2. Inspection Issues in the Analytical Laboratory: An FDA Perspective Yvonne McKnight Chemist US Food and Drug AdministrationPhone: 215-597-4390 x4619 200 Chestnut Street, Rm. 1005Fax: 215-597-5728 Philadelphia, PA 19106Email: yvonne.mcknight@fda.gov

3. Overview  Introduction to / reminder of basic regulations  Basic preparation for an FDA inspection  Recent trends of “Objectionable Findings” on 483s on 483s

4. 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

5.  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 § 5.31(a)(1) – Enforcement Activities

6. 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

7. 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

8. 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

9. 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

10. 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

11. 21 CFR 211 § 194 – Laboratory Records (a) (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

12. 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

13. 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

14. 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

15. 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

16. 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

17. 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.

18. 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.

19. 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

20. 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.

21. Basic preparation for an FDA inspection  What type of inspection – PAI, cGMP, for cause, API  Probable areas for us to examine  raw data for product testing, stability testing  methods (including validation information)  SOPs  instrumentation  laboratory environment  OOS results  employee training

22. 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

23. 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

24. 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.

25. 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

26. 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.

27. 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.

28. The Top 10 List 2) The responsibilities and procedures applicable to the quality control unit are not in writing and/or fully followed.

29. 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 ofperformance. 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

30. 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)

31. 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)

32. Recent Examples of 483 cites

33. Thank you! Are there any questions?