On August 17, 2016, the U.S. Food and Drug Administration (FDA) published a final rule regarding substances that are “generally recognized as safe” or GRAS. This rule formalizes the steps food manufacturers must take to ensure GRAS substances are safe for human consumption and reaffirms a process that has worked extremely well for many years. The FDA has created a number of resources to help stakeholders comply with the rule, including a frequently asked questions (FAQ) document that was updated in October 2016 to incorporate provisions of the final rule. A copy of the FAQ is available here while other FDA GRAS resources are available here.
The rule finalizes a 1997 proposed rule that replaced the GRAS affirmation process with the GRAS notification procedure, under which the industry has been operating for nearly 20 years. The final rule codifies many of the concepts found in the proposed rule and does not represent a major shift in FDA’s thinking or regulatory policies towards GRAS substances. In fact, the final rule mandates many of the common procedures that International Food Additives Council (IFAC) members were already conducting voluntarily under the proposed rule. As such, the final rule includes many useful clarifications and procedures that IFAC members strongly support. While it does not fundamentally alter the GRAS concept or create over burdensome requirements, it provides a clearer explanation of how general recognition of safety is demonstrated under the law, what is expected when a company makes a GRAS determination and what companies must do when submitting a GRAS notification to the Agency for review.
The GRAS concept, which is rooted in the 1958 Food Additives Amendment to the Food, Drug and Cosmetic Act, is intended to address ingredients that have a long history of use or where a general recognition of safety exists in the public domain. Over the last two decades, FDA’s proposed GRAS notification system has evolved and the quality and rigor of GRAS notifications have also generally improved. Most manufacturers that have submitted a GRAS notification under the proposed rule will not find much in the final rule that is new or that FDA has not previously communicated to submitters. However, as the final rule becomes effective on October 17, 2016, IFAC notes the following highlights and key differences between the proposed and final rules which are intended to help IFAC members and their customers navigate the requirements of the final rule:
- The final rule defines the following terms (among others) which were not defined in the proposed rule: “GRAS,” “GRAS notice,” “notified substance,” “notifier,” “qualified expert” and “supplement.”
- While the proposed rule suggested that GRAS notifiers could incorporate into a GRAS submission data and information previously submitted to the Agency, the final rule makes it expressly clear that such information can be incorporated.
- FDA makes it clear in the final rule that the Agency would like GRAS submissions to be more uniform in format. As such, the final rule specifies that GRAS notifications must contain seven parts and lays out the information that is needed in each part.
- To provide greater clarity regarding a notified substance, the Agency now requires that an “appropriately descriptive term” of the notified substance be submitted rather than the “common or usual name” (as was included in the proposed rule).
- The final rule now includes a requirement that the notifier must identify any data or information in the notice that should be exempt from disclosure under the Freedom of Information Act (FOIA) (e.g., trade secret, commercial or financial information that is privileged or confidential).
- To avoid incomplete submissions and ensure that all submissions accurately reflect all information about the substance, the final rule expressly requires that the notice be signed to certify that is complete, representative, and balanced. Balanced means it must include favorable and unfavorable information known to the notifier and pertinent to the evaluation of the safety and GRAS status of the use of the substance. While this was common practice under the proposed rule, it is now mandatory.
- In regard to information that may not support GRAS status, the final rule requires that the submitter either: (1) Identify, discuss, and place in context, data and information that are, or may appear to be, inconsistent with the conclusion of GRAS status; or (2) state that the notifier has reviewed the available data and information and is not aware of any data and information that are, or may appear to be, inconsistent with the conclusion of GRAS status.
- This implies that the submitter must be thorough in his or her review of the body of literature and include reference to any information that could be relevant to the determination in the notification.
- The final rule also explicitly states that source information including applicable data and information at the sub-species level (e.g., variety, strain) for a notified substance of natural biological origin be provided. This is in addition to genus and species information that was noted in the proposed rule. This reflects FDA’s current thinking on the issue and is consistent with other FDA documents such as the revised draft guidance on New Dietary Ingredient Notifications.
- Greater clarity is provided in regard to what must be provided to describe the manufacturing method. FDA now requires a description of sufficient detail to evaluate the safety of the notified substance as manufactured; trade secret information may be included so long as it is clearly marked as confidential and not subject to FOIA disclosures.
- The final rule expressly requires relevant information on the physical or other technical effect the notified substance is intended to produce when necessary to demonstrate safety, including the quantity of the notified substance required to produce such effect. This information was generally provided in notices under the proposed rule, but is now mandatory.
- In order to help FDA calculate the impact on dietary exposure of the intended use of the substance, the final rule expressly requires the notifier to consider dietary exposure, regardless of whether the conclusion of GRAS status is through scientific procedures or through experience based on common use in food. The final rule also creates two distinct parts for dietary exposure:
- Part 3, which addresses how much of the notified substance consumers would eat as part of the total diet (including exposure from its intended use and all sources in the diet), as well as how much consumers would eat of other substances (e.g., contaminants or byproducts); and
- Part 6, which requires the submitted to address the safety of the notified substance, considering all dietary sources and taking into account any chemically or pharmacologically related substances in such diet.
- While notifications under the proposed rule commonly included a “comprehensive discussion,” the final rule requires a narrative (Part 6 of a GRAS notice), and a list of supporting data and information (Part 7 of a GRAS notice). The narrative is intended to provide FDA with greater understanding of the basis on which the GRAS conclusion is being made.
- In the narrative, FDA also requires an explanation of how there could be a basis for a conclusion of GRAS status if qualified experts generally do not have access to non-public, safety related data and information.
- The final rule also provides greater clarity in regard to the review process itself. For example:
- The final rule permits the notifier to submit a timely “amendment” to a GRAS notice before FDA makes a determination and allows the notifier to ask FDA to cease review.
- It also states that FDA will conduct an initial evaluation of the submission to determine whether to file it as a GRAS notice for evaluation within 30 days as specified in the proposed rule. In the proposed rule FDA was only obligated to acknowledge receipt.
- When a submission is filed as a GRAS notice, FDA is required to send a letter informing the notifier. If a submission is not filed, FDA will must inform the notifier and provide reasons for not filing the submission as a GRAS notice.
- FDA is obligated to respond to the notifier within 180 days of filing (as opposed to 90 in the proposed rule) based on FDA’s evaluation of the notice. FDA may extend this response window by 90 days on an as needed basis. If extended FDA will inform the notifier “as soon as practicable” but no later than within 180 days of filing.
- If FDA ceases review or responds to a submission, the notifier is entitled to submit a “supplement” to a GRAS notice addressing the FDA response.
IFAC and its member companies strongly supports this final rule and believes its requirements largely reflect industry best practices under the 1997 proposed rule. However, the final rule brings certainty and clarity about FDA’s expectations for GRAS determinations and notifications to the Agency. IFAC continues to be very supportive of GRAS, which represents the pinnacle of public and private sector collaboration, but also supports FDA’s continued efforts to strengthen the process. Further, IFAC welcomes forthcoming Agency guidance documents intended to clarify its interpretation of what it means for a substance to be GRAS and minimize conflicts of interest in GRAS expert panels. GRAS offers industry and FDA many benefits and shifts the resource burden of determining safety of some substances to industry while allowing FDA resources to be directed at activities that have the greatest impact on public health, such as implementing the FDA Food Safety Modernization Act. The GRAS process, and this final rule, provides a clear legal framework under which food manufacturers can bring innovative, safe food and beverage products to market to meet consumer demands.
IFAC and its members look forward to working with FDA and other stakeholders to implement this final rule and achieve our common goal of maintaining the safest food supply in the world. Moving forward, all stakeholders should make GRAS conclusions and submit GRAS notifications following FDA’s final rule. To help companies navigate future submissions, IFAC is updating its GRAS Best Practices Guide to include all of the requirements in the final rule. The updated GRAS Guide will be made available in the near future.