Rough Draft: Dietary Supplement Industry Arguments Against FDA's NDI Draft Guidance

February 8, 2012

Industry urges FDA to take another stab at NDI draft guidance.

Saying that the dietary supplements industry is unsatisfied with FDA’s new dietary ingredient (NDI) draft guidance is an understatement.

Atrium Innovations, whose brands include Douglas Laboratories and Garden of Life, put it thusly in draft guidance comments it sent FDA in December:

"Atrium Innovations firmly believes in the intended principle underlying the Draft Guidance-namely, ensuring consumer safety. We are committed to supporting a comprehensive regulatory framework comprised of pragmatic rulemaking coupled with vigorous enforcement-all designed to promote consumer safety and ensure continued access to safe and effective dietary supplements.

However, we believe that the Draft Guidance, in its current form, would establish a substantial and unprecedented premarket regulatory process for New Dietary Ingredients (“NDIs”) that is tantamount to obtaining FDA approval for dietary supplement products, contrary to both the letter and Congressional intent of the Dietary Supplement Health and Education Act of 1994 (“DSHEA”). We question why, after 17 years, FDA has promulgated such stringent guidelines, as we do not believe that a consumer safety crisis exists to merit such action by the Agency. The Draft Guidance’s unnecessarily burdensome and costly requirements will have the additional unintended consequences of stifling innovation in our industry, as well as limiting consumer access to currently available, traditionally used, safe and effective supplements."

Atrium Innovations’ comments capture the big-picture problems many see in the current version of the draft guidance. Many have asked FDA to discard this version of the guidance and start again.

Industry members also emphasize that they do ultimately want long-awaited guidance explaining FDA’s views on when NDI notifications are required and which ingredients require them-just not this version.

“We as an industry need to have guidance that [reflects] DSHEA compliance, and we will work with FDA in order to accomplish that goal,” stated John Gay, formerly CEO and executive director of the Natural Products Association (NPA; Washington, DC), during a December press conference. 

DSHEA’s own principle authors criticized the draft guidance, stating that it strays too far from the laws they wrote. In late December, Senators Orrin Hatch (R-UT) and Tom Harkin (D-IA) wrote to FDA Commissioner Margaret Hamburg, MD, asking the agency to withdraw the current guidance and replace it with a version that “does not undermine the balance Congress struck in DSHEA to provide consumers with access to safe, affordable dietary supplement products.”

In this article, we’ve compiled a sampling of comments sent to FDA, delving into what are considered the guidance’s biggest problem areas.
 

Duplicative Notifications

The draft guidance specifies that a new NDI notification should be filed for every product containing a new dietary ingredient-any dietary ingredient introduced to the U.S. market after October 15, 1994-rather than only requiring notifications for new dietary ingredients. Even if an ingredient supplier already filed an NDI notification for a new dietary ingredient, product manufacturers would still need to file separate notifications for every finished product containing the ingredient. In addition, any change to a finished product would necessitate a new notification. This includes changes such as the addition of new ingredients, even those with a long history of safety; a higher daily intake level; an altered target population; or revised conditions of use.

This rule seeks to ensure that all new products or ingredient combinations featuring an NDI are reasonably expected to be safe. At least that’s what FDA says.

Many contend that a product-specific regulation flies in the face of DSHEA. “By definition, under DSHEA, a ‘dietary ingredient’ is simply a component of a dietary supplement or product, not the product itself,” Atrium Innovations wrote FDA. “Other areas of DSHEA clearly refer to the ingredient, if read in context.”

In its comments, the United Natural Products Alliance (UNPA; Salt Lake City, UT) stated: “UNPA believes FDA’s proposed policy is tantamount to requiring new drug approval requirements for dietary supplements in the same manner that changes to the labeling, manufacture, or formulation of a new approved drug are subject to similar requirements.”

Independent nonprofit research and education organization the American Botanical Council (ABC; Austin, TX) compared the draft guidance’s stipulations as “tantamount to the creation of a new legal category-a New Dietary Supplement.”

It added, “ABC is not aware of any statutory language or precedent for the creation of such a new legal or regulatory category.”

Many said that asking companies to submit duplicative notifications makes no sense, and that it should be sufficient for an ingredient notification to list (although not necessarily all-inclusively) ingredient combinations with which the NDI is known to be safe. Thus, if an existing ingredient notification already covers an ingredient combination featured in a finished product, the finished-product manufacturer should not have to submit a duplicative notification.

“[T]here is nothing to be gained by requesting the duplicative generation and submission of such data,” wrote the Council for Responsible Nutrition (CRN; Washington, DC) and the Consumer Healthcare Products Association (CHPA; Washington, DC), which jointly filed comments. “FDA has not publicly identified even one instance in the past 17 years where the ingredient-based [notification] approach has resulted in a safety problem with the finished dietary supplements containing such ingredients.”

The American Herbal Products Association (AHPA; Silver Spring, MD) pointed out that FDA itself has already filed, without objection, ingredient notifications that contain very specific information about an ingredient but that only describe in general some of the dietary supplements that might contain the ingredient in the future.

“FDA’s ‘acknowledgements’ of ingredient-focused NDI notifications without objection over the years demonstrate its open endorsement of an ingredient-focused approach,” CRN/CHPA added. “The agency cannot now argue it was unaware of the industry’s interpretation and past practices, particularly when it clearly condoned and accepted them.”

Another concern is that a product-specific rule could require that finished-product marketers seek detailed ingredient information to fulfill their own notifications-including proprietary data protected under an ingredient supplier’s trademark.

CRN’s vice president of scientific and regulatory affairs Douglas “Duffy” MacKay, ND, told Nutritional Outlook:

"The guidance specifies that notifications are to include sufficient detail to enable FDA to understand the overall process used to make the NDI, including specifications, detailed description of each step of the production process, and flow diagrams of the manufacturing process. Manufacturers of NDIs often consider much of this information proprietary and consider it a business risk to share this information downstream. Some suppliers’ manufacturing trade secrets are the core of their differential advantages and business model. A supplier with very proprietary processes may be okay with sharing this information with a manufacturer it has a strong relationship with; however, sharing the information with a contract manufacturer that has hundreds of clients is another story."

AHPA also advised FDA to refrain from publishing any data or unpublished studies a company identifies as trade secret and said FDA should consider “almost any reason as acceptable, including, for example, a company’s expressed view that disclosure of the material identified as such would create a business disadvantage of any sort….” AHPA added that FDA should only make public unpublished studies if FDA has the explicit consent of the submitter and, if applicable, the company that funded the study.

Finally, industry members objected to the significant resources, both time and monetary, that duplicative notifications would cost both industry and FDA.

First, if the product-specific rule holds and companies are required to retroactively submit finished-product notifications, it will not only cost companies but FDA may end up with a notifications logjam. In a December webcast hosted by UNPA, FDA itself noted what it considers a high number of outstanding notifications that should have been filed. Webcast speaker Daniel Fabricant, PhD, director of the agency’s division of dietary supplement programs, said that FDA has so far received approximately only 730 NDI notifications since the agency began reviewing notifications almost two decades ago. “At present, there are roughly 55,600 dietary supplement products on the market, and the Institute of Medicine has estimated that 1000 new dietary supplements are introduced to the market each year....If you look at the numbers, it would appear that there’s a significant lag in compliance.”

Those who submitted comments questioned whether FDA could handle a flood of retroactive filings. Some pointed out that in the case of the GRAS process, the agency became flooded with GRAS reviews and as a result ended up also instituting the self-affirmed GRAS route to handle the work. “The magnitude of this FDA-projected backlog is reminiscent of what caused the breakdown of the GRAS affirmation petition process. The NDI notification avalanche would precipitate an even greater failure,” CRN and CHPA predicted.

Commenting on the cost to industry, AHPA posed a hypothetical but frightening scenario:

"AHPA notes that private-label manufacturers may package the same or similar bulk liquid, powder, pill, or other dosages for many clients, labels, or brands; as an example, one member company has informed AHPA they package the same bulk material under hundreds of different brand names or labels; and this represents just one of many hundreds of bulk products the member manufactures for private label. In other cases, companies package variations of the basic formula under different brands or labels, with minor changes made to the flavor, excipients, other dietary ingredients, or other specifications. AHPA further notes that FDA has estimated the cost of filing a NDI notification to be $410. AHPA is not at this time commenting on the accuracy of FDA’s estimates, although AHPA believes they may be too low. However, assuming the estimates are correct, if FDA were to insist on a separate NDI notice for each dietary supplement, one member company alone would be forced to spend in excess of $41,000 dollars on filing the NDI notices related to just one of their bulk products containing an NDI."

UNPA informed FDA in its comments that it is commissioning its own industry cost-benefit survey. “The findings of the survey will be submitted to FDA as additional comments...However, our initial estimates indicate economic impact in the form of revenue losses to the industry caused by such interruptions in production feared to be in billions of dollars-not to mention such revenue losses in turn causing shrinking employment opportunities on companies’ production lines.”

 

Chemical Alteration and Synthetic Ingredients

The draft guidance implies that the only manufacturing processes that FDA considers as not chemically altering an ingredient-thus waiving the need for an NDI notification-are 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.

Also alarmingly, the draft guidance states that synthetic botanical ingredients are not considered dietary ingredients.

Industry members argue that these, too, are misreadings of DSHEA. “Neither DSHEA nor its legislative history requires or permits FDA to restrict the processes that do not result in chemical alteration to this very short list,” argued CRN/CHPA. “Adopting this restrictive list would significantly expand the category of NDIs requiring notification.”

Atrium Innovations criticized the guidance’s short list for failing to give credit to manufacturing advancements:

"The Draft Guidance would have the industry turn the clock back to 1994 and disregard all innovation since, or at the very least, require expensive and complicated NDI submissions based on improvements in safety, stability, or environmental impact. This policy, with its regulatory burden and expense, would accomplish the opposite of the Draft Guidance’s intent to promote consumer safety, by creating disincentives for industry to pursue technologies that would otherwise promote consumer safety..."

Moreover, should the manufacturing process used determine NDI status? No, some said-as long as the resulting ingredient is not chemically changed. CRN/CHPA contend:

"Even complete synthesis of nature-identical ingredients in the food supply does not constitute chemical alteration. If the final product is chemically identical, as confirmed by analytical methods, to the ingredient found in nature, there is simply no basis in the statute to assert that the manufacturing method triggers an NDI notification. Scientific policy does not support the existence of a pre-specified list of processes that do or do not result in chemical alteration. The only inquiry under the statute is whether the material generated at the conclusion of a process is chemically identical to the material found in the food supply."

They cited FDA’s allowance of genetically modified foods in commerce as an example of the agency’s past position that a manufacturing method should not matter if there is no substantive change to the finished product. If the agency were to adopt a different attitude toward NDIs, “[it] would completely contradict the agency’s longstanding regulatory policy,” they said.

Moreover, UNPA and others pointed to past instances in which FDA has condoned synthetic ingredients. “FDA has a longstanding policy prohibiting statements that natural vitamins are superior to synthetic vitamins,” UNPA wrote. Synthetic botanicals, it argued, should be treated no differently.

Significantly, FDA has already acknowledged, without objection, NDI notifications for synthetic botanical ingredients. Also, although the GRAS process is different from the NDI process, many say that FDA’s allowed GRAS affirmations for both natural and synthetic riboflavin, vitamin A, and vitamin D reflect the agency’s past thinking on the issue of synthetics.

 

Grandfathered Ingredients

FDA has long maintained that it does not formally recognize any lists of “grandfathered” ingredients compiled by industry groups.

However, industry members have long urged FDA to consider these lists as reference points for industry to use in determining whether or not ingredients might be NDIs. At the very least, NPA wrote, FDA should accept the submitted industry lists as a “rebuttable presumption of pre-DSHEA status.”

Citing limitations on how long companies keep old records, UNPA and other groups have also argued that many companies, especially companies that weren’t in business pre-DSHEA, might have trouble providing the physical evidence to prove that their ingredients were on the market pre-DSHEA. This is where grandfathered lists again might serve purpose.

CRN’s president and CEO Steve Mister told Nutritional Outlook:

"As we get further and further away in time from the passage of DSHEA, there will be new companies that want to get into this space. As of right now, it sounds like FDA is saying that you have to provide pre-1994 evidence before you can go to market because nothing is really safe unless you can prove it was marketed before 1994. So at the very least, it would be nice to have a modified grandfathered list that at least lists the ingredients everybody agrees are grandfathered. And then a new market entrant can say, “Okay, I know I can at least market these ingredients; I know these were grandfathered.”

 

Probiotics

Some say it’s unclear whether or not the draft guidance permits probiotics as dietary ingredients. The guidance states: “Not all bacterial microorganisms are dietary ingredients, and a microorganism that is not a dietary ingredient cannot be an NDI…bacteria that have never been consumed as food are unlikely to be dietary ingredients…FDA does not have a separate regulatory category or definition for dietary ingredients consisting of live or viable microorganisms.”

Declaring all probiotic ingredients non-dietary ingredients would be wrong, AHPA pointed out. “Various species of probiotic and other dietary ingredients were firmly a part of the food and/or ‘dietary supplement’ industries prior to DSHEA becoming law (e.g., acidophilus milk; brewer’s yeast used as a source of B vitamins and micronutrients).”

Industry members are asking FDA to clarify its position on probiotics. Suggesting that the draft guidance’s wording is too vague, UNPA wrote, “UNPA finds these statements to be confusing and troubling and requests that FDA confirm that probiotics, fungi, and other similar live or viable microorganisms and substances are recognized within the definition of dietary ingredients...”

Supplements firm Jarrow Formulas pointed out that several probiotic ingredients are already GRAS affirmed as safe, with no FDA objections.

 

The Wrong Standard

DSHEA states that NDI notifications must show that an ingredient is “reasonably expected to be safe”-rather than holding supplements to the more-stringent food-additive standard of “reasonable certainty of no harm” or the GRAS standard of “generally recognized as safe.” However, some say that in the current NDI draft guidance, FDA appears to try to impose the food-additive standard. On this point, UNPA told FDA:

"Congress intentionally established a different safety standard for NDIs, fully understanding the existing safety standard for food additives. Congress did so, recognizing that dietary ingredients are largely derivatives of foods and other dietary components found in the human diet and for which there is often an existing history of consumption and use...The agency now proposes to reset the NDI safety standard from a reasonable expectation of safety to the different food-additive safety standard of reasonable certainty of no harm. FDA does not have the statutory authority or administrative authority to amend the NDI safety standard that was established in Section 413 of DSHEA.

[In the draft guidance,] the agency refers to the Redbook, which is FDA’s authoritative guide for safety and toxicology standards for food additives, as a general guideline for NDI safety dossier development. Based on recent conversations with NDI applicants, it appears that FDA is already requiring NDI submitters to develop and propose NDI ‘safety packages’ based on Redbook principles. The direct economic impact of this new and unauthorized safety standard is already being felt by the supplement industry."

CRN/CHPA pointed out that because the NDI process is a notification process only-and not a premarket approval process-dietary supplements should not be held to a premarket approval safety standard like that for food additives. They explained:

"FDA does not ultimately determine whether the [NDI] ingredient is in fact safe or generally recognized as safe. As discussed previously, a manufacturer or distributor at best receives an “acknowledgement” from FDA, stating that the agency’s acceptance of the notification for filing is a procedural matter and does not constitute a finding by FDA that the NDI or the supplement containing the NDI is safe or not adulterated. In fact, DSHEA squarely imposes the burden of proof on FDA to show that a dietary supplement is adulterated. In light of the fact that FDA makes no safety determinations based on NDI notifications, and merely “acknowledges” and “files” them, together with the fact that the agency bears the burden of proof to show adulteration, it would be completely inappropriate for the agency to hold NDIs to the rigorous standards that it applies to products that are subject to a lengthy and conclusive premarket approval process."

But one might ask the question: If FDA shouldn’t use the food-additive standard when handling NDI notifications, then what standard should it use?

CRN’s Mister said, “Well, I think that is the black box we’re trying to figure out. That question right there is what led us to call for guidance years ago, because there were so many [NDI notification] rejections and we wanted to know what exactly is the process that goes on within the agency in which they determine that certain ingredients are not reasonably expected to be safe.”

He continued, “In our mind, we know that it is something less than the food-additive standard; and we know that it has to be more than just an affidavit saying, ‘This is safe. I’ll swear this is safe.’ That’s not enough. So what is the standard? Really, that is the million-dollar question. That’s what the agency was charged with answering but instead they just jumped to the Redbook and said, ‘Oh, the food-additive standard.’ And as we say in the comments, we know that it’s not because Congress and the courts both expressly told FDA it will not be the food-additive standard.”

 

Whose Burden of Proof?

While companies bear the burden of submitting NDIs for genuinely new dietary ingredients, DSHEA says that the burden to prove that an ingredient is in fact an NDI-and not a grandfathered ingredient-rests solely on FDA, not on industry. But this is not what the draft guidance seems to imply.

Instead, the guidance infers that if companies cannot furnish evidence proving that their ingredients are grandfathered, they are automatically required to submit an NDI. In its comments, AHPA wrote:

"The draft guidance strongly implies that companies that market dietary supplements that contain only pre-DSHEA dietary ingredients have an affirmative burden to prove or to have evidence that each of these ingredients was marketed in the U.S. before October 15, 1994, and is therefore not a NDI. This implication is apparent where the draft guidance identifies the kind of documentation that a company would “need to” show that an ingredient was marketed before October 15, 1994, and what such documentation “should” consist of or include. But [DSHEA] does not require marketers of dietary supplements that consist only of pre-DSHEA dietary ingredients to have documentation that these ingredients were marketed in the U.S. before October 15, 1994. If there were such a requirement it is apparent that companies that were in business before DSHEA was passed in 1994 would have a competitive advantage over companies that were founded after that date, as only those earlier businesses could have such pre-DSHEA records readily in their possession."

CRN/CHPA pointed out that in the event of a dispute, DSHEA says FDA has the burden of proving whether or not an ingredient requires an NDI notification. However, “In the Draft Guidance, FDA would not only reverse this burden and place the burden of proof on industry, but it would require parties to produce contemporaneously created written documentation to prove non-NDI status. This policy lacks any legal or rational justification.”

When asked the question of who bears the burden of proof during UNPA’s December webcast, FDA’s Fabricant stated that in the event of a dispute, companies would still likely need to provide some type of evidence to prove grandfathered status.

“I would think that depending on the argument made, a judge or a court could look at either side of things,” he said. “[For those] basing their reasons for being on the market solely on [the fact] that they know that they’re grandfathered…if that met a challenge, how [would they] affirmatively [fight] that challenge?...I would think that generally…the expectation is that someone [will need to] have something to substantiate that [claim]. It can’t just be faith-based. There’s got to be an objective measure, because as we’ve said, how do you make that [determination] otherwise?”

However, beyond that, Fabricant did not specifically answer the question of whether grandfathered ingredients not in dispute would still need to maintain evidence providing their status. “I don’t know that I can answer per se, because again…it’s something that we’re certainly looking at…and I think that’s something where there may be some changes.”

 

Making New Law

It’s clear that industry’s interpretation of DSHEA’s laws and FDA’s own interpretation of those laws stand far apart. Seriously far apart.

Some have gone so far as to say that by straying so far from DSHEA’s laws, the draft guidance is in fact FDA’s attempt to unlawfully establish new laws. “The guidance is not supposed to be setting new policy,” said CRN’s Mister to Nutritional Outlook. “It’s supposed to be articulating the existing law and the understanding of the law by the agency. That’s what a guidance is.”

In closing comments, CRN/CHPA wrote:

"In its attempts to upset the balance of DSHEA and to impose new substantive obligations on the dietary supplement industry, FDA has far exceeded the permissible boundaries of a guidance document. The agency cannot institute new regulatory requirements while avoiding formal public input under the appropriate legal framework. The Draft Guidance would represent significant and sudden reversals of FDA’s historical policies…and would impose requirements that can lawfully be proposed and considered only by notice-and-comment rulemaking.

Each of the points we have raised in these comments is consistent with what the dietary supplement industry has been stating and doing for nearly two decades. None of this can come as a surprise to the agency. It is clear that FDA has failed to acknowledge or incorporate much of the feedback we have given the agency over the years. The agency has used this Draft Guidance as an opportunity to announce new and previously unheard-of policies that stand in direct contradiction to both the statute and past agency practice. Courts have looked disfavorably upon reversals in agency policy and practice, and thus we challenge FDA’s potential ability to enforce these punitive and radical policy shifts.

DSHEA was an act of deliberate legislative intervention to end years of enforcement abuses and impermissible restrictions on the marketing of dietary supplements. But the Draft Guidance would bring a return to the pre-DSHEA regime."

And NPA said, “Safety is, of course, of the utmost importance but there are ways to protect safety without doing unnecessary economic harm....NPA believes the draft guidance will have a chilling effect on the dietary supplement industry if enforced as it is currently written. The industry is composed predominantly of small businesses, and the high costs of complying with this draft guidance would drive many out of business.”

With the comment period closed and the ball now in FDA’s court, one of industry’s biggest concerns moving forward is whether or not the agency is operating under the draft guidance’s problematic guidelines as it evaluates new NDI notifications. With this in mind, NPA wrote to FDA: “[W]hile any guidance document does not constitute a legal requirement, NPA urges that FDA make clear that it is not already following this draft guidance when making enforcement decisions.”

 

Sidebar 1: “We’re On the Same Page”

Although individual dietary supplement associations, including AHPA, CHPA, CRN, NPA, and UNPA, separately filed comments with FDA, they released a joint statement emphasizing a united front.

“While the groups submitted separate comments to reflect their own membership priorities, FDA should focus on the common themes in their respective submissions, rather than look for points of disparity as indicating any substantive differences of opinion among the groups,” they stated.

CRN’s president and CEO Steve Mister told Nutritional Outlook, “I think the associations are putting forth different nuances on how the agency might address the problem. That’s not to say that we are absolutely wedded to our approach versus someone else’s. The trade associations are all on the same page here-that the document is fundamentally flawed and needs to be rewritten. We’re pretty united on this.”

 

Sidebar 2: Don’t Forget About These Other Points of Contention

Investigational New Drugs (INDs): In its draft guidance comments to FDA, NPA stated:

"The draft guidance reiterates the DSHEA provision that if an ingredient is part of a publicly available, substantial investigational new drug application (IND), it cannot be a dietary ingredient unless it was first marketed as a dietary ingredient. Many researchers have found they are required to file an IND in order to get clearance from institutional review boards (IRB) to conduct any clinical research. Because of this, it is unclear what “substantial clinical investigation” includes. Much more guidance is needed on this definition."

Guidelines for Safety Testing: In the guidance, FDA spends several pages discussing the types of tests and testing data the agency believes would help in assessing NDI safety. The question remains whether these lists are too prescribed-and possibly too restrictive.

AHPA indicated to FDA that it may follow up with further comments on this and other sections. Meanwhile, NPA stated, “[T]he tests prescribed in this draft guidance go far beyond what is required to conclude a dietary ingredient will be ‘reasonably expected to be safe.’ NPA cautions that FDA’s guidelines should not establish inflexible requirements.”

In an interview with Nutritional Outlook, CRN’s president and CEO Steve Mister added:

"We’re a broad category with a lot of very different kinds of ingredients. So I don’t think we’re looking for [FDA] to spell out the exact tests that must be performed. What we’re saying is that the statute does not allow you to narrow it to [a pre-specified list].

You need a framework that’s specific enough to give a company some guidance so that they know the likelihood of whether or not their notification will be objected to if they go to FDA now with this data. But at the same time, the framework has to be flexible enough to account for this very broad category of ingredients. It needs to have some ability to adapt as the industry grows.

I think you can be flexible and clear at the same time. You can have broad standards that have to be met and have flexibility with regard to individual ingredients."

 

Sidebar 3: Could Compendia Help?

In comments to FDA, the U.S. Pharmacopeia (USP) suggested that its compendial standards could play a larger role in the NDI process and in draft guidance.

In fact, FDA already references USP in the current version of the guidance, stating, for instance, that manufacturers can use USP’s specifications for microbial and heavy metal limits. However, says Gabriel Giancaspro, PhD, USP’s director of dietary supplements, “USP believes that our standards offer much more and ultimately can be used by a manufacturer to meet all of the quality specifications expected by FDA.”

As such, he says, “USP believes there are opportunities to cite these public standards as resources for manufacturers in the final version of the NDI guidance.”

USP standards can be used in identity specification and in ensuring that products meet their appropriate strength, purity, and composition. In NDI notifications, companies could relay to FDA whether or not their ingredients meet compendial specifications.

Importantly, USP monographs also specify any known safety issues associated with a particular ingredient; however, because USP monographs do not address recommended conditions of use, nor suggested doses, companies may still need to provide that and related safety information to FDA.

USP’s compendial standards could also be used to ensure that no matter what processing changes an ingredient goes through, the end product adheres to the same quality specifications outlined in a USP monograph for that ingredient-which could play a role in the draft guidance areas of synthetic ingredients, chemical alteration, and calls for duplicative notifications.

“Basically, if the end product specifications are the same as the public standards, regardless of the method of production, FDA could grant an exemption for the requirement of NDI notification,” Giancaspro says. “USP has vast experience providing public specifications for generic prescription drugs that are manufactured by different methods and yet meet common compendial acceptance criteria for quality, purity, identity, and strength. USP’s comment asserts that FDA could grant an exemption to the NDI notification requirement where the same ingredient is produced by a different manufacturing process but the end product meets the same public quality specifications as set forth in a USP monograph….”

USP also pointed out that “recognition of compliance with USP’s compendial standards as an exemption to the NDI notification requirement would further ease the administrative burden associated with notifications, while still being protective of consumers.” Also, it added, companies proving they adhere to public standards like a USP monograph might also be spared the necessity of sharing trade secret information in an NDI notification.