FDA draft Guidance on new dietary ingredients: Do you need to file?
Thursday, July 27, 2017
This article first appeared in Tablets & Capsules.
The August 2016 draft Guidance on new dietary ingredients (NDIs) broadened the definition of what the FDA considers an NDI, leading many manufacturers to wonder if they should submit notifications for products they've had on the market for years. This article explains the issues and discusses steps manufacturers should take to avoid FDA action.
Since the Dietary Supplement Health and Education Act (DSHEA) became law in 1994, companies have needed to prove the safety of their dietary supplement ingredients before products reached the market. Ingredients that were marketed in the U.S. prior to Oct. 15, 1994, however — a period known as pre-DSHEA — were grandfathered in and considered safe by the FDA.
Post-DHSEA, any manufacturer planning to use a new dietary supplement ingredients must submit a new dietary ingredient notification (NDIN) prior to distribution. If a notification receives no comment from the FDA, the manufacturer can market products containing the ingredient.
That seems straightforward, but manufacturers may have to do some research to prove that the ingredients they used in their products are pre-DHSEA because there is no FDA list of pre-DSHEA ingredients. Furthermore, while lists of pre-DSHEA ingredients compiled by the Council for Responsible Nutrition (CRN), the National Nutritional Foods Association or other organizations may be helpful, the Agency doesn't recognize them.
And even if manufacturers can prove their ingredients were marketed pre-DSHEA, they may still be required to file an NDIN, according to the August 2016 draft Guidance. It's important to understand this draft Guidance, because in many cases the FDA interprets guidances, even draft guidances, as de facto regulations.
The August 2016 draft Guidance on NDIs, which replaces one issued in July 2011, expands the definition of NDIs to include pre-DHSEA ingredients that have been significantly altered. Alteration includes changing the manufacturing process, changing the dosage form in which the ingredient is used, combining ingredients and/or using extraction processes and/or delivery systems different from those used before 1994.
Changes that require NDINs
How different is different enough to warrant an NDIN?
"Where it becomes a gray area for manufacturers is in the definition — or interpretation — of what constitutes a chemical, manufacturing, and/or use change of an ingredient that was on the market prior to October 1994," said Tara Lin Couch, an EAS independent advisor for dietary supplements. "The FDA has provided a very broad definition, so broad that some trade organizations such as the CRN estimate that 50 to 60 percent of dietary supplement products on the market need NDINs."
Chemical alteration, according to the draft Guidance, includes any "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."
The Guidance cites several processes that chemically alter an ingredient, including hydrolysis, chromatography, distillation and filtration. If enforced, that standard would require NDINs for many ingredients already on the market, including botanical extracts used in conventional foods.
The draft Guidance also says a combination of ingredients — including combinations of pre-DSHEA ingredients, combinations of a pre-DSHEA ingredient and an approved NDI, or combinations of NDIs — need separate notifications. The idea here is that although an individual pre-DSHEA ingredient may be considered safe, the combined ingredients may interact, posing new health risks.
One example cited in the 2016 Guidance is combining huperzine A, an NDI the FDA has reviewed with no comment, with yohimbe bark, a pre-DSHEA ingredient. Together those ingredients can cause low blood pressure, low heart rate, gastrointestinal distress and irregular heartbeat.
Techniques that improve product effectiveness by increasing bioavailability and purity or that use different solvents would also require a notification. Without an NDIN, those changes put manufacturers at risk. Cara Welch, a senior advisor in the FDA's Office of Dietary Supplements, said that the Agency "intends to take into account the magnitude of change in a composition or structure and whether it would affect the ingredient’s safety" when evaluating manufacturing changes.
"If it is a chemical change, it is self-explanatory [that the ingredient would need an NDIN]," Couch said. "But if there is no chemical change, [some may argue] that it is not really a new ingredient."
Yet, she also said that new delivery methods, such as extended-release tablets and softgels, are considered manufacturing changes and should be reported to the FDA: "Even if it is the same vitamin profile, these different dosage forms would require an NDIN."
Own-label distribution and contract manufacturing
In some cases, companies that outsource production aren't familiar with the FDA's manufacturing requirements. But as anyone who has read an FDA warning letter pertaining to GMP can attest, contracting out manufacturing doesn't release a company of responsibility for product safety. The same is true for an own-label distributor (OLD), a company that markets and distributes turnkey products manufactured by another entity.
"OLDs may not even be aware that they have to submit," Couch said.
No matter who actually manufactures a product, the OLD is responsible for ensuring legal marketing and compliant production. The same is true of ingredient selection: It's the responsibility of the OLD, not the contract manufacturer.
The FDA does allow a confidential NDI master file, which is similar to what is sometimes included in a new drug application. The master file should contain an ingredient’s "manufacturing, specifications and other identity information," which a company can authorize others to reference in their notifications.
When filing an NDI, an OLD should ask its manufacturer for the master file to save time and money on safety research.
Action on NDINs
The FDA's 2016 NDI draft Guidance state that 5,560 new dietary supplements enter the market every year and that more than 55,660 dietary supplements are on the market. Considering that only 4,000 dietary supplements were on the market in 1994, it's odd that the FDA has evaluated only 750 NDIs as of December 2014.
Since a goal of the draft Guidance "is to improve the rate of compliance with the NDI notification requirement," the Agency may begin by looking for manufacturers who should have filed NDINs. In fact, in March 2016, the FDA sent warning letters to companies that used Acacia rigidula leaves or bark in their dietary supplement products.
According to Couch, bigger manufacturers are filing now. Manufacturers with smaller staffs and fewer resources could have some difficulties filing NDINs, as they often require years of study development, literature reviews, and tens of thousands of dollars.
Even when a company has thoroughly prepared, the FDA may ask for more evidence of an ingredient's safety. The American Herbal Products Association reports that from November 2015 to October 2016 the FDA had no comments on only 25 percent of the NDINs it reviewed.
The GRAS alternative
Designating an ingredient as Generally Recognized as Safe (GRAS) is another way manufacturers can demonstrate the safety of ingredients used in dietary ingredients. Often, these are ingredients widely used in conventional foods. If a company can obtain GRAS designation for an ingredient, that ingredient can also be used in dietary supplements as long as it isn’t further chemically altered.
The steps required to gain GRAS designation are similar to those of an NDIN, and the process costs about the same. GRAS has also been on the books longer, so more people understand the submission process.
The draft Guidance and GRAS guidelines differ slightly, however, in how they address safety. The Guidance requires evidence that an ingredient have a "reasonable expectation of safety" under the proposed conditions of use of the dietary supplement, whereas GRAS requires proof of a "reasonable certainty that no harm will result" from the proposed use.
The difference could make it easier for manufacturers to use the GRAS approach to get their ingredients or products on the market. The only drawback to the GRAS route is speed. Under GRAS, the FDA has 180 days to respond, while the NDIN approach requires a response within 75 days.
Regardless of whether you submit an NDI or GRAS notification, the process is challenging. Whether you succeed depends largely on citing studies that show a reasonable expectation of safety under conditions of use and/or the recommendations on the product's label.
Impact on innovation
During the comment period for the August 2016 draft Guidance, many manufacturers and other stakeholders expressed concerns about the broad definition of NDIs and the impact it would have on the industry.
Dan Fabricant, chief executive officer and executive director of the Natural Products Association, said that the draft Guidance creates an economic burden that "could harm small businesses and create a chilling effect on innovation, and lead to fewer submissions from legitimate firms, while encouraging fly-by-night companies to operate through NDI 'piggybacking' until they are caught."
Considering that it took five years for the Agency to publish a revised draft, it may be a while before a Guidance on NDIs is finalized. Until then, dietary supplement manufacturers should exercise caution.
Copyright CSC Publishing, Inc. Used with permission.
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