The NDI Rulebook, Rebuilt One Piece at a Time

What FDA has finalized, what changed, and what the industry is still waiting on.

Dr. Corey Hilmas, MD/PhD, Chief Scientific Affairs and Regulatory Officer

October 20, 2026

One draft, three documents

In August 2016, FDA released a revised draft guidance on new dietary ingredient (NDI) notifications. It tried to cover everything at once: which ingredients qualify, when to notify, how to file, and what evidence to include. Industry asked FDA to break it up, and FDA has been doing that ever since.

The first piece aimed at finalization arrived in March 2024, when FDA finalized the procedures section as New Dietary Ingredient Notification Procedures and Timeframes. The second piece arrived in October 2026, when FDA finalized the identity and safety sections as Identity and Safety Information About the NDI. The pages they replaced now read “RESERVED” in the draft.

Source: the draft guidance’s October
2026 Document History.

What is now different from draft and finalized

The 2024 guidance covers the mechanics: who must notify, the 75-day clock, what makes a notification incomplete, electronic filing, confidentiality and pre-notification meetings. The 2026 guidance covers the content: how to establish identity and how to show the product is reasonably expected to be safe. Together, they tell a notifier how to file and what to file.

Compared with the 2016 draft and the 2024 sketch of notification content, five areas stand out in the 2026 final:

1. One safety narrative, not two. The 2024 paper template listed separate narratives for the supplement and the NDI. The 2026 final asks for one comprehensive narrative that matches the safety template in FDA’s online submission system.

2. Identity becomes a playbook. Specification tables should list each test, specific acceptance criteria and the full analytical method, with extra detail for botanicals, extracts, salts, isomers, enzymes, fermentation products and live microbes I don’t think this is a surprise for anyone.

3. Conditions of use come with a number. Notifiers should calculate the maximum total daily intake (serving size times servings per day) and state the conditions of use up front. I don’t view this to be a change but rather than explicitly stating the obvious.

4. Safety evidence gets a framework. FDA sets 25 years of widespread use as a general minimum for history of use, defines daily chronic use strictly, matches studies to data gaps, gives new approach methods (NAMs) a role, and sets safety factors with an EDI/ADI ratio of 1 or less. This approach is no different than what FDA has always used. It relies on a properly referenced citation for historical use requiring up to 25 years, and the EDI/ADI ration of 1 or less has always been the case. The EDI should never be larger than the ADI.

5. Microbes and nanomaterials have virtually no change. Any species that includes human pathogens (e.g., E. coli, E. faecium, Salmonella, modified/weakened strains of pathogens, etc.) is considered inappropriate. I don’t think FDA has made a real change here as it has always viewed pathogens as problematic when considering food ingredients. Nanomaterials up to 1,000 nm with size-driven effects call for contacting FDA before filing. This number of 1,000 nm falls in line with what FDA views as nanomaterials so FDA could not settle on 1-100 nm materials.

Table 1. Differences between the draft and final guidance

This table lists only the points where the October 2026 final guidance differs from the draft. Items the final restates without change (for example, the 75-day filing requirement, full copies of cited publications, and English translations) are left out. Section numbers in parentheses point to the source: “draft” for the 2016 revised draft, “2024” for the March 2024 Procedures and Timeframes final guidance, and plain numbers for the 2026 final. In the current draft, Sections VI.A–C read “RESERVED,” so draft-side entries for those topics come from the draft’s remaining text, definitions and Document History, and from the 2024 final that replaced its procedures section.

#	Topic	Draft guidance (2016 revised draft, with its procedures section as finalized in March 2024)	Final guidance (October 2026, Identity and Safety Information About the NDI)
1	Status and docket	Draft, “Not for Implementation”; docket FDA-2011-D-0376. Procedures section finalized separately in March 2024 (FDA-2011-D-0386).	Final guidance, October 2026; new docket FDA-2025-D-6501. Still nonbinding.
2	Issuing office	CFSAN, Office of Dietary Supplement Programs (2024 final: ODSP and Office of Regulation and Policy).	Human Foods Program (Office of Food Chemical Safety, Dietary Supplements & Innovation, and Office of Policy, Regulations and Information & International Engagement).
3	Structure	Identity and safety content sat in three subsections (VI.A–C) of one large guidance; history of use and other evidence of safety shared one subsection (VI.B, questions numbered to 42).	Standalone document: definitions, six Q&A sections (IV–IX) and Appendix A, 59 questions. History of use, other evidence of safety and emerging disciplines are now separate sections.
4	Questions retired	VI.B.20, 24, 26, 27, 30, 34 and VI.C.2 were part of the draft.	No destination listed in the draft’s Document History; these 7 questions are now shown as RESERVED and effectively dropped.
5	Safety testing table	Table 3.	Appendix A Standard Safety Testing Table, plus a separate table of when history of use alone is sufficient.
6	Describing the NDI	Ingredient category and basis, manufacturing with process controls, composition, and a spec sheet “preferably in table form”; prior NDIN number requested (2024 III.D).	17 questions (IV.1–17): example specification tables with tests, specific acceptance criteria and full analytical methods; ties to 21 CFR 111.70(b); added data for 10 ingredient types. Prior NDIN number not mentioned.
7	Describing the supplement	NDI level, other ingredients, manufacturing, spec sheet and conditions of use (2024 III.E).	Adds evidence that other ingredients are food grade, an example supplement spec table (Table 2) and stability data to support any expiration or “use by” date (IV.18).
8	Conditions of use	Serving form, size, frequency, duration, target and excluded populations; lifetime daily use by all ages assumed unless restricted (2024 III.E).	Same assumption, plus a calculated maximum total daily intake (serving size × servings per day) and maximum NDI per serving, stated up front in the administrative section (IV.19).
9	Safety narrative	One objective evaluation and explanation (2024 III.F); the paper template lists separate narratives for the supplement and for the NDI.	A single comprehensive narrative matched to the online safety information template, covering intake, toxicity, non-dietary ingredients, NOAEL, ADI and margin of safety (V.2).
10	What to leave out	No efficacy-only data, unrelated reviews or promotional material (2024 III.G).	Adds that you need not list every historical use and should skip superfluous data (VI.7); efficacy-only trials rarely support safety (IX.1).
11	Unpublished studies	Complete description of data and methods (2024 III.O).	Also cite an authoritative protocol source, justify the protocol choice and explain any deviations (VII.5).
12	Botanicals	Latin binomial with author, plant part, unusual forms and controlled growing conditions (2024 III.D).	Adds ICN nomenclature, taxonomic identity tests, cultivation and harvest details, a curated voucher specimen and exclusion of known adulterant species (IV.10–11).
13	Live microbes	Bacteria named by binomial and strain (2024 III.D); pathogenic species such as Salmonella or E. coli are not dietary ingredients (draft IV.C.6).	Each strain is a separate ingredient; identity by whole genome sequencing or a recognized repository; any species that includes human pathogens is inappropriate (names E. coli, E. faecalis, E. faecium); heat-killed microbes need full characterization (IV.17, VIII.1).
14	Nanomaterials	A process change producing 1–100 nm particles needs a new notification (draft IV.A.13).	Covers engineered materials up to 1,000 nm with size-driven effects; contact FDA before submitting (VIII.2).
15	Multiple NDIs in one product	Combining NDIs creates a new NDI; scenario recommends testing the combination (draft IV.C.5).	New question: provide data on the combination, or on each NDI plus an explanation of why the combination raises no new concerns (V.3).
16	History of use	No minimum length stated in the remaining draft text or the 2024 final.	25 years of widespread use as a general minimum, consistent with the EU novel foods rule; U.S. or foreign data allowed; mean and 90th-percentile intake expected (VI.2–3).
17	Chronic vs. intermittent use	Chronic = exposure over 3 months; daily use broken by non-use still counts as chronic (draft definitions).	Daily chronic = at least once a day, every day, for 3+ months in a row; anything less is intermittent, including non-daily lifetime use (VI.9).
18	Estimated daily intake (EDI)	Highest possible intake from the proposed use plus background intake from other dietary sources (draft definitions).	Highest total daily intake under the proposed conditions of use; background dietary intake not mentioned (III, IX.2).
19	New definitions	Not defined in the draft’s definitions list.	Adds acceptance criteria, alternative methods (NAMs), EDI/ADI ratio, in-process controls, quality control and traditional medicine (III).
20	New approach methods (NAMs)	Not addressed.	Fit-for-purpose NAMs may help fill data gaps but are unlikely to suffice alone; quality criteria for in vitro and in silico studies (VII.1, VII.3, VII.7).
21	Safety calculations	Draft refers readers to question VI.C.8 for the ADI, which is now reserved (draft IV.B.3).	Margin of safety recommended even with a history of use; safety factors of 100, 1,000 or 2,000; EDI/ADI of 1 or less (IX.2–6).
22	FDA requests during review	FDA may request more information and reset the 75-day clock (2024 IV.C).	Adds that FDA may request data on known toxicities if missing and may run its own calculations on any submitted study (VII.15, IX.1).
23	What FDA’s response means	A no-objection letter is not an independent finding of safety (2024 IV.D).	States plainly that FDA does not approve NDI notifications and no approval is issued at any point (II).
24	Online submission system	“CFSAN Online Submission Module” (COSM) (2024 III.I).	Same system, renamed “Centralized Online Submission Module” (V.2, footnote 16).
25	Pre-notification meetings	Voluntary; request by email; may be denied; FOIA caveat (2024 V).	Suggested when unsure whether other evidence of safety is needed (VI.6) and before any nanomaterial notification (VIII.2).

What the industry is still waiting on

The questions that decide whether an ingredient can be sold at all, and whether a notification is needed, are still in draft. The 2026 final tells you what to put in a notification. It does not tell you, with final authority, whether your ingredient qualifies or whether you need to notify in the first place.

The table below lists the open items, what the current draft says about each, and why each one matters.

Still waiting on	Where the draft stands now	Why it matters
Ingredient eligibility (draft IV.D.1–5)	Synthetic copies of botanical constituents, extracts or concentrates are not dietary ingredients unless used as conventional food (vanillin is the example). Contaminants, food contact substances and secondary direct additives generally do not qualify. Changing a structure does not carry dietary-ingredient status over.	Decides whether an ingredient can be in a supplement at all, before any notification question arises.
What counts as an NDI (draft IV.A.1–10)	Only U.S. marketing as a dietary ingredient before October 15, 1994 counts. Conventional food use and foreign marketing do not. Affidavits without records from the time are generally not enough.	Determines whether you must notify and sets a high documentation bar.
A “grandfathered” ingredient list (draft IV.A.11)	There is no authoritative pre-DSHEA list, and FDA does not accept industry lists as proof. FDA says it is prepared to build one from records industry supplies.	Every firm still has to keep its own pre-1994 marketing records.
Manufacturing changes (draft IV.A.12–13)	Changes that alter identity, purity, bioavailability or toxicity create an NDI. Solvent extraction of a pre-DSHEA ingredient creates an NDI. A change to nanoscale particles needs a new notification.	Process upgrades and reformulations may trigger new notifications.
Chemical alteration exception (draft IV.B.1–5)	“Food supply” means conventional food only. Solvents other than water or aqueous ethanol, and extractions with a filtration step, generally count as chemical alteration.	Controls which food-derived NDIs can skip notification.
When a notification covers your product (draft IV.C.2–3, 5, 7)	Each supplement firm must notify unless an existing notice covers the same NDI and conditions of use. Scenarios cover higher doses, new combinations and supplier notices.	Shapes how far firms can rely on a supplier’s or another company’s notification.
NDI master files (separate April 2024 draft)	Moved out of the 2016 draft into its own draft guidance, which is not yet final.	The confidential pathway for supplier identity and manufacturing data is still unsettled.
Drug exclusion (draft IV.D.7–12)	Ingredients first approved as drugs, or first studied under an IND with public substantial clinical investigations, are excluded. FDA’s NDI review does not consider this bar, and no exception regulations have been issued.	Can block an ingredient regardless of its safety evidence.
Microbial ingredients (draft IV.C.6)	There is no separate category for live microbes. Bacteria never consumed as food are unlikely to be dietary ingredients.	Eligibility of novel strains, now paired with the 2026 final’s strain-level identity expectations.
Definitions and decision tree (draft VII–VIII)	Still in draft. The draft’s EDI includes background diet and its “chronic” differs from the 2026 final. The draft still points to question VI.C.8, now reserved.	Two sets of definitions are in use until FDA reconciles them.

FDA’s dietary supplement industry page also lists other related documents that remain drafts, including a draft policy on certain NDIs and dietary supplements subject to premarket notification.

Loose ends between the documents

Until the rest of the draft is finalized, notifiers will work across three documents with slightly different vocabularies. Two examples stand out. The draft still defines estimated daily intake (EDI) to include background intake from other foods, while the 2026 final does not. The draft also treats daily use with breaks as chronic, while the 2026 final calls anything short of every day for three months in a row intermittent.

What to do now

1. Use the 2024 guidance for how to file and the 2026 final for what to file. Build one safety narrative, include a maximum daily intake in your conditions of use, and check specification tables against the 2026 examples.

2. Seek experts who can evaluate the regulatory status of your ingredient prior to investing in an NDI notification. Test eligibility against what has already been written in draft: dietary-ingredient category, pre-1994 U.S. marketing records, manufacturing changes, chemical alteration and the drug exclusion. These are the issues most likely to give regulatory pause and concern, and they are the ones FDA has not finalized.

3. Identify you safety and identity gaps through a written gap assessment to understand where you are along the process toward gaining an NDI acknowledgement.

4. Partner with regulatory experts you can trust to fill in your safety and identity gaps and conduct scientific preclinicals for safety and chemistry studies for identity.

5. Watch the dockets for the next final piece and comment on the open questions while they are still open.

Sources: FDA, Dietary Supplements: New Dietary Ingredient Notifications and Related Issues (revised draft, October 2026 Level 2 revision of the August 2016 draft); FDA, New Dietary Ingredient Notification Procedures and Timeframes (final, March 2024); FDA, New Dietary Ingredient (NDI) Notifications and Related Issues; Identity and Safety Information About the NDI (final, October 2026); FDA, Information for Industry on Dietary Supplements.

Have questions about your ingredient’s regulatory pathway? Connect with our team at

KGK Science- Sales