1. Regulatory Challenges in the Cell Preparation Facility Adrian Gee Center for Cell & Gene Therapy Regulatory Challenges in the Cell Preparation Facility Adrian Gee Center for Cell & Gene Therapy

2. Overview Regulation of Cell Therapy products Current regulatory strategy Critical issues for regulatory compliance by Cell Preparation Facilities Required reporting Resources

3. Background FDA classifies Cell Preparation Facilities as drug manufacturers FDA required to ensure that drugs are safe and effective Initially applied existing drug regulations to cell therapy product manufacturing –products are Investigational New Drugs –manufacturing to comply with Good Manufacturing Practices (GMP)

4. New Approaches Left “traditional” cell therapies unregulated –Bone Marrow Transplants –Peripheral Blood Progenitor Cell Transplants Resulted in new regulations in 2005 Intended to address risk of communicable disease transmission Required manufacturing according to Good Tissue Practices

5. GMP or GTP? Regulations are NOT mutually exclusive Primary regulatory strategy based on perceived risk: –to donor –to product during manufacturing degree of ex vivo manipulation –to recipient Most cell therapy products must be manufactured under GMP regulations

6. Regulatory Strategy Donor of cells assessed for eligibility –infectious disease testing –risk behavior assessment –not required for autologous products –use of ineligible donors acceptable under Urgent Medical Need provision Manufacture using a controlled, reproducible and auditable process

7. Critical Areas Standard Operating Procedures Facility issues Training Quality Product Handling & Processing Product Release & Administration

8. Critical Areas Standard Operating Procedures –All aspects of operations: SOP for SOPs –Appropriate document control record of SOP release & implementation staff review and training updated annually archived appropriately

9. Critical Areas Facility –annual FDA registration –environmental control –environmental monitoring –equipment: qualification, calibration, cleaning, maintenance –maintenance

10. Critical Areas Facility –supplies selection release specifications, testing, management vendor audits (visits or questionnaire) water quality –cleaning, maintenance –waste management –pest control

11. Critical Areas Training –job description –qualifications –initial training –annual retraining –annual training in GMP/GTP –assessment of aseptic technique –competency and proficiency records

12. Critical Areas Quality Program –error and deviation detection & reporting –corrective actions and follow-up –dealing with positive test results post- administration –products prepared but not used –complaints from customers –audit program –annual quality report

13. Critical Areas Product receipt, release and return Product quarantine –for ineligible/pending eligibility –clearly identified area –appropriate labeling Product storage and expiration Product recall

14. Critical Areas Process controls Process validation –started at Phase 1 –completed before Phase 3 Labeling and label controls –correct product name –required language: Autologous use only etc. –appropriate warnings: Reactive test for... etc.

15. Product Release Certificate of Analysis –identity –purity –potency Tests used – CFR compliant? Sensitivity of testing method Review of results Released through QA Appropriate labeling

16. Product Administration Prescription for administration Record of removal from inventory Appropriate cross-checks Record of additional manipulation and retesting Record and investigation of adverse reactions

17. Required Reporting Annual establishment registration Annual IND report Dear Cell/Gene Therapy letter response –all products manufactured –manufactured and not used Response to 483’s Documentation of SAEs

18. Resources FDA website –GMP and GTP regulations CBER website –Guidances Validation of sterility testing Inspections –Points to Consider –“What’s New at CBER” alerts –CBER presentations

19. Resources Professional Societies –ISCT –ISSCR –AABB –ICCBBA Accrediting Agencies –FACT –AABB –CAP Professional Standards –FACT –AABB –USP Consultants

20. Conclusions Cell Preparation Facilities are under regulatory scrutiny Regulations are still evolving –recent guidances for CMC sections & pancreatic islets Ignorance cannot be used as an excuse Good faith efforts are appreciated Communication is essential

21. Acknowledgements CAGT Colleagues NHLBISCCTPACT NHLBISCCTPACT