Å·ÃÀÊìÅ®ÂÒÂ×

Although US Food and Drug Administration (FDA) pre-approval is not required for dietary supplements, if a supplement contains an ingredient that has not been marketed in the United States before October 15, 1994, the FDA requires a pre-market notification (NDI notification) be submitted to the Agency, as the ingredient is considered a “new dietary ingredient” (NDI). As the dietary supplement industry continues to innovate and expand to meet market demands, it is expected there will be an increased need to submit new dietary ingredient notifications to the Agency.

The basics of the FDA’s NDI guidance were reviewed and answers to the most frequently asked questions regarding NDI notification requirements were provided in the first installment of this series of three articles on the subject of new dietary ingredients. In this article, exceptions to notification requirements for certain new dietary ingredients that have a history of use in conventional food will be outlined. Additionally, several factors to be contemplated prior to submitting an NDI notification will be covered. The third and last article in the NDI series will provide an overview of the NDI notification procedure, and the information an NDI notification must contain will be summarized. Furthermore, as it appears in the FDA’s guidance for industry, a decision tree for determining whether NDI notification is needed, will be depicted.

Exceptions to notification requirements for certain NDIs with a history of use in conventional foods

New dietary ingredients (NDIs) that have a record of use in conventional foods are the exception to NDI notifications. A notification is not required when the new dietary ingredient, together with all other dietary ingredients in the dietary supplement, have previously been used in the food supply as articles for food. Nevertheless, there must be a history of these ingredients being present in a form where the food has not been chemically modified or altered. Substances that are added to conventional foods must meet safety standards for conventional food ingredients, and those food standards are more demanding than the standards applied to dietary ingredients used in dietary supplements. The stricter standards applied to foodstuffs provides the basis for the exceptions for substances with a history of use in conventional foods, as those ingredients have already been evaluated and approved for use. As detailed in the FDA’s NDI guidance, the Agency interprets “present in the food supply” to be:

• “Present in the food supply” as the conventional food supply, and/or
• A dietary ingredient that has been “present in the food supply as an article used for food” is a conventional food or conventional food ingredient.

Manufacturers and distributors of dietary supplements should take note of the fact that the FDA does not consider prior use of an ingredient in a dietary supplement a means of establishing a prior “presence in the food supply”. The purpose of the NDI notification requirement is to ensure dietary ingredients that have not previously been widely consumed are evaluated for safety before they are introduced to the marketplace.

This distinction is critical, as a smaller portion of the population consume dietary supplements than conventional foods. Moreover, the history of use for dietary supplements is typically shorter than those of conventional food ingredients. Consequently, less information is typically available concerning the safety of the substance in question if the ingredient only has a history of prior use in dietary supplements.

NDI exceptions due to conventional food history: Frequently asked questions

Does an NDI notification need to be submitted for a dietary ingredient that is a new dietary ingredient but has been affirmed for listed by the FDA as generally recognized as safe (GRAS) for direct addition to food OR has been approved as a direct food additive in the U.S.?

No, an NDI notification does not need to be submitted to the Agency if the dietary ingredient meets the following requirements:

• Has been used in the food supply (conventional foods), and
• Will be used as a dietary ingredient without any chemical alteration.

The dietary ingredient would be exempt from the notification requirement under section 413(a)(1) of the Federal Food, Drug and Cosmetic Act (FD&C Act) (21 U.S.C. 350b(a)(1)) if the NDI has been legally marketed in the U.S.:

• As an ingredient for use in conventional food without chemical alteration, and
• Has been introduced into the food supply because of such marketing.

Likewise, ingredients marketed in conventional foods outside of the United States are exempt from NDI notification if they also have not been chemically altered. However, it is important to note that the NDI adulteration standard still applies. Therefore, it may be advisable for manufacturers and/or distributors of dietary supplements to submit a voluntary new dietary ingredient notification to the FDA in these instances.

Does the adulteration standard apply to a new dietary ingredient that has been classified as GRAS for direct addition to food or approved as a direct food additive in the U.S.?

Yes. The adulteration standard in the FD&C Act applies to all NDIs, including new dietary ingredients which do not require an NDI notification. Even if an ingredient was not marketed as a dietary ingredient in the U.S. prior to October 15, 1994, it is still considered an NDI, and therefore, the adulteration standard applies.

According to the adulteration standard, any supplement containing the new dietary ingredient is considered to be adulterated unless adequate information is available to reasonably establish that the ingredient does not present a significant or unreasonable risk of illness or injury.

What should manufacturers or distributors of dietary supplements do if an NDI has been present in the food supply as an article used for food without chemical alteration and the supplement contains more of the new dietary ingredient than has been used in conventional foods?

In these instances, the FDA guidance recommends that manufacturers or distributors of dietary supplements consult with the Agency about their reasoning and basis for concluding that adequate information is available to support the conclusion that incorporation of the NDI in a dietary supplement will not present a significant or unreasonable risk of illness or injury. In situations where a supplement contains a significantly higher level of an NDI than has been used in conventional foods, it may be prudent to submit a voluntary NDI notification.

Chemical alteration is continually cited within the guidance. What are some examples of processes that chemically alter an article of food that is present in food supply?

The FDA cited the following processes in industry guidance as those that the Agency would most likely consider to be examples of processes that involve chemical alteration. These processes would likely impact the safety profile of a dietary ingredient. Please note these are examples only, and do not represent a comprehensive or complete list of processes that would result in chemical alteration of a dietary ingredient.

• A process that makes or breaks chemical bonds, unless the bonds created by the process are reversed when the ingredient is dissolved in water or during ingestion. An example of such a process is hydrolysis.

  ---

• The removal of some components of a tincture or solution in water, which results in changes to the chemical or molecular composition or structure of the mixture. Examples include chromatography, distillation and filtration.

  ---

• The use of solvents other than water or aqueous ethanol to make an extract or tincture. The official legislative history of the Dietary Supplement Health and Education Act of 1994 (DSHEA) specifies that “solution in water” and “tincture” (solution in aqueous ethanol) are not processes that chemically alter a food. However, other solvents typically alter the composition of the extract in significantly different ways, generally by extracting different types of constituents than are extracted using water and aqueous ethanol.

  ---

• High temperature baking or cooking of an ingredient that has not previously been baked or cooked, unless the process results in only minor loss of volatile components with no other changes to the chemical or molecular composition or structure of the ingredient.

  ---

• Changing the manufacturing method for an ingredient in such a way that the chemical or molecular composition or structure is considerably different. Examples include changes that alter the composition of materials used to make the ingredient, the use of a different solvent, or the use of a chromatographic matrix, as opposed to a passive filter.

  ---

• The application of nanotechnology resulting in new or altered chemical properties of the ingredient.

  ---

• Changing agricultural or fermentation conditions to alter the chemical or molecular composition or structure of the ingredient. Examples include sprouting garlic or fermenting yeast via the use of a medium containing large amounts of sodium selenite, thus creating large amounts of organic selenium compounds.

  ---

• Fermentation using a fermentation medium different from the one used to make conventional foods in the food supply. For example, the use of a defined commercial growth medium to produce a microorganism that was previously made by fermenting milk into dairy products, such as yogurt or cheese.

  ---

• The use of a botanical ingredient that is at a different life stage than the life stage of the botanical ingredient used as a conventional food. Examples include making an extract from unripe, instead of ripe, apples, or using the mycelium rather than the fruiting body of a fungus.

Other frequently asked questions about when NDI notifications are necessary

Can safety data for a range of conditions of use that applies to multiple products be included in a single NDI notification?

Yes, the FDA accepts notifications that cover multiple dietary supplements. A single notification can include safety data for a range of doses, varying daily intake levels, or other variations in conditions of use. Those variations in conditions of use may include:

• Serving size;
• Duration of use;
• Frequency of intake;
• Target population;
• Dosage form, and/or
• Different formulations of pre-DSHEA ingredients in combination with the NDI.

However, the FDA recommends submitting safety data up to, and including, the highest dose and daily intake level, while indicating any lower daily intake levels that the NDI may be marketed for. Applicants should take care to include statistically relevant data points that support the safety analysis, such as a range of daily intake levels.

NDI notifications are public records, and manufacturing specifications and other proprietary information would be helpful to support the FDA’s evaluation of an NDI. What can NDI applicants do to protect sensitive information?

An applicant can submit a confidential “NDI master file” to the FDA that contains sensitive information, including manufacturing methods, specifications, and other necessary information to fully describe the ingredient, as part of a single NDI notification. If an applicant chooses to include a confidential NDI master file with the NDI notification, they must reference the contents of the master file within the NDI notification.

The FDA anticipates most submitters will identify the contents of their NDI master files and ingredient specifications as trade secrets. Thus, the details of NDI master files will only be discussed with the submitting firm. However, applicants do have the option to authorize other firms or partners to discuss the contents of the NDI master file with the FDA. If this is of interest, applicants can take necessary steps to cite additional authorized parties within the NDI master file document.

I submitted an NDI notification for a dietary supplement that I manufacture or distribute and have decided to manufacture or distribute a different supplement containing the same NDI. Does another NDI notification need to be submitted for the new supplement?

A few factors need to be considered to determine the path forward in this scenario, including:

• What was covered in the previously submitted NDI notification;
• How the FDA responded, and
• How different the proposed conditions of use for the NDI in the new supplement are when compared to what was evaluated in the original notification.

A separate NDI notification for a different supplement containing the same NDI does not need to be submitted if the following criteria are met, as stated in the FDA guidance:

• The single-serving dose and daily intake level of the NDI specified in the labeling of the new supplement are less than or equal to the highest single serving dose and daily intake level evaluated in the original NDI notification;
• The new supplement does not combine the NDI with other dietary ingredients that were not included in the original NDI notification;
• The target populations for the new supplement are the same as, or a subset of, the target populations specified in the original NDI notification;
• All other conditions of use are the same as or more restrictive (e.g., lower dose and daily intake, shorter duration of use) than the conditions of use described in the prior NDI notification; and
• The FDA did not express safety or other regulatory concerns in response to the prior NDI notification.

Can I rely on data from another NDI notification or master file when I submit my NDI notification?

Yes, but only if one of the following scenarios applies:

• You submitted the previous NDI notification or master file that you are looking to reference;
• The previous notification (or even a portion of the notification) you want to rely on is public, or
• The person who submitted the previous notification or master file provides written permission (e.g., a signed letter from original notifier/submitter) stating that you are authorized to use their information. Additionally, the original notified/submitter must include the period of time for which the authorization is valid. If their authorization does not include the entire NDI master file or notification, the letter needs to specify exactly what part(s) of the notification you are authorized to use.

As previously discussed, NDI master files typically contain trade secrets, which may include manufacturing processes and specifications. The original notifier has no obligation of any kind to share any trade secrets or confidential commercial information with other manufacturers or distributors. Furthermore, written authorization to reference a previously submitted NDI notification or master file does not grant any rights or permissions to see or copy the notification or master file, unless explicit, written consent is provided allowing another party to do so.

Even if permission is granted to reference confidential safety information in another firm’s previously submitted NDI notification or master file, your notification must demonstrate that your firm understands enough about the original NDI’s confidential safety information to have a basis to conclude that consumption of the NDI in your product will reasonably be expected to be safe under the conditions of use detailed within your notification.

My dietary supplement contains microbial ingredients. Should I notify the FDA about this?

Yes, if it is a new dietary ingredient (NDI) that has not been present in the food supply as an article used for food in a form in which the food has not been chemically altered. Not all bacterial microorganisms are dietary ingredients, and a microorganism that is not a dietary ingredient cannot be an NDI.

When are bacterial microorganisms considered to be NDIs?

If the bacterial microorganism is a dietary substance (an intentional constituent of food) or falls into one of the dietary ingredient categories listed in 21 U.S.C. 321(ff)(1), defined as “a product (other than tobacco) intended to supplement the diet that bears or contains one or more of the following dietary ingredients:”

• 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; or
• A concentrate, metabolite, constituent, extract, or combination of any ingredient described above.

A CDMO can help you navigate and understand dietary supplement regulations

A consultative partner with experience navigating regulatory submissions can be invaluable to your understanding and compliance to regulatory requirements for dietary supplements. Moreover, partnering with a contract development and manufacturing organization’s (CDMO) team of industry-leading scientific experts can help you to identify opportunities to solidify the credibility of your product offerings, certify the purity of dietary supplement products, and refine formulations to optimize efficacy. Connect with us today to explore a partnership with Element and learn more about our experience and expertise in supporting dietary supplement portfolios throughout the entire product development life cycle.