FDA Generally Recognized As Safe (GRAS) 101

Generally recognized as safe (GRAS) (1) is the U.S. Food and Drug Administration (FDA) designation that a chemical or substance added to food is considered safe.

What Is GRAS?

Under sections 201(s) and 409 of the Federal Food, Drug, and Cosmetic Act (FFDCA) (2), any substance that is intentionally added to food is a food additive, that is subject to premarket review and approval by FDA, unless the substance is generally recognized, among qualified experts, as having been adequately shown to be safe under the conditions of its intended use, or unless the use of the substance is otherwise excepted from the definition of a food additive.

Furthermore, under this Act, and FDA's implementing regulations in Title 21 Code of Federal Regulations (CFR) 170.3 and 21 CFR 170.30, the use of a food substance may be GRAS either through scientific procedures or, for a substance used in food before 1958, through experience based on common use in food under 21 CFR 170.30(b), general recognition of safety through scientific procedures requires the same quantity and quality of scientific evidence as is required to obtain approval of the substance as a food additive. General recognition of safety through scientific procedures is based upon the application of generally available and accepted scientific data, information, or methods, which ordinarily are published, as well as the application of scientific principles, and may be corroborated by the application of unpublished scientific data, information, or methods.

Under 21 CFR 170.30(c) and 170.3(f), general recognition of safety through experience based on common use in foods requires a substantial history of consumption for food use by a significant number of consumers.(1)

History of GRAS

On January 1, 1958, the FDA established the Food Additives Amendment of 1958. Under the Amendment to the Federal Food, Drug, and Cosmetic Act, any substance intentionally added to food is a food additive and is subject to pre-market approval by FDA unless the use of the substance is generally recognized as safe (GRAS) (or otherwise excepted from the definition of food additive – e.g., color additive).     

On August 31, 1960, assistant general council of the FDA, William W. Goodrich addressed the annual meeting of the FFDCA, which was the forthcoming March 6, 1961, effective date of the enforcement provisions of the "Food Additives Amendment of 1958", referred to as GRAS. (3)

By 1961, the FDA had amended its regulations to include a list of 700 food substances that were exempt from the then-new requirement before putting them on the market. (3) During the 1960s, many manufacturers requested FDA’s opinion on whether their conclusions of GRAS status were justified and received opinion letters. In 1969, FDA removed one substance, cyclamate salts from its GRAS list as a result of safety questions, and then-President Nixon directed the FDA to reexamine the safety of GRAS substances. In the 1970s, FDA announced that it was conducting a comprehensive review of presumed GRAS substances and established rulemaking procedures to affirm the GRAS status of substances that were either on the GRAS list or the subject of a petition (GRAS affirmation). To eliminate the resource-intensive rulemaking procedures, in 1997, FDA proposed to replace the GRAS affirmation petition process with a notification procedure (GRAS notification). Several iterations of the GRAS rule have been created over the years with the most recent occurring in 2010 as part of the greater updated CFR guidelines released by the FDA. (2)

FDA GRAS Rules

On April 17, 1997, the FDA published the proposed GRAS rule in the Federal Register. (4) Ingredients to be added to foods in the US require GRAS status or approval from FDA as a food additive. It is important to understand that it is the intended use of an ingredient that is GRAS, not the ingredient itself. Subjects that need to be addressed include but are not limited to toxicology, microbiology, chemical stability, metabolism processes by the body, etc. This proposed rule was finalized in August of 2016, allowing for an Independent GRAS Conclusion process, while leaving the FDA GRAS Notification process as voluntary.

Recognition of a substance as safe requires reasonable certainty in the minds of competent scientists that the substance is not harmful when used as intended. GRAS self-affirmation requires a complete review and assessment of the safety of the ingredient. The process of achieving GRAS self-affirmation requires a consensus of safety by a panel of experts who are qualified by training and expertise to evaluate the safety of food. (5)

FDA Guidance for GRAS

When a conclusion of GRAS status is through scientific procedures, general recognition of safety is based upon the application of generally available and accepted scientific data, information, or methods, which ordinarily are published, as well as the application of scientific principles, and may be corroborated by the application of unpublished scientific data, information, or methods. Such methods should be well defined and accepted as best practice protocols so as to not obscure the data. For example, there could be no basis for a conclusion of GRAS status if trade secret information, or other non-public information, is required for qualified experts to reach a conclusion that the notified substance is safe under the conditions of its intended use. It is therefore recommended that the company or individual submitting the request minimize the amount of non-public information provided to a GRAS panel. An exception relates to data and information that could raise a question about the safety of the substance under the conditions of its intended use. It is recommended that the data and information that the proponent or organizer provides to a GRAS panel include a description of all data and information that could raise such a safety question, regardless of whether those data and information are publicly available. Doing so is appropriate to make the data and information provided to the GRAS panel complete, representative, and balanced and would be consistent with the requirements as have been established for a GRAS notice. (6) Thus, having increased reliability of the results of the GRAS submission will make a finding more efficient and likely for the FDA.

Failure to Qualify

When a use of a substance does not qualify for the FDA GRAS exemption, that use of the substance is subject to the premarket approval mandated by the FFDCA. In such circumstances, the FDA can take enforcement action to stop distribution of the food ingredient and foods containing it on the grounds that such foods are or contain an unlawful food additive. (7)

GRAS Designation

In short, the GRAS designation typically exists in one of the three forms described below:

1. Self-affirmed. The manufacturer of this chemical or substance had performed all necessary research, including the formation of an expert panel to review safety concerns, and is prepared to use these findings to defend its product's GRAS status;

2. FDA-pending. The manufacturer has performed all the aforementioned due diligence and submitted to the FDA for GRAS approval;

3. No comment. The FDA has reviewed a product's GRAS claim and responded with "no comment”, i.e., no further challenges on the product's GRAS status.

References

1. FDA. (2019). “Generally Recognized as Safe (GRAS)”. Food and Drug Administration. https://www.fda.gov/food/food-ingredients-packaging/generally-recognized-safe-gras

2. NPA. (2020). “Generally Recognized As Safe (GRAS)”. Natural Product Association. https://www.npanational.org/regulatory/food-and-drug-administration-fda/generally-recognized-safe-gras/

3. heinonline.org. 2010-11-27. "Address to the FFDCA concerning GRAS".

4. https://www.federalregister.gov/documents/2016/08/17/2016-19164/substances-generally-recognized-as-safe

5.  AIMBR. (2020). “GRAS” https://aibmr.com/natural-products-industry-compliance-consultation/gras-self-determination-gras-independent-conclusions-generally-recognized-as-safe-safety-studies/

6.  FDA “Best Practices for Convening a GRAS Panel: Guidance for Industry”. (2017) https://www.fda.gov/regulatory-information/search-fda-guidance-documents/draft-guidance-industry-best-practices-convening-gras-panel

7.  https://www.regulations.gov/document?D=FDA-2012-N-0021-0007

About the Author:

Lin Zhang, M.D., senior director of a health care industry company in the United States. With the experience in clinical medicine, biotechnology, health industry and other fields, he is responsible for the research and development of plant medicine, functional food and health products. He was a clinician and worked for the National Cancer Institute, FDA and the National Cancer Center of Japan for many years. 

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