FDA TSE Advisory Committee MeetingOctober 25, 2001

Topic 2Amino 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 ReviewCenter for Biologics Evaluation and Research

Food and Drug Administration

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)

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

Production of Amino Acids

Microbial Fermentation Chemical Synthesis Hydrolysis [Chemical or Enzymatic]

– Vegetal Proteins– Animal Proteins

Avian (feathers) Mammalian (hide, hair, fat, bone, other)

Amino Acids in FDA-Regulated Drugs

Active Ingredients Excipients Reagents

Amino Acids in FDA-Regulated Drugs (cont)

As Active Ingredients (drug substance):– Oral Dosage Forms– Total Parenteral Nutritions– Large Volume Parenterals

Active Ingredients

Restriction: – In compliance with 1996 FDA Policy

No bovine-derived amino acids from BSE countries No restriction on other ruminant sources

Amino Acids in FDA-Regulated Drugs (cont)

As Excipients:– Buffer components (glycine, histidine)– Stabilizing agents (glycine)– Antioxidants (methionine, cysteine)

Amino Acids in FDA-Regulated Drugs (cont)

As Reagents:– Components in buffers – Components in peptide synthesis– Components in cell culture media

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

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”

Suppliers’ Response to Request for Information

Supplier Amino Acid SourceABC L-Cysteine Animal Extraction

ACD L-Cysteine Chemical SynthesisAC L-Cysteine Bact. FermentationADE L-Serine Animal ExtractionBD L-Serine Chemical Synthesis

DF L-Serine Bact. FermentationADE L-Alanine Chemical SynthesisADF L-Alanine Bact. Fermentation

Amino Acid Manufacturers

•Ajinomoto Inc. *

•Daiichi Pharmaceutical Co. Ltd.

•DeGussa AG *

•Kyowa Hakko Inc.

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.

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.

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.

TSEAC 25 October, 2001Topic 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?

TSEAC 25 October, 2001Topic 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?

TSEAC 25 October, 2001Topic 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?

TSEAC 25 October, 2001Topic 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?