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The intent of the FDA’s Dietary Supplements: New Dietary Ingredient Notifications and Related Issues: Guidance for Industry is to help manufacturers and distributors of dietary ingredients and supplements determine whether a premarket safety notification must be submitted to the Agency for a product that contains or is considered to be a new dietary ingredient (NDI). Such premarket safety notifications are frequently referred to as NDI notifications.

In the first of this three-part series of articles regarding new dietary ingredients, a dietary ingredient was defined, along with a summary of the NDI guidance. Additionally, several frequently asked questions about NDI notification requirements were addressed. A review of notification requirement expectations for certain NDIs with a history of use in conventional food, along with considerations for NDI notification submissions, were outlined in the second article. This third and final article in the NDI series will provide an overview of the NDI notification procedure, as well as a summary of the information to be included in an NDI notification. Furthermore, a decision tree for NDI notification (Figure 1), as it appears in the FDA’s guidance for industry, can be found within this article.

What to include in an NDI notification

As a high-level summary, the NDI notification should include:

• Identity information about the NDI and dietary supplement;
• History of use or other evidence of safety, and
• A summary of the basis of the conclusion for safety.

A suggested outline for the specific information to include in an NDI notification can be found in Table 1.

Table 1. Suggested outline of required information to be included in new dietary ingredient (NDI) notification submissions to the FDA

Identity information in an NDI notification: Frequently asked questions

When preparing an NDI notification for submission not the FDA, what types of identity information should be included?

The FDA recommends including the following information concerning the identity of a new dietary ingredient:

• The name of the new dietary ingredient, its trade name (if different), and any other names the NDI is known by;
• A description of the physical properties of the NDI, including a description of the chemical or molecular composition or structure of the new dietary ingredient, or both;
• Controls and/or acceptable ranges for batch-to-batch variability, when applicable;
• The identity and level of any impurities and contaminants which may be present in the NDI or dietary supplement;
• Any additional information specific to the type of dietary ingredient, including vitamins, minerals, amino acids, constituents, metabolites, and other discrete entities, salts, enzymes, covalently modified derivatives of a dietary ingredient, mixtures, botanicals, extracts and concentrates, ingredients produced during fermentation, and live microbial ingredients, and
• A description of the identity of other dietary ingredients and other ingredients in the dietary supplement.

The FDA also recommends establishing identity specifications for the new dietary ingredient and components of the NDI and supplement that are applicable to establishing the foundation for the safety of the dietary supplement. A detailed description of the identity specifications in table form, as shown in the guidance in section V.I.A.5, should also be included in the notification.

For manufactured NDIs, the manufacturing process should be described, and the details of any manufacturing processes applicable to the safety and identity of the NDI should be thoroughly documented.

For manufactured NDIs, how much detail should be included in the manufacturing process descriptions?

An understanding of the overall process used to make the new dietary ingredient and the dietary supplement product is critical for FDA review. However, detailed descriptions of manufacturing can be limited to processes that are relevant only to the safety and identity of the NDI, if such processes can be isolated and identified.

What is a specification?

A specification is defined in the FDA guidance for industry as a set of standards that have been developed by the manufacturer or distributor of a material. In this instance, that would be the manufacturer or distributor of an NDI or a dietary supplement. The specification includes standards for:

• Each of the components of the material, and
• For the material as a whole.

In an NDI notification, specifications should include critical safety attributes, and may omit attributes that are not relevant to the safety or identity of the new dietary ingredient. The specification sheet should include the following:

• A list of tests;
• The acceptance criteria for each test, and
• The analytical methods used to support the acceptance criteria.

Acceptance criteria are defined as numerical limits, ranges, or other criteria for the tests described. The decision to accept or reject the ingredient or product being analyzed is based upon acceptance criteria. Therefore, acceptance criteria should be specific, rather than vague or ambiguous.

Analytical methods are critical, as they support acceptance criteria. The description of analytical methods within an NDI notification should include a detailed set of instructions to be followed precisely for the results to be accepted for the stated purpose. The analytical method description should include:

• All steps, from preparing the test sample to reporting the results of the analysis;
• A complete description of the analytical method (regardless of whether it is proprietary or included as a publication), and
• Details of the method (e.g., description of the chromatographic column, solvent elution conditions, source and authenticity of any reference standards).

All of this information must be provided, as it is critical to provide the basis for understanding how a method is used to identify analytes of interest.

What specifications for processes and ingredients should be included in an NDI notification?

Specifications for the components included in supplements must be established by distributors and manufacturers of dietary supplements, per 21 CFR 111.70(b). The requirements for component specifications include:

• The identity speciation for each component;
• Component specifications necessary to ensure that specifications for the purity, strength, and composition of dietary supplements manufactured using the components are met, and
• Limits on the types of contamination that may adulterate or may lead to adulteration of the finished product.

NDI notifications should provide a detailed description of specifications in table form as illustrated in the guidance in section V.I.A.5.

If a dietary supplement product contains a mixture of ingredients, what additional identity information should be submitted?

The identity and level of each ingredient in the dietary supplement should be detailed in the NDI notification, including both dietary and other ingredients used for technical or functional effects (e.g., binders, fillers, and color additives). Additionally, the following should be included in the NDI notification:

• A description as to how the ingredient combination relates to the history of safe use or other evidence of safety of the dietary supplement in which the NDI will be present, and
• A statement addressing the bioavailability of the ingredients as formulated, including the use of any binders or fillers that influence the bioavailability of any of the dietary ingredients in the supplement.

What information should be included if the NDI or dietary supplement will include an expiry or “use by” date on the label?

If the NDI or dietary supplement contains an expiry or “use by” date on packaging, data should be included in the NDI notification to demonstrate:

• No new degradants will form during the labeled shelf life under the storage conditions specified in the NDI notification, and
• The NDI or supplement will continue to meet critical safety attributes of identity, strength, and purity through the labeled expiry or “use by” date.

History of use or other evidence of safety in an NDI notification: Frequently asked questions

What safety information is needed to support an NDI notification?

An NDI notification must contain information that forms the basis upon which the conclusion that a dietary supplement containing a new dietary ingredient will be reasonably expected to be safe under labeled conditions of use, per 21 U.S.C. 350b(a)(2). Generally, this includes:

• An adequate history of safe use;
• Safety studies; or
• Both.

Should a history of safe use and safety testing data be submitted for an NDI?

It depends on whether the history of use evidence alone is adequate to support the safety of an NDI in a supplement. The following should be included in an NDI notification:

• Evidence of a history of safe use;
• Other evidence of safety, including clinical testing, animal testing, or both, or
• Some combination of history of use and other evidence of safety.

The safety testing recommendations vary, and are dependent upon the documented, historical use of the new dietary ingredient as well as the proposed use of the NDI. Table 2 illustrates the FDA’s recommendations for NDI notification safety testing recommendations in a matrix format.

Table 2. Safety testing recommendations matrix for new dietary ingredient (NDI) notification submissions

How do I determine whether historical use was “daily chronic” or “intermittent”?

Daily chronic use refers to ingestion at least once a day, every day, for at least three months in a row, and includes long-term use as well. For the purposes of an NDI notification, intermittent use is considered to be less than daily chronic use, and can be either daily and finite in duration, or non-daily and lifetime in duration.

What factors are helpful in determining whether to submit animal or human safety studies in addition to history of use data?

The FDA’s Dietary Supplements: New Dietary Ingredient Notifications and Related Issues: Guidance for Industry states the best way to determine whether history of use data provides a sufficient basis for a reasonable expectation that a dietary supplement containing an NDI will be safe is to compare the conditions of use proposed in the NDI notification with the documented historical conditions of safe use. The following examples are cited by the Agency’s guidance as situations where the FDA would typically recommend supplementing history of use data with additional animal or human safety studies:

• Higher proposed per-serving intake level or total daily intake level;
• Longer proposed duration of consumption than historically reported (e.g., notification states that the NDI will be marketed with labeling which recommends or implies continuous daily use for improved digestive function, but the history of safe use involves only infrequent, short-term use for indigestion);
• Different proposed routes of administration (e.g., data regarding the historical use of a substance as a poultice or by injection ordinarily would not be sufficient to support the safety of an NDI for use in a dietary supplement, which by definition is intended for ingestion);
• A change from historical use which may increase potential toxic effects (e.g., the NDI will be sold as capsules of a ground leaf, but the form historically used was a tea made from the plant’s roots), and/or
• A change in the target population (e.g., history of safe use has been established in adults, but the NDI will be used in a dietary supplement marketed for use by young children).

What are some sources of safety testing protocols that can be used for testing NDIs and dietary supplements?

Useful guidelines for safety testing include:

• ;
• ; and
• .

Summary for the basis for the conclusion of safety in an NDI notification: Frequently asked questions

Should an NDI notification include separate safety profiles for the NDI and the dietary supplement product that will use the NDI?

Yes. The FDA recommends that two safety profiles be used in the discussion of history of use and other evidence of safety:

• The first safety profile should include a comprehensive safety profile evaluating the safety of the new dietary ingredient, and
• The second should contain a dietary supplement narrative explaining why the information in the notification has provided the basis for the conclusion that, when used under the recommended or suggested conditions detailed on the product label, the supplement containing the NDI is reasonably expected to be safe.

What should be included in a comprehensive safety profile for an NDI?

NDI safety profiles should contain objective summaries of all available human and animal toxicological information, including both published and unpublished safety studies, as well as any other relevant information for the NDI safety assessment. This includes:

• Historical use of the NDI;
• Intake level, frequency and duration of historical use;
• Description of size and characteristics of the population that consumed the NDI;
• Quantitative and qualitative comparison of ingredients tested in safety studies cited with the NDI;
• Acceptable daily intake (ADI) for the NDI and an explanation of how it was calculated, and
• The basis for the margin of safety for the NDI and how the margin of safety was calculated.

If the NDI comprehensive safety profile contains trade secrets or confidential commercial information, such information should be identified accordingly within the submission.

NDI resources

The NDI regulatory guidance can be overwhelming. Figure 1 provides a quick reference NDI decision tree to help you to determine if your dietary ingredient meets the requirements for NDI notification.

Figure 1. Decision tree for new dietary ingredient (NDI) notification

Navigating NDI regulations and required data

An FDA-registered, experienced contract research organization (CRO) and/or contract development and manufacturing organization (CDMO) can help dietary supplement manufacturers and distributors navigate regulatory requirements and regulations. ºÚÁϲ»´òìÈ’s consultative teams of scientists have decades of experience formulating, analyzing and advancing dietary supplement products, and have a proven track record of supporting successful regulatory submissions.