Expectations for Facilities & cGMPs

1. Expectations for Facilities & cGMPs Biological Response Modifiers Advisory Committee Meeting October 9, 2003 Nicholas Obiri, Ph.D. CBER

2. Scope • Regulatory Authority • Facility Design Principles • Environmental and Process Control • Aseptic Processing

3. Regulatory Authority • Public Health Service Act Section 351 • Authority for licensing biological products when certain conditions are met

4. Regulatory Authority contd. • Title 21 CFR Section 601.2(d) • Approval of an application shall constitute a determination that the establishment(s) and product meet applicable requirements to ensure the continued safety, purity and potency of such products. • The requirements include the applicable regulations (21 CFR 210-211; 600s; 800s).

5. A QUALITY PRODUCT QA/QC VALIDATION/QUALIFICATION ROUTINE MONITORING PROCESS COMPONENTS EQUIPMENT ENVIRONMENT RAW MATERIALS

6. Broad overview of facility and control issues • Appropriate facility design • A controlled environment • Equipment qualification • Adequate measures to control cross contamination • Adequate measures to control mix-up of patient materials

7. Broad overview of facility and control issues • Control of incoming raw materials • Independent Quality Assurance/Quality Control staff • Records and documentation

8. Facility Design Principles • Influenced by the nature of the source material • Tissue derived vs Cell culture • Single vs multiproduct operations • Critical manufacturing areas designed for aseptic processing

9. Facility Design Principles contd. • Process Flow: • Designed to control the manufacturing environment (personnel and process) • Adequate and separate areas for various activities (receipt of materials, testing, manufacturing) • Material Mix-up • Material and personnel flows designed to maximize efficiency and minimize product mix-ups

11. Environmental Control Air Quality • HEPA-filtered air in manufacturing areas; higher level of control for critical manufacturing steps • Use pressure cascade to protect the product • High pressure to low pressure • Pressure sink to protect other manufacturing areas and personnel

12. Environmental Control • Need to qualify the HVAC system to confirm that the equipment, its control and circulation systems meet expected performance or quality standards (Monitored under static and dynamic conditions) • Pharmaceutical grade reagents and supplies (Water, Process Air, Utility Gasses)

13. Process control • Validation • Process (demonstrate manufacturing consistency, aseptic processing) • Equipment • Demonstrate concurrent control over other facility systems (e.g. HVAC) • Qualified personnel

14. Quality System • Vendor audit • Material qualification • Oversight of process • Change control • Personnel training • Investigation of deviations, recalls, product complaints, Medwatch program

15. A QUALITY PRODUCT QA/QC VALIDATION/QUALIFICATION ROUTINE MONITORING PROCESS COMPONENTS EQUIPMENT ENVIRONMENT RAW MATERIALS

16. Aseptic Processing • A processing approach in which product manufacture occurs under environmental and processing conditions that assure minimal opportunity for contamination from the environment or personnel.

17. Aseptic Processing • Since terminal sterilization is not a feasible option for islets, the final product has to be assembled by introducing the aseptically processed final formulation into a sterilized container and sealed with a sterilized closure system in a high-quality environment

18. Aseptic Processing • Required for all open manipulations and connections involving product • Involves trained and qualified personnel • Must be validated (media challenge)

19. Aseptic Processing • Typically occurs in class 100 environment under laminar air flow (BSC) with appropriate environmental monitoring e.g. viable and non-viable airborne particulate monitoring • May also occur in “Closed” systems (Requires validation)

20. Summary • Design compliance into the facility plans. Advisable to seek CBER input prior to construction. • Establish a thorough qualification/validation program • Maintain an effective QA/QC unit to assure maintenance of quality standards and regulatory compliance

21. Summary contd. • Maintain aggressive approach to compliance with aseptic processing requirements

22. Resources For questions on facilities and manufacturing operations, including arrangements for pre-approval inspection: Director Division of Manufacturing and Product Quality FDA, CBER 1401 Rockville Pike, 200S, HFM-670 Rockville, MD 20852-1448 Ph.: (301) 827-3031

23. Acknowledgement • John A. Eltermann, M.S, R.Ph., Director, DMPQ • John Finkbohner, Ph.D., Deputy Director, DMPQ • DMPQ Review Staff