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Agency Response Letter GRAS Notice No. GRN 000604

Agency Response Letter GRAS Notice No. GRN 000604

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See also Generally Recognized as Safe (GRAS).


CFSAN/Office of Food Additive Safety

April 27, 2016

Matthew Dahabieh, Ph.D.
Renaissance BioScience Corporation
Suite 410 - 2389 Health Sciences Mall
Vancouver, British Columbia, CANADA
V6T1Z3

Re: GRAS Notice No. GRN 000604

Dear Dr. Dahabieh:

The Food and Drug Administration (FDA) is responding to the notice, dated October 14, 2015, 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 October 19, 2015, filed it on November 2, 2015, and designated it as GRAS Notice No. GRN 000604. Renaissance BioScience Corporation (RBSC) provided FDA with additional information in amendments on December 23, 2015 and March 15, 2016.

The subject of the notice is a strain of baker's yeast (Saccharomyces cerevisiae) that degrades asparagine under nutrient rich conditions where asparagine degradation is ordinarily repressed (referred to as asparagine-degrading yeast for the purpose of this letter). The notice informs FDA of the view of RBSC that asparagine-degrading yeast is GRAS, through scientific procedures, for use in a variety of grain-based foods, potato-based foods, and coffee and coffee substitutes at a level of 0.5 to 5 percent yeast on a yeast dry weight basis.[1]

RBSC discusses the identity and development of asparagine-degrading yeast. RBSC states that asparagine-degrading yeast was developed from an industrial bread yeast strain of S. cerevisiae obtained from a yeast manufacturer. Conventional bread yeast can degrade asparagine; however, asparagine degradation in conventional yeasts is ordinarily repressed under nitrogen rich conditions. To develop asparagine-degrading yeast, RBSC explains that it used classical mutagenesis and adaptive evolution techniques along with two different selective pressures. The first selective pressure was growth in media containing D-asparagine as the sole nitrogen source. The second selective pressure was growth in media containing D-asparagine as the sole nitrogen source as well as methylamine (a non-metabolizable ammonia analog) to simulate repressive conditions. The asparagine-degrading yeast strain was selected based on its ability to grow on D-asparagine in the presence of methylamine. RBSC characterized the ability of the selected strain to degrade asparagine under repressive conditions by growing it in nitrogen-rich, yeast extract media supplemented with asparagine. RBSC concludes that asparagine-degrading yeast degrades asparagine under nitrogen-rich growth conditions.

RBSC discusses the method of manufacture of asparagine-degrading yeast. The process begins with an asparagine-degrading yeast inoculum. The manufacturer uses a fermentation process to scale up the inoculum from laboratory cultures to fed-batch cultures under aerobic conditions. The manufacturer feeds the cultures with sterilized molasses and other nutrients to obtain a yeast harvest. After the fermentation process, the manufacturer then processes the yeast harvest into a fresh cream yeast product or active dry yeast form. To produce the fresh yeast cream form, the manufacturer uses centrifugation to concentrate the yeast solids. To produce the active dry yeast form, the manufacturer extrudes compressed yeast cream and dries it. RBSC explains that its GRAS determination for the asparagine-degrading yeast is based on common, industrially accepted, food manufacturing standards for baker’s yeast. In addition, asparagine-degrading yeast is manufactured according to good manufacturing practice from appropriate food grade starting materials.

RBSC considers dietary exposure to asparagine-degrading yeast from the intended uses. In foods where baker’s yeast is typically used as an ingredient, RBSC considers asparagine-degrading yeast to be substitutional for commercially available baker’s yeast. In foods where baker’s yeast is used as a processing aid, and not as an ingredient, RBSC considers the amount of asparagine-degrading yeast present in the final product to be minimal relative to the amount present when used as an ingredient. Therefore, the dietary exposure to asparagine-degrading yeast would be equivalent to that of typical baker’s yeast currently in use.

RBSC discusses the safety of asparagine-degrading yeast. RBSC describes S. cerevisiae as a commensal organism that is normally found on the human body, in the air, and in many foods consumed by humans. S. cerevisiae strains have been used in the production of baked goods, wine, and beer for more than five thousand years. RBSC describes the parent strain used to develop asparagine-degrading yeast as a strain of S. cerevisiae with a history of safe use in the baking industry. RBSC provides data from test reports confirming that asparagine-degrading yeast is genetically and phenotypically comparable with the commercial strain of S. cerevisiae from which it was derived, except for asparagine-degradation under nitrogen-rich conditions. RBSC cites the use of yeast in winemaking (GRNs 000120, 00175, 000350) and in fermented foods (GRNs 000353 and 000422) to support the safety of S. cerevisiae for use in food production.

RBSC also explains that the process of mutagenesis is not expected to alter the nonpathogenic and nontoxigenic nature of asparagine-degrading yeast. In support of its conclusion, RBSC cites published references as well as examples of microorganisms developed using classical mutagenesis techniques that have been the subjects of GRAS notices previously evaluated by FDA.

Potential Labeling Issues

In describing the intended use of asparagine-degrading yeast, RBSC raises a potential issue under the labeling provisions of the Federal Food, Drug, and Cosmetic Act (FD&C Act). This issue consists of RSBC’s discussion in the GRAS notice about the carcinogenic potential of acrylamide. Under section 403(a) of the FD&C Act, a food is misbranded if its labeling is false or misleading in any particular. Section 403(r) of the FD&C Act lays out the statutory framework for the use of labeling claims that characterize the level of a nutrient in a food or that characterize the relationship of a nutrient to a disease or health-related condition. If products that contain asparagine-degrading yeast bear any claims on the label or in labeling, such claims are the purview of the Office of Nutrition and Food Labeling (ONFL) in the Center for Food Safety and Applied Nutrition. The Office of Food Additive Safety neither consulted with ONFL on this labeling issue nor evaluated the information in your notice to determine whether it would support any claims made about asparagine-degrading yeast on the label or in labeling. 

Section 301(ll) of the FD&C Act

Section 301(ll) of the FD&C Act prohibits the introduction or delivery for introduction into interstate commerce of any food that contains a drug approved under section 505 of the FD&C Act, a biological product licensed under section 351 of the Public Health Service Act, or a drug or a biological product for which substantial clinical investigations have been instituted and their existence made public, unless one of the exemptions in section 301(ll)(1)-(4) applies. In its review of RBSC’s notice that asparagine-degrading yeast is GRAS for the intended uses, FDA did not consider whether section 301(ll) or any of its exemptions apply to foods containing asparagine-degrading yeast. Accordingly, this response should not be construed to be a statement that foods that contain asparagine-degrading yeast, if introduced or delivered for introduction into interstate commerce, would not violate section 301(ll).

Conclusions

Based on the information provided by RBSC, as well as other information available to FDA, the agency has no questions at this time regarding RBSC’s conclusion that asparagine-degrading yeast 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 asparagine-degrading yeast. As always, it is the continuing responsibility of RBSC 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 000604, as well as a copy of the information in this notice that conforms to the information in the GRAS exemption claim (proposed 21 CFR 170.36(c)(1)), is available for public review and copying at www.fda.gov/grasnoticeinventory.

Sincerely,

Dennis M. Keefe, Ph.D.
Director
Office of Food Additive Safety
Center for Food Safety and Applied Nutrition


[1] RBSC discusses the role of asparagine in the formation of acrylamide in food. Acrylamide is produced when the amino acid asparagine reacts with reducing sugars in food during cooking. Increasing asparagine degradation and reducing the levels of asparagine in the food prior to its exposure to heat has the potential to reduce acrylamide formation.