Considerations in Making GRAS Determinations

On Dec. 18, 2002, the Food and Drug Administration (FDA) and the Federal Trade Commission (FTC) held a joint press conference announcing FDA's new policy officially allowing qualified health claims for conventional foods. This event, coupled with the previous Pearson v. Shalala decision, is sure to increase the development and use of functional ingredients to supply the increasing consumer demand for "functional foods," already a multibillion-dollar market and growing. Inclusion of a value-added substance (i.e., functional ingredient) into food provides some apparent marketing advantages, but to be added to food, a substance must first be approved for use in food, either via a food additive petition or obtaining GRAS (generally recognized as safe) status.

One obvious source of functional food ingredients is dietary supplement ingredients. The Dietary Supplement Health and Education Act (DSHEA) not only provided appropriate definitions for these materials, but also changed the framework for safety determinations, labeling and claims, as well as nutritional support statements. DSHEA dramatically increased the interest, availability and use of dietary supplements ... and drove innovative dietary supplement companies to explore new ingredients and new uses.

Dietary supplement ingredients used in conventional foods can be positioned to provide beneficial nutrients that promote good health and help protect against disease. But more importantly, adding an ingredient that carries a health claim to a conventional food can create a "value-added" functional food with that same health claim. For such a nutraceutical to migrate into conventional food use, it must meet the obligatory regulatory requirements for a food additive, such as via a food additive petition (21CFR170.3(e)(1)), or a determination that the potential food additive is GRAS (21CFR170.30). The most commonly sought method for ingredient approval is a GRAS determination using unbiased, "qualified experts." FDA deems suitable qualified experts as "experts qualified by scientific training and experience to evaluate the safety of food and food ingredients" (21CFR170.3(i)(3)). If the GRAS route is selected, the decision to notify FDA of the GRAS determination prior to marketing these products is voluntary (21CFR170.36).

Laboratory Work & Scientific Experts

There are two routes to take for a GRAS determination by experts: 1) through proof that the ingredient enjoyed common use in food by a significant number of consumers prior to Jan. 1, 1958; or 2) through scientific procedures. Most ingredients are new, and GRAS determinations will involve a qualified panel of experts and rigorous scientific procedures.

There are essentially four major criteria that are used by qualified experts to determine the GRAS status of a food ingredient:

A common misconception is that once an ingredient is determined GRAS, it can be added to any food or beverage for any reason at any amount. Nothing could be further from the truth, since an ingredient is determined to be GRAS for 1) a particular food(s) and/or beverage(s); 2) for a specific technical effect; and 3) at a specific use level. Therefore, in order to make a GRAS determination, the qualified experts must know what levels are to be added to what foods and which technical effect(s) are intended for the ingredient's functionality. There are currently 43 food categories (21CFR170.3(n)) and 32 technical effects (21CFR170.3(o)) listed by FDA.

GRAS determination requires that a thorough description of the ingredient's specifications be provided. This includes establishing an adequate physico-chemical identity along with its method of preparation and the ingredient's stability under the conditions of use. Commercial, synthetic products are rarely 100-percent pure, and this is even more rare for natural products. Analysis of the ingredient's purity will be required along with a general description of the ingredient's manufacturing method. Also important is confirmation that the ingredient will not significantly change during manufacture and storage.

A GRAS determination for a compound is essentially a risk assessment; risk is a function of that compound's intrinsic hazard (toxicity) multiplied by the level of exposure to that compound. In the case of a food ingredient, the exposure is the total consumption level. Qualified experts need to use, or have provided, details only available from proprietary and/or subscription-only consumer intake surveys. Only then will they be able to determine the total amount of a specific ingredient that is likely to be consumed by a judicial evaluation of the foods, food categories, and use levels. Successful GRAS determinations have access to and properly utilize these detailed consumption analyses.

Hazard assessment involves knowledge of the ingredient's metabolic fate and the pharmacokinetics of movement into and out of a living organism, along with toxicology data. An understanding of the metabolism and pharmacokinetics allows an estimation of the actual tissue exposure to the ingredient, which of course is the most relevant exposure parameter. In addition, ingredients that are completely metabolized into non-toxic metabolites and rapidly excreted from the body are generally looked upon favorably by those experts making the GRAS determination. The specific toxicology data needed to satisfy that component of an ingredient's hazard assessment depends on the ingredient and its use. In addition, the panel of qualified experts often draws upon toxicologic and metabolic data from other structurally related compounds to corroborate or bolster the data on the ingredient under GRAS review. This comparison of the actual ingredient with other closely related chemicals allows the appropriate use of analogy in determining an ingredient's safety.

Thus, a GRAS determination for a functional food ingredient will be based upon data that is specific to its intended use. While not a requirement for a GRAS determination, FDA will review scientific substantiation of any health claims for an ingredient to be considered functional. There is a tremendous amount of research directed at discovering the active components responsible for the health-promoting effects of many foods. These active components are the functional food ingredients of the future. The GRAS determination mechanism allows a sound and readily accessible method for assuring that these functional ingredients can be added to foods so that their promise of promoting good health can be fully achieved.

J. Craig Rowlands, Ph.D., is a toxicology consultant with the Burdock Group. James C. Griffiths, Ph.D., is director of toxicology at the Burdock Group. The Burdock Group (www.burdockgroup.com) is a consulting firm with on-staff toxicologists who perform toxicology and risk assessments, and efficacy assessments for food and beverage ingredients and dietary supplements.