Food

Agency Response Letter GRAS Notice No. GRN 000254

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CFSAN/Office of Food Additive Safety

November 18, 2008

James T. Heimbach, Ph.D.
JHeimbach LLC
923 Water Street
P.O. Box 66
Port Royal, VA 22535

Re: GRAS Notice No. GRN 000254

Dear Dr. Heimbach:

The Food and Drug Administration (FDA) is responding to the notice, dated May 9, 2008, that you submitted on behalf of BioGaia AB (BioGaia) 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 May 9, 2008, filed it on May 29, 2008, and designated it as GRAS Notice No. GRN 000254.

The subject of the notice is Lactobacillus reuteri strain DSM 17938. The notice informs FDA of the view of BioGaia that L. reuteri strain DSM 17938 is GRAS, through scientific procedures, for use as an ingredient in processed cheeses, yogurt, ice cream, fruit juices, fruit drinks, processed vegetables, processed vegetable drinks, beverage bases, energy bars, energy drinks, and chewing gum at a level up to 109 colony forming units (cfu) per serving, and in a drinking straw at a level of 109 cfu per straw.1

As part of its notice, BioGaia includes the report of a panel of individuals (BioGaia's GRAS panel) who evaluated the data and information that are the basis for BioGaia's GRAS determination. BioGaia considers the members of its GRAS panel to be qualified by scientific training and experience to evaluate the safety of substances added to food. BioGaia's GRAS panel evaluated the identity and characteristic properties of L. reuteri, including L. reuteri strain DSM 17938, the potential exposure resulting from the intended uses of L. reuteri strain DSM 17938, as well as published studies. Based on this review, BioGaia's GRAS panel concluded that the intended use of L. reuteri strain DSM 17938 as an ingredient in the categories of foods listed above is GRAS based on scientific procedures.

BioGaia discusses the identity and characteristic properties of L. reuteri strain DSM 17938. L. reuteri strain DSM 17938 is a Gram-positive and non-spore-forming heterofermentative lactic acid bacterium. This strain of L. reuteri is derived by deletion of two antibiotic resistance plasmids (pLR581 and pLR585) from an original strain deposited in the American Type Culture Collection (ATCC) that is referenced as strain ATCC 55730. Deletion of the two plasmids was achieved by use of a protoplast-formation technique, following published microbiological procedures. Based on analysis of an unpublished genome sequence of L. reuteri strain DSM 17938, BioGaia concludes that there is no presence of any gene or gene cluster known to be involved in virulence or antibiotic resistance. BioGaia also concludes that L. reuteri strain DSM 17938, except for the deletion of plasmids pLR581 and pLR585, is substantially equivalent to its parent strain L. reuteri ATCC 55730. Additionally, BioGaia concludes that the evidence demonstrating the safety of strain ATCC 55730 is equally applicable to strain DSM 17938. BioGaia reports that the parent organism, L. reuteri strain ATCC 55730, has been sold in the United States and internationally as an ingredient in a variety of dairy products including yogurts, and as a dietary supplement.

BioGaia states that the production of the L. reuteri strain DSM 17938 ingredient is based on standard fermentation techniques. BioGaia states that all of the fermentation medium components are food-grade materials. BioGaia provides food grade specifications for the L. reuteri strain DSM 17938 ingredient.

BioGaia estimates the daily intake for the L. reuteri strain DSM 17938 ingredient. Based on the intended use level of 109 cfu per serving or per straw and the sum of the 90th percentile intakes for the foods where L. reuteri strain DSM 17938 is intended for use, BioGaia estimates the maximum consumer intake of L. reuteri strain DSM 17938 would be 109 to 1010 cfu per day.

BioGaia discusses the safety of the L. reuteri strain DSM 17938 ingredient. BioGaia notes that L. reuteri is part of the indigenous human microflora and has been isolated from the oral cavity, breast milk, and gastrointestinal tract of humans. In its safety evaluation, BioGaia discusses data from published studies in which rats, mice, pigs, and monkeys were fed various strains of L. reuteri. The notice summarizes published studies in which human adults, children or infants consumed L. reuteri strain ATCC 55730 or other strains of L. reuteri. BioGaia also discusses data from an unpublished study in human adults who consumed L. reuteri strain DSM 17938. BioGaia concludes that there is no evidence of a safety hazard based on these studies. BioGaia considers that the safety of L. reuteri strain DSM 17938 is shown by establishing its identity and characteristic properties, and demonstrating its lack of pathogenic or other risk factors. Based on the data and information it discusses, BioGaia concludes that the intended use of L. reuteri strain DSM 17938 resulting in a maximum anticipated exposure of less than 1010 cfu per day is GRAS.

Standards of Identity

In the notice, BioGaia states its intention to use L. reuteri strain DSM 17938 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

Under section 403(a) of the Federal Food, Drug, and Cosmetic Act (FFDCA), a food is misbranded if its labeling is false or misleading in any particular. In describing the intended use of L. reuteri strain DSM 17938 and in describing the information that BioGaia relies on to conclude that L. reuteri strain DSM 17938 is GRAS under the conditions of its intended use, BioGaia raises a number of potential issues under the labeling provisions of the FFDCA. These issues are the purview of the Office of Nutrition, Labeling and Dietary Supplements (ONLDS) in the Center for Food Safety and Applied Nutrition. The Office of Food Additive Safety neither consulted with ONLDS on these labeling issues nor evaluated the information in your notice to determine whether it would support any claims made about L. reuteri DSM 17938 on the label or in labeling.

Section 301 (ll) of the FFDCA

The Food and Drug Administration Amendments Act of 2007 that was signed into law on September 27, 2007, amends the FFDCA to, among other things, add section 301(ll). Section 301(ll) of the FFDCA prohibits the introduction or delivery for introduction into interstate commerce of any food that contains a drug approved under section 505 of the FFDCA, 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 BioGaia's notice that L. reuteri strain DSM 17938 is GRAS for use in processed cheeses, yogurt, ice cream, fruit juices and drinks, processed vegetables and drinks, beverage bases, energy bars and drinks, and chewing gum, and for incorporation in drinking straw, FDA did not consider whether section 301(ll) or any of its exemptions apply to foods containing L. reuteri strain DSM 17938. Accordingly, this response should not be construed to be a statement that foods that contain L. reuteri strain DSM 17938, if introduced or delivered for introduction into interstate commerce, would not violate section 301(ll).

Conclusions

Based on the information provided by BioGaia, as well as other information available to FDA, the agency has no questions at this time regarding BioGaia's conclusion that L. reuteri strain DSM 17938 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 L. reuteri strain DSM 17938. As always, it is the continuing responsibility of BioGaia 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 000254, 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 via the FDA home page at http://www.fda.gov. To view or obtain an electronic copy of the text of the letter, follow the hyperlinks from the "Food" topic to the "Food Ingredients and Packaging" section to the "Generally Recognized as Safe (GRAS)" page where the GRAS inventory is listed.

Sincerely,

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


1The drinking straw consists of a polypropene straw containing freeze-dried L. reuteri strain DSM 17938 suspended in a droplet of food-grade canola oil.

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