Required Materials for GRAS Application: A Guide for U.S. FDA Compliance

Introduction

GRAS substances refer to food ingredients or materials that are considered safe for consumption either due to a long history of common use in food or based on scientific consensus among qualified experts. These include certain food additives and food-contact substances. For companies aiming to introduce new ingredients or maintain compliance in the U.S. market, understanding how to properly prepare GRAS application materials is essential.

This article provides a practical guide on how to prepare robust GRAS materials for FDA review. We will cover the critical components of the application—including substance identification, manufacturing process, specifications, dietary exposure assessment, history of food use, and safety justification—while highlighting key considerations and common pitfalls.

GRAS Application Materials: Substance Information

The substance information section mainly includes substance identification, manufacturing process, specifications, physical/technical effects, etc. It is one of the most important parts of a GRAS application.

Since the essence of GRAS is to prove the safety of the substance, the information provided must be complete and accurate. More than half of the FDA’s objections in GRAS reviews come from issues in this section. Therefore, companies must clearly describe all specification parameters and related analyses of the substance.

Substance Identification: This is the foundation of GRAS certification. The identification method provided by the applicant must accurately identify the substance. This is especially critical for plant-derived substances.

Manufacturing Process: The full process and related parameters should be clearly described. It should be stated whether the process complies with U.S. cGMP standards. Each raw material used in the process should be evaluated, listed, and noted if it is food-grade, and what standards it meets. If GMO technology is involved, it must be fully explained. For chemically synthesized substances, whether solvents or heavy metals are present should also be addressed.

Specifications: These should be set based on the characteristics of the substance, production methods, and raw materials. Limits on solvents, heavy metals, microorganisms, mycotoxins, etc., should be included. If international or national standards exist, it’s recommended to reference them. At least three non-consecutive batches must undergo full testing.

GRAS Application: Dietary Exposure Assessment

This part involves a quantitative assessment of how much of the substance people may consume through all sources, including food use and background exposure. This is a key component of the risk assessment, helping determine whether the substance is safe under the intended conditions of use.

GRAS Application: History of Food Use

This refers to whether the substance was widely consumed by a large number of people in food before 1958. It doesn’t necessarily have to be in the U.S.—data from other countries or regions can also be used. If 1958 data is unavailable, more recent consumption history (e.g., from the past few decades) can also serve as supporting safety evidence.

GRAS Application: Safety Justification

This focuses on how to use existing data to demonstrate the substance is safe. In addition to toxicology data, long-term food use history (even if not before 1958) can also be used as part of the reasoning.

• Toxicology Studies: These are the most important, including (but not limited to) acute toxicity, 90-day subchronic toxicity, genotoxicity, etc. Clinical studies and ADME (absorption, distribution, metabolism, and excretion) are also valuable.

• Published Literature: Since GRAS requires public, peer-reviewed evidence, the safety justification should include published data, expert evaluations, and articles from both the applicant and third parties. Negative findings should also be included to maintain objectivity.
• Allergenicity: If the substance or its ingredients contain proteins or potential allergens, allergen testing and discussion of risks are necessary.

What If the Substance Is New and Lacks Public Data?

For new substances, especially synthetic ones, if there is no available published data, the applicant must first conduct toxicology studies (including acute oral, 90-day, and genotoxicity), publish the results in peer-reviewed journals, and only then proceed with the GRAS application.

Special Reminder for FDA GRAS Applicants: Managing Trade Secrets

Once a GRAS notification is submitted to FDA, the materials become public, including experimental data and production process details. Even if trade secrets are removed, the FDA may still ask for clarification.

At that point, the applicant must either disclose the information or withdraw the application. Therefore, it’s recommended that applicants prepare in advance and evaluate the risks carefully before submitting.

How REACH24H Can Help?

REACH24H’s seasoned food compliance team has extensive experience in U.S. GRAS applications and can assist you with:

• Feasibility analysis
• Literature research and toxicology review
• Expert panel coordination
• GRAS dossier drafting and FDA interaction

Contact us to learn more about our one-stop GRAS consulting services and accelerate your entry into the U.S. market.