The U.S. Food and Drug Administration opened a 30-day public comment period (www.regulations.gov, docket number FDA-2026-N-2047) following the March 27 public meeting. The Agency was seeking stakeholder input on four key questions:
1. What is your view on whether the phrase “dietary substance for use by man to supplement the diet by increasing the total dietary intake,” as used in DSHEA, can include substances that have never been part of the diet?
2. When existing dietary ingredients are produced using emerging technologies such as synthesis, cell culture, precision fermentation, or recombinant production, at what point does a change in production methodology meaningfully alter the ingredient’s identity, composition, or safety profile—and therefore warrant additional regulatory scrutiny or data submission?
3. How should production technologies be characterized, e.g., in a new dietary ingredient notification—including potential byproducts, impurities, and structural or functional variations—to ensure that FDA can adequately assess the resulting ingredient?
4. For ingredient types such as peptides, proteins, enzymes, and microbials, what scientific criteria are important in determining the identity of a substance? For these ingredient types, what scientific criteria are important in determining whether two substances are sufficiently similar to be considered the same dietary ingredient for regulatory purposes?
Question 1: What is a ‘dietary substance’?
According to the Dietary Supplement Health and Education Act (DSHEA), a dietary supplement is defined as: (A) a vitamin, (B) a mineral, (C) an herb or other botanical, (D) an amino acid, (E) a dietary substance for use by man to supplement the diet by increasing the total dietary intake, or (F) a concentrate, metabolite, constituent, extract, or combination of any dietary ingredient from the other categories listed above.
The Agency’s first question focuses on part (E), which Scott Bass, principal at Scott Bass Life Sciences LLC and one of the architects of DSHEA, has called the “innovation section”.
The comments to FDA reflected a broad agreement from industry trade associations, independent experts, and some private individuals that FDA’s current interpretation of 201(ff)(1)(E) (“dietary substance for use by man to supplement the diet by increasing the total dietary intake”) is too narrow, not supported by statute or legislative history, and increasingly misaligned with modern science and manufacturing.
They consistently argue that Congress intended 201(ff)(1)(E) to be a forward-looking, catch-all innovation category, not limited to substances already present in the conventional food supply.
In his submitted comments, Bass provided extensive legislative history showing Congress explicitly contemplated ingredients like co-enzyme Q10, glucosamine, probiotics, and synthesized compounds, many of which were not commonly consumed as food.
In addition, the Consumer Healthcare Products Association (CHPA), the Council for Responsible Nutrition (CRN), the Natural Products Association (NPA), the United Natural Products Alliance (UNPA), the International Probiotics Association (IPA), and the Global Organization for EPA and DHA Omega-3s (GOED) all argued that a “commonly used as food” test imposes a requirement that does not appear in the statutory text and contradicts the intent of the New Dietary Ingredient (NDI) provision.
“DSHEA’s safety-focused provisions governing “new dietary ingredients” reflect an expectation that dietary substances would include those beyond food present in the usual or common diet,” stated comments from NPA. “Section 413(a)(1) exempts NDIs from notification if a product contains ‘only dietary ingredients which have been present in the food supply as an article used for food in a form in which the food has not been chemically altered’. Therefore, Congress must have anticipated that NDIs subject to notification to FDA under section 413(a)(2) would include dietary ingredients that are not present in the food supply.
“FDA’s narrow interpretation of section 201(ff)(1)(E) — and the associated risks to companies that FDA will reject an NDIN based on a conclusion that an ingredient does not meet the definition of a “dietary substance” — likely results in fewer NDI notifications to the agency and greater reliance on a pathway to market that the Trump administration has scrutinized: GRAS (generally recognized as safe) self-affirmation"
Natural Products Association
The industry trade associations stressed that Congress separated eligibility from safety, using NDIs and adulteration authority, and not categorical exclusions, to manage risk.
IPA pointed out that microbial exposure occurs through many non-food pathways, including the soil, plants, and other incidental dietary sources, making “food origin” an unscientific proxy for probiotic eligibility.
“Because incidental microbial exposure plays an important role in shaping the gut microbiome, these microorganisms may also be appropriate for use in dietary supplements, provided they are adequately characterized to become intentionally used, particularly for individuals with limited access to other nutritional sources of beneficial microbes,” stated IPA. “Limiting probiotic benefits only to strains already considered part of the “food supply” is not supported by available safety data or risk‑based regulatory principles.”
Scott Jackson, founder and principle of biotechnology consulting firm The NEST and former group leader at the National Institute of Standards and Technology (NIST), concurred: “[…] interpreting DSHEA, which was enacted in 1994, to limit dietary ingredients only to substances with a documented history of dietary presence is unnecessarily restrictive, particularly given that our understanding of the microbiome of the food supply and the human gut was extremely limited at the time.”
On the other hand…
Some comments provided an alternative interpretation, however, stating that the definition must retain some anchoring to the human diet, so as not to become a limitless category for novel compounds.
The American Herbal Products Association (AHPA) argued that “materials that are wholly novel, are not present in humans or created through a natural human biological process, and have never previously been ingested by humans should be excluded from the dietary ingredient category.
“However, AHPA believes that substances that are the same as or similar to those historically consumed by humans or present in humans, but which are produced by modern techniques (as opposed to traditional food preparation processes), should qualify as dietary substances and generally be regulated as New Dietary Ingredients (NDIs).”
Samantha Magdaleno, a private individual, concurred with this position, stating in her comments that a dietary substance “must have a real connection to the human diet. That connection can come from direct consumption, presence in food, or a clear relationship to dietary intake. Completely novel substances without that connection should not qualify under this category.”
Question 2: Producing existing dietary ingredients using emerging technologies
This question again yielded strong consensus from industry stakeholders, with many stating that the manufacturing method alone should not define identity or trigger new regulatory status. The focus must be on the finished ingredient’s measurable characteristics, they stated.
For example, CHPA, CRN, IPA, Scott Jackson, and NOĒSIS (a company developing oral delivery formats for dietary ingredients intended to support cognitive performance) all urged FDA to adopt a product- and risk-based approach, evaluating whether production changes materially alter: Structure or sequence; impurity profile; bioactivity or bioavailability; and stability or exposure.
“A change in production method alone should not be treated as a proxy for risk or as automatically creating a new ingredient,” wrote CHPA.
Question 3: How should production technologies be characterized in an NDI notification?
Industry comments aligned on the position that NDINs (New Dietary Ingredient Notifications) should provide what FDA needs to assess safety and identity, with the elements to include: High‑level process description (focused on identity‑relevant steps); starting materials/inputs relevant to allergens or toxic residues; finished‑ingredient specifications (identity tests, purity, limits); impurity and byproduct profiles; and stability and shelf‑life considerations.
“In the more than 30 years since DSHEA’s enactment, advances in manufacturing, including synthesis, cell culture, and precision fermentation, have enabled production of safe, consistent, high-quality ingredients. These methods often improve purity without altering the fundamental identity or safety of the ingredient,” stated CRN in its comments.
“Regulatory evaluation should focus on whether manufacturing changes materially affect identity or safety. When no significant changes occur, companies should have access to efficient mechanisms (e.g., meetings with FDA) to confirm continued compliance.”
AHPA emphasized consumer transparency regarding source and production method, especially where modern techniques mimic traditional botanicals.
“FDA should take steps to ensure that product labeling accurately differentiates ingredients produced using traditional techniques and sourced from agriculturally grown botanicals vs. similar ingredients produced using modern techniques to create compounds found in botanicals. Ingredient labeling and associated implicit and explicit product and ingredient descriptive claims should retain such distinctions in manufacturing and sourcing as may best produce an informed marketplace,” wrote AHPA.
“We ask that the agency consider requiring this source information in the Supplement Facts panel’s declaration of the ingredient (e.g. “Saffrosides (from cell culture)” vs “Saffron Extract (Crocus sativus) (Stigma)” and not view it as prohibited intervening material under 21 C.F.R. § 101.2(a).”
Question 4. Scientific criteria for identity and “sameness” for peptides, proteins, enzymes, and microbials
Addressing this question specifically, CHPA outlined a number of criteria for both identity and sameness. For identity of peptides/proteins, this would be the amino acid sequence (or defined mixture profile) and the molecular weight/size distribution. For enzymes, the primary identity should focus on catalytic function (reaction catalyzed). For microbials (ie. probiotics), it is the genus/species and strain-level identification (where relevant).
Weighing in on microbials, IPA called on the FDA to recognize that microbial species with a history of safe use in food may qualify under Section 201(ff)(1)(E), since core characteristics such as morphology, metabolism, and physiology are generally shared at the species level, while functional benefits and clinical effects are typically strain-specific.
“At the same time, strain-level review remains appropriate for safety-related factors such as taxonomic identity, antimicrobial resistance, toxigenicity, pathogenicity, manufacturing controls, and finished product specifications,” added IPA. The same principles would apply to postbiotics (non-viable microorganisms), they said.
One the question on “sameness”, commenters noted that two substances may be considered the same dietary ingredient if they share: Primary identity; comparable functional attributes within specifications; and no new safety‑relevant impurity differences.
The take home
FDA is still updating the docket and this articles does not represent an exhaustive review of all comments submitted. Despite this limitation, the vast majority of comments reviewed by NutraIngredients were united on a central theme: That eligibility for dietary supplement ingredients should be broad and innovation-forward, safety should be rigorous, evidence-based, and enforced through DSHEA’s existing tools.
