NDI Notification: New Dietary Ingredient Premarket Process Explained

What Is a New Dietary Ingredient (NDI)?

The Dietary Supplement Health and Education Act of 1994 (DSHEA) defined two categories of dietary ingredients for regulatory purposes: those marketed in the U.S. before October 15, 1994 (the date DSHEA was enacted), and those not marketed before that date. Ingredients in the second category are classified as New Dietary Ingredients (NDIs).

Under Section 413(d) of the FD&C Act (21 U.S.C. §350b(d)), a dietary supplement containing an NDI is deemed adulterated unless:

• The supplement contains only dietary ingredients that have been present in the food supply as articles used for food in a form in which the food has not been chemically altered, OR
• There is a history of use or other evidence establishing that the dietary ingredient, when used under the conditions recommended or suggested in the labeling, will reasonably be expected to be safe, AND a 75-day premarket notification has been submitted to FDA

The NDI notification system is the dietary supplement industry's primary premarket safety review mechanism. Unlike drugs, dietary supplements do not require FDA approval before marketing — but NDIs do require this premarket notification with safety evidence.

When Is an NDI Notification Required?

An NDI notification is required when all of these conditions are met:

1. The dietary ingredient was not marketed in the U.S. before October 15, 1994
2. The ingredient is not present in the food supply as an article used for food in a form in which the food has not been chemically altered
3. The ingredient will be marketed as or in a dietary supplement

Determining whether an ingredient qualifies as an NDI can be complex. FDA's 2016 Draft Guidance on NDI Notifications provides additional clarity on several common scenarios:

• Chemically altered ingredients: If an ingredient existed in the food supply before 1994 but has been chemically altered (e.g., through extraction processes, synthetic manufacturing, or structural modification), the altered version is a new dietary ingredient requiring notification.
• New extracts of old ingredients: A new extraction method or solvent system applied to a traditional ingredient may create an NDI, particularly if the resulting extract has a significantly different chemical profile.
• Synthetic versions: Synthetic versions of naturally occurring ingredients are considered NDIs even if the natural version was marketed before 1994.
• Probiotics and live microorganisms: Probiotic strains not used in dietary supplements before 1994 are NDIs, regardless of their food use history.

The 75-Day Premarket Notification Process

The NDI notification must be submitted to FDA at least 75 days before the dietary supplement containing the NDI is introduced into interstate commerce. Here is the process:

1. Prepare your submission. The notification must include:
   • The name of the new dietary ingredient
   • A description of the dietary supplement containing the NDI, including use conditions (dosage, frequency, duration)
   • The history of use or other evidence of safety establishing reasonable expectation of safety under the conditions of use recommended in labeling
   • The basis for concluding the ingredient is a dietary ingredient rather than a drug, food additive, or other regulated article
2. Submit to FDA. NDI notifications are submitted to the Office of Dietary Supplement Programs (ODSP) within the Center for Food Safety and Applied Nutrition (CFSAN). Submissions can be made electronically through FDA's submission portal.
3. Wait 75 days. You must wait a minimum of 75 calendar days from the date FDA receives your notification before marketing the product. FDA may respond during this period with questions or objections.
4. FDA response. FDA reviews the notification and may:
   • Issue no objection — You may proceed with marketing after the 75-day period
   • Raise safety concerns — FDA may request additional information or state that the evidence is insufficient
   • Identify the ingredient as not a dietary ingredient — If FDA determines the substance is a drug, food additive, or is otherwise excluded from the dietary supplement definition

Important: An NDI notification is not an approval. Even if FDA does not object, the manufacturer remains responsible for the safety of the product. FDA can take enforcement action after marketing if safety issues arise.

Safety Evidence Requirements

The strength of your NDI notification depends on the quality and quantity of safety evidence you provide. FDA expects a risk-based approach — novel synthetic ingredients require more evidence than ingredients with a long history of use in food or traditional medicine.

Types of safety evidence, from strongest to weakest:

• Human clinical trials: Controlled studies in humans at the intended dose and duration provide the strongest evidence. Ideally, randomized, double-blind, placebo-controlled trials.
• Animal toxicology studies: Acute, subchronic, and chronic toxicity studies conducted according to GLP (Good Laboratory Practice) standards. Include NOAEL (No Observed Adverse Effect Level) determinations and appropriate safety margins.
• In vitro studies: Genotoxicity, mutagenicity, and cytotoxicity assays provide supporting data but are rarely sufficient on their own.
• Published literature: Peer-reviewed studies on the ingredient or closely related substances can support safety, but FDA expects the studies to be directly relevant to the proposed conditions of use.
• History of use: For ingredients with traditional use (e.g., Ayurvedic herbs, traditional Chinese medicine), documented historical use can support safety. However, traditional use alone is generally insufficient for chemically altered or concentrated forms.
• Self-affirmed GRAS: If the ingredient has been self-affirmed as Generally Recognized as Safe (GRAS) for food use through a qualified scientific panel, this can support an NDI notification, though food GRAS does not automatically apply to dietary supplement use.

FDA's 2016 draft guidance recommends a "tiered" approach where more novel ingredients require more robust evidence. Ingredients with extensive food use history may need only published literature, while entirely novel synthetic ingredients may need full toxicology packages.

Grandfathered Ingredients and the Pre-DSHEA List

Dietary ingredients marketed in the United States before October 15, 1994 are "grandfathered" and do not require an NDI notification. However, there is no official, comprehensive FDA list of grandfathered ingredients. This creates significant ambiguity:

• No master list exists. FDA has stated it does not maintain an authoritative list of pre-DSHEA ingredients. The burden is on the manufacturer to demonstrate that an ingredient was marketed before October 15, 1994.
• Evidence of pre-DSHEA marketing: Acceptable evidence includes published product catalogs, sales records, advertisements, published formulations, and industry publications from before October 1994.
• Industry lists: Trade organizations such as the American Herbal Products Association (AHPA) and the United Natural Products Alliance (UNPA) have compiled lists of ingredients believed to be pre-DSHEA, but these lists are not FDA-endorsed.
• Same form and conditions: Even if an ingredient is grandfathered, using it at significantly higher doses, in a different form (e.g., concentrated extract vs. whole herb), or for a different target population than its pre-1994 marketing may trigger NDI notification requirements.

When in doubt, filing an NDI notification is the safer course of action. Marketing a supplement with an ingredient that FDA later determines to be an NDI without proper notification makes the product adulterated under federal law.

Common NDI Notification Pitfalls

FDA has publicly listed common reasons for NDI notification objections:

• Insufficient safety evidence. The most common objection. Providing a few published studies without connecting them to your specific product's conditions of use is insufficient.
• Ingredient is not a dietary ingredient. If FDA determines the substance is actually a drug (e.g., has been investigated as a new drug under an IND), it cannot be marketed as a dietary supplement regardless of NDI notification.
• Missing identity information. The notification must clearly identify the ingredient, including its chemical characterization, botanical source (if applicable), and method of manufacture.
• Conditions of use not specified. The notification must state the exact conditions of use (dose, frequency, duration, target population) for which safety evidence is being provided.
• Safety extrapolation errors. Using safety data from a different form, dose, or population without appropriate scientific justification for the extrapolation.

Before submitting an NDI notification, ensure your dietary supplement facility is properly registered with FDA and that your manufacturing operations comply with 21 CFR Part 111 cGMP requirements.