One common question I frequently receive from manufacturers and distributors of dietary supplement products is whether or not they need to file a new dietary ingredient (NDI) notification for their products. While this inquiry can often be fact-specific, there are three main analytical steps that one can follow to answer this question.

Under the Federal Food, Drug, and Cosmetic Act (FDCA), the manufacturer or distributor of an NDI or dietary supplement that contains an NDI must submit a notification to FDA at least 75 days before introducing or delivering the product for introduction into interstate commerce, unless the NDI and any other dietary ingredients in the 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. The FDCA defines an NDI as “a dietary ingredient that was not marketed in the U.S. prior to October 15, 1994.”

Step 1: Make Sure All Ingredients in the Supplement are Dietary Ingredients

The first step is determining whether all ingredients are “dietary ingredients.” If an ingredient does not qualify as a dietary ingredient, it may not be used in dietary supplement products. The FDCA defines a “dietary ingredient” as a “vitamin; mineral; herb or other botanical; amino acid; dietary substance for use by man to supplement the diet by increasing the total dietary intake; or a concentrate, metabolite, constituent, extract or combination” of any of the above. As indicated in the recently published Draft Guidance on NDI notifications, FDA has significantly limited the definition of a “dietary ingredient.” For example, the agency interprets the term “dietary substance” as “an intentional constituent of food”—which is a very narrow interpretation.

Step 2: Determine If Any of the Ingredients are NDIs

The Draft Guidance reiterated the agency’s previously articulated position that the fact an ingredient appears on one of the industry-compiled lists of dietary ingredients that were marketed prior to October 15, 1994 (i.e., lists of “grandfathered” dietary ingredients) is insufficient evidence that an ingredient is not an NDI. To demonstrate that a dietary ingredient was marketed in the U.S. prior to October 15, 1994, “written business records, promotional materials, or press reports with a contemporaneous date prior to October 15, 1994” are expected. For example, sales records, manufacturing records, commercial invoices, magazine advertisements, mail-order catalogues or sales brochures would be examples of adequate evidence.

Significantly, FDA appears to take the position that certain changes, including higher dosage, different route of administration, and longer duration of use, may require an NDI notification even though the ingredient was marketed prior to October 15, 1994. I believe, however, that this position is not supported by the FDCA.

Even if an ingredient is an NDI, it does not necessarily trigger the premarket notification requirement. The manufacturer or distributor should next determine whether this NDI has been used as an article for food in a form in which the food has not been chemically altered.

Step 3: Determine Whether the NDI Has Been Used as an Article for Food

An NDI notification is not required for a dietary supplement containing the NDI as long as the supplement contains only dietary ingredients that have been present in the food supply as articles used for food in a form in which the food has not been chemically altered.

Importantly, however, the adulteration standard in the FDCA applies to all dietary supplements that contain an NDI. Thus, even if the supplement contains only dietary ingredients that have been present in the food supply as articles used for food in a form in which the food has not been chemically altered, a dietary supplement containing an NDI is adulterated unless there is adequate information to provide reasonable assurance that the NDI does not present a significant or unreasonable risk of illness or injury. Manufacturers and distributors could satisfy this requirement by taking a self-determined “GRAS” position that the substance is generally recognized, among qualified experts, as having been adequately shown to be safe under the conditions of its intended use.

Under the FDCA and FDA’s regulations, the use of a food substance may be GRAS either through scientific procedures or, for a substance used in food before 1958, through experience based on common use in food. Under FDA’s regulations, general recognition of safety through scientific procedures requires the same quantity and quality of scientific evidence as is required to obtain approval of the substance as a food additive and ordinarily is based upon published studies, which may be corroborated by unpublished studies and other data and information. In addition, general recognition of safety through experience based on common use in foods requires a substantial history of consumption for food use by a significant number of consumers.

Despite the benefit of the self-determined GRAS position, it is important that it be taken with a degree of caution. If FDA does not consider the ingredient GRAS, it will take the position that the dietary supplement is not lawfully marketed regardless of the NDI notification status. In other words, if you cannot easily convert your self-determined GRAS position into a GRAS notification to FDA, your notification is not worth the paper it is written on and will provide you no solace if FDA challenges the status of your NDI.