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  1. GRAS Notice Inventory

Agency Response Letter GRAS Notice No. GRN 000597

Recently Published GRAS Notices and FDA Letters

See also Generally Recognized as Safe (GRAS).

CFSAN/Office of Food Additive Safety

February 29, 2016

Madhu Soni, Ph.D.
Soni & Associates, Inc.
749 46th Square
Vero Beach, FL 32968

Re: GRAS Notice No. GRN 000597

Dear Dr. Soni:

The Food and Drug Administration (FDA) is responding to the notice, dated August 24, 2015, that you submitted on behalf of Sanzyme Limited (Sanzyme) in accordance with the agency’s proposed regulation, proposed 21 Code of Federal Regulations (CFR) 170.36 (62 FR 18938; April 17, 1997; Substances Generally Recognized as Safe (GRAS); the GRAS proposal). FDA received the notice on August 26, 2015, filed it on September 10, 2015, and designated it as GRAS Notice No. GRN 000597.

The subject of the notice is a preparation of Bacillus coagulans SNZ1969 spores (B. coagulans spore preparation). The notice informs FDA of Sanzyme’s view that B. coagulans spore preparation is GRAS, through scientific procedures, for use as an ingredient in baked goods and baking mixes; beverages and beverage bases; breakfast cereals; chewing gum; coffee and tea; condiments and relishes; confections and frostings; dairy product analogs; fruit juices; frozen dairy desserts and mixes; fruit and water ices; gelatins, puddings, and fillings; grain products and pastas; hard candy; herbs, seeds, spices, seasonings, blends, extracts, and flavorings; jams and jellies; milk; milk products; nuts and nut products; plant protein products; processed fruits; processed vegetables and vegetable juices; snack foods; soft candy; soups and soup mixes; sugar; and sweet sauces, toppings, and syrups at a level not to exceed 2 x 109 colony forming units (cfu)/serving[1]. Sanzyme states that B. coagulans spore preparation is not intended for use in meat and poultry products under USDA jurisdiction or for uses in foods intended for infants and toddlers.

As part of its notice, Sanzyme includes the statement of a panel of individuals (Sanzyme’s GRAS panel) that evaluated the data and information that are the basis for Sanzyme’s GRAS determination. Sanzyme considers the members of its GRAS panel to be qualified by scientific training and experience to evaluate the safety of substances added to food. Sanzyme’s GRAS panel evaluated the identity, method of production, product specifications, and dietary exposure, as well as published and unpublished studies supporting the safety of B. coagulans spore preparation. Based on this review, Sanzyme’s GRAS panel concluded that B. coagulans spore preparation produced in accordance with current good manufacturing practices (cGMP) that meets its established food grade specifications is GRAS under the conditions of its intended use.

Sanzyme provides information on the identity of B. coagulans spore preparation. B. coagulans spore preparation is a dark grayish white powder. The B. coagulans SNZ1969[2] strain was isolated from green malt in 1949. B. coagulans SNZ1969 is a rod-shaped, gram-positive, slightly acidophilic, aerobic bacterium. The 16S rRNA sequence of the strain is >99% similar to that of B. coagulans ATCC 7050.

Sanzyme describes the manufacture of B. coagulans spore preparation. All processing aids, fermentation media, and diluents are either approved food additives or are GRAS for their intended uses. The batch fermentation is started from a seed culture of B. coagulans SNZ1969 and is fermented under pH- (by adding hydrochloric acid or sodium hydroxide) and temperature-controlled, aseptic conditions. After fermentation and sporulation, the biomass undergoes centrifugation. The biomass is then spray-dried under standardized conditions before packaging. The final powder is standardized with food grade maltodextrin or lactose. Sanzyme states that there are no allergens in the final spore preparation, which is produced in accordance with cGMP for food ingredients.

Sanzyme provides specifications for B. coagulans spore preparation. Sanzyme also provides limits for heavy metal and microbial contaminants. Sanzyme states that analysis of five non-consecutive lots of B. coagulans spore preparation demonstrates compliance with these specifications.

Sanzyme estimates the dietary exposure to B. coagulans spore preparation. Sanzyme intends to use B. coagulans spore preparation in the same food categories and at the same use level (2 x 109 cfu/serving) described in GRN 000399.[3] Sanzyme expects the use of its B. coagulans spore preparation to be substitutional for that described in GRN 000399. Therefore, the estimated dietary exposure of 3.6 x 1010 cfu/day discussed in GRN 000399 also applies to Sanzyme’s intended use of its product.

Sanzyme discusses published and unpublished information supporting the safety of B. coagulans spore preparation. In 21 CFR 184.1372, B. coagulans is described as a nonpathogenic, nontoxigenic production microorganism for glucose isomerase enzyme preparation. ATCC classifies B. coagulans as a biosafety level 1 organism not known to cause disease in healthy adult humans. Sanzyme cites published summaries of acute and short term animal studies. In the acute study, male rats were administered up to 5 grams/kilogram (g/kg) containing at least 5 x 109 spores/g without mortality. Dogs, rabbits, and guinea pigs received up to 50 g/kg body weight (bw) of the organism as a powdered preparation for seven days followed by a 10 day recovery period without adverse effects. Sanzyme cites a published study in which 29 volunteers (11 male and 18 female) consumed 4 x 108 cfu of B. coagulans SANK 702581 in food for eight weeks. Sanzyme reports that the volunteers underwent a physical examination, in addition to hematological and blood chemistry analyses. No adverse effects were observed. Sanzyme also discusses unpublished data reported from an independent laboratory showing that B. coagulans SNZ1969 is sensitive to several commonly prescribed antibiotics.

Based on the totality of the available data and information, Sanzyme concludes that B. coagulans spore preparation is GRAS under the conditions of its intended use.

Standards of Identity

In the notice, Sanzyme states its intention to use B. coagulans spore preparation in several food categories, including foods for which standards of identity exist, located in Title 21 of the CFR. We note that an ingredient that is lawfully added to food products may be used in a standardized food only if it is permitted by the applicable standard of identity.

Potential Labeling Issues

In describing the intended use of B. coagulans spore preparation and in describing the information that Sanzyme relies on to conclude that B. coagulans spore preparation is GRAS under the conditions of its intended use, Sanzyme raises a potential issue under the labeling provisions of the Federal Food, Drug, and Cosmetic Act (FD&C Act). This issue consists of the potential beneficial health effects of B. coagulans bacteria, particularly with regards to gastrointestinal health, as discussed by Sanzyme in its notice. 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 B. coagulans spore preparation 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 B. coagulans spore preparation 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 Sanzyme’s notice that B. coagulans spore preparation is GRAS for the intended uses, FDA did not consider whether section 301(ll) or any of its exemptions apply to foods containing B. coagulans spore preparation. Accordingly, this response should not be construed to be a statement that foods that contain B. coagulans spore preparation, if introduced or delivered for introduction into interstate commerce, would not violate section 301(ll).


Based on the information provided by Sanzyme, as well as other information available to FDA, the agency has no questions at this time regarding Sanzyme’s conclusion that B. coagulans spore preparation 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 B. coagulans spore preparation. As always, it is the continuing responsibility of Sanzyme 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 000597, 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.


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

[1] Reference amounts customarily consumed per eating occasion, 21 CFR 101.12.

[2] B. coagulans SNZ1969 was originally designated B. coagulans SANK 70258.

[3] GRN 000399 describes the intended use of a preparation of B. coagulans strain GBI-30, 6086 spores and was submitted by Ganeden Biotech, Inc. In a letter dated July 31, 2012, FDA stated that the agency had no questions at that time in response to GRN 000399.

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