Agency Response Letter GRAS Notice No. GRN 000457
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CFSAN/Office of Food Additive Safety
December 16, 2013
Hyman, Phelps and McNamara, P.C.
700 Thirteenth Street N.W., Suite 1200
Washington, DC 20005
Re: GRAS Notice No. GRN 000457
Dear Ms. McColl:
The Food and Drug Administration (FDA) is responding to the notice, dated February 6, 2013, that you submitted on behalf of Avitop GmbH (Avitop) 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 February 7, 2013, filed it on February 8, 2013, and designated it as GRAS Notice No. GRN 000457.
The subjects of the notice are Bacteroides xylanisolvens DSM 23964 and pasteurized fermented milk (PFM) produced with B. xylanisolvens DSM 23964. The notice informs FDA of the view of Avitop that B. xylanisolvens DSM 23964 is GRAS, through scientific procedures, for use in the production of PFM. The notice also informs FDA of the view of Avitop that PFM is GRAS, through scientific procedures, for use as an ingredient in food and for direct consumption.
As part of its notice, Avitop includes a report from a panel of individuals (Avitop’s GRAS panel) that evaluated the data and information that are the basis for Avitop’s GRAS determinations. Avitop considers the members of its GRAS panel to be qualified by scientific training and experience to evaluate the safety of substances added to food. Avitop’s GRAS panel evaluated the identity and characteristic properties of PFM and B. xylanisolvens DSM 23964, as well as the method of manufacture, composition and specifications, estimates of dietary exposure, and published and unpublished data and information supporting the safety of PFM and B. xylanisolvens DSM 23964. Based on this review, Avitop’s GRAS panel concluded that both PFM and B. xylanisolvens DSM 23964 produced in accordance with current good manufacturing practices (cGMP) and meeting established specifications are GRAS under the conditions of the intended use.
Avitop describes the identity of B. xylanisolvens DSM 23964. B. xylanisolvens is a non-motile, rod-shaped, anaerobic Gram-negative bacterium known to be a normal component of human fecal microflora.
Avitop discusses the manufacture of B. xylanisolvens DSM 23964, stating that it is manufactured from single-strain starter cultures derived from a well-characterized cryopreserved mother culture, through three propagation steps using sterile, defined culture media. Each propagation step is checked to ensure purity prior to final recovery, washed, and concentrated as a frozen or lyophilized product. Avitop confirms that its B. xylanisolvens DSM 23964 starter culture is produced in accordance with cGMP for foods. The final product is tested for purity and viability of B. xylanisolvens DSM 23964. Avitop demonstrates the reproducibility of the manufacturing process, and compliance with specifications, with data from three nonconsecutive batches.
Avitop describes the identity of PFM, noting that PFM is a pasteurized low-fat or skim milk product produced through fermentation by B. xylanisolvens DSM 23964. It may be in liquid, semi-liquid, or spray-dried forms.
Avitop discusses the manufacture of PFM. Pasteurized low-fat or skim milk is fermented by a B. xylanisolvens DSM 23964 culture under anaerobic conditions, using food-grade materials under cGMP. The fermented product is pasteurized and either processed and packed for direct consumption or spray-dried for use as a fermented milk powder. Avitop provides specifications for the fermented milk products produced with B. xylanisolvens DSM 23964 that include microbiological limits and include tests for viable B. xylanisolvens DSM 23964.
Avitop intends to use B. xylanisolvens DSM 23964 to ferment low-fat and skim milk in the production of PFM. Avitop intends to use PFM as an ingredient in food as well as for direct consumption. Avitop notes that spray dried PFM powder will be used by food processors, in a manner similar to yogurt powder currently on the market, in fillings and coatings for foods such as cereals, granola bars, fruits and nuts. Avitop calculates a mean and 90th percentile daily intake for B. xylanisolvens DSM 23964 from the intended uses to be 4.06 x 1011 cells per day (cells/d) and 8.03 x 1011 cells/d respectively, based on estimates of potential daily intake of milk nonfat solids present in yogurt. This corresponds to a mean and 90th percentile intake of B. xylanisolvens DSM 23964, at 0.244 grams per day (g/d) and 0.482 g/d respectively. Avitop also calculates the mean and 90th percentile daily intake of fermented milk products produced with B. xylanisolvens DSM 23964 to be 11.4 g/d and 22.5 g/d based on U. S. food consumption data of yogurt (14 grams of non-fat milk solids per 100 ml yogurt).
With regard to B. xylanisolvens DSM 23964 safety, Avitop cites a published study noting that a significant proportion of all bacteroides occurring in human feces are B. xylanisolvens, and there have been no reports of pathogenicity. Avitop notes that this study also reports that no known virulence factors were identified and confirms the absence of pathogenicity in an abscess formation test in mice. Further, Avitop reiterates that PFM produced with B. xylanisolvens DSM 23964 is pasteurized. Avitop states that published in vitro studies indicate that both heat-inactivated and non-heat-inactivated B. xylanisolvens DSM 23964 were not mutagenic or clastogenic. Further, Avitop states that the results of a published 90-day oral toxicity test in mice demonstrate that B. xylanisolvens DSM 23964 is not toxic at levels of daily intake up to 3.3 x 1012 heat-inactivated bacteria per kg body weight.
Avitop notes that PFM is similar to traditional fermented low fat and skim milk products, like yogurt, with a long history of safe use in food. Avitop also describes a published, three-week, placebo-controlled human study in which the highest dose group consumed 1012 cells per day with the PFM. The study reports no adverse effects on clinical measures or subjective side-effects that could be attributed to exposure.
Standards of Identity
In the notice, Avitop states its intention to use PFM 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.
The Food Allergen Labeling and Consumer Protection Act of 2004 (FALCPA) amends the Federal Food, Drug, and Cosmetic Act (FD&C Act) to require that the label of a food that is or contains an ingredient that bears or contains a “major food allergen” declare the presence of the allergen (section 403(w)). FALCPA defines a “major food allergen” as one of eight foods or food groups (i.e., milk, eggs, fish, Crustacean shellfish, tree nuts, peanuts, wheat, and soybeans) or a food ingredient that contains protein derived from one of those foods. PFM contains protein derived from milk and thus would require labeling under FALCPA. Issues associated with labeling food are the responsibility of the Center for Food Safety and Applied Nutrition’s Office of Nutrition, Labeling and Dietary Supplements.
Section 301(ll) of the FD&C Act
The Food and Drug Administration Amendments Act of 2007, which was signed into law on September 27, 2007, amends the FD&C Act to, among other things, add section 301(ll). 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 Avitop’s notice that PFM and B. xylanisolvens DSM 23964 are GRAS for the intended uses, FDA did not consider whether section 301(ll) or any of its exemptions apply to foods containing PFM and B. xylanisolvens DSM 23964. Accordingly, this response should not be construed to be a statement that foods that contain PFM and B. xylanisolvens DSM 23964, if introduced or delivered for introduction into interstate commerce, would not violate section 301(ll).
Based on the information provided by Avitop, as well as other information available to FDA, the agency has no questions at this time regarding Avitop GmbH’s conclusion that PFM and B. xylanisolvens DSM 23964 are 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 PFM and B. xylanisolvens DSM 23964. As always, it is the continuing responsibility of Avitop 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 000457, 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