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What does GRAS mean to you? If you are involved in the food industry, GRAS refers to the phrase, “generally recognized as safe,” that is part of the Food Additives Amendment of 1958. That law requires the U.S. Food and Drug Administration (FDA; Rockville, MD) to ensure that all food additives are safe. If you are a food manufacturer using GRAS-affirmed substances, it means that you can rest easy, because the ingredients you are putting into your products are safe for their intended use. It doesn’t mean that the final product will taste better, look more appealing, or be more nutritious. And it doesn’t mean you can do anything you want with a GRAS ingredient. For example, something that was GRAS affirmed as a bulking agent in baked goods cannot be assumed to be GRAS when used as a binder in a dietary supplement. To get a better idea of what GRAS really means for you, let’s step back a little bit and describe the GRAS review process.
Congress recognized that many substances added to foods may not need a formal premarket review by FDA to assure their safety, especially those substances in common use prior to 1958 and those that would be generally recognized as safe. Originally, FDA published a list of those substances, the GRAS list. FDA made no attempt to validate the safety of the GRAS list substances until 1969, when President Richard Nixon directed FDA to critically evaluate the evidence of their safety. FDA turned to the Life Sciences Research Office (LSRO; Bethesda, MD) to conduct the scientific assessment of more than 400 substances. Those LSRO reviews are contained in over 150 reports available from LSRO or the FDA Web site. Manufacturers that desired to use an ingredient not on the GRAS list could petition to affirm the GRAS status. Because many companies chose to do that, in 1997 FDA proposed new rules to get out of the GRAS-affirmation business. The process proposed in 1997 would have eliminated the FDA GRAS affirmation process and replaced it with two alternatives, GRAS self-affirmation and GRAS notification. Though this rule was never finalized, you would never know the difference. Over the past 10 years, FDA has been responding to about 25 GRAS notifications per year. No one knows how many GRAS self-affirmations there have been, but most experts estimate that the self-affirmations vastly outnumber the notifications. To understand why, we need to elaborate on the different processes.
Self-affirmation doesn’t mean the manufacturer or supplier can wave a wand over the product and affirm “it seems safe to me.” Self-affirmation is intended to replace the rigorous FDA affirmation review and is a process best left in the hands of experts. In fact, the Food Additives Amendment requires that the review be conducted by experts qualified by scientific training and experience to evaluate the safety of the ingredient. The qualified experts will review the available scientific evidence. This evidence includes a full characterization of the physical and chemical properties of the substance, description of the composition of the product and any processing residues or impurities (including certificates of analysis), product specifications, analyses of multiple lots, and a well-defined production process. All source materials must be well characterized.
The GRAS review is not a general affirmation of safety; it is a review of a specific substance for a specific use or uses. These uses must be identified from a list of 32 technical effects and 43 food categories listed in the regulation. The intended level of use must also be specified.
In addition to all of the above, the expert panel must review the totality of the relevant published literature, both positive and negative findings, that pertain to the safety of the substance in question and related substances. Safety data can include testing on cells and animals and human studies, evidence of history of use, and adverse-event reports. This information must be published because of the requirement to be generally recognized. The expert panel reviewing the information will be affirming that other qualified experts will also recognize the substance as safe for its intended use, and that recognition will not be possible if those other experts cannot readily obtain the information.
The expert panel will also be reviewing information about the natural occurrence and previous history of use (if any) and the intake of the substance from natural sources or already approved uses to determine how much of the substance is being consumed by the public. Safety is a relative term; too much of almost anything can be toxic. The experts will want to know that the intended use of the substance in addition to consumption from all other sources will not exceed a safe level.
All of the information is usually compiled into an information package (dossier) for review by the expert panel. There is a lot of information to be considered by the expert panel, and compiling it is not for the faint of heart or for the amateur. Many pitfalls abound. The process will go more smoothly and more quickly if you engage an organization or individual with experience in GRAS reviews.
Even with the advice and guidance of experienced facilitators in preparing a complete dossier, the expert panel may still require additional information before they will sign off on it. Prior to including the additional required information in the dossier for re-review by the expert panel, those studies have to be designed, conducted, written up, and published, a process that can take two years or more. This process is conducted confidentially, so no one need know about the decision to undertake this additional work or to abandon the process, even if the expert panel had some reservations prior to a successful completion.
The final evaluation is summarized in a GRAS monograph. This monograph, signed by all members of the expert panel, should include the unanimous conclusion of the expert panel that the substance is both safe and generally recognized as safe for its intended use. That is a GRAS self-affirmation. The manufacturer can stop right here and market the product. FDA need not ever know that the GRAS self-affirmation process was undertaken, yet the public can be assured that their food supply is safe. Most manufacturers and ingredient suppliers do stop at this point and go further only if their customers require GRAS notification.
If one or more key customers will not accept your product without an FDA review, then you may consider voluntarily submitting the GRAS review monograph to FDA for review. This process is called GRAS notification, and you are the notifier. Since 1997, FDA will not affirm any substance as GRAS; rather, FDA will review the notifier’s GRAS monograph and respond either (a) that FDA has no questions about the notifier’s conclusion of GRAS status (a so-called ‘no objection’ letter), or (b) the notice does not provide a basis for a conclusion of GRAS status, or (c) at the notifier’s request, cease to evaluate the notice without prejudice.
In contrast to self-affirmation, GRAS notification is a public process; the GRAS monograph and all correspondence, including the FDA final response, are posted and available for viewing on the FDA Web site. Proprietary information and trade secrets may be redacted, but FDA’s response is out there for the world to see (for better or for worse, as the case may be). FDA staff can be very helpful and can be consulted at any time prior to or during the notification process. Getting an FDA pre-read may help avoid an embarrassing outcome.
Whether a self-affirmation or a notification, all the information and the resultant monograph should be cataloged and filed in a secure place. If there is ever a problem, it must be accessible for the day FDA comes calling. Moreover, the evaluation of safety is your continuing responsibility. New information is produced daily providing a constantly evolving understanding of our world. If any of this new information casts doubt on the conclusions in the GRAS monograph, the totality of the evidence should be re-evaluated. Thus, it is a good idea to periodically update the information package.
Using GRAS ingredients is a part of good manufacturing practices (GMPs) and responsible product stewardship. Reputable manufacturers will insist on validating the GRAS status of the substances they put into their products and that it matches their intended use.
One point of confusion merits further discussion. All of the above refers to foods, not to dietary supplements. Though the required information may be very much the same, the regulatory process is significantly different. New dietary ingredients must be approved by FDA prior to marketing. GRAS self-affirmation or GRAS notification will not replace new dietary ingredient approval. Neither does FDA approval as a new dietary ingredient confer GRAS approval; remember, FDA no longer affirms GRAS status. However, a discussion of new dietary ingredients is a topic for another day.
Michael Falk, PhD, is the executive director of the Life Sciences Research Office (LSRO; Bethesda, MD) and secretary of the board of directors. He has held those positions since joining the organization in 1998. For more information about LSRO, visit its Web site at www.lsro.org.