Why NDIN Submissions Fail - How to Get Your Submission Right the First Time

Why NDIN Submissions Fail - How to Get Your Submission Right the First Time

Benjamin Arceneaux, Hasseb Khan

Executive Summary

Even strong safety data can fail if the FDA submission isn’t built correctly. This article breaks down the NDIN pathway, why many notifications receive FDA objection letters, and how the NDIN process compares to the GRAS framework. Additionally, this article highlights the most common regulatory pitfalls, particularly gaps in manufacturing detail, ingredient characterization, and safety evidence, any of which can derail an otherwise solid dossier. Finally, this article outlines how a more strategic, well-prepared approach can significantly improve the chances of a successful submission and a smoother path to market.

Introduction

In the United States, manufacturers, distributors, and finished product brands who wish to market dietary supplements that contain novel ingredients, called new dietary ingredients (NDI), need to notify the Food and Drug Administration (FDA). An NDI is defined as a dietary ingredient that was not marketed in the U.S. before October 15, 1994. To sell dietary supplements containing an NDI in the U.S., companies are required to submit an NDI notification (NDIN) to the FDA at least 75 days in advance of marketing the product. The main purpose of an NDIN is to show that the ingredient can reasonably be expected to be safe when used as directed.

Generally, the NDIN must include detailed identity information, including the source of the ingredient, its production process, specifications, and quality assessment. Furthermore, it must also contain pertinent information on the conditions of use, such as the intended population, dosage form, and recommended intake level. Finally, companies must include safety data, including toxicological studies and relevant literature, to provide evidence supporting the safety of the ingredient under the intended conditions of use.

Differences Between NDIN and GRAS

There are key differences between the NDIN and Generally Recognized as Safe (GRAS) pathways. First and foremost, they differ in regard to which products they apply to. If an ingredient is intended for use in conventional foods or beverages, companies may choose the GRAS pathway. If the ingredient is being added to a dietary supplement and was not on the U.S. market before 1994, the NDIN pathway is required, unless the NDI has been legally marketed in the U.S. as an ingredient in a conventional food product (e.g., if it is GRAS and there is proof of the ingredient's presence in the U.S. food supply).

The two pathways also differ in what kind of evidence is needed. For GRAS, the pivotal safety data must be generally available (i.e., published), and the safety conclusion must be generally accepted, which is defined in regulation as recognized among “qualified experts.” To establish general recognition among qualified experts, an Expert Panel is often recruited to assess and verify supporting scientific studies and agree that the ingredient is safe under the conditions of its intended use. For NDIN, companies may use their own internal, unpublished research supporting the safety of their ingredient. Another difference related to safety evidence is that for GRAS, an ingredient must be safe for use by anyone in the general population, from young children to adults, including pregnant and breastfeeding women, the elderly, and those with health complications. By contrast, an NDIN can specify that products containing the ingredient will include phrasing on the label that excludes certain populations. For example, a label may state that the product is not intended for use by children under 18 years of age.

There is also a significant difference in how these pathways are reviewed. For NDIN, companies are required to submit their notification to the FDA, which reviews the notification within 75 days. For GRAS, notification to the FDA is currently optional according to existing regulations. When notified, the FDA reviews the GRAS notice within 180 days of acceptance for filing. However, there is no regulated timeframe for accepting a GRAS notice for filing. Current GRAS review times may be 8 months to over a year. Alternatively, when a GRAS dossier is not notified to the FDA, this is typically referred to as a Self-Affirmed GRAS. Both FDA-notified and Self-Affirmed GRAS dossiers must meet the same requirements established in 21 CFR 170.30 and demonstrate that there is sufficient scientific evidence and general recognition among qualified experts that there is reasonable certainty that the ingredient is not harmful under the intended conditions of use.

Choosing between NDIN and GRAS is not about choosing the easier option; it is about choosing the right one. The decision depends on several important factors, such as what the ingredient is, whether it will be used in a supplement or a food product, what safety information is available, and what the company's goals are. In some cases, there are ingredients that may fall under one pathway, while others may qualify for both NDIN and GRAS, depending on how they are intended to be used.

Why Do NDINs Fail?

Upon review, the FDA will send a response letter to the notifier. Examples of common responses from the FDA include:

• Letter of acknowledgment without objection;
• Letter listing deficiencies that make the NDIN incomplete under 21 CFR 190.6;
• Objection letter raising concerns with the adequacy of the identity information or safety information (e.g., identifying gaps in the history of use or determining that the safety information on the NDI does not support the conditions of use); and
• Letter raising other regulatory issues with the ingredient or product (e.g., the ingredient is not a dietary ingredient under 21 U.S.C. 321(ff) (1), or the product does not satisfy all parts of the dietary supplement definition under 21 U.S.C. 321(ff)).
• Even though the NDIN process has been around for many years, the FDA still issues objection and incomplete letters in response to many submissions. This can be due to a number of factors that make it difficult for the FDA to properly review and evaluate the submission.

First, the FDA needs to clearly understand what the ingredient is, where it comes from, how it is manufactured, and whether its composition and quality are consistent. In relation to this, companies need to provide detailed information such as manufacturing details, compositional data, and certificates of analysis. This is especially important for plant extracts, probiotics, and fermented ingredients because differences in cultivation, extraction, fermentation, or processing methods can significantly affect the final ingredient composition. If the ingredient identity or manufacturing details are unclear or incomplete, the FDA cannot properly evaluate the ingredient.

Some companies assume that natural ingredients or those that are traditionally used may only require minimal safety evidence. However, this assumption is incorrect and may increase the risk of receiving an objection or incomplete letter. The FDA expects detailed evidence supporting the safety of the ingredient, and if relying on evidence from traditional use, the safety narrative must demonstrate the qualitative and quantitative equivalence of the ingredient. This typically includes published scientific literature, including genotoxicity testing to determine whether the ingredient or any contaminants can cause DNA damage, oral toxicity studies assessing short- and long-term toxicity, and human clinical studies evaluating safety, tolerability, and adverse effects.

The FDA also requires clear information about how the ingredient will be used, including who will consume the product, the recommended dose, how often it will be taken, and whether it will come as a capsule, powder, drink, or liquid. The FDA may also consider the duration of use and whether certain groups could be more sensitive to the ingredient. If this information is unclear or not well supported, it can raise concerns during the FDA review process.

Even when the supporting evidence for consumer safety is strong, certain factors can compromise the FDA review process. Issues such as disorganized reports, missing sections, incomplete specifications, missing appendices, inconsistent data, incompletely translated documents, or unclear supporting documents can give the FDA reason to reject the submission or ask questions. In some cases, important details such as manufacturing information, study reports, or certificates of analysis may be missing or not clearly presented. These issues increase the likelihood of receiving an incomplete letter from the FDA.

What Are the Advantages of NDIN over GRAS?

Despite the perceived challenges, the NDIN pathway has several strategic advantages over GRAS. First, there is no requirement for pivotal safety data such as toxicology studies to be publicly available or published in a peer-reviewed journal. This means that a company’s safety data can be redacted from public view in an NDIN, whereas in a GRAS submission this data must be published and described in the publicly available dossier. This redaction from public view allows a company to protect its intellectual property and prevent other companies from leveraging its data to support the safety of a competing ingredient.

Another key advantage of the NDIN pathway is the FDA review time. By law, the FDA has 75 days to review an NDIN, while current estimates for GRAS review range from about 8 months to a year and potentially longer depending on the questions that result from the FDA’s review. Therefore, the NDIN pathway can drastically shorten the time to market for a new ingredient.

The third advantage of the NDIN pathway is the ability to exclude certain subpopulations via product labeling. For example, if a company’s goal is to market its ingredient exclusively to adults, the NDIN can specify that labeling will include a statement that the product is not intended to be used by children under 18 years of age. This allows a company to focus its safety data on the adult population and potentially avoid additional studies such as reproductive and developmental toxicity studies or clinical studies in adolescent populations. This differs from GRAS, wherein the safety narrative must establish that the ingredient is expected to be safe for anyone in the general population, from cradle to grave. Thus, depending on the company’s goals and intended use of its ingredient, the NDIN pathway may present an attractive alternative to GRAS.

Conclusion

The NDIN process can be complicated for companies trying to market their new ingredients. However, issues associated with this process can easily be avoided. The primary factor influencing failed NDINs is unclear or missing information in the dossier. Therefore, the process can be more manageable if companies take the time to understand all the requirements. For companies that want to market new dietary ingredients, the NDIN pathway offers several benefits. It gives companies a predictable review timeline, maintains confidentiality of pivotal safety data, and creates a recognition of safety from the FDA. Choosing between NDIN and GRAS is not always simple. It is important to keep in mind that the right pathway depends on a number of factors, such as what the ingredient is, where it will be used, what safety information is available, and what the company wants to achieve.

To understand the right regulatory pathway for your ingredients, contact SGS Nutrasource. With a success rate of about 90% for NDINs submitted to the FDA, you can be confident in the quality and scientific rigor of your submissions.

About the Authors

Hasseb Khan 
Regulatory Scientist

Hasseb is a Regulatory Scientist who holds a Bachelor of Science from the University of Waterloo and a Master of Biomedical Sciences with a specialization in toxicology from the University of Guelph. At Nutrasource, he contributes to GRAS dossiers and New Dietary Ingredient Notifications for food and dietary supplement ingredients, drafting toxicological safety summaries, conducting dietary intake and exposure assessments, and interpreting toxicology studies ranging from acute to sub-chronic and genotoxicity endpoints. Hasseb is fluent in both English and French and is currently an associate member of the Society of Toxicology.

Benjamin Arceneaux

Junior Toxicologist

Ben is a Junior Toxicologist with undergraduate and master’s degrees from the University of Guelph, specializing in toxicology. Ben also has a strong background in nutritional science, with research experience involving the role of omega-3s in inflammation. During his time at Nutrasource, Ben has worked with the Regulatory Sciences team to evaluate the safety of food and dietary supplement ingredients on behalf of our clients. This has resulted in several successful GRAS and NDIN submissions. This work has also led to an interest in New Approach Methods (NAMs) for evaluating the safety of new chemicals. Ben is currently an associate member of the Society of Toxicology.

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