OR WAIT null SECS
What have we learned in the past year, and how should industry proceed in 2020?
The 2011 publication of FDA’s draft guidance on new dietary ingredients (NDIs) caused an uproar in the supplement industry and raised a host of concerns, as previously discussed in this and other publications.1,2 In response to comments received on the 2011 draft guidance, in 2016 FDA issued a revised draft guidance with the aim of more fully answering questions, per their perspective, surrounding the New Dietary Ingredient notification (NDIN) process. The 2016 revised draft guidance greatly overlapped with the topics covered in the 2011 version but was nearly twice as long due to the more detailed explanations provided in the question-and-answer format.
Now, more than three years later, the guidance has not been finalized, and most industry concerns regarding the draft guidance remain. So where are we now in 2020? As we look ahead, it is unclear whether finalization of the guidance is near, and we suspect that challenges surrounding the future regulatory status of hot-topic ingredient hemp cannabidiol (CBD) for use in foods and supplements will further affect FDA’s timeline.
(Editor's note: For further reading about NDI concerns, click here.)
2019, a Year in Review: FDA Meetings on Master Files, Synthetic Ingredients, and More
In the first half of 2019, FDA held private meetings with industry as well as hosted a public meeting on May 16, 2019, to discuss the NDIN process. Comments from the public meeting were heavily skewed to calls for FDA to incentivize industry compliance with the NIDN requirements by enforcing existing regulations and developing a master file program which would allow companies who had invested time and money in the required testing for a successful NDIN submission to protect that investment.
Under a master file system, Company A would submit an NDIN for a dietary ingredient. Company A could then license the use of its safety data to Company B, a company wishing to use the same ingredient from the manufacturing method specified in Company A’s NDIN. Company B might need to do its own studies to expand the application of the NDIN master file for new doses or new combinations of ingredients, but it could rely, at least in part, on data in the NDIN master file. This system would provide for some intellectual property protection for Company A, while enabling multiple companies to take advantage of the same master file.
Other public comments have called on FDA to reconsider its stance on synthetic dietary ingredients. Per the latest draft guidance, FDA only recognizes as dietary ingredients synthetic forms of vitamins and amino acids-and no other synthetic ingredients. The agency does not seem to think that there were any synthetic versions of botanical constituents on the market prior to October 15, 1994-the date delineating NDIs requiring NDINs from “old” dietary ingredients, which do not require NDINs. However, until the agency authorizes a list of “grandfathered” ingredients, it will remain a point of contention whether or not some synthetic ingredients were on the market prior to the cut-off date.
Many speakers at FDA’s May 16, 2019, public meeting also suggested reconsideration of the meaning of “chemically altered” and “manufacturing change” as mentioned in FDA’s draft guidance. The guidance states that ingredients that were previously the subject of a submitted NDIN but that have been chemically altered or altered due to a manufacturing change might require submission of a new NDIN. Due to numerous technological advancements that occurred over the 17 years between passage of the Dietary Supplement Health and Education Act of 1994 (DSHEA) and FDA’s 2011 first attempt at a draft guidance on NDINs, many have questioned whether a change in manufacture should really require a new NDIN-or simply a demonstration of equivalence to a prior NDI. This issue could also be addressed by a master file system.
Where Are We Now? Recent NDIN Activity
Evaluating the current status of the most recent NDIN submissions proves challenging, since FDA’s Submitted 75-Day Premarket Notifications for New Dietary Ingredients webpage3 was lasted updated on May 15, 2019. According to the list of NDINs submitted from 1995 to the present, available as a downloadable spreadsheet, there have been at least 135 NDINs submitted to FDA for review since January 1, 2017. Of these submissions:
The relatively high number of NDINs which failed to obtain a successful nod from FDA-an acknowledgement letter-makes the situation seem especially bleak for those currently considering introducing an NDI into the marketplace. However, a closer look at the unsuccessful submissions provides valuable insight in identifying pathways toward a successful submission.
Why Did 70% of the NDINs Fail?
A review of the “rejection” response letters issued by FDA indicates that the NDINs rejected did not meet FDA’s requirements in at least one of six general categories:
Approximately 53% (n=50) of the unsuccessful NDINs did not meet two or more of these requirements. For some, these failures were more procedural in nature-i.e., the submission package contained incomplete references. However, there were instances where significant deficiencies in the submission were identified, though there were a few instances where FDA disagreed with the notifier’s conclusion of safety of the new dietary ingredient.
Here, we can take a deeper look at why some of these NDINs did not meet FDA’s bar.
1. Does the ingredient meet FDA’s definition of a dietary ingredient?
In 39 response letters, FDA noted that the ingredient defined in the NDIN submission did not meet the definition of dietary ingredient under 21 U.S.C. § 321(ff) and stated:
A dietary supplement means, among other things, a “product (other than tobacco) intended to supplement the diet that bears or contains one or more of the following dietary ingredients: (A) a vitamin; (B) a mineral; (C) an herb or other botanical; (D) an amino acid; (E) a dietary supplement for use by man to supplement the diet by increasing the total dietary intake; of (F) a concentrate, metabolite, constituent, extract, or combination of any ingredient described in clause (A), (B), (C), (D), or (E).
For many of these rejected submissions, it’s readily apparent that the subject doesn’t meet the definition of a dietary ingredient, as is the case for topical ointments, salves, and other personal care–type products, which accounted for at least 15 rejected NDINs. Other common reasons why FDA rejected the submissions included the use of the ingredient in conventional foods, and statements by the submitter, or legal regulations, that indicated the ingredient qualified as a drug.
It’s important to note that only four of the 39 notifications that FDA rejected on the basis that the ingredient didn’t meet the definition of dietary ingredient were identified as having a secondary reason for rejection. If we omit those 35 NDINs that were rejected solely on the basis of not meeting the definition of a dietary ingredient, then the success and failure percentages are adjusted to 28% and 59%, respectively.
FDA has also made it clear that synthetic forms of most dietary ingredients (with the exception of certain vitamins and amino acids, as noted above) or ingredients produced via fermentation processes, for example derived from engineered E. coli, are ineligible for consideration as dietary ingredients. This issue is a matter of concern for industry as noted by various commenters at the May 16, 2019, FDA public meeting. It was also discussed at the 2019 Rocky Mountain Dietary Supplement Forum. It remains to be seen whether FDA will soften its stance toward synthetic ingredients on a larger scale.
Of the 28 NDINs that were successful-NDINs that received acknowledgement letters-36% (n=10) were for ingredients extracted from botanical sources; 21% (n=6) were for probiotic-category ingredients; and the remaining submissions were for protein/peptide preparations (n=3), algae-derived ingredients (n=3), or other less-categorizable ingredients (n=5).
2. Have the ingredient specifications and manufacturing process been adequately addressed?
FDA noted in its response letters that 54% (n=51) of the rejected NDINs did not contain enough detail regarding the quality parameters of the ingredient and/or the manufacturing process to sufficiently evaluate the safety of the NDI. While many manufacturers understandably wish to protect proprietary processes, enough information about the process and resulting material should be provided to support the assertion that the ingredient is safe for consumption. As noted previously, a master file system might alleviate IP concerns, allowing for a more complete submission for review by FDA.
3. Does the ingredient have a prior history of use?
Another category that proved problematic for 48% (n=45) of the rejected NDINs was the history-of-use or other evidence of safety-in-use requirement. Many of the submissions lacked sufficient detail to establish a history of use, and in a number of notifications, the requirement was ignored entirely. FDA considers these NDINs incomplete.
4. Has an intake assessment been provided?
Under 21 CFR 190.6, NDINs must include information regarding the use levels of the NDI in the dietary supplement. Information about the levels of the NDI per serving and maximum daily servings of the supplement is essential for assessing safety. The proposed uses and use levels should be specific enough to determine an estimated daily intake of the ingredient, which should be supported by safety data in the published literature. A general “take one serving per day” statement is insufficient, whereas a statement indicating “a maximum daily intake of 2 grams per day” of a well-characterized material is likely to provide the necessary specificity. FDA noted that an insufficient intake assessment was observed in 18% (n=17) of the rejected NDINs.
5. Is the safety assessment complete, and does it support safety-in-use?
Ultimately, the purpose of an NDIN is to prepare a complete evaluation of an NDI to support the finding that there is reasonable expectation that the ingredient will not present “significant or unreasonable risk of illness or injury” under the proposed conditions of use. Under 21 CFR 190.6, notifiers are required to provide a basis for the expectation of safety. An evaluation of peer-reviewed, published literature is necessary to support a determination of safety for the NDI. A review of FDA’s response letters found that nearly 40% (n=35) of the rejected NDINs lacked a safety assessment entirely, presented an insufficient safety narrative, or the published literature did not support safety-in-use.
6. Are full-text references included in the submission package?
In addition to providing a basis for the expectation of safety, an additional requirement of each submission per 21 CFR 190.6(b)(4) is that the “notification shall be accompanied by reprints or photostatic copies of those references” cited in support of the notification. Submitting an incomplete NDIN package is a procedural issue that occurred in six of the rejected NDINs. While most were cited as having additional deficiencies, one submission appears to have been rejected solely for not providing the complete full-text references cited in the dossier.
NDIs Compared to the GRAS Notification Process
Ingredients that will be added to food are subject to premarket approval by FDA unless they are Generally Recognized as Safe (GRAS)5 by qualified experts under the intended conditions of use. Notification to FDA of a GRAS conclusion is a voluntary process. Since January 1, 2017, FDA has filed 203 GRAS Notices (GRNs), based on the most recent update of FDA’s GRAS Notice Inventory6, which occurred on January 17, 2020. Of these submissions:
In the past, FDA has also issued “no basis” response letters to GRNs, indicating that the notice was insufficient to provide a basis for a GRAS conclusion; however, none have been issued since 2011.
Considering only the GRNs that have been closed by FDA and not currently pending review, the success and failure rates can be adjusted to 83% and 17%, respectively. The failure rate for NDINs is striking (70% public rejections) when compared to the lower failure rate for GRNs (17% rejections), especially considering that GRNs answer to a higher safety standard of “reasonable certainty of no harm” exists-versus NDIs, for which the safety standard is that the ingredient will not present “significant or unreasonable risk of illness or injury” under the proposed conditions of use.
Of the 164 GRNs that have been closed as of January 15, 2020, 23% (n=38) could be categorized as extracts from botanical sources, 12% (n=20) were for ingredients in the steviol glycosides category, 12% (n=20) were for enzyme preparations, 10% (n=16) were for probiotic-category ingredients, and the remaining submissions were for oligosaccharides (n=10), antimicrobial ingredients (n=11), and other less-categorizable ingredients (n=49).
Many of the GRN submissions were for ingredients manufactured by fermentation (n=64), enzyme reactions (n=13), or chemical processes (n=9), which by all indications provided by FDA would prohibit them from qualifying as new dietary ingredients.
How to Plan and Prepare for an NDI Submission
While significantly more NDINs are rejected by FDA than accepted, the numbers are skewed by those submissions rejected not because of legitimate safety concerns, but rather for ineligibility of the ingredients or incomplete notification packages. For those interested in submitting a successful NDIN, special focus should be paid to the quality of the information contained in the notification package as well as completeness.
Analyzing Your Ingredient for the Appropriate Regulatory Pathway to Market
Before deciding on the 75-day Premarket NDIN pathway, one should first analyze the ingredient to assess the correct strategy to market versus another pathway. Ask the questions:
Once the ingredient analysis is completed, there are some additional questions and due-diligence tasks to ask in order to help you solidify your determination. These questions and recommendations cover the regulatory requirements listed by FDA, which define who is required to submit the NDIN for a dietary ingredient.
1. Which are you?7
a) Manufacturer who intends to market a new dietary ingredient
b) Manufacturer who intends to market a dietary supplement that contains a new dietary ingredient
c) Distributor who intends to market a new dietary ingredient
d) Distributor who intends to market a dietary supplement that contains a new dietary ingredient
2. Review FDA responses to previously submitted NDINs for similar ingredients.3
3. Review the suggested checklist to ensure:
It is important to note that FDA, as noted in the preamble of the final rule, has an expectation that the submitter “did consider the evidence of safety that is available in the scientific literature and from examination of reports of adverse effects associated with the use of a new dietary ingredient.”8
Submitting an NDIN
Per FDA final rule, 21 CFR Part 190 [Docket No. 96N-0232] Premarket Notification for a New Dietary Ingredient, an NDIN is to be submitted 75 days prior to its introduction into the marketplace.9 The CFSAN Online Submission Module (COSM) New Dietary Ingredient Notification Step-by-Step Submission Guide gives detailed, step-by-step directions for submitting an NDIN electronically and serves as a checklist for the information FDA requires for its review. The table below is a suggested outline for the information required for an NDIN submission.
New Electronic Submissions Portal at FDA
NDIN submissions to FDA can be either electronic or via hard copy (often accompanied by the NDIN on a certified virus-free CD ROM). As of September 6, 2019, in keeping with the Agency’s ongoing modernization efforts, FDA’s electronic system was changed from the FDA Unified Registration Listing System (FURLS) database to its new system, the CFSAN Online Submission Module (COSM). FDA has provided help guides for an electronic submission using the new system:
Often, reviewing a successful NDIN submission for a similar ingredient will provide a good indication as to the level of detail preferred by FDA. Another option is to retain the services of an experienced consultant who can provide specific feedback and help prepare a complete and robust NDI notification.
A review of FDA’s step-by-step electronic submission guidance should also be completed, as this guidance provides further details on the information FDA expects in the notification. Finally, it’s important to verify that your ingredient meets the regulatory requirements for a new dietary ingredient. Many NDINs are “rejected” because the ingredient does not meet the definition of a dietary ingredient per the statute 21 U.S.C. 321(ff)(1) (i.e., the manufacturing process produces a synthetic copy of the natural constituent and is not used for food or drink as part of the human diet).
For ingredients manufactured using fermentation, enzyme reactions, or chemical processes, a GRAS conclusion-either independent (self-affirmed GRAS) or submitted to FDA-is the most feasible option.
Based on comments from industry resulting from both private and public meetings with FDA, it is clear that there is a divergence of opinion on how to move forward with NDIN enforcement, regulation, and compliance. The implementation of a master file system should be considered as a good first step towards inviting industry to look at the NDIN process as viable and reasonable. Currently, a Drug Master File (DMF) system is used for human drug products and has proven successful in allowing drug companies to protect their investments by providing to FDA confidential, detailed information about their facilities, processes, or articles used in manufacturing, processing, packaging, and sorting of their products, while also allowing other companies to reference, with permission, this information without making intellectual property public to competitors. This is not the case with GRAS submissions, where very little (if any) information can be redacted as confidential upon submission to FDA.
There are still many questions to be answered by industry and FDA with regard to the definitions of “chemically altered” and “manufacturing change” due to technological advancements that have occurred over the past 17 years. A reconsideration of the current meanings would require an amendment to the law.
The authors hope this article will provide food for thought regarding the current NDIN process as it stands, as well as guidance on how to decide if submitting an NDIN is a viable pathway for your ingredient and to ensure a complete and thorough submission is presented to FDA.
About the Authors:
Katrina Emmel, PhD, is the founder and president of KemmelCal Inc. (www.kemmelcal.com), a chemistry and regulatory consulting company. She is experienced in analytical method selection, data review, and establishing product specifications for ingredients used in foods and dietary supplements. Dr. Emmel has over eight years of experience in drafting, reviewing, and serving as an Expert Panelist for GRAS evaluations.
Evelyn Cadman is the owner and principal consultant for FDA Compliance Simplified (www.FDASimplified.com), offering technology evaluation, product development, and regulatory affairs services to the food, cosmetic, nutritional supplement, and biotech industries. She has worked in regulatory affairs and product development for FDA-regulated products since 1997.
Cheryl Dicks is managing partner of Live Well RACE and CBD Compliance Simplified (www.CBDComplianceSimplified.com). With over 20 years’ experience in the dietary supplement and pharmaceutical arenas, the company offers its clients support in product development, manufacturing, cGMP compliance, clinical trial development, quality management system development, and regulatory agency support and filings.