Inspection Issues in the Analytical
Laboratory:
An FDA Perspective
Yvonne McKnight
Chemist
US Food and Drug Administration
200 Chestnut Street, Rm. 1005
Philadelphia, PA 19106
Phone: 215-597-4390 x4619
Fax: 215-597-5728
Email: yvonne.mcknight@fda.gov
Overview
 Introduction to / reminder of basic
regulations
 Basic preparation for an FDA inspection
 Recent trends of “Objectionable Findings”
on 483s
Basic Regulations
• The
Food, Drug and Cosmetic Act (FD&C Act, the
Act) § 704(a)(1) – officers or employees are
authorized to enter any factory, warehouse,
establishment or vehicle used to transport or hold
food, drugs, devices or cosmetics and labeling
21 CFR § 5.31(a)(1) – Enforcement Activities
 allows employees of the FDA to conduct
examinations, inspections and
investigations; collect samples; have
access to and to copy and verify records;
to make seizures of items under the Act;
supervise compliance operations for the
enforcement of the Act
21 CFR § 211.166 – Stability Testing
(a) There shall be a written testing program;
it will assess stability of characteristics of the
drug products; results of the testing will
determine appropriate storage conditions
and expiration dating.
- sample size, test interval
- storage conditions for retained samples
21 CFR § 211.166 – Stability Testing
(cont’d.)
(a) the program will also contain
- reliable, meaningful and specific test
methods
- testing of the drug product in the same
container-closure system as the one used
for the finished dosage form
- reconstituted drug products will be
tested at the time of dispensing and after they
are reconstituted
21 CFR § 211.166 – Stability Testing
(cont’d.)
(b) an adequate number of batches of each
drug product will be tested to determine an
appropriate expiration date; all records of
testing will be maintained; accelerated
studies can be performed at the same time
as full shelf life testing
21 CFR § 211.165 –
Testing and release for distribution
(a) for each product batch, there shall be
appropriate laboratory determination of
satisfactory conformance to final specifications
for the drug product
(b) microbiological testing for products required to
be free of objectionable microorganisms
(c) sampling plans will be in written procedures
21 CFR § 211.165 –
Testing and release for distribution (cont’d.)
(d) to be approved and released, product testing
shall meet acceptance criteria and appropriate
statistical quality control criteria.
(e) validation must be established and
documented
(f) drug products which fail specifications or other
relevant QC criteria shall be rejected
21 CFR 211 § 194 – Laboratory Records
(a)Laboratory records shall include complete
data from all tests performed to assure
compliance with established specifications and
standards
- sample description identifying: source,
quantity, lot number (or other code), date taken
and date received for testing
21 CFR 211 § 194 – Laboratory Records
(cont’d.)
- methods used in testing must be stated
- amount of sample used for each test
- complete record of all data obtained during
testing
- all calculations performed (including units of
measurement, conversion factors and
equivalency factors
21 CFR 211 § 194 – Laboratory Records
(cont’d.)
- a statement of sample results of the tests
and how they compare with established
standards of identity, strength, quality and
purity
- initials or signature of the person doing the
testing, the date(s) testing was performed
- reviewer’s initials or signature
21 CFR 211 § 194 – Laboratory Records
(cont’d.)
 records of method modifications shall be
maintained and include data to verify that results
are just as accurate and reliable as those
obtained by the original method
 records of testing and standardization of
laboratory reference standards, reagents and
standard solutions
 complete records of periodic calibration of
laboratory instruments, apparatus, gauges and
recording devices
 complete records of all stability testing
Records and Reports
21 CFR § 211.180
(a) Any record specifically associated with a batch
of drug product shall be retained for at least:
- one year after the expiration date of the batch,
or
- three years after the distribution of the batch
Records and Reports
21 CFR § 211.180
(b) Any record pertaining to a component, drug
product container, closure or labeling of a batch
of drug product shall be retained for at least:
- one year after the expiration date of the batch,
or
- three years after the distribution of the batch
Records and Reports
21 CFR § 211.180
(c) All records (and copies of records) shall be
readily available for authorized inspection during
the retention period.
- subject to photocopying or other means of
reproduction as part of inspection.
Records and Reports
21 CFR § 211.180
(d) Required records may be retained as original
records, true copies or other accurate
reproductions. If reduction techniques are used,
such as microfilming, a suitable reader must be
readily available.
Records and Reports
21 CFR § 211.180
(e) Maintain records so that they can be used to
evaluate the drug product at least annually to
see if changes in specifications, manufacturing
or control procedures need to be made. Provide
for review of:
- representative number of batches
- complaints, recalls, returned or salvaged
drug products and investigations conducted
Records and Reports
21 CFR § 211.180
(f) Establish procedures to ensure that
responsible officials of the firm are
informed in writing of any: investigations
conducted relative to complaints, returned
drug products and drug product salvaging,
recalls, regulatory actions / observations of
the FDA.
Basic preparation for an FDA inspection
 What type of inspection – PAI, cGMP, for
cause, API
 Probable areas for us to examine
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raw data for product testing, stability testing
methods (including validation information)
SOPs
instrumentation
laboratory environment
OOS results
employee training
Basic preparation for an FDA inspection
(cont’d.)
Data discarded without logical or
scientifically sound reason
Method modifications without supporting
data
Use of white-out or pencil (and erased data)
Data on scrap paper (Post-Its™)
Blank pages in consecutive entries
Basic preparation for an FDA inspection
(cont’d.)
Inadequate failure investigations
QA/QC procedures
Data integrity problems
Reject or quarantine area
Lack of method validation / stability
indicating method / stability data
The Top 10 List
10) Drug production and control records are
not reviewed / approved by the quality
control unit to determine compliance with
established / approved procedure before
batch release.
9) Routine calibration / inspection / checking
of equipment is not performed according
to a written program to ensure proper
performance.
The Top 10 List
8) Employees are not trained in their particular
functions, cGMPs or written procedures
required by cGMPs.
7) No scientifically sound:
- specifications
- standards
- sampling plans
- test procedures
to assure appropriate identity, strength,
quality and purity of drug components
The Top 10 List
6) Before final release of product, there was
no satisfactory determination of
conformance to specifications for
identification and strength of each active
ingredient.
5) Production and control records for each
batch of drug product are not prepared
and/or complete.
The Top 10 List
4) There are no written procedures for
production / process controls to ensure
that the drug products have identity,
strength, quality and purity they claim to
possess.
3) Processes that may cause variability of
in-process materials or drug product are
not monitored by appropriate control
measures.
The Top 10 List
2) The responsibilities and procedures
applicable to the quality control unit are
not in writing and/or fully followed.
The Top 10 List
1) Written production and process control
procedures are not followed in the
execution of production and process
control functions and/or documented at
the time of performance.
*as of 4-11-2005
Recent Summary
Pre-Approval Citations (total citations 108)
Laboratory Controls
(18)
Test Methods
(16)
Batch Failure Review
(13)
Laboratory Performance
(12)
Instrument Calibration
(9)
QC Responsibilities
(8)
Process Procedures, establishing
(8)
Batch Failure Investigation
(8)
Validation
(8)
Investigation Follow-up
(8)
Recent Summary
GMP Inspection Citations (total citations 1,933)
Process Procedures, following/documenting
(321)
QC Responsibilities
(256)
Process Procedures, establishing
(188)
Product Testing and Release
(185)
Batch Production and Control Records
(182)
Validation
(176)
Training
(173)
Laboratory Controls
(164)
Production Record Review
(145)
Compliant Procedures
(143)
Recent Examples of 483 cites
Thank you!
Are there any questions?