GRAS is an acronym for Generally Recognized as Safe. GRAS status is a regulatory designation first introduced by the U.S. Food and Drug Administration (FDA) as part of the 1985 Food Additives Amendment to the Federal Food, Drug and Cosmetic Act (FD&C Act). Its purpose was to exempt certain food ingredients from the definition of food additive.
Companies typically choose the GRAS determination pathway for a substance if they feel there is substantial consensus, outside the FDA, “among experts qualified by scientific training and experience to evaluate” and determine “their safety as having been adequately shown through scientific procedures . . . to be safe under the conditions of their intended use (21 U.S.C. § 321(s).”
In today’s post we highlight five important facts about GRAS filings that you should you be aware of when considering this regulatory route for your food ingredient.
How did the voluntary GRAS notification process come about?
Because the 1958 amendment gave new power to the FDA to clear food additives only if they were safe before they could be sold, Congress did not want the FDA to be flooded with petitions asking them to affirm the safety of flour, salt, gelatin, sugar and hundreds of other familiar and commonly used food ingredients.
The FDA promptly compiled a list of GRAS substances but acknowledged that the list was incomplete. The FDA also published the procedural regulations for GRAS status in 21 CFR 170.35(d) as shown below:
(d) The food ingredients listed as GRAS in Part 182 of this Chapter or affirmed as GRAS in Part 184 or Sec. 186.1 of this Chapter do not include all substances that are generally recognized as safe for their intended use in food. Because of the large number of substances the intended use of which results or may reasonably be expected to result, directly or indirectly, in their becoming a component or otherwise affecting the characteristics of food, it is impracticable to list all such substances that are GRAS.
In 1997, the FDA abandoned the original GRAS affirmation petition process and proposed procedural regulations that allow for the voluntary submission of GRAS notifications. Although the regulations for GRAS notifications are still not final to date, the FDA accepts notifications and posts the review on their website.
What is the difference between self-determined GRAS and an FDA-GRAS Notification?
A GRAS determination can be either self-determined, independent of the FDA, or submitted to the FDA in the form of a notification for the Agency’s assessment. FDA notification of GRAS status for a substance to be used in food or may come in contact with food for human consumption becomes publically available information. Often, a company will choose to perform a self-determined GRAS assessment rather than FDA notification in order to keep certain information proprietary and to control the release of the information up on request. Often this information is proprietary manufacturing information.
Both regulatory pathways--the self-determined GRAS or FDA GRAS notification--are performed by appropriately qualified scientific entities, such as GRAS Associates, on behalf of sponsoring firms. The findings result in establishing compliance with FDA regulations for the subject food ingredient.
It is important to note that a self-determined GRAS status should be of the same scientific rigor as a GRAS notification submitted to the FDA. Often a sponsoring company, after having obtained self-determined GRAS status, may voluntarily elect to “notify” the FDA and subsequently get their opinion. This constitutes the FDA GRAS notification process, and a favourable review results in feedback from the FDA that is referred to as a “no questions” letter.
An organization may seek an FDA-endorsed GRAS status for a number of reasons. For example, some of the larger food processing companies require that an ingredient supplier obtain an FDA-endorsed status through the notification procedures and will not accept a self-determined GRAS status. In addition, having acceptance by the FDA following review of the submitted GRAS notification allows for stronger marketing messaging.
Is it the sponsor’s decision to seek an FDA-endorsed GRAS status?
The option to notify the FDA remains voluntary and with the sponsor. There have been situations, however, around the importation of a substance in which the substance is not identified as an approved food additive or in the FDA GRAS Inventory list. In these cases, Customs/FDA have requested proof of compliance by the supplier and importation is blocked until information is provided.
Another example where FDA GRAS notification status was found to be essential was with ingredient usage in infant formulas. Self-affirmed GRAS was not deemed acceptable by the Infant Formula review team at the FDA, so the self-determined dossier was subsequently submitted to the FDA for review.
In most scenarios, self-determined GRAS meets the needs of all parties. In some cases it does; however, it may be deemed productive to have direct communications with the FDA at the beginning stages of discussion to ensure that there are no impediments that would need to be addressed. This can be accomplished by asking the Agency for a pre-review of the GRAS document.
What is a Preliminary GRAS Assessment?
Due to the inherent uncertainties of the scope of effort needed for some ingredients, GRAS Associates often recommends first undertaking a Preliminary GRAS Assessment (PGA) where we focus on identifying what scientific literature is publicly available on the subject matter, a preliminary assessment of the probability of the substance achieving GRAS status and identification of any gaps in the scientific knowledge to achieve the end goal. This then requires undertaking a triage to ascertain which articles address aspects of safety – such as manufacturing/production processes, purity/specifications and overall composition, toxicology testing including in vivo and in vitro studies, along with any pharmacokinetics investigations and clinical testing.
More than just locating and identifying pertinent articles and information that will have a bearing on safety and an eventual GRAS determination, appropriate preliminary judgment is required in order to extract maximum value from such studies to reduce the likelihood that any additional testing would be needed to support the intended food uses a client has identified.
Once the literature search and triage have been completed, summarization of the selected articles occurs which results in a preliminary report (but not a comprehensive dossier) that is shared with two expert panel members. The two expert panel members undertake their review of the information to make a probability judgment as to whether or not the available information will reasonably support a GRAS finding for the intended food use conditions or if non-trivial gaps or deficiencies exist that must be addressed to meet the safety requirement of “reasonable certainty of no harm under the intended conditions of use.”
Following the Preliminary GRAS Assessment, we provide our clients with our best projection as to what is likely to emerge from the completed evaluation that will include full preparation of the GRAS dossier with detailed review by a fully constituted Expert Panel. An additional advantage of the preliminary step is that the client then has the option to decide whether or not to proceed with the Comprehensive GRAS Assessment without committing to the full project.
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