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Due to uncertainties over the NDI draft guidance, some wonder whether the popular GRAS system will still be a viable option for supplement manufacturers looking to exempt themselves from submitting NDI notifications to FDA.
In August, FDA shook up the dietary supplement and food industries with two major releases: the agency's final rule for Generally Recognized as Safe (GRAS) ingredients in food on August 12 and the agency's revised new dietary ingredient (NDI) draft guidance for dietary supplements on August 11. Although the GRAS rule focuses primarily on ingredients in the food supply, and the NDI guidance centers on dietary supplement ingredients, the two do intersect in one important way: namely, that the GRAS system has served as an alternate route to market for firms looking to use food ingredients in dietary supplements as well.
If an ingredient has GRAS standing, FDA’s NDI draft guidance says that firms may then use the ingredient in dietary supplements without undergoing dietary supplement NDI notification. But with uncertainty still surrounding the NDI draft guidance, questions linger about whether the popular GRAS system will still be a viable option for supplement manufacturers seeking an NDI notification exemption. Ahead, we touch on some of those gray areas.
Words to Worry About?
Back in the first version of the NDI draft guidance released in July 2011, FDA stated that if an ingredient has either been “listed or affirmed by FDA” as GRAS or has been “self-affirmed” as GRAS, a company does not need to submit an NDI notification, as long as the ingredient has been “used in the food supply and is to be used as a NDI without chemical alteration.” In the revised August 2016 draft guidance, FDA still maintains that if an ingredient has been “listed or affirmed by FDA” as GRAS and is present in the food supply, a NDI notification is not needed. Still, experts point to possible differences between the old and revised guidance drafts that could be confusing.
First, it’s unclear why the new NDI guidance still refers to GRAS ingredients that are “listed or affirmed by FDA” as GRAS, says John Endres, ND, chief science officer for regulatory consultant AIBMR Life Sciences (Seattle, WA). In its GRAS final rule, FDA announced, as it was expected to, that agency is officially ending the GRAS petitioning process and retaining only the GRAS self-conclusion process, with the option for firms to voluntarily notify FDA of their GRAS conclusions. By eliminating the petitioning process in the GRAS final rule, FDA in effect no longer affirms GRAS status. So it’s confusing that FDA mentions “listing by FDA” or “affirming by FDA” at all, Endres says.
“I don’t think that’s what they mean, because that means that those ingredients have to be listed in 21 CFR 184 or 186. Those are affirmed ingredients. And the FDA GRAS final rule has eliminated the petition process for FDA to affirm ingredients,” Endres says. “I think what they mean is if you get the letter of no objection to a GRAS conclusion.”
Then there is the fact that the new NDI draft guidance no longer mentions self-affirmed GRAS conclusions, instead referring only to GRAS conclusions. The omission of self-affirmed is not necessarily surprising, though, says Bob McQuate, PhD, cofounder and senior vice president, sales and business development, for regulatory consultancy GRAS Associates (Bonita Springs, FL).
According to McQuate, FDA may have left out mentions of self-affirmation due to the intense criticism FDA has faced over the GRAS system’s voluntary-notification provision from U.S. senators, the U.S. Government Accountability Office (GAO), The Pew Charitable Trusts, and others. These critics say that FDA does not have a good handle on the safety of all GRAS ingredients in the food supply because companies aren’t required to notify FDA of GRAS status.
“I don’t suspect that it was accidental” that FDA left self-affirmed out of the NDI guidance, McQuate says. “I think they intentionally took it out, and it may have been for no reason other than that they didn’t want to have critics pointing out that they’re advocating more self-affirmed procedures.” He adds, “I believe there has been some recognition that they don’t want to be promoting self-affirmed GRAS as a basis to avoid the new dietary ingredient notification process.”
The general consensus of the experts interviewed for this article is that there isn't a problem here. Companies can indeed use GRAS self-conclusions (the only type of GRAS conclusion that now exists under the GRAS final rule) to seek NDI notification exemption-provided of course, that they meet all the GRAS legal requirements, including showing that the ingredient is safe based on evidence in the public domain and ensuring reviews are conducted by competent experts.
“We can still do what we’ve been doing,” Endres says.
More Clarity Needed on Chemical Alteration and Use in Food Supply?
Companies may have more-pressing questions about other areas where the GRAS rule and NDI draft guidance intersect. Some may consider these points to be minor, while others may find them more concerning.
For instance, Endres says, there’s no firm consensus yet on what chemical alteration means when FDA’s revised NDI guidance states that GRAS ingredients are only eligible for exemption if they are “used in the food supply (i.e., in conventional foods)” but “without chemical alteration.”
“The operative word is chemical alteration,” Endres says. “What does that mean?”
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Some may wonder, for instance, whether now formulating an ingredient into a dietary supplement product instead of a food product would be considered a form of chemical alteration in and of itself. “What I’ve been told is that it would be against the law for FDA to say that just because your ingredient is in a cookie, you can’t put it into a supplement,” Endres says. However, he adds, if FDA did for some reason deem the ingredient to be chemically altered once in supplement form, this would obviously be a problem for companies.
There may also be lingering uncertainty around what FDA considers as an ingredient “being in the food supply.” Does an ingredient firm merely need to show that the company marketed its ingredient for sale in food products, or does the firm instead have to prove that the ingredient was actually formulated into a finished product and purchased and consumed (and thus in the food supply)?
Back in the July 2011 NDI draft guidance, FDA stated that an ingredient had to be used in the food supply. It also specifically defined marketed as “physically offering the article for sale at a retail establishment, listing it for sale in a catalog or price list, or through advertising or other promotion, if the promotion makes clear that the article is available for purchase.” Some interpret this to mean that the ingredient only need be marketed for sale as a food ingredient, even if, at the end of the day, the ingredient was not actually consumed in a finished food.
According to Endres, however, in the revised draft guidance, “They’re making [their wording] a little stronger. FDA’s kind of making it sound more like they really would like to see it in a food,” he says.
Some companies are already taking this route. “Lawyers I’ve talked to over the years would say, ‘Just get it into a food,’” Endres says. “And I know of companies that literally just start up a new company, put the ingredient into a nutrition bar, sell it on the market, and then shut the company down” just so they can say that the ingredient has been used in the food supply, he adds.
GRAS Route Still Preferred for Many Reasons
The main takeaway is that a GRAS conclusion is still a route to NDI exemption. “I believe it still remains in place as a viable option,” says GRAS Associates’ McQuate.
Moreover, McQuate says, companies may want to try the GRAS route first. “I still think it’s preferable for the regulated industry to consider going GRAS, whether self-determined or through notification to the agency, as their primary strategy for authorization," he says. Why? "You have a broader umbrella through GRAS” because ingredients can be used in both food and dietary supplements, he says. Add to that the fact that companies have had a much higher success rate throughout the GRAS process compared to the NDI process, and the GRAS route looks like the way to go if you’re able to.
There is also the matter of cost. According to George Burdock, PhD, founder of regulatory consultancy The Burdock Group (Orlando), the cost of a NDI notification may eclipse that of a GRAS review.
He points out, for instance, that the amount of information companies may include in a GRAS notification may differ. “Historically, some GRAS notifiers would follow the notification instructions and send in bare-bones information and possibly include a one-page GRAS Expert Panel decision,” Burdock says. “At our company, we prepared the notification as per the instructions, but would also include the GRAS dossier, which included all the scientific information and rationale as to why a substance is GRAS. Because there has never been a mandated number and kinds of animal studies to be performed for a GRAS determination, the volume of GRAS dossiers was fairly consistent in volume and cost.”
But for a NDI notification, Burdock says, “like a food-additive petition, literally all the relevant information, often including the raw data from animal studies, needs to be included, making both the volume and price for a NDI notification much higher than a GRAS.”
The types of studies required to support a NDI notification versus a GRAS conclusion may also differ, he says. “According to the draft NDI guidelines, the mandated studies to be performed [for a NDI notification] would likely be much more extensive, with costs being substantially higher” compared to those for a GRAS notification. Whereas the cost of animal studies for a GRAS notification (such as in vitro and in vivo mutagenicity/genotoxicity studies) “could be kept within the $200,000 range,” he says, the types of studies required for a NDI notification (such as two 90-day studies, a pharmacokinetic study, teratology study, reproductive study, and a chronic toxicity study and/or carcinogenicity study) “could easily run upwards of $1.5 million to perform."
"This cost would be in addition to the preparation of the NDI notification," he says.
It’s understandable if companies worry even as they move forward with pursuing GRAS conclusions as a route to NDI exemption. Some may wonder whether their work will be wasted if FDA decides, due to uncertainties over the NDI draft guidance, that their GRAS conclusions are not sufficient to exempt them from submitting a NDI notification.
Endres says that when FDA released the new NDI guidance, companies in the middle of their GRAS conclusion projects came to AIBMR asking, “’How does this affect us? In other words, are we only going to be able to sell as a food, or will we be able to sell this in a supplement?’ That’s been a really, really big question.”
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“Their big concern is if they’re going down the GRAS route, is this NDI draft guidance document going to affect their ability to sell their ingredient as a raw material for use in dietary supplements?” Endres says. Is FDA “going to come back to us and say we have to do [the GRAS submission] over again?”
GRAS/NDI consultants say that more clients are nevertheless seeking GRAS status these days. Endres points to a recent influx of pending GRAS notices in FDA’s GRAS database.
“FDA just updated their GRAS notice database to June 30, and there are so many pending GRAS notices," he says. "There’s a mad rush to get as many GRAS notices in as possible before the GRAS final rule goes into effect in October.” He questions how FDA will be able to deal with all of these notices. “FDA could be inundated with so many GRAS notifications that they just can’t handle it,” he says.
For his part, Burdock adds, “It is quite likely that manufacturers may go the GRAS route, but what does this say about the Office of Dietary Supplements (ODS), when it must depend on the Office of Food Additive Safety (OFAS) to make decisions on safety? Why is ODS willing to defer to OFAS expertise? Is it because it does not understand the concept of ‘significant or unreasonable risk’ [the NDI safety standard for dietary supplement ingredients]? Were the draconian new draft guidelines for NDIs designed to be difficult simply to divert the flow of applications to OFAS?”
Also, says Burdock, “I understand that the [NDI] draft guidance is the culmination of 20+ years of interfacing with NDI notification submitters, some of whom are experts at parsing words or redefining words, but the attempt to thwart future encounters with parsers with such granular details will eventually result in [the Office of Dietary Supplements] tying its own hands and/or simply discouraging future submitters that there is any chance of success for a NDI notification.”
And, finally, for what it's worth, not everyone recommends using the GRAS system as an NDI workaround. In a September interview with Nutritional Outlook, Dan Fabricant, executive director and CEO of the Natural Products Association said this: "I don't encourage people to do that. I think if you're going to market as a supplement, go NDI. If you're going to market as a food, go GRAS. Don't play regulatory hopscotch."
Nutritional Outlook magazine