1. QC/QA Mary Malarkey Director, Division of Case Management Office of Compliance and Biologics Quality Center for Biologics Evaluation and Research March 21, 2001

2. QC/QA = CGMP ä Preparation of products for administration to humans, including clinical trials ä GLPs are not GMPs ä CGMPs cover manufacturing, controls, testing and documentation ä Difference between Quality Assurance and Quality Control not addressed

3. Quality Control Unit 21 CFR 211.22 ä Approve/reject all components, intermediates, products ä Approve/reject procedures/specifications ä Review records; ensure investigations are conducted ä Adequate laboratory facilities for testing ä Responsibilities and procedures in writing ä (Should be independent from production)

4. QC vs. QA proposed revision to 211 ä Some confusion over QC vs. QA (names, functions, requirements) ä QC - generally testing activities to assure that specifications adhered to ä QA- oversight responsibilities (“the QC of QC”) - auditing methods, results, systems and processes; trending

5. Other Regulations ä Good Laboratory Practices ä 21 CFR 58.35 “Quality Assurance Unit…..shall be responsible for monitoring each study to assure management that the facilities, equipment, personnel, methods, practices, records and controls are in conformance with the regulations in this part….shall be entirely separate from and independent of the personnel engaged in the direction and conduct of the study.”

6. Other Regulations ä Good Tissue Practices (proposed rule) ä 21 CFR 1271.3(oo) - “Quality Program…This program includes preventing, detecting and correcting deficiencies that may lead to circumstances that increase the risk of introduction, transmission, or spread of communicable disease.”

7. QC and QA Dear Sponsor Letter 3/6/2000 ä Summary of QC/QA programs. Brief description of system for preventing, detecting and correcting deficiencies that may: ä compromise product integrity or function ä lead to possible transmission of adventitious infectious agents

8. QC and QA: Dear Sponsor Letter ä Identify each individual who has authority over the QC/QA program(s) ä Provide date of last QC/QA audit of: ä your operations ä contract manufacturers, vendors and other partners

9. QC and QA: Dear Sponsor Letter ä Unique considerations for these products: ä QC and/or QA may be one individual ä most “QC”, that is testing, may be contracted out; ä most validation/qualification activities contracted out; ä many vendors involved, e.g. water, media ä facility may be used by multiple sponsors

10. General Considerations ä DOCUMENTATION - approval/review ä Batch Production Records (211.188 & 211.192) ä Equipment - cleaning and use (211.182) ä Laboratory Records (211.194) ä Standard Operating Procedures (211.100) ä “Distribution” Records (211.196) ä Complaint Files (211.198) ä SHOULD ALLOW TRACEABILITY

11. Prevent Deficiencies - 1 ä Testing of all cell and viral banks ä review of SOPs, protocols, results from test lab ä Testing, or certification, of components ä example; media -> animal derived materials BSE free countries (1/6/98 FR notice) ä Screening of patients or use of universal precautions

12. Prevent Deficiencies - 2 ä Facility ä adequately designed, validated ä equipment calibrated, qualified, certified ä maintenance and monitoring procedures ä requalification procedures in place ä cleaning procedures in place for equipment and facility (variety of cleaning agents) ä segregation procedure in place

13. Prevent Deficiencies - 3 ä Manufacturing process (vector and product) ä controls developing ä validation of aseptic processes ä operator training and qualification ä procedures for deviations from process or other deviations associated with production ä testing of product; review of all records associated with lot - > release

14. Detection Considerations ä Monitoring ä facility ä personnel ä Testing ä components ä in-process ä final product ä Trending

15. Correction Considerations ä Importance of traceability ä Procedures for investigations (211.192) should extend to other lots of product ä Procedures for corrective actions ä Procedures for handling of complaints or AEs that may be associated with manufacturing ä Procedures for notification

16. Examples -1 ä Sterility test failure ä perform identification ä review records on components ä review records on equipment cleaning and use ä review environmental and personnel monitoring records

17. Examples- 1 ä Isolate identified as S. epidermidis ä Personnel monitoring result - same organism ä Retrain and requalify operator ä Increase routine monitoring of operator

18. Examples - 2 (actual) ä Mold contamination of in-process cells ä investigation inconclusive ä Mold contamination of in-process cells ä trace both flasks to shelf in incubator ä monitor incubator ä isolate same mold ä Corrective action - addition of fungicidal agent (was using only IPA)

19. Description of Program ä Should hit on points previously described which should ensure prevention, detection and correction of deficiencies that may compromise product. ä Distinguish between testing (QC) and oversight (QA) activities

20. Identification of Authority ä Should be separate from “production” which is sometimes the sponsor ä Should have ultimate authority to release/reject, i.e. shouldn’t be producing, testing, reviewing, releasing ä Ideal - separate unit with ultimate reporting to sponsor, but authority, i.e, sponsor should accept decision

21. QC/QA Audits ä Date of last audits for the following should be provided……. ä Later paragraph suggests that a plan for audits should be in place: what needs to be audited, how audited, frequency of audits

22. QC/QA Audits ä Manufacturing operations (211.180) ä annual ä representative number of batches ä all associated records and deviations, complaints ä responsible individual must be notified of results

23. QC/QA Audits ä Vendors (211.84) ä could be quite an undertaking given number of components; audit may entail testing of certain lots of components to ensure C of A accurate. Certification by vendors. ä Contract Manufacturers ä most likely testing - cell and viral banks, final product; should be reviewing and approving SOPs, validation protocols used

24. QC/QA Audits ä Contract Validation Activities ä should be involved in plans and implementation ä should “pick up ball,” that is, maintain validated state through proper monitoring and maintenance activities ä revalidation/requalification/recertification programs

25. Conclusion ä Sponsors should be in compliance with CGMPs with respect to QC/QA functions ä Problem areas: ä Lack of documentation ä Lack of traceability ä No separation between QC/QA and other operations

26. Mary Malarkey OCBQ/DCM301-827-6201