New Dietary Ingredient Notifications: 75-Day FDA Filing, Safety Basis and the Master File Strategy

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. 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.

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 'Has not been chemically altered' is the trip-wire — the FDA's 2016 draft guidance reads this strictly: extraction with solvents other than water or aqueous ethanol, fermentation that changes the chemical profile, hydrolysis, concentration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. FDA has issued warning letters where a self-asserted food-supply exemption did not meet the regulation's standard.

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. 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.

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. 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.

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. 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.