Agency Response Letter GRAS Notice No. GRN 000231
CFSAN/Office of Food Additive Safety
May 29, 2008
Matias Diez, Pharm. D.
Mead Johnson & Company
2400 W. Lloyd Expressway
Evansville, IN 47721-0001
Re: GRAS Notice No. GRN 000231
Dear Dr. Diez:
The Food and Drug Administration (FDA) is responding to the notice, dated August 1, 2007, that you submitted 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 this notice on August 2, 2007, filed it on August 9, 2007, and designated it as GRAS Notice No. GRN 000231.
The subject of the notice is Lactobacillus casei subsp. rhamnosus strain GG. The notice informs FDA of the view of Mead Johnson & Company (Mead Johnson) that L. casei subsp. rhamnosus strain GG is GRAS, through scientific procedures, for use as an ingredient in exempt hypoallergenic infant formula powder with extensively hydrolyzed casein and oils containing docosahexaenoic acid and arachidonic acid and without medium-chain triglyceride oil1 (hereinafter referred to as infant formula powder) at a level of 108 colony forming units per gram (cfu/g) of infant formula powder that is intended for consumption by term infants from the time of birth. Mead Johnson notes that the intended use of L. casei subsp. rhamnosus strain GG does not encompass use by infants who might have immune problems.
Mead Johnson includes the report of a panel of individuals (Mead Johnson’s GRAS Panel) who evaluated the data and information that are the basis for Mead Johnson’s GRAS determination. Mead Johnson considers the members of its GRAS panel to be qualified by scientific training and experience to evaluate the safety of substances added to food.
Mead Johnson discusses the identity and characterization properties of L. casei subsp. rhamnosus strain GG. The notifier states that L. casei subsp. rhamnosus strain GG is nonpathogenic, nontoxigenic, and that it is not known to produce exotoxins. Mead Johnson states that L. casei subsp. rhamnosus strain GG contains no plasmids, and its risk for disseminating antibiotic resistance is lower than plasmid-containing bacteria.
Mead Johnson describes the method of manufacture of, and provides specifications for, the L. casei subsp. rhamnosus strain GG ingredient. Mead Johnson states that the production of the L. casei subsp. rhamnosus strain GG ingredient is based on standard fermentation techniques.
The notifier states that L. casei subsp. rhamnosus strain GG is manufactured using food grade hydrolyzed whey permeates and hydrolyzed whey/casein proteins as growth media in the fermentation process. After fermentation, L. casei subsp. rhamnosus strain GG is concentrated by ultra filtration, washed with sterile water to remove impurities such as fermented media components, followed by addition of saccharose as a cryoprotectant. The dried L. casei subsp. rhamnosus strain GG ingredient will be incorporated into the dry blending manufacture of the infant formula powder.
The notifier reports that the raw materials used in the production of the L. casei subsp. rhamnosus strain GG ingredient meets the specifications in the Food Chemical Codex, Joint FAO/WHO Expert Committee of Food Additives, or the Code of Federal Regulations.
Mead Johnson intends to use L. casei subsp. rhamnosus strain GG in infant formula powder at levels not to exceed 108 cfu/g of powdered formula. This level of L. casei subsp. rhamnosus strain GG is intended to ensure a minimum concentration of 106 cfu/g throughout the 12-18 month shelf life of the infant formula powder. Based on 108 cfu/g of L. casei subsp. rhamnosus strain GG, with normal dilution of the infant formula powder in water according to label directions (i.e., 13.5 g/ 100 mL) and assuming an average daily formula intake of 800 milliliters, Mead Johnson estimates that the daily intake of L. casei subsp. rhamnosus strain GG would be approximately 108-1010 cfu per day.
Mead Johnson discusses data from published and unpublished studies that include in vitro testing methods, genetic sequencing, animal models, and studies in human subjects using the bacterium L. casei subsp. rhamnosus strain GG. Mead Johnson states that the complete genome of L. casei subsp. rhamnosus strain GG has been sequenced, concluding that there is no evidence of a safety hazard from this genomic data. Mead Johnson also concludes that L. casei subsp. rhamnosus strain GG has shown no adverse impact on nutritional, metabolic, or immune parameters at the level intended for use in infant formula powder.
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. In describing the intended use of L. casei subsp. rhamnosus strain GG and in describing the information that Mead Johnson relies on to conclude that L. casei subsp. rhamnosus strain GG is GRAS under the conditions of their intended use, Mead Johnson raises a number of 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 Mead Johnson’s notice to determine whether it would support any claims made about L. casei subsp. rhamnosus strain GG 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. Mead Johnson should be aware that FDA’s response to Mead Johnson’s GRAS notice does not alleviate the responsibility of any infant formula manufacturer who intends to market an infant formula that contains L. casei subsp. rhamnosus strain GG to make the submission required by section 412.
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 Mead Johnson’s notice that L. casei subsp. rhamnosus strain GG is GRAS for use in infant formula powder, FDA did not consider whether section 301(ll) or any of its exemptions apply to foods containing L. casei subsp. rhamnosus strain GG. Accordingly, this response should not be construed to be a statement that foods that contain L. casei subsp. rhamnosus strain GG, if introduced or delivered for introduction into interstate commerce, would not violate section 301(ll).
Based on the information provided by Mead Johnson, as well as other information available to FDA, the agency has no questions at this time regarding Mead Johnson’s conclusion that L. casei subsp. rhamnosus strain GG 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. casei subsp. rhamnosus strain GG. As always, it is the continuing responsibility of Mead Johnson 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 000231, as well as a copy of the information in this notice that conforms to the information in the proposed GRAS exemption claim (proposed 21 CFR 170.36(c)(1)), is available for public review and copying on the homepage of the Office of Food Additive Safety (on the Internet at http://www.cfsan.fda.gov/~lrd/foodadd.html).
Laura M. Tarantino, Ph.D.
Office of Food Additive Safety
Center for Food Safety and Applied Nutrition
(1)Mead Johnson notes that this formula meets the definition in 21 CFR 107.50 (b), being an infant formula generally available at retail level.