Proposed in August, the new rule would replace FDA’s voluntary notification system for substances considered GRAS with a mandatory program covering substances used in human and animal food.
“GRAS is about the safety of a substance under its particular conditions of use,” said Dr. Kristi Muldoon Jacobs, director of the Office of Premarket Additive Safety of the Human Foods Program at FDA, during the 25-minute webinar. “GRAS is not a general or inherent property of a substance.”
The agency is asking interested parties to review the proposal and submit comments before the public comment period closes on Dec. 9.
Gaps in the current GRAS pathway
Under the current system, companies may submit GRAS conclusions to the FDA for evaluation but are not required to do so.
According to the agency, this has created information gaps about substances added to food, compounded by a changing food supply that now includes thousands of additives—and a fair portion of which it says lack adequate safety data. Also noted were cases in which questions about a substance’s safety remain unresolved after a notifier asks the FDA to cease its review and then markets the substance based on its own GRAS conclusion instead.
“Our lack of a complete understanding of what substances are being used in the food supply impedes our ability to efficiently carry out our role to prohibit the use of unsafe additives in food and protect public health,” Muldoon Jacobs said.
During a fireside chat hosted at the Council for Responsible Nutrition’s Convergence conference last week, Cara Welch, director of the Office of Dietary Supplement Programs (ODSP), stated that she has no objection to ingredients already used in the conventional food supply also being used in dietary supplements as the pathway is clearly established in the dietary supplement framework.
Her concern is with manufacturers that specifically use regulatory pathways to avoid FDA review both on the conventional food supply and dietary supplement sides, such as making a self-affirmed GRAS determination for a novel ingredient, introducing it nominally into the conventional food supply and then relying on the exemption under Section 413(a)(1) of the Federal Food, Drug, and Cosmetic (FD&C) Act from filing a new dietary ingredient notification.
“I would prefer that new ingredients, where the intended use is to be in dietary supplements, come into the dietary supplement program and get reviewed by the dietary supplement reviewers against the dietary supplement safety standard,” Welch said. “That is my preference, and I suspect that is widely shared with the audience […]; that is something that I hear a lot from responsible industry.”
§8. New Dietary Ingredients, amending Chapter IV of the Federal FD&C Act
”SEC. 413. (a) IN GENERAL.- A dietary supplement which contains a new dietary ingredient shall be deemed adulterated under section 402(f) unless it meets one of the following requirements:
“(1) The dietary supplement contains only dietary ingredients which have been present in the food supply as an article used for food in a form in which the food has not been chemically altered.
“(2) There is a history of use or other evidence of safety establishing that the dietary ingredient when used under the conditions recommended or suggested in the labeling of the dietary supplement will reasonably be expected to be safe and, at least 75 days before being introduced or delivered for introduction into interstate commerce, the manufacturer or distributor of the dietary ingredient or dietary supplement provides the Secretary with information, including any citation to published articles, which is the basis on which the manufacturer or distributor has concluded that a dietary supplement containing such dietary ingredient will reasonably be expected to be safe."
Rend Al-Mondhiri, partner and co-chair of the Regulatory Practice Group at Amin Wasserman Gurnani LLP, also highlighted that Section 413(a)(1) of the FD&C Act is “not a blanket exemption for ingredients that have GRAS status (self-affirmed or otherwise)” and that ingredients must have been actually used in a food product after that food supply basis is established and then used in a dietary supplement in a form that has not been chemically altered.
“I would also caution industry on inviting FDA to clarify how the rule affects dietary supplements, because the answer might limit the exception’s availability,” she added.
“Industry would be better served by understanding the statutory requirements, evaluating how the proposed rule could affect the regulatory status of each dietary supplement ingredient currently being marketed and taking inventory to ensure there’s a paper trail supporting each ingredient’s regulatory status. Companies should also look at excipients and other non-dietary ingredients since those ingredients need their own basis for lawful use in supplements.”
Moving towards mandatory GRAS
If finalized, the mandatory GRAS rule would require those introducing a substance into interstate commerce under the GRAS provision to notify the FDA of the basis for that conclusion, unless an exception applies. The agency said the requirement would be deemed met once the FDA files the notice.
Officials continue to emphasize that the proposal would not create a new premarket review program for GRAS uses. Instead, the FDA could consider whether a notification requirement had been met when prioritizing substances for post-market review through its systematic reassessment program.
The proposal includes a one-year, time-limited pathway for streamlined submissions covering qualifying substances already in interstate commerce before the effective date of a final rule. Submitters would include identifying information and details about intended uses, food categories, use levels and purpose, along with evidence that the substance was already on the market. This information would then be published in a public list.
“This would provide a streamlined way for us to gain insight into substances already in use in the market under the GRAS provision, engage with industry and make such information publicly available,” Muldoon Jacobs said.
She cautioned that publication of a streamlined submission would not mean the FDA had reviewed or endorsed the substance’s GRAS status. The agency could ask follow-up questions or determine that a full GRAS notice or food additive petition must be submitted, and any such determination would also be made public.
The proposal sets a compliance date of 18 months after the effective date of a final rule. It would also revise the threshold-of-regulation (ToR) process, which currently applies to food-contact uses involving extremely low exposure, so that qualifying substances used directly or indirectly in food could seek an exemption.
Muldoon Jacobs described the threshold as 0.5 parts per billion in the diet or “roughly the weight of a single grain of rice spread out across a person’s entire lifetime of food consumption.” Uses involving carcinogenic substances would remain excluded.
The FDA stressed that mandatory notices would help confirm that GRAS conclusions have a scientific basis, identify potentially unsafe substances and make more information available to the public.
“The proposed rule, if finalized, can help strengthen public confidence in FDA’s ability to oversee the safety of the U.S. food supply,” Muldoon Jacobs said.
‘A more practical approach’?
Ashish Talati, FDA and FTC regulatory attorney and founding member of the Talati Law Firm, commented that while FDA’s webinar did not offer much additional clarification beyond what was already published in the proposed GRAS rule, he expects that industry will submit comments addressing FDA’s legal authority to require mandatory GRAS notifications, the extent to which one company may rely on another company’s GRAS notification and whether FDA has sufficient resources to manage a significant increase in submissions.
“One area I think deserves more discussion is the proposed streamlined notification process,” he said. “FDA made it clear during the webinar that just because an ingredient appears on the streamlined list doesn’t mean the agency has reviewed or agreed with its GRAS status. If that’s the case, why limit this process to just one year? Why not make it permanent?”
He suggested that companies could provide FDA with basic information about their ingredients and intended uses, while those seeking FDA review of their GRAS conclusions could continue to submit full GRAS notices voluntarily, as they do today. Under this approach, if an ingredient raised potential safety concerns or questions, FDA could request additional information and determine whether further regulatory action was warranted.
“I think this would be a more practical approach,” Talati said. “It would give FDA greater visibility into the ingredients being used in the food supply, which is one of the main goals of the proposed rule, without requiring every company to go through the full GRAS notification process. It would also allow FDA to focus its resources on ingredients that actually raise questions.”
