Agency Response Letter
GRAS Notice No. GRN 000090
Jack Harris
Enzyme Technical Association
1800 Massachusetts Ave., N.W.
Second Floor
Washington, DC 20036
Re: GRAS Notice No. GRN 000090
Dear Mr. Harris:
The Food and Drug Administration (FDA) is responding to the notice, dated November 8, 2001, 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); the GRAS proposal). FDA received the notice on November 16, 2001, and designated it as GRAS Notice Nos. GRN 000088, GRN 000089 and GRN 000090 (as explained below).
The subject of the notice is a group of ten microbially derived enzyme preparations, i.e., carbohydrase, pectinase, protease, glucose oxidase and catalase enzyme preparations from Aspergillus niger, carbohydrase and protease enzyme preparations from Aspergillus oryzae, carbohydrase enzyme preparation from Rhizopus oryzae, invertase enzyme preparation from Saccharomyces cerevisiae, and lactase enzyme preparation from Kluyveromyces marxianus. The notice informs FDA of the view of the Enzyme Technical Association (ETA) that these enzyme preparations are GRAS, through common use in food, for use as enzymes in catalyzing specific reactions in the processing of food. Each of the enzyme preparations is used at levels not to exceed current good manufacturing practice. These enzyme preparations are also the subjects of a GRAS affirmation petition (GRP 3G0016) submitted by the Ad Hoc Enzyme Technical Committee (now known as ETA) to FDA in 1973 and amended a few times thereafter. In its notice, the ETA requested that FDA convert the filed GRAS affirmation petition GRP 3G0016 for these ten enzyme preparations to a GRAS notice 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)).
For administrative expediency, FDA divided ETA’s GRAS notice into three separate GRAS notices. GRN 000088 includes invertase from Saccharomyces cerevisiae, and lactase from Kluyveromyces marxianus. GRN 000089 includes carbohydrase, pectinase, protease, glucose oxidase and catalase from Aspergillus niger. GRN 000090 includes carbohydrase and protease from Aspergillus oryzae, and carbohydrase from Rhizopus oryzae. In this letter, FDA responds to GRN 000090.
Carbohydrase enzyme preparation from Rhizopus oryzae is approved as a food additive for use in the production of dextrose from starch (21 CFR 173.130; 29 FR 14663; October 28, 1964). Because the agency considered that the safe use of carbohydrase enzyme preparation from R.oryzae was established by the food additive regulation, FDA’s review of GRP 3G0016 did not include whether the data and information in GRP 3G0016 established that this safe use is generally recognized. Consistent with its view during the evaluation of GRP 3G0016, FDA did not evaluate, during its review of GRN 000090, whether carbohydrase enzyme preparation from R. oryzae is GRAS through experience based on common use in food.
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, as well as substances used as stabilizers, preservatives or diluents. Enzyme preparations may also contain constituents derived from the source organism and constituents derived from the manufacturing process, e.g., components of the fermentation media or the residues of processing aids. In GRP 3G0016, ETA includes data and information about the technical effect of each enzyme component, the source microorganism (i.e., A. oryzae), and the method of manufacture.
Carbohydrase enzyme preparation from A. oryzae is an enzyme preparation obtained from the culture filtrate resulting from a pure culture fermentation of a non-pathogenic and non-toxicogenic strain of A. oryzae. The preparation contains alpha-amylase (EC 3.2.1.1) or glucoamylase (EC 3.2.1.3), which catalyzes the hydrolysis of starch or starch polysaccharides in food.
Protease enzyme preparation from A. oryzae is an enzyme preparation obtained from the culture filtrate resulting from a pure culture fermentation of a non-pathogenic and non-toxicogenic strain of A. oryzae. The preparation contains peptide hydrolases, such as alkaline proteinase (EC 3.4.21.14), aspartic proteinase (EC3.4.23.6), and neutral proteinase (EC 3.4.24.4), which catalyze the hydrolysis of proteins or polypeptides in food.
The source microorganism for each of the enzyme preparations described in GRN 000090 is A. oryzae. The general taxonomy and characteristics of A. oryzae are described in standard compendia (Ref. 1). In GRP 3G0016, ETA includes publications that describe generally accepted microbiological techniques that are used in the manufacture of the enzyme preparations from A. oryzae. All microbial strains used in enzyme manufacture are started from a pure laboratory culture of A. oryzae and grown in a sterile liquid nutrient medium or sterile moistened semisolid medium. Generally accepted microbiological techniques are used to exclude contaminating organisms and to avoid development of substrains from within the culture itself. Although specific conditions of fermentation vary from manufacturer to manufacturer, common fermentation procedures, which have been described in the literature, are: (1) the submerged culture method, and (2) the semisolid culture method. During fermentation by either method, the pH, temperature, disappearance of certain ingredients, purity of culture, and level of enzyme activity are carefully controlled. The fermentation is harvested at the point where laboratory tests indicate that maximum production of enzyme activity has been attained.
In GRP 3G0016, ETA includes publications that show that carbohydrase and protease from A. oryzae are excreted into the fermentation medium. In the submerged culture method, the extracellular location of the enzyme means that no extraction step is needed, and the microorganism and other insoluble matter are removed from the fermentation medium by filtering or centrifuging. In the semisolid culture method, the enzyme is extracted either directly from the moist material, or later after the culture mass has been dried, followed by further processing steps such as clarification, evaporation, precipitation, drying and grinding.
Each of the enzyme preparations described in GRN 000090 meets the general and additional requirements in the monograph on enzyme preparations in the Food Chemicals Codex, 4th ed. (1996), pp. 128-135.
The statutory basis for ETA’s determination that carbohydrase and protease enzyme preparations from A. oryzae are GRAS for their intended use is through experience based on common use in food before 1958. Under 21 CFR 170.30(c)(1), general recognition of safety through experience based on common use in food is based solely on food use of the substance prior to January 1, 1958, and ordinarily is based upon generally available data and information.
In GRP 3G0016, ETA includes an article, published in 1952 (Ref. 2), that states that fungal carbohdrase was used in brewing and baking and in the production of corn syrup. Although the article published in 1952 does not specify A. oryzae as the fungal source of carbohydrase, ETA also includes an article, published in 1957 (Ref. 3), that states that fungal carbohydrase was used in starch conversion, baking, brewing, syrup production and production of other food products and specifically identifies A. oryzae as the source fungus. ETA also includes another article, published in 1958 (Ref. 4), that states that fungal carbohydrase was used in starch conversion, baking, and processing cereal products, fruit juices and other food products and identifies the source fungus as A. oryzae.
In GRP 3G0016, ETA includes an article, published in 1952 (Ref. 2), that states that fungal protease was used in brewing and baking. ETA also includes an article, published in 1957 (Ref. 3), that states that fungal protease was used in baking and beer and ale production. Although these articles do not specify A. oryzae as the fungal source of protease, ETA also includes another article, published in 1957 (Ref. 5), that states that fungal protease was used in the chilling of beer, meat tenderizing, and baking and specifically identifies A. oryzae as the source fungus. ETA also includes an article, published in 1958 (Ref. 4), that states that fungal protease was used in baking, processing cereal products, manufacturing beer and ale, and meat tenderizing and identifies the source fungus for the protease enzyme preparation as A. oryzae.
Based on the information provided by ETA, as well as the information in GRP 3G0016 and other information available to FDA, the agency has no questions at this time regarding ETA’s conclusion that carbohydrase and protease enzyme preparations from A. oryzae are 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 these enzyme preparations. As always, it is the continuing responsibility of each manufacturer to ensure that food ingredients that the firm markets are safe, and are otherwise in compliance with all applicable legal and regulatory requirements.
Because the protease enzyme preparation from Aspergillus oryzae would be used to tenderize meat, FDA consulted with the Labeling and Consumer Protection Staff of the Food Safety and Inspection Service of the United States Department of Agriculture (FSIS) during its evaluation of GRN 000090. FSIS has determined that ETA has not provided any data to support the suitability of protease enzyme preparation from A. oryzae for use in meat and poultry products. Suitability relates to the effectiveness of an ingredient in performing the intended purpose of use and the assurance that the conditions of use will not result in an adulterated product or one that misleads consumers. FSIS concludes that ETA needs to provide data that establish that the protease enzyme preparation is being used at the lowest level necessary to achieve the intended technical effect in the specific meat and poultry products to which application is desired. FSIS requests that ETA be advised to seek regulatory guidance from FSIS about the use of protease enzyme preparation from A. oryzae in meat and poultry products. ETA should direct this inquiry to Dr. Robert Post, Director, Labeling and Consumer Protection Staff, 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 of his office is (202) 205-0279 and the telefax number is (202)205-3625(1).
In accordance with the interim policy discussed in the GRAS proposal (62 FR 18938 at 18954), FDA has not committed any resources to review of GRP 3G0016 since November 16, 2001, the date that we received your conversion request.
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 ETA’s notice that conforms to the information in 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, /s/ Alan M. Rulis, Ph.D. Director Office of Food Additive Safety Center for Food Safety and Applied Nutrition |
| cc: | Dr. Robert Post, Director Labeling and Consumer Protection Staff Office of Policy, Program Development and Evaluation Food Safety and Inspection Service 300 12th Street, SW, Room 602 Washington, DC 20250-3700 |
1. Monographs on "Aspergillus niger Group" and "Aspergillus flavus Group", in Raper, K. B. and Fennel, D. I., “The genus Aspergillus,” Williams and Wilkins Company, Baltimore, Maryland, pp. 293-334 and 357-404 (1965).
2. Reed, G., “Industrial enzymes - Now speed natural processes,” Food Engineering, 24: pp. 105-109 (1952).
3. Underkofler, L.A. and W. J. Ferracone, “Commercial enzymes - Potent catalyzers that promote quality,” Food Engineering, 29: pp. 123-133 (1957).
4. Underkofler, L.A., R.R. Barton, and S.S. Rennet, “Microbiological process report - Production of microbial enzymes and their applications,” Applied Microbiology, 6: pp. 212-221 (1958).
5. Kirk, R.E. and Othmer, D.F. (eds.), "Enzymes, Industrial" in Encyclopedia of Chemical Technology, First Supplement Volume, Interstate Cyclopedia, Inc., New York, NY (1957).
(1)FSIS also informed FDA that ETA has not provided any data to support the suitability of carbohydrase enzyme preparation from A. oryzae for use in meat and poultry products. In its notice, ETA does not describe any uses for this enzyme preparation in meat and poultry products.
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