There is no requirement in the law or in the regulations that a generally recognized as safe (GRAS) determination (so-called “self-GRAS”) must be reported to the Food and Drug Administration (FDA); in fact the Federal Register notice describing the GRAS Notification program[1] makes it abundantly clear that GRAS notification is a voluntary process. However, because of a provision in the Food Safety Modernization Act,[2] evidence supporting the GRAS status of a substance may soon be required to be available for review if or when demanded by FDA. Conceivably, GRAS status could also be negated for a substance if, in the opinion of FDA, the opinion of an expert panel (on whose opinion the GRAS determination is based) is “no more substantive than the decorative umbrella in a tropical cocktail.”[3] Further, who would be held accountable for an inadequate GRAS? Lately, FDA has been trending toward assigning blame to executives behind the action, not exclusively their contractors. How did this happen and how did we get to this point?
In the early 1950’s it was determined by Congress that an approval process was needed for ingredients added to food. However, because there were hundreds of ingredients already being added to food, a food additive petition process to address hundreds of ingredients was deemed impractical, in addition to which many ingredients (such as spices) had been in use for hundreds of years with no reported safety issues. At this point, Congress decided that it would be most effective to divide these food ingredients into two categories: food additives, which would require a formalized approval process by FDA, and substances that are determined GRAS, the vetting of which would be carried out by appropriately trained and experienced experts. The expert opinion could be based on safe use of the ingredient prior to January 1, 1958 or for an ingredient not used before the 1958 cut-off date, scientific procedures (e.g., animal testing) were to be employed in order to determine safety. No ingredients were grandfathered; even those in use prior to the cut-off date had to be reviewed for safety and as determined somewhat later by FDA, the data supporting the safety of the GRASed ingredient had to be published, although the actual public declaration of a GRAS determination was not required.
In the early 1970’s, because questions arose regarding some of the early GRASed ingredients (including saccharin), FDA had many ingredients reviewed by an outside committee (which used the acronym SCOGS[4]) and FDA started a GRAS affirmation process. That is, ingredients determined GRAS would be evaluated within FDA and designated GRAS affirmed and incorporated into 21 CFR[5] as part 184. Industry saw the affirmation process as valuable, as it provided a means of showing their customers that FDA agreed with the manufacturer’s determination of GRAS. Although some industry GRASed substances were affirmed and included into §184, the affirmation process eventually became bogged down and collapsed under its own weight, primarily because: (1) FDA reviewed the affirmation to the same level of detail as a food additive petition which soaked up considerable agency resources; (2) no time limit was imposed on FDA to complete its review of a GRAS affirmation as there was for a food additive petition; and (3) because the material which was already GRAS could be legally marketed, calls for more data from FDA often went ignored. A congressional inquiry (The Shays Report) was critical of FDA for the GRAS affirmation program. A summary of the inquiry findings as presented by Dr. Alan Rulis[6] is provided in Table 1.
Fast forward to today – there have been 539 GRAS Notifications, 41 are pending and FDA “no objection” for 376, a relatively high percentage, with an industry average of 75% acceptance.[9] So then, why not notify all GRAS determinations? There are three principal reasons: (1) loss of proprietary use and loss of return on investment, (2) the six month notification review period and occasional arbitrariness of the FDA reviewers and, (3) as alleged in recent reports – nefarious reasons for non-disclosure.
The first reason: By far the most often heard complaint about the notification process is its open and transparent outcome (although the process itself may be rather opaque). A posting a GRAS determination on the FDA website results in the loss of proprietary information and investment by the original submitter – other companies can and do piggy-back on the submitter’s investment, giving them an unfair competitive advantage.
The second reason: Although FDA has been fairly consistent in adhering to the notification review period of six months, many manufacturers feel this is an unreasonable delay and, there is of course, the occasional moving of goal posts by FDA. One FDA employee, whose name is withheld, admitted that some notifications to which “no objection” was made several years ago, would not withstand the level of scrutiny applied today. Speculation about what would be appropriate at one time and not another and why, is reminiscent of the findings by Congressman Shays (refer again to Table 1). While it is still permissible to market a substance after having been withdrawn or even a letter stating “Notice does not provide a basis for a GRAS determination”[10] (because the substance is still GRAS), many industry and the public, see the notification process as a pre-market approval process and feel a substance that was not “accepted” by FDA to be unacceptable for consumption or use in a product. For their part, FDA has done little to disabuse the public of the notion that a successful GRAS notification is not a pre-market approval requirement.
The third reason: Recent reports from the GAO[11] and the Pew Institute have added considerable energy to the debate with both reports recommending compulsory notification of all GRAS ingredients. As a rationale for compulsory notification, both reports described scary scenarios of thousands of unidentified ingredients in the food supply, often approved by persons with conflicted interests or dubious motives using unvetted safety data. While the author can understand this indulgence in speculation, it is without merit, because to the author’s knowledge, there has not been a GRAS substance later to be taken off the market as the result of cover up of any potential safety concern. Notwithstanding the foregoing, some bad actors have undoubtedly manipulated the GRAS process; as a company we have heard some potential clients describe a strategy offered by competitors that included a two-tiered pricing (and testing requirement) system, the choice of which is predicated upon whether the manufacturer intends to subject the GRAS FDA scrutiny via the GRAS notification process. This has always seemed to us at Burdock Group to be a foolish option, as FDA may well see the substance on an ingredient label or simply find the ingredient advertised as GRAS when trolling the internet (as FDA does on a frequent basis) and demand to see documentation of the GRAS determination (as is allowed under FSMA). We have always maintained that there is only one standard for a GRAS – one for which FDA will logically have no issue i.e., “no objection,” whether notified or not.
The rationale for a thorough and substantive data package to support the GRAS, as well as a skilled expert panel has become even more important as the result of three factors. The first factor is the advent of FSMA, which places an even more affirmative burden on FDA to ensure safety in the food supply. In an article in Food Chemical News[12] Sonali Gunawardhana (former regulatory counsel at CFSAN) is reported to have assured her audience that “FSMA rules would change the GRAS system as it stands today” because the authority of FDA to request records related to food have been expanded and would place the burden on the company to demonstrate that an ingredient is GRAS.
The second factor mandating a substantive GRAS dossier is that simply showing a document signed by an expert panel will likely not be enough, considering Dr. Keefe’s earlier mentioned remark (see above) that FDA no longer feels an expert panel has the final word on the safety-in-use of a substance. Obviously, a “GRAS lite” supported by inadequate testing and/or unpublished safety testing, would not pass muster even with the most lenient of expert panels. In essence, FDA will make the final decision as to whether a substance is GRAS, not the expert panel – an unfortunate waste of thousands years of collective experience and a loss to consumer safety.
Lastly, those manufacturers who had relied on the consultant or expert panel to act as a firewall for potential blow back from customers who have had products recalled as the result of a finding of “not GRAS” by FDA, should have been disabused of that notion in a recent newsletter item by Paul Hyman and Katie Bond of Hyman, Phelps and McNamara.[13] The authors cite warning letters from FDA to dietary supplement distributors which include references to United States v. Park and its predecessor, United States v. Dotterweich, referring to vicarious liability rather than strict liability in cases involving cGMP violations by contractors – meaning that company executives can be held liable for the actions of their contractors. It is not much of a leap from GMP inspections to GRAS; that is, if FDA finds an ingredient about which there is no public record of regulatory status, under FSMA, FDA can demand proof of safety from the manufacturer; if the evidence of safety is found to be inadequate, the manufacturer may well experience the greatest penalty with the executives of the manufacturer conceivably being subject to jail terms and fines.
“Anything worth doing is worth doing right.”[14] Shaving off a few dollars with a bargain-basement/unsupported GRAS may lower the cost of entry into the market, but may ultimately result in the loss of the use of a substance and, the reputations of the manufacturer and its executives. Burdock Group has the highest percentage of successful GRAS notifications of any consulting group and stands behind the safety of at least an equal number of non-notified GRAS determinations. We can assist you in remaining compliant and help you get it right the first time, thereby avoiding expensive “do-overs,” remedial measures, and potential legal liability.
References
[1]“Substances Generally Recognized As Safe: Proposed Rule” Federal Register 62:18938-18964. April 17, 1997.
[2] Code of Federal Regulations §102
[3] Dennis Keefe, Director of FDA’s Office of Food Additive Safety quoted in Food Chemical News, April 19 2013, p. 5. Copyright, Informa Ltd.
[4] Select Committee on GRAS Substances
[5] Code of Federal Regulations
[6] Dr. Rulis was Director of the FDA’s Office of Food Additive Safety (1995–2004).
[7] Alan M. Rulis and Laura M. Tarantino, Food Ingredient Review at FDA: Recent Data and Initiatives to Improve the Process, 24 Regulatory Toxicology and Pharmacology 224, 226 (December 1996).
[8] Receipt of a “no basis letter” does not mean the substance is not GRAS and the product may continue to be marketed, although such a letter could provide a basis for FDA to pursue the issue and eventually declare the substance as being an unapproved food additive and require its removal from the food supply.
[9] The author hastens to add that Burdock Group has an 85.7% acceptance rate.
[10] Even if the issue of contention was not based on safety.
[11] FDA Should Strengthen Its Oversight of Food Ingredients Determined to Be Generally Recognized as Safe (GRAS) http://www.gao.gov/new.items/d10246.pdf
[12] Food Chemical News 55(3):1 & 6, April 5, 2013.
[13] http://www.fdalawblog.net/fda_law_blog_hyman_phelps/2013/05/fda-cites-park-doctrine-in-a-different-context.html (accessed 16October14)
[14] Hunter S. Thompson