FDA Publishes Final New Dietary Ingredient (NDI) Guidance for Industry Addressing FAQs About NDI Notification (NDIN) Submissions

On October 19, 2026, the U.S. Food and Drug Administration (FDA) announced the availability of a guidance for industry entitled “New Dietary Ingredient (NDI) Notifications and Related Issues; Identity and Safety Information About the NDI: Guidance for Industry” (Guidance).   

This document finalizes portions of the 2016, “Dietary Supplements: New Dietary Ingredient Notifications and Related Issues; Revised Draft Guidance for Industry,” specifically addressing in new sections:

1. Identity information for the NDI and dietary supplement,
2. History of use or other evidence of safety, and
3. The basis for concluding that the NDI is reasonably expected to be safe.

This guidance focuses on questions concerning identity and safety characterization.  Notably, FDA eliminated references to a broad “comprehensive safety profile,” replacing it with a “safety narrative” required for all NDINs.

Legal Background

Under section 201(ff)(1) of the Federal Food, Drug, and Cosmetic Act (FD&C Act), a dietary ingredient is any one of the following:  a vitamin, a mineral, an herb or other botanical, an amino acid, a dietary substance for use by man to supplement the diet by increasing the total dietary intake, or a concentrate, metabolite, constituent, extract, or combination of any dietary ingredient from the preceding categories.

1. Definition of an NDI:  An NDI is a subclass of dietary ingredient, specifically a dietary ingredient that was not marketed in the United States in a dietary supplement before October 15, 1994.  See section 413(d) of the FD&C Act. 
2. NDI Submission Requirement:  Under section 413(a)(2) of the FD&C Act, NDI manufacturers or distributors must submit an NDIN at least 75 days before introducing an NDI (or a supplement containing an NDI) into interstate commerce, unless the ingredient has been present in the food supply as an article used for food without chemical alteration. Id.; see also 21 CFR 190.6. 
3. Consequences of Non-Compliance: Failure to submit an NDIN renders the dietary supplement adulterated under section 402(f) of the FD&C Act.

The Guidance expands upon the NDIN requirements found at 21 CFR 190.6(a) and 190.6(b)(2), (3), and (4) and provides FDA’s current thinking on how to satisfy these requirements.

Below we highlight key aspects of the Guidance.

Key Aspects of the Guidance

1. What’s New?

Two themes running through the Guidance are FDA’s willingness to utilize new technologies as well as openness to scientific flexibility.

FDA added several new definitions, including a definition for Alternative methods (also referred to as new alternative methods or new approach methods (NAMs)). By formalizing this term, FDA affirms NAMs are legitimate means to help demonstrate NDI safety.  Additionally, this definition affirms FDA’s commitment to increasing scientific flexibility for safety testing and NAMs integration into its programmatic areas. 

The agency also introduced or expanded definitions for concepts such as:

• Acceptable Daily Intake (ADI)
• Estimated Daily Intake (EDI)
• EDI/ADI Ratio
• Margin of Safety    

While the Guidance provides areas for scientific flexibility, defining these terms indicates that FDA also expects standardized mathematical proof of safety.

In defining concepts like Live Microbial Dietary Ingredient, FDA recognized the emerging areas that also present unique safety considerations.  Overall, the new information included in the definitions section spotlights the emphasis specific safety information as well as precise categories within the NDI context.

Outlined below are key pieces of information contained in each section of the Guidance.  These sections are the restructured versions of the VI. A-VI. C from the 2016 draft revised guidance.

2.Identity Information Matters More than Ever

In Section IV, FDA states up front that it cannot evaluate safety of an NDI unless it first understands exactly what the ingredient is; essentially, it cannot consider the whole without understanding the parts.

The Guidance provides detailed recommendations for establishing the identity of both the NDI and the finished dietary supplement. Companies should be prepared to provide physical and chemical characterization data, analytical testing results, manufacturing information, product specifications, and validated analytical methods.

FDA also emphasizes that identity information must be linked to any historical use or scientific studies relied upon to support safety. For manufacturers, this means NDINs increasingly resemble comprehensive scientific dossiers rather than simple ingredient descriptions.

Overall, industry should be prepared to compile a comprehensive scientific analysis that includes verifiable identification and safety information as well as a detailed manufacturing process which ensures risk mitigation parameters.

3. New Focus on Safety Narrative

Section V addresses what FDA expects to see in the “safety narrative” for an NDIN, which builds on the requirements contained in 21 CFR 190.6(b)(4). Rather than relying on a broad collection of studies, companies should develop a clear scientific explanation of why the ingredient and finished product can reasonably be expected to be safe under the proposed conditions of use.

According to FDA, a strong safety narrative should address:

• Expected consumer exposure
• Daily intake estimates
• Margin of safety calculations
• Supporting toxicology studies
• Ingredient and excipient safety
• Any differences between historical and proposed use

FDA explains that if the NDIN contains more than one NDI, the submission can demonstrate safety by providing either “(1) safety data on the combination of NDIs and a description of the individual constituents; or (2) safety data on the individual NDIs and an explanation of how the combination of NDIs does not present any new safety concerns.”

Importantly, FDA expects manufacturers to consider the safety of both the ingredient and the finished dietary supplement product. Fundamentally, a successful safety narrative makes a reasoned scientific argument that connects the ingredient-level safety to the finished product with robust, supportive data.

4. Historical Use Data Can Help, But There Are Limits

Section VI addresses the History of Use and outlines what constitutes “adequate” historical safety data, as well as data gaps requiring additional testing.  In the guidance, FDA states that if a company is relying solely on history of use data, the agency “generally recommends 25 years of widespread use to be the minimum to establish a history of safe use.”  This is another place where FDA shows flexibility, specifically by opining on how shorter timeframes may be accepted if supported by additional evidence.

In certain instances, history alone may not be enough if the proposed product differs significantly from historical consumption patterns. Examples include:

• Higher dosage levels
• Longer periods of use
• Different delivery systems
• Concentrated extracts

When those differences exist, FDA may expect additional studies to bridge the gap between historical experience and modern use.

In short, adequate historical data can suffice to support NDIN; however, if there are differences in areas such as the dosage or intended delivery system(s), complete submissions will need additional studies to bridge the gap.

5. Other Evidence May be Necessary

Section VII describes an “adequate” history of safe use as well as provides a deep dive into what a NDIN should include where there are data gaps between historical human exposure and the proposed product’s conditions of use. The guidance outlines the various methods that can be used to demonstrate safety; notably, FDA highlights that while NAMs can be used to address safety, they “are unlikely to be sufficient to demonstrate safety on their own.”  If historical use data are insufficient, FDA expects companies to provide additional evidence supporting safety, such as:

• Animal toxicology studies
• Dose-response analyses
• Studies establishing a No-Observed-Adverse-Effect Level (NOAEL)
• Emerging scientific approaches such as NAMs

When historical use is insufficient to cover the proposed conditions of use, the NDIN will need “other evidence of safety” to pass FDA review.

6. Special Considerations for Probiotics and Nanotechnology

FDA devotes special attention to certain emerging product categories in section VIII, where the guidance discusses unique considerations regarding live microbials and nanomaterials. 

For live microbial ingredients, companies should thoroughly characterize microbial strains and address potential toxin production and viability. For nanomaterials and products developed using nanotechnology, FDA recommends engaging early with the Office of Dietary Supplement Programs through a pre-NDIN meeting due to the unique scientific and safety questions these products may raise.

7. Numbers Matter

Section IX focuses on the quantitative aspects that ultimately form the basis for a finding of “reasonable expectation of safety.”  One message of the Guidance is that safety conclusions must be supported by data.

FDA outlines expectations for calculating and justifying NOAEL values, EDI, ADI, and Margin of Safety. This section breaks safety down to a mathematical bottom line, and NDINs must contain the data to meet the quantitative bottom line.

Takeaways

The Guidance reflects FDA’s continued shift toward more rigorous, science-based NDIN submissions. Companies preparing NDINs should:

1. Review ingredient identity testing and characterization procedures.
2. Assess whether historical use data adequately support current conditions of use.
3. Develop a well-supported safety narrative connecting all available evidence.
4. Evaluate whether additional studies are needed to fill safety gaps.
5. Consider early FDA engagement for novel ingredients, probiotics, or nanotechnology-related products.

Ultimately, the Guidance signals that FDA wants NDINs supported by clear scientific reasoning, robust data, and objective safety calculations that demonstrate why a new dietary ingredient can reasonably be expected to be safe.

Please contact Rachael Vieder Linowes ([email protected]), Kyla Kaplan ([email protected]), or Jamie Woodside ([email protected]) if you have any questions or need assistance with outreach to FDA’s ODSP or filing a NDIN.