Inspection Issues in the Analytical Laboratory: An FDA Perspective Yvonne McKnight Chemist US Food...

Inspection Issues in the Analytical Inspection Issues in the Analytical Laboratory:Laboratory:

An FDA PerspectiveAn FDA Perspective

Yvonne McKnightYvonne McKnightChemistChemist

US Food and Drug AdministrationUS Food and Drug Administration Phone: 215-597-4390 x4619Phone: 215-597-4390 x4619200 Chestnut Street, Rm. 1005200 Chestnut Street, Rm. 1005 Fax: 215-597-5728Fax: 215-597-5728Philadelphia, PA 19106Philadelphia, PA 19106 Email: [email protected]: [email protected]

OverviewOverview

Introduction to / reminder of basic Introduction to / reminder of basic regulationsregulations

Basic preparation for an FDA inspectionBasic preparation for an FDA inspection

Recent trends of “Objectionable Findings”Recent trends of “Objectionable Findings” on 483son 483s

• 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

Basic Regulations

allows employees of the FDA to conduct allows employees of the FDA to conduct examinations, inspections and examinations, inspections and investigations; collect samples; have investigations; collect samples; have access to and to copy and verify records; access to and to copy and verify records; to make seizures of items under the Act; to make seizures of items under the Act; supervise compliance operations for the supervise compliance operations for the enforcement of the Actenforcement of the Act

21 CFR § 5.31(a)(1) – Enforcement Activities

21 CFR 21 CFR § § 211.1211.166 – Stability Testing66 – Stability Testing

(a) There shall be a written testing program;(a) There shall be a written testing program;

it will assess stability of characteristics of theit will assess stability of characteristics of the

drug products; results of the testing willdrug products; results of the testing will

determine appropriate storage conditionsdetermine appropriate storage conditions

and expiration dating.and expiration dating.

- sample size, test interval- sample size, test interval

- storage conditions for retained samples- storage conditions for retained samples

21 CFR 21 CFR § § 211.1211.166 – Stability Testing66 – Stability Testing(cont’d.)(cont’d.)

(a) the program will also contain(a) the program will also contain- reliable, meaningful and specific test- reliable, meaningful and specific test

methodsmethods- testing of the drug product in the same- testing of the drug product in the same

container-closure system as the one usedcontainer-closure system as the one usedfor the finished dosage formfor the finished dosage form

- reconstituted drug products will be- reconstituted drug products will betested at the time of dispensing and after theytested at the time of dispensing and after theyare reconstitutedare reconstituted

21 CFR 21 CFR § § 211.1211.166 – Stability Testing66 – Stability Testing(cont’d.)(cont’d.)

(b) an adequate number of batches of each(b) an adequate number of batches of each

drug product will be tested to determine andrug product will be tested to determine an

appropriate expiration date; all records ofappropriate expiration date; all records of

testing will be maintained; acceleratedtesting will be maintained; accelerated

studies can be performed at the same timestudies can be performed at the same time

as full shelf life testingas full shelf life testing

21 CFR 21 CFR § § 211.165 –211.165 –Testing and release for distributionTesting and release for distribution

(a) for each product batch, there shall be (a) for each product batch, there shall be appropriate laboratory determination of appropriate laboratory determination of satisfactory conformance to final specifications satisfactory conformance to final specifications for the drug productfor the drug product

(b)(b) microbiological testing for products required to microbiological testing for products required to be free of objectionable microorganismsbe free of objectionable microorganisms

(c)(c) sampling plans will be in written proceduressampling plans will be in written procedures

21 CFR 21 CFR § § 211.165 –211.165 –Testing and release for distribution (cont’d.)Testing and release for distribution (cont’d.)

(d) (d) to be approved and released, product testing to be approved and released, product testing shall meet acceptance criteria and appropriate shall meet acceptance criteria and appropriate statistical quality control criteria.statistical quality control criteria.

(e) validation must be established and (e) validation must be established and documenteddocumented

(f) drug products which fail specifications or other (f) drug products which fail specifications or other relevant QC criteria shall be rejectedrelevant QC criteria shall be rejected

21 CFR 211 § 194 – Laboratory Records21 CFR 211 § 194 – Laboratory Records

(a)Laboratory records shall include completedata from all tests performed to assurecompliance with established specifications andstandards

- sample description identifying: source, quantity, lot number (or other code), date taken and date received for testing

21 CFR 211 § 194 – Laboratory Records21 CFR 211 § 194 – Laboratory Records(cont’d.)(cont’d.)

- methods used in testing must be stated- methods used in testing must be stated

- amount of sample used for each test- amount of sample used for each test

- complete record of all data obtained - complete record of all data obtained during testingduring testing

- all calculations performed (including - all calculations performed (including units of measurement, conversion factors and units of measurement, conversion factors and equivalency factorsequivalency factors


- a statement of sample results of the tests - a statement of sample results of the tests and how they compare with established and how they compare with established standards of identity, strength, quality and standards of identity, strength, quality and puritypurity

- initials or signature of the person doing the - initials or signature of the person doing the testing, the date(s) testing was performedtesting, the date(s) testing was performed

- reviewer’s initials or signature- reviewer’s initials or signature


records of method modifications shall be records of method modifications shall be maintained and include data to verify that results maintained and include data to verify that results are just as accurate and reliable as those are just as accurate and reliable as those obtained by the original methodobtained by the original method

records of testing and standardization of records of testing and standardization of laboratory reference standards, reagents and laboratory reference standards, reagents and standard solutionsstandard solutions

complete records of periodic calibration of complete records of periodic calibration of laboratory instruments, apparatus, gauges and laboratory instruments, apparatus, gauges and recording devicesrecording devices

complete records of all stability testingcomplete records of all stability testing

Records and ReportsRecords and Reports21 CFR § 211.18021 CFR § 211.180

(a) Any record specifically associated with a batch (a) Any record specifically associated with a batch of drug product shall be retained for at least:of drug product shall be retained for at least:

- one year after the expiration date of the batch,- one year after the expiration date of the batch,

oror

- three years after the distribution of the batch- three years after the distribution of the batch


(b) Any record pertaining to a component, drug (b) Any record pertaining to a component, drug product container, closure or labeling of a batch product container, closure or labeling of a batch of drug product shall be retained for at least:of drug product shall be retained for at least:

- one year after the expiration date of the batch,- one year after the expiration date of the batch,oror

- three years after the distribution of the batch- three years after the distribution of the batch


(c) All records (and copies of records) shall be (c) All records (and copies of records) shall be readily available for authorized inspection during readily available for authorized inspection during the retention period.the retention period.

- subject to photocopying or other means - subject to photocopying or other means of reproduction as part of inspection.of reproduction as part of inspection.


(d) Required records may be retained as original (d) Required records may be retained as original records, true copies or other accurate records, true copies or other accurate reproductions. If reduction techniques are used, reproductions. If reduction techniques are used, such as microfilming, a suitable reader must be such as microfilming, a suitable reader must be readily available.readily available.


(e) Maintain records so that they can be used to (e) Maintain records so that they can be used to evaluate the drug product at least annually to see if evaluate the drug product at least annually to see if changes in specifications, manufacturing or control changes in specifications, manufacturing or control procedures need to be made. Provide for review of:procedures need to be made. Provide for review of:

- representative number of batches- representative number of batches

- complaints, recalls, returned or salvaged drug - complaints, recalls, returned or salvaged drug products and investigations conductedproducts and investigations conducted


(f) Establish procedures to ensure that (f) Establish procedures to ensure that responsible officials of the firm are responsible officials of the firm are informed informed in writingin writing of any: investigations of any: investigations conducted relative to complaints, returned conducted relative to complaints, returned drug products and drug product salvaging, drug products and drug product salvaging, recalls, regulatory actions / observations of recalls, regulatory actions / observations of the FDA.the FDA.

Basic preparation for an FDA inspectionBasic preparation for an FDA inspection

What type of inspection – PAI, cGMP, for What type of inspection – PAI, cGMP, for cause, APIcause, API

Probable areas for us to examineProbable areas for us to examine raw data for product testing, stability testingraw data for product testing, stability testing methods (including validation information)methods (including validation information) SOPsSOPs instrumentationinstrumentation laboratory environmentlaboratory environment OOS resultsOOS results employee trainingemployee training

Basic preparation for an FDA inspection Basic preparation for an FDA inspection (cont’d.)(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 Basic preparation for an FDA inspection (cont’d.)(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 ListThe Top 10 List

10) Drug production and control records are 10) Drug production and control records are not reviewed / approved by the quality not reviewed / approved by the quality control unit to determine compliance with control unit to determine compliance with established / approved procedure before established / approved procedure before batch release.batch release.

9) Routine calibration / inspection / checking 9) Routine calibration / inspection / checking of equipment is not performed according of equipment is not performed according to a written program to ensure proper to a written program to ensure proper performance.performance.


8) Employees are not trained in their particular 8) Employees are not trained in their particular functions, cGMPs or written procedures functions, cGMPs or written procedures required by cGMPs.required by cGMPs.

7) No scientifically sound:7) No scientifically sound:- specifications- specifications- standards- standards- sampling plans- sampling plans- test procedures- test procedures

to assure appropriate identity, strength,to assure appropriate identity, strength,quality and purity of drug componentsquality and purity of drug components


6) Before final release of product, there was 6) Before final release of product, there was no satisfactory determination of no satisfactory determination of conformance to specifications for conformance to specifications for identification and strength of each active identification and strength of each active ingredient.ingredient.

5) Production and control records for each 5) Production and control records for each batch of drug product are not prepared batch of drug product are not prepared and/or complete.and/or complete.


4) There are no written procedures for 4) There are no written procedures for production / process controls to ensure production / process controls to ensure that the drug products have identity, that the drug products have identity, strength, quality and purity they claim to strength, quality and purity they claim to possess.possess.

3) Processes that may cause variability of 3) Processes that may cause variability of in-process materials or drug product are in-process materials or drug product are not monitored by appropriate control not monitored by appropriate control measures.measures.


2) The responsibilities and procedures 2) The responsibilities and procedures applicable to the quality control unit are applicable to the quality control unit are not in writing and/or fully followed.not in writing and/or fully followed.


1)1) Written production and process control Written production and process control procedures are not followed in the procedures are not followed in the execution of production and process execution of production and process control functions and/or documented at control functions and/or documented at the time ofthe time of performance.performance.

**as of 4-11-2005as of 4-11-2005

Recent SummaryRecent Summary

Pre-Approval Citations (total citations 108)Pre-Approval Citations (total citations 108)Laboratory Controls (18)Laboratory Controls (18)Test Methods (16)Test Methods (16)Batch Failure Review (13)Batch Failure Review (13)Laboratory Performance (12)Laboratory Performance (12)Instrument Calibration (9)Instrument Calibration (9)QC Responsibilities (8)QC Responsibilities (8)Process Procedures, establishing (8)Process Procedures, establishing (8)Batch Failure Investigation (8)Batch Failure Investigation (8)Validation (8)Validation (8)Investigation Follow-up (8)Investigation Follow-up (8)

Recent SummaryRecent Summary

GMP Inspection Citations (total citations 1,933)GMP Inspection Citations (total citations 1,933)Process Procedures, following/documentingProcess Procedures, following/documenting (321) (321)QC Responsibilities (256)QC Responsibilities (256)Process Procedures, establishing (188)Process Procedures, establishing (188)Product Testing and Release (185)Product Testing and Release (185)Batch Production and Control Records (182)Batch Production and Control Records (182)Validation (176)Validation (176)Training (173)Training (173)Laboratory Controls (164)Laboratory Controls (164)Production Record Review (145)Production Record Review (145)Compliant Procedures (143)Compliant Procedures (143)

Recent Examples of 483 citesRecent Examples of 483 cites

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Inspection Issues in the Analytical Laboratory: An FDA Perspective Yvonne McKnight Chemist US Food...

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