Agency Response Letter GRAS Notice No. GRN 000407
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CFSAN/Office of Food Additive Safety
April 10, 2012
Ray A. Matulka, Ph.D.
801 North Orange Street Suite 710
Orlando, FL 32801
Re: GRAS Notice No. GRN 000407
Dear Dr. Matulka:
The Food and Drug Administration (FDA) is responding to the notice, dated September 20, 2011, that you submitted on behalf of Inovo Biologic, Inc. (Inovo Biologic) 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 October 11, 2011, filed it on October 14, 2011, and designated it as GRAS Notice No. GRN 000407.
The subject of the notice is a polysaccharide complex of konjac glucomannan (konjac), sodium alginate, and xanthan gum (polysaccharide complex KAX ). The notice informs FDA of the view of Inovo Biologic that polysaccharide complex KAX is GRAS, through scientific procedures, for use at levels up to seven percent as an ingredient to provide dietary fiber or to provide thickening or a stabilizing effect in yogurts, milk shakes and fruit smoothie-type drinks, frozen yogurt, ice cream bars, puddings, white and whole wheat breads, cookies, breakfast bars, granola-type bars, noodles, whole wheat cereals, meatless lasagna and macaroni/cheese, fruit juices, fruit juice bars, cereal beverages, and medical foods.
Our use of "polysaccharide complex KAX" in this letter should not be considered an endorsement or recommendation of that term as an appropriate common or usual name for the purpose of declaring the substance in the ingredient statement of foods that contain that ingredient. Title 21 CFR 101.4 states that each ingredient must be declared by its common or usual name. In addition, 21 CFR 102.5 outlines general principles to use when establishing common or usual names for nonstandardized foods. 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.
In a previous GRAS notice, dated February 23, 2010, Inovo Biologic had informed FDA of the view that polysaccharide KAX is GRAS, through scientific procedures, for its intended use at a 90th percentile consumption level of 13,070 milligrams/day (mg/d). FDA received the notice on February 24, 2010, and designated it as GRAS Notice No. GRN 000328. FDA responded to Inovo Biologic by letter, stating that FDA considered that Inovo Biologic's intended use of polysaccharide complex KAX described in GRN 000328 would exceed permitted levels of sodium alginate affirmed as GRAS under 21 CFR 184.1724. Additionally, 21 CFR 184.1(b)(2) specifies that any use of sodium alginate not in full compliance with such established limitation requires a food additive regulation. In GRN 000407, Inovo Biologic states they have modified the maximum percentage of sodium alginate that may be used in the production of polysaccharide complex KAX from 30 percent to 14 percent or less. The notifier states that the intended levels of sodium alginate indicated in notice GRN 000407 do not exceed 0.98 percent sodium alginate in the designated foods, as served. Inovo Biologic incorporates by reference information in GRN 000328.
As part of its notice, Inovo Biologic includes the report of a panel of individuals (Inovo Biologic's GRAS panel) who evaluated the data and information that are the basis for Inovo Biologic's GRAS determination. Inovo Biologic considers the members of its GRAS panel to be qualified by scientific training and experience to evaluate the safety of substances added to food. Inovo Biologic's GRAS panel discusses the identity, specifications, method of manufacture, proposed estimated dietary intake, and published and unpublished studies on polysaccharide complex KAX and its constituents. Based on this review, Inovo Biologic's GRAS panel concludes that polysaccharide complex KAX is GRAS, by scientific procedures, under the conditions of its intended use.
Polysaccharide complex KAX is described in the notice as an off-white granular powder composed of the food-grade, regulated components, konjac, sodium alginate, and xanthan gum. The three water-soluble polysaccharides are processed by blending, followed by agglomeration with water, and subsequently dried and tested against finished product specifications which include limits for the presence of ash, protein, heavy metals and microbes. Using survey data from the United States Department of Agriculture, Inovo Biologic estimates the 90th percentile daily intake of polysaccharide complex KAX for individuals consuming the food groups selected for the addition of polysaccharide complex KAX perthis GRAS evaluation at 8,700 mg/d (145 mg/kilogram body weight/d).
Inovo Biologic provides information regarding the absorption, distribution, metabolism and elimination for the individual components of polysaccharide complex KAX. Inovo Biologic reviews the published safety data and regulatory status for the individual component polysaccharides.  Inovo Biologic also discusses published studies conducted using polysaccharide complex KAX. Polysaccharide complex KAX was well-tolerated in rats when evaluated at up to 5% of the diet, and was nonmutagenic in both the Ames bacterial reverse mutation assay and the mammalian erythrocyte micronucleus test. Additionally, Inovo Biologic cites a published 21-day randomized, double-blind, placebo-controlled study conducted to evaluate the tolerance of polysaccharide complex KAX when ingested by 54 healthy male and female subjects at 5,000 mg/d for seven days then 10,000 mg/d for 14 days. The authors concluded the complex was well-tolerated when used in food.
Standards of Identity
In the notice, Inovo Biologic states its intention to use polysaccharide complex KAX 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.
Potential Labeling Issues
In describing the effects of viscous fiber on appetite, blood glucose, and serum cholesterol in support of polysaccharide complex KAX, Inovo Biologic raises potential issues under the labeling provisions of the Federal Food, Drug, and Cosmetic Act (the 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 polysaccharide complex KAX 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 polysaccharide complex KAX on the label or in labeling.
In its notice, Inovo Biologic informs FDA that one intended use of polysaccharide complex KAX is use in medical foods. Section 5(b) of the Orphan Drug Act (ODA) defines a medical food as a food that is formulated to be consumed or administered enterally under the supervision of a physician and that is intended for the specific dietary management of a disease or condition for which distinctive nutritional requirements, based on recognized scientific principles, are established by medical evaluation. Section 403(q) of the Federal Food, Drug, and Cosmetic Act (FD&C Act) lays out the statutory framework for nutrition labeling of food products. Section 403(r) of the FD&C Act lays out the statutory framework for health claims and nutrient content claims. Under section 403(q)(5)(A)(iv) of the FD&C Act and FDA's implementing regulations in 21 CFR 101.9(j)(8), the requirements for nutrition labeling do not apply to medical foods as defined in section 5(b) of the ODA. Under section 403(r)(5)(A) of the FD&C Act and FDA's implementing regulations in 21 CFR 101.13(q)(4)(ii) and 21 CFR 101.14(f)(2), the requirements for nutrient content claims and health claims, respectively, do not apply to medical foods as defined in section 5(b) of the ODA. For your information, FDA's response to Inovo Biologic's notice that polysaccharide complex KAX is GRAS for use in medical foods does not address the question of whether any particular food product that contains polysaccharide complex KAX as an ingredient would be a medical food within the meaning of section 5(b) of the ODA and, thus, would be exempt from the requirements for nutrition labeling, nutrient content claims, and health claims.
Section 301(ll) of 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 Inovo Biologic's notice that polysaccharide complex KAX is GRAS for the intended uses, FDA did not consider whether section 301(ll) or any of its exemptions apply to foods containing polysaccharide complex KAX. Accordingly, this response should not be construed to be a statement that foods that contain polysaccharide complex KAX, if introduced or delivered for introduction into interstate commerce, would not violate section 301(ll).
Based on the information provided by Inovo Biologic, as well as other information available to FDA, the agency has no questions at this time regarding Inovo Biologic's conclusion that polysaccharide complex KAX 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 polysaccharide complex KAX. As always, it is the continuing responsibility of Inovo Biologic 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 000407, 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
 FDA considers polysaccharide complex KAX a mixture that exhibits viscosity, rheology, and sedimentation properties different from that of the raw components.
 The use of konjac powder as a binder in meat and poultry products in which starchy vegetable flours are permitted is listed in FSIS Directive 7120.1 "Safe and Suitable Ingredients Used in the Production of Meat and Poultry Products." Sodium alginate is regulated by FDA under 21 CFR 184.1724 as a texturizer, formulation aid, stabilizer, thickener, firming agent, flavor adjuvant, emulsifier, flavor enhancer, surface active agent. Xanthan gum is regulated by FDA under 21 CFR 172.695 as a stabilizer, emulsifier, thickener, suspending agent, bodying agent, or foam enhancer.