Some ingredient types, such as probiotics and synthetic botanicals, may have extra work on their hands as a result of FDA’s revised NDI draft guidance.
Depending on who you ask, FDA’s revised new dietary ingredient (NDI) draft guidance either spells out an exorbitant cost burden on the dietary supplement industry or a semi-acceptable regulatory framework that industry will have to live with. But aside from debating the NDI guidance’s impact on industry as a whole, there does seem to be some consensus among industry experts that a few particular categories of ingredients could have some added challenges to deal with.
For instance, ingredient firms working with probiotics or synthetic botanicals-also known as “synbots”-may expect to have some extra work on their hands if the latest NDI draft guidance language makes it into the final guidance. While the path to market may still be open for these ingredient types, there will likely be a few more bumps in the road and possible detours along the way.
“Some have more work than others,” Dan Fabricant, CEO and executive director of the Natural Products Association (NPA; Washington, DC), told Nutritional Outlook. “People want it to be easy all the way through. I think what we’re seeing is there are some categories where we’re going to have more work and that’s the reality.”
Despite industry resistance, FDA’s latest NDI draft guidance is relatively consistent with its 2011 stance that synthetic herbal/botanical ingredients are not dietary ingredients. One exception the latest draft guidance does offer is that a synthetic botanical which has “been used as a lawfully marketed ingredient in the conventional food supply” may qualify as a dietary ingredient, with FDA providing the examples of vanillin and cinnamic acid as two synbots that fit this description.
But what if FDA decides a certain synthetic botanical doesn’t fall into that category? Examples of synthetic botanicals currently on the market include resveratrol, 5-HTP, L-theanine, astaxanthin, and synthetic caffeine, noted Loren Israelsen, president of the United Natural Products Alliance (UNPA; Salt Lake City), in a September–8 UNPA webinar on the new NDI guidance. Ingredients like these clearly occupy a prominent place on the market, and many of them already have submitted NDI notifications.
“A curious fact is that some of these ingredients were submitted as NDIs and FDA did not object to them,” Israelsen said. “So there are several synthetic botanicals currently sold that have been through the NDI process. There seems to be a disconnect in what FDA’s practice has been versus what they are saying in the guidance.”
In fact, there are already indications FDA is taking another look at synthetic botanical ingredients with its draft guidance approach in mind. Yesterday, FDA released a Federal Register notice (FDA-2016-N-2523) requesting comments on its “tentative conclusion that vinpocetine is not a dietary ingredient and is excluded from the definition of dietary supplement in the Federal Food, Drug, and Cosmetic Act (FD&C) Act.” Vinpocetine, FDA explains, is a synthetic compound that does not have a history of food use, and it therefore does not qualify as a dietary ingredient.
What makes this action by FDA even more remarkable is the fact that vinpocetine has five acknowledgments from FDA already in its NDI database, NPA noted. For that reason, NPA’s Fabricant condemned FDA’s action on vinpocetine as “a form of double jeopardy” that “sets a bad precedent and is no environment to conduct business in.”
Other Options for Synbots
But even if more synthetic botanicals like vinpocetine encounter similar resistance from FDA in efforts to achieve-or simply hold on to-NDI status, Fabricant still sees other paths to market for synthetic botanicals.
“If I wanted to synthetically make an ingredient that’s only been in a botanical to this point and put it in a dietary supplement, there are a lot of ways I could get to the market,” Fabricant says. “I could go through a food additive petition notice. I could make it a [Generally Recognized as Safe (GRAS)] ingredient. I could do a lot of things. I could introduce it to the food supply and then introduce it to the dietary supplement supply.”
As a result of FDA’s hardline approach to synthetic botanicals, the GRAS approach will likely become more attractive to many companies working with a synbots, as long as their ingredients also have a history of use in the conventional food supply, Michael McGuffin, president of the American Herbal Products Association (AHPA; Silver Spring, MD), told Nutritional Outlook. But he also says FDA’s stance on synbots is a “missed opportunity” because the more companies turn to self-affirmed GRAS rather than NDI notifications, the less notification information FDA actually receives.
“I don’t think [FDA] really wants us to go around the NDI notification process through a self-affirmed GRAS process, but I think the law allows us to,” McGuffin says. “And if the agency wants to provide guidance that helps us through the NDI notification process, then we’ll move back toward that way. But we haven’t seen that guidance, at least for synthetic constituents.”
Companies working with probiotic ingredients may also find they have some extra work in front of them, as FDA will be looking for more than just genus and species information in many NDI notifications for probiotics, Corey Hilmas, MD, PhD, NPA’s senior vice president of scientific and regulatory affairs, explained in an August–17 NPA “emergency” webcast on the NDI guidance.
“For those who have strains where the genus and species have been acknowledged as an NDI, but your particular strain has not, watch out,” Hilmas said. “In the interim you may want to find out how homologous your strain is to a strain that has been acknowledged by the agency.”
Hilmas added that when establishing a history of safe use, “a strain, for example, that is 95% homologous to a strain already acknowledged by FDA is an easier sell than one that is only 45% homologous.” In some cases, probiotic firms may have to embark on 90-day rodent studies and/or human tolerability studies to confirm the safety of their probiotics at a strain level.
Consequently, many probiotic companies may have an added cost to consider as a result of FDA’s call for strain-specific NDIs, although a company that doesn’t list its probiotic at the strain level on product labels may be able to avoid that level of regulatory scrutiny, Hilmas added.
“If folks want to use a strain to differentiate themselves, that’s fine,” NPA’s Fabricant told Nutritional Outlook. “The expectation I think is that if you’re going to differentiate yourself you have the data to do it as well-that you’re not just doing it for the marketing. You actually have the marketing plus the science behind it.”
Another factor to consider is the growth medium used to grow a probiotic. If a probiotic was previously grown in a dairy-derived growth medium but a company chooses to switch to a vegetarian growth medium, “according to FDA, you need a new NDI notification,” explained Ashish Talati, a member of law firm Amin Talati & Upadhye, during a webinar hosted by the Council for Responsible Nutrition (CRN; Washington, DC) and Informa earlier today.
“FDA considers the manufacturing process of the ingredients that are liable at the time of ingestion to be an intrinsic part of the identity of that ingredient,” explained Talati. “Here I recommend companies in the probiotic space file comments because certainly there is a possibility where [changing growth mediums] may not affect [the probiotic’s] identity.”
Nutritional Outlook Magazine