FDA Issues GRAS Final Rule, Officially Ushers In Voluntary Notification

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Just one day after FDA finally issued its revised new dietary ingredient (NDI) draft guidance for dietary supplements, the agency today released its Generally Recognized as Safe (GRAS) final rule for food ingredients (for humans and animals). As widely expected, the agency has officially replaced the GRAS petitioning/affirmation system with a voluntary GRAS notification system.

If the GRAS notification system sounds familiar, it’s because the system has been in practice for nearly 20 years. In 1997, FDA issued a proposed final rule introducing the concept of a voluntary notification process that would exist concurrently with FDA’s more resource-intensive GRAS petitioning process.

Under the petitioning process, individuals could petition FDA to review the safety information for an ingredient not currently on the list of ingredients FDA considers GRAS. Through this petitioning process, if FDA reviewed the data and decided to add the ingredient to the GRAS list, it would issue a new GRAS regulation through rulemaking-a resource-intensive process.

To ease the burden, in 1997, the agency introduced the concept of an additional voluntary notification process. Under this voluntary notification process, individuals could ask qualified experts to instead review an ingredient’s safety data and determine whether or not the ingredient was GRAS. Individuals could then voluntarily notify FDA that the ingredient had been deemed GRAS. Even if an individual chose not to notify FDA, as long as qualified experts deemed the ingredient as GRAS, it could be sold in food.

Before today, FDA had not issued a final GRAS rule cementing this voluntary notification process even though many companies have been operating under voluntary notification, versus petitioning, in the two decades since FDA issued its 1997 proposed rule.

With the new final rule today, however, FDA confirmed it is officially doing away with the petitioning process and ushering in the notification process.

“This rule announces that we are replacing the former GRAS affirmation petition process with a GRAS notification procedure,” the final rule confirms. For those who voluntarily choose to notify the agency of a GRAS finding, the rule states that “any person may notify us of a claim that a particular use of a substance is exempt from the statutory premarket approval requirements based on the notifier’s determination that such use is GRAS. Under the proposed notification procedure, we would evaluate whether the submitted notice provides a sufficient basis for a GRAS determination and whether information in the notice or otherwise available to us raises issues that lead us to question whether use of the substance is GRAS.”

Key Takeaways

Here are some of the major takeaways from the 300-plus-page final rule, which encompasses FDA’s final decisions and responses to a broad range of comments the agency received when it reopened the GRAS proposed-rule commenting period back in 2010.

The Process

Once FDA receives a GRAS notification, the agency will file it, evaluate the data, and respond within 180 days. Companies are still free to market the ingredient in the meantime, as long as it has been deemed GRAS. The agency will issue one of three types of response letters: 1) “No objections,” 2) “insufficient basis” (insufficient basis to demonstrate GRAS status), or 3) “cease to evaluate” (for instance, if a company requests that the agency stop evaluating the GRAS notification).

Language

The agency will no longer use the term GRAS determination; rather, it will use the word conclusion (e.g., “conclusion of GRAS status”). The word notice will refer to a GRAS submission, and submitters are called notifiers.

GRAS Database

FDA will continue making public the GRAS notifications the agency has filed on its online GRAS Notices Inventory website. “We proactively disclose to the public information about each GRAS notice that we have filed for evaluation, including the name and address of the notifier; the name of the notified substance; the intended conditions of use of the notified substance; and the statutory basis for the conclusion of GRAS status (i.e., through scientific procedures or through experience based on common use in food),” the rule states.

Qualified Experts and Substantiation

In the final rule, FDA spends a lot of time emphasizing that data supporting an ingredient’s GRAS status must include data that is “generally available” and “generally accepted.” Therefore, the agency stressed, private company scientific data may not qualify an ingredient as GRAS if the data is not “generally available” and “generally accepted.” Companies can still provide other forms of data, however, and the final rule notes that, “In most cases, a submitted GRAS notice described a mixture of information published in peer-reviewed journals, information (such as in textbooks) that was generally available in a form other than a peer-reviewed journal, and unpublished information.”

The final rule also clarifies that the opinion of an expert panel may not always alone satisfy the requirement for “generally available” and “generally accepted” evidence. FDA says it plans to issue another draft guidance addressing GRAS panels specifically and that the guidance will also be open to public comment.

Existing GRAS petitions
The final rule says all GRAS petitions already submitted to FDA should be converted to GRAS notifications instead.

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FDA Argues for Notification System

Historically, one of the biggest critiques of the voluntary GRAS notification system is that companies can choose not to notify the agency of new GRAS ingredients on the market, meaning that FDA does not review the safety of every single GRAS ingredient on the market. For this reason, some comments the agency received during the 2010 comment period questioned whether getting rid of the petitioning process, the most-stringent arm of the GRAS program, is a bad idea.

In the final rule, FDA responded to these comments by pointing out that the number of GRAS notifications the agency has received thus far outpaces the small number of GRAS petitions received, meaning that more companies already favor the notification route over petitioning.

The agency says in the final rule, “We believe that our filing of more than 600 GRAS notices for substances used in human food is evidence that the substitution of a GRAS notification procedure for the GRAS affirmation petition process has benefits for consumers, FDA, the regulated industry, and other stakeholders…We note that CFSAN filed more than 600 GRAS notices during the time period 1998 through 2015…for an average of approximately 34 GRAS notices per year, including 69 GRAS notices filed during 2014 and 51 GRAS notices filed during 2015. By contrast, during that time CFSAN finalized six GRAS affirmation regulations. We believe that the ongoing submission of GRAS notices is evidence that our response to a GRAS notice can support the marketing of a food substance.”

The agency also disagreed with arguments that the voluntary notification system means more companies may choose not to notify FDA at all.

“We disagree that the notification procedure we are establishing in this rule will reduce the incentive for producers to notify us. As already noted in Response 24, CFSAN has filed more than 600 GRAS notices between 1998 and 2015, for an average of approximately 34 GRAS notices per year,” the final rule states. “In contrast, as discussed in section IV.L of CFSAN’s 2010 experience document (Ref. 18), between 1987 and 1996 CFSAN received a total of fewer than 100 GRAS affirmation petitions, with an average of approximately 8 GRAS affirmation petitions per year. These data support the expectation we expressed in the proposed rule that the substitution of a GRAS notification procedure for the GRAS affirmation petition process would result in our increased awareness of the composition of the nation’s food supply and the cumulative dietary exposure to GRAS substances.”

In a public statement announcing the new final rule, FDA continued to encourage companies to notify the agency: “The FDA strongly encourages companies to inform the agency of GRAS conclusions through the notification procedure finalized with today’s rule. While the FDA can question the basis for an independent GRAS conclusion, whether notified or not, and take action as appropriate, the notification procedure yields important information that aids the agency’s food safety monitoring efforts.”

The agency also responded to comments questioning whether FDA’s review of ingredients under the notification process would be of lesser quality than reviews conducted for petitions (the “affirmed process,” as FDA calls it). To this, the agency replied, “We disagree that the notification procedure is less protective of food safety than the affirmation petition process. In the proposed rule, we stated that our response to a GRAS notice would not be equivalent to an agency affirmation of GRAS status because we would neither receive nor review the detailed data and information that support the GRAS determination (62 FR 18938 at 18951). These comments may have misinterpreted that statement to mean that we would not conduct a substantive evaluation of the summary information that we receive in a GRAS notice. This is not the case.”

Finally, the agency pointed to the notification system as providing the agency with more enforcement flexibility that could ultimately benefit consumers: “We believe that the GRAS notification procedure provides us with greater flexibility to respond to safety concerns that may arise about a substance that is the subject of a GRAS notice, compared to a substance that is the subject of a GRAS affirmation regulation, which would require rulemaking to revoke.”

Look for continued Nutritional Outlook coverage of the GRAS final rule in the weeks to come.

Also read:

The Future of GRAS Regulations

A New Database to Keep Track of GRAS Self-Determinations

GRAS vs. NDI

Jennifer Grebow
Editor-in-Chief
Nutritional Outlook magazine
jennifer.grebow@ubm.com