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 VALIDATION/QUALIFICATION ROUTINE MONITORING QA/QC ENVIRONMENT EQUIPMENT RAW MATERIALS COMPONENTS PROCESS

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 VALIDATION/QUALIFICATION ROUTINE MONITORING QA/QC ENVIRONMENT EQUIPMENT RAW MATERIALS COMPONENTS PROCESS

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 1.John A. Eltermann, M.S, R.Ph., Director, DMPQ 2.John Finkbohner, Ph.D., Deputy Director, DMPQ 3.DMPQ Review Staff