April 19, 2000

Ms. Lori Gregg
Novo Nordisk BioChem North America, Inc.
77 Perry Chapel Church Road
Box 576
Franklinton, NC 27525

Re: GRAS Notice No. GRN 000034

Dear Ms. Gregg:

The Food and Drug Administration (FDA) is responding to the notice, dated November 16, 1999, that you submitted 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 your notice on November 17, 1999 and designated it as GRAS Notice No. GRN 000034.

The subject of the notice is aspartic proteinase enzyme preparation obtained from a strain of Aspergillus oryzae that contains a recombinant gene encoding an aspartic proteinase derived from Rhizomucor miehei. The notice informs FDA of the view of Novo Nordisk BioChem North America, Inc. (Novo Nordisk) that this aspartic proteinase enzyme preparation is GRAS, through scientific procedures, for use as a tenderizing agent in the meat industry when used at minimum levels necessary to accomplish the intended technical effect in accordance with current good manufacturing practices. Typical use levels range from 0.05 to 0.10 AU/kg meat.⁽¹⁾

In your notice, you describe (1) a published review article about the safety of the host microorganism, A. oryzae; (2) scientific publications and recommendations issued by international organizations on the safety of enzymes used in food processing, including enzymes derived from genetically modified microorganisms; (3) published scientific articles that discuss the safety of the various components of the production organism, including the host organism, and the components of the genetic material that is introduced into the host organism; (4) the basis for your conclusion that the presence of a gene encoding resistance to the antibiotic ampicillin is not a concern; (5) chapters in several books that discuss the manufacturing process, which includes standard methods for the fermentation, processing, and formulation of the enzyme preparation; and (6) unpublished oral toxicity and genetic toxicity studies conducted with the subject aspartic proteinase enzyme preparation.

According to your notice, the enzyme component of the subject enzyme preparation is present in a milk-clotting enzyme preparation that is derived from R. miehei. The R. miehei-derived enzyme preparation has been used in food since 1969, and was approved for use in cheese production in 1972 (21 CFR 173.150(a)(4)). In addition, the specific enzyme preparation that is the subject of your notice was approved for use as a milk-clotting enzyme preparation in 1997 (21 CFR 173.150(a)(5)).

According to your notice, the enzyme preparation meets the specifications for enzyme preparations provided in the Food Chemicals Codex (4th ed., 1996). The enzyme preparation also meets the specifications for enzyme preparations provided by the Joint Expert Committee on Food Additives (JECFA; a joint committee of the Food and Agriculture Organization/World Health Organization).

Based on the information provided by Novo Nordisk, as well as other information available to FDA, the agency has no questions at this time regarding Novo Nordisk's conclusion that aspartic proteinase enzyme preparation obtained from a strain of Aspergillus oryzae that contains a recombinant gene encoding an aspartic proteinase derived from Rhizomucor miehei 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 enzyme preparation. As always, it is your continuing responsibility to ensure that food ingredients that you market are safe, and are otherwise in compliance with all applicable legal and regulatory requirements.

FDA consulted with the Labeling and Additives Policy Division (LAPD) of the Food Safety and Inspection Service (FSIS), United States Department of Agriculture, regarding the use of aspartic proteinase enzyme preparation as a tenderizing agent in the meat industry. Based upon the information submitted by Novo Nordisk, FSIS concluded that the subject aspartic proteinase enzyme preparation would be suitable as a tenderizer for raw meat cuts, provided that the enzyme preparation is used as described in the notice, the use level does not exceed 0.1 percent, and water solutions of the enzyme preparation that are applied or injected into raw meat do not result in a weight gain of more than 5 percent. FSIS noted that 9 CFR Parts 317 and 381 describe labeling requirements that apply to the use of proteolytic enzymes in meat or poultry products. FSIS also pointed out that, in the past, the use of enzyme preparations as meat tenderizers has been the subject of rulemaking at FSIS, because such food ingredients change the characteristics of meat or poultry beyond the consumer's expectation of "meat" or "poultry." If you have any questions about whether the use of aspartic proteinase enzyme preparation as a tenderizing agent in the meat industry requires rulemaking under the statutes that FSIS implements, you should direct your inquiry to Dr. Robert Post, Director, LAPD, Office of Policy, Program Development and Evaluation, Food Safety and Inspection Service, 300 12th Street, SW, Room 602, Washington, DC 20250-3700. The telephone number for LAPD is (202) 205-0279 and the FAX number is (202) 205-3625.

In accordance with proposed 21 CFR 170.36(f), a copy of the text of this letter, as well as a copy of the information in your notice that conforms to the information in proposed 21 CFR 170.36(c)(1), is available for public review and copying on the Office of Premarket Approval's homepage on the World Wide Web.

⁽¹⁾AU = Anson Units. This is a measure of enzyme activity for a proteolytic enzyme.

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