ODI, NDI, GRAS

Audit of the regulatory status of ingredient for use in foods and/or dietary supplements in the US, in order to define whether the ingredient is an old dietary ingredient (ODI) or has to be notified to the Food and Drug Administration (NDI or GRAS notification depending on the case).

Service details

Methodology

Review of the regulatory status of the native ingredient before processing (plant, animal product, other source…), for use in foods and/or dietary supplements, in the US

Analysis of the regulatory status of the processed ingredient (extract, powder, concentrate…) depending on the process: extraction ratio, selectivity of active compounds, solvents, technological auxiliaries.

Deliverable

An overview of the regulatory status of the native ingredient before processing in U.S.

A detailed analysis of the status of the processed ingredient intended for marketing as per regulations and quality standards.

Our recommendation for an optimized regulatory strategy, including a presentation of suitable procedures to achieve authorization for the marketing of the ingredient.

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    IV. Determining Whether a New Dietary Ingredient (NDI) Notification Is Required

    A. What Is a New Dietary Ingredient?

    1. What do the terms “dietary ingredient” and “new dietary ingredient” mean?

    As defined in section 201(ff)(1) of the FD&C Act (21 U.S.C. 321(ff)(1)), a “dietary ingredient” is any one of the following:

    • (A) A vitamin;
    • (B) A mineral;
    • (C) An herb or other botanical;
    • (D) An amino acid;
    • (E) A dietary substance for use by man to supplement the diet by increasing the total dietary intake; or
    • (F) A concentrate, metabolite, constituent, extract, or combination of any ingredient described in (A), (B), (C), (D), or (E).

    An NDI is defined as a dietary ingredient that was not marketed in the U.S. before October 15, 1994 (21 U.S.C. 350b(d)). Thus, to be an NDI, a substance must be a dietary ingredient.

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

    No. Because “new dietary ingredient” is defined to mean a dietary ingredient that was not marketed in the U.S. before October 15, 1994, a substance cannot be a new dietary ingredient unless it is also a dietary ingredient.

    3. Must I submit an NDI notification for a dietary ingredient marketed in the U.S. prior to October 15, 1994?

    No. Dietary ingredients marketed prior to October 15, 1994 (“pre-DSHEA dietary ingredients”) are not NDIs and, therefore, do not require an NDI notification. See questions IV.A.4, IV.A.7 and IV.A.10 for more on how FDA interprets the terms “marketed” and “dietary ingredient” in the definition of an NDI (21 U.S.C. 350b(d)).

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

    It depends. The use of an ingredient in a conventional food before October 15, 1994, does not determine whether the ingredient is an NDI. What matters is whether the ingredient was marketed as a dietary ingredient — meaning that it was marketed in or as a dietary supplement, or for use in a dietary supplement — in the U.S. before October 15, 1994. Therefore, an ingredient that was used to make a conventional food before October 15, 1994, is still an NDI unless the ingredient was also marketed as a dietary ingredient in the U.S. before October 15, 1994. For example, an ingredient used to color a conventional food before October 15, 1994, would be an NDI unless it was also marketed before October 15, 1994, in or as a dietary supplement, or as a dietary ingredient for use in a dietary supplement.

    We recognize that the present definitions of “dietary supplement” and “dietary ingredient” were not added to the FD&C Act until after October 15, 1994, and that many products now marketed as dietary ingredients for use in dietary supplements were marketed under other product categories, such as foods for special dietary use or food additives. Therefore, we interpret “dietary ingredient” to refer to ingredients that (1) if marketed today, would qualify as “dietary ingredients” under 21 U.S.C. 321(ff)(1); and (2) when marketed before October 15, 1994, were intended for use as or in a product that would now be a “dietary supplement” as defined in 21 U.S.C. 321(ff) and that would not also meet the definition of a drug. See questions IV.A.7 and IV.A.10 for more about FDA’s views on the meaning of “marketing” and “dietary ingredient” in the NDI definition.

    a. Is an NDI notification required for a dietary supplement containing an NDI 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?

    No, an NDI notification would not be required in this situation because of the exception to the notification requirement for dietary supplements that contain 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 (21 U.S.C. 350b(a)(1)). See questions IV.B.4 and IV.B.5 for FDA’s view on what “chemically altered” means.

    Example: Ingredient X is a food additive that was approved for use to sweeten baked goods in 1993 and was marketed for that use before October 15, 1994, but was not marketed for use as a dietary ingredient in dietary supplements before that date. ABC Company wants to market a supplement that contains Ingredient X, and it plans to use the same form of Ingredient X used as a sweetener in baked goods. Ingredient X will be the only dietary ingredient in the supplement, which will be called “X-cellent.” Although Ingredient X is an NDI because it was not marketed as a dietary ingredient before October 15, 1994, ABC Company is not required to submit an NDI notification for X-cellent because Ingredient X has been present in the food supply as an article used for food in a form in which the food has not been chemically altered, and it is the only dietary ingredient in the supplement.

    b. Does the adulteration standard in 21 U.S.C. 342(f)(1)(B)9 apply to a dietary supplement containing an NDI even when an NDI notification is not required?

    Yes. The adulteration standard in 21 U.S.C. 342(f)(1)(B) applies to all dietary supplements that contain an NDI, even in situations when no notification is required because 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. See section IV.B for more information about chemical alteration and the exception to the NDI notification requirement for certain NDIs that have been present in the food supply as conventional foods.

    5. Is a substance that was a component of a conventional food marketed before October 15, 1994, an NDI if the component was not a dietary ingredient marketed in the U.S. before October 15, 1994?

    Yes, assuming the component meets the definition of a dietary ingredient. The mere presence of a substance as a component of a conventional food that was marketed before October 15, 1994, does not establish that the substance was marketed as a dietary ingredient before that date. Similarly, the fact that a minor component may have been isolated as part of an analytical chemical procedure to examine the composition of the previously marketed food before October 15, 1994, is not sufficient to establish that the component is a pre-DSHEA dietary ingredient or even that it is a dietary ingredient at all. If it is not a dietary ingredient, it is ineligible to be an NDI. If the food component fits into one of the dietary ingredient categories (for example, if it is a metabolite or extract of another dietary ingredient) but was not marketed as a dietary ingredient before October 15, 1994, it would be an NDI. On the other hand, if the substance was marketed as a dietary ingredient before that date (in addition to its marketing for conventional food use), then it is not an NDI. (See questions IV.A.4, IV.A.7, and IV.A.10 for FDA’s views on the meaning of “marketing” and “dietary ingredient” in the NDI definition.)

    6. Is a substance that was an ingredient in a dietary supplement marketed before October 15, 1994, an NDI?

    The answer depends on whether the substance was used as a dietary ingredient or for some other purpose (e.g., excipient or processing aid) in the pre-DSHEA dietary supplement. If the substance was added to the supplement as a dietary ingredient, it is not an NDI and may be used in dietary supplements without submitting an NDI notification to FDA.

    If the substance was not added to the pre-DSHEA dietary supplement as a dietary ingredient, however, the analysis becomes more complicated. If the substance was directly added to the pre-DSHEA dietary supplement, intended to become a component of the finished dietary supplement and have a technical effect in it, and was GRAS or approved as a food additive for that use, the substance would be an NDI. However, because most secondary direct food additives,10 indirect food additives,11 food contact substances,12 and other indirectly added substances are not intended to have a technical effect in or become components of the finished food (see question IV.D.4), you would first have to consider whether such a substance fits into one of the dietary ingredient categories in section 201(ff)(1) of the FD&C Act (21 U.S.C. 321(ff)(1)) to determine whether it is an NDI. If the substance does not fit into any of the dietary ingredient categories, it would not be either an NDI or a pre-DSHEA dietary ingredient. Rather, it could not be used as a dietary ingredient in a dietary supplement at all.

    7. What does “marketing” a dietary ingredient mean?

    FDA considers “marketing” a dietary ingredient to mean selling or offering the dietary ingredient for sale (1) as or in a dietary supplement, (2) in bulk as a dietary ingredient for use in dietary supplements, or (3) as an ingredient in a blend or formulation of dietary ingredients for use in dietary supplements. A dietary ingredient may be “marketed” by offering the article for sale online or at a retail establishment, listing it for sale in a catalog or price list, or through advertising or other promotion, if the promotion makes clear that the article is available for purchase. “Coming soon” advertisements would not qualify.

    If a dietary supplement containing an NDI is sold before the manufacturer or distributor submits a required NDI notification or less than 75 days after the notification is submitted, the sale of the product is not evidence that the dietary supplement or NDI was lawfully marketed.

    8. Is a dietary ingredient marketed outside the U.S. prior to October 15, 1994, considered to be an NDI if it was not marketed in the U.S. before that date?

    Yes. Submitting documentation that the ingredient was marketed in any other country before this date does not establish that the ingredient is not an NDI. The only kind of marketing that is relevant to whether a dietary ingredient is an NDI is marketing in the U.S. before October 15, 1994.13

    9. What documentation does FDA recommend to show that a dietary ingredient was marketed prior to October 15, 1994?

    Documentation to show that a dietary ingredient is not an NDI should consist of written business records, promotional materials, or press` reports with a contemporaneous date prior to October 15, 1994. Examples include sales records, bills of lading, sales contracts, manufacturing records, commercial invoices, magazine advertisements, mail order catalogs, or sales brochures.

    Documentation should include adequate information to establish that marketing took place in the U.S.: the identity (e.g., chemical or botanical name) of the marketed ingredient, including its form (e.g., ground herb, water extract, oil), and whether the ingredient was marketed as a dietary ingredient or for some other purpose. For example, advertising in body building magazines could be adequate evidence of marketing as a dietary ingredient. On the other hand, advertising or other references in gardening or landscaping magazines would not likely serve as adequate evidence of the marketing of a botanical or herb as a dietary ingredient.

    We would also consider GRAS and food additive regulations in the Code of Federal Regulations as documentation that an ingredient was marketed as a dietary ingredient before October 15, 1994, if the regulation covers use of the substance as a nutrient supplement, became effective before October 15, 1994, and contains identity specifications that the ingredient meets. Although references published before October 15, 1994, such as the 1992 edition of Herbs of Commerce,14 may be supportive, we are unlikely to regard a listing in Herbs of Commerce as being solely determinative of whether a dietary ingredient was marketed as such before October 15, 1994 because this listing may not specify necessary information such as the plant part and/or extract type. If you rely on Herbs of Commerce as evidence that your dietary ingredient is not an NDI, we recommend that you maintain additional documentation showing that the botanical was marketed as a dietary ingredient before October 15, 1994. The documentation should specify the plant part from which the botanical dietary ingredient was derived, and for botanical extracts it should also specify the extract type.

    Affidavits attesting to recollection of when a dietary ingredient was first marketed generally would not be adequate to show that an ingredient was marketed prior to October 15, 1994, unless supported by contemporaneous written records. Because memory can be unreliable, especially when the event in question took place more than thirty years ago, we are not likely to regard such an affidavit alone, without any sort of objective, verifiable documentation from the time of marketing, as an adequate basis to establish pre-DSHEA marketing of a substance as a dietary ingredient for use in or as a dietary supplement.

    10. Is marketing an ingredient for any use prior to October 15, 1994, sufficient to conclude that it is not an NDI?

    No. FDA does not consider the marketing of an ingredient as a conventional food, as a drug, or for any other non-food use, to be evidence that an ingredient is not an NDI. Unless the ingredient was marketed as a dietary ingredient for use in or as a dietary supplement prior to October 15, 1994, it is an NDI.

    11. Is there an authoritative list of dietary ingredients that were marketed prior to October 15, 1994 (a so-called “grandfathered list” or “old dietary ingredient list”)?

    Not currently. Some trade associations and other industry groups have compiled lists of “old dietary ingredients,” 15 though FDA is unable to verify the accuracy of these lists because we have not seen documentation showing that the ingredients on such lists were marketed as dietary ingredients prior to October 15, 1994. The lists contain ingredients FDA believes are unlikely to have been marketed as dietary ingredients, like acetaminophen or pharmaceutical glaze, and mixtures that are only vaguely described, like “sterol complete premix.” Moreover, the introduction to one trade association list16 states that the association did not independently verify that the substances on the list were in use before October 15, 1994. The cover page of the list specifically states, “This list is compiled solely for reference purposes and does not constitute verification that any specific dietary ingredient was or was not marketed as a dietary supplement before October 15, 1994.” The trade association’s introduction to the list also states, “There is no definitive list of ‘grandfathered’ dietary ingredients. The best policy is for any company to maintain its own records confirming long-term use of an ingredient.” Because of the uncertainty about the existence of supporting evidence, FDA does not accept the inclusion of an ingredient on an industry list of pre-DSHEA dietary ingredients as proof that the ingredient is not an NDI. However, in response to comments, we are prepared to develop an authoritative list of pre-DSHEA ingredients, based on independent and verifiable data. Because FDA does not generally have access to marketing records for dietary ingredients and dietary supplements, the documentation of pre-DSHEA marketing would have to be supplied by industry.

    FDA’s current thinking is that the two main factors for placing an ingredient on an authoritative list of pre-DSHEA ingredients would be: (1) adequate documentation of marketing for use as or in a dietary supplement in the U.S. before October 15, 1994: and (2) a precise description of the identity of the ingredient marketed. Records offered to support an item’s inclusion on the list should specify the date of marketing in the U.S. and clearly identify the ingredient marketed on that date. Documentation of an ingredient’s identity should be sufficiently precise to uniquely identify the ingredient. See question IV.A.9 for the kinds of documentation FDA recommends to show that a dietary ingredient was marketed prior to October 15, 1994.

    Including an ingredient on FDA’s list of pre-DSHEA dietary ingredients would represent our view that the evidence is adequate to conclude that the dietary ingredient in question is not “new” and, therefore, not subject to the NDI notification requirement. The mere fact that an ingredient is not on the list would not, however, establish that the ingredient is an NDI or that dietary supplements containing that dietary ingredient are adulterated for failure to notify. Rather, the omission of an ingredient from the list would be regarded as neutral and would not affect the ingredient’s regulatory status. Whether FDA would investigate dietary ingredients not on the list to determine whether an NDI notification should have been submitted would typically depend on factors relating to public health, such as potential for risk, extent of public exposure to the ingredient, and association with adverse events.

    Although only one instance of marketing as a dietary ingredient before October 15, 1994 (pre-DSHEA marketing) need be shown to establish that an ingredient is not an NDI, each dietary supplement manufacturer and distributor is responsible for determining whether each dietary ingredient in each of its dietary supplements is an NDI and ensuring that the firm complies with the NDI notification requirements, if applicable. For ingredients that are not on FDA’s list of pre-DSHEA dietary ingredients, a firm could either maintain its own records of the pre-DSHEA marketing of a dietary ingredient or rely on another firm or organization’s records, with that entity’s permission.

    12. If I change the manufacturing process for a dietary ingredient that was marketed in the U.S. prior to October 15, 1994, does that make the ingredient an NDI?

    The answer depends on the extent to which the manufacturing process change affects the resulting ingredient. As discussed in a separate FDA guidance on manufacturing changes,17 such changes may affect the identity of the food substance or its safety and suitability for certain conditions of use. Manufacturing changes may also affect the purity of a food substance, such as the amounts of impurities and contaminants in the food substance.

    Any changes in your manufacturing process that alter the identity of the ingredient will convert a previously marketed dietary ingredient into an NDI. Manufacturing changes that alter the physicochemical structure or properties, purity and impurities, or biological properties (such as bioavailability or toxicity) of the ingredient result in an NDI. 18 For example, using a solvent to prepare an extract from a pre-DSHEA dietary ingredient creates an NDI because the final extract contains only a fractionated subset of the constituent substances in the original dietary ingredient. A manufacturing change which changes the ingredient in a way that leads to alteration of the serving level or conditions of use of the product is another example of a significant change which is likely to create an NDI.

    In addition, changes that alter the identity of the source material for an ingredient may create an NDI. For example, using a different part of a plant (e.g., using an extract of plant leaves where the root extract from the same plant is a pre-DSHEA dietary ingredient) would create an NDI. If the ingredient produced by the new manufacturing process is an NDI, an NDI notification is required unless the NDI has been present in the food supply as an article used for food in a form in which the food has not been chemically altered (see Section IV.B). On the other hand, if the manufacturing changes do not alter the identity of the ingredient (e.g., there are no changes in physicochemical structure or properties and no changes in purity, impurities or biological properties such as bioavailability or toxicity) then the regulatory status of the pre-DSHEA ingredient does not change and no NDI notification is needed.

    Note that the question of whether a manufacturing change creates an NDI is different from the question of whether the manufacturing change constitutes chemical alteration, and different standards apply. The “chemically altered” standard in section 413(a)(1) of the FD&C Act (21 U.S.C. 350b(a)(1)) governs only the manufacturing of dietary ingredients that have been “present in the food supply” as articles “used for food” (i.e., conventional foods and their ingredients)19 and is applied to determine whether an NDI notification is required for a conventional food ingredient that was not marketed as a dietary ingredient before October 15, 1994. In general, a broader range of manufacturing changes would create an NDI by changing the identity of a dietary ingredient than would “chemically alter” an article of food present in the food supply. For example, solution in water or tincture may change the composition of a pre-DSHEA dietary ingredient enough to make it an NDI for which a notification is required. However, solution in water or tincture would not constitute a “chemical alteration” of a conventional food ingredient (see questions IV.B.4 and IV.B.5), and therefore, no NDI notification would be needed when a tincture or solution in water made with a conventional food ingredient is used as a dietary ingredient.

    It should also be noted that some manufacturing changes may alter the identity of the ingredient to the point that it no longer meets the definition of a dietary ingredient (see question IV.D.5). Firms planning a manufacturing change are encouraged to consult with FDA on any questions as to whether such a change would create an NDI or an ingredient that does not meet the definition of a dietary ingredient.

    13. Should I submit a new NDI notification if I change the manufacturing process for an NDI that is the subject of a notification for which I have received an acknowledgment without objection from FDA?

    That depends on the nature of the change to the manufacturing process. If the manufacturing change does not alter the chemical or molecular composition or structure of the dietary ingredient or the specifications needed to describe the ingredient, it is not necessary to submit a second NDI notification. On the other hand, a manufacturing process change intended to produce an ingredient with particles in the 1 nm to 100 nm (approximate) nanoscale range may alter the chemical or molecular composition or structure of the NDI. In that case, the previously submitted notification for a related substance manufactured without using nanotechnology would not cover the ingredient made with the new manufacturing process, and a separate NDI notification with safety information taking into account the smaller particle size of the resulting new ingredient would then be required.

    If you are planning a manufacturing change, we encourage you to consult with FDA on whether such a change would create a different NDI or a substance that is no longer a dietary ingredient.21 (See questions IV.A.12 for additional discussion on manufacturing changes that affect the identity of an ingredient.)

    12. If I change the manufacturing process for a dietary ingredient that was marketed in the U.S. prior to October 15, 1994, does that make the ingredient an NDI?

    The answer depends on the extent to which the manufacturing process change affects the resulting ingredient. As discussed in a separate FDA guidance on manufacturing changes,17 such changes may affect the identity of the food substance or its safety and suitability for certain conditions of use. Manufacturing changes may also affect the purity of a food substance, such as the amounts of impurities and contaminants in the food substance.

    Any changes in your manufacturing process that alter the identity of the ingredient will convert a previously marketed dietary ingredient into an NDI. Manufacturing changes that alter the physicochemical structure or properties, purity and impurities, or biological properties (such as bioavailability or toxicity) of the ingredient result in an NDI. 18 For example, using a solvent to prepare an extract from a pre-DSHEA dietary ingredient creates an NDI because the final extract contains only a fractionated subset of the constituent substances in the original dietary ingredient. A manufacturing change which changes the ingredient in a way that leads to alteration of the serving level or conditions of use of the product is another example of a significant change which is likely to create an NDI.

    In addition, changes that alter the identity of the source material for an ingredient may create an NDI. For example, using a different part of a plant (e.g., using an extract of plant leaves where the root extract from the same plant is a pre-DSHEA dietary ingredient) would create an NDI. If the ingredient produced by the new manufacturing process is an NDI, an NDI notification is required unless the NDI has been present in the food supply as an article used for food in a form in which the food has not been chemically altered (see Section IV.B). On the other hand, if the manufacturing changes do not alter the identity of the ingredient (e.g., there are no changes in physicochemical structure or properties and no changes in purity, impurities or biological properties such as bioavailability or toxicity) then the regulatory status of the pre-DSHEA ingredient does not change and no NDI notification is needed.

    Note that the question of whether a manufacturing change creates an NDI is different from the question of whether the manufacturing change constitutes chemical alteration, and different standards apply. The “chemically altered” standard in section 413(a)(1) of the FD&C Act (21 U.S.C. 350b(a)(1)) governs only the manufacturing of dietary ingredients that have been “present in the food supply” as articles “used for food” (i.e., conventional foods and their ingredients)19 and is applied to determine whether an NDI notification is required for a conventional food ingredient that was not marketed as a dietary ingredient before October 15, 1994. In general, a broader range of manufacturing changes would create an NDI by NDI for which a notification is required. However, solution in water or tincture would not constitute a “chemical alteration” of a conventional food ingredient (see questions IV.B.4 and IV.B.5), and therefore, no NDI notification would be needed when a tincture or solution in water made with a conventional food ingredient is used as a dietary ingredient.

    It should also be noted that some manufacturing changes may alter the identity of the ingredient to the point that it no longer meets the definition of a dietary ingredient (see question IV.D.5). Firms planning a manufacturing change are encouraged to consult with FDA on any questions as to whether such a change would create an NDI or an ingredient that does not meet the definition of a dietary ingredient.20

    B. Exception to Notification Requirement for Certain NDIs with a History of Use in Conventional Food

    1. When is a notification not required for an NDI?

    A notification is not required when the NDI and all other dietary ingredients in the dietary supplement have been present in the food supply as articles used for food in a form in which the food has not been chemically altered. See questions IV.B.4 and IV.B.5 for FDA’s current thinking on when a dietary ingredient has been “chemically altered” from the form in which it is used in the food supply.

    FDA interprets the phrase “present in the food supply” to refer to the conventional food supply. Accordingly, we interpret a dietary ingredient that has been “present in the food supply as an article used for food” to mean a conventional food or conventional food ingredient. We do not consider prior use in dietary supplements to constitute presence in the food supply. Interpreting “food supply” to include dietary supplements for purposes of this exemption from the NDI notification requirement would expand the exception to the point that it would risk swallowing the rule, as prior use in even one dietary supplement manufactured in small quantities and distributed over a small area would exempt all dietary supplements containing the NDI from the notification requirement, even if the intake level and conditions of use were much different. Moreover, such an interpretation would not make sense in light of the purpose of the NDI notification requirement, which is to ensure that dietary ingredients that have not been widely consumed receive a safety evaluation before reaching the marketplace. Because dietary supplements are generally consumed by a narrower segment of the population than conventional foods and typically have a shorter history of use than conventional food ingredients, prior use in a supplement or supplements typically provides less information about a substance’s safety than prior use in conventional food. In addition, substances added to conventional foods must meet the safety standards for conventional food ingredients, which are more demanding than those that apply to dietary ingredients used in dietary supplements.

    2. Am I required to submit an NDI notification for a dietary ingredient that is an NDI, but has been (a) listed or affirmed by FDA as generally recognized as safe (GRAS) for direct addition to food or (b) approved as a direct food additive in the U.S.?

    No, as long as the following conditions are met. The direct food additive or GRAS substance (1) has been used in the food supply (i.e., in conventional foods) and (2) is to be used as a dietary ingredient without chemical alteration. (See questions IV.B.4 and IV.B.5 for further discussion on chemical alteration.)

    If the NDI has been legally marketed in the U.S. as an ingredient for use in conventional food and has been introduced into the food supply as a result of such marketing, it would be exempt from the notification requirement under section 413(a)(1) of the FD&C Act (21 U.S.C. 350b(a)(1)) 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. Similarly, ingredients marketed in conventional foods outside the U.S. are exempt from the NDI notification requirement if they are not chemically altered. However, as discussed in the following question, the NDI adulteration standard still applies, and voluntary NDI notification may be advisable.

    3. Does the adulteration standard in 21 U.S.C. 342(f)(1)(B) apply to an NDI that has been listed or affirmed by FDA as GRAS for direct addition to food or approved as a direct food additive in the U.S.?

    Yes. The adulteration standard in section 402(f)(1)(B) of the FD&C Act (21 U.S.C. 342(f)(1)(B)) applies to all NDIs, including NDIs for which a notification is not required. In other words, if an ingredient was not marketed as a dietary ingredient in the U.S. before October 15, 1994 (see questions IV.A.4, IV.A.7 and IV.A.10), it is an NDI and the adulteration standard for NDIs applies. That standard provides that a dietary supplement containing the NDI is adulterated unless there is adequate information to provide reasonable assurance that the ingredient does not present a significant or unreasonable risk of illness or injury.

    If the intake level of the NDI resulting from its use under the conditions recommended or suggested in the labeling of the dietary supplement is the same as or lower than the intake level approved in a food additive regulation or specified in a GRAS regulation and overall cumulative intake of the NDI from dietary sources is the same as or lower than the acceptable daily intake (see question VI.C.8), FDA is likely to conclude that there is adequate information to provide reasonable assurance of safety, assuming that other conditions of use remain unchanged. 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. For example, if an ingredient generally used in microgram quantities to flavor food is placed in a capsule with a serving level of hundreds of milligrams, a safety analysis would be necessary to determine the safety of the much higher intake level in the dietary supplement. In the absence of adequate information to provide reasonable assurance that the higher intake level of the NDI in the dietary supplement is safe, the dietary supplement would be adulterated.

    Although an NDI notification is not required for a dietary supplement that contains an NDI that has been present in the food supply as an article used for food without chemical alteration, even if the dietary supplement contains more of the NDI than is used in conventional foods, FDA recommends that you consult with us about your basis for concluding that there is adequate information to provide reasonable assurance that the use of the NDI in the dietary supplement will not present a significant or unreasonable risk of illness or injury.22 As with any new dietary supplement you intend to market, you should assure yourself that the product is safe under its labeled conditions of use before distributing it. To that end, it may be advisable to submit a NDI notification voluntarily when a dietary supplement contains a significantly higher level of an NDI than is used in conventional foods. FDA has reviewed and intends to continue reviewing voluntarily submitted notifications for NDIs that are exempt from the notification requirement under 21 U.S.C. 350b(a)(1) because they have been present in the food supply as articles used for food in a form in which the food has not been chemically altered.

    Like higher daily intake levels, combining an NDI with other dietary ingredients could also present safety risks, as discussed in question IV.C.2 below.

    4. What are examples of processes that chemically alter an article of food present in the food supply?

    Below are some examples of processes that FDA would likely consider to involve chemical alteration. These processes would also be likely to affect the safety profile of a dietary ingredient. The examples below are intended only for the purpose of illustration and are not a comprehensive list of processes that result in chemical alteration. See question IV.B.5 for further discussion on chemical alteration.

    • A process that makes or breaks chemical bonds, unless the bonds created by the process are reversed when the ingredient is dissolved in water (e.g., creation of a soluble salt) or during ingestion. Example: hydrolysis.
    • Removal of some components of a tincture or solution in water, which changes the chemical or molecular composition or structure of the mixture. Examples: chromatography, distillation, and filtration.
    • Use of solvents other than water or aqueous ethanol to make an extract or tincture. The official legislative history of DSHEA specifies that “solution in water” and “tincture” (solution in aqueous ethanol) are not processes that chemically alter a food.23 However, other solvents typically alter the composition of the extract in significantly different ways, usually 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 causes 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 such that the chemical or molecular composition or structure is significantly different. Examples: changes that alter the composition of materials used to make the ingredient, use of a different solvent, or use of a chromatographic matrix instead of a passive filter.
    • Application of nanotechnology that results 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: sprouting garlic or fermenting yeast using a medium containing large amounts of sodium selenite to create large amounts of organic selenium compounds.
    • Fermentation using a fermentation medium different from the one used to make conventional foods in the food supply. Example: use of a defined commercial growth medium to produce aa microorganism previously made by fermenting milk into dairy products like yogurt or cheese.
    • 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: making an extract from unripe instead of ripe apples or using the mycelium instead of the fruiting body of a fungus.

    5. What processes for manufacturing a dietary ingredient from an article of food present in the food supply do not result in chemical alteration?

    As set forth in the Congressional Statement of Agreement between the House and Senate sponsors of DSHEA, “[T]he term ‘‘chemically altered’ does not include the following physical modifications: minor loss of volatile components, dehydration, lyoph[i]lization, milling, tincture or solution in water, slurry, a powder, or solid in suspension.”24 FDA considers this list to represent examples of manufacturing processes that do not involve chemical alteration, but not necessarily a complete list of such processes.

    FDA views “chemical alteration” specifically within the context of section 413(a)(1) of the FD&C Act, which creates an exemption from the NDI notification requirement for NDIs that have been “present in the food supply” as “article[s] used for food in a form in which the food has not been chemically altered.” Because this exemption is for articles that are used for food and present in the food supply (conventional foods and their ingredients), it applies to ingredients that meet the safety standards for conventional foods and have a history of safe use as food. These safeguards provide some confidence that such ingredients are likely to be safe when used in dietary supplements at comparable levels, as long as they are not chemically altered from their form in conventional food.

    A process that chemically alters an ingredient found in the food supply can introduce contaminants, solvents, or impurities whose safety is unknown.25 Such a process may result in an ingredient that not only differs from the source ingredient but also has an unknown safety profile. See question IV.B.4 for further discussion on chemical alteration. A well-characterized starting material may result in no change to the identity of the material after processing, in which case an NDI notification would not be required. However, dietary supplements and dietary ingredients that are complex mixtures introduce more variability into the processing. Therefore, their identity is more likely to change during processing.

    In general, FDA considers a process that does not result in chemical alteration to mean a process that: (1) involves an ingredient composed of one single raw material, or derived from a single raw material using a manufacturing process that involves only physical steps (e.g., water extraction and condensation); and (2) does not involve attempts to selectively increase the concentration of particular active ingredients or cause a chemical reaction (other than esterification) that would modify the covalent bonds of any substance in the original material. This type of process is unlikely to affect the safety profile of the ingredient in question or of dietary supplements containing the ingredient.

    Some of the processes characterized as “physical modifications” in the Congressional Statement of Agreement (milling, slurry, powder, or solid in suspension) do not alter the chemical or molecular composition or structure of the ingredient. FDA views such changes as unlikely to create a change in the safety profile of an ingredient being used in conventional food. Dehydration, lyophilization, or making a tincture, solution in water, or slurry can be said to change the composition of the ingredient, but only by changing the amount of water (or ethanol, in the case of a tincture). FDA regards such a minor change in composition as extremely unlikely to change the safety profile of an ingredient used in conventional food. Similarly, a minor loss of volatile components during processing is unlikely to change the safety profile of an ingredient used in conventional food. In a typical extraction, however, the first step is solution in water or another solvent, followed by filtration to remove undissolved material.

    This is a much larger change in the composition of the ingredient. FDA generally regards extraction that includes a filtration step or that involves the use of a solvent other than water or alcohol (aqueous ethanol) as a process that chemically alters the source ingredient and therefore triggers the NDI notification requirement for the resulting dietary ingredient.

    As industry develops new technologies and processes other than those described as physical modifications in the Congressional Statement of Agreement, we encourage you to consult with us when considering whether a notification is needed in a particular situation, as well as before submitting an NDI notification.26 We intend to evaluate any new technology or process based on our guidance on chemical alteration as set forth in this document. We also intend to consider whether or not the technology or process would affect the safety profile of the dietary ingredient and the dietary supplement in which it is used.

    We are willing to consider arguments supported by science demonstrating that particular manufacturing processes do not actually result in a chemical alteration or have any effect on the safety profile of the ingredient. In such cases, we encourage manufacturers and distributors to arrange a pre-notification meeting with FDA to discuss their basis for this belief.

    3. Does the adulteration standard in 21 U.S.C. 342(f)(1)(B) apply to an NDI that has been listed or affirmed by FDA as GRAS for direct addition to food or approved as a direct food additive in the U.S.?

    Yes. The adulteration standard in section 402(f)(1)(B) of the FD&C Act (21 U.S.C. 342(f)(1)(B)) applies to all NDIs, including NDIs for which a notification is not required. In other words, if an ingredient was not marketed as a dietary ingredient in the U.S. before October 15, 1994 (see questions IV.A.4, IV.A.7 and IV.A.10), it is an NDI and the adulteration standard for NDIs applies. That standard provides that a dietary supplement containing the NDI is adulterated unless there is adequate information to provide reasonable assurance that the ingredient does not present a significant or unreasonable risk of illness or injury.

    If the intake level of the NDI resulting from its use under the conditions recommended or suggested in the labeling of the dietary supplement is the same as or lower than the intake level approved in a food additive regulation or specified in a GRAS regulation and overall cumulative intake of the NDI from dietary sources is the same as or lower than the acceptable daily intake (see question VI.C.8), FDA is likely to conclude that there is adequate information to provide reasonable assurance of safety, assuming that other conditions of use remain unchanged. 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. For example, if an ingredient generally used in microgram quantities to flavor food is placed in a capsule with a serving level of hundreds of milligrams, a safety analysis would be necessary to determine the safety of the much higher intake level in the dietary supplement. In the absence of adequate information to provide reasonable assurance that the higher intake level of the NDI in the dietary supplement is safe, the dietary supplement would be adulterated.

    Although an NDI notification is not required for a dietary supplement that contains an NDI that has been present in the food supply as an article used for food without chemical alteration, even if the dietary supplement contains more of the NDI than is used in conventional foods, FDA recommends that you consult with us about your basis for concluding that there is adequate information to provide reasonable assurance that the use of the NDI in the dietary supplement will not present a significant or unreasonable risk of illness or injury.22 As with any new dietary supplement you intend to market, you should assure yourself that the product is safe under its labeled conditions of use before distributing it. To that end, it may be advisable to submit a NDI notification voluntarily when a dietary supplement contains a significantly higher level of an NDI than is used in conventional foods. FDA has reviewed and intends to continue reviewing voluntarily submitted notifications for NDIs that are exempt from the notification requirement under 21 U.S.C. 350b(a)(1) because they have been present in the food supply as articles used for food in a form in which the food has not been chemically altered.

    Like higher daily intake levels, combining an NDI with other dietary ingredients could also present safety risks, as discussed in question IV.C.2 below.

    5. What processes for manufacturing a dietary ingredient from an article of food present in the food supply do not result in chemical alteration?

    As set forth in the Congressional Statement of Agreement between the House and Senate sponsors of DSHEA, “[T]he term ‘‘chemically altered’ does not include the following physical modifications: minor loss of volatile components, dehydration, lyoph[i]lization, milling, tincture or solution in water, slurry, a powder, or solid in suspension.”24 FDA considers this list to represent examples of manufacturing processes that do not involve chemical alteration, but not necessarily a complete list of such processes.

    FDA views “chemical alteration” specifically within the context of section 413(a)(1) of the FD&C Act, which creates an exemption from the NDI notification requirement for NDIs that have been “present in the food supply” as “article[s] used for food in a form in which the food has not been chemically altered.” Because this exemption is for articles that are used for food and present in the food supply (conventional foods and their ingredients), it applies to ingredients that meet the safety standards for conventional foods and have a history of safe use as food. These safeguards provide some confidence that such ingredients are likely to be safe when used in dietary supplements at comparable levels, as long as they are not chemically altered from their form in conventional food.

    A process that chemically alters an ingredient found in the food supply can introduce contaminants, solvents, or impurities whose safety is unknown.25 Such a process may result in an ingredient that not only differs from the source ingredient but also has an unknown safety profile. See question IV.B.4 for further discussion on chemical alteration. A well-characterized starting material may result in no change to the identity of the material after processing, in which case an NDI notification would not be required. However, dietary supplements and dietary ingredients that are complex mixtures introduce more variability into the processing. Therefore, their identity is more likely to change during processing.

    In general, FDA considers a process that does not result in chemical alteration to mean a process that: (1) involves an ingredient composed of one single raw material, or derived from a single raw material using a manufacturing process that involves only physical steps (e.g., water extraction and condensation); and (2) does not involve attempts to selectively increase the concentration of particular active ingredients or cause a chemical reaction (other than esterification) that would modify the covalent bonds of any substance in the original material. This type of process is unlikely to affect the safety profile of the ingredient in question or of dietary supplements containing the ingredient.

    Some of the processes characterized as “physical modifications” in the Congressional Statement of Agreement (milling, slurry, powder, or solid in suspension) do not alter the chemical or molecular composition or structure of the ingredient. FDA views such changes as unlikely to create a change in the safety profile of an ingredient being used in conventional food. Dehydration, lyophilization, or making a tincture, solution in water, or slurry can be said to change the composition of the ingredient, but only by changing the amount of water (or ethanol, in the case of a tincture). FDA regards such a minor change in composition as extremely unlikely to change the safety profile of an ingredient used in conventional food. Similarly, a minor loss of volatile components during processing is unlikely to change the safety profile of an ingredient used in conventional food. In a typical extraction, however, the first step is solution in water or another solvent, followed by filtration to remove undissolved material.

    This is a much larger change in the composition of the ingredient. FDA generally regards extraction that includes a filtration step or that involves the use of a solvent other than water or alcohol (aqueous ethanol) as a process that chemically alters the source ingredient and therefore triggers the NDI notification requirement for the resulting dietary ingredient.

    As industry develops new technologies and processes other than those described as physical modifications in the Congressional Statement of Agreement, we encourage you to consult with us when considering whether a notification is needed in a particular situation, as well as before submitting an NDI notification.26 We intend to evaluate any new technology or process based on our guidance on chemical alteration as set forth in this document. We also intend to consider whether or not the technology or process would affect the safety profile of the dietary ingredient and the dietary supplement in which it is used.

    We are willing to consider arguments supported by science demonstrating that particular manufacturing processes do not actually result in a chemical alteration or have any effect on the safety profile of the ingredient. In such cases, we encourage manufacturers and distributors to arrange a pre-notification meeting with FDA to discuss their basis for this belief.

    C. Other Questions About When an NDI Notification Is Necessary

    1. May I submit a single NDI notification that contains safety data for a range of conditions of use and covers multiple products?

    Yes. We accept notifications that cover multiple dietary supplements and include safety data for a range of doses, daily intake levels, and/or other variations in conditions of use (e.g., serving size, duration of use, frequency of intake, target population, dosage form, or different formulations of pre-DSHEA ingredients in combination with the NDI). We recommend you submit safety data up to and including the highest dose and daily intake level, but indicate any lower daily intake levels at which the NDI may be marketed and include research that evaluates statistically relevant data points, such as a range of daily intake levels, to strengthen the safety analysis. FDA has received a number of notifications that cover a range of doses and daily intake levels. These notifications are publicly available in the NDI notification docket on www.regulations.gov. Contact FDA’s Office of Dietary Supplement Programs for more information.

    You may also submit a confidential “NDI master file” to FDA which contains the manufacturing, specifications and other identity information needed to completely describe the ingredient. You may incorporate by reference the contents of the master file into an NDI notification. You may also authorize other firms to reference the contents of the master file in notifications describing the ingredient they obtain from you. FDA expects that most submitters will identify the contents of NDI master files and ingredient specifications as trade secrets (see question V.A.16) and will only discuss them with the firm which submitted them.

    If you are a dietary supplement manufacturer or distributor and either you or the manufacturer or distributor of the NDI have submitted an NDI notification that covers the conditions under which the NDI will be used in your supplement, you need not submit a new notification for the use of the NDI in that supplement. However, if you are planning to market a product that exceeds the highest daily intake level or single-serving dose for which safety information was submitted in the previous NDI notification, you should submit a new notification because the previous NDI notification does not cover the higher single-serving or daily intake level. Similarly, if the NDI is not identical to the NDI evaluated in the previous NDI notification, the dietary ingredients to be combined with the NDI in your product differ from those in the product that was the subject of the previous notification, or any other conditions under which the NDI will be used in the new product were not evaluated in the original notification, a new notification should be submitted. See questions IV.C.2 and IV.C.3.

    2. If I submit an NDI notification for a dietary supplement that I manufacture or distribute and then decide to manufacture or distribute a different supplement that contains the same NDI, should I submit another NDI notification?

    The answer depends on what was covered in your previous NDI notification, on how FDA responded, and on the extent to which the NDI’s proposed conditions of use in your new dietary supplement differ from those evaluated in the notification. If you have already submitted an NDI notification for a dietary supplement containing an NDI, you need not submit a separate notification for a different dietary supplement containing the same NDI if the following criteria are met:

    • 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 your original NDI notification;
    • The new supplement does not combine the NDI with other dietary ingredients that were not included in your original NDI notification;
    • The target populations for the new supplement are the same as, or a subset of, the target populations specified in your original 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 your prior NDI notification; and
    • FDA did not express safety or other regulatory concerns in response to your prior NDI notification.

    As discussed in question IV.C.1, you may submit a NDI notification that contains safety information about a range of daily intake levels and/or other conditions of use for dietary supplements containing the NDI. Once you have submitted a notification for an NDI that covers multiple conditions of use, you may market as many dietary supplements containing that NDI as you wish without submitting another notification, as long as the bulleted criteria above are met. Put another way, if the conditions of use for the dietary supplement you plan to market are within the conditions of use evaluated in your original notification and FDA did not object to that notification, you may market the supplement without submitting another notification.

    However, if any of the bulleted criteria above are not met, you should submit another NDI notification. For example, suppose you want to market a dietary supplement with a higher daily intake level of the NDI than the level evaluated in your original notification. In general, the risk from a substance is likely to increase as intake increases above levels safely consumed in the past. A higher intake level of some substances could present toxicity risks to consumers. If you have not evaluated safety information for the higher daily intake level, you do not have an adequate basis on which to conclude that a dietary supplement containing the NDI at that higher level will reasonably be expected to be safe.

    The same principle applies for other changes in conditions of use, such as combining the NDI with dietary ingredients other than those that were in the dietary supplement evaluated in the original NDI notification. When dietary ingredients are combined, they can interact. In some cases, these interactions can present risks to consumers. For example, adverse effects—such as low blood pressure, low heart rate, gastrointestinal distress, and in severe cases, irregular heartbeat—may occur when a new dietary ingredient with cholinesterase-inhibiting properties (such as huperzine A or galantamine) is combined with another dietary ingredient that is a cholinergic agonist (e.g., yohimbe bark extract). To have a basis to conclude that a dietary supplement that combines an NDI with one or more pre-DSHEA dietary ingredients will reasonably be expected to be safe, it is necessary to consider whether the addition of the other dietary ingredients will affect the safety of the NDI or the resulting dietary supplement.

    The same analysis applies to other conditions of use that are outside the scope of the original notification. If the information in your original notification is insufficient to provide a basis to conclude that your new dietary supplement will reasonably be expected to be safe, then the statutory requirement for the “manufacturer or distributor of the dietary ingredient or dietary supplement” to provide FDA with “information . . . which is the basis on which the manufacturer or distributor has concluded that a dietary supplement containing such dietary ingredient will reasonably be expected to be safe” (21 U.S.C. 350b(a)(2)) has not been met. It is your responsibility to meet it by conducting a safety evaluation and submitting a notification with data about the safety of the NDI under the conditions of use in your proposed dietary supplement.

    3. If a dietary supplement manufacturer or distributor has submitted an NDI notification prior to marketing a dietary supplement with the NDI, and I intend to market a dietary supplement containing the same NDI, should I also submit an NDI notification?

    Yes. Section 413(a)(2) of the FD&C Act (21 U.S.C. 350b(a)(2)) states that a dietary supplement that contains an NDI is deemed adulterated unless, among other things, the manufacturer or distributor of the dietary ingredient or the dietary supplement submits an NDI notification at least 75 days before introducing it into interstate commerce. Note that, in situations where the NDI manufacturer or distributor has not submitted a notification, the statute deems a dietary supplement that contains the NDI to be adulterated unless the manufacturer or distributor of “the” dietary supplement (that particular dietary supplement), not “a” dietary supplement (some other dietary supplement containing the NDI) has submitted a notification. Accordingly, if the NDI manufacturer or distributor has not submitted a notification covering the conditions of the NDI’s use, each manufacturer or distributor of a supplement containing the NDI must submit an NDI notification with “information, including any citation to published articles, which is the basis on which the manufacturer or distributor has concluded that a dietary supplement containing such dietary ingredient will reasonably be expected to be safe” (21 U.S.C. 350b(a)(2)). The supplement manufacturer or distributor may meet the requirement to provide safety information either by conducting its own safety evaluation or relying on a safety evaluation conducted by another entity, such as a previously submitted NDI notification (see question IV.C.4). Once the manufacturer or distributor of the supplement has submitted an NDI notification to FDA, that firm need not submit further notifications for other supplements containing the same NDI if the conditions of use of the other supplements are within the conditions of use evaluated in the firm’s original notification (see question IV.C.2).

    4. When I submit an NDI notification, may I rely on data from another NDI notification or master file?

    Yes, if one of the following applies:

    • you submitted the previous notification or master file,
    • the previous notification (or portion of a previous notification) on which you wish to rely is public, or
    • the person who submitted the previous notification or master file gives you written permission to rely on non-public information from that notification. If you are relying on non-public information from another firm’s NDI master file or from another notification, you should provide FDA with documentation (such as a signed letter from the other notifier) showing that you are authorized to use the information, and the duration of that authorization. If the authorization does not extend to the entire master file or notification, the authorization from the previous notifier should specify the part(s) of the notification you are authorized to use.

    Manufacturing processes and specifications needed to establish the identity of an NDI are usually trade secrets that are not available in the NDI docket. It should be noted that the original notifier is under no obligation to share with other manufacturers and distributors any trade secrets or confidential commercial information that were part of the basis for a safety conclusion for the original notifier’s product. A written authorization to reference a notification or master file in NDI notifications does not include the right to see or copy the notification or master file unless the submitter otherwise specifies. Note that while one firm may authorize another to reference confidential safety information in a subsequent notification, that subsequent notification must demonstrate that the submitting firm understands enough about that safety information to have a basis to conclude that consumption of the NDI in the new product will reasonably be expected to be safe under the conditions of use described in its notification.

    5. Can FDA provide examples with an explanation to help distinguish situations in which separate notifications are required for dietary supplements containing the same NDI from situations in which the same NDI notification covers multiple dietary supplements?

    Two important factors you should consider when deciding whether to submit a notification for a dietary supplement containing an NDI that was the subject of a previous notification are:

    1. Are the NDI’s conditions of use in the second product within the conditions of use evaluated in the previous notification?

      If not, you should submit a separate notification for the second product because the safety evaluation in the previous notification did not include any consideration of the new conditions of use in the second dietary supplement and therefore cannot provide a basis to conclude that the NDI will reasonably be expected to be safe under those conditions of use.
    2. Who was the previous notifier and what is that entity’s relationship (e.g., same firm, supplier, or competitor) to the manufacturer or distributor who intends to market the second product?

      See questions IV.C.2 and IV.C.3 and the examples below for more about how the answer to this question affects whether an NDI notification for the second product is necessary.

    In each of the scenarios below, assume that FDA has acknowledged the filing of the first NDI notification and has not raised any safety or regulatory concerns in response to that notification.

    Scenario 1: Ingredient Supplier A submits a notification for NDI-A1 and a master file describing its manufacturing process. Supplement Manufacturer X intends to market a single-ingredient dietary supplement containing a dietary ingredient (NDI B1) that purports to be the same as NDI-A1, but is made by a different dietary ingredient manufacturer, Ingredient Supplier B.

    Analysis: Manufacturer X should submit an NDI notification for the use of NDI-B1 in its single-ingredient dietary supplement because Supplier B has submitted no NDI notification for NDI-B1 (see question IV.C.3). However, if Manufacturer X can establish that NDI-B1 is the same as NDI-A1 and Supplier A’s prior notification covers the conditions of use of NDI-A1 in Manufacturer X’s single-ingredient dietary supplement, then the NDI notification for the new supplement made with NDI-B1 could simply consist of data showing that NDI-B1 is identical to NDI-A1, a reference to the safety evaluation in Supplier A’s notification, and a signed authorization from Supplier A for Manufacturer X to use any non-public safety data from A’s notification and the manufacturing master file. On the other hand, if Manufacturer X cannot establish that NDI-B1 is the same as NDI-A1, X’s notification will have to contain safety information specific to NDI-B1 because a different NDI requires its own safety evaluation.28

    Scenario 2: Ingredient Supplier A submits a notification for NDI-A2. Supplier A’s notification includes safety information for a dietary supplement tablet containing NDI-A2 as the sole dietary ingredient in a formulation with several non-dietary ingredients used as binders and fillers. Supplement Manufacturer X wants to use the same level of NDI-A2 in a dietary supplement tablet with NDI-A2 as the sole dietary ingredient, but in a formulation with different non-dietary ingredients used as binders and fillers.

    Analysis: Manufacturer X does not need to submit an NDI notification because the only difference between Manufacturer X’s product and the formulation described in Supplier A’s notification is a change in non-dietary ingredients (i.e., inactive ingredients). However, Manufacturer X should evaluate whether the change affects the safety of the dietary supplement and document the basis for its conclusion before marketing the product.

    Scenario 3: Ingredient Supplier A submits a notification for NDI-A3 that includes safety information for single-ingredient dietary supplement formulations containing up to 500 mg/day of the NDI. Supplement Manufacturer X is using NDI-A3 in a single-ingredient dietary supplement at a level of 250 mg/day but wants to increase the amount of NDI-A3 to 500 mg/day.

    Analysis: Because Supplier A’s initial notification included safety information for NDI-A3 up to 500 mg/day, Manufacturer X does not need to submit a notification for either the 250 mg/day or 500 mg/day formulation, assuming all other conditions of use are the same as those evaluated in Supplier A’s notification.

    Scenario 4: Ingredient Supplier A submits a notification for NDI-A4. Supplier A’s notification includes safety information for a dietary supplement containing NDI-A4 in combination with vitamin A, vitamin C, sodium, calcium, and iron. Supplement Manufacturer X intends to use NDI-A4 in a dietary supplement at recommended doses and daily intake levels that do not exceed the high end of the range evaluated in Supplier A’s notification. Manufacturer X’s supplement will also contain some, but not all, of the vitamins and minerals included in Supplier A’s notification. All other conditions of use will be the same as those evaluated in A’s notification.

    Analysis: Manufacturer X does not need to submit another notification because Supplier A’s notification covers all the conditions of NDI-A4’s use in Manufacturer X’s new product.

    Scenario 5: Company Q wants to market a supercritical fluid extract of Convallaria majalis L. The plant is on an industry list of pre-DSHEA dietary ingredients.

    Analysis: Company Q must submit an NDI notification. Even though this botanical appears on an industry list of old dietary ingredients, it has historically been used only as an herbal drug, so a history of use in food has not been established. In addition, supercritical fluid extraction was not commonly used prior to 1994, and there is no evidence of extracts like this having being marketed as food prior to 1994.

    Scenario 6: Company Q received an acknowledgment letter without objection in response to its NDI notification for the Convallaria majalis L. supplement described in Scenario 5. Now Company Q wants to market the ingredient in combination with another dietary ingredient, an extract from Nerium oleander L., which has been the subject of an NDI notification from one of Company Q’s competitors, Company Y. Company Y received an acknowledgment letter without objection in response to its notification. Both notifications discussed the safety of the extracts in depth and described manufacturing procedures and specifications for cardiac glycosides. The notifications also included results from clinical testing or testing in a non-rodent species appropriate for the evaluation of cardiac risk.

    Analysis: Company Q must submit a new notification for the combination. A combination of two NDIs is itself an NDI. Although the notifications included in depth discussions of the safety of the extracts, each of the plants is known to contain glycosides with potent cardiotoxic activity and it is difficult to predict the toxicity of the combination. The new notification should include a discussion of the safety of the combination, which is likely to be an in-depth discussion because both ingredients affect the same organ system. Given the overlapping toxicological endpoint and the severity of the potential toxicity, we would recommend that the new notification include results from safety testing of the combination. However, in a notification for a combination of two NDIs with no specific safety problems where each of the NDIs had been the subject of a prior notification to FDA that was acknowledged without objection, the section of the new notification discussing the safety of the combination could be brief.

    6. Should I notify FDA about a microbial ingredient in my dietary supplement?

    Yes, if it is an 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 (21 U.S.C. 350b(a)(1)).

    However, not all bacterial microorganisms are dietary ingredients, and a microorganism that is not a dietary ingredient cannot be an NDI. For example, pathogenic species of bacteria, such as Salmonella species or Escherichia coli, are not dietary ingredients even though they may have been inadvertently present in foods as contaminants. Bacteria that have never been consumed as food are unlikely to be dietary ingredients.

    A bacterial microorganism is a dietary ingredient if it is a dietary substance (an intentional constituent of food) or otherwise falls within one of the dietary ingredient categories listed in 21 U.S.C. 321(ff)(1). For example, bacteria that are used to produce fermented foods that are eaten without a cooking or pasteurization step (e.g., lactic acid bacteria used to produce cheese or yogurt) could be “dietary substances for use by man to supplement the diet by increasing the total dietary intake,” which are defined as dietary ingredients in section 201(ff)(1)(E) of the FD&C Act (21 U.S.C. 321(ff)(1)(E)). FDA does not have a separate regulatory category or definition for dietary ingredients consisting of live or viable microorganisms.

    7. If I want to market a dietary supplement containing several pre-DSHEA ingredients that haven’t previously been marketed together, do I have to submit an NDI notification?

    No. The NDI notification requirement applies only to dietary supplements that contain at least one NDI. If each of the dietary ingredients in a dietary supplement was marketed in the United States before October 15, 1994, marketing these ingredients together for the first time in the same dietary supplement does not create an NDI or trigger the NDI notification requirement.

    8. Can FDA provide visual aids to help me decide whether I should submit an NDI notification?

    Yes. The following table illustrates when an NDI notification is required and when the NDI adulteration standard applies. In addition, Section VIII. Appendix: Decision Tree for NDI Notification has a decision tree to walk you through the steps of deciding whether to submit an NDI notification.

    Table 1: Definition of New Dietary Ingredient (NDI), Requirement for NDI Notification and Applicability of NDI Adulteration Standard

    New Dietary Ingredient (NDI) NDI notification required? NDI adulteration standard applies?
    A dietary ingredient that was marketed in the U.S. before October 15, 1994 No No No
    A dietary ingredient that was NOT marketed in the U.S. before October 15, 1994, AND was present in the food supply as an article used for food which has Yes See a) or b) Yes
    a) not been chemically altered Yes No Yes
    b) been chemically altered Yes Yes Yes
    A dietary ingredient that was NOT marketed in the U.S. before October 15, 1994, AND was NOT present in the food supply as an article used for food. Yes Yes Yes
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