Submitting a Generally Recognized as Safe (GRAS) Notice to FDA remains voluntary (see previous post here). However, many food manufacturers and other responsible parties opt to submit their GRAS Assessment to FDA for review.
There are three methods for submitting a GRAS Notice to FDA:
Notifiers can submit their GRAS Notice to FDA’s Electronic Submission Gateway;
Notifiers can send an electronic copy of the GRAS Notice with associated forms and attachments on physical media (CD or DVD-ROM) that as been verified free of viruses; or
Notifiers can send a hard copy of the GRAS Notice with associated forms and attachments.
Regardless of the submission method, the GRAS Notice must follow the guidelines established in the Final GRAS Rule in the Federal Register, which became effective on October 17, 2016. Often, food manufacturers will use an agent—someone familiar with the submission process—to submit a GRAS dossier on their behalf.
Once FDA receives a GRAS Notice, it undergoes an initial cursory review to ensure that the dossier is complete and meets the standards established in the Final GRAS Rule.
If the GRAS Notice meets the requirements, FDA officially files the submission and assigns it a GRAS Notice GRN) number. A formal “acknowledgement” letter is then issued by FDA, and the formal review process begins. In the past, the initial review period was approximately 30 days from receipt, but through recent experience, the timing has increased to ~45-60 days from receipt.
FDA can exercise the option to “decline-to-file” a GRAS Notice, and a formal letter informing the notifier of that decision is issued. Reasons for FDA to opt to “decline-to-file” a submission vary, and can range from insufficient formatting to the determination that the submission is substantially similar to a previously reviewed GRN.
Once a GRN is filed, FDA’s 180-day review window begins. FDA has the option to extend the review by an additional 90-days on an as-needed basis, and will inform the notifier in writing within the initial 180-day review period.
Ultimately, there are three potential outcomes to a GRAS Notice submission:
“No questions”: FDA has no questions regarding the notifier’s conclusion of GRAS for the subject ingredient, and a “no questions” letter is issued. It should be noted that a “no questions” letter is not an affirmation that FDA considers the ingredient to be GRAS, but rather that FDA does not question the notifier’s conclusion of GRAS. Ultimately, it is still up to the manufacturer to ensure that their ingredient is safe and compliant with all other regulatory requirements.
“Insufficient basis”: FDA concludes that the GRAS Notice does not provide a basis for a GRAS conclusion for the subject ingredient under the intended conditions of use. An “insufficient basis” letter is issued to the notifier.
“Cease to evaluate”: FDA stops reviewing the GRAS Notice per the notifier’s request, and issues a “cease to evaluate” letter. This outcome is generally prompted when significant deficiencies are noted in the dossier, which are often outlined in the response letter. These deficiencies can include incomplete bibliographic references, inconsistent data, language issues, and lack of detail on intended uses and use levels. The notifier has the option to revise and resubmit the dossier at a future time.
In 2017, Hanlon et al. published a review of FDA’s GRAS Notice program. The authors evaluated the first 601 GRAS Notice submissions, and found that 81% (n = 485) of the GRNs received a “no questions” letter, 17% (n=99) of the GRNs were “withdrawn,” and 3% (n=17) of the GRNs received an “insufficient basis” letter.
Since the Hanlon et al. review, at least 246 GRAS Notices have been submitted to FDA as of June 14, 2019. Of these, 45 GRNs are pending review. For the 201 GRNs that have received a response from FDA, 81% (n=162) have received a “no questions” letter and the notifier has asked FDA to cease to evaluate 19% (n=39) of the submissions. There were no instances of an “insufficient basis” response from FDA.
If you’d like to learn more about the FDA submission process or if you have any other questions about GRAS, please feel free to reach out directly.
The next blog in this series will cover Steviol Glycosides: a League of Their Own.
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📷 1: Bernd Klutsch on Unsplash
📷 2: Katrina Emmel
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Hanlon, P.R., Frestedt, J., Magurany, K. (2017) GRAS from the ground up: review of the Interim Pilot Program for GRAS notification. Food Chem. Toxicol. 105, 140-150.