Regulatory Pathways of Food Ingredients in the USA: GRAS, NDI, FAP, and CAP

In the US, safety is the core of the regulation compliance for food ingredients. Currently, there are four main pathways for food ingredient compliance in the US: Food Additive Petition (FAP), Color Additive Petition (CAP), an independent conclusion of Generally Recognized As Safe (GRAS) status, and the Dietary Ingredient (DI) pathway.

The first three pathways apply to conventional food ingredients. In contrast, the DI pathway applies to a separate category of food ingredients that have their own unique regulatory framework, in which DIs are defined and categorized as new DIs (NDI) or pre-DSHEA DIs. CIRS Group has conducted a brief analysis of the key points of these four pathways, aiming to enable entrepreneurs to select their optimal compliance pathway based on the characteristics of products.

FAP

1. Food additives require premarket FDA approval via a petition process followed by a rulemaking process and promulgation of a regulation in Title 21 of the US Code of Federal Regulations (21 CFR).

2. Definitions and applicable situations

• 2.1 Section 201(f) of the Federal Food, Drug, and Cosmetic Act (FFDCA) defines the term food to mean (1) articles used for food or drink for humans or other animals, (2) chewing gum, and (3) articles used for components of any such article.
• 2.2 Section 201(s) of the FFDCA defines the term food additive to mean any substance the intended use of which results or may reasonably be expected to result, directly or indirectly, in its becoming a component of food or otherwise affecting the characteristics of any food (including any substance intended for use in producing, manufacturing, packing, processing, preparing, treating, packaging, transporting, or holding food; and including any source of radiation intended for any such use).
  • 2.2.1 The definition of food additive and the requirement to file a premarket FAP for FDA approval applies to any substance meeting the above definition that is not otherwise, by law, excepted from the definition.

3. Key process

Prepare the FAP → Submit the FAP → FDA review and rulemaking (usually takes 1-3 years) → Upon completion of the rulemaking process, a regulation defining the food additive and its authorized use conditions is added to 21 CFR.

4. Advantages and disadvantages

• Advantages: It is the only pathway available when there is no general recognition of the safety of the intended use of the ingredient. The ability to keep key safety data confidential (however, that does not prevent competitors from developing and marketing ingredients in full compliance with the language of the regulation)
• Disadvantages: Potentially higher costs and longer timelines, suitable for companies with sufficient budgets. Some substances that are food additives may also meet the definition of a food additive and require both a FAP and a CAP.

CAP

1. Color additives require premarket FDA approval via a petition process followed by a rule-making process and promulgation of a regulation in 21 CFR.

2. Color additives are an exception to the definition of a food additive pursuant to section 201(s)(3) of the FFDCA.

3. Definitions and applicable situations

• 3.1 Section 202(t) of the FFDCA defines the term color additive to mean any material that is a dye, pigment, or other substance made by a process of synthesis or similar artifice, or extracted, isolated, or otherwise derived, with or without intermediate or final change of identity, from a vegetable, animal, mineral, or other source, and that when added or applied to a food, drug, or cosmetic, or to the human body or any part thereof, is capable (alone or through reaction with other substance) of imparting color thereto.
  • 3.1.1 A substance may be excepted from the definition of a color additive by regulation.
  • 3.1.2 Food ingredients such as cherries, green or red peppers, chocolate, and orange juice which contribute their own natural color when mixed with other foods are not regarded as color additives.
    • 3.1.2.1 However, if the above type of ingredients are used deliberately to impart color (such as beet juice to color pink lemonade), they are color additives and require a color additive petition.
  • 3.1.3 Materials meeting the definition of a color additive, but for which the intended use is solely for purposes other than coloring are still color additives and require a CAP unless the color imparted is clearly unimportant insofar as the appearance, value, marketability, or consumer acceptability of the food.

4. Key process

Prepare the CAP → Submit the CAP → FDA review and rulemaking (usually takes 1-3 years) → Upon completion of the rulemaking process, a regulation defining the color additive and its authorized use conditions is added to 21 CFR.

5. Advantages and disadvantages

Any substance meeting the definition of a color additive, and that is not excepted from the definition of a color additive requires a CAP. As such, there are no comparable and contrastable advantages and disadvantages.

GRAS – a flexible and efficient compliance pathway

1. GRAS conclusions do not require FDA approval.

2. GRAS conclusions are an exception to the definition of a food additive pursuant to section 201(s) of the FFDCA.

3. Definition and applicable situations

• 3.1 Section 201(s) of the FFDCA defines a GRAS substance as any substance that is generally recognized, among experts qualified by scientific training and experience to evaluate its safety, as having been adequately shown through scientific procedures (or, in the case of a substance used in food prior to January 1, 1958, through either scientific procedures or experience based on common use in food) to be safe under the conditions of its intended use.
  • 3.1.1 Intended use in the above definition has the same connotation as in the definition of a food additive above (i.e., a use resulting in the substance, directly or indirectly, becoming a component of food or otherwise affecting the characteristics of any food.
  • 3.1.2 Safe in the above definition means reasonable certainty that the substance is not harmful under its intended conditions of use and, when based on scientific procedures, requires the same quantity and quality of scientific evidence as required to obtain approval for a food additive.
  • 3.1.3 GRAS status applies to ingredients used in conventional foods (including beverages) when the data, information, and methods that establish the reasonable certainty of safety of its intended use are publicly available and generally accepted by qualified experts (as defined above) throughout the scientific community without ANY genuine dispute.

4. Any person (e.g., individual, partnership, corporation, association, or other legal entity) can make an independent conclusion of GRAS status (ICGS, formerly known as Self-Determined GRAS) so long as they have a basis for the conclusion.

• 4.1 Any person making an ICGS should have assembled and evaluated the evidence that forms the basis of that conclusion.
• 4.2 A person making an ICGS is the “proponent” of the ICGS.
• 4.3 There is no current requirement to inform the FDA or anyone else of an ICGS.

5. The proponent (or their agent) commonly organizes a GRAS panel of qualified experts to evaluate the scientific procedures that form the basis of their conclusion.

6. Voluntary FDA GRAS notice:

• 6.1 The FDA has established a voluntary GRAS notification program through which a proponent of an ICGS may notify the FDA of their conclusion via submission of a GRAS notice.
  • 6.1.1 A proponent of an ICGS who submits a GRAS notice is the “notifier” of the GRAS notice.
  • 6.1.2 There is no legal or regulatory requirement to submit a GRAS notice to the FDA; the GRAS notification program is entirely voluntary, and there is no legal difference between an ICGS and a GRAS notice.
• 6.2 Upon receipt of a GRAS notice, the FDA will send an acknowledgment letter to the notifier (or their agent) and place the notice in a queue for preliminary evaluation to determine whether to file the submission as a GRAS notice.
• 6.3 Upon filing of a GRAS notice the FDA will begin a 180-day evaluation period.
• 6.4 During evaluation, the FDA may ask questions of the notifier, and the notifier may make subsequent amendments to the GRAS notice.
• 6.5 Following the evaluation of a GRAS notice, the FDA will issue a response letter to the notifier of one of the following types:
  • 6.5.1 The FDA has no questions.
  • 6.5.2 At the notifier’s request, the FDA has ceased evaluation of the GRAS notice.
  • 6.5.3 The FDA concludes there is an insufficient basis for a GRAS conclusion.
• 6.6 Following the response letter, the GRAS notice, any amendments, and the response letter will be posted to the FDA GRAS Notices Inventory database where they will be publicly accessible.
• 6.7 The FDA response letter with no questions is not an FDA approval and does not trigger rulemaking and promulgation of a regulation in 21 CFR.

7. Key processes:

• 7.1 Before the initiation of an ICGS project, a feasibility analysis is recommended to identify any data gaps in publicly available information necessary to form the basis of an ICGS.
  • 7.1.1 Data gap analysis could identify the need to conduct and/or publish studies to support safety (timeline depended on studies necessary and publication times).
  • 7.1.2 If no data gaps are identified, the proponent may proceed directly to an independent conclusion.
• 7.2 ICGS: Prepare the dossier (typically 3–6 months) → Assemble a qualified GRAS panel → Submit for expert review (typically within 4 weeks) → Obtain expert panel signatures → Archive internally (no submission to the FDA required).
• 7.3 Voluntary FDA GRAS notice: Complete the dossier (typically 1 week to convert ICGS) → Submit GRAS notice to the FDA → FDA preliminary evaluation of filling of a GRAS notice (typically 4–6 months) → FDA evaluation and provide feedback within 180 days (or 270 days in special cases) → Receive the “No Questions Letter” → The materials are published on the FDA website.
  • 7.3.1 In most cases, a pre-submission meeting with the FDA is highly recommended before submitting a GRAS notice.
    • 7.3.1.1 A slide deck presentation is required to be submitted to the FDA for evaluation at least two weeks before the scheduled meeting date.
    • 7.3.1.2 In most cases, the FDA feedback can be incorporated into the GRAS notice within a few days; however, when the FDA indicates that more extensive work is needed, the submission should be delayed as necessary.

8. Comparison of ICGS and FDA GRAS Notice:

• ICGS has a shorter timeline, allowing companies to quickly enter the US market after completing the process, whereas the FDA GRAS notice typically takes an additional 9–14 months after submission.
• Companies generally do not publicly disclose the dossier for ICGS, while the FDA publishes the full set of submitted materials for FDA GRAS notices.
  • It is important to note that while the ICGS and its contents may remain with the company, all data, information, and methods required to establish the basis of safety must be publicly available.
• While there is no legal or regulatory distinction by the FDA between an ICGS and a GRAS notice, an ICGS lacks FDA evaluation which may reduce its perceived “authority”.
• Some GRAS substances may also meet the definition of a food additive and require both an ICGS (whether submitted as a GRAS notice or not) and a CAP.

4. DI – Exclusive threshold for dietary supplements

1. Definitions:

• 1.1 Section 201(ff) of the FFDCA defines a DI as:
  • 1.1.1 A vitamin
  • 1.1.2 A mineral
  • 1.1.3 An herb or other botanical
  • 1.1.4 An amino acid
  • 1.1.5 A dietary substance for use by humans to supplement the diet by increasing the total dietary intake; or
  • 1.1.6 A concentrate, metabolite, constituent, extract, or combination of any ingredient described above.
• 1.2 Section 201(ff) of the FFDCA defines a dietary supplement as a product (other than tobacco) intended to supplement the diet that bears or contains one or more DIs.
• 1.3 Section 413(d) of the FFDCA defines the term new dietary ingredient (NDI) as a DI that was not marketed in the United States before October 15, 1994.
• 1.4 Section 413(d) of the FFDCA also states that the term NDI does not include any dietary ingredient that was marketed in the United States before October 15, 1994.
  • 1.4.1 Such DIs are referred to by the FDA as pre-DSHEA DIs because they were marketed in the United States before the enactment of the Dietary Supplements Health and Education Act of 1994 (DSHEA).
  • 1.4.2 Pre-DSHEA DIs are commonly referred to as old DIs (ODI).

2. Legal and regulatory considerations:

• 2.1 Pre-DSHEA DIs can be used freely in or as dietary supplements without the need for any specific authorization.
  • 2.1.1 A company using a pre-DSHEA DI in or as a dietary supplement should maintain documentation that the ingredient was marketed in or as the pre-DSHEA equivalent of a dietary supplement in the United States before October 15, 1994.
  • 2.1.2 FDA recommends that such documentation “should consist of written business records, promotional materials, or press reports (e.g., sales records, bills of lading, sales contracts, manufacturing records, commercial invoices, magazine advertisements, mail order catalogs, or sales brochures) with a contemporaneous date before October 15, 1994.”
  • 2.1.3 Several industry trade associations maintain lists of ODIs
  • 2.1.4 The FDA does not currently recognize any of these lists as proof of ODI status.
• 2.2 In accordance with section 413(a)(2) of the FFDCA, unless exempt, at least 75 days before introducing or delivering an NDI into interstate commerce, the manufacturer or distributor of an NDI must submit a pre-market NDI notification to the FDA demonstrating that the recommended or suggested conditions of use of the NDI are reasonably expected to be safe.
  • 2.2.1 Like GRAS notices, the FDA’s evaluation of an NDI notification is not an approval process and does not result in rulemaking and promulgation of a regulation in 21 CFR.
  • 2.2.2 Unlike the voluntary GRAS notification procedure, the submission of a 75-day pre-market NDI notification is not voluntary; it is required by law.
• 2.3 In accordance with section 413(a)(1) of the FFDCA, an NDI that has been present in the food supply as an article used food in a form in which the food has not been chemically altered is exempt from the requirement to submit a 75-day pre-market NDI notification.
  • 2.3.1 For the purposes of section 413(a)(1) “an article used for food” means an article used for conventional food (including beverages).
  • 2.3.2 Section 413(a)(1) of the FFDCA is sometimes referred to by industry as the “GRAS exemption”; however, this designation is technically incorrect.
    • 2.3.2.1 It is not the GRAS status of an ingredient that exempts its use as an NDI from the requirement to submit an NDI notification; rather it is the legal presence of the ingredient in the food supply.
    • 2.3.2.2 GRAS status is one way that an ingredient can legally be added to food in the United States. FAPs and CAP are also pathways by which this may be achieved.
    • 2.3.2.3 Making a GRAS conclusion for an ingredient but then never adding the GRAS substance to a conventional food does not trigger the exemption to the requirement to submit an NDI notification pursuant to 413(a)(2).

3. NDI notifications:

• 3.1 Upon receipt of an NDI notification, the FDA will file the notification, initiating the 75-day premarket waiting/review period, and send an acknowledgment of receipt to the notifier (or their agent).
  • 3.1.1 The notifier of an NDI is the manufacturer or distributor of the NDI or a dietary supplement containing the NDI.
• 3.2 During the evaluation of an NDI notification, the FDA may ask questions of the notifier, and the notifier may make subsequent amendments to the NDI notification.
• 3.3 If the FDA determines that new material submitted by the notifier is a substantive amendment, the FDA will reset the filing date, starting a new 75-day pre-market waiting/review period.
• 3.4 Following the evaluation of the NDI notification, the FDA may respond to the notification with one of the following response letter types:
  • 3.4.1 Letter of acknowledgment without objections.
  • 3.4.2 Letter listing deficiencies causing the NDI notification to be deemed incomplete
  • 3.4.3 Objection letter raising safety concerns.
  • 3.4.4 Letters raising other regulatory issues (e.g., not a dietary ingredient)
• 3.5 Failure of the FDA to respond to an NDI notification does not constitute a finding by the agency that the NDI or the dietary supplement that contains the NDI is safe or is not adulterated under section 402 of the FFDCA.
• 3.6 No less than 90 days following the filing date of an NDI notification, the FDA will place all information contained in the notification that is not trade secret or otherwise confidential commercial information on public display.

4. Key process:

Prepare the dossier → Submit the NDI notification to the FDA → The FDA reviews (within 75 days unless there are substantive amendments), and sends the letter of acknowledgment without objection → Upon passage of the final 75-day premarket notification waiting period, the NDI or dietary supplement containing the NDI can be marketed.

5. Considerations:

• Sufficient safety evidence, such as historical use data and toxicological studies, must be provided for an NDI notification.
• Dietary supplements containing an NDI that has not been present in the food supply as an article used food in a form in which the food has not been chemically altered and that fail to complete an NDI notification are deemed adulterated under section 402(f) of the FFDCA and their introduction or delivery for introduction into interstate commerce is prohibited under section 301(a) of the FFDCA.

5. Comparison and recommendation

The core of US food ingredient regulation lies in ensuring safety. Through scientific planning and professional support, companies can successfully introduce new food ingredients into the US market. Enterprises can choose the optimal compliance pathway based on the type, intended use, and budget of their food ingredients. Below are some relevant recommendations:

- Prepare safety evidence, such as toxicological studies and other relevant data in advance after engaging CIRS Group to perform a feasibility assessment (i.e., gap analysis).

- Select the optimal regulatory pathway based on the type and intended use of the ingredient, balancing cost, timeline, and regulatory authority.

- Consult professional organizations to ensure an efficient and accurate compliance process, avoiding delays or legal risks.

About CIRS

The Food Division of CIRS Group was established in 2012 and has a professional team specializing in US GRAS notices. The CIRS Food Division has extensive experience in various fields, covering GRAS, new food ingredients, new food additives, food contact materials, synthetic biology foods, EU Novel Foods, dietary supplements, and special dietary foods.

CIRS operates a fully-owned subsidiary in the US. By leveraging the expertise of the CIRS USA and the international team, it is able to provide enterprise various US food services, including but not limited to:

• US FDA GRAS Notice;
• US New Dietary Ingredient (NDI) Notification;
• US Animal Food GRAS Conclusions;
• US FDA Dietary Supplement Structure/Function Claim Notification;
• US FDA Registration of Food Facilities; and
• US Food Label/Advertisement Information Review

If you need any assistance or have any questions, please get in touch with us via service@cirs-group.com.