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In accordance with the Federal Food, Drug, and Cosmetic Act (FD&C Act), manufacturers and distributors who wish to market dietary supplements containing “new dietary ingredients” must submit a premarket safety notification (also referred to as an NDI notification) to the US Food and Drug Administration (FDA) for these new ingredients.

A new dietary ingredient (NDI) notification is required to be submitted to the FDA unless the new dietary ingredient and any other dietary ingredients present within the dietary supplement “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” (21 U.S.C. 350b(a)(1)).

The FDA’s NDI guidance and process will be explored in a 3-part series of articles. In this first installment, a dietary ingredient will be defined, the basics of the NDI guidance will be explored, and some of the most frequently asked questions about whether an NDI notification is required will be answered. The second article in the NDI series will delve into exceptions to notification requirements for certain NDIs with a history of use in conventional food and additional considerations for NDI notification submissions. The third and final article in the NDI series will provide an overview of the NDI notification procedure, as well as what needs to be included an NDI notification. Finally, a decision tree for NDI notification, as it appears in FDA’s guidance for industry, will be provided within the last article.

Defining dietary supplements and ingredients

21 U.S.C. 321(ff) defines a “dietary supplement” as any product, other than a tobacco product, which is intended to supplement the diet and contains “dietary ingredients”. This definition is limited to ingestible products (e.g., tablets, capsules, softgels, powders, liquids, etc.) that are not considered to be a conventional food or an item that could be deemed a meal or diet. Any currently approved drugs or biological products, or any drug or biological product that is authorized for investigation, do not fall under this category, unless the product in question had already been marketed as a dietary supplement prior to receiving regulatory approval or authorization.

Within the definition of a “dietary supplement” in 21 U.S.C. 321(ff)(1), a “dietary ingredient” is described as:

• A vitamin;
• A mineral;
• An herb or other botanical;
• An amino acid;
• A dietary substance for use by man to supplement the diet by increasing the total dietary intake, and/or
• A concentrate, metabolite, constituent, extract, or combination of any ingredient described above.

A brief explanation of new dietary ingredient (NDI) notifications

According to the FDA’s Dietary Supplements: New Dietary Ingredient Notifications and Related Issues: Guidance for Industry, NDI notifications must be submitted at least 75 days before the product is introduced to the market. Furthermore, the distributor or manufacturer of the new dietary ingredient or supplement submitting the NDI notification must provide the Agency with the information that has informed the applicant’s basis for their conclusion that the dietary supplement containing the NDI will reasonably be expected to be safe under the conditions of the recommended or suggested use detailed on the product label. This information needs to include any citations to published articles.

The FDA will deem that the dietary supplement containing the NDI is adulterated if:

• The required premarket notification is not submitted to the FDA, and/or
• There is no history of use or other evidence showing that the NDI, when used as recommended or suggested on the product label, is reasonably be expected to be safe, even if the required notification has been submitted to the Agency.

The onus is on the manufacturer/distributor to assess dietary ingredients used within their dietary supplement products and make the determination as to whether an NDI submission is warranted. If there is uncertainty regarding whether a dietary ingredient is considered a new dietary ingredient, an NDI notification may still be submitted to the FDA. Regardless of submission requirements, the responsibility remains with the manufacturer/distributor to ensure their dietary supplements are safe and unadulterated.

NDI premarket notifications: Required information

• The FDA’s NDI regulations specify the information the manufacturer and/or distributor must include in premarket NDI notification submissions (21 CFR 190.6(b)):
• Name and complete address of the manufacturer or distributor submitting the NDI notification;
• The name of the NDI that is the focus of the premarket notification, and
• If the NDI is a botanical, its Latin binomial name must be included as well as the name of the scientist who gave the substance its Latin binomial name;
• A description of the dietary supplement that contains the NDI, including:
• Level of the NDI in the dietary supplement, and
• Conditions of recommended or suggested use on the supplement label, or if no conditions of use are recommended or suggested in the labeling, the ordinary conditions of use of the supplement;
• History of use or other evidence of safety establishing that the dietary ingredient, when used under the recommended conditions stated on the supplement label, will reasonably be expected to be safe, and
• The signature of a person authorized by the manufacturer or distributor to sign the notification on its behalf.

When is a new dietary ingredient notification required? Answers to frequently asked questions

Can a substance that is not a dietary ingredient be an NDI?

No. Upon close review of the description of a “new dietary ingredient," it becomes clear that the definition applies to dietary ingredients which were not marketed in the U.S. before October 15, 1994. Therefore, a substance must be a dietary ingredient to be eligible for new dietary ingredient classification.

Is an ingredient that was used to make a conventional food marketed before October 15, 1994, an NDI?

The answer to this question is more complicated than the prior query, and, essentially, it depends. The fact alone that an ingredient has been used in a conventional food prior to October 15, 1994, does not establish whether that ingredient is an NDI. Rather, what does matter is whether the ingredient in question was marketed as a dietary ingredient within the same timeframe. The ingredient must have been marketed in or as a dietary supplement, or for use in a dietary supplement, in the U.S. before October 15, 1994.

In short, the ingredient is considered an NDI unless it was also marketed as a dietary ingredient in the U.S. prior to October 15, 1994.

What is the “NDI adulteration standard”?

The NDI adulteration standard is set forth in 21 U.S.C. 342(f)(1)(B). That section of the United States Code states that any dietary supplement containing an NDI is considered to be adulterated unless sufficient information that provides reasonable assurance the NDI does not pose a significant or unreasonable risk of illness or injury is available.

In the event that an NDI notification is not required, does the adulteration standard still apply to a dietary supplement containing an NDI?

Yes. The adulteration standard applies to all dietary supplements that contain an NDI, even when no NDI notification is required. This is due to the fact that the supplement contains only dietary ingredients which have been present in the food supply, and those ingredients have been utilized for food in a form in which there has been no chemical alteration of the food.

What is the intention of the FDA guidance when it refers to “marketing” a dietary ingredient?

The FDA considers the following scenarios to meet the description of “marketing” a dietary ingredient.

When an ingredient is sold or being offered for sale:

• As or in a dietary supplement;
• In bulk as a dietary ingredient for use in dietary supplements, or
• As an ingredient in a blend or formulation of dietary ingredients for use in dietary supplements.

The ingredient can be listed for sale:

• Online;
• At a retail establishment;
• In a catalog or price list, and/or
• Through advertising or other promotion, if the promotion makes it clear that the ingredient is available for purchase.

It is important to note that “coming soon” advertisements do not qualify or meet the FDA’s criteria for “marketing” a dietary ingredient.

If a supplement containing an NDI is sold before an NDI notification is submitted or it is less than 75 days after the NDI is submitted, does the FDA consider the dietary supplement or NDI to be lawfully marketed?

Per the FDA, the sale of the product within this period of time is not evidence that the supplement or NDI was lawfully marketed.

If a dietary ingredient was marketed outside the U.S. prior to October 15, 1994, is it still considered to be a new dietary ingredient (NDI)?

Yes. One cannot establish that the ingredient is not an NDI by providing the FDA with documentation demonstrating that the ingredient was marketed in any other country before the October 1994 date. The only kind of marketing that is recognized and accepted by the FDA concerning whether a dietary ingredient is an NDI is marketing that took place within the United States before October 15, 1994.

What are some examples of documentation that FDA recommends to show that a dietary ingredient was marketed in the U.S. prior to October 15, 1994?

According to the FDA guidance, documentation demonstrating a dietary ingredient is not an NDI should include:

• Written business records;
• Promotional materials, and/or
• Press reports with a date prior to October 15, 1994.

This can include:

• Sales records;
• Bills of lading;
• Sales contracts;
• Manufacturing records;
• Commercial invoices;
• Magazine advertisements;
• Mail order catalogs, and/or
• Sales brochures.

It is important to keep in mind that documentation should include sufficient information to establish that marketing took place in the United States. To prove this, marketing materials provided to the Agency should clearly state:

• The identity of the marketed ingredient (e.g. chemical or botanical name);
• Its form (e.g. ground herb, water extract, oil, etc.), and/or
• Whether the ingredient was marketed as a dietary ingredient or for some other purpose.

For example, advertisements in body building magazines are more likely to be considered adequate evidence of marketing as a dietary ingredient, whereas advertising or references to a botanical or herb as a dietary ingredient in gardening or landscaping magazines and publications would likely not be considered adequate evidence of marketing.

This is a lot of information. Is there a quick reference that can help manufacturers and distributors of dietary supplements determine whether a dietary ingredient is, in fact, an NDI?

Yes. Table 1 provides a quick reference guide that can help manufacturers and distributors of dietary supplements determine whether the ingredient in question is an NDI, as well as whether an NDI notification is required, and finally, whether the adulteration standard applies, which is also summarized in the FAQ section above.

Table 1. Definition of new dietary ingredient, requirements for NDI notification, and the applicability of the NDI adulteration standard

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