BLOOD PRODUCTS ADVISORY COMMITTEE March 15, 2002

1. BLOOD PRODUCTS ADVISORY COMMITTEEMarch 15, 2002 Topic 4—Bacterial and Fungal Contamination of Human Tissue Intended for Transplantation

2. Introduction and Background Ruth R. Solomon, M.D. Human Tissue Staff OBRR, CBER, FDA

3. ISSUE • Recent Clostridium sordellii sepsis and death following knee surgery in a recipient of a fresh tissue allograft from a cadaveric donor • Investigations by Minnesota Dept. of Health, CDC, and FDA • Additional reports of bacterial and fungal contamination of musculoskeletal tissue allografts

4. Discussion at BPAC • Current and future FDA regulations that address this issue---R. Solomon, OBRR, CBER • Microbial Contamination and Cross Contamination during Processing of Tissue—M. Malarkey, OCBQ, CBER, FDA • Investigation of Allograft –Associated Infections—M. Kainer, DHQP, NCID, CDC • Tissue Bank Perspective—T. Eastlund • Eye Bank Perspective—M. Lemp • Committee discussion

5. Current FDA Regulations21 CFR, part 1270 • FDA has been regulating human tissue intended for transplantation since 1993 • Interim Rule—12/14/93; Final Rule—7/29/97 (effective 1/26/98) • Legal authority—section 361 of PHS Act—Control of Communicable Diseases • Main focus is on donor screening and testing for HIV, Hepatitis B, and Hepatitis C • Very few requirements re: processing

6. Subpart C-Procedures/Records1270.31 Written Procedures • 1270.31(d) There shall be written procedures prepared, validated, and followed for prevention of infectiousdisease contamination or cross-contamination by tissue during processing. • Infectious disease can include, but is not limited to, bacteria and fungi.

7. Current regulations, cont. • Compliance with 1270.31(d) [and all requirements in part 1270] is determined during inspection of the establishment. • 21 CFR, part 1271, subparts A and B, published 1/19/01, effective 4/4/01 • Requires establishment registration and product listing

8. Future FDA Regulations(proposed, but not finalized) • Suitability Determination for Donors of Human Cellular and Tissue-Based Products; Proposed Rule 9/30/99 • Current Good Tissue Practice for Manufacturers of Human Cellular and Tissue-Based Products; Inspection and Enforcement; Proposed Rule 1/8/01

9. GTP Proposed Requirements that may impact current events • 1271.150--requirements are intended to prevent the introduction, transmission, and spread of communicable disease through the use of cell and tissue products, by helping to ensure that the products do not contain communicable disease agents and the the products do not become contaminated during manufacturing. [Manufacturing includes recovery, processing, storage, labeling, packaging, or distributing]

10. GTP, cont. • 1271.160—establishment and maintenance of a quality program, whose functions would include— • Investigating product deviations and complaints • Ensuring that appropriate corrective actions are taken—both short term and long term • Performing audits • Reporting to management

11. GTP, cont. • 1271.220—Process controls • Control and monitor manufacturing processes to ensure that each product is not contaminated and is manufactured so as to prevent transmission of communicable disease by the product • In-process monitoring and control—representative sampling, control of product until required inspection and tests are completed, specified requirements are met

12. GTP, cont. • 1271.230—Process validation • Where the results of a process cannot be fully verified, the process shall be validated. • Validated processes have to be monitored to ensure that the specified requirements continue to be met. • When changes to or deviation from a validated process occur, re-validate. • Any process-related claim in labeling or promotional materials shall be based on a validated process.

13. GTP, cont. • 1271.265—Receipt and distribution • Procedures are established for receiving, and accepting or rejecting products for processing, distribution or any other step in manufacturing. • Each incoming product is inspected for contamination.

14. GTP, cont. • 1271.290—Tracking • Maintain a method of product tracking that enables tracing from donor to recipient, and recipient to donor.

15. GTP, cont. • 1271.350—Reporting of: (1) adverse reactions involving the transmission of a communicable disease, if the adverse reaction is fatal, life-threatening, results in permanent impairment of a body function or permanent damage to a body structure, or necessitates medical or surgical intervention, and (2) product deviations that could lead to the above.

16. Charge to the Committee • General discussion of possible mechanisms to prevent bacterial and fungal contamination and communicable disease transmission by human tissue, keeping in mind the continuing data collection efforts, as follows : • Ongoing investigations (epidemiologic studies) to identify risk factors associated with Clostridium infection post-allograft—CDC and States (CDC will discuss possible risk factors)

17. Charge, cont. • Survey of tissue banks to determine current processing methods and quality control procedures—CDC and AATB • Development of new sterilizing methods which would eliminate bacterial spores, without adversely affecting tissue allograft quality