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U.S. Department of Health and Human Services

Food

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Agency Response Letter GRAS Notice No. GRN 000216

CFSAN/Office of Food Additive Safety
May 18, 2007

Mr. David Joy
Keller and Heckman LLP
1001 G Street, NW
Suite 500 West
Washington, DC 20001

Re: GRAS Notice No. GRN 000216

Dear Mr. Joy:

The Food and Drug Administration (FDA) is responding to the notice, dated November 20, 2006, that you submitted on behalf of Amano Enzyme Inc. (Amano) in accordance with the agency's proposed regulation, proposed 21 CFR 170.36 (62 FR 18938; April 17, 1997; Substances Generally Recognized as Safe (GRAS); the GRAS proposal). FDA received this notice on November 22, 2006, filed it on November 27, 2006, and designated it as GRAS Notice No. GRN 000216.

The subject of the notice is lipase enzyme preparation derived from Rhizopus oryzae. The notice informs the FDA of the view of Amano that lipase enzyme preparation from R. oryzae is GRAS, through scientific procedures, for use as an enzyme to produce tailored triglycerides intended for use in infant formula.

Commercial enzyme preparations that are used in food processing typically contain an enzyme component, which catalyzes the chemical reaction that is responsible for the technical effect of the enzyme preparation, and substances used as stabilizers, preservatives or diluents. Enzyme preparations may also contain constituents derived from the production organism and constituents derived from the manufacturing process, e.g., components of the fermentation media or the residues of processing aids.

The notice includes information about the technical effects of lipases, which hydrolyze triglycerides of fatty acids. Lipase also catalyzes the interesterification of edible fats and oils. Amano provides general information about the identity of lipase enzyme preparation. Lipase from R. oryzae is identified by the following classification numbers: EC No. 3.1.1.3 and Chemical Abstract Service Registry No. 9001-62-1. In assessing the safety of the enzyme itself, Amano states that enzymes generally do not raise safety concerns. Amano also discusses the history of safe use of lipases in food processing.(1)

Amano considers the safety of the production organism as the prime consideration in assessing the safety of an enzyme preparation intended for food use. The notice states that a nonpathogenic and nontoxogenic organism can be assumed to produce safe food ingredients when used in conjunction with current Good Manufacturing Practices (GMPs). Amano cites a well received published article for evaluating the safety of the production strain.

In its notice, Amano cites published comprehensive reviews and studies that support the safety of microbial enzyme preparations used in food processing. Amano also presents published toxicity data for: a 90-day rat gavage study; three genotoxicity studies: an Ames assay, a mouse lymphoma forward mutation assay, and a chromosome aberration assay; and, a third study which included a pathogenicity study of the production organism, R. oryzae, using mice. Amano concludes that these tests show that the lipase enzyme preparation does not exhibit mutagenic activity or toxic effects under the specified testing conditions.

Amano states that the materials used in the fermentation and recovery processes for the enzyme concentrate are common ingredients used in the enzyme industry. Additionally, Amano states that the materials are suitable food grade materials. The enzyme preparation is produced following GMPs.

The lipase enzyme preparation is produced by submerged fed-batch pure culture fermentation of an R. oryzae strain. During all steps of fermentation, physical and chemical control measures are taken and microbiological analyses are performed to ensure the absence of foreign microorganisms and to confirm the identity of the production strain. Amano states that its specifications for lipase enzyme preparation comply with the purity criteria recommended for enzyme preparations as described in the Food Chemical Codex, 5th Edition, 2003.

Based on the information provided by Amano, as well as other information available to FDA, the agency has no questions at this time regarding Amano's conclusion that lipase enzyme preparation is GRAS under the intended conditions of use. The agency has not, however, made its own determination regarding the GRAS status of the subject use of lipase enzyme preparation. As always, it is the continuing responsibility of Amano to ensure that food ingredients that the firm markets are safe, and are otherwise in compliance with all applicable legal and regulatory requirements.

In accordance with proposed 21 CFR 170.36(f), a copy of the text of this letter responding to GRN 000216, as well as a copy of the information in this notice that conforms to the information in the proposed GRAS exemption claim (proposed 21 CFR 170.36(c)(1)), is available for public review and copying on the homepage of the Office of Food Additive Safety (on the Internet at http://www.cfsan.fda.gov/~lrd/foodadd.html).

Sincerely,
Laura M. Tarantino, Ph.D.
Director
Office of Food Additive Safety
Center for Food Safety and Applied Nutrition




(1)Amano states that, in most cases, the enzyme preparation will be loaded to, and immobilized on, a carrier in the reactor prior to the enzyme catalyzed reaction. FDA notes that it is the responsibility of companies using the enzyme preparation in its immobilized form to ensure that all substances utilized in conjunction with this use are safe, and are otherwise in compliance with all applicable legal and regulatory requirements.