Agency Response Letter GRAS Notice No. GRN 000495
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CFSAN/Office of Food Additive Safety
May 30, 2014
1620 Pinetree Drive
Pittsburg, PA 15241
Re: GRAS Notice No. GRN 000495
Dear Mr. Moore:
The Food and Drug Administration (FDA) is responding to the notice, dated December 18, 2013, 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 the notice on December 19, 2013, filed it on January 2, 2014, and designated it as GRAS Notice No. GRN 000495. In an amendment dated February 25, 2014, Clasado provided clarifying information about a specification.
The subject of the notice is galacto-oligosaccharides (GOS). The notice informs FDA of the view of Clasado, Inc. (Clasado) that GOS is GRAS, through scientific procedures, for use as an ingredient in term infant formula and follow-on formula at up to 7.2 grams per liter (g/L) of reconstituted or ready-to-consume product.
As part of its notice, Clasado includes the statement of a panel of individuals (Clasado’s GRAS panel) that evaluated the data and information that are the basis for Clasado’s GRAS determination. Clasado considers the members of its GRAS panel to be qualified by scientific training and experience to evaluate the safety of substances added to food. Clasado’s GRAS panel evaluated the identity, manufacturing, specifications, conditions of use, estimated dietary exposure, and safety information. Based on this review, Clasado’s GRAS panel concluded that GOS produced in accordance with good manufacturing practices is GRAS under the conditions of its intended use.
Clasado notes that GOS was the subject of previous GRAS notices and that slight differences in the manufacturing conditions (e.g., enzyme source organism, reaction time, temperature, pH) are employed by each manufacturer. These differences in manufacturing conditions typically yield mixtures consisting of oligosaccharides that contain between 2 and 8 sugar moieties. GOS, produced by the activity of β-galactosidases, contains beta linkages in 1→2, 1→3, 1→4, or 1→6 anomeric configurations. The specific β-galactosidase enzyme used in the reaction influences the particular linkages and molecular weight distribution observed between different preparations.
Clasado describes the identity and composition of the GOS that is the subject of GRN 000495. The final product is composed of GOS and also contains glucose, galactose, and residual lactose. The galacto-oligosaccharides are between 2 and 8 saccharide units in length, with one saccharide unit being a terminal glucose and the remaining saccharide units being galactose.
Clasado describes the manufacturing process for GOS. GOS is manufactured from food-grade lactose via the transgalactosylation activity of a β-galactosidase enzyme preparation.1 Food-grade lactose is dissolved in heated water; the solution is heated and then cooled to the appropriate synthesis temperature. Next, the buffered enzyme preparation is added to the lactose solution.After the synthesis reaction is completed, the solution is cooled, diluted, and filtered to remove the enzyme preparation and residual milk proteins and peptides. The GOS solution is heat-sterilized, cooled, and evaporated to a concentration in excess of 70% total solids prior to cooling, filtering, and packaging. GOS is manufactured as syrup and also as a spray-dried powder, which is produced from the syrup. During production of the powder, the syrup is filtered to remove monosaccharides before spray-drying with maltodextrin or whey protein concentrate, and calcium phosphate is added as an anti-caking agent.
Clasado provides specifications for GOS syrup. These include minimum levels of dry matter (DM) (≥ 70%) and total galacto-oligosaccharides (≥ 57% DM). The specifications also include moisture (≤ 30%), protein (< 0.3%), lactose (< 26% DM), glucose (< 23% DM), galactose (> 0.8% DM), and heavy metal specifications including lead (< 0.1 milligram per kilogram (mg/kg)), cadmium (< 0.1 mg/kg), and mercury (< 0.1 mg/kg). Clasado also provides limits for microbial contaminants, including Chronobacter sakazakii (not detected in 25 g). Clasado provides the results of non-consecutive batch analyses to demonstrate that GOS meets specifications. In addition, Clasado states that GOS is stable under ambient and accelerated storage conditions for at least 6 months.
Clasado intends that GOS will be substitutional for other GOS preparations currently used in foods. Clasado discusses the dietary exposure to GOS under the intended conditions of use and notes that exposure to GOS was estimated in previous GRAS notices (e.g., GRNs 000236, 000286, and 000334). The previously notified estimates were conducted using survey data from the National Center for Health Statistics’ 2003-2004 National Health and Nutrition Examination Survey and predict that 80% of the U.S. infant population is expected to consume GOS from these intended uses. Clasado states that among infants aged 0 through 6 months, the mean and 90th percentile dietary exposures of GOS from the consumption of infant formula containing GOS at the maximum intended use level of 7.2 g/L was calculated as 5.9 and 8.5 g per person per day (g/p/d), respectively. Among infants aged 7 through 12 months, the dietary exposure to GOS was calculated as 5.2 and 7.9 g/p/d at the mean and 90th percentile, respectively. Clasado states that only 3.7% of toddlers aged 1 to 2 years were found to consume GOS from its use in infant formula, and the corresponding estimated exposure was calculated to be 2.8 and 6.6 g/p/d at the mean and 90th percentile, respectively.
Clasado incorporates GRNs 000236, 000286, and 000334 by reference and includes an update of the literature for the time period through August 2013. The notifier describes in detail the chemical identity and structure of GOS, as well as the relevant absorption, distribution, metabolism and elimination pathways that are general scientific principles. Briefly, GOS is fermented by colonic bacteria to produce innocuous metabolites (e.g., short chain fatty acids, CO2 and H2) that are common fermentation products of the normal diet. In addition, the notifier discusses published animal studies. Furthermore, the notifier provides a safety discussion regarding published clinical trials. Published clinical trials where pre-term and term infants have consumed infant formula with up to 7.2 g/L of GOS, have shown that GOS is safe, well-tolerated, and does not adversely affect infant growth. Finally, the notifier discusses that the European Commission Scientific Committee on Foods and Food Standards Australia New Zealand have published opinions authorizing the safe use of GOS in infant formula preparations.
Potential Labeling Issues
In describing the intended use of GOS and the data from the published human studies that Clasado relies on to conclude that GOS is GRAS under the intended conditions of use, Clasado raises 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 GOS 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 (OFAS) 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 GOS on the label or in labeling.
The Food Allergen Labeling and Consumer Protection Act of 2004 (FALCPA) amends the 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. GOS may require labeling under FALCPA, because it may contain protein derived from milk. Although issues associated with labeling food are the responsibility of ONLDS, issues associated with FALCPA exemptions are the responsibility of the Food Allergen Coordinator in the OFAS.
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. Clasado should be aware that FDA’s response to Clasado’s GRAS notice does not alleviate the responsibility of any infant formula manufacturer who intends to market an infant formula that contains GOS 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 Clasado’s notice that GOS is GRAS for the intended uses, FDA did not consider whether section 301(ll) or any of its exemptions apply to foods containing GOS. Accordingly, this response should not be construed to be a statement that foods that contain GOS, if introduced or delivered for introduction into interstate commerce, would not violate section 301(ll).
Based on the information provided by Clasado, as well as other information available to FDA, the agency has no questions at this time regarding Clasado’s conclusion that GOS 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 GOS. As always, it is the continuing responsibility of Clasado 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 000495, 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
1 β-Galactosidase enzyme preparation is the subject of GRN 000485.