NDI Notification

An NDI Notification is a premarket safety notification, not an approval application. The Dietary Supplement Health and Education Act of 1994 (DSHEA) created a two-tier system: dietary ingredients marketed in the US before October 15, 1994 (so-called 'old' or 'grandfathered' dietary ingredients) require no premarket filing; any dietary ingredient not marketed before that date is a New Dietary Ingredient (NDI) and requires a §413 notification at least 75 days before introducing the supplement containing it into interstate commerce, unless the NDI has been 'present in the food supply as an article used for food in a form in which the food has not been chemically altered' — a narrow exemption almost nobody qualifies for cleanly.

• The manufacturer or distributor of the dietary supplement that contains the NDI (not the ingredient supplier — though many suppliers also file 'master file'-style NDIs to support multiple customers).
• Any ingredient not marketed as a dietary ingredient in the US before October 15, 1994 — including isolated constituents of grandfathered ingredients (e.g. a specific bioactive isolated from an old herb at a level not present in food).
• Most synthetically-produced botanicals (FDA's long-standing position: a chemical copy of a plant constituent is not the same as the plant constituent and is an NDI).
• Most novel forms of an old ingredient (changes in extraction solvent, in nano-particle size, in conjugate, in chelate, in spray-dried form) — FDA has historically taken an expansive view here.
• Probiotic strains not marketed pre-1994 (the strain-level identity matters; the genus or species being old does not grandfather a specific strain).

What does NOT require an NDI notification: a 'food supply' NDI that is present in the food supply as an article used for food in a form in which the food has not been chemically altered (§413(a)(1)). The 'not chemically altered' bar is narrow — extraction, concentration, encapsulation and combination with other ingredients have all been argued by FDA to constitute chemical alteration in past objection letters. Many manufacturers file an NDI even when they believe they qualify for this exemption, as a defensive position.

1. Name and complete address of the manufacturer or distributor submitting.
2. Name of the new dietary ingredient with the description (including the Latin binomial name for botanicals — genus, species, part used, processing).
3. Description of the dietary supplement(s) that contain the NDI: name, intended use, labelled conditions of use, daily intake level, target population.
4. The history of use or other evidence of safety establishing that, when used under the conditions recommended or suggested in the labelling of the dietary supplement, the NDI will reasonably be expected to be safe.
5. Signature of the responsible person at the submitting firm.

The 'evidence of safety' section is where 95% of the work — and 95% of FDA's objection letters — live. FDA's 2024 revised draft guidance is the most current and detailed view of what they consider sufficient: dose-response data, animal toxicology where human history is thin, NOAEL/UF-based intake calculations, pharmacokinetics, contraindications, drug-interaction data, and comparison of the proposed dose to any dose with established safety history. A history-of-use case must establish the form, the dose, the duration and the population it has historically been used in.

The 75 calendar days begin running on the date FDA receives the notification. During that window, FDA reviews and may issue an objection letter, an acknowledgment letter (effectively 'we filed it, we have no objection at this time'), or — increasingly common — a 'filed without prejudice' or 'inadequate basis' letter that does not formally object but signals problems. If FDA issues an objection letter, marketing the supplement containing the NDI exposes the firm to enforcement (Warning Letter, seizure, injunction). FDA's letters are public, indexed in the NDI database, and routinely scrutinised by competitors and trade press.

• Master-file NDI by the supplier — the ingredient manufacturer files first, supports customer NDIs by reference, and absorbs the safety-evidence cost as a moat.
• GRAS self-affirmation as an alternative path for ingredients used in conventional food — useful when the ingredient has dual food / supplement use, but does not eliminate the NDI obligation for supplement use.
• Pre-NDI meeting with FDA's CFSAN — increasingly common to scope the safety package before filing.
• Combined NDI for related forms — one filing covering several closely-related forms of an ingredient (e.g. several mineral chelates), reducing repeat work.
• Defensive 'no objection' filings — submitting an NDI even where the firm believes the §413(a)(1) exemption applies, to lock in a documented filing date.
• Trade-association joint filings — historically used to defend traditional botanical ingredients with shared industry interest.

Filing the NDI is the beginning, not the end. The labelled conditions of use, daily intake and target population in the filing become the legal envelope the supplement must operate inside. Manufacturing must conform to the identity and specification described in the filing — which feeds directly back into §111.75 identity testing and §111.70 specifications. Material safety information that emerges post-market (adverse event reports, new toxicology, drug-interaction signals) must be evaluated against the filing and, if material, may require an updated notification. The DSHEA serious adverse event reporting rule (15-day mandatory reporting to FDA) applies regardless of NDI status, but a serious-AER on an NDI ingredient triggers heightened scrutiny of the original safety basis.

Searches like 'NDI notification SOP', '21 CFR 190.6 compliance', 'NDI tracking software', 'new dietary ingredient documentation' or 'NDI safety evidence dossier' come from a specific buyer profile: a regulatory affairs lead at a brand or contract manufacturer that is about to launch — or has just launched — a product containing an ingredient with NDI exposure. The buying motion is typically narrow but high-value: they need a regulatory dossier system, an NDI-status flag on the ingredient master, evidence-of-use records, and a clean linkage from the NDI filing to every product, batch and label that depends on it.

• NDI-status flag on the ingredient master — every dietary ingredient is tagged as Grandfathered (pre-1994), NDI Filed (with filing date, FDA acknowledgement reference, master-file pointer if supplier-supported), NDI Pending, Exempt (§413(a)(1) basis documented), or Unknown/Risk.
• Filing record store — the NDI filing PDF, FDA correspondence (acknowledgement / objection / supplementary), the safety dossier and supporting references live in a controlled, versioned location with two-person sign-off on changes.
• Conditions-of-use envelope — labelled daily intake, target population, dosage form recorded against the NDI; any product master that exceeds or contradicts the envelope surfaces as a regulatory exception.
• Forward traceability — every product / batch / label that consumes the NDI ingredient is auto-linked to the NDI record; a regulatory action on the NDI maps directly to affected products in minutes.
• AER linkage — serious-AER records (the 15-day mandatory reports) are flagged when the product contains an NDI ingredient, surfacing the original safety basis for re-evaluation.
• Supplier master-file pointer — when the supplier holds the master NDI, the supplier's reference is stored on the ingredient and on the supplier scorecard; supplier change requires re-evaluation of the NDI coverage.
• Industry-aware UI — supplement-industry workspaces surface NDI status on ingredient and BOM screens; pharma / device workspaces do not see this field at all.