The U.S. Food and Drug Administration (FDA) has issued final new dietary ingredient notification guidance that sets out what manufacturers and distributors should include in the identity and safety sections of an NDIN. Published in October 2026 by the Human Foods Program, the document affects any company planning to market a dietary supplement that contains an ingredient not sold in the United States before October 15, 1994.
The guidance finalizes Sections VI.A, VI.B and VI.C of FDA’s 2016 revised draft guidance on new dietary ingredient notifications. Other portions of that draft remain open, and FDA says it plans to finalize them individually. Comments on the document can still be submitted under docket FDA-2025-D-6501.
What the Guidance Covers
The notification requirement traces back to the Dietary Supplement Health and Education Act of 1994 (DSHEA), the law that established the modern U.S. framework for dietary supplements. DSHEA amended the FD&C Act to define dietary ingredients and added section 413, which created the NDI pathway and set October 15, 1994 as the cutoff for what counts as a new ingredient. If you need a refresher on the basics, see how FDA classifies an NDI.
Under section 413(a)(2), a notification must reach FDA at least 75 days before the product enters interstate commerce. FDA does not approve these notifications, but a supplement can still be deemed adulterated if the submission fails to establish a history of use or other evidence of safety. As with all FDA guidance, the recommendations are not legally binding unless a specific regulation or statute is cited.
The document is organized around three questions. What is the ingredient, how safe is it under the proposed conditions of use, and does the evidence in the notification support that conclusion? FDA’s final guidance on NDI notifications, identity and safety information answers each in detail, and several of its recommendations are more specific than earlier drafts.
Identity Information Now Expected in an NDIN
FDA recommends that notifiers present identity specifications in table form, listing each test, its acceptance criteria and the analytical method used. The agency states that criteria must be specific. A chromatogram that simply “matches the reference sample” is not informative unless the peaks, heights and locations are described. Manufacturing descriptions can be limited to the steps relevant to identity and safety, provided in-process controls and quality attribute testing are included.
The guidance also sets ingredient-specific expectations. These include the following.
- Botanicals need the Latin binomial with author citation, the plant part used, and documentation of a curated voucher specimen.
- Extracts and concentrates need concentration ratios, solvent details, marker content and a batch-to-batch standardization approach.
- Enzymes need a validated activity assay and acceptance criteria for activity per serving.
- Fermentation-derived ingredients need the full media formulation, vessel and conditions, and controls against contamination or genetic drift.
- Live microbial ingredients need strain-level identification, a deposited reference strain, and an assessment of antibiotic resistance and virulence factors.
History of Safe Use and Gaps in the Evidence
Where a notification relies on history of safe use alone, FDA generally recommends at least 25 years of widespread use. It also expects the historical intake to be equal to or higher than the proposed intake. A steroid hormone present in nanogram amounts in milk, for example, would not support a concentrated extract containing milligram amounts. If you are deciding which route fits your ingredient, compare the differences between GRAS and NDI.
Frequency of use now has a defined meaning. Daily chronic use means ingestion at least once a day, every day, for at least three months. Anything less is intermittent. When history reflects intermittent use and the proposed use is daily chronic, FDA treats that as a safety gap that should be addressed. Traditional medicine use may support a notification, but the guidance advises supplementing it with other evidence because composition and conditions of use often differ.
Other Evidence of Safety and Alternative Methods
When gaps exist, FDA points to genetic toxicity batteries, animal studies and human studies, and it says the choice depends on the gap being addressed. A 90-day subchronic oral study remains a common route to a NOAEL, while reproductive studies are relevant mainly when a product is intended for pregnant or lactating women, infants or children.
The guidance also gives explicit support to new approach methods, including in vitro assays and in silico modelling. FDA states these are unlikely to be sufficient alone, but they can fill gaps or strengthen other data when the notifier shows the method is fit for purpose.
Safety calculations carry weight too. FDA recommends a margin of safety (NOAEL divided by the estimated daily intake) even when history of safe use is the basis. For animal data, it describes a combined safety factor of 1,000 when two subchronic studies exist, one rodent and one non-rodent. A single rodent study may be acceptable at a factor of 2,000 if no toxicity occurs at the maximum tolerated dose. The EDI to ADI ratio should be 1 or less.
What This Means for Your Business
If your company is preparing an NDIN submission, the guidance works as a checklist for what reviewers expect to see. Quality Smart Solutions advises comparing your current dossier against the specification table format, the identity requirements for your ingredient type and the intake comparison between historical and proposed use. Gaps in any of these areas are easier to resolve before you submit than during FDA review, and the practical guide to completing an NDIN submission covers the wider process.
If your notification is already in progress, check whether your safety narrative explains why particular studies were selected or omitted, since the guidance asks for that reasoning directly. If you are considering new approach methods, plan how you will document validity and scope. For support with an NDIN notification for dietary supplements, you can find the service details on the Quality Smart Solutions website.
Frequently Asked Questions
Does this guidance replace the entire 2016 revised draft guidance?
Not yet, and that is a common point of confusion. FDA finalized only Sections VI.A through VI.C, and the remaining sections stay in draft status until they are individually finalized. Treat the final sections as current, monitor FDA for later updates, and review FDA’s NDI notification process for the submission steps in the meantime.
Is a pre-NDIN meeting with FDA still an option?
Yes, and the guidance encourages it in specific situations. FDA says notifiers unsure about whether to submit other evidence of safety may request a meeting through the Office of Dietary Supplement Programs. For ingredients involving nanomaterials, the agency recommends contacting it before submitting. Meeting materials may be disclosed under FOIA unless they qualify as confidential commercial information.
Do I need to run new animal or human studies for every NDIN?
No, although many companies assume otherwise. FDA does not recommend additional data when the proposed intake is the same as or lower than a documented history of safe use in the same or a broader population. Human clinical studies are not required under the FD&C Act, though they may be useful where existing data leave a gap.
Key Takeaways
- FDA finalized identity, history of use and safety summary recommendations for NDINs in October 2026.
- Specification tables should list tests, acceptance criteria and analytical methods in specific terms.
- History of safe use alone generally calls for at least 25 years of widespread use at equal or higher intake.
- New approach methods are supported but unlikely to be sufficient on their own.
- Margin of safety and EDI to ADI calculations belong in the safety narrative, even for ingredients with historical use.
Conclusion
The final guidance gives you a clearer picture of how FDA expects identity and safety evidence to be organized and justified. If you are planning an NDIN, review your documentation against it now, so any gaps surface well before the 75-day review window begins. To discuss how this applies to your ingredient, speak with a regulatory specialist at Quality Smart Solutions about NDIN submission support.
