After issuing the first of what will be several guidance documents on New Dietary Ingredient Notifications (NDINs), the premarket safety notification process required of novel ingredients, the U.S. Food and Drug Administration (FDA) released a draft guidance document on Apr. 3 detailing its plans for a proposed Master File program.
 
FDA’s draft “New Dietary Ingredient Notification Master Files for Dietary Supplements: Guidance for Industry” replaces its 2016 draft guidance. Electronic comments can be submitted within 60 days at https://www.regulations.gov/ with the docket number: FDA-2024-D-0706.
 
The Dietary Supplement Health and Education Act (DSHEA) of 1994 requires companies to notify the agency at least 75 days before introducing new dietary ingredients to market, offering identity and safety information.
 
However, the agency has estimated that more than 4,600 NDI notifications should have been submitted and were not. Instead of jeopardizing public release of confidential information related to manufacturing and clinical research of proprietary ingredients, many companies have utilized the Generally Recognized As Safe (GRAS) process, which allows for self-affirmation following assessment among scientific experts to verify ingredient safety.
 
The agency’s draft guidance stated: “FDA hopes that, by describing how to submit and use Master Files, this guidance will help the industry to more easily comply with the requirement to submit NDINs. Accordingly, this guidance provides recommendations on how to establish, update, and close a Master File, as well as recommendations regarding how a Master File owner can authorize other parties to reference the Master File in an NDIN.”
 
NDI master files contain “identity, manufacturing, and/or safety information relating to a new dietary ingredient” that a Master File owner submits to FDA for use in evaluating a potential future NDIN or by others, such as a manufacturer or business partner.
 
According to the draft guidance, supplement manufacturers would be able to identify information the master filer believes to be confidential commercial information (CCI) or trade secrets.
 
Protections for this sensitive information, built into the NDIN process through a master file program, similar to the FDA’s master file program for drugs, is believed to be necessary for greater industry participation in the NDIN process.

Guidance Details

According to the 9-page guidance document, companies would be required to submit a cover letter laying out the information that would be submitted through an NDIN Master File, information about the master file owner, a table of contents, a list of each person authorized to reference the master file and any limits on the authorization. 
 
“Although some or all of the data in an NDIN Master File may be trade secret information, or CCI and generally exempt from public disclosure, there is no presumption that any particular information in the Master File is trade secret information or CCI,” the agency said. “We recommend that the Master File owner clearly identify any information in the NDIN Master File that the Master File owner believes is trade secret or CCI.”
 
The guidance also details the process for updating or closing a master file, as well as how people authorized to use the master file can access its contents. A letter of authorization from the master file owner can specify whether an authorized party can access the full master file, or it could simply lay out which parts of the master file an authorized party can use.
 
Upon receipt, FDA will conduct a substantive review of an NDIN master file. Once the agency receives an NDIN that relies on scientific information from the accompanying master file, it will review the master file as part of its standard NDIN review. FDA won’t conduct a scientific review of an NDIN master file without the NDIN.

Industry Responses

The Consumer Healthcare Products Association (CHPA) and Council for Responsible Nutrition (CRN) offered generally positive responses, but key questions remain.
 
“CHPA is pleased to see FDA move forward on its commitment to release a separate draft guidance document this year on master files,” said Duffy MacKay, senior vice president of dietary supplements at CHPA. “We have been a longtime supporter of a master file system for NDINs that will establish a framework to safeguard scientific data supporting an NDIN on a specific ingredient, preventing its unauthorized use by firms marketing similar, but not identical, ingredients.”
 
“A well-implemented master file system has the potential to benefit both industry and FDA by increasing submissions, enhancing public safety, and spurring product innovation and investments in science,” MacKay added. “Overall, this system should encourage companies to increase investments in research that demonstrates the safety of new ingredients and finished products.”
 
CHPA is currently reviewing the draft guidance in detail, he said, “but is generally pleased with the concept, while also recognizing FDA enforcement of the NDI regulation is critical for the master file system to realize its full potential. We appreciate FDA’s ongoing efforts to advance this guidance, which will foster innovation and scientific development.”
 
CRN President and CEO Steve Mister said it’s “a positive development” that FDA is moving ahead with its draft guidance. “In 2020, CRN developed an NDI master file framework for dietary supplements to protect our members’ investments and intellectual property, and this is clearly a step in the right direction, incorporating many of the elements we put forward.”
 
However, he added, “meaningful enforcement alongside guidance is crucial in supporting responsible companies desiring to innovate, to protect investment while doing so, and to fairly compete. FDA must deter bad actors who circumvent the law thereby posing risk to public safety. So, while we welcome this draft guidance, we, at the same time, strongly urge FDA to publicly announce its resolve to enforce proper use of master files.”
 
The agency has yet to address the issue of “borrowed science,” experts have cautioned. After a company submits an NDIN, in which most information is publicly available, competitors then bring to market similar ingredients that were developed based on data lifted from that freshly-submitted NDIN, using that same data in a GRAS affirmation.
 
“Too many companies are going to market without submitting an NDI notification for their ingredient because another firm has done the hard work,” said Daniel Fabricant, PhD, president and CEO of the Natural Products Association (NPA), when FDA published its initial draft guidance in March. “This piggybacking is unacceptable and does not allow the agency the opportunity to review their manufacturing processes or product specifications. This should raise bright red safety flags.” 

---

About the Author: Mike Montemarano has been the Associate Editor of Nutraceuticals World since 2020. He can be reached at mmontemarano@rodmanmedia.com.