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U.S. Department of Health and Human Services

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'Agency Response Letter GRAS Notice No. GRN 000132

CFSAN/Office of Food Additive Safety
December 12, 2003

Alice Caddow
c/o Gary Yingling
Enzyme Technical Association
1800 Massachusetrs Ave., N.W., Second Floor
Washington, D.C. 20036-1800

Re: GRAS Notice No. GRN 000132

Dear Ms. Caddow:

The Food and Drug Administration (FDA) is responding to the notice, dated June 10, 2003, 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 June 18, 2003, filed it on June 20, 2003, and designated it as GRAS Notice No. GRN 000132.

The subject of the notice is lactase enzyme preparation from A. niger. The notice informs FDA of the view of The Enzyme Technical Association (ETA) that lactase enzyme preparation is GRAS, through scientific procedures, for use as an enzyme to hydrolyze lactose in dairy products. This enzyme preparation is also a subject of the GRAS affirmation petition (GRP 3G0016) submitted by the Ad Hoc Enzyme Technical Committee (now known as ETA). In its notice, ETA requested that FDA convert the filed GRAS affirmation petition (GRP 3G0016) for this enzyme preparation 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).

Commercial enzyme preparations that are used in food processing typically contain an enzyme component, which catalyzes the chemical reaction that is responsible for its 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. ETA's notice provides information about each of these components of the lactase enzyme preparation from A. niger.

In assessing the safety of the enzyme, ETA states that several lactase preparations are considered to be GRAS and have been used in food for at least 20 years and therefore have been ingested by man for many years. ETA cites published articles stating that enzyme proteins do not generally raise safety concerns. ETA describes specific lactase enzyme preparations that have been used in food, including the following:

  • Lactase enzyme preparation from Candida pseudotropicalis, which FDA affirmed as GRAS (21 CFR 184.1387)
  • Lactase enzyme preparation from Kluyveromyces lactis, which FDA affirmed as GRAS (21 CFR 184.1388)
  • Lactase enzyme preparation from Kluyveromyces marxianus, which ETA determined to be GRAS for use in foods in general as an enzyme in accordance with current good manufacturing practice (GRAS Notice No. GRN 000088)

ETA describes the catalytic activity of the lactase as hydrolyzing the terminal, non-reducing beta-D-galactose residues in beta-D-galactosides. Lactase is the common name for beta-D-galactoside galactohydrolase and is identified by the following classification numbers: Chemical Abstracts Service Registry No. 9031-11-2 and EC number 3.2.1.23.

In assessing the safety of the production organism, A. niger, ETA cites scientific review articles in support of its view that the safety of the production organism is the prime consideration in assessing the safety of an enzyme preparation intended for use in food. ETA also cites a publication of the International Food Biotechnology Council which concludes that if the production microorganism is nontoxigenic and nonpathogenic and the manufacturing process is conducted using current good manufacturing practices, the food or food ingredient produced from that microorganism is safe to consume. ETA considers A. niger to be nontoxigenic and nonpathogenic based on published criteria for safety assessment and a long history of safe use documented in numerous scientific publications.

ETA describes the manufacturing process for the lactase enzyme preparation, which is produced from a nontoxigenic and nonpathogenic strain of A. niger by pure culture fermentation . The fermentation procedure is carried out by submerged culture fermentation of A. niger, or the microorganism may be grown on a solid or semi-solid medium held in large trays or drums. The fermentation conditions are monitored, and the culture is periodically tested for microbiological contamination. Any contaminated fermentation is rejected. Following fermentation, a multi-step recovery process includes purification and concentration of the product. The enzyme preparation can be formulated as a liquid or a dry product, and it is standardized according to the product specifications. ETA states that the raw materials used in the fermentation and stabilizers, diluents, and/or preservatives used in the formulation of the enzyme are all suitable for general use in food. The enzyme preparation complies with the general and additional requirements for enzyme preparations set forth in the Food Chemicals Codex, 4th edition (1996).

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 the lactase enzyme preparation from A. niger 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 lactase enzyme preparation. 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.

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 the date that we received ETA's 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 your 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,
Laura M. Tarantino, Ph.D.
Acting Director
Office of Food Additive Safety
Center for Food Safety
     and Applied Nutrition