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Among the sticking points: GRAS ingredients, synthetic ingredients, finished products, changes in manufacturing, and drug ingredients.
FDA today published to the Federal Register its long-awaited guidance on new dietary ingredients (NDI). The guidance is meant to provide industry with guidelines such as in what instances NDI notifications are necessary, the process for notification submissions, and, most importantly, what information the agency is looking for in notifications.
Under the rules of the Dietary Supplement Health and Education Act (DSHEA) overseeing supplements, marketers are required to submit an NDI premarket notification to FDA if the ingredient has not been marketed in the United States prior to DSHEA’s implementation date of October 15, 1994. Notifications are meant to provide evidence, such as citations to published articles, etc., that the NDI is “reasonably expected to be safe” for human consumption. Ingredients with evidence showing they were marketed in dietary supplements before October 15, 1994, are considered grandfathered and do not require an NDI notification. NDI notifications must be submitted to FDA at least 75 days before an NDI ingredient is introduced to market-if not, a product containing the ingredient is considered adulterated.
Notably, no established, FDA-approved list of grandfathered ingredients exists-nor will it. Instead, the agency advises each company to ensure it has its own evidence to indicate that its ingredients were marketed prior to October 15, 1994.
Without formal guidance in place from FDA, the dietary supplements industry has been submitting NDI notifications on its own to the agency since the passage of DSHEA, with more than 700 NDI notifications submitted so far, according to FDA. A large number of those notifications have been rejected, due to reasons the agency highlights in each individual response letter. (For more information on the reasons for rejection, see the American Herbal Products Association/AHPA’s subscription-only database that compiles all of the NDI notifications submitted, including notification objects.)
The new draft guidance is not law but does reveal FDA’s thinking about NDI notifications and what requirements the agency is looking for. The comment period is now open until October 3, and industry members are highly encouraged to submit their thoughts on the proposed guidance before FDA issues a finalized version.
Among the areas in the guidance that spark concern:
GRAS-Affirmed Ingredients [Editor’s note: This one was surprising to us]:
In the guidance, FDA states that ingredients deemed Generally Recognized as Safe (GRAS), either by FDA or self-affirmation, for use as a food additive may not need an NDI notification if the ingredient is not altered. “If the NDI was legally marketed in the U.S. as an ingredient for use in conventional food, it would qualify under section 413(a)(1) of the FD&C Act (21 U.S.C. 350 b(a)(1)) as an ingredient exempt from the notification requirement because it has been present in the food supply as an article used for food in a form in which the food is not chemically altered….However, the same is not necessarily true if the intake level of the NDI in the dietary supplement is higher than that resulting from conventional food use of the NDI.”
FDA states that if any new manufacturing practices implemented after 1994 changes the chemical composition or structure of the ingredient, there’s a chance the ingredient may no longer be a grandfathered ingredient but instead a new dietary ingredient. This includes the use of different solvents or different parts of the botanical, higher baking or cooking temperatures that could cause loss of “volatile components,” changing agricultural or fermentation conditions, or using a botanical at a different life stage (e.g., unripe versus ripe).
Synthetic ingredients are out. The guidance clearly states that “a synthetic copy of a constituent of a botanical was never part of the botanical and thus cannot be a ‘constituent’ of the botanical that qualifies as a dietary ingredient under section 201(ff)(1)(F) of the FD&C Act (21 U.S.C. 321(ff)(1)(F).” Last week, the Council for Responsible Nutrition published its thoughts on the matter of NDIs and synthetic ingredients, prior to the guidance publication.
Ingredients that have been approved as a new drug or licensed as a biologic cannot be considered dietary ingredients. The guidance states that“…an ingredient that has been approved as a new drug or licensed as a biologic can be a dietary ingredient for use in a dietary supplement if, and only if, prior to such approval or licensing, the ingredient was marketed as a dietary supplement or as a food.” This includes ingredients authorized for investigational new drug (IND) applications-although FDA may make exceptions.
If an NDI notification was originally submitted for an ingredient but the ingredient is now being used in a new finished product, a new NDI notification may be required for that product unless “the new supplement does not have other dietary ingredients that were not included in your original NDI notification.”
Industry members, including associations, are in the process of digesting the guidance’s contents and evaluating it for its potential impact on industry.
“Even though the guidance is not binding, we should all be concerned about any attempt by FDA to use this forum to change the rules and practices that have been accepted and in place for 17 years,” stated Michael McGuffin, president of AHPA. “At the same time, it appears that the agency has learned from the process of reviewing submitted notifications, and has described, for the first time, at least some of its expectations for the content of NDI notifications.
There was also some praise for FDA for meeting its deadline for guidance release. (The Food Safety Modernization Act, which became law in January, required FDA to release the long-awaited NDI guidance by July 3.)
Steve Mister, president and CEO of the Council for Responsible Nutrition, stated: “CRN is pleased that FDA has announced the formal release date for the long-awaited NDI draft guidance document and made the pre-publication version available for review. The dietary supplement industry has eagerly awaited this guidance in the hope that it will provide clarity and an appropriate framework for introducing new ingredients and products into the supplement marketplace.
As FDA has reminded us, this draft guidance document describes the agency’s interpretation of the requirements for NDIs-it is not a new regulation and does not create new rights or responsibilities for the industry. Nevertheless, this draft guidance does represent an important step for the dietary supplement industry-and for the Agency-as it demonstrates further implementation of the requirements of the Dietary Supplement Health and Education Act (DSHEA) and will give companies clearer understanding of FDA’s expectations under the law.
We will now thoughtfully review the guidance which we view as FDA’s best thinking on the subject and will respond with the industry’s best thinking, which we trust FDA will take seriously. This guidance has potential for short- and long-term implications for our industry and for our consumers’ ability to have access to in-demand products and we want to be sure the guidance is appropriate, reasonable and practical for industry and the more than 150 million consumers who use dietary supplements year after year.”
Several associations, including AHPA (TBD), CRN (September 14 online), the Natural Products Association (July 11 online) , and the United Natural Products Alliance (July 26-27 in Salt Lake City, UT), will be holding webcasts and educational sessions to provide industry members with more insight on the new draft guidance.