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Industry should remain on high alert over whether FDA's "chemical alteration" language in its revised new dietary ingredient draft guidance will require a broad swath of industry companies to submit NDI notifications, expert says.
The dietary supplements industry may be satisfied with some parts of FDA’s new dietary ingredient (NDI) draft guidance, but on one issue at least, industry should remain on high alert-namely, whether manufacturing processes the agency considers as chemically altering an ingredient will require a broad swath of industry companies to submit NDI notifications (NDIN). The Natural Products Association (NPA; Washington, DC) hosted an “emergency webinar” on Wednesday, August 17, less than a week after the revised draft guidance was released. During the webinar, speaker Ashish Talati pointed to concerning language preserved from the original July 2011 draft guidance, plus new language introduced in the new revised version, that he says will “impact everyone.”
“The manufacturing changes and chemical alteration [portion of the guidance] are two of the biggest things that will impact everyone-or the majority of companies,” said Talati, a member of law firm Amin Talati & Upadhye. “Companies need to understand that.”
An ingredient marketed as a dietary supplement ingredient in the U.S. prior to the passage of the Dietary Supplement Health & Education Act (DSHEA) on October 15, 1994, is generally considered grandfathered and does not require a NDIN. But FDA’s stance that certain manufacturing changes may render an ingredient so significantly different from its pre-DSHEA version that it can no longer be assumed safe may require some grandfathered ingredients to undergo the NDI process anyway in order to prove they are safe.
Representing FDA during the webinar, Cara Welch, PhD, senior advisor at FDA’s Office of Dietary Supplements, said that what the agency is concerned with is the degree of change that takes place between one generation of an ingredient and the next.
“FDA intends to take into account the magnitude of change in a composition or structure and whether it would affect the ingredient’s safety,” she said. “And that’s really what it comes down to here: we are here to protect the public health. The first and foremost direction of our priorities is effecting the safety of ingredients, effecting the safety of products.”
According to Welch, many of the stakeholder comments FDA received following its July 2011 draft guidance criticized the list of processes that FDA listed as exempt from the NDI provision as “too narrow.” At the time, FDA’s list included only the following processes listed in a Congressional Statement of Agreement as part of the original DSHEA legislation: minor loss of volatile components; dehydration; lyophilization; milling; and formation of a tincture or a solution in water, a slurry, a powder, or a solid in suspension. These minor manufacturing changes wouldn’t change an ingredient enough to alter its safety, the agency said.
In the new draft guidance, FDA purposefully revised the text to more explicitly explain what the agency considers to be manufacturing processes that result in chemical alteration. The good news for industry is that the agency now clarifies that the Congressional Statement of Agreement should be considered merely an example of a list of processes exempt from the NDI rule. It’s not an “all-inclusive list,” Welch said. Indeed, Talati said, “FDA does indicate that they intend to continue to evaluate evolving technologies. I think that reflects a broader CFSAN position that they are a science-based agency. At least they will consider new technologies and scientific reasoning.”
But some specifics FDA added to the draft guidance birth new concerns. The revised guidance cautions that an NDIN is needed if changes to an ingredient’s manufacture alter the “physicochemical structure or properties, purity and impurities, or biological properties (such as bioavailability or toxicity) of the ingredient.”
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Unfortunately, those parameters may ensnare many of the modern manufacturing techniques industry now widely employs to create ingredients that are better absorbed or more effective than their pre-DSHEA counterparts. Consider, for instance, Talati said, the types of processes that can change the physicochemical structure of an ingredient-a no-no according to the NDI guidance-including common changes related to pH, solubility, particle size, melting or boiling point, or refractive index. What's more, today’s practice of making ingredients more bioavailable may be considered as changing an ingredient’s biological properties.
Processes to strengthen ingredient purity and decrease impurities would also widely be considered beneficial-but, again, in FDA’s eyes could trigger the need for an NDIN. Concentrating active constituents to increase an ingredient’s potency would also be on the radar. And ingredient extracts and tinctures could call for an NDIN if they use solvents other than water or aqueous ethanol. “I think this is a big one,” Talati said, adding that many companies today may use solvents other than water or aqueous ethanol.
Other factors the agency would take into consideration are serving level, conditions of use, and source material, according to the guidance.
The takeaway, said Talati? “Those are some of the things FDA is saying, or at least in this guidance is saying, could change the identity” of an ingredient.
Over the years, many have argued that by not bringing newer manufacturing practices under the umbrella of an NDI exemption, FDA would in effect punish firms for advancing the state of the industry. “It’s almost like if you innovate, you might have to have an NDI,” Talati said. “I think this will impact many, many companies.”
Those concerns that surfaced back in July 2011 are still present with the revised draft guidance. During NPA’s webcast, Welch said FDA is especially encouraging firms to submit public comments regarding manufacturing processes and chemical alteration. “We invite comments on any aspect of the draft guidance, of course, but we do want to hear specifically on what processes alter the identity of an ingredient, thus creating a new dietary ingredient,” she said.
She said FDA is also encouraging industry to provide examples of instances in which a manufacturing process may chemically alter an ingredient in one case, but not in another. “Are there certain processes, maybe a tincture or another process, that sometimes result in chemical alteration and sometimes do not?” she asked.
Finally, Welch said, the agency is encouraging stakeholders to back up their arguments with scientific evidence. “We are a science-based organization, and we are especially interested in receiving scientific information that shows whether a particular process actually results in chemical alteration.”
Talati likewise also encouraged industry to submit comments seeking greater clarity from FDA.
"[In FDA's eyes], a broader range of manufacturing changes would create an NDI by changing the identity of a dietary ingredient. So it’s very important that companies understand what that change means and file comments with FDA,” he said.
Nutritional Outlook magazine