Ceased FDA GRAS Reviews: What Happened and Why it Matters

Understanding the US FDA’s regulations and policies is vital for companies that intend to export their food materials to the US market. However, in recent years several companies have ceased their submitted GRAS Notice, and it's important to understand the reasons why.

Ceased substance evaluations 2022-2025 and the  reasons why

CIRS Group has compiled statistics on the withdrawal of GRAS dossiers from 2022 to 2025. According to the statistics, there have been applications to the FDA for the withdrawal of 29 substances. The reasons for withdrawal and their proportions are as follows:

Note: Many withdrawal notices involve multiple issue categories. Therefore, proportions are calculated based on the frequency of each appearing in all withdrawal notices (29 withdrawal notices).

Common reasons for GRAS notice withdrawal

1) Safety concerns

Issues related to insufficient toxicological studies, metabolism research, or other safety-related data, as well as misinterpretations of key safety assessments, make it impossible to establish the substance’s safety. For example, in the withdrawal notices for GRN 987 2'-FL and GRN 992 White mulberry (Morus alba Linn) leaf extract, the FDA cited insufficient safety data.

2) Quality specifications

Issues related to the purity, impurity levels, and overall quality standards of the substance. For example, in GRN 1007 Bacillus subtilis strain R0179, the FDA raised concerns about the heavy metal specification limits.

3) Dietary exposure estimation issues

Issues related to inaccurate, excessive, or missing dietary exposure estimates. For example, GRN 962 Rice bran wax was withdrawn because the estimated dietary exposure for children exceeded the limit set by 21 CFR 172.890.

4) Manufacturing process and impurities

Concerns about the chemicals used in the production process, impurity control, and detection methods. For instance, GRN 1128 Algal oil (≥35% DHA) from Schizochytrium sp. was withdrawn due to issues related to chemical substances and impurities in the production process. The FDA noted the use of cobalt salts during manufacturing, but no cobalt residual detection in the final product.

5) Impact on special populations

The GRAS process imposes strict requirements on substances affecting special populations, such as infants, diabetics, or individuals with kidney disease. Insufficient safety assessments for these groups have led to multiple withdrawals. For example, GRN 1023 Monosodium L-5-methyltetrahydrofolate was withdrawn due to inadequate evaluation of its effects on infants.

6) Lack of supporting data

The lack of sufficient research data to support the GRAS conclusion is a key concern for the FDA. Many substances have been withdrawn due to missing critical studies. For instance, GRN 1012 Powdered sap from Angelica keiskei (ashitaba) containing 8% chalcones (ashitaba sap) and GRN 1044 Calcium disodium ethylenediaminetetraacetic acid were both withdrawn due to a lack of essential supporting data.

7) Other issues

Some cases involve unique concerns, such as improper classification of microbial strains. For example, GRN 1028 was withdrawn because the FDA determined that the two microbial species under evaluation were not closely related enough to be assessed together, requiring separate GRAS notices.

CIRS recommendations

From recent GRAS withdrawal cases, it is evident that safety remains the FDA’s primary focus. To improve the likelihood of successful GRAS determination, CIRS recommends that companies:

- Provide comprehensive safety data, including toxicology studies, human clinical trials, and ADME (absorption, distribution, metabolism, and excretion) data.

- Use scientific and reasonable methods to estimate dietary exposure under the intended conditions of use.

- Ensure strict control over impurities in the manufacturing process.

- Establish rigorous food-grade quality specifications to meet FDA standards.

A scientific, well-structured, and rigorous GRAS dossier is essential for facilitating a smooth FDA evaluation process and improving the chances of successfully obtaining GRAS status.

About CIRS

The Food Division of CIRS Group was established in 2012 and it has a professional team specializing in US GRAS notice. The CIRS Food Division has extensive experience in various fields, covering GRAS, new food ingredients, new food additives, food contact materials, synthetic biology foods, EU Novel Foods, dietary supplements, and special dietary foods.

CIRS operates a fully-owned subsidiary in the US. By leveraging the expertise of the CIRS USA and the international team, it is able to provide enterprise various US food services, including but not limited to:

• US FDA GRAS Notice;
• US FDA Dietary Supplement Structure/Function Claim Notification;
• US New Dietary Ingredient (NDI) Notification;
• US FDA Registration of Food Facilities; and
• US Food Label/Advertisement Information Review.

If you need any assistance or have any questions, please get in touch with us via service@cirs-group.com.