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CFSAN/Office of Food Additive Safety
August 31, 2009
James T. Heimbach, Ph.D., F.A.C.N.
923 Water Street
P.O. Box 66
Port Royal, VA 22535
Re: GRAS Notice No. GRN 000281
Dear Dr. Heimbach:
The Food and Drug Administration (FDA) is responding to the notice, dated January 20, 2009, that you submitted on behalf of Fonterra Co-operative Group (Fonterra) 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 January 30, 2009, filed it on February 4, 2009, and designated it as GRAS Notice No. GRN 000281.
The subject of the notice is Lactobacillus rhamnosus strain HN001 produced in a milk-based medium (hereinafter referred to as L. rhamnosus strain HN001 in this letter). The notice informs FDA of the view of Fonterra that L. rhamnosus strain HN001 is GRAS, through scientific procedures, for use as an ingredient in milk-based powdered term infant formula that is intended for consumption from the time of birth, as well as in milk-based powdered follow-on formula, at a level of 108 colony forming units per gram (cfu/g) of the formula powder. Fonterra states that products containing L. rhamnosus strain HN001 are not intended for the feeding of immunocompromised infants.
21 CFR 101.4 states that all ingredients must be declared by their common or usual name. In addition, 21 CFR 102.5 outlines general principles to use when establishing common or usual names for nonstandardized foods. Our use of “L. rhamnosus strain HN001 produced in a milk based medium” or “L. rhamnosus strain HN001” in this letter should not be considered an endorsement or recommendation of any of these terms as an appropriate common or usual name for the purpose of declaring the substance in the ingredient statement of foods that contain that ingredient. Issues associated with labeling and the appropriate common or usual name of a food are the responsibility of the Office of Nutrition, Labeling, and Dietary Supplements (ONLDS) in the Center for Food Safety and Applied Nutrition.
Fonterra includes the report of a panel of individuals (Fonterra’s GRAS Panel) who evaluated the data and information that are the basis for Fonterra’s GRAS determination. Fonterra considers the members of its GRAS panel to be qualified by scientific training and experience to evaluate the safety of substances added to food. Fonterra’s GRAS panel evaluated the method of manufacture, method of production, estimates of dietary exposure, as well as published and unpublished studies. Based on this review, Fonterra’s GRAS panel concluded that L. rhamnosus strain HN001 produced in a milk based medium, that meets established food grade specifications, is GRAS under the conditions of its intended use.
Fonterra discusses the identity and characteristic properties of L. rhamnosus strain HN001 and cites published literature supporting the nonpathogenic and nontoxigenic nature of L. rhamnosus strain HN001. Fonterra notes that L. rhamnosus strain HN001 was isolated from cheddar cheese and has been consumed in New Zealand for at least twenty years. In addition, Fonterra states that Lactobacilli strains have been used in the manufacture of fermented milk products for more than 75 years. Fonterra further states that L. rhamnosus strains are commensal organisms naturally found in the human gut. Fonterra states that antimicrobial susceptibility testing showed that L. rhamnosus strain HN001 is susceptible to a broad range of antibiotics, but is intrinsically resistant to certain classes of antibiotics. Fonterra discusses sequencing analyses that reveal that these resistances are not plasmid encoded and are unlikely to be transferred to other bacteria.
Fonterra describes the method of manufacture of the L. rhamnosus strain HN001, noting that each step in the production of L. rhamnosus strain HN001 is performed in accordance with current good manufacturing practices. Fonterra states that the production of the L. rhamnosus strain HN001 is based on standard fermentation techniques. L. rhamnosus strain HN001 is manufactured in a growth medium based on hydrolyzed casein and other food-grade components (e.g., yeast extract, glucose, mineral salts, buffers). After fermentation is completed, L. rhamnosus strain HN001 is concentrated by centrifugation and a cryoprotectant (containing maltodextrin, sucrose, ascorbic acid) is added. The L. rhamnosus strain HN001 ingredient is then lyophilized, milled, and packed under nitrogen. Fonterra states that microbiological purity and compliance with specifications are verified for each lot of L. rhamnosus strain HN001 before release.
Fonterra intends to use L. rhamnosus strain HN001 in milk-based powdered term infant formula and milk-based powdered follow-on formula at levels not to exceed 108 cfu/g of the formula powder. This level of L. rhamnosus strain HN001 is intended to ensure a minimum concentration of 106 cfu/g throughout the shelf life (12-18 months) of the infant formula powder. Fonterra estimates the concentration of L. rhamnosus strain HN001 in the prepared formula would be 1.35 x 109 cfu per 100 milliliters (mL), based on standard addition levels for powder in water used to prepare formula for consumption. Assuming a mean intake of 800 mL of formula per day, Fonterra estimates the mean intake of L. rhamnosus strain HN001 would be approximately 109 to 1010 cfu per day.
Fonterra discusses data from published and unpublished studies that include in vitro testing methods, genetic sequencing, animal models, and studies in human subjects (adults and infants) using the bacterium L. rhamnosus strain HN001. Fonterra states that the body of evidence confirms the safety of L. rhamnosus strain HN001. Fonterra concludes that L. rhamnosus strain HN001 added to milk-based infant formula and milk-based follow-on formula at 108 cfu/g of the formula powder is safe for term infants.
Potential Label Claims
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. Section 403(r) of the FFDCA 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. In describing the intended use of L. rhamnosus strain HN001 and in describing the information that Fonterra relies on to conclude that L. rhamnosus strain HN001 is GRAS under the conditions of its intended use, Fonterra raises a potential issue under these labeling provisions of the FFDCA. If products that contain L. rhamnosus strain HN001 bear any claims on the label or in labeling, such claims are the purview of ONLDS. The Office of Food Additive Safety neither consulted with ONLDS on this labeling issue nor evaluated the information in your notice to determine whether it would support any claims made about L. rhamnosus strain HN001 on the label or in labeling.
Intended use in infant formula
Under section 412 of the FFDCA, a manufacturer of a new infant formula must make a submission to FDA, providing required assurances about the formula, at least 90 days before the formula is marketed. Fonterra should be aware that FDA’s response to Fonterra’s GRAS notice does not alleviate the responsibility of any infant formula manufacturer who intends to market an infant formula that contains L. rhamnosus strain HN001 to make the submission required by section 412.
Section 301(ll) of the FFDCA
The Food and Drug Administration Amendments Act of 2007, which 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 Fonterra’s notice that L. rhamnosus strain HN001 is GRAS for use in milk-based powdered term infant formula and in milk-based powdered follow-on infant formula, FDA did not consider whether section 301(ll) or any of its exemptions apply to foods containing L. rhamnosus strain HN001. Accordingly, this response should not be construed to be a statement that foods that contain L. rhamnosus strain HN001, if introduced or delivered for introduction into interstate commerce, would not violate section 301(ll).
Based on the information provided by Fonterra, as well as other information available to FDA, the agency has no questions at this time regarding Fonterra’s conclusion that L. rhamnosus strain HN001 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. rhamnosus strain HN001. As always, it is the continuing responsibility of Fonterra 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 000281, 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.
Mitchell A. Cheeseman, Ph.D.
Office of Food Additive Safety
Center for Food Safety and Applied Nutrition