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See also Generally Recognized as Safe (GRAS).
CFSAN/Office of Food Additive Safety
April 28, 2016
Madhu Soni, Ph.D., FACN, FATS
Soni & Associates, Inc.
749 46th Square
Vero Beach, FL 32968
Re: GRAS Notice No. GRN 000601
Dear Dr. Soni:
The Food and Drug Administration (FDA) is responding to the notice, dated September 15, 2015, that you submitted on behalf of Sabinsa Corporation (Sabinsa) 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 September 21, 2015, filed it on October 5, 2015, and designated it as GRAS Notice No. GRN 000601.
The subject of the notice is a preparation of Bacillus coagulans strain MTCC 5856 spores (B. coagulans spore preparation). The notice informs FDA of the view of Sabinsa 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 maximum level of approximately 2x109 colony forming units per serving (cfu/serv).
As part of its notice, Sabinsa includes the report of a panel of individuals (Sabinsa’s GRAS panel) that evaluated the data and information that are the basis for Sabinsa’s GRAS determination. Sabinsa considers the members of its GRAS panel to be qualified by scientific training and experience to evaluate the safety of substances added to food. Sabinsa’s GRAS panel evaluated: 1) the identity of B. coagulans strain MTCC 5856; 2) the method of manufacture and specifications for B. coagulans spore preparation; 3) the intended use of and estimated dietary exposure to B. coagulans spore preparation, and 4) data and information supporting the safety of the intended uses of B. coagulans spore preparation. Based on this review, Sabinsa’s GRAS panel concluded that B. coagulans spore preparation that meets its established food grade specifications is GRAS under the conditions of its intended use.
Sabinsa discusses the identity of B. coagulans strain MTCC 5856. B. coagulans is a gram-positive, catalase positive, spore-forming, rod-shaped, lactic acid producing bacterium, commonly found in soil, air, and dust. B. coagulans strain MTCC 5856 was isolated from green malt in 1949. B. coagulans strain MTCC 5856 was identified genetically, morphologically, and biochemically. The strain has been deposited in the Microbial Type Culture Collection and in Gene Bank under the accession number B. coagulans MTCC 5856.
Sabinsa describes the manufacture of B. coagulans spore preparation. A pure culture of B. coagulans strain MTCC 5856 is inoculated into a sterile fermentation medium. Following fermentation, the culture is centrifuged to separate the bacterial biomass from the medium. The biomass is then mixed with demineralized water and is filtered. The filtrate is spray-dried, concentrated, and mixed with maltodextrin to achieve the desired spore concentration. Sabinsa states that the final product does not contain any major food allergens from the fermentation medium. Sabinsa states that B. coagulans spore preparation is manufactured according to current good manufacturing practices, and that the materials used during the manufacturing process have either been approved as food additives or have been determined to be GRAS.
Sabinsa provides specifications for B. coagulans spore preparation. Sabinsa states that B. coagulans spore preparation is a pale brown to brown powder or a white to off white powder. Sabinsa also provides limits for heavy metals and microbial contaminants. Sabinsa provides analytical data from five non-consecutive lots of B. coagulans spore preparation to demonstrate compliance with set specifications.
Sabinsa estimates the dietary exposure to B. coagulans spore preparation. Sabinsa intends to use B. coagulans spore preparation in the same food categories and at the same use levels (2x109 cfu/serv) as described in GRN 000399. Sabinsa expects that the use of B. coagulans spore preparation would be substitutional with the subject of GRN 000399. Therefore, based on the assumption that males aged 51 years and older consume the largest number of servings of food per day (18.2 servings per day), the estimated dietary exposure of 3.64x1010 cfu per person day (cfu/p/d) provided in GRN 000399 would also be applicable to Sabinsa’s intended use of the ingredient described in GRN 000601.
Sabinsa discusses published and unpublished data and information supporting the safety of consumption of B. coagulans spore preparation. Sabinsa incorporates by reference the safety information provided in previous GRAS notices describing the intended uses of other B. coagulans spore preparations (GRNs 000399 and 000526), noting that FDA had no questions in response to these GRAS notices. Sabinsa also discusses several published human studies using other strains of B. coagulans, including studies up to one year in duration and also in infants and children and notes that no adverse effects were observed. Sabinsa summarizes an unpublished human study designed to investigate the safety and tolerability of its B. coagulans spore preparation. Healthy adult volunteers received either a placebo or a tablet containing 2 x 109 cfu B. coagulans spore preparation daily for 30 days. No treatment-related differences in hematology, clinical chemistry parameters, or bowel habits were observed between the control and treatment groups. These results were further corroborated by other unpublished human studies in which volunteers received Sabinsa’s B. coagulans spore preparation and no adverse events were observed.
Sabinsa also discusses unpublished in vitro tests showing that B. coagulans strain MTCC 5856 is sensitive to clinically-used antibiotics. Sabinsa describes that the genetic sequencing and bioinformatic analyses show that B. coagulans strain MTCC 5856 neither contains genes encoding antibiotic resistance, nor does it contain genes homologous to those encoding toxins produced by pathogenic Bacillus spp. The results of unpublished in vitro assays further confirmed the absence of cytotoxicity.
Based on the totality of the available data and information, Sabinsa concludes that B. coagulans spore preparation is GRAS under the intended conditions of use.
Standards of Identity
In the notice, Sabinsa 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 Code of Federal Regulations. 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 Sabinsa relies on to conclude that B. coagulans spore preparation is GRAS under the conditions of its intended use, Sabinsa 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 the intended uses of B. coagulans spore preparation, particularly with regards to gastrointestinal health, as discussed by Sabinsa 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 Sabinsa’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 Sabinsa as well as other information available to FDA, the agency has no questions at this time regarding Sabinsa Corporation’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 Sabinsa 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 000601, 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
 Uses in meat and poultry products under U.S. Department of Agriculture jurisdiction were specifically excluded from the intended uses described in the notice.
 Reference amounts customarily consumed per eating occasion, 21 CFR 101.12.
 Sabinsa reports 99.5% homology between B. coagulans MTCC 5856 and the B. coagulans reference strain ATCC 7050, as determined by 16S rDNA analysis.
 In a letter dated July 31, 2012, FDA noted that it had no questions at this time regarding Ganeden’s conclusion that B. coagulans spore preparation is GRAS under the intended conditions of use.