The GRAS Process: Does it Need an Overhaul?
The following is an adaptation of a recent article published by the Food and Drug Law Institute (FDLI) in their June 2012 newsletter.
Recent statements made by the American Heart Association (AHA) and the U.S. General Accountability Office (GAO) have been critical of the Generally Recognized as Safe (GRAS) process for determining the safety of food ingredients. The overall concern stated by these organizations is that there is a lack of transparency to the process of the GRAS determinations for food ingredients, and to a lesser extent, an implied conflict of interest and a lack of accountability among those commissioned to determine the safety of a substance and, further, that U.S. Food and Drug Administration (FDA) review is necessary to confirm the safety of food ingredients. A general discussion of GRAS and the GRAS process is necessary to dispel the misconceptions which form the basis of the some of these complaints. The FDA has defined GRAS by a comparison to a food additive:
“GRAS” is an acronym for the phrase Generally Recognized as Safe. Under sections 201(s) and 409 of the Federal Food, Drug, and Cosmetic Act (the Act), 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 excluded from the definition of a food additive.[1]
The GRAS process is a science-driven procedure to evaluate the safety-in-use of a substance to be added to food products at levels sufficient to provide the intended use. The scientific information must have been made publicly available to meet the common knowledge aspect of the safety of the ingredient. In addition, there must be both general availability of the ingredient safety information, as well as general acceptance of the safety of the ingredient by experts in the scientific community, who are knowledgeable in determining the safety of food ingredients.
In this this knowledge-driven age, consumers are paying closer attention to the foods they eat, and are searching for answers about the positive attributes of food they eat (e.g., extra-nutritional benefits), as well as any potential downside to the food (e.g., saturated fats). Parallel to this movement of consumer awareness is an agenda-driven cadre of interest groups who feel the integrity of the 50+ year old system for determining safety has broken down and increased oversight of food ingredients by FDA is needed. However, the interest in the safety of food ingredients is not much different from the concerns decades ago. Public concern over increasing use of chemicals in foods and food processing was part of the initiative for Congress in 1958 to enact the Food Additives Amendment as part of the Food, Drug and Cosmetics Act (the Act) of 1938. The core of the 1958 amendment was to require that, before a new ingredient could be used in food, the safety of the ingredient must be demonstrated. Congress established a science-based safety standard that required producers of food ingredients to demonstrate “to a reasonable certainty” that no harm will result from the intended use of an ingredient. Critical to this discussion, the 1958 amendment defined the terms “food additive” and “unsafe food additive”, and incorporated the concept of a “generally recognized as safe” (GRAS) substance, as stated above.
Exempted from the definition of a “food additive” are those substances that are generally recognized, among experts qualified by scientific training and experience to evaluate their safety (“qualified experts”), as having been adequately shown through scientific procedures (or, in the case of a substance used in food prior to January 1, 1958, through either scientific procedures or through experience based on common use in food) to be safe under the conditions of their intended use. The exemption from the necessity of submitting a food additive petition to FDA for every food ingredient underscores the fact that Congress in 1958 recognized that FDA was not the sole entity able to determine the safety of food ingredients. A GRAS substance must be shown to be “generally recognized” as safe under the conditions of intended use, with the proponent of the GRAS exemption having the burden to prove that the use of the substance is “generally recognized”, by showing that there is a consensus of expert opinion (although unanimity among experts is not required) regarding the safety of the use of the substance as intended. The safety standard for GRAS food ingredients is the same as for food additives (i.e., reasonable certainty of no harm).
The AHA recently called into question the GRAS process, questioning the very basics of GRAS, on the basis that the current process allows food manufacturers to make their own GRAS determinations, not providing enough transparency or oversight by the FDA in the process. The AHA has stated in a letter to the U.S. Department of Agriculture’s Food Safety & Inspection Service (FSIS) that the AHA is concerned that “the FDA cannot ensure the sufficiency of all new GRAS determinations because it only reviews the ones that are sent to it,” implying that FDA is only able to review and evaluate food ingredients for which a notification has been submitted. The AHA also stated in the letter that “the current process relinquishes too much of the Agency’s authority to food manufacturers and does not do enough to ensure the safety of substances that are added to foods.”(statement within letter), suggesting that FDA’s oversight process does not help ensure the safety of all GRAS substances.
The submission by AHA follows a report released by the GAO entitled FDA should strengthen its oversight of food ingredients determined to be generally recognized as safe (GRAS). In this report, the GAO concluded that FDA may be limited in detecting potentially harmful substances being added to food under the GRAS process because FDA lacks information about the substances companies have determined GRAS, but have not notified to FDA as having GRAS status. This statement suggests that substances are being added to the U.S. diet for which there is no scientific evidence that the substances are safe, or that the data upon which to evaluate the safety of a GRAS substance is not publicly available.
FDA currently has sufficient authority to evaluate the safety of food ingredients (whether notified to FDA or not) and take the necessary course of action to maintain the safety of food and food ingredients, as indicated by the three principles discussed below.
Issue #1 – FDA is only able to review and evaluate food ingredients for which a notification has been submitted
Response: FDA has the ability to review and evaluate any food ingredients utilized in the United States food supply. The evaluation of food ingredients by the FDA is a continual, on-going process that is not limited only to those substances that are submitted to FDA. The FDA maintains a process by which marketed food product labels are evaluated and, if warranted, additional information is requested or FDA issues a letter outlining the reasoning by which FDA believes that an ingredient contained in food is not in compliance with current regulations (including GRAS status). This action by FDA is exemplified by a number of warning letters sent by FDA to various food manufacturers through the past 16 years and posted on the FDA website: http://www.fda.gov/ICECI/EnforcementActions/WarningLetters/default.htm. Warning letters issued to companies in which the GRAS status of ingredients has come into question indicates that FDA has, at any time, the ability to review food ingredients and to request additional information on the scientific basis used to substantiate use in food (e.g., GRAS, food additive, or food contact substance), or to request the removal of an ingredient if adequate documentation is not provided to satisfy FDA that GRAS status has been achieved.
Issue #2 – Substances are being added to the U.S. diet for which there is no scientific evidence that the substances are safe.
Response: The scientific evidence utilized to substantiate the safety of substances that have been determined GRAS for their intended use must meet the “generally recognized” standard. The Federal Food Drug and Cosmetic Act (Section 201(s)), and additional comments provided by FDA describe the general principles for evaluating the safety of food additives, and define the eligibility for classification of food ingredients as generally recognized as safe (GRAS). According to FDA comments, “general recognition of safety may be based only on the views of experts qualified by scientific training and experience to evaluate the safety of substances directly or indirectly added to food.” FDA has also commented that “general recognition of safety through scientific procedures shall ordinarily be based upon published studies which may be corroborated by unpublished studies and other data and information.” FDA issued a proposed rule to the GRAS process in 1997, in which FDA has indicated that the descriptor “which ordinarily are published” suggests that the usual process to meet the “generally recognized” standard is to show that the information is published in a peer-reviewed scientific journal, satisfying the common knowledge element. Historically, the basis for concluding that there is expert consensus (the second facet of the “generally recognized” standard) has included publication in secondary sources, convening an expert panel, or relying on an opinion or recommendation of an authoritative body.
Issue #3 – FDA’s oversight process does not help ensure the safety of all GRAS substances.
Response: FDA has the tools in order to ensure the safety of GRAS substances. FDA is responsible for protecting the public health by assuring that foods are safe, wholesome, sanitary and properly labeled (http://www.fda.gov/AboutFDA/Transparency/Basics/ucm194877.htm). The GRAS process has been in place for over 50 years, and during that process FDA has utilized several methods to provide guidance and oversight to the industry concerning the evaluation of substances as GRAS according to scientific procedures. First, FDA issues Warning Letters regarding food ingredients that FDA believes do not meet the GRAS standard. FDA at any time has the ability to contact a food manufacturer to request information to substantiate the GRAS status of a food ingredient. Second, FDA regularly issues and updates guidance documents that discuss the elements of the GRAS process, to provide additional information to help the food industry better understand FDA’s thoughts on various components of the GRAS process. In 1982, FDA published the “Redbook” (aka Toxicological Principles for the Safety Assessment of Direct Food Additives and Color Additives Used in Food) to describe the types of data, criteria to evaluate the need for additional scientific studies, and minimum acceptable protocols for typical toxicological studies utilized to evaluate the safety of food ingredients. In 2000, FDA altered the name to Toxicological Principles for the Safety Assessment of Food Ingredients, and in so doing confirming that the guidance applies to the broad range of substances added to food, and not only food or color additives. Along with international guidelines developed by international organizations, such as the Organization for Economic Co-Operation and Development (OECD) for the evaluation of the safety of food ingredients, the FDA Redbook provides a framework for the evaluation of substances that are added to food. In this way, FDA (by way of the Redbook guidance document) provides critical information to industry on the development of safety information for a food ingredient, whether determined by industry as a GRAS substance, or submitted to FDA under a food additive petition. Third, as a part of the 1997 proposed rule for the GRAS process, FDA implemented a voluntary process by which companies may notify FDA that the company has determined that a substance is GRAS under the intended conditions of use. FDA may either agree with the company’s determination of GRAS status and provide a response that FDA “does not object” to the determination of GRAS status at this time, or that FDA finds that the notice does not provide a basis for a GRAS determination. FDA publishes the notification and the response letter provided by FDA on the FDA website for public view. Since the notification procedure was implemented in 1997, FDA has received 428 notifications (as of May, 2012) that FDA found acceptable for filing for their evaluation of the GRAS status of food ingredients under the intended conditions of use. FDA has stressed that if, after issuing a 90-day response letter, questions develop for the agency regarding the GRAS status of a use of a substance, FDA may subsequently advise the notifier, which could ultimately result in FDA stating that the use of a substance is not GRAS, but is a food additive subject to section 409 of the Act. Conversely, the receipt of a letter from FDA stating that a notification of a company’s determination of the GRAS status of an ingredient does not mean that the ingredient cannot be marketed, only that the FDA does not agree with the company on the GRAS status of the ingredient. However, as stated above, FDA may, at a later date, request that products that contain the ingredient be removed from the market. Taken together, FDA’s review of ingredients already on the market, the release of guidance documents that describe the elements necessary to determine the safety of food ingredients, and a voluntary notification process, help to ensure that the substances determined GRAS are safe under the intended conditions of use.
The suggestions by the AHA and GAO to require all GRAS determinations to be notified to FDA would have a significant impact on current FDA resources, as it would require a significant increase in the FDA budget to evaluate every GRAS determination and provide an appropriate response to each notification. The Flavor and Extract Manufacturing Association (FEMA) alone reviewed 61 new GRAS flavoring substances in 2011 that were not submitted through the FDA notification process. The current voluntary process has not resulted in a plethora of FDA-initiated food recalls specifically due to the lack of safety of a food ingredient, and therefore does not require mandatory notification of all GRAS substances.
In summary, the determination that a substance is “generally recognized as safe” under the conditions of its intended use, has been a part of the food regulatory arena for over 50 years. FDA has the regulatory authority to request that the scientific evidence utilized to substantiate the GRAS status of an ingredient be submitted to FDA for evaluation, and has utilized this authority to request the removal of ingredients from food products. The scientific evidence utilized to determine that a substance is “generally recognized as safe” must meet both the standard of “general availability” and of “general acceptance” by the scientific community of experts knowledgeable in food safety. The “general availability” standard is usually met through publishing the safety studies critical to determining the safety of the substance in peer-reviewed scientific journals, while the “general acceptance” criteria is met through the convening of expert panels, evaluation of the substance by authoritative bodies, or discussions in secondary publications. Finally, FDA has the tools, through direct action on food products in the market or by providing guidance documents outlining defining essential components that should be evaluated during the GRAS process, to ensure the safety of food in the US. The current process to review the safety of food ingredients has been sufficient to maintain the safety of food ingredients for U.S. consumers.
References
[1] http://www.fda.gov/Food/FoodIngredientsPackaging/GenerallyRecognizedasSafeGRAS/default.htm; site last visited July 19, 2012.