FDA’s new dietary ingredient notification draft guidance draws questions even from firms that expect compliance will not require drastic changes in their processes.

At Pharmavite, one of the supplement industry's largest players, executive Paul Bolar says the firm is glad to see the long-awaited guidance finally published and is reviewing its potential implications.

"I think there are a few areas where we feel they may be a little overly restrictive and we're certainly going to have to analyze this further to see what the full impact is going to be," said Bolar, VP of quality and regulatory affairs for the Northridge, Calif., company.

FDA officially published the guidance July 5, aiming to clarify what it considers a new dietary ingredient – a distinction based on whether an ingredient was grandfathered when the Dietary Supplement Health & Education Act passed in 1994 – and what safety information the agency expects from an NDI notification dossier.

Industry stakeholders immediately were alarmed by a number of the guidance document's provisions, including FDA's stance that synthetic botanical constituents cannot be dietary ingredients and new strains of bacteria, such as probiotics, unlikely will be (Also see "Synthetics Stance In NDI Guidance Raises Red Flag For Industry" - Pink Sheet, 11 July, 2011.).

Ingredient Combos Trigger NDI Questions

Another chief concern among supplement manufacturers is the notion that a product combining an old and new dietary ingredient, or combining multiple old ingredients to create a new molecular entity, would trigger the need for an NDI submission.

Such an expectation from FDA could impact a firm like Pharmavite, which markets supplements under the Nature Made brand and frequently launches new stock-keeping units featuring ingredient combinations.

"When we're talking about the addition of substances that have well-known safety profiles … I just really don't see the need for that degree of pre-clearance for those kinds of formulation changes," Bolar said.

In focusing on ingredient combinations and interactions, FDA seems to be applying a pharmaceutical framework to supplements, he added. "I don't think it's warranted in many cases."

Bolar said he could recall Pharmavite submitting just one NDI notification to FDA in the past decade. While the firm does not expect short-term impacts from the guidance, he foresees a strong likelihood of preparing more notifications down the road.

Proof Burden May Filter Down To Suppliers

Though the legal responsibility for NDI notifications falls on finished product manufacturers and distributors, the influence of the guidance likely will filter down to ingredient suppliers, too.

Debbie Trinker, VP of regulatory and legal affairs at Kemin Health, says the guidance is "a game-changer" that will force many manufacturers to look more closely at ingredients and seek tangible evidence of their legal status.

For example, FDA's stringent documentation requirement means companies may have to dig deep to prove their dietary ingredients were marketed prior to DSHEA, or else submit an NDI notification.

Additionally, the agency expects submissions for otherwise grandfathered ingredients now made using a different manufacturing process or solvent resulting in a "significantly different" chemical composition.

"A likely consequence of this is that finished supplement manufacturers will be pushing back on ingredient suppliers to justify the basis upon which their dietary ingredients are lawfully on the market" as dietary ingredients or as generally recognized as safe food components, she said.

Trinker said Kemin's ingredients, marketed to the nutraceutical and food industries, all are grandfathered ingredients, NDIs acknowledged by FDA or GRAS for food applications.

With the guidance in hand, Des Moines, Iowa-based Kemin plans to prepare documentation files for its ingredients to give the firm's customers assurance of their legal status.

When adding ingredients with “well-known safety profiles … I just really don't see the need for that degree of pre-clearance for those kinds of formulation changes." – Pharmavite regulatory VP Paul Bolar

While many ingredients elsewhere on the market may require NDI notifications to FDA, Trinker said Kemin's ingredient development process likely will not change under the guidance.

"The new dietary ingredients that we have in the pipeline, part of our innovation process already takes into account an evaluation of whether they're new dietary ingredients, whether they would be exempt, and then the type of data we would need to support their safety," she said.

"So there's more clarity from FDA and there's a broader interpretation of when these notifications are going to be required that we'll be taking into consideration. But it's already been part of our process."

Separately, Trinker said the guidance raises questions about FDA's NDI enforcement plan and capabilities, given that she expects industry to submit significantly more NDI notifications to the agency.

Daniel Fabricant, FDA's chief supplement official, says the NDI review team's resource situation is up in the air as budgetary pressures hit the agency and any NDI enforcement activity in the immediate future is not a result of the draft guidance (Also see "NDI Guidance Protects Public Health And Allows Innovation – FDA's Fabricant" - Pink Sheet, 11 July, 2011.).

Guidance Captures Rigor Of Safety Assurance

Like Kemin, Claire Kruger of Spherix Inc. believes the guidance offers few surprises to companies already following proper protocols for ingredient safety determinations.

The notification process laid out by FDA, which many in industry are labeling as onerous and stifling to innovation, also is essential for safeguarding public health, said Kruger, CEO of the Bethesda, Md.-based consulting and ingredient development firm.

"It's the same scientific rigor and standard that's used worldwide to ensure safety of products for consumers," she said. "So it's a very good process; it's not a new process; it's not an overly burdensome process."

Far from being anti-innovation, the guidance document's safety evaluation provisions actually could enhance innovation by forcing firms to develop a better understanding of their ingredients' beneficial properties, Kruger said.

She also is undeterred by other parts of the guidance. Kruger said a company, for example, can use straightforward analytical methods to determine whether a combination of dietary ingredients produces different effects than the constituents in isolation, and thus whether it needs a separate NDI notification.

Further, she says FDA's exclusion of synthetic versions of botanical extracts as dietary ingredients is warranted.

Both natural botanical constituents and synthetic equivalents come with impurity concerns, but synthetics are more likely to be contaminated with manufacturing processing aids rather than other naturally derived components, Kruger said.

Such variations make it difficult to compare botanicals and synthetics, "and that's why generally they would be dealt with very differently," she added.

Ultimately, Kruger said FDA is not asking industry to act any differently than Spherix's clients already do when putting together an NDI notification or GRAS affirmation dossier.

The cost of analytical work may pose a hurdle to some firms, but she says it's an essential prerequisite for developing a supplement product.

"I think if a company cannot prepare sufficient information to meet the standard of safety set by DSHEA, they shouldn't put the product out on the market," Kruger said.

By Dan Schiff

NDI Guidance Sparks Questions Even From Firms Ready To Comply

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