Common-use GRAS determinations are no longer common.
By Carrie Kennedy, PMP, RAC, and George Burdock, PhD, Burdock Group
It’s a thought disturbing to some: since 1938, drugs have required FDA premarket approval, but it was not until 1958 that ingredients added to food had a similar requirement. The end of the 20-year delay and subsequent regulatory changes came about as the result of several converging issues. These issues included the rapid growth of the post–World War II population (the baby boomers) and the benefits of chemical advances made during the war, especially in pesticides and food preservation, which led to a demand for the convenience food we have today.
When regulators finally began developing these requirements for foods in the early 1950s, Congressional hearings-the Delaney Hearings-on the issue of food chemicals made it plain that a balance between four competing issues had to be met:
Having successfully balanced the aforementioned issues, the 1958 Amendment to the Federal Food, Drug, and Cosmetic Act was written into law, codifying the requirements for ingredient approval.1 In a commendably pragmatic move, Congress decided that ingredients, such as spices, that had been safely used for hundreds or even thousands of years and thus had already demonstrated safety through prolonged use could be declared Generally Recognized as Safe (GRAS). Further, GRAS ingredients could be determined to be such by two methods: “scientific procedures” (a safety decision based on animal testing) or “common use in food.” Common use in food required that a company demonstrate that a substance had been safely used in food prior to January 1, 1958. Those ingredients that could not meet the GRAS criteria would need to undergo the more complicated food additives process, which requires approval by FDA.
In either approach to GRAS-scientific procedures or history of use-the basis of whether an ingredient qualifies as GRAS depends on the intended use of that ingredient. An ingredient’s intended use must be described in a company’s support of its GRAS determination, along with the physical and chemical characteristics of an ingredient, its origin, estimated daily intake, and the foods to which it may be added. Of note, an often-overlooked aspect of the GRAS process are the methods by which an ingredient is manufactured and by which quality and safety controls are implemented.2
In execution, GRAS determinations require there to be common knowledge about the substance within the scientific community, usually through peer-reviewed publication, as well as the convening of an expert panel to determine if the substance is GRAS.3 As a result, every GRAS determination has a sound basis in science.
The Challenges of GRAS by Common Use
The general recognition of safety by common use in food is not achieved through grandfathering per se, because a GRAS determination still requires a review by experts to confirm that the historical exposure level was safe at less than or equal to the proposed estimated daily intake as a result of the new, modern use. The first several hundred ingredients affirmed as GRAS likely drew heavily on this historical-use provision-either as whole-food products (such as cloves or dill) or their historically produced extractives listed in 21 CFR 172.510. However, in the modern scientific and regulatory climate, obtaining GRAS by common use is potentially the hardest path by which a food ingredient can become federally compliant. As a result, the common-use GRAS route is now rarely used.
For common-use GRAS, a manufacturer must provide at least two independent pieces of information documenting the ingredient’s common use. This information must also demonstrate that the specifications and (generally the same) process at the time of the GRAS evaluation match those processes pre-dating 1958.3 This is often a challenging task because the literature and documentation supporting manufacturing processes and food quality were lacking prior to the 1950s, a question addressed in the 1958 Food Additive Amendment.1 Further, techniques used to isolate a substance have evolved substantially since 1958, enabling a manufacturer to isolate a previously elusive substance with potentially greater purity and in much larger quantities, for instance, such that the new isolate can be used in higher quantities not available in pre-1958 years. And therein lies the rub: because the use of a higher quantity of the ingredient is not supported by a history of safe use, the ingredient may not be eligible for the common-use GRAS provision.
Potentially making things even more challenging, the regulation (21 CFR 170.30(c)) notes that FDA “should” be consulted and concur with a determination of GRAS on the basis of common use if historical data is cited from a country other than the United States. In fact, this suggestion holds no enforceable weight because notifying FDA of any GRAS determination is entirely optional; companies that do choose to submit their GRAS determinations to FDA to review do so voluntarily. Still, the word “should” in the regulation likely influences some.
Until 1983, there were no common-use GRAS guidelines for foods of non-U.S. historical origin. In 1983, FDA’s requirement that information supporting common use in food had to derive from the United States was overturned in a court appeal regarding a substance used in China prior to January 1, 1958.4 The decision from the appeals court was essentially that safe consumption of food is not an exclusive habit of U.S. citizens and, therefore, evidence from other countries must be given equal consideration as historical support in a common-use GRAS evaluation.
While the court’s decision led some to believe that a flood of ingredients from outside the United States would likely gain approval for addition to food in the United States by means of common-use GRAS-a belief expected to be bolstered by an increase in GRAS filings with FDA for foreign foods-what actually happened was quite different. In fact, data indicate a conceivable disappearance of common-use GRAS determinations in the early 2000s. (See Figure 1 below.)
To create Figure 1, we determined the number of common-use GRAS ingredients versus those GRAS ingredients resulting from formal ingredient filings with FDA from industry. The number of common-use GRAS ingredients is based on estimates presented by FDA staff. Approximately 20% of the ingredients eventually included in Section 184 of the Code of Federal Regulations (for common-use ingredients) were included as a result of industry-submitted GRAS affirmations. The net remaining ingredients in Section 184 were presumed to have originated on the basis of common use prior to review by the Select Committee on GRAS Substances.5
In reviewing a search of the current FDA GRAS Notification (GRN) database, less than 1% of those GRAS notifications describing a record filing by means of the common-use method of GRAS were acknowledged with “No Questions” from FDA.7 All other historical-use submissions were either found to not have a basis for GRAS or were resubmitted through scientific procedures and then met with “No Questions.”7 Just three notifications (covering 10 enzyme preparations as food processing aids), and one notification (covering three herbal preparations for herbal tea flavors which received favorable FDA responses), are the sole ingredients FDA has acknowledged on the basis of common use in the last 18 years. (See Table 1 below.7)
Why the Decline of Common-Use GRAS Determinations?
The steep decline in common-use GRAS filings/findings warrants at least some speculation as to the origin of the trend. There are two historically accepted explanations for its decline: 1) that most of the substances that could be supported by history of use have already been GRAS affirmed and/or were simply added to food with the presumption they were GRAS, and/or 2) that the substances were not notified because FDA might not have agreed with the basis of the GRAS (i.e., an “inadequate basis for GRAS” letter would have been issued).1 The most likely explanation is that both of these forces have been at work in influencing common-use GRAS filings to date.
There is another previously unexplored explanation, too, centering on the advances made in food ingredient production over time. The majority of food additives and ingredients reviewed and approved for use in the late 1950s and throughout the 1960s were approved for use in their natural state or in a state (e.g., extract, oil) that could be developed in a lab and transferred to large-scale production, with minimal effort or risk, and that were deemed to resemble the ingredient pre-1958 (based upon science of the time). As time passed, and given the cultural, industrial, and technological shifts that happened in the 1980s through 2010s, however, the further from 1958 a GRAS determination was reviewed, common use as an argument for safety became progressively less possible because fewer and fewer cases could be made that a product and its use, including the level of consumption, were equivalent to a pre-1958 version. (As an example, see Figure 2 showing growth in the number of patents filed related to food and technology, and food and extraction, pre-2000 compared to number filed in 2001–2016.)
Technology plays a continual role in improving an ingredient’s properties, including increasing production efficiency as well as the ability to measure the ingredient in use. Each iteration of product improvements successively enhances the precision of extraction, product purity, and yield. While a majority of the raw materials in use today originate from the same food commodities present pre-1958, their processing, the final ingredients, and their intended use have grown further from their point of embarkation more than a half-century ago.8
Advancing Common Use through the Modern Science of GRAS
The decision to allow historical use or common use of a food substance as a route to GRAS determination has been an undisputed success. Since its creation in 1958, the common-use provision of GRAS has saved companies time and large investment required to bring products to market, while promoting innovation in food science. How can we ensure that common-use GRAS remains a viable route to companies seeking GRAS affirmation?
First, we suggest that the cut-off date be changed. Instead of requiring that all common-use substances be used in the market prior to January 1, 1958, the provision should be changed to allow any substance having been in common use for at least 20 years prior. This also benefits ingredients of non-U.S. historical origin. Although substances used in the U.S. would have already been determined to be GRAS or have been approved as a food additive, substances in use in any other country (for example, an EU country, ANZUS, or China) would become eligible if they were used for at least 20 years. Currently, use of such foreign substances do not qualify for the common-use GRAS provision if the period of historical use was January 1, 1958, through the present, amounting to an omission of more than 50 critical and modern years of food safety, solely because the product was in use outside America’s borders.
There is no disputing that a substance in a food should only be used at a level shown to be safe; however, to limit the common-use provision to those uses prior to January 1, 1958, fails to capitalize on a successful process for vetting substances for safety. What better measure of safety than safe use by consumers for a fixed period of time in the era of food-safety modernization, at home or abroad?
The current cut-off date may be a crucial reason why we have seen the use of common-use GRAS determinations fall off in recent years. Simply put, the date is outdated. We therefore propose that FDA extend the common-use provision to include the safe use of a food ingredient to 20 relative years in order to eliminate this arbitrary cut-off date to allow food manufacturers to more easily innovate with a global supply of historically safe ingredients.
Burdock Group is a scientific and regulatory consulting firm specializing in the food/beverage, dietary supplement, personal care, and pet food industries. Services include GRAS affirmation, claims substantiation, label reviews, NDI notifications, and nanotechnology risk-assessment.