trying to
ern supplier quality program. determine how to edit and align existing documents
than if we just wrote new ones. I’d like to suggest
we de-commission all current documents and re-
THE STORY: PART FOUR place them with a totally new and modern system. I
Art remembered the phrase as he drove into the think it could be done faster and better this way. We
parking lot on Monday. “It doesn’t matter the sport, break from the past; we focus on the future; and it’s
there is no off-season anymore.” Art certainly felt sustainable. Plus, it will be easier for the employees.
like he’d been going full-speed ever since Crooneart They only need to learn the new system, rather than
bought MedicHose last year. Although he felt some

82 Conducting Audits, Gap Assessments & Corrective Actions Volume II

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trying to learn about a hundred adjustments we potential energy. If you’re a drag on the situation,
made to the old system. What do you think?” she her energy might not overcome your resistance.
asked earnestly. One can calculate the threshold value that must
“Whew, that’s a lot to think about. Start all over? I be achieved for potential energy to become kinetic
don’t know. You have to admit, our current system energy” He paused before continuing. “I think it’s a
works. If it weren’t for Roger…” fine idea, but I caution that neither of you should be
Sophie interrupted. “Roger was part of the prob- convinced it’s significantly easier. I just think it’s the
lem, I agree. But Roger was not the system and the right thing to do.”
system was not capable of detecting that we had a Joel asked Art to refresh his memory about So-
problem. If we took a more risk-based approach, we phie’s background. “Didn’t she already implement a
could make this work for us.” supplier quality system at Crooneart?” he asked.
Art intoned, “Risk-based approach? You know “You know, you’re right. Maxime mentioned that,”
how that sounds to me? It sounds like a buzzword. Art replied. “Maybe I am the ‘drag’ that needs to be
‘Risk-based’ means you don‘t have the resources to overcome.”
do it right so you hide behind a buzzword,” he said Throughout the next week, Art thought about
flatly. both conversations. He decided it was time to show
Sophie replied that she felt pretty strongly that real progress. Art looked back to the quality plan
any repair would take longer than was practical. Art that had been written and approved as part of their
said, “OK, you can try and convince me, but it will commitment to the Crooneart audit. He saw that he
be mostly an uphill push.” was not in a position to make “little tweaks and ad-
“I see. Thank you for your time.” She rose to leave. justments.” The program was broken and it needed
“Perhaps later…I have a meeting to attend.” to be replaced.
Art thought about their conversation. He decided
that he had over-reacted and realized he was some- It is difficult to define the right path when faced
what defensive. Sophie was right, at least in part. The with a decision about modifying a system or trying to
current system “may work” and “could be fixed” but create something totally new. Regardless of the choice,
at what cost? And he didn’t really know all its weak change takes energy, either the energy to create a new
points, just the ones he had tripped over recently. system or the energy to overcome the inertia of the old
He thought it could be patched, but maybe she was system. It is not even as simple as the choice between
right: just start all over again. those two options. If one opts for the new system, the
He rubbed his face. There really is no off-season. people, who have lived with the old system, will bring
He decided to call Joel for another opinion. their ‘histories’ into the task of developing the new
Over lunch, Art filled Joel in on the conversation one. This makes the energy calculations that much
with Sophie. As Joel listened, he thought back to his more difficult. There is no easy answer; it will always
first high school physics class. When Art finished, be a question of what is right for your organization.
he waited for Joel to respond.
“Well, I believe you find yourself in a situation MAKING THE DECISION
that’s all too common these days. There is so much At his staff meeting the following week, Art’s team
to be done; it’s hard to know precisely where to start. assessed the current situation. They had more than
I’m sure you remember the old adage, ‘If you have 100 suppliers located around the world. Only 10%
time to do it over, you must have had time to do it had had an onsite visit in the previous 36 months.
right the first time.’ In fact, it had been more than five years since most
“What Sophie is suggesting is for you to do it of the suppliers had been audited. Over half of the
right this time. She’s willing to provide the kinetic suppliers had responded to a questionnaire in the
energy to get you there, but you need to provide last 24 months indicating no major changes in fa-
the momentum to see it through. Right now she is cilities, process, or management.

83 Conducting Audits, Gap Assessments & Corrective Actions Volume II

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MedicHose had about 10 different procedures • Our procedures need to define how and how
that directly detailed their supplier quality plan with much control we expect to exercise over pur-
another 35 or so that were indirectly connected as chased items and services.
• We need to have records of acceptable suppliers,
references, or as part of a separate system, like pur- contractors, and consultants.
chasing or material control. • We need to establish and maintain data regard-
To Sophie’s surprise, Art asked her to share her ing our requirements for each supplier, which
idea that they start from scratch with the rest of the needs to include an agreement that the supplier
team. At first, Sophie was frustrated with him that will notify us if they do anything that might
change what we buy from them.
he had not allowed her to prepare for this meeting.
But then she realized that she already knew what
When she finished her outline, she turned and
she wanted to say. She had done this before. She
realized most everyone was furiously taking notes.
cleared her throat and began.
Sophie said, “Actually I will forward the slides about
“Arthur and I have been discussing how to best
these requirements to all of you.” Art was smiling.
modernize our supplier quality management sys-
Sophie looked at him with a puzzled look. She
tem. As you know, in our quality plan we’ve com-
thought to herself, “He is a strange American.”
mitted to Crooneart that we will be making signifi-
Sophie told the team, “These really are the basic
cant improvements. We’ve debated whether we will
requirements for a supplier system. We can make it
make adaptations to our current system or develop a
more complex, but that just makes the system more
completely new system from the ground up,” Sophie
difficult to manage.”
announced. Art noticed that she did not indicate
Art’s staff did not discuss the issue for very long.
who was advocating for which proposal.
The realization came to each of them that their most
“There are pros and cons to both. It may be much
practical course was to allow Sophie to lead the
faster to revise our current system. We can revise
implementation of a new system and not to spend
our procedures and retrain employees rather sim-
much time in debate. However, the question regard-
ply. However, we will merely have the old system
ing how long this might take to implement was on
with new elements,” she explained.
everyone’s mind. Sophie suggested that MedicHose
“We can also start over. We would decommission
could accelerate their project if they would adopt
our current MedicHose procedures and implement
many of the Crooneart policies and procedures and
a new system, based on Crooneart’s global policies,
make only minimal changes, based on local require-
which factor in various aspects of risk including
ments, for the remainder. It was agreed.
business risk, compliance risk, and quality risk. This
Art adjourned the meeting and asked Sophie if she
would allow more flexibility to target certain sup-
could remain for a few minutes. When the others
pliers. Of course, this will require new thinking and
had gone, he began, “That was pretty impressive.”
perhaps more time to implement.”
“Arthur, I am confused. I thought you were op-
Sophie asked for a moment to start up her com-
posed to such a course of action,” Sophie replied.
puter. “I happen to have a presentation in my com-
“I was. I mean…I wasn’t sure what was right. We
puter that details these requirements.” She explained
all talk about the value of having a ‘new set of eyes’
to the group that there are some basic requirements
to look at our processes, and here I was with just
that a modern supplier management system must
that situation, and I was resisting what those eyes
have. On the screen she displayed:
• We will need procedures to ensure that all were telling me. But as I thought about it—and real-
purchased products and services, including ized you’ve done this before—it seemed to make so
contractors and consultants, meet specified re- much sense. I knew that you would have no trouble
quirements including quality requirements. in front of the staff. I think I was right.”
• We must evaluate and select potential suppli- “Yes, I think you were right; however, perhaps
ers, contractors, and consultants on their ability
to meet all our specified requirements, and we next time you could give me a little time to prepare.”
need to document our evaluation. She smiled and peered over her glasses.

84 Conducting Audits, Gap Assessments & Corrective Actions Volume II

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Art replied, “You’re right. I should have done that. to justify. More time and money to work with your
But your performance in front of the staff only con- suppliers decreases the chances of having a significant
firms that your approach is correct.” problem. If you don’t have problems, then manage-
“Thank you, Arthur. But please tell me. Are all ment sometimes doesn’t understand the need to be at
Americans like you?” the supplier. It can be a difficult balancing act, and it
can result in “budget time” decisions that make going
IMPLEMENTING THE NEW PROGRAM out to the suppliers that much more difficult. This di-
Over the next weeks, Sophie and the team worked chotomy is enhanced as the distance (i.e., “travel ex-
to implement the Crooneart supplier management penses”) increases. Auditing a supplier that is across
system. the street is easy; the one that is on the other side of
They refreshed the approved supplier list, which the globe is obviously harder.
at first appeared to be a monumental task, but actu-
ally only took a few weeks. They had assembled the Art commented, “Sophie, I’m really impressed
new files for the supplier documentation and were how quickly the new system is falling into place.
now in the process of collecting the various pieces I never would have believed that replacing the old
of information from the former system used by SQA system could be done easily.”
MedicHose. Sophie replied, “Well, it was much harder the first
Sophie had hired a contractor to go through the time. When we implemented this program at the
email archives on Roger’s computer. The job was to home office, it was a much larger task. I was strug-
find anything related to suppliers, delete it if it was gling to understand why some of the companies
‘trivial correspondence,’ place it in the supplier’s file were even on the approved supplier list!”
if it was related to contracts or product quality, and Art said he understood. “Sometimes a supplier is
challenge everything else. In that way, the volumes added to the list for a good reason, but then it just
of communications were reduced to the significant sits there.”
few for each supplier, and the most recent docu- Sophie laughed, “Seriously, we even had sev-
ments were in front. eral local restaurants on the list, like pizza places. It
As they started to evaluate the supplier files, it was based on an accounting department SOP that
became obvious why to most recent documents would not allow them to pay anyone not on the ap-
needed to be in front. One could just scan through proved supplier list. Consequently, the ASL became
the files and get a fairly good picture of how recently huge, and compliance with certain supplier quality
each supplier had been contacted or reviewed or requirements became impossible.”
audited. It wasn’t a pretty picture. Roger had come Art thought about this but he didn’t quite see the
to rely more and more on surveys completed by connection. Sophie continued, “If your SOP re-
the suppliers themselves. And when Art looked at quirement is to visit five percent of your suppliers,
the Supplier Questionnaire, it didn’t make him feel and you have 81 suppliers, the math is relatively easy
much better. Although it covered the general topics, and so is the execution. But if you have 481 suppli-
it certainly didn’t go to much depth. ers, you need to visit two suppliers a month. Not so
When Art looked at the standard operating pro- easy any more.”
cedures that were the basis of the old MedicHose
program, he could see how they had been changed As with any portion of the quality system, the first
over time to require less actual surveillance at the requirement for a supplier quality assurance program
supplier’s site. He didn’t remember this being the is that it must be sustainable. Is there a right number
direction they had agreed on, but…. (a “magic” number) of audits that need to be conduct-
ed each year? If there is such a number, we haven’t
The situation at MedicHose is not that rare. Fund- found it yet, but the key is to find a meaningful way
ing for an effective supplier program can be difficult to “assess the supplier base.” The application of the

85 Conducting Audits, Gap Assessments & Corrective Actions Volume II

Patrick Klemens and James Kaar

Pareto principal works for most situations. It may ement is accomplished in a way that is not unlike
be that 20% of your suppliers represent 80% of your decommissioning equipment or even a facility.
purchases, or perhaps 20% of your suppliers represent The actual regulatory requirements for a supplier
80% of your non-conformances. On the other hand, quality management system are relatively simple.
maybe there are two suppliers that are absolutely But supplier quality systems tend to become more
crucial to your business, so you need to see them at complicated over time. One reason for this is that
least once a year. Your supplier program should be the SQA system is often audited, which allows for
designed to focus on the significant few, however you many auditors to evaluate and offer opinions (i.e.,
define it. findings) about the system. Part of maintaining this
system is ensuring that if changes are made, they are
Art thought for a moment. He turned to Sophie made to enhance the system, not because it is easier
and said, “Honestly, when Maxime brought you to to change than to push back on an audit finding.
MedicHose, I wasn’t sure if you were here because Supplier quality management, like any other por-
he wanted ‘his person’ here to keep an eye on things tion of the quality system, must be maintained to be
or he wanted ‘his person’ here because he had confi- effective. The removal of non-active suppliers from
dence in your abilities to get things done.” the approved suppliers list is as important as making
Sophie looked surprised. “I never knew you had sure new suppliers get added. Similarly, as the busi-
those thoughts.” ness changes and new products are developed, the
Art quickly replied, “I’m not implying you had critical suppliers may change, so the system should
bad intentions—only that I didn’t really know what change to reflect this.
Maxime’s intentions were. But you are really good at Unique perspectives are identified when new
this. Did you see how the staff followed your every people or consultants examine your quality system.
word? This is a good start.” New points of view and experience can challenge
Sophie relaxed. “I hadn’t thought you might be old practices and suggest new solutions. Even if no
concerned about my presence. Maxime is not like changes are made, the discussion regarding the ad-
that. His decisions are always based on what’s right equacy of the current system is healthy and neces-
for the company. It’s never personal with him.” sary.
“Good to know,” Art replied. “I hope you under- Over time, the elements of what we know to con-
stand that I’ve been here a long time and this is the stitute a modern supplier quality management pro-
most change we’ve ever experienced. It’s been hard gram have changed. With the rapid globalization of
going through the acquisition and all. I’m glad you supply chains in addition to the expansion of global
are here and this is done.” regulatory requirements, it is critical to ensure sup-
“It’s not done.” Sophie said. “In fact, it’s just started. pliers, irrespective of geography, are able to meet
We haven’t yet talked about how we want to imple- our specifications. To meet this expectation requires
ment a supplier evaluation program and supplier a focused and flexible quality system based on pa-
corrective actions.” tient risk and product performance imperatives.
Art sighed and thought, “Yup, there is no off- The global supply chain brings additional travel
season anymore.” costs when one needs to get to the supplier’s site. A
global supply chain also brings hidden quality costs
LESSONS LEARNED to an organization that has had the luxury of nearby
Regulated quality systems are based upon version- suppliers for many years.
controlled policies and procedures. It’s common In the part five, we’ll see if the newly implemented
practice to make adaptations to procedures and supplier management system is effective.
update the revision to reflect the change. However,
there are times when a ‘revisionist method’ is not
appropriate. Decommissioning a quality system el- Originally published in Journal of GXP Compliance Volume
16 Number 3

86 Conducting Audits, Gap Assessments & Corrective Actions Volume II

Patrick Klemens and James Kaar

About the Authors

Patrick Klemens is director of Business Excel-
lence and Training at ­Abbott where he manages
the R&D deployment of Lean Six Sigma. He is
president of Ascend, Inc., a management-con-
sulting group. He may be reached by e-mail at

James Kaar formed Quality Focus, a regula-

tory compliance and quality consultancy that
provides quality system development, contract
auditing as well as other services to clients
ranging from start-up to Fortune 500 compa-
nies. He may be contacted by e-mail at kaar54@

87 Conducting Audits, Gap Assessments & Corrective Actions Volume II

Patrick Klemens and James Kaar

The Business of Auditing and Auditing

the Business: Part V
Patrick Klemens and James Kaar

Welcome to the fifth article in the series “The thought-provoking. Reader comments, questions
Business of Auditing and Auditing the Business.” and suggestions are welcome. Please contact Patrick
This article continues to explore the elements of the Klemens , James Kaar or the IVT Network editorial
quality audit as we see how an experienced qual- staff.
ity professional in a changing business manages an
evolving quality organization. THE PEOPLE
A quality audit is an important tool for any busi- Art: Vice President of Quality for MedicHose, a med-
ness to employ. When effectively used as an internal ical component company. Art is responsible for the
audit, the business will gain greater understanding overall compliance of the MedicHose quality system.
of its compliance to applicable regulations and in-
ternal requirements. Further, the business can criti- Dave Gwinnett:  Quality systems auditor.
cally evaluate the suitability of its procedures and
the health of the relationships within its functions. Joel:  Quality assurance consultant with ex-
This scrutiny can come with a price. As we see in the pertise and credentials including American
story below, stresses and conflicts during an audit Society of Quality (ASQ), Certified Quality
can develop. Both the management team and the Auditor, and a Black Belt in Lean Six Sigma.
audit team share the responsibility to ensure that all Joel is a long-time personal friend of Art.
audit activities remain professional and focused.
Similarly, auditors carry certain responsibilities Maxime Boukent:  Corporate Vice President for
too. Recognizing the fact that all audits are disrup- Quality at Crooneart, Inc. Maxime has global re-
tive to the business, the savvy auditor will develop sponsibility for quality and reports to the CEO.
a more collaborative audit plan that will serve both
parties. The auditors must be observant and open Sophie Gaverbos:  Director of Supplier QA at
to the interpretations provided by the auditees. The MedicHose. Sophie is on assignment to MedicHose
auditors’ findings need to be fully vetted, and final in the US from headquarters in Belgium. She re-
observations must be understood for the system ports locally to Art and globally to Maxime. She has
failure that they represent as well as for the oppor- been tasked with assuring that the MedicHose sup-
tunity for future improvement. plier quality  program is compliant, efficient, and
After the findings have been assessed and agreed, sustainable.
the quality manager must employ both technical
and organizational skills in order to be able to devel-
op meaningful audit responses. Further, the quality THE COMPANIES
manager must ensure both comprehensive and ef- MedicHose. was a family-owned company located
fective corrective and preventative actions (CAPA) in southeastern Minnesota. MedicHose has been in
for the audit to have lasting value. It’s an accepted business for 40 years and has a good quality repu-
fact that the best audits have no value if meaningful tation. Crooneart, an old-line European company
action is not taken. headquartered in Brussels, Belgium, has recently
We hope you find these articles informative and purchased MedicHose. Changes resulting from the

88 Conducting Audits, Gap Assessments & Corrective Actions Volume II

Patrick Klemens and James Kaar

acquisition have begun in earnest. Some of his staff thought that it was too much too
fast. Others argued that they were merely catching-
In previous installments, we learned that Crooneart, up to industry standards. At a recent staff meeting,
a diverse European healthcare firm had acquired Art asked his old friend and sometime consultant,
MedicHose. Art, the VP of Quality for MedicHose, Joel, to come in and share his perspective on the
had been dealing with integration issues from the industry as he’s seen from inside other firms.
Crooneart acquisition while also managing internal Art explained that, in an earlier staff meeting,
problems and vendor quality issues. He asked his old they had tried to map out their supplier process as it
friend and consultant, Joel, to come in and help him existed, but there were some fairly significant gaps.
sort things out before the new owners began their in- Art went on, “Originally we thought we would just
depth audit. The audit by Crooneart went reasonably scrap our old system and move forward using the
well, but exposed a significant gap in the quality audit Crooneart process. As the gaps were identified, each
program at MedicHose, especially related to supplier issue was assigned to someone on the team. But as
approval. To help accelerate the remedies, Crooneart we evaluated things, filling the gap sometimes was
had installed a woman from the home office in Bel- just a matter of updating an existing procedure, and
gium to assist MedicHose in their upgrade to a more some required additional procedures to be drafted.
modern and effective quality audit program. In the end, we’re ending up with a hybrid of the two
systems. Sophie took on the bulk of the activities,
THE STORY–PART 5 and she and I shared the overarching task of making
MedicHose (the recently purchased subsidiary of sure that everything fit together in a system.” 
the European medical manufacturer Crooneart) has Joel thanked Art for the update and then launched
been a company in turmoil.  into a “50,000 foot overview” as he described the
For many months, the staff has juggled competing current state of the industry. US Food and Drug Ad-
priorities. Lately though, things were starting to feel ministration, for one, had recognized the problems
just slightly more normal. The acquisition and the with many supplier control or management systems. 
tedious integration had been completed, including “The agency has been putting additional empha-
the tough corporate audit (not to mention the per- sis on these systems during investigations. While
sonnel changes). Of course, there were the “regular” supplier controls are not specifically spelled out as
crises and emergencies that all businesses handle, part of the QSIT, the  Quality Systems Inspection
but at least the immediate need to address findings Technique, they are easily included in the section
from theCrooneart audit had passed. Now they on ‘Production and Process Controls’.”  
were faced with trying to implement everything that Dave Gwinnett (a quality systems auditor at Med-
Crooneart wanted. Art, the VP of Quality at Medi- icHose for more than five years) interjected that
cHose, felt he had survived the ordeal fairly well. In FDA had never audited them, and that their noti-
fact, he felt as though they had actually come out fied body hadn’t had any problems with the system
better for the effort. as it was. Joel continued, “Well, that may be true,
Art looked at the all the new three-ring binders on but the fact is that this company has problems with
his shelf. His quality system had been reviewed top its supplier management program and that has been
to bottom, and numerous changes were made. In recently demonstrated very clearly.”
recent weeks, they had created a whole new docu- Joel told the staff that it is not unusual to have
ment section to describe the new supplier qual- audit findings regarding the supplier management
ity management program. He was pleased with the program, and he reminded them that it was better
program (despite his initial reservations). Sophie, to find it during a corporate audit than to have a
the “Belgian import” from Crooneart’s home office, regulator find it. Joel said, “Now we have the time to
had really done a fine job of defining the require- fix the problems with our system, without the pres-
ments and building the new system.  sures of ‘timely response’ or other challenges.”   

89 Conducting Audits, Gap Assessments & Corrective Actions Volume II

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Joel finished his discussion by explaining that processes as well as how information flows in their
although FDA is only one of the regulatory agen- system.
cies in the world, it is by far the most rigorous, and
the other agencies frequently follow the lead of the
“The FDA has stated that if there is a problem with
supplier controls, it is only a matter of time before
your notified body focuses in the same area.”
Sophie interrupted Joel’s commentary. “Excuse
me,” she began, “but I don’t think the FDA is the
most rigorous regulator any longer. Certainly, they
have helped to set a very high standard; however, I
think it’s fair to say that the European Union [EU]
has imposed newer and more rigorous requirements
in recent years.”
Joel smiled and acknowledged her point, “So-
phie, I suspect you are right. As we sit here in
Minnesota, I sometimes forget that other regu-
lators impact our business. The EU has shown
itself in recent years to be a leader when it comes
to device and pharmaceutical regulations.
Thanks for reminding us of this new reality.”

Supplier controls are usually defined as having an

Approved Supplier List (ASL), having procedures for
evaluating and approving suppliers (questionnaires,
audits, etc.), and on-going management and surveil-
lance of the approved suppliers (surveys and audits).
Another aspect of supplier management comes from
the requirement for contract review. This is an impor-
tant activity regardless of which side of the contract
one is on. In the FDA regulated industries, a key sec- The group mapped their recent changes to the
tion of the contract is the requirement for notification system and realized their changes were significant.
of change. It is imperative to know if a supplier is Had they gone too far, too fast?  Did these changes
changing some aspect of a purchased component that to their audit program fit well with the rest of their
is part of a registered device or pharmaceutical. The quality system?  Further, they tried to evaluate if
seller is equally interested in having a well-defined the changes they had made to their audit program
contract as it spells out his requirements for the buyer. would have prevented the issues they had experi-
Specifications and the requirements for the business enced with Central PolyCrys (see previous articles
relationship are of equal importance to both the buyer in this series).
and the seller.
There are several difficulties in making changes to a
Joel then suggested that they “whiteboard” section of the quality system. First and foremost, after
MedicHose’s newly updated quality audit program. the changes are implemented, they must be integrated
Whiteboarding, Joel explained, was a technique to ensure the quality system remains cohesive. Often
to help personnel visualize both the actual work overlooked is the risk that the new or changed proce-

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dures do not connect into the existing system. There is Sophie stood and pointed to several flip charts on
a risk that contradictions can occur that lead to non- the wall. “I’d like to walk you through our current
compliance. process for supplier evaluation and then discuss
Another challenge is remembering that no function- what improvements are necessary.” Everyone could
ing quality system is all good or bad (even in the face see that she had already “whiteboarded” several
of a recent difficult audit). The key remains to fix the ideas on the wall for their benefit.
issues that have been recognized and keep the parts of Dave Gwinnett interrupted the meeting as he
the system that are working. Today, this is thought of had done earlier when Joel was there. He parroted
as continuous improvement. Sophie and said, “Improvements are necessary!” 
Dave’s sarcasm was obvious to everyone in the
Joel and Art’s staff sat back in their chairs and room, except Sophie. As a non-native speaker, she
looked at the whiteboard depicting their updated did not recognize that his tone of voice was mock-
supplier quality system. Art spoke first. ing her.
“I’d like to thank everyone for your efforts to help Art watched in distress as Dave continued. “Yes,
make this new system a reality. I’m confident that our current supplier evaluation system is rather,
we would not have had the incoming material fail- hmm, should I say, elementary?”  He turned to
ures with Central PolyCrys if we were operating like laugh with the room, but no one else was laughing.
this.” Most of the team just looked at their papers. Sophie
Joel explained that there was little sense in making continued brightly, “Yes, one might say it is elemen-
wholesale changes, or even any changes at all, if the tary, but I was thinking it is too hard to manage. I
resulting system was essentially the same as before. have a plan to modernize and simplify it as well as
He said the value of the whiteboarding exercise was bring it into line with the standards at Crooneart.”
to allow for their procedures and processes to be “That’s what we need,” Dave exclaimed. “We
examined, but, even so, there had been some grum- must work even harder to achieve the standards of
bling. It was tedious!  And they still weren’t done. Crooneart!”
Later in the day, as Art sat in his office, he thought Sophie continued, “Exactly, and when our systems
about all that had been done. They had made sig- are aligned, we will be able to evaluate all the sup-
nificant progress in their audit program and had pliers, globally, and then trim the supplier base so
perhaps resolved a weakness in the system. He was that the best suppliers get more business from us.”
feeling better as his assistant knocked on his door Sophie seemed excited that her proposals were be-
and brought him back to reality.  ing so well received.
“Art, your staff is gathering in the conference
room for Sophie’s Scorecard meeting. Are you join- Supplier evaluation is a requirement of the regula-
ing them?” she asked. tions, but the interpretation of the requirement rests
“Oh…yes. Thanks for the reminder. I just need to with the organization. Performance data could be as
grab these binders and a cup of coffee, and I’ll be simple as a spreadsheet or as complex as one wishes.
off.” The question becomes one of sustainability. A  risk
Though much had been done towards improving management model that allows the company to spend
their audit program, his team was now focused on their time where it is the most valuable to the orga-
establishing their supplier evaluation program and nization drives the best supplier activities. They have
their supplier corrective action system. Art could not allowed the procedure to dictate that all suppliers
feel the tension in the room as he sat down. He are created equal.
didn’t know what was wrong, but clearly something
had happened since the staff met with Joel. At that point, Art told Dave he had heard enough
He turned to Sophie and asked her to start the sarcasm. Sophie looked surprised. 
meeting. “Dave, if you would change your tone, I’d be will-

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ing to listen to your concerns,” Art said slowly and were limited to systems within MedicHose). Dave
directly. agreed before he realized that this audit would be
Dave exhaled loudly. “I’m sorry, but I’ve been led by Sophie, and then assessed by the quality staff
working here a long time. We’ve all known there as part of their ongoing effectiveness checks.
were things we ought to do better. Anyone remem- As Dave left the room with his new assignment,
ber Roger? He worked his butt off for this place he felt like he had just dodged one bullet (but maybe
and he’s not even here anymore.” Dave turned and another one was heading his way). Now he was ex-
looked at Art. “Who’s next? It seems only one per- pected to work directly with Sophie. Perhaps he’d
son here gets your attention anymore.” finally have a chance to have his say in the direction
Art bristled. He wanted to explode but held his of things around here. 
tongue.  Art paused before he returned to his office and
“Folks, this meeting is over. We’ll continue our thought, That went better than it might have. Every
supplier evaluation meeting later in the week. You once in a while I get lucky around here...
all can go now. Dave, would you stay, please?”
Although this column is intended to address audits
As described in a previous installment, organiza- and auditing, it is almost impossible to cover any
tions must overcome the very real human tendencies business topic without discussing people. Good audi-
to resist change (positive or negative) and “fear any- tors are developed over time and take a great deal of
thing new.” This inertia is another one of the difficul- pride in being able to do what they do. The situation
ties that must be overcome to truly change the system at MedicHose was already stressful due to the acquisi-
or prevent it from slipping back to the “old ways.” tion. Then there were significant findings about the
supplier quality assurance (SQA) function, a manger
After the room had cleared, Art closed the door was impacted, and the list goes on. It is probably no
and turned back to Dave. Art began, “Dave, I know surprise that Dave is showing some signs of burnout.
you have been here for a while, and you have made It may be more of a surprise that there aren’t more
it abundantly clear that you don’t agree with the di- “Daves” in the department. Art showed great self-con-
rection the company has taken on this and other ef- trol and good management judgement when he tried
forts. So why don’t you tell me what you think needs to sort through what was driving Dave’s outburst. He
to be done?”   succeeded at bringing Dave back into the change pro-
It turned into a fairly long one-on-one. Art rec- cess just when it appeared that Dave had “quit.”
ognized that he was agreeing with some things
Dave was saying, although Art didn’t share those As they prepared for the first audit under the
thoughts with Dave. While Dave may have some new procedures, it became increasingly evident
valuable insights, Art couldn’t have Dave become that the changes would be obvious to the supplier.
a disruptive element in the group. Plus, he wasn’t Sophie and Dave agreed that the best path would
sure if this might be a part of Sophie’s monthly re- be to increase the length of the opening meeting
port back to her bosses at Crooneart. Art wanted and discuss the changes with Central PolyCrys. Art
to empower Dave, but only so long as he felt Dave was not willing to use that strategy, “We’re not go-
was behaving properly. He decided to ask Dave one ing to air our problems to Central PolyCrys. They
more question, “Dave, do you want to be part of the are our supplier, it’s none of their business.”
problem or part of the solution?” Sophie started to push back, but Dave beat her to
Dave agreed that he wanted to help. He suggested it. “We’ve been talking for weeks about a new system
he could be a better team player if he really had a that allows us to partner with the suppliers. Maybe
voice. Art responded that he could appreciate that. I’m just confused. What is the working definition of
Art then suggested that Dave be a guest auditor on this ‘partnering’?”
an upcoming supplier visit (usually Dave’s audits Art took a deep breath and started to launch into

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further resistance, but then thought better of it. to follow audit trails as they develop. As with so many
“Okay,” he said, “help me understand how telling considerations in the audit function, there is not one
our suppliers about our new procedures will make right answer. If one is auditing a gamma steriliza-
us better partners. Don’t forget that these changes tion facility, the checklist should be very detailed and
are being driven by the audit findings.”  indexed to the various standards while auditing a
Dave continued his analysis. “Well, first of all, I contract packager may require a different approach.
don’t think it is necessary to get into all the details of
the audit, but I do think they are going to recognize The next meeting to continue designing the sup-
the changes as we implement them. If we don’t tell plier evaluation card was a little less tense. Dave
them, we run the risk of seeming like we think they seemed much more willing to listen to Sophie’s
won’t notice or, even worse, making it seem like ideas, and likewise her slides showed more of a mix-
these changes are no big deal.” ing of the Crooneart and MedicHose procedures.
Sophie added, “If we want the suppliers to be re- Art saw that the program would provide rebates,
sponsive to our needs, they need to see what’s in it a percentage of the dollar volume of the preceding
for them. That’s where the supplier evaluation pro- year, to the suppliers based on their performance
cess comes in. Also, we need them to be responsive against several criteria. “I don’t recall discussing the
to the supplier corrective action program.” rebates prior to this,” he said. “Are we sure that this
Art thought for a few moments. “Okay, I’m not is the way we want to go?”  
sure this is the right direction, but I will give it some Sophie replied that it was consistent with the
thought. Now, can we look at the questionnaire that Crooneart program, and “if we want to use the pro-
we will be using for the audit?” gram to drive the consolidation of our supplier base,
Sophie reminded Art of the changes they had this is a good way to do it.”
made to the audit procedure and forms. “Remember The next week, Sophie and Dave conducted the
when we decided that part of our problem may have audit at to Central PolyCrys. Art asked Joel to stop
been caused by a focus on filling in the boxes rather by for a chat. 
than really investigating the various systems?” “Hi Art,” Joel said as he burst into Art’s office. “It
Art remembered. The Crooneart process had an looks like the old place but feels very different.”
attachment to the audit procedure that was a very “Hey Joel, good to see you,” Art replied. “It’s hard
brief summary of the regulatory requirements. At- to see all the changes when you’re in the middle of
tached to it were several pages, broken up into large them. I hope you’re right. We’ve worked hard on a
sections, with section titles that linked to the re- lot of fronts since that meeting months ago when
quirements. Sophie and Art had modified it slightly, Maxime was here.”
so the requirements were broken out by US, EU, and “And I’d say that everyone here gets a lot of credit.
”rest of the world” designations. He knew there was Too often I see companies that know things are
value in the form, and he was hoping it would drive wrong but can’t, or won’t, assign the resources need-
better audits, but there was something a little more ed to fix it. They can make all kinds of excuses, like
comforting about a checklist. ‘no one ever cited us,’ ‘where is that requirement in
the regs,’ or even ‘let’s fix it next year when we have
How one prepares for an audit is as important as more time.’ You guys took on the challenge now in-
how the audit is executed. There are many schools of stead of later.”
thought. One school is that well-defined audit check- At the end of the week, Art read the draft report
lists assure that audits are consistent. While this is emailed by Sophie and Dave from Central PolyCrys.
indeed true, there are those who worry that checklists There certainly was a lot to digest. The good news
don’t drive good audits, just fill-in-the-form behavior. was that Central PolyCrys was very supportive of
Another school of thought is that one wants a very the new supplier management procedures. He was
loose agenda to allow the auditor maximum freedom also very happy to see that Dave Gwinnett’s contri-

93 Conducting Audits, Gap Assessments & Corrective Actions Volume II

Patrick Klemens and James Kaar

butions to the audit had paid off. who considers the so-called “law of unintend-
The bad news, on the other hand, was a bigger ed consequences” when making changes.
concern. He set up a meeting with Sophie and Dave • Experience has shown that changes to sys-
tems and procedures have impact beyond the
to discuss their opinions about those sections. quality system. As quality system changes are
“So you’re telling me that the change in test meth- made, the impact on employees must also be
ods at PolyCrys was notified to us?” Art asked. considered.
Dave nodded. “They showed us a copy of the no- • An effective risk management system will al-
tification form that was sent. But it gets worse. They low the firm to prioritize and address areas
of need with the right resources. A risk man-
track response time for these notifications, and we agement system will prevent deployment of
appear to be a problem customer based on our very resources and efforts to low-risk issues.
poor response time.” • Partnering with suppliers means not only a
Art proceeded to state the obvious, “So we make redesign of the quality system, but a redesign
a bunch of changes to our supplier management of the firm’s overall attitude towards its part-
ners. This includes senior management, legal,
system, and the part that needs better management purchasing, and others in addition to quality.
is us, the customer!?” • As with all aspects of the quality program, a
Dave continued, “We went back through the new flexible and responsive approach to audits
files, but we couldn’t find the notification form from (versus a checklist approach) will yield the
them. I’m sure we wouldn’t have thrown something most information and allow the firm to focus
on what’s important.
like that away as we were working on the files. But
something about this situation rang a bell for me,
and it appears that there was an internal audit find- Originally published in Journal of GXP Compliance Volume
ing about poor response time to suppliers a couple 17 Number 1
of years ago.”
Art pushed back in his chair. “Well, that’s amaz-
ing. It takes a problem in our lab that seems to point
to the supplier that actually turns out to be us.”
About the Authors
“I guess the good news is that since we hadn’t
Patrick Klemens is director of Business
know it at the time, we upgraded our supplier qual-
Excellence and Training at Abbott where he
ity system and now have the proof it works.”
manages the R&D deployment of Lean Six
As Art walked back to his office he realized there
Sigma. He is president of Ascend, Inc., a man-
was one more area that needed his attention. It
agement-consulting group. He may be reached
had been in the background since the quality sys-
by e-mail at pkinfo@ameritech.net.
tem project had started. It had even surfaced in his
thoughts a few times, but the Central PolyCrys Au-
James Kaar formed Quality Focus, a regula-
dit had driven the point home. What was going on
tory compliance and quality consultancy that
with his internal audit program?
provides quality system development, contract
auditing as well as other services to clients
LESSONS LEARNED ranging from start-up to Fortune 500 compa-
• Firms that use proven techniques like white- nies. He may be contacted by e-mail at kaar54@
boarding, process mapping, value-added
mapping, etc. gain valuable insights into their comcast.net.
operations and also allow everyone engaged
in the process to have a similar understanding
of the issues.
• As changes are made to a quality system, firms
must ensure that contradictory requirements
are not established that lead to non-compli-
ance. Further, it is the wise quality manager

94 Conducting Audits, Gap Assessments & Corrective Actions Volume II

Patrick Klemens and James Kaar

The Business of Auditing and Auditing

the Business: Part VI
Patrick Klemens and James Kaar

Welcome to the sixth article in the series The Busi- mative and thought-provoking. Reader comments,
ness of Auditing and Auditing the Business. This ar- questions, and suggestions are welcome. Please
ticle continues to explore the elements of the quality contact  Patrick Klemens,  James Kaar, or the  IVT
audit as seen by an experienced quality professional Editorial Staff.
in a changing business as he manages an evolving
quality organization. THE PEOPLE
A quality audit is an important tool for any busi- Art: Vice President of Quality for MedicHose, a med-
ness to employ. When effectively used as an internal ical component company. Art is responsible for the
audit, the business will gain greater understanding overall compliance of the MedicHose quality system.
of its compliance to applicable regulations and in-
ternal requirements. Further, the business can criti- Dave Gwinnett: Quality systems auditor.
cally evaluate the suitability of its procedures and
the health of the relationships within its functions. Joel:  Quality assurance consultant with expertise
This scrutiny can come with a price. As seen in the and credentials including American Society of
story below, stresses and conflicts during an audit Quality (ASQ), Certified Quality Auditor, and a
can develop. Both the management team and the Black Belt in Lean Six Sigma. Joel is a long-time
audit team share the responsibility to ensure that all personal friend of Art.
audit activities remain professional and focused.
Similarly, auditors carry certain responsibilities Maxime Boukent:  Corporate Vice President for
too. Recognizing the fact that all audits are disrup- Quality at Crooneart, Inc. Maxime has global re-
tive to the business, the savvy auditor will develop sponsibility for quality and reports to the CEO.
a more collaborative audit plan that will serve both
parties. The auditors must be observant and open Sophie Gaverbos: Director of Supplier QA at Medi-
to the interpretations provided by the auditees. The cHose. Sophie is on assignment to MedicHose in
auditors’ findings need to be fully vetted, and final the US from headquarters in Belgium. She reports
observations must be understood for the system locally to Art and globally to Maxime. She has been
failure that they represent as well as for the oppor- tasked with assuring that the MedicHose supplier
tunity for future improvement. quality program is compliant, efficient, and sustain-
After the findings have been assessed and agreed, able.
the quality manager must employ both techni-
cal and organizational skills in order to be able to
develop meaningful audit responses. Further, the THE COMPANIES
quality manager must ensure both comprehensive MedicHose was a family-owned company located
and effective corrective and preventative actions for in southeastern Minnesota. MedicHose has been
the audit to have lasting value. It’s an accepted fact in business for 40 years and has had a good qual-
that the best audits have no value if meaningful ac- ity reputation. Crooneart, an old-line European
tion is not taken. company headquartered in Brussels, Belgium, has
The authors hope these articles are found infor- recently purchased MedicHose. Changes resulting

95 Conducting Audits, Gap Assessments & Corrective Actions Volume II

Patrick Klemens and James Kaar

from the acquisition have begun in earnest. that Sophie join them.
As they made themselves comfortable in the small
In previous installments, we learned that Medi- conference room at the local library, Art asked Joel
cHose had been acquired by Crooneart, a diverse the reason for the odd location. Joel answered that it
European healthcare firm. Art, the VP of Quality for is surprising how often someone overhears a small
MedicHose, had been dealing with integration issues piece of a conversation, or even a piece of a sentence,
from the Crooneart acquisition while also manag- and then fills in the rest of the details themselves.
ing internal problems and vendor quality issues. He “If someone sees the three of us talking, they will
asked his old friend and consultant, Joel, to come in immediately think we’re going to change something
and help him sort things out before the new owners else. Your teams have worked very hard to get to this
began their in-depth audit. The audit by Crooneart point and I don’t want to create undo anxiety.”
went reasonably well but exposed a significant gap in Then, Joel asked Art why he thought there were
the quality audit program at MedicHose, especially problems with the internal audits. Art launched into
related to supplier approval. To help accelerate the his analysis. 
remedies, Crooneart had installed a woman from the “The system obviously wasn’t working because the
home office in Belgium to assist MedicHose in their notification from Central Polycrys had been sent to
upgrade to a more modern and effective quality audit MedicHose but hadn’t worked its way through our
program. system.”  Worse yet, he continued, “there had been
an internal audit item in the past, but it wasn’t fixed!
THE STORY—PART SIX There were other problems that we have seen as
For many months, MedicHose (the not-so-recently we’ve worked through the various system changes
purchased subsidiary of the European medical and then there were the audit findings from recent
manufacturer Crooneart) has been trying to ad- customer and the Crooneart audits. The internal
dress the merger of its quality system with that of system is obviously broken.”
Crooneart. Art is the VP of Quality at MedicHose. Joel listened attentively, and, when Art was fin-
He felt the company had turned a corner (actually ished, he said he would like to ask a few questions.
several corners), and it was in much a much better “How many managers are auditors, either trained or
position than he had originally envisioned it would not?” 
be by now. Art replied that the managers were too busy with
Nonetheless, there had been problems along the day-to-day operations of the company to per-
the way. It took time, but the new supplier quality form audits. Then Joel responded, “But didn’t you
management program was in place and had dem- tell me that the audits were essential to managing
onstrated that there were issues with their own the company’s compliance to the regulations?” Art
internal audit program. Art had always understood admitted that he felt that was true, “…but there are
the inter-relationships of the various elements of the no requirements for managers to be auditors.”
quality system and the need for and value of a good
internal audit system. That was why this latest news The internal audit program is a requirement of
had hit him so hard. He was sure that this was one the regulations, just like supplier management, but
area that was covered. implementing the requirement is more delicate. The
As he had done so often since the acquisition, Art organization recognizes the need to have auditors,
called his old friend and consultant, Joel, to come but it may send signals about the importance of these
in and talk about internal audits and how to make audits simply by who is chosen to perform them. Per-
them stronger. Joel suggested they meet somewhere formance of internal audits is key to the organization
off-site for their first detailed review. Joel reasoned getting a true picture of how their system is working.
“…so their discussions remain private until they
were ready.” Joel also surprised Art by suggesting Joel asked who was responsible for auditing the

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internal audit system. Art replied that it was part of that fails then you want a customer audit or a cor-
his responsibilities. “And you are sure that you are porate audit to find it. The last thing you want is for
performing a thorough audit of the process?” Joel the problem to be defined during an FDA [US Food
asked. Art bristled, even though he knew where and Drug Administration] investigation or an audit
Joel was going. “So if I’m the auditor and there is a by your notified body.”
problem, it’s my fault?” Art asked. Joel laughed, “I “Are you sure that everyone understands that
guess you have me there. We know that auditing is they should be working with the internal auditors
a sampling activity, and yet we are surprised when to really give a complete review to their areas?” Joel
something is missed.” continued. “As I said earlier, auditing is a sampling
Joel continued, “Is the internal audit program in- activity, so you are never going to ’see everything’
cluded in your management review?”   during an audit. Are the area managers happy when
Art said, “Of course it is, it is a requirement of the the internal audit fails to ‘discover’ the problem they
ISO [International Organization for Standardiza- know they have?”
tion] standard.”   “Why don’t we all think about this for a couple of
Then Joel asked a peculiar question, “How many days, and then we can meet again. For homework
slides are prepared for the financial portion of the I’d like you two to think about ways to re-invigorate,
management meeting?”   re-vamp, renew, or whatever the right word is,
Art said he wasn’t sure, maybe 15 or so.  your internal audit program. I’ll put together some
Joel said “…and how many detail the internal au- thoughts about what I’ve seen that works and what
dits?”   doesn’t. Art, why don’t you call me and let me know
Art looked uncomfortable, but even more inter- when you two are ready for the next meeting?”
esting was Sophie’s reaction. At the next meeting, Joel started the conversation
“Surely you don’t expect the company to place the by indicating just how difficult the task in front of
same emphasis on the audits that it places on its bot- them actually was going to be. “I went back through
tom line?” she said.  some old audits, of other firms,that I had performed
Joel stated that he understood very well that there and, frankly, I can’t find much to add to this conver-
are different priorities for everyone at the manage- sation. My benchmarking suggests that really good
ment review, but is the company sending everyone internal audit programs are very rare.”
the right message? Art exhaled slowly. “Do you mean there isn’t a
good way to do this, or do you mean it is really dif-
Compliance, or the lack of it, costs time, money, and ficult?”
other types of resources. A bad regulatory investiga- Joel said, “It is really difficult. The best programs
tion (audit) can stop a company from gaining ap- are risk-based and concentrate on the specific key
proval of a new product, impacting their time to mar- risks identified by management. They don’t neces-
ket, sales, and profits from the new product. Fixing sarily cover every aspect of the quality system each
items from an audit that didn’t go well can distract year, but they spend more time concentrating on
employees from what they should really be undertak- the areas that need the most work.”  
ing. Saving money on compliance activities is usually Art interrupted and told Joel that his procedure
a temporary savings at best. required that the entire quality system be reviewed
each year. Joel continued, “The regulations just
Joel persisted. “How much has been spent, so far, require you to have an internal audit process and
developing your new quality systems? Believe me schedule. The company gets to decide the sched-
when I say there is a direct impact on the bottom line ule and what method it uses to decide. Maybe you
when a company is out of compliance. I think we’ve should think about changing your procedure.”
talked about this before, but you want the problems
to be discovered by your internal audit program. If Well-defined audit checklists assure that audits are

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consistent. A samplechecklist can also be used to help works.

provide objective evidence to an outside auditor that • Finding the same non-conformance that was
the program satisfies the regulatory requirements. As cited in the previous audit (obviously it’s not
an issue or it would have been fixed).
mentioned in an earlier article, there is the concern • Auditee responds by making it a personal
that checklists don’t drive good audits but rather a matter, such as “There goes my raise for this
“filling-in-the-form” type of behavior. Likewise, an year!” or “Man, I’m going to catch it for this
internal audit schedule that assures that the entire one.”
quality system is reviewed may be easier to defend, • The auditor believes that management just
wants an audit performed but doesn’t re-
but it may cause a company to spend scarce resources ally care about the outcome (“This can be an
on areas that don’t require any attention. outcome of over-emphasizing the regulation
aspect of internal audit rather than the value
Joel continued, “Last week we talked about wheth- to the company,” Joel added).
er your managers could serve as auditors. But if you
look at internal audit programs in general, I think Joel switched subjects, “And these are just some
you would find that we usually have “lower-level” aspects that may affect an auditor. There is an en-
people auditing “higher-level” people. So, one of the tirely different list of perceptions that can affect the
key features of an effective audit program has to be audit itself. Internal audit programs tend to get wa-
transparent operations that value the audit without tered down or de-emphasized either by procedure
regard to company hierarchy or the positions of the or by budget.”
individuals involved.” Sophie stopped Joel to ask if there was a right way
Art said that he felt that his program absolutely or a better structure for an internal audit program.
satisfied this basic tenant. “Our auditors operate in- Joel reminded her that their homework assignment
dependently without any fear of reprisal. If they find had been to come up with just that answer. Then he
a problem, they are supposed to write it up.” asked Sophie what she and Art had talked about. 
She outlined that they had discussed that some
It has been previously noted that the intent of this type of “benefits sharing” from the savings that un-
column is to discuss audits and auditing, and the dif- derlie the audit program. Because non-conformanc-
ficulty in covering any business topic without discuss- es cost money, fixing the system saves the money of
ing people. Good internal auditors also take time to a non- compliant system at the time of a regulatory
become good at and comfortable with their duties. It audit. 
is even harder if the audit function is a “portion” of Joel suggested that there may be unintended con-
their job. Part of the time, they work with and rely on sequences if you were to do something like that.
the people they are then asked to audit. Most internal “What if it becomes a ‘bounty system’ that incentiv-
auditors understand that they walk a fine line and izes findings and/or creates bad feelings?”  
take a great deal of pride in being able to do what they Art added that maybe the system could include
do. The company needs to support these folks, perhaps rewards for the people that fix the problems too. Joel
more than any other employee, and yet too often this thought there were ways that this concept could end
support is pro forma. up being problematic as well. 
Joel explained. “I’ve seen an incentive system
Joel replied, “I hope you’re right, but your auditors work, but usually not for long. Too often, it creates
may find themselves in situations that create pres- its own problems. Most times, it works well for the
sures, implied, imagined or actual, and that the job first audit when everyone is onboard and trying to
doesn’t really warrant. Some of these pressures may find the best things to make the incentives work.
be social, or job-related, or from sources outside the But on the second, third, and subsequent audits, I
workplace. I’ve made a list of some potential sources have seen where people start to ‘game the system’ or
of stress for an auditor, but I’m sure there are more.” conspire to get the rewards without necessarily find-
• Auditing a department where a family friend ing the most important issues. My recommendation

98 Conducting Audits, Gap Assessments & Corrective Actions Volume II

Patrick Klemens and James Kaar

is to avoid an incentive-based audit system.” LESSONS LEARNED:

Sophie and Art thought about it briefly and agreed.  • An effective risk management system will al-
Art said, “The last thing we want to do is for people low the firm to prioritize and address areas of
to create issues in order to be rewarded during an need with the right resources. This also applies
audit. While I think our folks have great integrity, to the internal audit program. Though some-
what harder to manage, a risk management-
there must be a better way.” based internal audit system will focus limited
Joel smiled. “There is! When you can demonstrate resources in the appropriate areas and prevent
that audit performance, after several cycles, has time from being spent on filling out a check-
achieved a compliant status, you can share this with list for a low-risk department.
the entire company as a source of pride and excel- • If one is experiencing difficulty satisfying both
the regulations and the company’s needs with
lence. People need to know that their hard work has their current system, there are only two choic-
paid off and their company is better able to compete es: change the internal procedure or develop
and win.” a method where the current system yields a
Joel returned to his earlier description of ways that better result. These are the only options; not
audit programs get off track. “Management doesn’t meeting the intent of the regulations is not vi-
make a specific decision to weaken the audit pro- • Sometimes a company may want to conduct
gram, but if things are going smoothly, and the audit an internal assessment that is, essentially, a
program is truly effective, there will be fewer find- mock FDA investigation. This is a valuable
ings, so it becomes more difficult to demonstrate tool; however, not every audit should be this
the value of that same program.”    intense, and it could create stress in the work-
force. Competent internal auditors working
Art protested that his team knew the value of au- with area managers in a more collegial man-
dits, and, “I have never done anything to undermine ner will yield higher value results.
it!” Joel said that he understood, but pushed back • Ultimately, the key reasons for an internal au-
saying “you said yourself that the program wasn’t dit program is to meet the regulatory require-
working, that it was ‘broken,’ so I’m just trying to ment for an internal audit program; however,
more important is the second reason: to en-
figure out what needs to be fixed.” sure that systems are challenged and evalu-
Then Sophie said that she and Art had discussed ated on an ongoing basis. The findings from
a couple of other ideas, but now Joel’s conversation an internal audit program must be addressed
had made her think they were headed in the wrong in a timely manner with the same rigor as an
direction. She added, “At Crooneart, I know we have external audit.
some of the situations you have on your list. I also
know I’m here working with Art, but I can’t just Originally published in Journal of GXP Compliance Volume
close my eyes to the issues back home in Belgium.” 17 Number 2
Joel paused and then said, “I think we may have
an opportunity here, but it would require some
additional expense. What if the internal auditors
worked at the opposite facility? Have the auditors
from Belgium come here and send Art’s auditors to
the home office?” Art said there was no way they
would be able to fund a trip a month each direction,
but Joel reminded him that “The regulations only
require you to have a schedule, they don’t require
the schedule to be evenly divided by month. What if
you did half the system on each of two trips?”

99 Conducting Audits, Gap Assessments & Corrective Actions Volume II

Patrick Klemens and James Kaar

About the Authors

Pat Klemens has a comprehensive background in qual-
ity management and compliance spanning more than 30
years. His experience ranges from developing complete
quality systems for small biotech firms to managing global
quality and compliance programs for a multi-national cor-
poration. He is currently the director of Business Excel-
lence and Training at Abbott where he manages the R&D
deployment of Lean Six Sigma. He is president of Ascend,
Inc., a management-consulting group. He may be reached
by e-mail at klem123@ameritech.net.

Jim Kaar has worked in the quality sciences for more than
30 years. He was employed by Baxter Healthcare for more
than 25 years, beginning in a small manufacturing facil-
ity and continuing into Quality Project Management. Jim
left Baxter and formed Quality Focus, a regulatory com-
pliance and quality consultancy. Quality Focus provides
quality system development, contract auditing as well as
other services to clients ranging from start-ups to Fortune
500 companies. He may be contacted by e-mail at kaar54@

100 Conducting Audits, Gap Assessments & Corrective Actions Volume II

Patrick Klemens and James Kaar

The Business of Auditing and Auditing

the Business: Part VII
Patrick Klemens and James Kaar

The last of our story in the series  The Business of ternal auditors may hear about who is in trouble,
Auditing and Auditing the Business. and they know how “management really feels” even
Welcome to the last chapter in the “Audit Forum” if this knowledge is based on rumor. Management
story. needs to demonstrate a true desire to have compli-
This series has endeavored to provide an overview ance gaps found and to assure that there are no pu-
of a critical activity in compliance—auditing and nitive outcomes, at any level, as a result of internal
being audited. This series explored many dimen- audit findings. The goal remains to gain a better
sions of the audit process beyond the audit event to understanding of the business.
underscore the power of this oft-misunderstood Supplier audits also have an important business
quality tool.  component in. Similar to internal audits, conduct-
The importance of quality audit as one of the ing an audit of external suppliers carries certain
tools in a quality manager’s toolbox should not be responsibilities as well, and there can be damage to
underemphasized. It can (and does) touch many the supplier-customer relationship if one side feels
other aspects of the business. However, by its very “abused” during an audit. 
nature, an effective and integrated audit program is Whether it is an internal or external audit, the
difficult to achieve and maintain. There are inherent business gains greater understanding of its compli-
challenges to getting the desired and needed results ance to applicable regulations and internal require-
from various audit programs. As stated in the very ments. Further, the business can critically evaluate
first article, the company wants internal audit pro- the suitability of its procedures and the health of
gram to disclose any gaps in their systems before the relationships within its functions. Management
someone outside the company observes them, and needs to ask about specific action items in order
customer audits really need to be thorough so as to to increase opportunities that increase the overall
find any gaps before a regulatory body notes them. quality and compliance profile of the firm. 
However, too frequently, these activities are treated Effective management oversight comes with a
as “unnecessary” interruptions of “our business.” price; there are costs associated with maintaining
The author’s have discussed how to conduct an quality systems and regulatory compliance. How
audit both as an auditor and as the  auditee. The much do you add to the cost of the product when
author’s wanted to reflect the differences of these you ask for a change in the system? 
two roles and to illustrate how these two aspects are Each firm employing a quality audit has the choice
truly “opposite sides of the same table.” Establishing to make its audits as simple or complex as it likes.
rapport and good communication is key to a suc- It’s worth remembering that the real value of the
cessful outcome for both parties. It is also critical to tools occurs when audit responses are developed,
managing the emotional aspects of the audit envi- debated, and committed. 
ronment. We hope you have found these articles informa-
Internal auditors are part of the company, and they tive and thought-provoking. Please contact Pat-
are auditing fellow employees. It is management’s rick Klemens atpkinfo@ameritech.net, James Kaar
job to assure that personal relations don’t weaken at  kaar54@comcast.net  or  crubenstein@advanstar.
the results of the internal audit program. The in- com with any reader comments, questions, and sug-

101 Conducting Audits, Gap Assessments & Corrective Actions Volume II

Patrick Klemens and James Kaar

gestions. THE STORY

CURTAIN CALL: THE PEOPLE Art thought back to the video call with Maxime the
Art: Vice President of Quality for MedicHose, a week before. Video call?!  Since when did video calls
medical component company. Art is responsible for become a part of the corporate communications
the overall compliance of the MedicHose quality structure? Maxime was right, of course. It really
system. would have been too expensive to fly over just for
Sophie’s going-away party, but Art felt it was appro-
Roger: Director of Supplier QA. Roger was respon- priate to invite the boss. When Maxime indicated
sible for the MedicHose Suppler Quality Process, that he couldn’t attend, Art felt like he’d made a
including the approval and monitoring program mistake about not being more cost-conscious. He
and a casualty of the failure of his process. thought to himself, “It’s just so hard to know the
right thing to do with folks from other countries.”
Dave Gwinnett: Quality Systems auditor.  On the other hand, even though there was still
Michael:  Manager of Laboratory Systems at work to be done, it had felt good that Maxime told
MedicHose. His lab is responsible for incoming ma- him it was time for Sophie to return home to Bel-
terials analysis testing as well as final product test- gium. It felt like Maxime no longer needed to have
ing and release. “his person” working at MedicHose (or maybe Art
was now Maxime’s person at MedicHose).
Joel:  Quality Assurance (QA) consultant with ex- Art and Sophie would both be focused on the
pertise and credentials including ASQ Certified projects that were still working, but now it would be
Quality Auditor and a Black Belt in Lean Six Sigma. part of the weekly management call. 
Joel is a long-time personal friend of Art. Art was shaken from his reverie by Joel’s voice. 
“A guy could die of thirst around here.”  
Maxime Boukent: Corporate Vice President for Art laughed and asked his friend to have a seat.
Quality at Crooneart, Inc. Maxime has global re- “Good to see you, Joel, glad you could make it.”  
sponsibility for quality and reports to the CEO. “Me, too,” Joel said. “Consultants are always there
at the start of the project, but we don’t often get
Sophie Gaverbos:  Director of Supplier QA at asked to attend the victory celebrations at the end. I
MedicHose. Sophie is on assignment to MedicHose think it’s because people are afraid we’ll bill them for
in the US from headquarters in Belgium. She re- coming to the party.”  
ports locally to Art and globally to Maxime. She Art laughed again, “Well, this isn’t so much a vic-
has been tasked with assuring that the MedicHose tory celebration as it is a farewell party for Sophie.”  
supplier quality program is compliant, efficient, and “Oh, is Sophie going back to Belgium?” Joel
sustainable. asked. “She seemed to be enjoying working here, so
I thought she might want to stay.”  
THE COMPANY Art explained that it wasn’t so much a choice as a
MedicHose is a family-owned company located in statement Maxime had made during the last man-
southeastern Minnesota. MedicHose has been in agement call. 
business for 40 years and has a good quality repu- “I definitely have mixed feelings about Sophie
tation. Crooneart, an old-line European company leaving,” Art continued. “In the end, I’ve really en-
headquartered in Brussels, Belgium, has recently joyed working with her, and she is remarkably com-
purchased MedicHose. petent. However, tonight is a celebration and our
chance to bid ‘au revoir’ to our colleague. And here
she comes now.”
“Here comes who?” asked Sophie as she sat down

102 Conducting Audits, Gap Assessments & Corrective Actions Volume II

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with Joel and Art.  (if we’re not), and we find ourselves in the mode of
“The guest of honor,” said Joel. “Art was just say- fixing a problem we already knew we had but in a
ing tonight is a celebration to thank you for all your timeframe that we did not choose.
help and to bid you farewell.” 
“Well, I appreciate the kind words, but I would “Like we talked about very early, before Maxime
rather not be leaving as you know,” Sophie said.  came for an audit, before the lab problems, maybe
Art shot Joel a look, but Joel was looking at Sophie. before all of this. It always boils down to three ques-
He wondered what that exchange was all about. He tions.”
decided that this was a question for another time. Joel said, “I think you mean two questions. First,
Art said, “Joel and I were just going to get a drink. ‘Do you have a procedure?’ And then, ‘Do you fol-
Care to join us?” low the procedure?’” 
The evening progressed as these kinds of parties Art said that those were certainly two of the ques-
tend to do. Later, Joel and Art found themselves sit- tions. “But what about, ‘Are you doing something
ting at a table in the corner of the room. Art was beyond the procedure?’”
about to ask Joel what was going on with Sophie, but Joel said he thought that was the same as not fol-
Joel started talking before Art could ask.  lowing the procedure. Art continued, “Sure, it’s sort
“This has been a very long and difficult project,” of like that, but remember all the stuff we found
Joel remarked, “and you have been working very where we did things a certain way because that’s the
hard for a lot of months to get to this point.” Art way we’ve always done them?”  
agreed and started to ask his own question, but Joel “You mean ‘tribal knowledge’?” Joel asked. 
pressed on.  “Exactly,” said Art. “I think there are really three
“What do you think the hardest part of this proj- questions that are the ‘boil down’ of an audit.”
ect has been over the last several months?”  
Art started to answer, but then hesitated.  An ongoing theme throughout this story has been
“You know,” he said, “there have been a lot of the need to be flexible. Flexibility does not mean ig-
tough times, and I think I learned a lot during those noring situations that need to be corrected or doing
times, and I think the company has learned much the easy things first. However, one needs to know that
too. I’m just not sure we’re done with the learning or a “C” priority can become an “A” in no time at all.
the work. I mean we’ve completely changed some of Another piece of flexibility is recognizing when the
our systems, we’ve changed some of the people we situation is getting out of control and more resources
work with. There’s just a lot of change!” need to be focused on the task at hand.
Joel agreed with him. “Change is always difficult Auditors need flexibility in their toolkit in order to
and change always takes energy. So has all this make their task more manageable and to help build
change been the hardest part?”    rapport with the auditee.
Art looked at his friend and said, “Its all been hard An audit schedule is of value to both the parties,
and it’s all been worth it. It’s also so sad that so much but it can create stress if one party needs to adjust for
of it was avoidable. some reason and the other party can’t be flexible.
The use of an audit checklist versus having a list of
Frequently, we know that we have issues with our areas to cover and specific touchpoints is another area
systems; however, during the day-to-day activities of where decisions need to be made about flexibility.
a business, fixing a quality system issue is relatively
easy to postpone. We know what the problem is and “So you think managing all the change was the
we know what we need to do to fix it, so it really isn’t hardest thing that you went through?” Joel asked,
as pressing as the daily issues for which we don’t yet restarting their earlier conversation. 
have a solution. Then, the issue becomes an audit find- Art started to walk his previous response back a
ing (if we’re lucky) or a regulatory non-conformance little. “Well it certainly is a piece of the puzzle. There

103 Conducting Audits, Gap Assessments & Corrective Actions Volume II

Patrick Klemens and James Kaar

were so many things that we needed to fix, and try- all the resources a big company might have. However,
ing to figure out the priorities was not my usual way the regulations are the same regardless of the size of
of doing things. I’m afraid I sometimes used to con- the company. How one designs the system to meet the
fuse my team by asking for too many things in too regulations is the key to sustainability.
short of a time.”
Art said that probably the hardest thing that he Art admitted that the past several months had
personally had to do over the last several months changed his opinions about audits in many ways,
was to realize that planning was of critical impor- and not all of them had been for the better. Joel said
tance. He had to be the one to drive the plan and he was actually surprised by that because so many
resist letting the plan drive him. Joel said, “Can you good things had come out of these audits. “I thought
explain a little more about that?”   you had embraced or at least accepted that an audit
Art started with the list they had made to help was always an opportunity for future improvement
prioritize all the work he had in front of himself get- for the organization.”
ting ready for the corporate audit. “When you called Art replied that he understood all that. “You and
and asked how I was doing with that list, I have to Sophie have both taught me a great deal, and so have
confess, I hadn’t looked at for several days,” Art said. a lot of other people. I read and respond to audits
“After that I was so focused on the list that I prob- differently than I did before we started with more of
ably made other mistakes in my audit preparations.” a focus on the underlying system issues, and I write
Joel continued to play Devil’s Advocate. “Well it them differently too. I’m more focused on actual de-
certainly seems like you’ve come through all of this tails, you always call it objective evidence, and I al-
with a minimum of ‘scars’.”  ways want to make sure I’m not writing my opinions
“I don’t know if I really agree with  that  assess- as requirements. But even with all this great stuff,
ment,” Art said. “I’ve had to fire people and there is my biggest problems boiled down to people! People
still a bunch of work to do on our SOPs [standard not following perfectly good procedures; people
operating procedures] as well as on training. No, I slowly undermining the intent of the supplier pro-
think there has been some significant scarring.” gram, whether they knew they were doing it or not;
Joel smiled, “Well, there’s still a lot to do. That’s people not realizing the value of….well you get the
the whole problem with sustainability, there’s never idea.”
an endpoint. You get to a point where you can see Joel nodded, “If it weren’t for all these people, your
what you need to do from here on out, but it doesn’t job would have been much easier, but then who
mean that you won’t have to change course again, or would you be paid to manage? I agree that in the
that there won’t be any more big projects. Just like end the technical stuff is easy, but the people stuff is
with continuous improvement, a sustainable orga- where the work really comes in and where we spend
nization is never ‘done.’ But sustainability begs the the bulk of our effort. But I think you’ll agree; this is
question, ‘Will  this  fix work for  this  organization.’ always the way it is going to be. So our choices are
Everyone knows the stories about companies that embrace it and develop our people or learn robot-
won prestigious quality awards and went broke try- ics!”
ing to live up to the goals they set for themselves.”
Management and staff must continue to demon-
Sustainability is the common predicament for to- strate their commitment to quality. This is another
day’s quality professional. When working with fewer area that has been noted more than once. Slogans
resources to complete more tasks and satisfy their and posters aren’t meaningful to regulators. “Objec-
particular regulations, one needs to strike the right tive evidence” of compliance is what matters.
balance. MedicHose needs a compliant quality system
to maintain its certification, but they are a small com- The two friends laughed, and Art remembered a
pany, or at least a small division, and they didn’t have question he had been trying to ask all evening. 

104 Conducting Audits, Gap Assessments & Corrective Actions Volume II

Patrick Klemens and James Kaar

“Speaking of people, what was that exchange “Lessons Learned” tutorial prepared after the
between you and Sophie all about?” Joel looked audit that captures the areas that the auditors
puzzled, so Art continued, “When we were talking didn’t report.
• Procedures and processes need to be defined
about her return to Belgium she said you knew…”   in writing. It seems so simple, and yet it is the
Joel interrupted Art and explained, “Sophie really basis of so many audit findings.
likes it here, likes working with MedicHose, and • Managing an audit is more about managing
likes working with you. She and I were talking a perceptions than it is managing document
month ago or so. She was talking to me about stay- flow or the auditor’s time.
• A person’s intent, however good, is irrelevant
ing here as part of your organization. I thought you if they are unreliable, and there will always be
knew all this.” consequences.
Art was quiet for a few moments. “Actually I didn’t
know all that, but Maxime has already said it’s time
for her to go.”   Originally published in Journal of GXP Compliance Volume
17 Number 3
Joel asked, “Do you want her to stay, or not?”  
Art said, “Of course I want her to stay. I’ve already
told you how much she has added to the company
and how much she’s helped me.” About the Authors
Joel stood up, “Thanks for inviting me to the party,
but it’s time for me to go. Just one last thing though. Patrick Klemens is director of Business
Maxime is nothing if not a pragmatist. If you think Excellence and Training at Abbott where he
you can build a case why a global company should manages the R&D deployment of Lean Six
have a Belgian manager in the US affiliate, then I’d Sigma. He is president of Ascend, Inc., a man-
go for it if I were you. Remember, change takes en- agement-consulting group. He may be reached
ergy.” by e-mail at pkinfo@ameritech.net.
And with that the two friends shook hands, Joel
was gone, and Art was thinking if it was too late to James Kaar formed Quality Focus, a regula-
write an email to his boss……. tory compliance and quality consultancy that
provides quality system development, contract
WHAT ARE SOME THINGS auditing as well as other services to clients
WE HAVE LEARNED: ranging from start-up to Fortune 500 compa-
• When faced with a large task, one must parse nies. He may be contacted by e-mail at kaar54@
out the problem by creating a prioritize “To comcast.net.
Do List” that breaks down the task into mean-
ingful smaller steps: a map on how to “eat the
• Quality planning can be a valuable tool for ad-
dressing significant gaps in a quality system. It
should provide a well-defined outline for how
an organization intends to manage the indi-
vidual issues while also allowing for broader
timelines for larger projects.
• The notes one takes and the conversations
that take place during an audit are equally
important, if not more important, than the
audit report. One never looks at their quality
system more critically than during an audit.
Just because an auditor “missed” a clear gap
in a particular system doesn’t mean that the
problem doesn’t exist. There should also be a

105 Conducting Audits, Gap Assessments & Corrective Actions Volume II

Richard Poska and Ballard Graham

FDA 483 Responses—

Compliance Considerations
Richard Poska and Ballard Graham

Global Regulatory Viewpoint” addresses various regulatory and compliance topics includ-
ing newly published regulations from a global perspective. The content in this column is
intended to be useful to those who deal with pharmaceutical development, development
of CMC dossier sections, and guidances for manufacturing, validation, and CGMPs. The

objective of this column: Useful information.

Reader comments, questions, and suggestions are requested to help us fulfill our ob-
jective for this column. Readers are invited to submit manuscripts for publication in this
column. Please contact column coordinator Richard Poska at richard.poska@abbott.com
or journal coordinating editor Susan Haigney at shaigney@advanstar.com.

The following key points are discussed in this article:
• US Food and Drug Administration current good manufacturing practices
(CGMPs) provide fundamental requirements for pharmaceutical manufac-
• The FDA 483 is the official recording of FDA investigator observations from
an FDA inspection
• An inadequate inspection response is the primary reason for warning letters
being issued in 2008
• FDA’s Anita Richardson (Center for Biologics Evaluation and Research) dis-
cussed topics associated with writing an effective Form 483 response at the
5th Annual FDA and the Changing Paradigm for HCT/P Regulation confer-
ence in January 2009
• Responses to FDA 483s are not legally required; however, responses are
strongly recommended
• Responses may mitigate an FDA compliance decision for further action
• Responses demonstrate understanding and acknowledgement of the obser-
• Responses demonstrate a commitment to correct or voluntarily comply
with corrective actions
• Responses establish credibility with FDA
• Failure to respond, inadequate responses, or failure to adhere to promised
corrective actions make a firm susceptible to aggressive regulatory or legal
actions by FDA such as product seizure, legal injunction, and other actions
• After an inspection, an action plan should be quickly developed to address
each observation
• Effective responses should include a commitment statement from senior
leadership, should address each observation separately, should provide
corrective action accomplished planned, and should be specific, complete,
realistic, and deliver on commitments
• Effective responses must be timely, include timeframes for correction, verifi-
cation methods, monitoring of corrections, and supporting documentation
• FDA has implemented a Warning Letter Close-out Program
• The Enforcement Story, Fiscal Year 2008 summarizes FDA compliance activi-

106 Conducting Audits, Gap Assessments & Corrective Actions Volume II

Richard Poska and Ballard Graham

ties during 2008 and provides useful statistics and the Maximum Allowable Cost (MAC) program of
• Firms should be very familiar with their in- the Department of Health and Human Services (HHS).
coming materials and product supply chain Decisions regarding compliance with CGMP regula-
• Firms should fully understand the interac-
tions of the processes and systems that impact tions are based upon inspection of the facilities, sample
quality, safety, and effectiveness of their prod- analyses, and compliance history of the firm. These data
ucts are summarized in profiles that represent several years
• As part of responding to FDA 483 observa- of history of the firms. In consideration of the growing
tions, firms should also assess their general number of programs dependent upon CGMP assess-
internal compliance programs—Why were
483 deficiencies not detected internally? ment, agency policy must be consolidated in regard to
• FDA 483 observations may be caused or approval or disapproval of drug marketing applications,
intensified by inadequate audit manage- government purchasing contracts, etc., and the relation
ment (i.e., logistics, timelines of responses, of such determinations to regulatory action.
documentation retrieval, etc.) as well as soft CGMP deficiencies supporting a regulatory action
“people” skills.
also support decisions regarding non-approval of drug
marketing applications, government purchasing con-
INTRODUCTION tracts, candidates for MAC, etc. Therefore, the issuance
The United States Congress enacted requirements that of a warning letter or initiation of other regulatory action
all drugs must be produced in accordance with current based upon CGMP deficiencies must be accompanied
good manufacturing practices (CGMPs) more than 40 by disapproval of any pending drug marketing applica-
years ago. These requirements were intended to address tion, or government contract for a product produced
significant concerns about substandard drug manufac- under the same deficiencies. Similarly, disapproval of
turing practices by applying quality assurance and control any drug marketing application, government contract,
principles to drug manufacturing. The last comprehen- etc., based upon CGMP deficiencies must be accompa-
sive revisions to the regulations implementing CGMP nied by regulatory and/or administrative action against
requirements occurred more than 25 years ago. In ad- any other product produced under the same conditions.
dition, pre-market approval requirements, pertaining to An analysis by Hogan & Hartson cites inadequate in-
chemistry and manufacturing controls, have also been in spection responses as the top reason for warning letters
effect for many years to ensure quality manufacturing of to be issued by FDA (1). This emphasizes the timeli-
approved drugs. The CGMP and pre-approval programs ness of a presentation by FDA’s Anita Richardson of the
have been extremely successful, and pharmaceuticals Center for Biologics Evaluation and Research (CBER)
produced for American consumers are recognized as the that discussed topics associated with writing an effec-
world’s gold standard for safety and effectiveness. tive Form 483 response (2). These included the regu-
To ensure the quality of drug products, the US Food latory framework for FDA policies for writing an FDA
and Drug Administration has made an increasing num- 483; reasons for submitting well-reasoned, complete,
ber of commitments to programs, systems and initiatives and timely 483 responses; suggestions for activities fol-
to carefully monitor drug manufacturers’ compliance lowing an FDA inspection and 483 observations; and
with CGMP regulations. For many years, FDA has en- suggestions for an effective 483 response. The fact that
forced CGMP as part of its overall drug quality assurance this topic has been specifically addressed by FDA sug-
program. The approval process for drug marketing ap- gests that a significant part of the industry has not been
plications (i.e., original and abbreviated new drug appli- successful in basic CGMP compliance and subsequent
cations and antibiotic) includes a review of the manufac- responses. FDA 483 observations remain at a high level,
turer’s compliance with CGMPs. More recently, FDA has responses to 483 observations are not technically sound,
assumed additional roles in the area of assurance of drug and deficiencies are often not adequately corrected re-
quality involving good manufacturing practice through sulting in subsequent regulatory action. The issuance
such programs as the Government-Wide Quality Assur- of 483 observations and subsequent warning letters
ance Programs for drug purchase contracts by the De- undermine FDA confidence that a firm can consistently
partment of Defense and the Veterans Administration,

107 Conducting Audits, Gap Assessments & Corrective Actions Volume II

Richard Poska and Ballard Graham

manufacture safe and effective products. WHY SUBMIT A 483 RESPONSE?

Although a firm’s response to a FDA 483 represents an If your firm has been audited and the FDA investigators
internal group effort, the quality organization of a phar- have presented management with a 483, what should be
maceutical or medical device company shoulders the done? The first consideration is whether or not to devel-
major responsibility for providing an adequate response. op a response to the 483 and submit this response to the
In addition to responding to each specific observation, agency. Ms. Richardson’s presentation clearly stated that
the quality organization should look beyond these ob- responses to FDA 483s are not legally required. However,
servations. The quality assurance (QA) organization her presentation indicated that responses are strongly
must address the 483 in a comprehensive manner. In recommended. Responses are recommended for the fol-
brief, why were the observations not addressed as part lowing reasons:
of the organization’s compliance program and why did • Responses may mitigate an FDA compliance
the internal audit program not identify the deficien- decision for further action, such as an untitled
cies? Were these systemic problems or were they the letter or a warning letter. As a general rule,
result of poor audit management during the regulatory a warning letter should not be issued if the
agency concludes that a firm’s corrective ac-
agency visit? These and associated questions should be tions are adequate and that the violations that
addressed by the quality and compliance organization. would have supported the letter have been
corrected (4).
• Responses demonstrate to FDA and other
FDA 483 DEFINITION stakeholders an understanding and acknowl-
The FDA Form 483 (or “483”) is the official recording edgement of the observations
of FDA investigator observations from an FDA inspec- • Responses demonstrate to FDA and other
tion. It is presented to the organization being audited stakeholders a commitment to correct or vol-
untarily comply with corrective actions
at the conclusion of an inspection. The FDA 483 is the • Responses establish credibility with FDA.
starting point for discussion. The observations of the in-
vestigator should be the clear focus of the 483 response. There is concern on the agency’s part that there may
be a general lack of understanding as to what the FDA
FDA AUDIT PRIORITIZATION Form 483 represents. It is only one piece of the overall
Prioritizing sites for inspection has been a long-standing inspection process that the agency employs to make its
challenge for agency managers. In the past, FDA district decisions on the compliance status of the inspected firm.
offices have identified specific sites in their geographi- An FDA 483 contains the investigator’s observation and
cal areas for inspection each year. These decisions were is not the final agency decision on the “observation.” It is
made based on a variety of informally applied factors, thus imperative that a written response be submitted to
including, for example, a district manager’s knowledge the agency in a timely manner and prior to the agency’s fi-
of the inspectional history and corporate culture of the nal decisions on the merits of the observations. Failure to
district as well as the perceived risk to the public health of provide a response to an FDA 483 leaves you at the mercy
manufacturing errors. Even before the CGMP Initiative, of the investigator’s observations, and demonstrates to
the Center for Drug Evaluation and Research (CDER) the agency an inept attitude toward compliance. Firms
and the Office of Regulatory Affairs (ORA) prioritized that fail to respond to an FDA 483, submit an adequate
the use of inspectional resources. Three categories of response, or fail to promise corrective actions are placed
facilities were identified as high priority for inspections: on an aggressive inspection schedule—with low toler-
sterile drug product manufacturers; manufacturers of ance for non-compliance. Failure to respond, inadequate
other (non-gas) prescription drugs; and new registrants response(s), or failure to adhere to promised corrective
that have not been previously inspected. A more com- actions place a firm on a collision course for aggressive
plete discussion of the FDA risk-based approach to in- regulatory or legal actions by FDA.
spections is referenced (3). Although not required, responding to 483 observations
is the best way to prevent escalation of actions that FDA
can take against a company. These actions can include

108 Conducting Audits, Gap Assessments & Corrective Actions Volume II

Richard Poska and Ballard Graham

seizure of product, legal injunctions, not able to execute ter as a result of the FDA 483 response is discussed with
government contracts, failure to be issued export certifi- the initiating office.
cations, a hold on approvals of other of the firms pend-
ing new drug applications (NDAs), license suspension, WHAT TO DO FOLLOWING AN INSPECTION
refusals for export, and increased regulatory inspection A firm has many options for responding to a 483 that is
frequency. A company should also consider the unpre- issued following an inspection. The following are some
dictable intangible effects of bad press, such as was seen suggestions based on Ms. Richardson’s presentation (2):
with the KV regulatory actions (5, 6) that resulted in a • Develop an action plan to achieve immediate,
significant financial loss to the St. Louis-based company short-term, and long-term correction and to
in late November 2008. prevent recurrence (corrective and preventa-
A company also needs to recognize the importance of tive action [CAPA])
• Know when to seek outside assistance
handling GMPs in terms of disclosure to its shareholders. • Assess each observation
In 1999, Schering-Plough recalled an inhalation product • Focus on specifics
due to manufacturing deficiencies. In 2001, the company • Focus on system-wide implications
disclosed the full extent of its manufacturing problems • Focus on global implications
which apparently were more severe than originally re- • Consider affected products
• Consider root-cause analysis
ported and resulted in FDA withholding final approval • Focus on the regulatory requirements as-
for a new product. This resulted in lower earnings and sociated with the observation.
prompted a class action lawsuit against Schering-Plough
for violating federal securities laws by failing to disclose Some other considerations include assembling appro-
the alleged depth and severity of manufacturing issues. priate data to form the basis for all actions. There should
The lawsuit was settled for $165 million (7). be a scientific and technical basis for actions whenever
possible. The applications of observations to similar
HOW DOES FDA PROCESS 483 products produced in the same facility should be con-
RESPONSES? sidered. Voluntary removal of suspect product(s) from
Responses to FDA 483s are handled internally by the consumer channels should be considered, as well as the
agency as follows. voluntary shutdown of operations if deficiencies warrant
If the agency receives the Form FDA 483 response prior such action.
to submitting the draft “final” warning or untitled letter to After the FDA inspector has left, one of the best actions
Office of Chief Counsel (OCC), a copy of the Form FDA a company can take is to assemble a team immediately,
483 response (without the exhibits or the attachments) including management and legal counsel (if concerns
and the agency’s assessment of the response accompanies are severe), to evaluate and confirm a full understanding
the draft “final” warning or untitled letter. of the concerns that the inspector has noted in the 483.
If the agency receives the Form FDA 483 response Once there is internal consensus on the issues, the actions
while OCC is reviewing the draft “final” warning or can be broken into those needed to specifically write the
untitled letter, the center may notify the attorney that is 483 response (short term correction) as well as the long-
conducting the review. A copy of the Form FDA 483 re- term correction, which should include steps to prevent
sponse (without the exhibits or the attachments) and the the recurrence of the issue. In the case where the com-
agency’s assessment of the response (including whether pany truly believes that the observation is not warranted,
the response has changed the agency’s view on whether it is best to tactfully voice the concern during the closing
to issue the letter) may be submitted to the assigned at- meeting and when preparing a thorough, scientifically-
torney, added into the case file for the proposed action based, and thoughtful reply.
within Compliance Management System (CMS). The
review clock will stop when OCC is notified and restart ADDRESSING 483 OBSERVATIONS
upon OCC’s receipt of the Form FDA 483 response and Ms. Richardson’s presentation (2) provided the following
the agency’s assessment. Any change to the proposed let- suggestions for effectively responding to a 483:

109 Conducting Audits, Gap Assessments & Corrective Actions Volume II

Richard Poska and Ballard Graham

• Include a commitment statement from senior Manufacturers are encouraged to seek clarification of
leadership scientific or technical issues with the inspection team at
• Address each observation separately any time during an inspection. Although there are exist-
• Note whether you agree or disagree with ob-
servation ing processes to encourage dialogue between FDA and
• Provide corrective action accomplished or manufacturers, the processes described in this document
planned; tell FDA the plan. Be specific (ob- apply to CGMP questions raised during inspections and
servation by observation), complete, realistic, are intended to supplement the dispute resolution pro-
able to deliver what you promise, and address cesses currently in place, including the following:
affected products. • 21 CFR 10.75, Internal Agency Review of
• Provide timeframes for correction Decisions. Allows manufacturers to ask for a
• Provide method of verification and monitor- review of agency decisions at each successive
ing of corrections supervisory level through the chain of com-
• Consider submitting documentation of cor- mand, ending with the FDA Commissioner’s
rection when reasonable and feasible office.
• Be timely. • Center for Drug Evaluation and Research
(CDER)/CBER guidance for industry entitled
A well-written and carefully prepared FDA 483 re- Formal Dispute Resolution: Appeals Above the
sponse, founded in science, provides the agency with a Division Level (February 2000). Describes
documented record of a firm’s commitment to compli- procedures a sponsor may use to formally
appeal disputes to the office or center level
ance. Further, the firm demonstrates seriousness in on scientific and procedural issues that arise
responsibility and its desire to manufacture safe and ef- during drug development, new drug review,
fective products under the agency’s jurisdiction. It is im- and post-marketing oversight processes.
portant to not over-promise and fail to deliver—by doing The guidance may be found on CDER’s and
so; a firm’s credibility can be seriously tarnished. CBER’s websites.
• Investigations Operations Manual (IOM),
Of course, it is always best to avoid receiving 483 ob- Chapter 5, Subchapter 510. Describes pro-
servations during an inspection. Common sense “soft cesses for discussing inspectional observa-
skills” such as being respectful to the investigator and tions with a manufacturer. The IOM is avail-
acknowledging an understanding of the inspector’s con- able on the FDA ORA website (8).
cerns can influence the final action of the investigator. It
is always a good idea to confirm at the end of each day INDUSTRY PERFORMANCE
what concerns the inspector may have so as to minimize FDA has issued The Enforcement Story, Fiscal Year 2008
surprise observations. However, if a 483 is issued, then (9) in March 2009. This document provides a good over-
it is really important to consider assembling a multi- view of industry compliance performance during 2008.
functional team to consider the strategy for addressing For example, the most frequently cited categories of FDA
the concerns as well as a timetable for corrections. It is in observations during 2008 are listed in Table I.
the company’s best interest to treat the 483 responses with
very high priority.
A total of 104 warning letters were posted on the FDA
DISPUTE RESOLUTION website associated with CGMP violations during 2008
Disputes related to scientific and technical issues may and were issued to drug product manufacturers, active
arise during FDA inspections of pharmaceutical manu- pharmaceutical ingredient (API) manufacturers, medical
facturers to determine compliance with CGMP require- device manufacturers, and other firms. These warning
ments or during the agency’s assessment of corrective ac- letters often included comments on previous industry re-
tions undertaken as a result of such inspections. As these sponses to 483 observations and addressed inadequacies
disputes may involve complex judgments and issues that in the responses.
are scientifically or technologically important, it is criti- The FDA Enforcement Story (9) provides the following
cal to have procedures in place that will encourage open, example of an inadequate 483 response:
prompt discussion of disputes and lead to their resolution.

110 Conducting Audits, Gap Assessments & Corrective Actions Volume II

Richard Poska and Ballard Graham

“On May 8, 2008, the FDA Dallas District sent a warn-

Table I: Most frequently cited categories of FDA
ing letter to a Texas firm. An inspection conducted Janu- observations.
ary 14 through February 14, 2008, revealed that the meth- Number of 21CFR Refer- Deficiency
ods for the manufacture, processing, packing, or holding Observations ence

of product did not conform to CGMP regulations. The 887 211.22(d) QCU responsibilities
firm was also marketing new drugs and misbranded
drugs in violation of the Act. Violations of CGMP regu- 709 211.100(b) Adherence to production
lations included:
• Failure of the quality control unit (QCU) to 618 211.110(a) Production procedures
follow written procedures (validation)
• Failure to conduct complete investigations 553 211.100(b) Laboratory controls
• Failure to conduct adequate identity testing
for API containing tannates 518 211.100(a) Written procedures for
• Failure to provide 100% of the labeled amount production
of the active ingredient for drug product con- 506 211.192 Investigations
taining tannates
• Failure to conduct accelerated stability studies
as necessary 478 211.165(a) Testing and release
• Failure to correct deficiencies in dissolution
testing and establishing specifications 456 211.25(a) Personnel qualification
• Failure to qualify reference standards used in and training
the testing of products containing tannates 449 211.188 Batch record preparation
• Failure to maintain stability indicating testing and review
• Failure to establish the reliability of the sup- 397 211.67(b) Equipment cleaning and
plier’s analysis. maintenance

“The FDA considered the response dated March high quality drug products and to implementing a
26, 2008, addressing the deviations from the in- robust quality system with aggressive corrective ac-
spection observations as inadequate because the tions. Other points of the analysis include the fol-
firm failed to provide sufficient information to fully lowing:
assess the adequacy of the proposed corrective ac- • 80% of all warning letters were issued to do-
tions. Furthermore, the information submitted to mestic facilities
• Warning letters to drug product manufactur-
address many of the inspectional observations only ers exceed those written to API manufacturers
indicated that the observations will be corrected; • FDA is taking a more holistic, systematic and
however, a specific timeframe for implementing the risk-based approach to assessing GMP com-
proposed corrective actions was not indicated.” pliance, paying close attention to the quality
Table II lists randomly selected warning letters function, validation, and investigations.
from major companies available on the FDA web-
site (10). In all cases, the warning letter specifically FDA WARNING LETTER UPDATE PAGE
stated deficiencies in the firm’s responses to the FDA FDA reorganized the warning letter section on its website
483. Again, this indicates the need for industry to in September 2009. Changes include the following:
improve their responses to FDA 483 observations. • New postings. New postings occur every
A 2009 analysis conducted by the law firm of Ho- Tuesday. These are found under “Recently
Posted” with the date posted.
gan & Hartson (1) indicates that almost all of the • Closed out date. The warning letter table in-
more than 25 FDA-issued GMP related warning cludes a “Close Out Date” column.
letters were issued because responses failed to ade- • Additional changes. Additional formatting
quately address FDA concerns. Their report empha- and navigation improvements to help users
sizes the importance of having a written response search this section.
• The FDA “Warning Letters” page can be
that demonstrates a commitment to manufacturing

111 Conducting Audits, Gap Assessments & Corrective Actions Volume II

Richard Poska and Ballard Graham

Table II: FDA warning letters citing deficiencies in the firm’s response to an FDA 483.
# Drug product Country Procedures/ Records Scientific Approach Facilities/Systems Article Ref. #

1 7 USA 5 (2 repeat) 1 1 (1 repeat) (11)

2 5 USA 2 2 1 (12)
3 2 8 USA 6 2 2 (13)
4 3 Canada 1 2 0 (14)
5 6 18 USA 10 12 2 (15)
6 7 USA 5 2 0 (16)
7 5 USA 4 1 0 (17)

8 12 USA 8 4 0 (18)

9 5 USA 1 4 0 (19)

10 6 India 2 3 1 (20)

found at http://www.fda.gov/ICECI/Enforce- Story (9):

mentActions/WarningLetters/default.htm. “At the request of the FDA, on October 31, 2007, US
Marshals seized more than $300,000 worth of product,
WARNING LETTER including an antifungal product and other drugs for
CLOSE-OUT PROGRAM human and animal use, dietary supplements, and in-
The Warning Letter Close-Out Letter Program applies gredients to make those products. These products were
to warning letters issued on or after September 1, 2009. seized because some lacked FDA approval and all were
FDA may issue a close-out letter to firms when FDA has maintained under grossly unsanitary conditions. All of
completed an evaluation of corrective actions done by the finished products and raw materials were deemed
the firm in response to a warning letter. The letter will adulterated. The FDA considered NC Solution to be a
not be issued based on the content of the firm’s response drug because it was intended for use in the diagnosis,
to the warning letter. The corrective actions must have cure, or treatment of disease in people or animals. NC
been actually completed and verified by FDA, usually Solution was also a new drug because it was not generally
by a follow-up inspection. If the warning letter contains recognized as safe and effective for its intended uses.
violations that are not correctable by their nature, then no “This action was the culmination of concerted efforts
close-out letter will be issued. Future FDA inspections by the FDA to get the firm to follow the law when it
and regulatory activities may further assess the adequacy comes to manufacturing safe products for consumers.
of the corrections. If violations are observed during a In August and September, FDA inspectors found that
subsequent inspection or other means, FDA may initiate the company was still manufacturing drugs and dietary
enforcement action without further notice. supplements under unsanitary conditions, including
findings of insects and rodent filth on and around manu-
facturing equipment despite warning by FDA of similar
OTHER FDA ACTIONS serious violation in 1999. Following the 1999 inspection,
The FDA Enforcement Story (9) provides examples of oth- a company official told the FDA in January 2000 that the
er FDA actions following an FDA warning letter. These firm would stop manufacturing drugs.
examples demonstrate the breath of enforcement tools “The FDA’s action against the company was consistent
used by FDA to enforce drug CGMPs. The following with the Agency’s initiative on unapproved drugs, which
incidents may have begun with issuance of an FDA 483. pose potentially harmful risks to consumers.”

Example One Example Two

The following example is cited in the FDA Enforcement The following example is cited in the FDA Enforcement

112 Conducting Audits, Gap Assessments & Corrective Actions Volume II

Richard Poska and Ballard Graham


“On May 27, 2008, the FDA requested that a pharma- The cornerstone for the quality assurance organization
ceutical firm in Miami, Florida recall all Xiadafil VIP Tabs of a firm is their site compliance program. The program
sold in eight tablet bottles (lot #6K029) or blister cards of should minimally include the maintenance of procedures,
two tablets (lot #6K029-SEI) because the products con- company processes, and policies that may encompass raw
tained a potentially harmful, undeclared ingredient that material acceptance, product release, and even product
may dangerously affect a person’s blood pressure and can recall. The program should outline strategies to ensure
cause other life-threatening side effects. Although la- compliance by use of tools such as statistical process con-
beled as a dietary supplement and touted as “all-natural,” trols, annual product reviews, corrective and preventative
Xiadafil VIP Tabs were an illegally marketed drug that action (CAPA), change management and control, and in-
contained a potentially harmful undeclared ingredient. ternal audits, and vendor audit programs. A 483 observa-
FDA chemical analysis revealed that Xiadafil VIP Tabs tion suggests specific CGMP deficiencies implicating one
contained hydroxyhomosildenafil, which is an analog or more of the site quality systems. However, it further
of sildenafil, the active ingredient in Viagra, an FDA- represents a deficiency on the site quality program—why
approved prescription drug for erectile dysfunction (ED). did the organization not detect this deficiency before the
The undeclared ingredient may interact with nitrates regulatory agency found the deficiency? The site internal
found in some prescription drugs (such as nitroglycerin) audit program should be the firm’s simulation of an ex-
and can lower blood pressure to life-threatening levels. ternal regulatory agency audit, and a final check on the
Consumers with diabetes, high blood pressure, or heart site quality systems. The importance of a site internal
disease often take nitrates. ED is a common problem in audit program has been recently discussed by O’Donnell
men with these medical conditions. (21). FDA 483 observations may also involve the quality
“The safety and effectiveness of Xiadafil VIP Tabs is organizations of suppliers, outside vendors and contrac-
unknown. The product was promoted, sold over the tors, and third party manufactures, adding even more
Internet, given away as free samples at trade shows, and complexity to the entire situation. The 2007-2008 global
sold in health food stores nationwide. On May 13, 2008, heparin and glycerin incidents exemplify the complex
Florida officials issued a “stop sale” action at a distribu- and far-reaching scope of site compliance programs.
tion facility. This action required the firm to hold, intact,
violative Xiadafil VIP Tabs found on-hand at the facility.
The State of Florida’s action to control the supply of the THE REGULATORY INSPECTION
product, coupled with the formal requires by FDA to re- MANAGEMENT PROCESS
call this product from the marketplace, further reduced A company may influence the inspector’s judgment
the likelihood that unsuspecting consumers would use regarding the firm’s commitment to quality by how the
this potentially dangerous product. regulatory agency inspection is managed. Is it clear
“Alternative products like Xiadafil VIP Tabs were often who the lead representative of the company is and who
sought out because they were marketed as “all natural” will facilitate the inspection? Usually the soft “people”
or as not containing the active ingredients in approved, skills of this person are more of an asset than their actual
prescribed ED drugs. technical competence. The facilitator role is critical be-
“Because the manufacturing source of the active ingre- cause this person controls the tempo and mood of the
dients in many of these alternative products is unknown, inspection. It is important that the inspector facilitator
consumers should also be aware that the FDA has not try to keep emotion out of the inspection and be sure
verified the safety, efficacy, and purity of these ingredients. that information is supported by hard data. They should
“On July 24, 2008, US Federal marshals seized nearly ensure that information is provided to the regulator in a
$74,000 worth of Xiadafil VIP Tablets. The seizure action timely manner, and that it is the proper information to
protected the public from dietary supplements contain- address the inspector’s concerns. When it is necessary to
ing prescription drug ingredients that are potentially have an expert address the inspector’s concerns directly,
harmful.” it is the facilitator’s role to ensure that the best person is
chosen to address the question and is available to do so.

113 Conducting Audits, Gap Assessments & Corrective Actions Volume II

Richard Poska and Ballard Graham

Timely retrieval of supporting documentation is critical tion readiness and responses for a more complete discus-
during regulatory inspections. For example, how quickly sion of these topics (22,23,24), as well as her “Compliance
can research and development reports from other site Handbook for Pharmaceuticals, Medical Devices, and
locations be obtained and are appropriate contact people Biologics” (25).
identified? Other considerations such as meeting room
facilities, location and atmosphere of the meeting envi- REFERENCES
ronment, facility tours, computer availability, fax avail- 1. FDANewsAlert.com, “GMP Warning Letters Reflect
ability, other necessary facilities, etc. should be addressed Bad Inspection Response,” May 14, 2009, http://www.
to prepare for an actual audit. fdanewsalert.com/id574.html (accessed on June 9,
2009). Also http://www.hhlaw.com.
2. Richardson, Anita, “Writing an Effective 483 Re-
CONCLUSIONS sponse,” 5th Annual FDA and the Changing Paradigm for
The 2009 Anita Richardson presentation provides useful HCT/P Regulation, University of Rhode Island and Phar-
suggestions for a framework for responses to observa- ma Conference, Las Vegas, NV, January 2009.
3. FDA, Pharmaceutical cGMPs for the 21st Century – A
tions, which has been identified as a major reason for
Risk-Based Approach, Final Report Fall 2004, Septem-
FDA to issue warning letters. Companies should focus ber 2004, http://www.fda.gov/cder/gmp/gmp2004/
on problems based on risk analysis. Review of warning risk_based_method.htm
letters indicates ongoing problems with basic GMP re- 4. FDA, Regulatory Procedures Manual, http://www.fda.
quirements. Review of warning letters further indicates gov/ora/compliance_ref/rpm/pdf/ch4.pdf
5. FDA News, “FDA Takes Action Against KV Pharma-
widespread problems with responses. Following Ms.
ceutical Company,” March 2, 2009, http://www.fda.
Richardson’s suggestions should help improve quality gov/NewsEvents/Newsroom/PressAnnouncements/
and comprehensiveness of responses. Recent FDA and ucm149535.htm
ICH initiatives, including quality by design, indicate the 6. FDA, News and Events, www.fda.gov/bbs/topics/
need for better technical understanding of products and news/2009/new01965.html; Also www.google.com/
processes. This understanding should be the basis for
7. FDA News, “Schering-Plough Settles Charges of GMP
responses to observations when appropriate. Problem Coverup,” FDANews.com, April 17, 2009, (ac-
Not only should a company focus on problems based cessed on 6/10/09). http://www.fdanews.com/qmn/
on risk analysis, but it should also be very familiar with newsletter/article?issueId=12585&articleId=116407
their product supply chain. This includes the API, ex- 8. FDA, Investigations Operations Manual (IOM), Chapter
5, Subchapter 510. http://www.fda.gov/ICECI/Inspec-
cipients, and container and closure systems in an effort
tions/IOM/default.htm, http://www.fda.gov/ora/in-
to fully understand the interactions of the processes and spect_ref/iom/iomtc.html
systems that impact quality, safety, and effectiveness of 9. FDA, The Enforcement Story, Fiscal Year 2008, Published
their products. Firms with complete understanding of March 2009.
these parameters, along with a thorough understanding 10. FDA Website, “Recently Posted Warning Letters,” www.
of product parameters and associated quality attributes,
11. FDA, Warning Letter issued to Caraco Pharmaceuti-
will be in a better position to avoid potential FDA 483 cal Laboratories, Detroit, Michigan, October 31, 2008,
observations. In addition, having this kind of substantial http://www.fda.gov/ICECI/EnforcementActions/
product knowledge will be beneficial for writing clear, WarningLetters/2008/ucm1048080.htm (accessed
valid procedures to manufacture products within the 6/10/09).
12. FDA, Warning Letter issued to Catalent Pharma So-
scope and intent of CGMPs. The considerations must be
lutions, Raleigh, NC, March 28, 2008, http://www.
monitored throughout the product lifecycle (i.e., begin- fda.gov/ICECI/EnforcementActions/WarningLet-
ning with development and including clinical manufac- ters/2008/ucm1048356.htm (accessed 6/10/09).
turing and continuing throughout the entire commercial 13. FDA, Warning Letter issued to Genzyme Corpora-
life of the product). The site compliance program includ- tion, Cambridge, MA, February 27, 2009, http://www.
ing internal audits and the audit management process are
ucm148998.htm (accessed 6/10/09).
basic to regulatory audit preparedness. 14. FDA, Warning Letter issued to Taro Pharmaceuticals,
The reader may consult Medina’s series on FDA inspec- Hawthorne, NY, February 5, 2009, http://www.fda.

114 Conducting Audits, Gap Assessments & Corrective Actions Volume II

Richard Poska and Ballard Graham

ucm148668.htm (accessed on 6/10/09).

15. FDA, Warning Letter issued to Merck and Company,
West Point, PA, April 28, 2008, http://www.fda.gov/
ucm1048323.htm (accessed on 6/10/09).
16. FDA, Warning Letter issued to Sandoz, Inc., Princeton,
NJ, August 12, 2008, http://www.fda.gov/ICECI/En-
forcementActions/WarningLetters/2008/ucm1048180. About the Authors
htm (accessed on 6/10/09).
17. FDA, Warning Letter issued to Steris Corporation,
Menton, OH, September 25, 2008, http://www.fda.gov/
Richard Poska is Director, Global Pharmaceu-
ICECI/EnforcementActions/WarningLetters/2008/ tical Regulatory Affairs, Strategic CMC Initia-
ucm1048125.htm (accessed 6/10/09). tives, Abbott, Lake County, Illinois. He may be
18. FDA, Warning Letter issued to GE Healthcare Integrat- reached at richard.poska@abbott.com. Richard
ed IT Solutions, Barrington, IL, August 12, 2008, http:// Poska is also column coordinator of “Global
gLetters/2008/ucm1048178.htm (accessed on 6/10/09).
Regulatory Viewpoint.”
19. FDA, Warning Letter issued to Haemonetics Corpora-
tion, Braintree, MA, December 4, 2008, http://www. Ballard Graham is Division Vice President,
fda.gov/ICECI/EnforcementActions/WarningLet- Compliance Oversight, Abbott Quality and
ters/2008/ucm1048055.htm (accessed 6/10/09). Regulatory, Abbott, Lake County, Illinois. He
20. FDA, Warning Letter issued to Ranbaxy Laborato-
ries Limited, India, September 16, 2008, http://www.
is a 32-year veteran of the US Food and Drug
fda.gov/ICECI/EnforcementActions/WarningLet- Administration, spending his last eight years
ters/2008/ucm1048055.htm (accessed 6/10/09). as District Director of the Atlanta Office of the
21. O’Donnell, Kevin, “Self Inspection and its Potential FDA.
Benefits Via ICH Q9,” Journal of GXP Compliance, Vol-
ume 12, #4, Summer 2008.
22. Medina, Carmen, “The FDA-Inspection Preparation
Master Plan: How to Design and Implement and In-
spection Readiness Program. Part 1 of 3,” Journal of
cGMP Compliance, Volume 4, #4, July 2000.
23. Medina, Carmen, “Perspectives on Managing and
Controlling the FDA-Inspection Process: How to Stay
on Course. Part 2 of 3,” Journal of cGMP Compliance,
Volume 5, #1, October 2000.
24. Medina, Carmen, “Responding to the FDA-483 and
Intercepting a Warning Letter: How to Prepare a Com-
prehensive, Far-Reaching, Integrated Response. Part 3
of 3,” Journal of cGMP Compliance, Volume 5, #2, January
25. Medina, Carmen, editor, “Compliance Handbook
for Pharmaceuticals, Medical Devices, and Biologics,”
Drugs and the Pharmaceutical Sciences, Volume 136.
Marcel Dekker, New York, 2004.

Originally published in Journal of GXP Compliance Volume

14 Number 1

115 Conducting Audits, Gap Assessments & Corrective Actions Volume II

Richard Poska and Ballard Graham

An Introduction to Cold Chain

Richard Poska and Ballard Graham

Welcome to “Supply Chain Forum.” ity, or potency rendering the product ineffec-
Control of the supply chain is an extremely im- tive.
portant topic in pharmaceutical and medical device • All storage and handling practices for cold
chain shipments are regulated per US Food
manufacturing. Supply chain involves all aspects of and Drug Administration current good
product manufacturing to some degree. Raw materi- manufacturing practices. There are special re-
als, intermediates, bulk product, packaged product, quirements governing infectious or hazardous
auxiliary materials such as filters and lubricants, and shipments as promulgated by the US Depart-
other myriad materials all come through the supply ment of Transportation and the International
Air Transport Association.
chain. The 2008 China heparin incident and the • United States Pharmacopeia 33 chapter
global diethylene incidents attest to the challenges <1079> “Good Storage and Shipping Practic-
and criticality of control of the supply chain and the es” also provides guidance for handling cold
material quality system. chain pharmaceutical products.
This feature provides a forum for compliance prac- • A structured approach to cold chain manage-
ment is recommended including packaging
titioners to share information about topics associated process and shipping validation. Transport
with the materials quality system. The information and storage are also included in the method-
provided will be helpful and practical so as to enable ology.
application in actual work situations. “Supply Chain • Written procedures are mandatory. Personnel
Forum” will address successful strategies, approaches, training is essential. Temperature monitoring
during shipping is highly critical.
and practices associated with this important aspect • Case studies demonstrating deficient cold
of pharmaceutical and device manufacturing. We chain control practices illustrate key points.
intend “Supply Chain Forum” to be a useful resource
that provides valuable information and enhances
compliance performance.
Cold chain can be defined as the supply and distri-
Reader comments, questions, and suggestions
bution chain for products that must be kept within
are needed to help us fulfill the column’s objective.
a specific temperature range. The shipping of a drug
Case studies illustrating actual experiences associ-
product that requires temperature controlled pack-
ated with supply chain management and control
aging is a challenge.
are most welcome. Please send your comments and
Environmental conditions are critical to ensure
suggestions to column coordinator Ernest Castiaux
drug product quality. If there is a loss of control
at Ecastiaux@hotmail.com or journal coordinating
in the cold chain at any time during the process, a
editor Susan Haigney at shaigney@advanstar.com.
temperature sensitive drug may lose its integrity,
stability, or potency. A temperature sensitive drug
KEY POINTS may become ineffective if exposed to inappropriate
The following key points are discussed: temperatures within the supply chain. Frequently,
• Cold chain can be defined as the supply and this means that during storage and transport the
distribution chain for products that must be
kept within a specific temperature range. drug temperature must be held between refrigera-
• Loss of control of required storage conditions tion temperatures of 2°-8° C.
may cause the product to lose integrity, stabil- The number of temperature-sensitive products

116 Conducting Audits, Gap Assessments & Corrective Actions Volume II

Richard Poska and Ballard Graham

is rapidly increasing. Most shipments of biologics tion protocol.” This thermal testing qualification
are transported via cold chain. The Biotechnology may be performed using a validated controlled
Industry Organization (BIO) has estimated that the temperature chamber or actual transit testing us-
average growth of temperature sensitive products ing the expected transport method and shipping
will be 15% per year and that this growth exceeds lanes (origin to destination). Certified test labs use
that of the rest of the pharmaceutical industry (1). validated environmental chambers to simulate the
ambient temperature that the package may encoun-
ter using standard profiles. These profiles simulate
the transit of the package through the distribution
All storage and handling practices for cold chain
channel with changes in temperature and duration.
shipments are regulated per US Food and Drug Ad-
The profiles are established by the International Safe
ministration current good manufacturing practice
Transport Association (ISTA) and cover both land
(CGMP) guidelines. 21 CFR 211.142 and 21 CFR
and air transport of various times and package con-
150 outline the basic requirements for the storage
figurations (6). Detailed test reports are necessary
and distribution of drug products (2). This regula-
in order to demonstrate support of the regulatory
tion also pertains to clinical sample shipments. The
distribution of clinical kits while ensuring that they
maintain proper temperature is just as critical as for
commercial drugs. Medical devices containing a AN APPROACH TO COLD CHAIN
drug or biologic product in combination will also MANAGEMENT
fall under these sections of the CGMPs. The need for special handling, regulatory consid-
Additionally, there are special requirements erations, and the increase in the quantity of items
governing infectious/hazardous shipments as pro- being shipped requires a structured approach in
mulgated by the US Department of Transportation order to ensure that the drug product moves from
(DOT) (3) and the International Air Transport As- the manufacturing point to the patient under the
sociation (IATA) (4). They pertain to protecting the correct environmental conditions. The packaging
product container from damage that could result process must be qualified via documented testing
in leakage and human exposure. There are many to ensure that the packaging configuration and
cold chain drug products that are governed by these transit method being used meets pre-determined
requirements. acceptance criteria with a high degree of assurance.
There have been several FDA 483 citations issued
for deficient shipping validation.
USP The cold chain system consists of not only the
In addition to the FDA Part 211 requirements
packaging of the insulated container with the ap-
and possible hazardous materials requirements,
propriate proven quantity of refrigerants, but also
the United States Pharmacopeia (USP) 33 chapter
the transport and storage of the drug product. All
<1079> “Good Storage and Shipping Practices”
of these elements should be analyzed, measured, un-
provides guidance for handling cold chain phar-
derstood, and qualified to ensure that the quality of
maceutical products (5). This chapter provides the
the product and patient safety is not compromised.
requirements for ensuring a product’s “identity,
There must be written procedures in place that
strength, quality, and purity” across the entire dis-
describe proper handling of the drug product when
tribution channel—from manufacturer to end user
it is being stored and transported. Personnel should
covering the handling and storage of products in
know how to monitor temperatures and how to re-
warehouses, during transit, and in pharmacies.
spond to conditions when the desired temperature
USP 33 <1079> “Good Storage and Shipping
is outside the allowed range. The method of moni-
Practices” states that “Operational and perfor-
toring the temperature of the drug product during
mance testing should be part of a formal qualifica-
storage and in transit is critical.

117 Conducting Audits, Gap Assessments & Corrective Actions Volume II

Richard Poska and Ballard Graham

The following two cold chain case studies exem- that the shipment never achieved a temperature of
plify failures in the respective firm’s approach to less than 8°C (temperature was high). The proper
cold chain management. product temperature range requirement was 2°-8°C.
An investigation indicated that the correct quan-
Case Study Number One tity and type of refrigerants were used and properly
The temperature monitor for a shipment indicated, configured within the insulated container. The re-
upon receipt, that the drug product exceeded 8°C for search determined that a pallet of refrigerants (gel
the duration of the shipment. The subsequent ex- packs) had arrived the day prior to the day of ship-
amination found that the shipment was packed into ment and were placed in the cold storage area. The
the correct container configuration according to the refrigerants had felt cold to the individual packing
approved standard operating procedure (SOP). All the container, so it was not noticed that the refrig-
prior shipments were received with the temperature erants were not thoroughly chilled and, therefore,
monitor indicating the product had remained within did not have the cooling capacity required. The root
the desired 2°-8°C temperature range. cause was determined to be that the refrigerants had
An investigation revealed that the qualification not been held long enough at the desired low tem-
of the insulated container and gel pack configura- perature.
tion had been performed retrospectively using ac- If refrigerants are not held at the desired cold
tual transit data from shipments that had occurred temperature, either frozen or cold, for a sufficient
during the winter. The temperature data for the amount of time, then the outer layer of the gel may
product shipments was within range and, therefore, feel cold, but the gel will not be at a uniform tem-
the configuration was qualified. When this ship- perature. When cases of refrigerants are received
ment was made during the late spring, at a much and stored on a pallet, several days in cold or frozen
higher ambient temperature, the configuration did storage are required to ensure complete chilling
not have enough cooling capacity to hold the tem- throughout prior to use.
perature and lacked sufficient insulating capacity to Procedures describing the preparation of refrig-
prevent the conduction of external heat to the drug erants must be clearly specified. This includes the
product payload. Thus the validation lacked a for- specific temperature range at which refrigerants are
mal qualification that took into account all of the stored, and the length of time refrigerants are stored
conditions expected during transit to demonstrate to prepare refrigerants for actual use in shipping.
that the packaging configuration met pre-deter- Simply feeling the refrigerants without documented
mined specifications. storage conditions traceability is not adequate.
Validation protocols for cold chain supply chains
should require representative worst-case maximum CONCLUSION
temperature exposure situations. When challeng- The special requirements for handling cold chain
ing the transportation of products that require pharmaceutical products can be challenging. How-
controlled moderate temperatures, worst-case high ever, they are manageable with proper preparation,
temperatures (summer conditions) and worst-case using qualified processes, and ensuring that proce-
low temperatures (winter conditions) should be dures are being correctly followed.

Case Study Number Two REFERENCES

1. White Paper, Sensitech Corporation, Beverly, Massa-
A shipment was prepared using a qualified container chusetts.
and an approved SOP. The configuration was vali- 2. Code of Federal Regulations, Title 21 Part 211 Current
dated by following Center for Drug Evaluation and Good Manufacturing Practice for Finished Pharma-
Research’s (CDER) General Principles of Process Vali- ceuticals, Subpart H, Holding and Distribution.
dation (7), yet the temperature monitor indicated 3. DOT, Federal Hazardous Materials Transportation
Law, Office of Hazardous Materials Safety, US Depart-

118 Conducting Audits, Gap Assessments & Corrective Actions Volume II

Richard Poska and Ballard Graham

ment of Transportation.
4. IATA, Packaging Instruction UN2814, 51st Edition, Dan-
gerous Goods Regulations, International Air Transport
Association, 2010.
5. USP, USP 33, <1079> “Good Storage and Shipping
Practices,” US Pharmacopeia.
6. ISTA, Test Procedures and Standards, International Safe
Transport Association.
7. 7. FDA, Guideline on General Principles of Process Valida-
tion, Center for Drug Evaluation and Research, United
States Food and Drug Administration, May 1987.


CGMP Current Good Manufacturing Practice
DOT US Department of Transportation
FDA US Food and Drug Administration
IATA International Air Transport Association
SOP Standard Operating Procedure
USP United States Pharmacopeia

Originally published in Journal of GXP Compliance Volume

14 Number 4

About the Author

Ernest Castiaux is a senior supply chain con-
sultant at Pharmatech Associates. He has more
than 30 years experience in operations and
supply chain management within the phar-
maceutical and bio-tech industries. He may be
reached by e-mail at ecastiaux@hotmail.com.

119 Conducting Audits, Gap Assessments & Corrective Actions Volume II

Peter Weichel

Conducting Valuable Preliminary

Peter Weichel

INTRODUCTION • Incomplete requirements and specifications

• Changing requirements and specifications
Running projects is common practice within many • Lack of executive support
businesses and industries. Some companies have de- • Technology incompetence
veloped a formal project office that provides a final • Lack of resources
project model and project handbook, whereas other • Unrealistic expectations
companies have a more informal structure for run- • Unclear objectives
• Unrealistic time frames
ning projects. • New technology
A generic and classic high-level model for project • Other.
lifecycles contains phases like conceptualization,
planning, testing, implementation, and closure (1). More recent studies have confirmed the low project
This model describes what will happen when the success rate even though it has improved over the past
decision to start a project has been taken. But before years. With this in mind, it makes sense to conduct a
a project has been decided, there is a phase—some- short preliminary investigation at an early stage and be-
times called the pre-analysis phase—that should be fore a project is started. Preliminary investigations can
completed. This pre-analysis phase is important to be used to prepare users at an early stage for potential
all projects, but is not covered well in the common future changes and thereby help anchor an upcoming
literature and is not always used in projects. It is a project. Ultimately, the preliminary investigation can
vital phase, because the lack of such an investigation reveal that a planned/requested project is not actually
can influence the future project. needed or will not add value to the business, thereby
The purpose of this article is to outline how a pre-anal- saving time and resources.
ysis can be performed. In this article the pre-analysis
is called preliminary investigation. The article tries to
provide a generic concept for conducting preliminary PRELIMINARY INVESTIGATIONS
investigations. It is based on the author’s personal expe- Preliminary investigations should be performed before
rience with managing projects in general. project conceptualization and project start. They should
be used to retrieve important data and information that
will later be used in project conceptualization (e.g., when
WHY PROJECTS FAIL writing the business case for the project). Basically, the
Many projects, especially IT projects, tend to fail when preliminary investigation looks at situations S0, S1, and
measured on parameters like budget, plan, quality, and S2 and their relations, as shown in Figure 1.
the resulting system. A famous research study conduct- Conducting a preliminary investigation should not
ed in 1995 in the United States by the Standish Group be a long or major task, as this could de-motivate or
surveying companies in different industries found that, actually prevent projects from starting. The prelim-
on average, only 16.2% of software projects are com- inary investigation should by definition be a quick
pleted on time, within budget, and with all features and and initial survey of situations S0, S1, and S2 before
functionalities as initially specified (2). In this study the a more detailed investigation is started. A period of
Standish Group also concluded that the following are one to three months is recommended, depending
the main reasons why software projects are challenged: on the project and the business processes in focus.
• Lack of user input Investigations longer than three months should not

120 Conducting Audits, Gap Assessments & Corrective Actions Volume II

Peter Weichel

S2: Implement new system/processes/technology

S0: Current situation

S1: Redesign current system/processes/technology

Figure 1:
Field in focus of the preliminary investigation.

be classified as preliminary investigations.

Who should conduct the preliminary investigation? The problem survey simply consists of the follow-
It is recommended that one person be put in charge of ing:
the investigation. If needed this could be supplemented • Description of the major problems existing
with one to three persons functioning as consultants, (user-friendly description, not technical)
• Categorization of the types of problems (or-
specialists, or reviewers in a reference group. The im- ganizational, technology, human resource
portant thing here is to avoid a large formal project problem, etc.).
group, as this could prevent a quick investigation and
instead turn the preliminary investigation into a long- Do not try to offer solutions, but simply describe
term project itself. problems.
A preliminary investigation should involve the ele- As with the problem survey, the benefit analysis
ments, methodologies, and output shown in Figure 2. simply consists of the following:
Other items can be included as well, but the most im- • Description of the benefits (user-friendly de-
portant ones are outlined in this article. It is important scription, not technical)
to remember that a preliminary investigation is not a • Classification of the benefits as quantitative
benefits and non-quantitative benefits.
scientific study and should not try to give definite an-
swers for every issue. The final product of the prelimi-
How is data and information obtained as input for
nary investigation should be a short report.
the scope definition, the problem survey, and the
benefit analysis?
The elements of the preliminary investigation include
the scope analysis, the problem survey, and the bene-
The user interview, the data analysis, and the question-
fit analysis. The purpose of these elements is to get a
naire can be used together, individually, or in combi-
clear understanding of the basis and objective of a fu-
nation to obtain data and information. The person in
ture project before the project work is actually started.
charge of the preliminary investigation should choose
Knowing these three elements (scope, problems, and
the methods that are best suited to the situation.
benefits) is essential for all project startups.
The user interview is done by interviewing relevant
The scope analysis can be done by simply asking the
users in the business and technology areas. Do not try
following questions:
• Who are the potential users? to interview every employee in the company, but find a
• Which departments or business areas could representative group. An agenda should be issued first,
be involved? and questions must be prepared beforehand (see Table
• What are the business processes (i.e., high-lev- I). The types of questions presented in Table I are active
el description, not detailed)? questions (also called “open questions”) in the sense that
• Are records or documents generated?
• Do regulatory requirements or standards ap- they require the interviewees to actively reflect on the sit-
ply (e.g., GLP, GCP, or GMP)? uations and not just answer yes or no. Interviewing users
• What kind of technology is used? could also be combined with a demonstration of the

121 Conducting Audits, Gap Assessments & Corrective Actions Volume II

Peter Weichel

Preliminary investigation:

Elements: Methodologies:
• Scope analysis (S1, S2) • User interview
• Preliminary vision (S1, S2)
• Problem survey (S0) • Data analysis
• Draft scope (S2)
• Benefit analysis (S1, S2) • Questionnaire
• List of identified problems (S0)
• List of identified improvements (S1)
• List of identified benefits (S1, S2)
Figure 2:
Elements, methodologies, and output of a preliminary investi- • List of key-stake holders (S0, S1, S2)
gation. • Preliminary URS (S2)
• Initial economic assessment (S2)
• Initial cost-benefit analysis (S1, S2)
• Current conclusion/recommendation

business activities or processes in action. person in charge of the preliminary investigation

Other parties than the real users could also be outlines the relevant questions.
interviewed. Company visits or visits by technol- Using questionnaires can be more difficult, because
ogy vendors could provide important data and the perception of written questions can be different
input (e.g., key figures indicating the price level of from person to person. Basically, questionnaires can
the technology on the market). At this stage the be issued on paper (i.e., P-surveys) or on electron-
purpose should only be to obtain initial economic ic media, for example the Internet (i.e., E-surveys).
assessments giving a hint of the price level of the Questionnaires should be tested before they are issued.
technology on the market. No price negotiations Professional courses are provided on how to prepare
or tender process should be started at this stage, good and useful questionnaires. Several courses can
because it is too comprehensive at this stage and is be found on the Internet that can help in avoiding the
done in later project phases. most common pitfalls when designing and writing
Data analysis is a broad term and somehow re- questionnaires.
flects the fact that it involves analyzing data from The advantage of using questionnaires is that peo-
the business processes. If, for example, the system ple participating can return their answers at their
currently in place uses an Access database for con- convenience. On the other hand, answering ques-
trolling documents (e.g., a complaint database) the tionnaires can be time consuming for people, and
data analysis could simply be to retrieve data from the number of respondents can sometimes be low
the system that answer the following questions: and, therefore, not representative.
• What is the lead time for records generated in Here it is important that the person in charge of the
the system? preliminary investigation actually asks what the pur-
• How many records have been generated over
the past years? pose and objective of issuing a questionnaire is. What
• Which users/departments have generated will be obtained that cannot be obtained by a user in-
most records over the past 24 months? terview? The person in charge of the preliminary inves-
tigation should ask the following questions:
In most electronic systems, this data can easily by • What is the purpose and objective of the ques-
retrieved by simple queries in the system, either di- tionnaire?
• What data/information do we want from the
rectly from the user interface or, alternatively, from respondents?
the system administrator using an appropriate query • What do we know before issuing the ques-
language behind the database application (e.g., SQL tionnaire?
or similar). The important thing here is that the • How will answers be analyzed, processed, and

122 Conducting Audits, Gap Assessments & Corrective Actions Volume II

Peter Weichel

TABLE I: Type of questions used in the user interview.
All together, the user interviews, the data analysis,
1. W
 hat are the three most critical issues with the current
and the questionnaire will collect important data and system?
information that will serve as input to the scope defi-
2. W
 hat are the three most important reasons/benefits for
nition, the problem list, the list of identified benefits, changing to a new system?
the potential key stakeholders, etc. This information is
analyzed and processed by the person in charge of the 3. W
 hat are the most important redesigns that can be made
to improve the current system?
preliminary investigation and presented in the prelimi-
nary investigative report. 4. Who are the most important user(s) of the current system?

THE OUTPUT direction the work in the future project should go. In
The processed results are collated and presented in case a decision has been taken during the preliminary
short form in the preliminary investigative report. The investigation the output could instead be written directly
results can be displayed in attachments to the report as a Project Charter for a future project.
(e.g., as lists or in bullet form). A fictional example of
a scope definition is provided in Table II. A fictional CONCLUSION
example of problems identified during the preliminary This article has been written with the objective of pro-
investigation is provided in Table III. viding an example of how a preliminary investigation
A good understanding of the problem area en- can be conducted. The example is presented in generic
sures that problems from the legacy world will not be form, independent from a specific project in mind.
transferred to the new or redesigned system/process/ Other approaches for performing preliminary investi-
technology when writing the final user requirement gations can be used. The important thing is that the per-
specification (URS) in later project phases. son in charge of the investigation chooses the approach
Not all the items listed in Figure 2 need to be output and methods most appropriate for the specific situation.
of the preliminary investigation. This depends on the
specific situation. The important thing is that the pre-
liminary investigation by definition does not offer defi-
1. H. Kerzner, Project Management—A Systems Approach to
nite or scientific answers to every issue. Interim results Planning, Scheduling, and Controlling, John Wiley & Sons, Inc.
could be used, as well. 2. The Standish Group International, Inc, The Standish Group
Chaos Report, 1995.


CFR Code of Federal Regulation
The final product is the preliminary investigative re- EDMS Electronic Document Management System
port. It is valuable to the upcoming project and serves GCP Good Clinical Practice
as a baseline or starting point of knowledge. The report GLP Good Laboratory Practice
provides, for example, valuable and useful information GMP Good Manufacturing Practice
when defining the vision in more detail and writing the QA Quality Assurance
QC Quality Control
business case of a coming project. It can also give initial R&D Research & Development
economic assessments of a future project or a specific SOP Standard Operating Procedure
technology on the market before a real tender process is URS User Requirement Specification
initiated. The report does not offer final answers to all
issues, but functions as a tool to help a project group de-
termine which direction the more detailed work should Originally published in Journal of GXP Compliance Volume
take. The preliminary investigative report should contain 14 Number 4
a conclusion or recommendation with regard to which

123 Conducting Audits, Gap Assessments & Corrective Actions Volume II

Peter Weichel

About the Author

Peter Weichel holds an M.S. degree from Uni-
versity of Southern Denmark. He is IPMA cer-
tified as a Project Management Associate and
works as a project manager in the pharmaceu-
tical industry. Peter can be reached at peterwe-

124 Conducting Audits, Gap Assessments & Corrective Actions Volume II

David Ingram

Technical Problem Solving

David Ingram


This article is intended for system validation and The terms “problem solving” and “improvement” or
continuous improvement practitioners supporting “continuous improvement” are often used in gener-
maintenance of validated systems. This article was al terms to mean the same thing. In order to solve
written with the assumption that the reader has a problem or to improve a system, it is critical to
some background in Lean Six Sigma tools and de- understand the data or information that led to the
fine, measure, analyze, improve, control (DMAIC) decision to take action in the first place. Action is
methodology. The methods discussed in this article generally warranted for one of the following two rea-
are from a validation perspective but are applicable sons: System performance has consistently under-
to problem investigation efforts in general. This ar- performed requirements or expectations for some
ticle describes a problem-solving methodology and period of time, or system performance has changed
basic supporting tools. It does not pretend to teach over time where the change could have been sudden
the problem-solving methodology and associated or gradual. The first situation requires an effort to
tool kit. Most of the common problem-solving and take the system to a new level of performance (i.e.,
improvement tools can be found in a web search improvement) while the second situation requires
or in a quality reference book such as Juran’s Qual- an understanding of why performance has changed
ity Control Handbook (1). Many books and quick so that it may be returned back to its previous state
reference guides have been written on the subject. (i.e., problem solving). This article focuses on the
Definitions of tools mentioned in this article are latter situation. While the tools applied within
provided in the Addendum. problem solving and improvement efforts are prac-
A common way to maintain a validated system tically the same, there is one unique question that
is through the use of a control plan (2). A control sets these two approaches apart. A problem-solving
plan generally describes how the system inputs (i.e., effort is specifically attempting to answer the ques-
controls) and outputs (i.e., performance character- tion “what caused the change in performance?” To
istics) are controlled and measured. An effective put this in perspective, consider problem solving to
control plan not only detects when performance has be a special case of improvement.
changed but also provides an action plan to ensure
performance remains stable and capable of meeting PROBLEM SOLVING METHOD
specification limits. Even in cases where compensat-
ing adjustments may be used to successfully address
A problem-solving effort is aided by a host of tools
an undesirable change in performance, this action
to help scope the problem and determine root cause.
should be viewed as a temporary measure while an
In particular, there are three tools that should be part
investigation of the root cause is conducted. This
of any problem-solving effort: Is-Is Not Diagram,
article focuses on a basic problem-solving approach
Cause and Effect Diagram, and Contradiction Ma-
to determine root cause.

125 Conducting Audits, Gap Assessments & Corrective Actions Volume II

David Ingram

Figure: Essence of problem-solving methodology.

Fact 1
Fact 2
Fact 3
Fact 4


trix. The Is-Is Not Diagram is a technique developed Quite often, immediate theories develop regard-
by Charles Kepner and Benjamin Tregoe (3). The ing the problem’s cause. These theories along with
Cause and Effect Diagram, also known as Fishbone other brainstormed potential causes are gathered
Diagram and Ishikawa Diagram, was developed in and documented using the Cause & Effect Diagram.
1950 by Kaoru Ishikawa. The Contradiction Matrix Once the facts (i.e., the Is/Is Not information) and
was developed in the 1990s (exact date/author un- potential causes are identified, each cause is tested
known) to help manage the problem-solving effort. against the facts to determine whether the facts
These tools and other common tools are described support the cause. Causes that are not supported
in this article. by one or more facts are generally eliminated from
The problem-solving methodology is performed further consideration. The basic approach is to find
in a team setting to identify root causes, solutions, the root cause(s) of the problem by process of elim-
and preventative controls associated with a perfor- ination. Causes that cannot be eliminated by the
mance change in some measured characteristic. facts are the candidates for root cause. The Contra-
The characteristic may be discrete (e.g., product diction Matrix is used to manage and document the
complaint) or continuous (e.g., part strength). The “elimination” process. It is common and expected
basic problem- solving approach is described in the that some causes will not have supporting or con-
Figure. tradicting facts or that some assumptions about the
The problem-solving methodology is a highly it- data are made. This occurs when facts about the
erative process that moves between gathering facts problem with respect to a cause are not known. In
about the problem and identifying potential causes. such cases, additional studies are run to collect the
The effort begins with constructing an Is/Is Not Di- relevant information. This becomes an iterative
agram by collecting facts that can be derived from process of data collection to eliminate (or support)
existing information. The Is/Is Not Diagram helps potential causes. This process continues until either
to scope and organize the information in terms of the root cause(s) is discovered or all potential caus-
what is related and is not related to the problem. es have been eliminated by the facts. In the event
Information is collected that describes what, where, that all causes are eliminated, the team will typically
when, and extent of the problem. Information con- hold additional brainstorming sessions (may in-
tained within the Is/Is Not Diagram must be factual clude new people based upon knowledge gained) to
in order to be useful in solving the problem. identify more potential causes to be screened. This

126 Conducting Audits, Gap Assessments & Corrective Actions Volume II

David Ingram

Table I: : Example of the Is/Is Not diagram.

Is (The Problem) Is Not (The Problem)

What Presence of flash (plastic on molded part) on product XYZ Other defects, other products

Top seal Bottom or side seals

Molding cavities 1-4 Molding cavities 5-8

Since October 9th Before

All three shifts One or two shifts only

Consistent rate: average is 2.3% across affected cavities

Extent Sporadic rate of occurrence
(p-chart is in control)

process provides a robust method to determine root instance, the example in Table I reveals several inter-
cause. In addition, it provides a sound documented esting facts with respect to the “where” and “when”
thought process even in the event root cause is not aspects. It is common for the Is/Is Not Diagram to ini-
determined. tially contain some opinions and/or assumptions. This
is okay as long as the final Is/Is Not Diagram contains
DMAIC METHODOLOGY FOR only confirmed facts. The Is/Is Not Diagram is a living
tool, meaning that information should be added as it
PROBLEM SOLVING becomes available.
DMAIC is arguably the most widely used improve-
The chronology, history, and background of the
ment methodology currently in use. This meth-
problem must be understood. Has this problem oc-
odology was modified to make it appropriate for
curred before? Has anyone else (internal or external
problem- solving efforts as defined in this article.
to the organization) attempted to solve this problem
High-level definitions of each phase are as follows:
• Define: Gather existing information about the or a similar one before? If so, what knowledge can
problem. Is/Is Not: where, what, when, extent. be leveraged from these previous efforts?
• Measure: Continue gathering information A timeline of the problem should be constructed.
and convert information to facts. This is best achieved by performing a time-ordered
• Analyze: Identify the potential causes. Screen analysis of the performance data using a control
causes against the facts. Eliminate causes not
supported by facts. Determine root cause(s). chart such as a change point analysis (4). This tool
• Improve: Identify and test potential solutions. provides insight regarding the timing and size of the
• Control: Implement solution. Deploy or ad- change. This analysis helps to address the “when”
just the control plan to prevent reoccurrence. question of the Is-Is Not Diagram. If the timing of
Institute and standardize new controls. the change can be well defined, it is appropriate to
begin to assess process inputs that may have changed
Define and Measure within this window. Consider changes to the input
The purpose of the define and measure phases is to categories described within the analyze section of
define and scope the problem. Throughout define this procedure.
and measure, information is gathered that helps to Additional define and measure tools are described
put a fence around the problem. The primary scop- in the addendum.
ing tool is the Is/Is Not Diagram (see Table I).
It is easy to see how this analysis can provide a wealth
of information with respect to determining root cause. Analyze
As typical with most problem-solving efforts, some of The purpose of the analyze phase is to identify po-
the information bits are more useful than others. For tential causes, screen the potential causes against

127 Conducting Audits, Gap Assessments & Corrective Actions Volume II

David Ingram

Table II: Example of the five outcomes of a potential cause compared against a fact.
Fact/Potential Cause Top seal only Cavities 1-4 Oct. 9th to present Constant defect rate

Major machine
(what maintenance (what maintenance X
maintenance on Nov. 15th
was performed?) was performed?)
Daily machine setup A A A
procedure changed in (what are the (what are the (what day did the N/A
October specific changes?) specific changes?) changes go into effect?)

New machine operators A A A N/A

the facts, and identify the root cause(s). to support or contradict the cause.
Potential causes need to be identified. Use team
brainstorming in conjunction with the Cause and Blank boxes and assumptions represent the need
Effect Diagram to identify potential causes. Con- to collect additional data assuming that no other
sider causes from the following categories: Method, existing facts can eliminate the cause. Only an “X”
Machine, Material, Man (people), Measurement, can eliminate a cause. A small example is provided
and Environment. An effective brainstorming ses- in Table II.
sion focuses on identifying potential causes while The first potential cause in Table II is eliminated
avoiding the temptation of judging their likelihood because at least one fact does not support the the-
as being the root cause. All potential cause theories ory. If major machine maintenance that occurred
should be captured regardless of their popularity. It on November 15th caused the flash defect, how
is important not to alienate team members by pre- does it explain the observation of flash occurring a
judging their cause theories as improbable. Instead, month earlier? The decision to eliminate this po-
the optimal approach is to let the facts dictate which tential cause is clear. The second cause is not. At a
theories have merit. When theories are challenged high level, a change in the setup procedure may be
against the facts it removes the emotional aspect supported by the facts if assumptions (A) are made.
and becomes very clear to the team members which The next step would be to collect additional data to
theories hold water and which do not. Potential turn (As) into (Os) or (Xs). There is no need to col-
cause screening is the next step. lect additional data against a particular cause once
Each potential cause is screened against the facts. an (X) is rendered. For example, there is no need to
This step involves testing each potential cause collect additional data with respect to the first cause
against the facts. For example, “if X is the root cause because an (X) is present in the row.
of the problem, how does it explain the Is and Is Not The Contradiction Matrix can grow quite large;
data?” What assumptions, if any have to be made? therefore, the strategy should focus on eliminating
Causes that cannot be explained by the is/is not data as many causes as quickly as possible. One useful
or where no reasonable assumption(s) can be made technique when constructing the Contradiction
are eliminated. The Contradiction Matrix is used to Matrix is to place the most unique facts in the first
document this screening process. Potential causes columns. These facts often serve to eliminate the
are listed in the first column of the matrix while the lion’s share of the potential causes, therefore elimi-
facts are listed across the top row. When comparing nating the need to complete the remaining columns.
a potential cause against a fact, the following five For example, there was a case where a higher saline
outcomes are possible: concentration was measured from a single fill noz-
• O = cause is supported zle on a filling machine that simultaneously filled
• X = cause is contradicted from eight nozzles. Yet only one particular fill noz-
• A = cause is supported with assumptions
• N/A = no relationship between cause and fact zle experienced higher saline concentrations. This
• Blank box = no factual information available fact is very unique and served to eliminate most of

128 Conducting Audits, Gap Assessments & Corrective Actions Volume II

David Ingram

Table III: Updated example reflecting theory regarding new machine operators.
No new operators
Fact/Potential Cause Top seal only Cavities 1-4 Oct. 9th to present Constant defect rate
since June
Major machine
maintenance on Nov. 15th
Daily machine setup
(what are the (what are the (what day did the
procedure changed in N/A N/A
specific specific changes go into
changes?) changes?) effect?)

New machine operators A A A A X

the brainstormed potential causes. For example, Potential solutions should be identified and
one of the potential causes was the possibility of an selected. Depending upon the root cause(s), the
elevated concentration of saline in the mix tank that solution may involve the use of mistake proofing
feeds all nozzles. If this were the root cause, how or optimization and variation reduction. If the
does it explain elevation in one nozzle but not the root cause was due to an error or omission, mistake
others? At best, this potential cause may survive if aproofing may be used to prevent or reduce future
reasonable assumption could be made. In this case, problems. For example, there was a case where a fil-
additional data would be required to either support ter was being incorrectly assembled into its housing.
or contradict the assumption. Another approach The solution was a redesign of the filter housing so
to eliminate causes is to quickly move across the that the filter could only be assembled in the prop-
columns of facts to determine if any stand out as er orientation, therefore eliminating human error
clearly contradicting the cause under review. that caused the problem. This solution was much
Additional data should be collected until the more robust than the typical action to retrain the
root cause is identified. The Contradiction Matrix operator. Sometimes, the problem is the result of a
provides a clear picture regarding what additional change in the performance average and/or excessive
data needs to be gathered. It would be unwise at variation. Efforts to better control the target (i.e.,
this point to conduct an all out data gathering blitz optimization) and reduce variation are considered
to remove the (As) or fill in the (blanks). Instead, with respect to root cause determination.
prioritize the remaining causes by likelihood and by In some cases, it may not be possible to put the
effort to gather the data. For example, it would be system back the way it was prior to the change. For
relatively easy to address the theory regarding “new example, the investigation may have confirmed that
machine operators” (see Table III). the change in performance was a result of a change
There are many tools and methods available to in the raw material formulation (where the custom-
help collect new information to address the (As) er was not initially informed). Given the current
and (blanks). In addition to the define and measure state, it may be impossible to go back to the old
tools listed in the Addendum, other tools include formulation. In this case, an improvement effort
Box-Plot, multi-vari chart, analysis of variance focused on other system inputs or new technologies
(ANOVA), t-Test, non-parameteric tests, and de- will be needed to achieve prior performance levels.
sign of experiments. More information on these The key test of root cause identification is the abil-
tools is available through the many sources as de- ity to turn the problem on and off using the solu-
scribed previously. Of course there are many other tion. This activity could be demonstrated as part
tools available as well. of a pilot deployment, when applicable. Once the
solution(s) is confirmed, a risk assessment should
Improve be performed to understand if the solution creates
The purpose of this phase is to identify and test po- any adverse effects on other performance measures
tential solutions. or the surrounding environment. Consider effect

129 Conducting Audits, Gap Assessments & Corrective Actions Volume II

David Ingram

on machine, methods, measurement, material, peo- CONCLUSION

ple, and environment. A failure mode and effect The problem-solving methodology described in this
analysis (FMEA) may be useful here. Performing a article provides a robust and logical thought process
pilot of the new process can provide valuable insight for determining root cause. Sometimes even our
to assessing risk. best efforts will not yield the root cause. However,
it is important to be able to logically demonstrate
Control and explain the methodology used. This may be-
The purpose of this phase is to prevent reoccurrence come particularly important if the effort is reviewed
of the problem. New controls should be instituted by outside auditors and others who are looking for
and standardized. The main activity is to finalize the demonstration of a systematic problem-solving
control plan for managing the process going for- method.
ward. The control plan may include items such as
implementing mistake proofing, instituting control REFERENCES
charting, and the use of sampling plans. System 1. Juran , J.M., Juran’s Quality Control Handbook, 4th edi-
revalidation is often necessary. tion, Mcgraw-Hill, August 1988.
2. Ingram,D., “Six Sigma and Process Validation Strate-
gies – Part II,” Journal of Validation Technology, Volume
ADDITIONAL CONSIDERATIONS 6 Number 4, August, 2000, pp 756-765.
Success can be achieved by having the right people, 3. Kepner, C. & Tregoe, B., The New Rational Manager,
right priorities, and right process. The effectiveness Kepner-Tregoe, Inc, Prinston NJ 1981.
4. Taylor Enterprises. Inc., Variation.com, Libertyville, IL,
of this methodology is directly related to the follow-
ing factors:
• Right people. Problem solving is a team
sport. It will not be accomplished success- ARTICLE ACRONYM LISTING
fully through an individual effort. It is rec- ANOVA Analysis of Variance
ommended that there be a team leader who is DMAIC Define, Measure, Analyze, Improve, Control
well versed in the problem-solving methodol- FMEA Failure Mode and Effect Analysis
ogy and associated tools. The team members
should include the process owner along with
other process experts. Consider individu-
als who are familiar with the process from a
method, machine, material, measurement,
people, and environment standpoint. ADDENDUM DEFINITION OF PROBLEM
• Right priorities. The problem-solving effort SOLVING TOOLS
must have strong management sponsorship
that is held accountable for root cause deter-
mination. One of the first indicators of sup- COMMON DEFINE
port is whether there is an actual team assem- AND MEASURE TOOLS
bled to tackle the issue. Lack of adequate team Check sheet: A check sheet is constructed as part
resources points to the fact that this problem of a data collection plan to gather specific informa-
is not a priority.
• Right process. It is recommended that the tion about the problem. Check sheets are freeform,
methodology described in this article include meaning they do not have a standard look or form.
the use of phase gate reviews that occur after Control chart/change point analysis: The primary pur-
each DMAIC phase to ensure the process pose of a control chart is to determine if the characteristic
is on track. Phase gate reviews involve the being measured is stable (“in control”) or if there has been
owner, team leader, and sponsors. Specific
deliverables for each phase should include the a statistical change in performance. Control charts provide
activities and tools outlined in this article. an understanding regarding the timing of the change. This
information aids in identifying the reasons or causes for the
change. Control charts may only be applied in situations
where data is time ordered. The data may be attribute like

130 Conducting Audits, Gap Assessments & Corrective Actions Volume II

David Ingram

defective units or continuous like bond strength. Com- the steps in a process.
mon control charts for attribute data include the p-chart Supplier input process output customer (SIPOC):
and c-chart. Common control charts for continuous data SIPOC is a tool that helps to understand the inputs
include the X-Bar/R chart, and Individuals Chart. The to and outputs of the process under investigation.
control charts described are best used to detect isolated This tool also connects the inputs and outputs to
or major shifts in performance. A second type of control suppliers and customers, respectively. It helps the
chart called a Cumulative Sum (Cusum) control chart is investigation team understand the big picture. Of-
useful for detecting smaller, sustained performance chang- ten used in conjunction with a process flow chart.
es. A software package called Change Point Analyzer is Timeline: There are two common timelines. The
available to perform the analysis. Change Point Analyzer first timeline is an analysis of the change in perfor-
can analyze both attribute and continuous data. mance. This information provides an understand-
Differences and changes: This tool adds a dimen- ing of when and to what extent the performance
sion to the Is/Is Not Diagram by specifically asking changed. This information provides the basis for
two questions: 1) what is different about Is vs. the the second timeline. Based upon the timing of the
Is Not Data and 2) if so, what input(s) may have change in the performance, a timeline depicting
changed that could explain the difference. potential input changes may be created. It’s import-
Is/Is Not Diagram: Key problem scoping tool to ant to determine the window of the performance
collect and organize the information pertaining to change first so that the search window of potential
what the problem is and is not. Information is col- input changes may be sufficiently narrowed.
lected that answer the questions what, where, when,
and extent of the problem. Those same questions Common Analyze Tools
are applied to understand what is not the problem. Affinity diagram: A tool used to organize ideas into
Measurement systems analysis (MSA): A tool to groups of related thoughts. This tool is commonly
understand the contribution of measurement vari- used following a brainstorming exercise.
ation relative to the total variation. Measurement Brainstorming: Tool used by a team of individ-
systems having excessive variation are not sensitive uals to come up with many ideas in a short period
enough to measure the process output. From a of time. A well-managed brainstorming session
problem-solving perspective, applying the tradi- does not consider the value of an idea but rather a
tional MSA approach is usually not relevant since focus to generate ideas. One common application
the measurement system was sensitive enough to for brainstorming is to generate potential causes of
detect a change that initiated the problem solving a problem. Brainstorming is commonly used to
effort. One valid consideration is to ask whether the generate potential solutions as well.
measurement system itself changed during the peri- Cause and effect diagram: A tool used in conjunc-
od of performance change. The other consideration tion with brainstorming to identify potential causes
is whether the team needs to develop a new or alter- to a particular problem. The tool helps the brain-
native method of measurement that provides bet- storming process by categorizing the causes into
ter information. For example, if the problem were method, measurement, material, machine (equip-
the observation of solution discoloration, the team ment), man (people), and environment.
would like to understand the chemical changes as- Contradiction matrix: A key tool to document the
sociated with discoloration and use going forward. cause screening process. Potential causes are listed
In cases where the measurement system is changed in the first column of the matrix while the facts are
or refined, traditional MSA studies may be needed. listed across the top row. When comparing a poten-
Problem statement: The problem statement is the tial cause against a fact, five outcomes are possible:
sentence form of the Is/Is Not Diagram. The prob- O=cause is supported, X=cause is contradicted,
lem statement should address the parameters stated A=cause is supported with assumptions, N/A = no
within the Is/Is Not Diagram. relationship between cause and fact, blank box=no
Process flow chart: A graphical representation of factual information available to support or refute

131 Conducting Audits, Gap Assessments & Corrective Actions Volume II

David Ingram

the cause. Blank boxes and assumptions represent

Originally published in Journal of Validation Technology Vol-
the need to collect additional data assuming that no ume 15 Number 1
other existing facts can eliminate the cause. Only an
“X” can eliminate a cause.
Common Improve Tools About the Author
Failure mode and effect analysis (FMEA): A meth-
od used by a team to assess risk. Common FMEAs David J. Ingram is director for Baxter’s Business
include product, process, and product usage. Ques- Excellence Program. David has over 25 years
tions addressed during an FMEA include; what experience in the validation and qualification
can fail; what are the effects of failure with respect of process equipment and critical systems. He
to people; environment and the system or process; consults extensively with Baxter’s manufacturing
what are the potential causes for failure and what facilities and R&D groups regarding application
controls currently exist to mitigate the failure or the of Six Sigma and validation concepts. Dave can be
cause of the failure. A risk priority number (RPN) reached by e-mail at ingramd@baxter.com.
is generated based upon probability of occurrence,
severity of the failure, and probability of failure or
cause detection. RPNs of several failure modes can
be compared to determine the highest risk failures.
These high risk failures require additional controls
to mitigate the overall risk.
Mistake proofing: Set of strategies used to elimi-
nate, mitigate, or detect process errors or omissions
in order to prevent them from becoming defects.
Optimization and variation reduction (OVR): A
strategy for continuous data to maximize product
or process capability. Optimization refers to setting
the average or aim of the process to the point that
maximizes the ability of the process to meet spec-
ification limits. Variation reduction improves the
potential process capability since the process width
becomes smaller relative to specification limits. The
combination of OVR together maximizes process

Common Control Tools

Control plan: The key mechanism to manage the
system or process inputs and outputs to ensure
the process performs at optimum effectiveness. A
sound control plan will prevent the problem from
Sampling plan: Method used to audit a process
by selecting and measuring a random set of units or
samples. Sampling plans have a unique operating
characteristic curve (OC Curve) that defines the
consumer and producer risk.

132 Conducting Audits, Gap Assessments & Corrective Actions Volume II

Paul L. Pluta

Compliance Case Study #7—Broken

Punches in Tablet Compressing
Paul L. Pluta

“Compliance Case Studies” discusses compliance situations useful to practitioners

in compliance and validation. Each case presented deals with a specific compliance
problem, elements of which are described to demonstrate strategy to solve compliance
problems. We intend this column to be a useful resource for daily work applications.
The main objective of this column: Useful and practical information.
Reader comments, questions, and suggestions are needed to help us fulfill our objec-
tive for this column. Case studies illustrating compliance issues submitted by readers
ImageZoo/getty images

are most welcome. Please send your comments and suggestions to journal coordinat-
ing editor Susan Haigney at shaigney@advanstar.com.


The following key points are discussed:
• This case study describes manufacturing of a tablet product in which an abrupt
and unexpected change in the manufacturing process occurred. Tablet com-
pressing became extremely difficult including breakage of tablet compressing
• Potential causes for the problem to be investigated were identified
• The observations of manufacturing operators regarding a change in the physi-
cal properties of the granulation were key to initiating the direction of the
investigation. Particle size distribution data confirmed these observations
• Actual observations of the manufacturing process by technicians in the tech-
nical support group identified the problem—under filling of the granulation
equipment. Equipment was under filled because high-density lactose was
used in processing. This problem would not have been quickly solved without
actual observation of the manufacturing process by the technicians
• Corrective and preventive actions involved with this event included restric-
tion of manufacturing to low-density lactose, developing a new powder den-
sity specification for incoming lactose, improvements in master production
records, training, and other activities
• A new policy and procedure for the evaluation of new formulation materials
at the site was developed
• The observations of manufacturing operators were key to suggesting the di-
rection of the investigation. The observations of the technical group, specifi-
cally the technicians in the technical group, were key to determining the root
cause of the problem.

This case study was provided to the Journal of GXP Compliance by a reader who
requested anonymity. The following circumstances describe an actual event.
A new tablet product containing a potent drug had been reliably manufactured
for a few months. The product was a small round tablet containing a few milli-

133 Conducting Audits, Gap Assessments & Corrective Actions Volume II

Paul L. Pluta

grams of potent active drug. The tablet formulation • Wet granulation was dried using a tray dryer
was composed of primarily lactose. After several • Dried granulation was sized using a sifter and
months of successful processing, the compressing impact mill combination
• Sized granulation, disintegrant, and lubricants
area reported several instances of broken punches were combined in a blender and mixed for 15
during tablet compressing. Broken punches had minutes
never occurred in past manufacturing of this prod- • Tablets were compressed on a rotary com-
uct. Manufacturing operators complained that the pressing machine.
dried granulation had too many fines and required
extreme compressing forces to compress acceptable COMPLIANCE EVENT
tablets. The high compression force resulted in bro- A small molecule pharmaceutical company received
ken punches. approval for a new sedative/hypnotic tablet product
This discussion provides the following: containing a highly potent active drug. Product
• Process background. A description of the was successfully manufactured for several months
product manufacturing process with no problems being experienced throughout
• Compliance event. A description of the the entire manufacturing process. After this period,
event, the key issues to be addressed, and ap-
plicable current good manufacturing practice tablet compressing abruptly became extremely dif-
(CGMP) requirements ficult. The granulation contained a greater propor-
• Investigation and discussion. Interviews and tion of fines (i.e., small particle size particles) than
actions conducted to investigate the event. had been previously observed. Tablet compression
Key information, activities, and analysis required much higher compressing force and slower
• Corrective action and preventive action
(CAPA). Actions and improvements imple- compressing speed to compress acceptable tablets.
mented. These included actions to correct the Broken punches resulted due to the high force re-
problem as well as prevent future occurrences quired in compressing. These problems occurred
• Post CAPA. Verifying and maintaining pro- abruptly and unexpectedly after a period of success-
cess performance ful processing.
• Post CAPA improvements. Improvements
implemented as result of knowledge gained The tablets able to be manufactured were accept-
from the compliance event. able tablets that passed in-process and final product
release requirements. However, tablet inspection
was required for metal punch fragments causing
PROCESS BACKGROUND additional time and manpower requirements for
The manufacturing process in this case study in-
manufacturing. Affected product was rejected. The
volved manufacture of a tablet product by a conven-
amount of rejected product was significant, exceed-
tional wet granulation process. Ingredients in the
ing 25% for several lots.
formulation included the active drug, a highly po-
tent sedative/hypnotic. Other inactive ingredients
in the formulation included lactose, a granulation What Are The Issues?
binder, water to dissolve the binder, disintegrant, There were several critical issues to be investigated
and lubricants. Lactose comprised approximately as follows:
90% of the total tablet weight. The tablet design was • Was all equipment operating properly?
a small round tablet approximately ¼ inch in diam- • Did manufacturing operators follow batch
record directions properly?
eter. The manufacturing process for the product • Were master production records and batch
included the following steps: records clearly written?
• Binder was dissolved in water • Were manufacturing operators adequately
• Active drug and lactose were added to granu- trained to perform the manufacturing pro-
lation equipment. A low intensity sigma blade cess?
granulator was used for granulating • Was this level of process variation expected
• Active drug and lactose were granulated with for the product?
binder solution • What caused the apparent and abrupt process

134 Conducting Audits, Gap Assessments & Corrective Actions Volume II

Paul L. Pluta

problem? the engineers. All equipment was current regard-

ing preventive maintenance. All calibration was
CGMP Requirements rechecked and found to be within tolerances.
Relevant good manufacturing practice (GMP)
requirements applicable to the event are listed as
Manufacturing Personnel Interviews
• Subpart D—Equipment Manufacturing and quality control personnel af-
• 211.67. Equipment cleaning and mainte- firmed that all batch record directions were per-
nance formed as specified. Manufacturing personnel who
• 211.68. Automatic, mechanical, and elec- had manufactured the various product lots were ex-
tronic equipment perienced and well trained. Several of the same oper-
• Subpart E—Control of Components and Drug
Product Containers and Closures ators had manufactured both successful and problem
• 211.80. General requirements batches of product. These operators commented that
• 211.82. Receipt and storage of untested the granulation process appeared to yield a greater
components, drug product containers, and proportion of small particle size fines that caused
closures problems in compressing. More fines prior to com-
• 211.84. Testing and approval or rejection of
components, drug product containers, and pressing may have been caused by an inadequate wet
closures granulation process, improper sizing of dried granu-
• Subpart F—Production and Process Controls lation such as by using wrong screen sizes, excessive
• 211.100. Written procedures; deviations blending causing granule fragmentation, or granule
• Subpart J—Records and Reports breakdown during storage prior to the compressing
• 211.186. Master production and control
records process. More fines being compressed would require
• 211.188. Batch production and control re- increased and more effective compressing through
cords. increased force and reduced machine turret speed.
Increased compression force exceeding the punch tip
INVESTIGATION AND DISCUSSION pressure limits would increase the likelihood of punch
Investigation and ultimate resolution of this event breakage.
required involvement of several groups. These in-
cluded personnel involved in the incident (manu- Technical Evaluation
facturing and quality assurance [QA]), personnel Technical personnel affirmed that there should have
responsible for equipment, and technical personnel been no problem with manufacturing under nor-
responsible for the product and process. There were mal circumstances. There had been no problems
many details that needed to be investigated or con- with manufacturing during development, in clinical
firmed. Personnel from all groups were interviewed product manufacturing, during process validation,
and interacted to address the issues. and during the initial manufacturing of product
post validation.
Equipment Operation Problems were not encountered during the initial
Engineering personnel checked equipment op- manufacturing of the product. The manufacturing
eration, maintenance, and calibration. Equipment process was successfully validated. There had been
investigated included wet granulation equipment, no manufacturing problems reported subsequent
sizing equipment including sifter and impact mill, to process validation. This product and formulation
blender, and compressing machine. The compress- were unique to the manufacturing facility—no similar
ing machine operation and calibration was especial- products of this type were manufactured at the site.
ly well reviewed. Broken punches could be caused The product had also been successfully manufactured
by compression machine errors in calibration, in development and for use in clinical trials many
machine set-up, or other compressing machine times without any similar problems.
problems. No equipment problems were noted by Review of manufacturing records and target process

135 Conducting Audits, Gap Assessments & Corrective Actions Volume II

Paul L. Pluta

parameters did not indicate any obvious problems in density lactose had been only recently obtained by site
processing. All manufacturing process data were con- purchasing. Other products at the site had not yet been
sistent with expected values. Sieve analysis of blended manufactured with the high-density lactose. When
granulation indicated a significantly smaller particle the formulation concentration of lactose was high as
size distribution in problem lots compared to his- with product with broken compressing punches, the
torical data with development and validation batches. significant difference in bulk density greatly affected
The confirmation of small particle size distribution in the manufacturing process. An inadequate granula-
problem lots strongly suggested a manufacturing ma- tion contributing to broken compressing punches
terial or manufacturing process problem. resulted.
Technical personnel then personally observed actual
performance of the manufacturing unit operations by CORRECTIVE AND PREVENTIVE
manufacturing operators. Granulation was the first
process to be observed. When the sigma blade mixer
The following CAPA and associated activities were
was filled with the prescribed weight of active drug
identified to correct the current problem and pre-
and lactose, the level of powder in the granulator was
vent future occurrences:
too low. A low level of powder will not be properly • Restriction of manufacturing to low-density
granulated. Improper granulation will result in an in- lactose
creased level of small particle size fines. The amount • New powder density specification
of powder added to the granulator was not sufficient • Trial runs with low-density lactose
for manufacturing an acceptable granulation. The ob- • Master production record enhancements
• Training
servations of the technical staff, specifically the techni- • Documentation
cians in the technical group, were key to identifying • Other products.
the cause of the granulation problem. This problem
would not have been solved without actual observa- Restriction Of Manufacturing
tion of the manufacturing process by the technicians. To Low-Density Lactose
Because lactose comprised more than 95% of the Lactose used in manufacturing of the subject prod-
powder in the granulator, technical personnel inves- uct was immediately restricted to the low-density
tigated the source of the lactose used in batches previ- lactose provided by the single supplier. This ensured
ously made. These included both acceptable batches that granulation equipment would be adequately
and problem batches. It was determined that the lac- filled to produce the desired granulation particle
tose came from two approved suppliers of lactose. File size distribution for all product lots currently in the
samples of individual lots of lactose were evaluated. manufacturing queue.
It was found that there was a significant difference
in powder density between the lots provided by each New Powder Density Specification
approved supplier. The density of material from one Multiple lots of lactose from both suppliers were
vendor was approximately twice that of powder from obtained. The site analytical laboratory thoroughly
the other supplier. Further investigation indicated that characterized the materials from both suppliers re-
acceptable product lots had used low-density (“fluffy”) garding physical properties such as powder density
lactose and problem batches of product had used and particle size. Powder density was determined
high-density lactose. The weight of low-density lac- to be the most relevant requirement for lactose. A
tose adequately filled the granulation equipment and new powder density specification was added to the
resulted in an acceptable granulation. The weight of site specifications for lactose which ensured future
high-density lactose did not adequately fill the granu- acceptance of only low-density lactose.
lation equipment and resulted in granulation with
excessive fine particle size distribution. Trial Runs With Restricted Lactose
The site had previously used only the low-density Several trial runs were conducted under the super-
lactose in manufacturing of its products. The high- vision of the technical staff using the low-density

136 Conducting Audits, Gap Assessments & Corrective Actions Volume II

Paul L. Pluta

lactose. All runs resulted in properly-filled granu- POST CAPA—

lation equipment. All runs resulted in the desired VERIFYING AND MAINTAINING
particle size distribution for the manufacturing
process. Tablet compressing was successful with all
Additional monitoring of product manufactured
runs. Compressing was accomplished at high speed
with low-density lactose indicated successful prod-
and with expected compressing force. No broken
uct manufacturing. Restricting manufacturing to
punches occurred.
low-density lactose completely solved the manufac-
turing problems. No broken punches occurred. No
Master Production Record Enhancement
similar problems with other products using lactose
Master production records were modified to pro-
were observed.
vide more detail in the granulation process. Di-
rections were added to assure proper filling of the
granulation equipment and remind operators that POST CAPA IMPROVEMENTS—NEW
under filling of granulation equipment would result MATERIALS EVALUATIONS
in substandard granulation. These additional direc- The root cause of the compliance event was determined
tions were part of each new batch record. to be the use of high-density lactose in manufactur-
ing. The high-density lactose met all internal speci-
Training fications in place at the time. These specifications
All personnel were trained on the revised manu- included all official compendia specifications. Even
facturing procedure for the granulation process as though all specifications were met and all areas were
stated in the new master production records. The compliant with internal policies and procedures, seri-
importance of granulation equipment being com- ous problems occurred in manufacturing. Changes
pletely filled was explained to all manufacturing were needed to prevent this type of problem from oc-
operators and quality assurance personnel. curring in the future.
Technical personnel developed a new procedure for
the evaluation of new materials at the site. This proce-
dure comprised the following general steps:
All work associated with this project was compiled • New material receipt. Purchasing receives a
and documented. Reports were written and filed sample of new material for evaluation. Prod-
for ready access. Process validation documentation ucts potentially manufactured using the new
was amended to clearly state that only lactose of a material are identified
specified powder density had been validated in the • Laboratory testing. The incoming materials
laboratory tests the material against current
original process validation. specification for the material
• Technical evaluation. The technical support
Other Products group evaluates the test results and also con-
ducts other testing as needed to evaluate the
Other products containing lactose manufactured at new material for use in the identified prod-
the site were reviewed. All products that might po- ucts. The technical support group either ap-
tentially be affected by the high-density lactose were proves or rejects the new material for use in
also prevented from using this lactose. Because the commercial manufacturing
high-density lactose was only recently approved at • Documentation. If the new material is ap-
proved by the technical group, incoming ma-
the site, these other products were originally devel- terial specifications are modified to include
oped with low-density lactose and had never been the new material as acceptable for use.
manufactured with the high-density lactose.
The key difference in the new procedure involved
laboratory testing and technical evaluation. Previously,
only laboratory testing against incoming specifications
was required to approve new material. The new proce-

137 Conducting Audits, Gap Assessments & Corrective Actions Volume II

Paul L. Pluta

dure required the technical group to evaluate the new tose in the formulation, the physical properties of
material for use in manufacturing. This evaluation lactose had a significant effect on the manufacturing
might include small-scale trials but could also include process of this product.
commercial-scale manufacturing if needed. Final re- Corrective and preventive actions involved with
sponsibility for acceptance of new material rested with this event included restriction of manufacturing
the technical group. to low-density lactose, developing a new powder
The procedure, if previously implemented, would density specification for incoming lactose, improve-
have prevented the use of high-density lactose in com- ments in master production records, training, and
mercial manufacturing that seriously affected manu- other activities. These activities were successful in
facturing and caused the broken punch problem. restoring successful manufacturing.
The root cause of the compliance event was de-
Purchasing And Incoming Quality Procedures termined to be the use of high-density lactose in
Procedures and policies associated with the use of manufacturing. Even though all specifications were
new materials from new suppliers or from currently met and all areas were compliant with internal poli-
approved suppliers were reviewed. Documents cies and procedures, serious problems occurred in
modified included purchasing and incoming qual- manufacturing. A new procedure for the evaluation
ity procedures. Purchasing staff was unaware of the of new materials at the site was developed. This new
problems that could be caused by inadvertent use of procedure required technical evaluation of new ma-
unapproved material. They had no understanding terials beyond simply meeting incoming specifica-
of the importance of physical properties that may tions. It required whatever testing was necessary to
not be routinely tested as part of incoming material assure successful manufacturing—even including
specifications. commercial-scale manufacturing. Procedures and
policies associated with the use of new materials
from new suppliers or from currently approved sup-
CONCLUSIONS pliers were modified as needed.
A case study involving manufacturing of a tablet Several points were significant in this compli-
product in which an abrupt and unexpected change ance incident. The observations of manufacturing
in the manufacturing process occurred. Tablet operators were key to suggesting the direction of
compressing became extremely difficult. Tablet the investigation. The observations of the technical
compression required much higher compressing group, specifically the technicians in the technical
force and slower compressing speed to compress group, determined the root cause of the problem.
acceptable tablets. Broken punches resulted due to Development of a new policy regarding evaluation
the high force required in compressing. of new materials by the technical group enabled
Potential causes for the problem were identified. future problems of this type to be eliminated. Dif-
These included equipment causes, process causes, ferent physical properties of inactive excipient was
personnel performance or training problems, and found to be the root cause of the problem. Several
other potential sources. Investigation and ultimate individuals on the site staff were unaware of the
resolution of this event required involvement of importance of physical properties that may not be
several groups. The observations of manufacturing routinely tested as part of incoming material speci-
operators that granulation process appeared to yield fications.
a greater proportion of small particle size fines was
key in identifying the cause of the problem and help-
ing with the direction of the investigation. Techni- ARTICLE ACRONYM LISTING
CAPA Corrective Actions and Preventive Actions
cal personnel ultimately determined that the cause CGMP Current Good Manufacturing Practice
of the problem was use of high-density lactose from GMP Good Manufacturing Practice
a new commercial source. Because the product be- QA Quality Assurance
ing manufactured required approximately 90% lac-

138 Conducting Audits, Gap Assessments & Corrective Actions Volume II

Paul L. Pluta

Originally published in Journal of GXP Compliance Volume

14 Number 3
About the Author
Paul L. Pluta, Ph.D., is a pharmaceutical scien-
tist with extensive technical and management
experience in the pharmaceutical industry. He
is editor-in-chief of the Journal of GXP Compli-
ance and the Journal of Validation Technology.
He is also adjunct associate professor at the
University of Illinois College of Pharmacy in
Chicago, Illinois USA. He is the editor of and
contributed chapters to Cleaning and Cleaning
Validation, published by Davis Healthcare In-
ternational in 2009. He may be reached at paul.

139 Conducting Audits, Gap Assessments & Corrective Actions Volume II