Agency Response Letter GRAS Notice No. GRN 000328
CFSAN/Office of Food Additive Safety
May 20, 2011
George A. Burdock, Ph.D.
Burdock Group Consultants
801 N. Orange Avenue
Orlando, FL 32801
Re: GRAS Notice No. GRN 000328
Dear Dr. Burdock:
The Food and Drug Administration (FDA) is responding to the notice, dated February 23, 2010, that you submitted on behalf of Inovo Biologic, Inc. (Inovo) 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 February 24, 2010, filed it on March 12, 2010, and designated it as GRAS Notice No. GRN 000328.
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 Inovo’s view that polysaccharide complex KAX is GRAS, through scientific procedures, for use as an ingredient 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, and cereal beverages.
FDA has evaluated the information that Inovo discusses in its GRAS notice as well as other data and information that are available to the agency. Data contained in Inovo’s notice does not substantiate that polysaccharide complex KAX is truly distinct from a mixture of ingredients that are already used in food. As such, the proposed uses of sodium alginate in polysaccharide complex KAX are outside the limitations established in 21 CFR 184.1724. FDA discussed these aspects with you prior to your submission of GRN 000328 on behalf of Inovo, and in the context of our evaluation of GRN 000328. FDA has concluded that the notice does not provide a sufficient basis for a determination that polysaccharide complex KAX is GRAS under the conditions of its intended uses.
Data and information Inovo relies on to conclude GRAS status
Inovo describes polysaccharide complex KAX as a proprietary product comprised of konjac, sodium alginate and xanthan gum of varying percentages and giving rise to a mixture having a desired viscosity. Inovo cites this viscosity relative to the viscosity of the individual components, as well as rheology, sedimentation, and spectral data, to support their assertion that polysaccharide complex KAX is a unique chemical entity.
Inovo provides information regarding the absorption, distribution, metabolism and elimination for the individual components of polysaccharide complex KAX. Inovo states that the precise degradation process taking place in the gut for the polysaccharide complex KAX is not definitively known, asserting it is unlikely that the individual components would “dis-agglomerate” or that the intestinal environment will reverse the agglomeration; despite its assertion, Inovo emphasizes safety data of the individual component polysaccharides. Inovo also describes published animal safety and human tolerance studies about polysaccharide complex KAX, and provided two patents.
Inovo acknowledges that FDA has affirmed sodium alginate as GRAS (21 CFR 184.1724) with specific limitations in use levels for various foods under 21 CFR 184.1(b)(2) for use as a texturizer, formulation aid, stabilizer, thickener, firming agent, flavor adjuvant, emulsifier, flavor enhancer and surface active agent.
FDA’s evaluation of the data and information in Inovo’s notice
FDA’s evaluation focused both on safety information and whether or not the polysaccharide complex KAX is truly distinct from a mixture of ingredients that are already used in food. FDA considers that the regulations that address the use of individual components in a mixture also address the use of a mixture.
Though Inovo cites physical property data, the notice does not provide information to demonstrate that polysaccharide complex KAX is a new substance. A study by Abdelhameed et al. (Ref. 1), provided in support of Inovo’s determination, states the ternary mixture is disrupted by increased ionic strength. The authors state, “[i]t is known from rheological studies that mixtures of polysaccharides in concentrated solution can interact synergistically.” The trademark name PGX® (called polysaccharide complex KAX in this letter) is a proprietary mixture studied as individual components and as a ternary complex. The authors also note that while changes in sedimentation rate are observed with the mixture, consistent with some interaction, the specific nature of the interactions between components would require study. Further, the reference by Harding et al. (Ref. 2) concludes that there is an absence of covalent interactions between polysaccharide molecules in the formulation. The authors studied possible covalent and non-covalent interactions in the polysaccharide complex KAX ternary mixture, and concluded that “[a]nalytical techniques established the absence of changes in primary covalent structure in any of the component polysaccharides which may have occurred when the product was manufactured.” Additionally, “rheological measurements confirmed that non-covalent interactions do occur in aqueous solutions of PGX®.”
Patent applications provided by Inovo (US 2008/0027024; US 2006/0228397) describe the subject of the notice as a “… dietary fiber composition prepared according to the methods of the invention [that] may comprise from about 48% to about 90% (w/w) glucomannan, from about 5% to about 20% (w/w) xanthan gum, and from about 5% to about 30% (w/w) alginate.” These patents describe methods of use for a dietary supplement that contains three fibers, and do not address the formation of a new entity.
In FDA’s view, data provided in the notice do not substantiate that the polysaccharide complex KAX is a new chemical entity, but simply a ternary mixture of variable proportions of konjac, sodium alginate and xanthan gum.
FDA considers that Inovo’s intended uses of polysaccharide complex KAX described in the notice would exceed permitted levels of sodium alginate. Under 21 CFR 184.1724(c) current uses of sodium alginate are affirmed as GRAS, in accordance with 21 CFR 184.1(b)(2), only within specific limitations. Further, 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.1 If Inovo intends to use sodium alginate outside the limitations in the GRAS affirmation regulation, an appropriate regulatory path is to submit a food additive petition to create a new regulation for such use. Another available option is to submit a citizen petition, filed under 21 CFR 10.30, to amend 21 CFR 184.1(b)(2).
The rulemakings that established 21 CFR 184.l(b)(2) and 21 CFR184.1724(c) bind FDA as well as the regulated industry. Inovo’s notice to FDA of its view that the use of sodium alginate as an ingredient in the manufacture of polysaccharide complex KAX is GRAS is not a substitute for the rulemaking that is required under the current regulatory structure.
FDA has evaluated the data and information in GRN 000328 as well as other available information. The notice does not provide a sufficient basis for a determination that polysaccharide complex KAX is GRAS under the conditions of its intended use.
In accordance with proposed 21 CFR 170.36(f), a copy of the text of this letter responding to GRN 000328, 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.
Mitchell A. Cheeseman, Ph.D.
Office of Food Additive Safety
Center for Food Safety and Applied Nutrition
- Abdelhameed AS, et al. (2010) An analytical ultracentrifuge study on ternary mixtures of konjac glucomannan supplemented with sodium alginate and xanthan gum. Carbohydrate Polymers. DOI:10.1016/j.carbpol.2010.01.043.
- Harding SE, et al. (2010) Studies on macromolecular interactions in ternary mixtures of konjac glucomannan, xanthan gum and sodium alginate. Carbohydrate Polymers 83:329-338.
1See FDA’s response letter to GRN 000014, dated May 26, 1999, for FDA’s discussion of the restriction imposed by 21 CFR 184.1(b)(2).