Академический Документы
Профессиональный Документы
Культура Документы
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FDA Inspections
Periodic (biennial) comprehensive cGMP
Pre-Approval Inspection(PAI)
“For cause”
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Foreign Inspections by Country in FY 2004
India
Others 14%
19%
Germany
Ireland 14%
4%
Spain
4%
Switzerland
4% Italy
10%
Japan
5%
China
France 7%
5%
Canada
United Kingdom
7%
7%
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Foreign Inspection in FY 2004 by Firm
Type
Intermediates
10%
API
51%
Dosage
27%
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FDA cGMPs for 21st Century
Initiative
Announced 8/2002; objectives include:
Encourage adoption of new technologies
Promote industry use of modern quality system
approaches
Encourage risk-based approaches which focus
on critical elements
Ensure FDA review, compliance and inspection
policies based on state-of-art pharmaceutical
science
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FDA cGMPs for 21st Century
Initiative
Systems Based Inspections
Risk-Based Approach to Manufacturing and Regulation
Pharmaceutical Inspectorate
PAT Guidance document/ PAT Team
Quality Systems Guidance document
Process Validation (Compliance Policy Guide revised;
Guidance being revised)
21 CFR Part 11 Electronic Records Guidance (risk-based;
geared toward GMP documents)
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Pharmaceutical Inspectorate
Cadre of most experienced investigators who are
dedicated to drug inspections
Intensively trained along with quality reviewers and
compliance staff in FDA headquarters (HQ)
Overall goal is to have PI work closely with HQ
personnel – more efficiently integrate review and
inspection functions
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Pharmaceutical Inspectorate
FDA Review staff, Compliance Officers and PI candidates
attended training modules which focused on:
Current Regulatory Programs
Advanced Quality Systems
PAT and Modern Pharmaceutical Technology
Risk Management
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Pharmaceutical Inspectorate
Field Investigators (18) from across U.S. make up the
Pharmaceutical Inspectorate
Screening process with certification board
Completed training with HQ personnel
One month detail working with HQ staff
Level III certification (highest level)
Conduct PAIs, complex drug inspections
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Process Analytical Technology
PAT is a system for designing, analyzing and
controlling manufacturing through “real time”
measurements of critical quality attributes of raw and
in-process materials and processes, with the goal of
ensuring final product quality.
See FDA Guidance document on PAT
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Process Analytical Technology
Examples of PAT applications:
Continuous real time measurements of content
uniformity of tablets during production (using near
Infra-Red)
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Process Analytical Technology
A process is generally considered well understood when:
All critical sources of variability are identified and
explained
Variability is managed by the process
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Process Validation
Life Cycle Approach
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Process Validation
FDA Compliance Policy Guide
“Process Validation Requirements for Drug Products
and Active Pharmaceutical Ingredients CPG
7132c.08”; revision date 12 March 2004
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System Inspections
Quality
Facilities and Equipment
Materials
Production
Packaging/Labeling
Laboratory Controls
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Most Common GMP Deficiencies by System – API/
Dosage Inspections for 2004/5
Materials
6%
Packaging and Labeling Laboratory
1% 19%
Quality
46%
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“State of Control”
Detailed inspection of a system so that the findings
reflect the state of control in that system for every
product (profile) class
If one of the six systems is out of control, the firm is
considered out of control
A system is considered out of control based on GMP
deficiencies which suggest lack of assurance of quality
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Quality System
Quality must be built into the process
Quality is not tested into the product
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Role of Management in QS
Management is responsible for:
Organizational structure
All Processes
All Procedures
Facilities & Resources
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Quality System Responsibilities
Assures overall compliance with cGMPs
Review and approval duties for:
1) Product Quality Reviews (at least annually)
2) Complaint reviews
3) Discrepancy/ failure investigations
4) Change Control
5) CAPA (Corrective And Preventive Action)
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Quality system (continued)
6) Reprocess/ Rework
7) Validation/ Revalidation
8) Rejects
9) Stability Failures/ Out of trend data
10) Quarantine products
11) Documented GMP & Job Related Training
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Laboratory Control System
Adequate lab facilities under the Quality Unit
which is independent from Production
Adequately staffed laboratories (supervisory and
bench personnel)
Written specifications for raw materials,
intermediates, APIs, labels & packaging
Written procedures for sampling, testing, approval
or rejection of materials and for the recording and
storage of data
Change control for written procedures
Method validation/ revalidation
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Laboratory Control System
Reference Standards (primary; secondary)
Equipment Qualification
Calibration: written procedures, schedule,
documentation
Validation and Security for computerized handling of
test results and related data; system for assuring
integrity of all lab data
Laboratory controls followed and documented
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Laboratory Control System
Written procedure (SOP) covering out of
specification “oos” results
Investigation of “oos” results conducted in a
timely manner as per SOP and documented
(complete records maintained). Conclusions from
“oos” investigations documented and corrective
actions/ need for addition investigation identified
and implemented.
“oos” review included in Product Quality Reviews
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Laboratory Control Records
Description of samples
Identification of method used
Raw data for sample/ standard preparation, reagents
Complete record of all data from testing
Record of all calculations
Statement of the test results; how compare with established
acceptance criteria
Signature of the person who performed each test; dates tests
performed
Date/ signature of second qualified person who reviewed
original test records for accuracy, completeness and
compliance with established standards
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Production System
Training (documented; job-related)
Master production and control records
Batch production and control records
Change control procedure
Contemporaneous, accurate and complete batch
production documentation
Implementation and documentation of in-process
controls, tests, and examinations
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Production system (continued)
Adequate written procedures & practice for charge-in
of materials
Identification of equipment with contents, stage of
manufacturing, status
Equipment cleaning records
Established time limits for completion of production
steps/ stages
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Production system (continued)
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Facilities & Equipment System
FACILITIES
Location, design, construction appropriate to facilitate
cleaning, maintenance, operations
Layout and air handling designed and constructed to
prevent cross-contamination
Flow of materials & personnel designed to prevent
mix-ups or contamination
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Facilities & Equipment System
Defined areas or other control systems to prevent mix-
ups or contamination
Incoming materials (id, quarantine)
Sampling area (prevent contamination)
Quarantine (intermediates, APIs)
Released materials
Rejection
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Facilities & Equipment System
EQUIPMENT
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Facilities & Equipment System
Lubricants, heating fluids or coolants (not contact/alter
product quality)
Closed or contained equipment
Inspection prior to use
************************************
Separate facilities or containment where needed
(penicillins, highly potent compounds etc.)
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Utilities
Qualified and appropriately monitored; drawings
should be available
Designed and constructed to prevent contamination or
cross-contamination
Recirculated air to production (same concern)
Permanently installed pipework should be
appropriately identified
Drains of adequate size with air break
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Water
Process water at minimum meeting WHO guidelines
for potable water
Justify quality of water used to achieve stated API
quality and establish specifications
Water treatment facilities validated
API to be used for incorporation into sterile dosage
form – water used in later stages should be monitored
and controlled for total microbial counts,
objectionable organisms and endotoxins
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Materials System
Written procedures for receipt, identification,
quarantine, storage, handling, sampling, testing
and approval or rejection of materials
System to evaluate suppliers (critical materials)
Purchased against agreed specification
Change control process for changing suppliers
Upon receipt check for correct labeling, seals
Before co-mingling bulk material, id/test
Assurances obtained from non-dedicated tankers
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Materials System
Identification on large storage containers and
associated manifolds, filling and discharge lines
Code given to received batches; status identity
At minimum, a specific identity test on incoming
batches; COA
Supplier evaluation should include three fully tested
batches; one fully tested batch/year
Written sampling plan with justification
Prevent contamination of sampled containers
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Materials System
Stored in manner to prevent degradation,
contamination, no adverse effect on quality
Drums, bags, boxes off the floor
First in, first out
Rejected materials identified and controlled under
a quarantine system
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Packaging & Labeling System
Written procedures for receipt, identification,
quarantine, sampling, examination and/or testing P&L
P&L should conform to specifications
Records maintained for each shipment (showing
receipt, examination & result)
Containers protective, clean, not alter product quality;
if re-used, cleaned & labeling defaced
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Labeling
Access to label storage area limited
Written procedures for reconciliation; investigation if
discrepancy
All excess labels with batch #, destroyed
Obsolete labels destroyed
Printing devices controlled to insure accuracy of label
(against batch record)
Print labels checked against master and a copy placed
into the batch record
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Packaging/ Labeling Operations
Documented procedures to assure correct packaging
materials/ labels used
Operations designed to prevent mix-ups
Labels: API name, batch #, storage conditions
Shipped API: Name/ address manufacturer; special
transport conditions; expiry/ retest date
Documented clearance before operations
Packaged/ labeled intermediates or APIs examined as
part of packaging (documented)
Seal employed to assure package integrity
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APIs are Drug Substances
FDA Food, Drug and Cosmetic Act definition of
drug includes “articles intended for use in the
diagnosis, cure, mitigation, treatment or
prevention of disease in man or other animals”
(no distinction between APIs & dosage forms)
Before ICH Q7A, FDA used dosage drug
regulations as guidance for API inspection
Still true (see next slide) , however, ICH Q7A
provides guidance on the application of those
cGMPs to APIs)
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From current FDA Compliance Program 56002 for
Drug Manufacturing Inspections:
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Current FDA Compliance Guide on
Process validation
From FDA Compliance Policy Guide “Process Validation
Requirements for Drug Products and Active Pharmaceutical
Ingredients CPG 7132c.08”; revision date 12 March 2004:
Validation of manufacturing processes is a
requirement of the Current Good
Manufacturing Practice (cGMP) regulations for
finished pharmaceuticals, and is considered an
enforceable element of current good
manufacturing practice for active
pharmaceutical ingredients (APIs) under the
broader statutory cGMP provisions of the
Federal Food, Drug, and Cosmetic Act”.
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Differences API/ Dosage Form
APIs involve purification steps
GMP controls tighter for later API steps
API impurity profile is critical focus and steps which
produce or remove impurities require greater control
and validation
Dosage forms do not involve purification
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Similarities APIs/Dosage Forms
Require demonstrated knowledge of process
and application of appropriate GMP controls to
assure safety, identity, strength, quality and
purity.
Systems in control to be in compliance
Life Cycle Approach to Validation (beyond the
initial “conformance batches”)
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Similarities include….
Processes for specific products vary in
complexity (either API or dosage can involve
complex or simple processes)
In-Process Controls
Finished Product Controls
Critical Steps/ Critical Process Parameters
Process Validation
Quality Assurance for consumer is based on
understanding & Control of Sources of Process/
Product Variability
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More Similarities…..
Science based approach for the establishment of
processes
Knowledge of process based on Process
Development work
Design Of Experiments (DOE)
Quality System (review/ trending)
Continuous Improvement possible within well
characterized process
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