1. FDA TSE Advisory Committee Meeting October 25, 2001 Topic 2 Amino Acid Production and the Associated Theoretical Risk of BSE Transmission from their Use in the Production of Biologics, Drugs and Medical Devices Gerald M. Feldman, Ph.D. Division of Monoclonal Antibodies Office of Therapeutics Research and Review Center for Biologics Evaluation and Research Food and Drug Administration

2.  CBER letters to manufacturers of biological products (1991)  Agency letters to manufacturers of FDA- regulated products (1993)  Agency letters to manufacturers of FDA- regulated products (1996)  CBER letters to manufacturers of vaccines and other biologics (2000)

3. Review of Tallow and Gelatin  Advisory Committee Recommendations: –1997: No bovine derived material from a country with BSE be a source for gelatin used in injectable, implantable, or ophthalmic products. Safe sourcing of gelatin when used for oral or topical applications

4. Production of Amino Acids  Microbial Fermentation  Chemical Synthesis  Hydrolysis [Chemical or Enzymatic] –Vegetal Proteins –Animal Proteins  Avian (feathers)  Mammalian (hide, hair, fat, bone, other)

5. Amino Acids in FDA-Regulated Drugs  Active Ingredients  Excipients  Reagents

6. Amino Acids in FDA-Regulated Drugs (cont)  As Active Ingredients (drug substance): –Oral Dosage Forms –Total Parenteral Nutritions –Large Volume Parenterals

7. Active Ingredients  Restriction: –In compliance with 1996 FDA Policy  No bovine-derived amino acids from BSE countries  No restriction on other ruminant sources

8. Amino Acids in FDA-Regulated Drugs (cont)  As Excipients: –Buffer components (glycine, histidine) –Stabilizing agents (glycine) –Antioxidants (methionine, cysteine)

9. Amino Acids in FDA-Regulated Drugs (cont )  As Reagents: –Components in buffers –Components in peptide synthesis –Components in cell culture media

10. Excipients and Reagents  Non-Restricted Sources: –Microbial fermentation –Chemical synthesis –Hydrolysis  poultry feathers  human and animal hair  other (bone, hide, fat)  sources not always identified

11. Sponsors’ Responses to Request for Information “No such inquiries were made in the past. Retrospective inquiries do not allow us to obtain full information on past supplies” “Amino acids are safe, since they are isolated by acidic or enzymatic total hydrolysis of proteins with subsequent ion-exchange chromatography” “Amino acids are safe, since they are subject to a multitude of chemical reactions and purification steps as they go from amino acid to final product”

12. Suppliers’ Response to Request for Information

13. Amino Acid Manufacturers Ajinomoto Inc. * Daiichi Pharmaceutical Co. Ltd. DeGussa AG * Kyowa Hakko Inc.

14. Charge to the Committee The TSEAC is requested to consider the safety of amino acids produced from ruminant derived materials from BSE and BSE risk countries with regard to the likelihood of transmission of the BSE agent.

15. Charge to the Committee (cont) If such a risk exists, the TSEAC is requested to consider the appropriate precautions that should be taken regarding the use of ruminant-derived amino acids in the manufacture of bio-pharmaceutical products, drugs or medical devices.

16. Charge to the Committee (cont) The committee is also asked to consider the potential risks and possible actions to be taken with regard to licensed, approved or investigational products that may be affected.

17. TSEAC 25 October, 2001 Topic 2: Safety of Amino Acids Question 1; Does the committee think that the current manufacturing process and control methods utilized by the manufacturers of amino acids can minimize the risk to allow bovine-derived amino acids from BSE countries to be used as reagents and excipients for the production of pharmaceutical products?

18. TSEAC 25 October, 2001 Topic 2: Safety of Amino Acids Question 2; If not, does the committee feel that there are any circumstances where the risk:benefit ratio would still be in favor of a subject receiving a product where suspect amino acids had been used in its manufacturing process?

19. TSEAC 25 October, 2001 Topic 2: Safety of Amino Acids Question 3; If not, does the committee think that the current manufacturing process and control methods utilized by the manufacturers of amino acids can minimize the risk to allow other ruminant-derived amino acids from BSE countries to be used as reagents and excipients for the production of pharmaceutical products?

20. TSEAC 25 October, 2001 Topic 2: Safety of Amino Acids Question 4; If the committee recommends removal of all ruminant- derived amino acids sourced from BSE countries for use as reagents and excipients in pharmaceutical production, is there a specific timeframe for this removal?