Beveridge & Diamond
 

FDA Reopens Comment Period for GRAS Notification Procedure

Beveridge & Diamond, P.C., January 24, 2011

On December 28, 2010, the Food and Drug Administration (“FDA”) reopened the public comment period for a 13-year-old proposal to establish formally a voluntary procedure by which companies may notify FDA of their determination that a substance intended for use in food is “generally recognized as safe” (“GRAS”) and FDA may respond.1  FDA has been accepting GRAS notifications as an interim measure since 1998.   

Given the passage of time since FDA first published its proposal on April 17, 1997, the reopened comment period provides manufacturers and other interested parties with an opportunity to raise concerns about FDA’s implementation of the notification procedure.  FDA is also soliciting further public comment on issues raised by earlier commenters, as well as issues identified in a Government Accountability Office (“GAO”) report published last year that urged FDA to strengthen its oversight of GRAS food ingredients.2 

Comments on the proposed rule are due by March 28, 2011. 

1.        Background:  What is GRAS?

While manufacturers of new food additives must obtain pre-market approval from FDA pursuant to the Federal Food, Drug, and Cosmetic Act (“FFDCA”), GRAS substances are exempt from the premarket approval requirement due to their status.3

FDA recognition of GRAS status is not a requirement for being GRAS; however, for commercial reasons, food manufacturers commonly seek FDA recognition.  FDA formerly used a GRAS petition process, which was lengthy.  Since 1998, FDA has been using the 1997 proposal for a GRAS notification process on an interim basis.

A GRAS determination can be based on either long experience in food (for food ingredients used prior to 1958) or scientific procedures.  Critically, such scientific procedures require the same quantity and quality of scientific evidence as is required to obtain approval of a food additive.  Ordinarily, the scientific procedures must be based on published studies, which may be corroborated by unpublished studies and other data.4  According to FDA, approximately one-half of the GRAS notices it evaluated during the interim period between 1998 and 2009 included the findings of an “expert panel” specially convened by the notifier to evaluate the data and information that were the basis for the notifier’s GRAS determination.  In most cases, these findings were included as a report in the GRAS notice but were not published in peer-reviewed journals.5 

2.        The GRAS Affirmation Petition Process

FDA’s existing petition process for affirmation of GRAS status is described at 21 C.F.R. § 170.35.  This resource-intensive process is no longer used.  Under that process, FDA would publish a notice in the Federal Register, request comments on the GRAS petition, comprehensively review the safety of the substance, draft a detailed explanation of why the use is GRAS, and publish that explanation in the Federal Register.  Each petition resulted in a rulemaking that allowed public comment, and FDA had to respond to the comments received.

FDA has not used this process since implementing the 1997 proposed rule on an interim basis in 1998.  The 1997 notice indicated that “FDA would not continue to commit resources to review of a GRAS affirmation petition” if a GRAS notification is received.6

3.        The GRAS Notification Process

In its 1997 proposal, FDA sought to:

  1. replace its existing voluntary GRAS affirmation petition process with a voluntary notification procedure whereby a manufacturer may notify FDA of its determination that a particular use of a substance in human food or animal feed is GRAS, and
  2. clarify the criteria described in its regulations whereby the use of a food additive substance is not subject to the premarket approval requirements of the FFDCA because it is GRAS. 

FDA’s 1997 proposal described the following major steps in the GRAS notification process:

  • A person will submit to FDA a notification that it has concluded that its food ingredient is GRAS.  The notification will include information on the chemical identity, manufacturing process, intended use, expected exposure, toxicity information, and comprehensive evidence of general recognition of safety. 
  • FDA will acknowledge receipt within 30 days and assign a GRAS registry number (“GRN”) to the submission.
  • FDA will post on its GRAS notification inventory website7 a notice that review of the GRAS notification is pending.  The posting will include the name of the submitter, the identity of the food ingredient, the intended use, and the GRN.
  • If FDA has concerns about the notification, it will inform the submitter, who may ask FDA to cease evaluation of the notification or submit additional information.
  • The 1997 proposal indicated that FDA’s review period would be 90 days, but since 2001 FDA guidance has indicated that FDA will try to address most GRAS notifications within 180 days.  According to FDA, since 1998 it has responded to approximately 12% of GRAS notices within 90 days while requiring more than 180 days to respond to more than 31% of GRAS notices.8
  • If FDA does not object to the notification, FDA will post on its GRAS notification inventory website a letter to the submitter indicating that “FDA has no questions.” 
  • Alternatively, FDA may conclude that the “notice does not provide a basis for a GRAS determination” (e.g., because the notice does not include appropriate data and information or because the available data and information raise questions about the safety of the notified substance), or a notice that the submitter has requested that FDA cease evaluation of the notification.

Although FDA’s letter does not represent official approval of a claim of GRAS status, a “no questions” response letter has generally proven sufficient to persuade customers that FDA regards the food ingredient as GRAS.  The notification, FDA’s response, and other “releasable information” are released pursuant to FDA’s implementation of the Freedom of Information Act.9

In the proposal, FDA invited interested persons to submit GRAS notifications as described in the proposed rule until FDA publishes a final rule.10  Thus, FDA has been implementing its proposed rule since 1998 notwithstanding the fact that it still has not yet issued a final regulations. 

During that time it has received an average of 26 GRAS notices per year.11  FDA’s on-line inventory of GRAS notifications includes 365 notices submitted since 1998.12  This inventory provides the name of each notified substance with a link to the text of FDA’s corresponding response letter, along with the nature of FDA’s response.13  The inventory also provides links to information from the notifier’s GRAS notification and any additional correspondence FDA has issued regarding the GRAS notice.  The FDA website provides guidance about the GRAS notification program.14 

Recent examples of GRAS notifications include ones for the use of caffeine in alcoholic beverages,15 for the use of a genetically-modified organism for use as a starter culture in alcoholic beverage fermentation to reduce hydrogen sulfide levels,16 and for the use of synthetic amorphous silica (silicon dioxide) down to the nanoscale for use as an anticaking agent, defoaming agent, stabilizer, adsorbent, carrier, conditioning agent, chill proofing agent, filter aid, emulsifying agent, viscosity control agent, or anti-settling agent in a variety of food categories.17

4.        The Newly Reopened Comment Period

The GAO Report concluded that “finalizing the 1997 proposed rule, which FDA considers interim policy, would firmly establish the framework and criteria for FDA’s voluntary notification program.  It would also reduce the inherent uncertainties for companies of working with an interim policy.”  GAO noted that FDA had not yet responded to the public comments received on the 1997 proposal.18  The December 2010 FDA notice is in large part a response to the GAO Report.

In reopening the comment period, FDA is seeking public comments that reflect developments and experience since its original proposal was first published.  In addition, the notice addresses GAO’s recent report, which recommended that FDA: (1) obtain more information about the use of engineered nanomaterials in food ingredients, (2) strive to minimize the potential for conflict of interest, and (3) issue guidance on how to document GRAS determinations. 

Among the 17 specific issues identified by FDA for further comment during the new period are:

  1. its proposed use of terms such as “scientific principles,” “studies,” and “procedures” in describing the “generally available and accepted” information that form the basis of a GRAS determination;
  2. whether to include a provision in the final rule expressly allowing a notifier to “incorporate by reference” publically available data that were previously submitted to FDA (FDA notes that, regardless of whether a notifier incorporates such information by reference, the Agency may take into account any relevant data or information that it may have from other sources in making its own determinations);
  3. what procedures should apply in connection with the submission of confidential information in a GRAS notice;
  4. what information must be submitted to sufficiently identify a notified substance, including – in light of GAO’s recent recommendation -- particle size and other chemical and physical properties of engineered nanomaterials that may be used to characterize them; and
  5. FDA’s proposed requirement that a notifier consider probable consumption of a substance and the cumulative effect of the substance in the diet in a notification submission.

FDA’s new request for comments reflects all of this prior experience while providing manufacturers with an important opportunity to identify additional issues for the Agency’s consideration before it finally promulgates the notification process. 

For more information about FDA’s proposed rule or the regulatory status of GRAS substances more generally, please contact Mark Duvall at mduvall@bdlaw.com or (202) 789-6090 or Alan Sachs at asachs@bdlaw.com or (410) 230-1345.

For a printable PDF, please click here.  


1 FDA, “Substances Generally Recognized as Safe: Reopening of the Comment Period,” 75 Fed. Reg. 81536 (Dec. 28, 2010).  FDA’s original proposal was published at 62 Fed. Reg. 18938 (Apr. 17, 1997).

2 GAO, “FDA Should Strengthen Its Oversight of Food Ingredients Determined to Be Generally Recognized As Safe” (Feb. 3, 2010) (available at: http://www.gao.gov/new.items/d10246.pdf) (“GAO Report”). 

3 The FFDCA definition of “food additive” excludes from that definition, and thus from pre-market review requirements for food additives, any food ingredient that is “generally recognized, among experts qualified by scientific training and experience to evaluate its safety, as having been adequately shown through scientific procedures (or, in the case of a substance used in food prior to January 1, 1958, through either scientific procedures or experience based on common use in food) to be safe under the conditions of its intended use.”  FFDCA § 201(s), 21 U.S.C. § 321(s).  In contrast, under FFDCA § 402(a)(2)(C)(i), a food additive is deemed to be adulterated if it has not been affirmatively approved by FDA under FFDCA § 409.  21 U.S.C. §§ 342(a)(2)(C)(i), 348.

4 See 21 C.F.R. § 170.30.

5 FDA’s experience with these notices is described in a memorandum dated November 4, 2010.  See Document ID No. FDA-1997-N-0020-0016 (available at http://www.regulations.gov, in Docket No. FDA-1997-N-0020) (“Experience Document”). 

6 62 Fed. Reg. at 18955.

7 The GRAS notification inventory is available at http://www.accessdata.fda.gov/scripts/fcn/fcnNavigation.cfm?
rpt=grasListing
.

8 Experience Document at 24.

9 Experience Document at 27.

10 62 Fed. Reg. at 18954.

11  A table indicating the specific number of GRAS notices filed by FDA each year is provided in the Experience Document at pages 36-37.  FDA also provides statistics on the disposition of every GRAS notice filed each year between 1998 and 2009.  Experience Document, at pages 11-12.

12  See FDA, “GRAS Notice Inventory,” available at:  http://www.accessdata.fda.gov/scripts/fcn/fcnNavigation.cfm?rpt=grasListing.

13 From 1998 through 2009, 79% of GRAS notices resulted in a “no questions” response, 16% were withdrawn, and 5% were found to provide an insufficient basis for a GRAS determination.  Experience Document at 10.

14  See FDA, “About the GRAS Notification Program,” available at: http://www.fda.gov/Food/FoodIngredientsPackaging/
GenerallyRecognizedasSafeGRAS/GRASNotificationProgram/default.htm

15 GRN 347, withdrawn at the submitter’s request.  FDA sent the submitter a warning letter about the use of caffeine in the alcoholic drink Four-Loco, http://www.fda.gov/ICECI/EnforcementActions/
WarningLetters/ucm234023.htm
, and issued a consumer update entitled “Serious Concerns Over Alcoholic Beverages With Added Caffeine,” http://www.fda.gov/ForConsumers/ConsumerUpdates/ucm233987.htm.

16 GRN 350 (pending).

17 GRNs 321 and 298.  FDA had no questions.  The submitter’s notification and FDA’s response letter both referred to colloidal silica, which the notification indicated is an aqueous dispersion of discrete amorphous silica particles having diameters of 1 to 100 nm.  FDA’s letter indicated that the submitter noted that most amorphous silica particles range from 100 nm to 1000 nm and do not exist as easily dispersible nanoparticles.

18 GAO Report at 17.

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