Many European innovative food and feed companies believe it is easier and faster to enter the market in the United States (US) than in the European Union (EU). In both jurisdictions, the safety of novel food and feed ingredients must be established before they can be introduced to the market. This time, my blog delves into the Generally Recognised as Safe (GRAS) regulatory pathway, exploring its significance, the processes involved, and how it compares to the EU regulatory framework.
In the US, human and animal food safety is governed by an extensive regulatory framework established under the Federal Food, Drug, and Cosmetic Act (FDCA). A key element of this regulatory framework is the “Generally Recognised as Safe (GRAS)” designation for human and animal food ingredients. The GRAS designation has been in place since 1958, when the US Congress passed the Food Additives Amendment to the FDCA. This amendment stipulated that substances can only be approved as food additives or used as GRAS substances if they are considered safe for consumption.
It should be noted that, in US regulatory terminology, animal feed is referred to as animal food, and the term “food additive” applies to both humans and animals.
The GRAS pathway plays a critical role in the food and feed industry. This is because the GRAS framework ensures that the food and feed consumed by people and animals meet the defined safety criteria, even for substances and ingredients that have not undergone the full FDA food additive approval process.
What is Generally Recognised as Safe (GRAS)?
GRAS is a regulatory designation defined under sections 201(s) and 409 of the FDCA. It refers to substances intentionally added to human or animal food that are recognised by qualified experts as safe under their intended conditions of use. When a substance is deemed GRAS, it is exempt from the FDA’s stringent premarket approval process required for food additives used in human and animal foods. This means that any substance or ingredient that is intentionally added to human or animal food is a food additive, which is subject to premarket review and approval by FDA, unless the substance or ingredient is GRAS.
For a substance to achieve GRAS status, its safety must be demonstrated through either (i) scientific procedures supported by robust, publicly available scientific evidence, or (ii) common use in food prior to 1958 based on substantial historical consumption data. While the latter approach is hardly applied anymore today, the former remains the primary route for most new food and feed substances and ingredients.
Free webinar: Q&A on termination of self-affirmed GRAS pathway
Massive regulatory developments in the United States are in process of terminating the self-affirmed GRAS pathway. In this Q&A session our experts respond to questions on how to prepare for potential reforms and what is changing and when in the regulatory landscape.
Scientific evidence: the core of GRAS determinations
At the heart of the GRAS designation lies scientific evidence. According to FDA regulations, the quality and quantity of evidence required for a GRAS determination are equivalent to those required for food additive approval. This ensures consistency in safety standards across regulatory pathways. Scientific evidence supporting food/feed GRAS status typically includes:
Human food
- Analytical Studies: Examining the chemical composition and purity of the food or feed substance/ingredient.
- Toxicological Studies: Assessing potential adverse effects in laboratory animals or humans.
- Human Dietary Exposure Assessments: Estimating the amount of the substance consumed under its intended conditions of use.
- Published Research: Peer-reviewed studies demonstrating safety at intended levels of use.
Animal food
In addition to those listed above:
- Target Animal Safety Studies: Assessing potential adverse effects in target livestock and companion animal species.
- Target Animal Dietary Exposure Assessments: Estimating the amount of the substance consumed under its intended conditions of use.
It is important to note that the public availability of this data is crucial for GRAS, and therefore, the FDA also publishes the submitted GRAS dossiers. While unpublished or proprietary data may be used to support scientific findings, the safety data used for the GRAS determination must be published in peer-reviewed journals. If this is not the case, the substance or ingredient does not satisfy the “generally recognised” requirements of the GRAS ruling. Additionally, both favourable and unfavourable scientific information must be considered in the GRAS determination.
Two routes to achieve GRAS status:
GRAS Notification to FDA and Self-Affirmed GRAS
GRAS Notification to FDA
This process involves submitting a GRAS notice to the Office of Food Additive Safety at the FDA’s Center for Food Safety and Applied Nutrition. The FDA reviews the dossier and may issue a “no questions” letter, indicating no objections to the GRAS determination. The FDA aims to evaluate the submitted GRAS notices within nine months. However, in recent times, this timeline appears to have lengthened. During the evaluation period, the FDA may request additional data and clarifying information through several rounds of communication.
While not mandatory, this GRAS route is often preferred by food and feed companies seeking FDA validation to enhance market credibility. Similarly, US food and feed distributors may favour the GRAS notice over the Self-Affirmed GRAS determination.
Self-Affirmed GRAS (also called an independent GRAS conclusion)
In this approach, manufacturers evaluate the safety data themselves and determine GRAS status. Unlike the GRAS notification process, this documentation is not submitted to the FDA but is retained by the company for potential formal food or feed inspection events. Self-affirmed GRAS offers greater flexibility and confidentiality, although the safety data requirements and quality standards are the same as those for FDA-reviewed GRAS notifications. This includes the condition that the safety data underpinning the GRAS determination must be published in peer-reviewed journals. The self-affirmed GRAS documentation may later be submitted as a GRAS notice to the FDA.
A GRAS panel to recognise the substance as safe
As discussed above, the FDCA stipulates that GRAS substances must be recognised as safe by qualified experts. To satisfy this requirement, manufacturers often convene so-called GRAS Panel to re-evaluate the safety of substance or ingredient that they have previously affirmed as safe. The experts on these GRAS Panel must be independent of the company seeking GRAS status and qualified to evaluate scientific and dietary exposure data as well as risk and safety assessments. They must possess the relevant scientific qualifications and expertise necessary to determine whether the available scientific data, information and risk/safety assessment methodologies establish that a substance or ingredient is safe under its intended conditions of use in food. The Panel’s findings and deliberations must be unbiased. While the Panel is not required to reach unanimous agreement, a general consensus is necessary to support the GRAS determination.
The GRAS Panel is not mandatory in either the GRAS notice process or the self-affirmed GRAS process. However, the industry generally considers it the best mechanism to demonstrate that the safety of a substance is recognised by qualified experts.
Components of a GRAS notice and self-affirmed GRAS
Whether through FDA notification or self-affirmation, a GRAS determination requires comprehensive documentation. The GRAS dossier shall contain seven parts pursuant to 21 CFR 170.203-170.285 (human food) and 570.203-570.280 (animal food). These are:
- Signed Statements and Certification: Information on the substance, intended use, and basis for GRAS status.
- Identity and Manufacture: Detailed descriptions of the substance and its production process.
- Dietary Exposure: Data on anticipated consumption levels.
- Self-Limiting Levels of Use: Identifying maximum limiting usage levels.
- Historical Use Evidence: Applicable only for substances used in food prior to 1958.
- Narrative: A thorough justification for the GRAS determination, based on scientific toxicological data and principles.
- Supporting Data: A list of all relevant studies, distinguishing between publicly available and proprietary data.
Certain data in the GRAS determination can be requested to be treated as confidential by the FDA. Typically, this relates to the manufacturing process used for the GRAS substance or ingredient.
Engaging with FDA in pre-submission meetings
For companies pursuing GRAS notification, the FDA encourages pre-submission meetings. These meetings provide an opportunity to clarify the FDA’s expectations for the intended substance or ingredient, identify potential gaps in safety data, and streamline the submission process. Engaging with the FDA early can save time and resources, reducing the risk of delays or rejections.
Medfiles expert’s thoughts on the GRAS procedure and how it relates to the EU procedure
In a world where food and feed innovations are accelerating, the GRAS pathway continues to play a vital role. However, there have been very recent voices in the US Congress suggesting that the GRAS procedure should be discontinued, arguing that it allows companies to declare their ingredients as safe without FDA approval and oversight. Time will tell where this ongoing debate will lead – if anywhere.
While the US GRAS determination is a unique procedure among the world’s jurisdictions, the essential scientific data requirements are the same as for any safety assessment. When compared to the EU, the notable differences are that the GRAS dossiers are not as extensive, as not all details need to be submitted for FDA review; the FDA does not adhere to standards similar to the EU’s transparency regulation; and the FDA engages with companies at an early stage of the process providing also scientific advice, unlike the EU. Interestingly, however, like the public GRAS dossiers, EU dossiers are also now being published.
I hope this blog has encouraged you to consider whether GRAS could be the pathway to the US food and feed markets. Over time, you might find that after generating sufficient revenue by selling ingredients in the US, you can expand your business into the EU or vice versa. For this purpose, it is essential to tailor the scientific data you generate so that it can be used for both GRAS and EU dossiers.
At Medfiles’ Food & Feed and Cosmetics Unit, we regularly work on highly fascinating GRAS projects for our clients. Personally, I have been conducting food and feed GRAS determinations since 2019. In this work, my expertise in human and farm animal risk assessment, gained since 2007 when I began my career at EFSA, proves invaluable.
My colleagues and I would be delighted to discuss your GRAS ideas and explore them further. I am confident that such discussions would be fruitful for both you and the Medfiles GRAS experts. Whether you need assistance with regulatory affairs for human food or animal feed, we are here to help. Backed by over 25 years of experience, Medfiles is a reliable partner in navigating food and feed regulations for the EU, UK, USA and beyond.
Author: Mari Eskola, Ph.D.
Senior Regulatory Affairs Expert, Team leader of Regulatory Science and Reports, Unit on Food and feed
Mari Eskola is a former staff member of the European Food Safety Authority (EFSA) and joined Medfiles in 2021. Since then, she has been involved in several projects on food, feed and cosmetics conducted for Medfiles’ clients. Mari is a food chemist specialised in analytical chemistry and in 2002, she obtained a PhD degree in food science. Mari has over 25 years of international expertise in the chemical and regulatory safety of food and feed from the European Union and European national organisations as well as from the industry. She has worked for 10 years at the EFSA, carrying out EFSA regulatory risk assessments of contaminants in foods and feeds, where she also worked as acting and deputy head of the EFSA Contaminants Unit.
In addition, Mari has food and feed research and regulatory expertise from various other European institutes, such as the European Commission Joint Research Centre (EC JRC), the European Chemicals Agency (ECHA), Teagasc in Ireland, the Austrian University of Natural Resources and Life Sciences and the former Finnish Food Safety Authority. Mari has international experience in managing projects and people, and she has authored several scientific publications comprising also many scientific EFSA opinions and risk assessments.
Free webinar: How to Register Food Ingredients and Dietary Supplements for the US Market: GRAS and NDI Explained
In this webinar, you will hear about complex US food regulations and how they can change. You will learn how to choose the correct registration route for your food ingredient, GRAS or NDI. We will also summarise the main requirements of GRAS and NDI registration and highlight the differences.
References
Faustman C et al. 2021. Ten years post-GAO assessment, FDA remains uninformed of potentially harmful GRAS substances in foods. Critical Reviews in Food Science and Nutrition.
FDA websites on GRAS at: https://www.fda.gov/
Final GRAS Rule, 2016. Federal Register / Vol. 81, No. 159 / Wednesday, August 17, 2016 / Rules and Regulations.
Neltner TG et al. 2011. Navigating the U.S. Food Additive Regulatory Program. Comprehensive Reviews in Food Science and Food Safety.
