New Dietary Ingredient Notifications: 75-Day FDA Filing, Safety Basis and the Master File Strategy
Section 413 of the FD&C Act, added by DSHEA in 1994, requires that any New Dietary Ingredient (NDI) — defined as a dietary ingredient not marketed in the United States in a dietary supplement before 15 October 1994 — be the subject of a notification to the FDA at least 75 days before introduction or delivery for introduction into interstate commerce, unless the ingredient 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.
In Short
- An ingredient is grandfathered — and exempt from NDI notification — only if it was marketed as a dietary ingredient in a dietary supplement in the US before 15…
- Section 413(a)(1) exempts an NDI from notification if it 'has been present in the food supply as an article used for food in a form in which the food has not been…
- The legal standard is 'reasonable expectation of safety' (not the food-additive 'reasonable certainty of no harm' standard, but FDA reviewers apply substantial…
The notification must contain the manufacturer's reasonable expectation of safety based on the intended conditions of use. The FDA's 2016 Revised Draft Guidance on NDI notifications clarified the agency's expectations on identity, manufacturing, history of use and safety narrative — and tightened enforcement against unnotified NDIs. This guide covers the grandfather question, the safety basis, the dossier, the master file strategy and the operating posture for ingredient and finished-product companies.
Is the ingredient an NDI? The 1994 grandfather question
An ingredient is grandfathered — and exempt from NDI notification — only if it was marketed as a dietary ingredient in a dietary supplement in the US before 15 October 1994. The burden of demonstrating pre-DSHEA status rests on the marketer, not the FDA.
More on is the ingredient an NDI? The 1994 grandfather question
Acceptable evidence includes dated invoices, labels, catalogues, advertisements, scientific literature and trade publications showing the ingredient (in the same chemical form and source) in a US-marketed supplement before the cut-off. The FDA does not maintain an official 'grandfather list'; industry associations (CRN, AHPA, UNPA) maintain consensus lists, but FDA does not endorse them as authoritative. A chemically altered form of an old ingredient (different extraction solvent, different ratio, different active marker) is treated as a new ingredient even if the source plant or organism is grandfathered. Practical test: if the form, extraction, concentration, source organism or production organism differs materially from documented pre-1994 marketing, treat the ingredient as an NDI.
The food-supply exemption — narrow and frequently misapplied
Section 413(a)(1) exempts an NDI from notification if it '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.' The exemption is narrower than it sounds. 'Food supply' means the conventional food supply (a foodstuff in the diet), not the supplement marketplace. 'Article used for food' means it has been consumed as a food, not as a flavour, colour or additive. 'Has not been chemically altered' is the trip-wire — the FDA's 2016 draft guidance reads this strictly: extraction with solvents other than water or aqueous ethanol, fermentation that changes the chemical profile, hydrolysis, concentration that changes the active-to-matrix ratio, esterification or salt-form changes, and microbial conversion all typically qualify as chemical alteration. Practical rule: if an ingredient marketing claim invokes the food-supply exemption, the dossier must affirmatively justify both food-supply presence and the absence of chemical alteration, with analytical comparability evidence.
More on the food-supply exemption — narrow and frequently misapplied
FDA has issued warning letters where a self-asserted food-supply exemption did not meet the regulation's standard.
Reasonable expectation of safety — what the dossier needs to show
The legal standard is 'reasonable expectation of safety' (not the food-additive 'reasonable certainty of no harm' standard, but FDA reviewers apply substantial scientific rigour). The dossier should cover: (1) ingredient identity — common name, chemical name, source organism with full taxonomy, manufacturing process, specifications, analytical methods, batch-to-batch consistency, marker compound identification; (2) intended conditions of use — daily intake, duration, target population (including any contraindicated subpopulations), supplement form, labelling; (3) history of use — documented use as a food or supplement in any jurisdiction, with dates, intake levels and population sizes; (4) safety data — published toxicology, ADME, sub-chronic and chronic studies, genotoxicity, reproductive and developmental toxicity, human clinical data, post-market surveillance; (5) regulatory status in other jurisdictions (EFSA Novel Food assessments, Health Canada NHP licences, TGA listings); (6) for botanicals, source identification down to part used, growing region, harvest method and adulteration controls.
More on reasonable expectation of safety — what the dossier needs to show
The 2016 draft guidance is explicit that the safety basis must match the intended conditions of use — a study at a lower dose does not support a higher labelled dose.
Master files — when, why and what
An NDI Master File is a confidential submission to the FDA containing detailed manufacturing, specification or safety information that an ingredient supplier wants to make available to multiple downstream finished-product NDI notifications without disclosing the information to each customer. The ingredient supplier files the master file and receives a reference number; downstream finished-product brand-owners cite the master file in their own NDI notifications and provide a letter of authorisation from the supplier permitting FDA access to the referenced sections.
More on master files — when, why and what
Master file strategy is the operating norm for ingredient suppliers selling a novel ingredient to multiple brand-owners: it preserves the supplier's trade secrets, accelerates the brand-owner notification, and consolidates safety review at FDA. The supplier's NDI notification establishes the baseline; brand-owner notifications focus on finished-product-specific factors — formulation, intended use, claims and labelling.
Operating posture — submission, FDA response, and life after filing
Notifications are submitted to CFSAN's Office of Dietary Supplement Programs (ODSP) at least 75 days before marketing. FDA responses fall into three buckets: (1) no objection (rare — silence after 75 days does not constitute approval but is permissive for marketing), (2) acknowledgement letter noting the filing without objection, (3) an FDA objection letter citing inadequate safety basis, identity ambiguity, food-supply-exemption misapplication or intended-use mismatch.
More on operating posture — submission, FDA response, and life after filing
An objection is not a rejection in the formal sense — the marketer may withdraw, modify and refile — but marketing the NDI in the face of an objection invites enforcement. Post-filing: the notification is published on the FDA website (with redactions for trade secret content); the safety basis must be re-evaluated and the notification refiled if the manufacturing process, source, specification, intended use, dose or claims change in ways that affect safety. FDA has stepped up enforcement on unnotified NDIs, including warning letters and import alerts. Brand-owners that contract for a 'novel' or 'patented' ingredient should require evidence of NDI status (accepted notification with submission ID, or documented exemption analysis) in supplier qualification.
Questions
Is the FDA's 2016 NDI guidance final?
No. The 2016 document is a Revised Draft Guidance for Industry — it represents the FDA's current thinking but is not legally binding. In practice, however, ODSP applies the draft guidance in its review of notifications, and notifications that ignore its expectations on identity, chemical alteration, safety narrative and intended-use scope are routinely objected to. Treat the draft guidance as operationally binding even though it is not legally finalised.
Does FDA acceptance of an NDI notification mean the ingredient is approved?
No. NDI notification is a notification regime, not an approval regime. An FDA letter of no objection means the agency does not have safety concerns based on the information submitted; it is not an endorsement of safety, efficacy or labelling claims. Marketing must still comply with all DSHEA requirements — 21 CFR 111 GMPs, structure/function claim substantiation and 30-day notification, label compliance, adverse-event reporting. New safety information that emerges post-filing may require refiling or withdrawal.
Can a finished-product company rely on a supplier's NDI notification?
Partially. A supplier's NDI notification covers the ingredient — identity, manufacturing, intrinsic safety basis. The finished-product company still owns the formulation-specific factors: combined intake at the labelled serving, interaction with other ingredients, intended population, claims, labelling. Where the finished product matches the intended conditions of use in the supplier's notification, the brand-owner can typically reference the supplier filing (via master file letter of authorisation) and add finished-product-specific safety justification. Where the brand-owner exceeds the supplier's intended dose, daily intake or population, the brand-owner generally needs its own notification.
What happens if we market an NDI without notification?
The product is deemed adulterated under section 402(f) of the FD&C Act. FDA enforcement options include warning letters, seizure, injunction, import alerts (for foreign suppliers) and — increasingly — referral to criminal enforcement where the conduct is wilful or coupled with disease claims. Practically, retailers and contract manufacturers also refuse unnotified NDIs as a condition of vendor onboarding, so the commercial consequence often arrives before the FDA does.
Practical orientation, not legal advice. Rules differ by jurisdiction; your quality and compliance team decides what applies.
The Dietary Supplement Operations Guide
What the label says. What the batch proves.
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- Labels, samples and recall
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