HCT/P Contamination Prevention and Biologic Product Sterility Regulations Applicable to PBSCs

1. HCT/P Contamination Prevention and Biologic Product Sterility Regulations Applicable to PBSCs Cell Therapy Liaison Meeting June 16, 2006 Ellen F. Lazarus, M.D. Division of Human Tissues Office of Cellular, Tissue, and Gene Therapies

2. C B E R HCT/P regulations addressing contamination • Current Good Tissue Practices (CGTP) • 21 CFR 1271.145* You must recover, process, store, label, package, and distribute HCT/Ps, and screen and test cell and tissue donors, in a way that prevents the introduction, transmission, or spread of communicable diseases. *Applies to all HCT/Ps, including “351” products

3. C B E R 21 CFR 1271.150 CGTP requirements (“361” products) You must follow CGTP requirements to prevent the introduction, transmission, or spread of communicable diseases by HCT/Ps (e.g., by ensuring that the HCT/Ps do not contain communicable disease agents, that they are not contaminated, and that they do not become contaminated during manufacturing). Communicable diseases include…those transmitted by bacteria, fungi, parasites, and TSE agents.

4. C B E R Specific CGTP provisions (“361” products) • Sec. 1271.160(b)(2): Quality program must ensure that procedures exist for sharing information pertaining to possible contamination • Sec. 1271.160(c): Facility controls to prevent contamination • Sec. 1271.195(a) and (c): Environmental control and monitoring where conditions could be expected to cause contamination • Sec. 1271.200(b): Equipment maintenance to prevent contamination

5. C B E R Specific CGTP provisions (“361” products, with exception) • Sec. 1271.215: Recover in a way that does not cause contamination • Sec. 1271.220(a): Process in a way that does not cause contamination • Sec. 1271.260(a): Control of storage areas to prevent contamination • Sec 1271.265(c)(2)*: You must not make available for distribution an HCT/P that is… contaminated… or that otherwise does not meet release criteria designed to prevent communicable disease transmission *Applies to all HCT/Ps, including “351” products

6. C B E R CGMP regulations addressing contamination and sterility (IND and licensed products) • 211.42 - Facility design and environmental control • 211.67 Equipment cleaning and maintenance • 211.84(d)(6) - Testing and approval of components, drug product containers and closures • 211.94(c) - Sterilization and depyrogenation of containers and closures • 211.100 - Production and process controls (process validation) • 211.110 - Sampling and testing of in-process materials and drug products

7. C B E R CGMP regulations addressing contamination and sterility (IND and licensed products) • 211.113 - Control of microbiological contamination • 211.142(b) - Storage • 211.160 - General requirements for laboratory controls • 211.165 - Testing and release for distribution • 211.165 (b) requires tests of each batch that should be free of objectionable microorganisms and • 211.165(f) failure to meet any specification means rejection unless successful reprocessing possible • 211.167 - Special testing requirements - requires sterility testing for products if purporting to be sterile

8. C B E R Sterility provisions of the Part 610 General Biological Products Standards (licensed products) • “The test” §610.12 (a) • Fluid Thioglycollate Medium - inoculum incubated at 30 to 350C for at least 14 days • Soybean-Casein Digest Medium – same process • Examined visually for evidence of growth on 3rd, 4th, or 5th day, on 7th day, and last day of test period • Alternate and equivalent methods also acceptable under §610.9; e.g., USP <71> or other method that is adequately validated • §610.12(g) Exceptions