Agency Response Letter GRAS Notice No. GRN 000392
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CFSAN/Office of Food Additive Safety
May 7, 2012
James T. Heimbach, Ph.D.
923 Water Street
P.O. Box 66
Port Royal, VA 22535
Re: GRAS Notice No. GRN 000392
Dear Dr. Heimbach:
The Food and Drug Administration (FDA) is responding to the notice, dated July 8, 2011, that you submitted on behalf of Pfizer Nutrition and BENEO-Orafti (Pfizer and BENEO), 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 July 22, 2011, filed it on July 27, 2011, and designated it as GRAS Notice No. GRN 000392.
The subject of the notice is oligofructose. The notice informs FDA of the view of Pfizer and BENEO that oligofructose is GRAS, through scientific procedures, for use as an ingredient in milk-based term infant formula powder at a maximum level of 3 grams per liter (g/L) of formula as consumed.
As part of its notice, Pfizer and BENEO include the findings of a panel of individuals (Pfizer and BENEO’s GRAS panel) who evaluated the data and information that are the basis for Pfizer and BENEO’s GRAS determination. Pfizer and BENEO consider the members of its GRAS panel to be qualified by scientific training and experience to evaluate the safety of substances added to food. Pfizer and BENEO’s GRAS panel reviewed information regarding the identity, composition, and characteristic properties of Pfizer and BENEO’s oligofructose and other fructans, the potential exposure of infants, published animal and human studies on the pharmacokinetics and safety of oligofructose, as well as the production processes and quality controls used by the manufacturer. Pfizer and BENEO’s GRAS panel concludes that oligofructose, produced in accordance with good manufacturing practices and meeting food-grade specifications, is GRAS for the intended use in milk-based term infant formula.
Pfizer and BENEO include information about the identity and composition of oligofructose. Oligofructose is described as a member of a group of compounds designated as fructan oligosaccharides, which also includes fructooligosaccharides (FOS) and inulin. Fructan oligosaccharides are described as predominately linear chains of fructose linked in a ß(2-1) configuration with a potential for branching and typically possess a terminal glucose moiety. Individual fructan products may be distinguished by their source, method of production, or degree of polymerization (DP-the number of fructose or glucose residues in the chain). Inulin is a naturally occurring fructan with a DP ranging from 2 to 60. Inulin can be enzymatically hydrolyzed to produce FOS or oligofructose. FOS generally refers to fructans with a DP < 10. Oligofructose refers to fructans with a DP of < 10 and more specifically with > 25% of the molecules having a DP ≥ 5 and < 75% with a DP ≤ 4. The oligofructose that is the subject of GRN 000392 has a DP generally in the range of 2 to 8 and predominantly (90%) in the range of 3 to 6.
Pfizer and BENEO describe the method of manufacture for oligofructose. The starting material is inulin extracted from chicory roots. Pfizer and BENEO state that chicory root is composed of approximately 15 to 17% inulin and that the DP range of chicory inulin is about 2 to more than 60. The chicory roots are washed and sliced, then extracted in hot water to yield raw juice. Food-grade calcium hydroxide is added to precipitate the non-inulin substances, including minerals, proteins, some sugars, and cell-wall particles, which are then removed by filtration. The filtrate is evaporated to produce raw inulin that will be subjected to crystallization or chromatography to remove salts and sugars. The inulin is hydrolyzed using a food-grade carbohydrase preparation. Pfizer and BENEO note that the enzyme preparation is obtained from Aspergillus niger and that this organism is safe for use in food production. The hydrolysis product is evaporated, subjected to heat treatment to reduce microbial load, decolorized with activated carbon, filtered and reheated. Finally, the oligofructose product is dried to a moisture content of 5%.
Pfizer and BENEO provide product specifications for oligofructose. The finished product contains 95% carbohydrates and 5% water. By specification, the carbohydrate portion contains oligofructose (≥ 93.2%) and digestible sugars (≤ 6.8%). In addition, Pfizer and BENEO provide limits for lead (< 0.02 milligrams per kilogram (mg/kg)), arsenic (< 0.03 mg/kg), microbial contaminants, pesticides, and heavy metals. Pfizer and BENEO also provide data on the oligofructose product for thermal stability, long-term shelf stability, and stability in the infant formula mix.
Pfizer and BENEO state that the maximum intended level of addition of the oligofructose product is 3g/L infant formula as consumed, which is equivalent to 23.6 mg oligofructose per g infant formula powder. Pfizer and BENEO discuss a published study that provides data on daily energy intake by formula-fed infants. In this study, the subpopulation with the highest intake per kg body weight per day (bw/day) is infants aged 14 to 27 days. The 90th percentile energy intake by this group is 141.3 kilocalories per kg bw/day (kcal/kg bw/day) for boys and 138.9 kcal/kg bw/day for girls. The infant formula produced by Pfizer, as well as most other standard formulas, contains 670 kcal/L as consumed. Therefore, Pfizer and BENEO estimate that for the highest intake subpopulation, the 90th percentile daily intake of oligofructose is 620 mg/kg bw/day. Pfizer and BENEO note that with a 20% overage allowance in the infant formula production process, this daily intake could be as high as 744 mg/kg bw/day.
Pfizer and BENEO summarize published studies to support their determination of safety for the consumption of the oligofructose product. Some studies were conducted with fructooligosaccharides in general, while other studies were conducted with Pfizer and BENEO’s specific oligofructose product. The cited studies include investigations conducted in animal models as well as in human infants and adults.
Pfizer and Beneo state that the metabolism studies of oligofructose in humans as well as animals are consistent in showing that nearly all ingested oligofructose reach the colon intact where they are almost entirely fermented by the colonic bacteria. The kinetics of bacterial fermentation is inversely proportional to the degree of polymerization of the fructan. Such near-complete fermentation of Pfizer and Beneo’s oligofructose product in the colon is consistent with that already reported for other fructans, including inulin.
Safety studies conducted in animal models include: acute toxicity studies; 4-6 week-long toxicity studies; subchronic toxicity studies; chronic toxicity and carcinogenicity studies; reproductive and developmental toxicity studies; and genotoxicity and mutagenicity studies in vitro. Pfizer and BENEO note that very large doses of fructans may result in cecal enlargement, which they consider to be a trophic effect and not a toxic effect. Pfizer and BENEO state that no consistent, statistically significant, dose-dependent effects were reported in animal studies. Pfizer and BENEO further state that the studies demonstrate that oligofructose is safe to consume, and there is no evidence of toxicity, carcinogenicity, mutagenicity or clastogenicity.
Pfizer and BENEO also summarize several studies conducted in a total of 2800 human infants fed fructans alone or fructans combined with galactooligosaccharides for varying periods of time. Among other studies, one study the notifier summarizes is a 12-week randomized, double-blind, multi-center trial that assessed the growth and tolerance in healthy full-term infants fed formula containing the oligofructose product of Pfizer and BENEO at either 1.5 g/L or 3 g/L. Pfizer and BENEO state that measurement of all parameters of growth and tolerance did not reveal any significant differences between the control and treated groups. Pfizer and BENEO also state that the oligofructose-containing formulas were well tolerated, with the 3.0 g/L group having fewer observed adverse events than the control group. Thus, Pfizer and BENEO cite and reiterate the authors’ conclusion that “the experimental cow's milk-based formula supplemented with either 1.5 or 3.0 g oligofructose is safe and supports normal infant growth.”
Based on the totality of evidence, Pfizer and BENEO conclude that studies conducted in human infants demonstrate that fructans are safe to consume for healthy term infants and that the addition of oligosaccharides to infant formula does not pose any likelihood of harm; thus, the intended use of the oligofructose in infant formula is GRAS.
Potential Labeling Issues
In describing data and information on clinical studies that Pfizer and BENEO rely on to conclude that oligofructose is GRAS under the conditions of its intended use, Pfizer and BENEO raise a potential issue under the labeling provisions of the Federal Food, Drug, and Cosmetic Act (FD&C Act). 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 oligofructose bear any claims on the label or in labeling, such claims 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 this labeling issue nor evaluated the information in your notice to determine whether it would support any claims made about oligofructose on the label or in labeling.
Intended use in infant formula
Under section 412 of the FD&C Act 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. Pfizer and BENEO should be aware that FDA’s response to Pfizer and BENEO’s GRAS notice does not alleviate the responsibility of any infant formula manufacturer who intends to market an infant formula that contains oligofructose to make the submission required by section 412.
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 Pfizer and BENEO’s notice that oligofructose is GRAS for the intended use, FDA did not consider whether section 301(ll) or any of its exemptions apply to foods containing oligofructose. Accordingly, this response should not be construed to be a statement that foods that contain oligofructose, if introduced or delivered for introduction into interstate commerce, would not violate section 301(ll).
Based on the information provided by Pfizer and BENEO, as well as other information available to FDA, the agency has no questions at this time regarding Pfizer and BENEO’s conclusion that oligofructose 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 oligofructose. As always, it is the continuing responsibility of Pfizer and BENEO to ensure that food ingredients that the firms market 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 000392, 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 http://www.fda.gov/grasnoticeinventory.
Dennis M. Keefe, Ph.D.
Office of Food Additive Safety
Center for Food Safety and Applied Nutrition