In the US, any new food ingredient is subject to premarket FDA approval via a Food Additive Petition unless it is generally recognized as safe (GRAS) by qualified experts for its intended use or it does not meet the definition of a food additive (such as color additives). Importantly, the same US regulatory process and standards of safety apply for ingredients developed using genetic engineering techniques as for those developed using conventional techniques. Here, we provide an overview of food ingredient safety determination & GRAS process, along with case studies using examples from the food tech industry.
FOOD ADDITIVE PETITION
The process for food additive safety determination was established by the 1958 Food Additives Amendment to the Federal Food, Drug, and Cosmetic Act (FD&C Act). Food additives are defined as “any substance the intended use of which results or may reasonably be expected to result, directly or indirectly, in its becoming a component or otherwise affecting the component of food”. Ingredients that are GRAS, or generally recognized as safe, are not considered food additives and do not require FDA premarket approval.
A food additive petition is submitted to the FDA to request an assessment of a new food additive. The food additive safety assessment involves a toxicology, chemistry, and environmental review. The petition must contain all supporting information & original scientific data, including details on the identity, proposed use, and probable exposure levels under the proposed use, as well as any pertinent study reports (i.e. including raw toxicological data). Once the petition is submitted, it takes at least two years for the FDA to make a final determination. Examples of food additives include antibiotics used in meat and meat by-products (i.e. bacitracin, ampicillin) and xanthan gum used as an emulsifier in cheese and animal feed. Generally, the food additive approval route is chosen if special safety controls need to be in place either for the manufacturing process or the intended use.
New food substances are exempt from premarket FDA approval if the substance is “generally recognized as safe” (GRAS). In order for a substance to be GRAS, there must be a consensus amongst qualified experts on the safety of the substance under the conditions of its intended use.
GRAS determination is made by scientists who are qualified to make the determination. The determination is often supported by a panel of independent experts, typically convened by a company, who independently review the assessment by the company of the safety of the substance based on publicly available scientific data and information. The pivotal information to form the basis of the GRAS conclusion has to be in the public domain, and preferably in peer-reviewed publications. This is in contrast to a food additive safety determination, which is performed by the FDA, often based on confidential data and information submitted directly to FDA.
Upon completion of a self-GRAS determination, companies may submit a notice to the FDA to support their self-GRAS conclusion through FDA’s GRAS Notification Program. Through this program, companies voluntarily inform the FDA of their GRAS self-determination with the goal of receiving a “No Questions Letter”. The notification procedure generally consists of the following steps:
- Industry submits a GRAS notification to the FDA. The GRAS notification contains information on the identity and proposed use of the substance, and a discussion on the basis for GRAS determination. The notification must also contain references to all supporting information & scientific data, including any pertinent studies.
- FDA reviews the GRAS notice to determine whether the notice provides sufficient basis for the submitter’s GRAS determination. FDA review time typically ranges from 6–9 months although recently it has taken FDA longer due to heavy workload.
- FDA response. The FDA may: 1) respond with a No Questions Letter to the GRAS determination, 2) conclude that there is a lack of sufficient basis for GRAS determination, or 3) cease to evaluate at the notifier’s request. FDA generally offers option 3) to the submitter and utilizes option 2) only if the submitter does not request the FDA to cease evaluating the GRAS Notice.
Case study: Perfect Day’s B-lactoglobulin
Perfect Day submitted a GRAS notice for their recombinantly produced B-lactoglobulin in May 2019. The protein is intended for use as a source of protein in food (i.e. as a substitute for traditional whey protein) and is produced in Trichoderma reesei, a filamentous fungi commonly used for industrial protein production. After the notice was filed by the FDA approximately one month after receipt as GRAS Notice 813, there was a seven month period of correspondence between Perfect Day and the FDA in which the FDA sought additional information about the identity, manufacturing specifications, and intended use of the protein product.
In March 2020, about 10 months from the time the GRAS notice was submitted, the FDA issued a “Letter of No Questions’’ about Perfect Day’s conclusion that its recombinantly produced B-lactoglobulin is GRAS under its intended conditions of use. The letter summarizes the identity of the subject of the notice, how it is constructed/manufactured, the method of validating the identity/composition, method of use, and Perfect Day’s basis for GRAS: 1). use of a non-toxigenic, non-pathogenic production host, Trichoderma reesei, with a history of safe use in producing food enzymes), and 2) production of a non-allergenic food protein with a long history of use in food. The letter additionally remarks on requirements regarding food and allergen labeling.
Case study: Impossible Foods’ soy leghemoglobin
The initial GRAS notice for Impossible Foods’ soy leghemoglobin (SLH) produced from Pichia Pastoris was submitted in September 2014 and filed the same month by the FDA as GRN 540. In this initial filing, the main justifications for IF’s self-affirmed GRAS determination were 1) the similarity between soybean leghemoglobin and other commonly consumed plant and animal hemoglobin, and 2) an extensive history of safe use/consumption of soy and other globin proteins.
After some correspondence with IF, the FDA concluded that contrary to IF’s argument, structural/functional similarities between SLH and other, commonly consumed proteins is not sufficient for establishing the safety of SLH for human consumption. The FDA additionally remarked that not all globin proteins are safe for human consumption, and that the history of the safe use of soy proteins referenced in the notice refers to the use of soy proteins from soybeans and not the use of soy leghemoglobin from soybean plant roots. IF thus requested the FDA to cease evaluation of its GRAS notice in November 2015.
In October 2017, after conducting in vitro genotoxicity and rodent toxicity studies, IF submitted the second GRAS notice for its soy leghemoglobin protein. The second notice included references to the new in vitro and animal studies assessing the toxicity and mutagenicity of SLH. FDA filed the notice that same month as GRN 737. The FDA responded with a request for clarification about the use of the soy leghemoglobin preparation and IF filed several amendments to its GRAS Notice. In July 2018, the agency issued a letter stating that it had no further questions about IF’s GRAS determination. The letter included additional notes on allergen labeling. In addition, as there is no GRAS provision for color additives and IF’s SLH might be used as a color additive. FDA informed IF of the potential need for a Color Additive Petition since SLH is red/brown in color. Indeed, in October 2018, IF submitted a petition to use SLH as a color additive in food, which it had to do in order to sell plant based burgers to consumers in retail stores where its color functionality is key, and the CAP was approved by the FDA in August 2019.
Food ingredients may achieve regulatory compliance through GRAS determination or through a food additive petition. These regulatory processes primarily differ in terms of 1) who has access to the scientific data and 2) who reviews the scientific data and other supporting information, and ultimately makes the final determination. A food additive safety determination is made by the FDA based on data included as part of the petition. In contrast, GRAS determination is made by the company, and may be supported by a panel of experts convened by the company or may leverage peer-reviewed safety data and information. A GRAS self-conclusion may be further supported by voluntary GRAS notification followed by an FDA “No Questions Letter”. As exemplified by the case studies, the time from initial notification to an FDA No Questions Letter may vary, but achieving GRAS status typically takes less time than achieving a food additive safety determination. Understanding the different regulatory processes for food ingredients can help ensure timely compliance with regulatory requirements and support transparency in the supply chain and to consumers.
Written by Wei Ng, PhD candidate & Helikon Associate. Many thanks to Vince Sewalt for constructive dialogue and feedback!