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Dr. Bigelow


How do you know if your novel ingredient is safe before you commercialize it in your food or dietary supplement product? There exists a process to self-affirm safety without having to wait 6 months for an FDA acknowledgement or wait 6 years for an FDA food additive approval. This process is called GRAS self-affirmation in which the company determines for themselves that the conditions of use of the novel ingredient in food or dietary supplement products is generally recognized as safe, or GRAS. For more than 50 years, many companies and trade groups have used GRAS self-affirmation as a means to expand the repertoire of ingredients used in foods and dietary supplements.

Is your novel ingredient even eligible for GRAS status? If so, from what sources, use levels, subpopulations for which consumption is intended should be considered and address in your GRAS determination? Manufacturers of ingredients typically request an acknowledgement of their GRAS self-affirmation before many food manufacturers will use the ingredient. This practice, however, has not been wide spread in the dietary supplement industry. As the food and dietary supplement industries consolidate, having your products containing novel ingredients on firm safety and regulatory grounds facilitate time-honored practices for sustaining and growing your business.


In the U.S., the Federal Food, Drug, and Cosmetic Act (section 201(s)), as amended in 1958, established a premarket approval process for food additives, and also recognized the existence of other substances generally recognized as safe for their intended use. Food additives are defined as substances, the intended use of which results or may reasonably be expected to result, directly or indirectly, in becoming a component of food or otherwise affecting the characteristics of food. Direct food additives (e.g., xylitol) are intentionally added to food whereas food contact substances (historically called indirect food additives) include substances and components used in food packaging.

Dietary ingredients are used in dietary supplements. Dietary ingredients are defined as a vitamin, mineral, an herb or other botanical, an amino acid, a dietary substance for use by man to supplement the diet by increasing the total dietary intake, and a concentrate, metabolite, constituent, extract, or combination of any ingredient described above (e.g., vitamin, etc.). Amendments made in 1994 mandated that dietary supplements and their ingredients are exempt from the food additive provisions and thus do not need FDA approval for use, yet manufacturers are required to notify the FDA regarding their safe use 75 days before ingredient or product commercialization. It has been proposed that the safety of dietary ingredients be determined through the same process used for determining GRAS status, yet there is no requirement for such.

The 1958 Food Additive Amendments also provided a legal mechanism in which industry could determine the safe use of ingredient with a long history of use in food without formally obtaining FDA approval for use as food additives. This mechanism is the determination, by self-affirmation (or self-determination), that a substance is general recognized as safe, or GRAS, for a particular use, or uses, in food or dietary supplements. Congress grandfathered the use of certain substances as GRAS, known historically to be safely used in food production, and also intentionally excluded this group of substances from premarket approval for food additives because of the history of their safe use. Although crafted as a short clause in the 1958 Food Additive Amendments, virtually all of the GRAS provisions are a regulatory construct promulgated by the FDA. Since the enactment of the Food Additive Amendments, the FDA has listed long-used GRAS substances in the Code of Federal Regulations (CFR). The FDA has affirmed the GRAS use of over 100 substances. Because of the provisions available for manufacturers to self-affirm without FDA involvement, not every substance with GRAS uses is listed in the CFR.

GRAS is further defined in the Act that a substance is generally recognized as safe among experts, who are qualified by scientific training and experience, to evaluate its safety under the conditions of intended use in food. GRAS status by self-affirmation can be determined by two routes: 1) by scientific procedures in which the same quantity and quality of data are required for determining GRAS status as that required for food additive approval, and common use in which substances used in food before 1958 are established as GRAS on the basis of reasoned judgment founded in experience with common food use, whether that experience is based on domestic or foreign consumption of the ingredient. For many ingredients under evaluation, a combination of scientific procedures and common food use routes are used to determine GRAS status. Obviously, the data requirements for determining GRAS status through scientific procedures are greater than those for common use, the former route being used for newly characterized food-borne substances or for a known ingredient derived from a novel source or process used in food or dietary supplements.

GRAS self-affirmation conducted independently of the FDA is legal determinations that allow manufacturers to use novel ingredients and substances not listed in the CFR. In making these independent determinations, the manufacturers assumes the responsibility of using a substance (as they already do for their products), that the data is publicly available to support a position for general recognition of safe use, and has determined that the substance may be safely used in food in a manner proposed by the manufacturer. Thus, one distinction between GRAS substances and food additives is the common knowledge aspect provided for by publicly available evidence for determining GRAS status. Dietary ingredients, too, do not require safety determinations to depend on publicly available evidence.

In practice, manufacturers of food or dietary supplement products may conduct GRAS self-affirmations and hold these determinations in abeyance in their files until challenged by a competitor or requested by the FDA. Manufacturers of ingredients used in food or dietary supplement products, who market ingredients to food and/or dietary supplement producers, can opt to share their GRAS self-affirmation with their customer, or if the customer wants some level of regulatory acceptance and recognition, the FDA established in 1997 a voluntary notification process in which the ingredient manufacturer can notify the FDA of the GRAS self-affirmation, which takes 6-12 months for FDA's acknowledgement of the manufacturer's GRAS self-affirmation. Most food and dietary supplement product manufacturers are satisfied once the FDA publishes their acknowledgement letter for the manufacturer's GRAS self-affirmation.

Eligibility Criteria for GRAS Use of Ingredients

A variety of criteria is used to determine which substances are eligible for GRAS self-affirmations. The FDA established in 1974 a comprehensive set of criteria (called eligibility "groups" of ingredients herein) that encompasses the types and variations of potential food ingredients eligible for GRAS consideration. Substances that are modified by novel processes (i.e., developed post-1958) are eligible for GRAS determinations; the Flavr-Saver® tomato developed through biotechnological processes serves as an example of the eligibility category. Substances, including foods, subject to breeding and selection that may result in an altered nutrient composition or toxicant content are eligible as well. In the 1990's, to raise the methionine content in soybeans, a protein from Brazil nuts was transfected into a variety of soybean. Through the development of the transfected soybean, it was found that the Brazil nut protein provoked allergic responses, and the project was scrapped; the transfected soybean was found not to be GRAS. Substances that are derived from GRAS substances, such as flavors or dietary supplement ingredients that distilled, isolated, extracted, and/or concentrated from botanicals, are eligible for GRAS determination. 'Nature-identical' substances that are synthetic counterparts of GRAS substances are eligible (fructooligosaccharides, for example). The last group of GRAS-eligible substances represents substances of natural biological origin intended for consumption for other than nutrient properties. The gum stabilizers (e.g., guar gum) and dietary fiber ingredients are examples of this group. In all, a wide variety of food-borne substances are potentially eligible for GRAS self-affirmation.

Overview of the GRAS Self-Affirmation Process

The following steps are undertaken to obtain a GRAS self-affirmation for the use of a food or dietary supplement ingredient, be it a newly-characterized food-borne substance or an existing ingredient derived from a novel source or by a novel method. Each substance is evaluated on a case-by-case basis, allowing for read-across for a group of structurally-related substances, taking into account the following variables: source, chemical structure, composition, incremental intake, intake in certain subpopulations, regulatory status from food/dietary supplement or other uses, potential toxicity, tolerance, nutritional effects; and the quantity and quality of the safety database of the substance under evaluation.

The GRAS self-affirmation maintains the highest level of objectivity when the process is conducted independently of the manufacturer, as follows. The manufacturer selects an outside firm to handle the GRAS self-affirmation process. The criteria that should be used to select an outside firm includes expected values of work performed, recognition by and experience in dealing with regulatory agencies, the ability to maintain confidentiality of the manufacturer's work (and not to share new-found knowledge and experience with the manufacturer's competitors), the "skill set" of the outside firm's staff to assemble the necessary documentation for the expert panels, ability to select an appropriate panel of experts with the expertise in the appropriate disciplines to resolve the particular safety issues involved in the self-affirmation of GRAS status, ability to assemble the panel quickly, as well as other factors. The manufacturer furnishes the outside firm with background technical information, and the firm drafts the GRAS dossier, and finalizes it after review and comment from the manufacturer regarding technical accuracy. The GRAS dossier contains information including the composition, identity, intended use(s), anticipated consumption, and safety and tolerance data for the substance undergoing evaluation. During drafting the GRAS dossier, most of the issues become apparent.

To further maintain independence from the manufacturer, the outside firm also selects the experts who serve on the GRAS panel who determines whether the use of the substance is indeed GRAS, based on common use or scientific procedures, or a combination of the two routes. The expert panelists should possess the scientific training and experience necessary to self-affirm the GRAS status for the specific use(s) of the substance under evaluation. The size of the panel, as a whole, should be adequate in number to contain the full complement of experts whose collective expertise represent the scientific disciplines (e.g., toxicology, clinical practice, chemistry, biochemistry, microbiology, etc.) needed to identify, elaborate, discuss, characterize, and resolve by consensus all anticipated issues and concerns related to determining the safe use of the substance. The "skill set" of the panel can be viewed as an array of overlapping expertise of scientific disciplines capable of dealing with the anticipated scientific issues.

It must be determined that before an expert is chosen for GRAS panel membership, that they are free of conflict of interest, be it financial, personal, or professional, actual or perceived for or against the manufacturer or its competitors. Bias is different, and is acceptable if it is based on scientific issues alone, as it is universally understood that expertise cannot be gained without developing some sort of intuitive bias and inclination, which can be based on experience. The GRAS panel should contain, as a whole, a balance of bias on the full gamut of issues related to the GRAS determination, and is composed in a manner that minimizes the likelihood of predilections and skewed judgment. Accordingly, subjective variability of the panelists, such as personal leanings not based on scientific data or "going with the conventional wisdom," should be avoided. These considerations are necessary to ensure scientific integrity that can objectively self-affirm GRAS status independent of the manufacturer.

The outside firm sends a copy of the draft GRAS dossier to each panelist in sufficient time before the panel convenes so that each panelist has enough time to adequately review the dossier for its content, identify issues and questions, and to become thoroughly conversant in the technical details regarding the proposed use of the substance. To abrogate the chance for undue influence or any perception of conflict, the panel convenes at a neutral site, such as the offices of the outside firm, or by teleconference or by videoconference, but not at the offices of the manufacturer or other interested parties, to determine whether the proposed use(s) of the substance are GRAS. The panelists review the data (see Appendices I and II), express their respective concerns, deliberates the issues, attempts to minimize bias in either direction, resolves the issues, and as a group, collectively uses reasoned judgment, based on the weight of the evidence, to arrive at a conclusion that the specific use(s) of the substance is GRAS in food or dietary supplements. It is also important that the panel should elaborate in writing on areas of uncertainty and their impact on the panel's conclusions regarding safe use. The outside firm prepares a statement of the conclusions that embodies the issues and concern deliberated and resolved during the expert panel meeting and this statement forms the basis of the GRAS self-affirmation. The panel may sign the conclusion statement if it is prepared at the end of the expert panel meeting, or if revisions need to be made to the statement and/or the dossier, or at the panel's request, the panelists may sign the conclusion statement individually at a later date.

Once the signed conclusion statement and the dossier are finalized, the scientific stage of the GRAS self-affirmation is complete, and the regulatory determination of GRAS proceeds. Regulatory acceptance of a GRAS self-affirmation depends on whether the information, upon which the GRAS self-affirmation is based, is published in the open literature. Publication of this information allows the scientific community to generally recognize that the use of the ingredient is safe, based on the available evidence. Unpublished information can serve as a basis for independent GRAS self-affirmation, but usually is published shortly after the GRAS determination has been conducted. Other factors for regulatory acceptance of the scientific determination include the composition of the expert panel, resident expertise to handle and resolve scientific issues, appropriate expertise to anticipate safety issues resulting from the intended use(s) of the substance, confirmation of the absence of conflict of interest, and the presence of a proper balance of bias in the panel as a whole.

Once the scientific and regulatory aspects of the GRAS self-affirmation have been established, the substance may be commercialized, based on the conclusion reached by the expert panel, either to consumers or to other manufacturers. The steps for conducting a self-affirmation of GRAS status for the use of ingredients in food or dietary supplement products have been elaborated herein. The ultimate goal of the GRAS self-affirmation process is to obtain regulatory acceptance of the safe and suitable use of the ingredient in food and dietary supplement products.


Scientific Criteria Used in Safety Evaluations

A review of the scientific criteria used in safety evaluations is elaborated herein to show the considerations used by the expert panelists to determine the GRAS status for the use of a substance in food or dietary supplement products. Because each substance under evaluation will differ as to its properties and use(s), the weight afforded to each scientific criterion will differ on a case-by-case basis. The discussion of the scientific criteria herein is cursory, and is provided to give an overview of the safety evaluation process.

Obviously, the specific use of the substance under evaluation is the first scientific issue at hand. Each use is distinct and separate, even if the substance has been GRAS affirmed by the FDA for another use. Likewise, substances that have been GRAS for a particular use are not automatically GRAS for another use in food or dietary supplement products. Moreover, mixing or combining two GRAS substances for a new use may not be GRAS (e.g., the use of certain stabilizers and calcium salts leading to precipitated calcium in the product). Each new use must be GRAS affirmed.

Several criteria dictate the extent of the safety data required to determine the safe use of novel ingredients, be they newly-characterized food-borne substances or existing ingredients derived from new sources or processes. One criterion, the composition of the mixtures or the chemical structure of the major constituent(s), once known, can often provide predictive information regarding the toxicity potential of the substance. Other chemically-related substances, with similar composition or structure of known toxicity potential and/or metabolic disposition, are often used as surrogate data to read across and predict the toxicity potential of the substance under evaluation. This practice has been used by the Flavor and Extracts Manufacturers' Association's GRAS Expert Panel since the 1960's to predict the safety for use of flavoring substances (historically, regulatory acceptance of this practice is also premised on the low use levels of flavorings in food and their low incremental intake).

Incremental intake is another criterion used to evaluated safety related to GRAS self-affirmation, and is defined as the expanded level of intake of adding the substance to the food supply versus its existing level of intake from its inherent presence in food. If incremental intake is 2-3 fold higher than existing intakes, the concern level is not raised significantly because many individuals consume 2-3 times the daily intake of the food(s) which contain the substance without noted adverse effects. This premise is consistent is also consistent with the common use route for determining GRAS status based on the history of safe use.

The source of the substance is another safety criterion: a substance derived from a food that is a major component of the diet would present a lower concern that a new substance derived from a non-food source, assuming all other scientific criteria (e.g., intake) are equivalent. Considerations of the manufacturing process are important because of the potential introduction of unwanted and potentially deleterious constituents. For example, reported changes in the purification process appeared to have rendered certain tryptophan products used as dietary supplements unsuitable for human use. Thus, when significant changes are made to the manufacturing process for an existing ingredient that results in a new analytical profile for the substance, a full compositional analysis and animal testing should be conducted to confirm safety. Accordingly, for new substances without an established manufacturing process, animal testing is typically conducted with combined lots from material manufactured in the pilot plant. Once adequate testing has been completed, identity and purity specifications are established for the substance based on the material tested for safety in animals.

The amount of safety data required for a GRAS self-affirmation typically involves some animal data, information on the metabolic fate of the substance in animals (and preferably in humans), and some human toleration data. Metabolic fate test results in animals, if similar to human test results, are often used to validate the human toleration data as predictive for safe use in food and dietary supplement products. In general, a higher level of use in food and dietary supplements predicates higher testing levels (doses) in animals, yet on a practical basis upper doses are limited to a maximum level in the diet (typically around 5% of chow), above which the interpretation of the animal test results is compromised by irrelevant physiological effects in the animals (e.g., causing response that are secondary to nutritional imbalances). A description of toxicology and metabolic fate tests follow this discussion.

It is important to emphasize that the amount of safety data required for a particular use of a substance is made on a case-by-case basis by the appropriate experts. Judgment of the extent of the database to support a safety determination takes into account the composition, the history of safe use, the incremental intake and the source of the substance, the nutritional impact of the use of the substance, the intake in certain subpopulations, the manufacturing process involved, the identity and purity specifications of the substance intended for human consumption, and the conditions of intended use of the substance.


Studies Used in Safety Evaluations

Metabolism. Metabolism studies are conducted to assess the fate of the substance, including absorption for the GI lumen into the body, distribution in body compartments, storage, accumulation potential, its conversion into metabolites, and its excretion from the body.

Toxicology Studies (in test animals unless otherwise specified)

Acute Toxicity. Single exposure in animals can provide early indicators of effects observed in studies using longer exposure of the test substance, but are often not used because of the short exposure duration relative to the intended duration of use. Assessing acute tolerance of food and dietary supplement ingredients for binge eating scenarios provide information needed to evaluate the safety of certain use/abuse scenarios.

Feeding. Animals are fed the substance for varying durations of exposure, and are the preferred route of administration because it mimics the intended use of the substance. Range finding studies, typically of 1 or 2 weeks in duration, are conducted to adjust the dose for subchronic feeding studies. Subchronic feeding studies, typically 1 to 3 months in duration, are conducted to assess the effect of the substance on growth and on individual organs and tissues. Chronic or lifetime feeding studies, as the name implies, last the lifespan of the animal, and are conducted to assess effects on growth, individual organs and tissues, carcinogenic potential, and survival (longevity).

Mutagenicity. Single exposure of the substance in a battery of mammalian or bacterial cells is used to assess the potential for causing mutations in the DNA, and the clastogenicity (i.e., chromosomal rearrangements) in whole animals.

Teratology. The substance is given to pregnant rats and/or rabbits during the gestational period to assess the potential for the substance to cause birth defects.

Reproductive Toxicity. The substance is given to the test animal during gametogenesis (i.e., the period of time when sperm and oocytes are formed), gestation, and throughout the lifespan of the two succeeding generations to assess the potential to cause reduced conception, litter size, fertility, etc.

Neurobehavioral Toxicity/Immunotoxicity. The substance is fed to the test animal, in varying durations of exposure, to assess changes in neurobehavioral and immunological endpoints. Relevancy of many of the animal endpoints to human risk is somewhat tenuous, especially for immunotoxicity studies.

Allergenicity. The substance is given to test animals to assess the allergenicity potential of the substance. However, in general, animal models for allergenic response via the oral route of administration are largely irrelevant to human allergenicity potential. In vitro tests of the substances against sera from persons of known related allergies are currently the best method to assess human risk.

Clinical Studies. The test substance is given repeatedly to human volunteers, in varying durations of exposure or doses, to assess their tolerance, clinical chemistry, excreta, etc., and to derive data for any intended marketing claims related to the nutritional and other beneficial physiological effects of the substance.

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Dr. Sandy Bigelow, Ph.D., is a Board Certified Toxicologist and a Research & Development Professional with over 20 years of experience in leading global technology responsibilities in the food, nutrition, personal care, and medical device industries. He has a proven ability to craft product opportunities based on the safety and efficacy of novel proprietary, bioactive ingredients used in food, nutritionals, personal care, medical device, and pharmaceutical products.

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