The U.S. Food and Drug Administration (FDA) has initiated a 30-day public comment period (www.regulations.gov, docket number FDA-2026-N-2047) that follows a public meeting held on March 27. The FDA is keen on gathering feedback from stakeholders on four crucial questions:
1. Do you believe the phrase “dietary substance for use by man to supplement the diet by increasing the total dietary intake,” as defined in the Dietary Supplement Health and Education Act (DSHEA), can encompass substances not previously part of the diet?
2. When existing dietary ingredients are developed through modern technologies such as synthesis, cell culture, precision fermentation, or recombinant production, at what point does a change in production technique significantly alter the ingredient’s identity, composition, or safety profile, thus requiring additional regulatory review or data submission?
3. How should production technologies be described in new dietary ingredient notifications, including potential byproducts, impurities, and structural or functional variations, to ensure the FDA can effectively assess the resultant ingredient?
4. For ingredients like peptides, proteins, enzymes, and microorganisms, what scientific criteria should determine the identity of a substance? Additionally, how should we evaluate whether two substances are similar enough to be classified as the same dietary ingredient for regulatory purposes?
Question 1: What Constitutes a ‘Dietary Substance’?
According to the 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 listed categories.
The FDA’s first question focuses on part (E), which Scott Bass, a principal at Scott Bass Life Sciences LLC and one of DSHEA’s architects, refers to as the “innovation section.”
Comments submitted to the FDA demonstrate widespread agreement among industry associations, independent experts, and various individuals that the agency’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 overly restrictive, not grounded in statute or legislative history, and increasingly misaligned with contemporary science and manufacturing practices.
These stakeholders assert that Congress intended 201(ff)(1)(E) to serve as a forward-looking, catch-all category for innovation, rather than being confined to substances already found in the conventional food supply.
Bass’s comments provided extensive legislative history, indicating that Congress deliberately contemplated ingredients like coenzyme Q10, glucosamine, probiotics, and synthesized compounds, many of which were not commonly included in diets.
Additionally, organizations such as the Consumer Healthcare Products Association (CHPA), the Council for Responsible Nutrition (CRN), the Natural Products Association (NPA), and several others argue that a “commonly used as food” criterion imposes an unwarranted requirement not found in the statutory text, which contradicts the intentions behind the New Dietary Ingredient (NDI) provision.
“The safe-use provisions for new dietary ingredients in DSHEA reflect an expectation that dietary substances would include those beyond what is commonly found in regular diets,” stated NPA comments. “Section 413(a)(1) exempts NDIs from notification if they contain only dietary ingredients already in the food supply, indicating that Congress anticipated NDIs requiring a notification to the FDA under section 413(a)(2) would involve dietary ingredients not found in the food supply.
“FDA’s restrictive interpretation of section 201(ff)(1)(E)—and the associated risks that the FDA may reject an NDIN based on its definition of a ‘dietary substance’—is likely resulting in fewer NDI notifications and increased reliance on a pathway to market that has been scrutinized: GRAS (generally recognized as safe) self-affirmation.”
Natural Products Association
Industry associations emphasized Congress’s separation of eligibility from safety, using NDIs and adulteration authority rather than categorical exclusions to manage risk.
IPA pointed out that microbial exposure can happen through numerous non-food pathways, including soil, plants, and incidental dietary sources, making “food origin” an inadequate criterion for probiotic eligibility.
“Since incidental microbial exposure is crucial to shaping the gut microbiome, these microorganisms may also be suitable for dietary supplements, assuming they are sufficiently characterized for intentional use, particularly for individuals lacking access to nutritional sources of beneficial microbes,” noted IPA. “Restricting probiotic benefits solely to strains already recognized as part of the ‘food supply’ isn’t supported by available safety data or sound regulatory principles.”
Scott Jackson, founder of the biotechnology consulting firm The NEST and a former group leader at the National Institute of Standards and Technology (NIST), concurred: “Restricting DSHEA, enacted in 1994, to dietary ingredients with a confirmed history of dietary presence is overly limiting, particularly as our understanding of the food supply microbiome and the human gut was quite primitive at that time.”
Conversely…
Some comments provided a differing perspective, arguing that the definition should maintain a connection to the human diet to prevent it from becoming an unlimited category for novel compounds.
The American Herbal Products Association (AHPA) contended that “materials that are entirely novel, those not naturally found in humans or created through inherent biological processes, and substances that have never been ingested by humans should not qualify as dietary ingredients.”
“However, AHPA insists that substances identical or similar to those historically consumed by humans, albeit produced by modern techniques rather than traditional food preparation methods, should be recognized as dietary substances and generally regulated as New Dietary Ingredients (NDIs).”
Samantha Magdaleno, a private commenter, echoed this sentiment, stating that a dietary substance “must have a tangible connection to the human diet. This connection can derive from direct consumption, presence in food, or a clear relationship to dietary intake. Completely novel substances lacking this connection should not be included under this category.”
Question 2: The Impact of Emerging Technologies on Existing Dietary Ingredients
A strong consensus emerged among industry stakeholders regarding this question, with many asserting that manufacturing methods alone should not define a substance’s identity or trigger new regulatory status. Instead, the focus should be on the measurable characteristics of the finished ingredient.
For instance, CHPA, CRN, IPA, Scott Jackson, and NOĒSIS—a company developing delivery formats for dietary ingredients aimed at enhancing cognitive performance—encouraged the FDA to adopt a product- and risk-based approach, evaluating whether production changes materially affect: structure or sequence; impurity profile; bioactivity or bioavailability; and stability or exposure.
“A change in manufacturing method on its own should not act as a measure of risk or automatically categorize it as a new ingredient,” asserted CHPA.
Question 3: Characterizing Production Technologies in NDI Notifications
There was a unified stance among industry comments suggesting that NDINs (New Dietary Ingredient Notifications) should contain all necessary details for the FDA to assess safety and identity. Essential elements to include are: high-level process descriptions (focused on identity-relevant steps); starting materials/inputs pertinent to allergens or toxic residues; finished ingredient specifications (identity tests, purity limits); profiles for impurities and byproducts; and considerations for stability and shelf-life.
“In the over three decades since the enactment of DSHEA, manufacturing advancements—including synthesis, cell culture, and precision fermentation—have facilitated the production of safe, consistent, high-quality ingredients. These methods frequently enhance purity without compromising the fundamental identity or safety of the ingredient,” stated CRN in their comments.
“Regulatory assessments should determine whether manufacturing changes materially affect identity or safety. When no significant changes arise, companies should have access to streamlined processes (e.g., meetings with the FDA) to confirm ongoing compliance.”
AHPA underscored the need for consumer transparency related to sourcing and production methods, especially when modern techniques parallel traditional botanicals.
“The FDA should ensure that product labeling accurately distinguishes ingredients sourced from traditional agricultural practices and those produced using modern techniques to create compounds found in botanicals. Product labeling and associated claims should uphold distinctions in production and sourcing that foster an informed marketplace,” wrote AHPA.
“We recommend that the agency consider requiring this source information in the Supplement Facts panel’s ingredient declaration (e.g., ‘Saffrosides (from cell culture)’ vs ‘Saffron Extract (Crocus sativus) (Stigma)’), and not perceive it as prohibited intervening material under 21 C.F.R. § 101.2(a).”
Question 4: Scientific Criteria for Identity and “Sameness” in Peptides, Proteins, Enzymes, and Microorganisms
In response to this query, CHPA identified several criteria for both identity and sameness. For peptides and proteins, relevant factors include amino acid sequence (or a defined mixture profile) and molecular weight/size distribution. For enzymes, primary identity should center on catalytic function (the type of reaction catalyzed). Regarding microorganisms (i.e., probiotics), genus/species and strain-level identification is essential.
On the topic of microorganisms, IPA urged the FDA to acknowledge that microbial species with a recorded history of safe use in food may be eligible under Section 201(ff)(1)(E), as core attributes such as morphology, metabolism, and physiology are generally consistent at the species level, while functional benefits and clinical effects are typically strain-specific.
“Simultaneously, strain-level evaluations remain pertinent for safety-related concerns including taxonomic identity, antimicrobial resistance, toxigenicity, pathogenicity, manufacturing controls, and specifications for finished products,” added IPA, asserting the same principles apply to postbiotics (non-viable microorganisms).
In discussing “sameness,” commenters indicated that two substances may be classified as the same dietary ingredient if they share: primary identity; comparable functional attributes within specifications; and no new safety-relevant impurity differences.
Key Takeaways
The FDA is still updating the docket, and this article does not aim to provide a comprehensive review of all submitted comments. Nonetheless, the majority of feedback analyzed by NutraIngredients emphasizes a central theme: dietary supplement ingredient eligibility should be expansive and innovation-driven, while safety measures must remain rigorous, evidence-based, and enforced through the existing frameworks established by DSHEA.
