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U.S. Department of Health and Human Services

Food

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Agency Response Letter GRAS Notice No. GRN 000020

CFSAN/Office of Premarket Approval

September 30, 1999

W. Martin Teague
Enzyme Bio-Systems Ltd.
2600 Kennedy Drive
Beloit, Wisconsin 53511-3992

Re: GRAS Notice No. GRN 000020

Dear Mr. Teague:

The Food and Drug Administration (FDA) is responding to the notice, dated April 19, 1999, submitted by Enzymes Bio-Systems Ltd. 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)). FDA received the notice on April 22, 1999 and designated it as GRAS Notice No. GRN 000020.

The subject of your notice is the pullulanase enzyme preparation obtained from a genetically engineered nonpathogenic, nontoxigenic, and asporogenic strain of Bacillus subtilis B1-163/pEB301 containing the pullulanase gene from a nonpathogenic and nontoxigenic strain of Bacillus naganoensis. The notice informs FDA of the view of Enzymes Bio-Systems Ltd. that pullulanase enzyme preparation derived from B. subtilis is GRAS, through scientific procedures, for use in hydrolyzing starch and starch-related compounds in the production of corn sweeteners, baked goods, and alcoholic beverages at minimum levels necessary to accomplish the intended effect in accordance with current good manufacturing practices.

Your notice describes: (1) published information about enzymes; (2) published information about pullulanase enzyme preparation; (3) published information about enzymes that are derived from genetically modified microorganisms for use in food processing; (4) published information regarding the safety of the various components of the production organism, including the host organism, the DNA derived from the donor organism, and vector DNA; (5) information to support your conclusion that the presence of bleomycin and kanamycin antibiotic resistance genes is not a concern, including an FDA draft guidance document on the use of antibiotic markers in transgenic plants and the published recommendations of the International Food Biotechnology Council; (6) the manufacturing process, which includes standard methods for the fermentation, processing, and formulation of the enzyme preparation; and (7) unpublished studies to support the safety of the pullulanase preparation from B. subtilis B1-163/pEB301.

Enzyme Bio-Systems Ltd. recommends that the pullulanase preparation be used at 0.0225 to 0.8 units per gram dry substance of starch in starch hydrolysis and alcoholic beverages and at 0.0225 to 10 units per gram dry substance of flour in bakery products. According to calculations in your notice, the "worst case" human exposure to the residues of the enzyme preparation would be 0.02 mg of total organic solids per kg body weight per day. According to your notice, the enzyme preparation meets the specifications for enzyme preparations provided in the Food Chemicals Codex (4th edition, 1996).

Based on the information provided by Enzymes Bio-Systems Ltd., as well as other information available to FDA, the agency has no questions at this time regarding your conclusion that the pullulanase enzyme preparation obtained from a genetically engineered nonpathogenic, nontoxigenic, and asporogenic strain of B. subtilis B1-163/pEB301 containing the pullulanase gene from a nonpathogenic and nontoxigenic strain of B. naganoensis 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 this pullulanase enzyme preparation. As always, it is the continuing responsibility of Enzymes Bio-Systems Ltd. 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 this letter, as well as a copy of the information in your notice that conforms to the information in proposed § 170.36(c)(1), is available for public review and copying on the Office of Premarket Approval's homepage on the World Wide Web.

Sincerely,
   
Alan M. Rulis, Ph.D.
Director
Office of Premarket Approval
Center for Food Safety and Applied Nutrition