FDA cGMP Inspections

Peking University 2005

Robert C. Horan, PhD

FDA Pharmaceutical
Inspectorate
New York District
 FDA Inspections
 Periodic (biennial) comprehensive
cGMP
 Pre-Approval Inspection(PAI)
 “For cause”

 Inspection may involve more than one

assignment and will verify corrections
to previous inspections.

 All inspections cover GMPs

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%
Foreign Inspection in FY 2004 by
Firm Type

Both API and Dosage Control Lab

2% Micronizer
9%
1%

Intermediates
10%

API
51%

Dosage
27%
 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
 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)
 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
 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
 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)
 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
 Process Analytical Technology
Examples of PAT applications:
 Continuous real time measurements

of content uniformity of tablets

during production (using near Infra-
Red)

 Near IR measurement of moisture

level during API drying process to
determine actual end of operation for
each batch
 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

“Quality cannot be tested into

products; it should be built-in or
should be by design.”
 Process Validation
Life Cycle Approach

 Process validation begins with process

development and continues beyond the
initial “validation” batches for as long as
product is manufactured/ marketed
 Sources of critical variability identified and
controlled
 Quality System role in maintaining
validated state (quality built in; not tested
into product)
 Process Validation
 FDA Compliance Policy Guide
“Process Validation Requirements for
Drug Products and Active
Pharmaceutical Ingredients CPG
7132c.08”; revision date 12 March
2004

 FDA Industry Guideline on Process

Validation – currently being revised
 System Inspections
 Quality
 Facilities and Equipment
 Materials
 Production
 Packaging/Labeling
 Laboratory Controls
Most Common GMP Deficiencies by System –
API/ Dosage Inspections for 2004/5

Materials
6%
Packaging and Labeling Laboratory
1% 19%

Facilities & Equipment

17%
Production
11%

Quality
46%
 “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
 Quality System
 Quality must be built into the process
 Quality is not tested into the product

 Assurance of Quality comes from

- Design of robust process based on
thorough knowledge of that process
and the sources of variability
- Effective Quality System in place
 Role of Management in QS
Management is responsible for:

 Organizational structure
 All Processes
 All Procedures
 Facilities & Resources

In short, everything to insure product

quality, customer satisfaction and
continuous improvement
Quality System Responsibilities
 Assures overall compliance with cGMPs
 Review and approval duties for:
• Product Quality Reviews (at least
annually)
• Complaint reviews
• Discrepancy/ failure investigations
• Change Control
• CAPA (Corrective And Preventive Action)
 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
 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
 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
 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
 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
 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
 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
Production system (continued)

 Deviations investigated and

documented contemporaneously with
investigation
 Process validation based on knowledge
of process (scientific basis for
identifying critical steps/ critical process
parameters/control points)
 Justification and consistency of in-
process specifications and final product
specifications
 Data/ information documented and
available to Quality Unit for review
 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
 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
 Facilities & Equipment System
EQUIPMENT

 Appropriate design, size, location, non-reactive

product contact surfaces
 Identification clearly marked
 Qualification (DQ, IQ,OQ, PQ)
 Calibration
 Preventive Maintenance schedule and procedures
 Cleaning procedures and validation
 Records of use, cleaning, maintenance
 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.)
 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
 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
 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
 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
 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

 Established re-test/ re-evaluation periods

 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
 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
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)
 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
From current FDA Compliance Program 56002 for
Drug Manufacturing Inspections:

(This is the compliance program for FDA Investigators;

this revision introduced Systems Inspections)

“The cGMP regulations are not direct requirements

for manufacture of APIs…….but they are guidance for
cGMP in API manufacture.”
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”.
 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
 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”)
 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
 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