Synthetics Stance In 'New Dietary Ingredient' Guidance Raises Red Flag For Industry

FDA's draft guidance on new dietary ingredient notifications already is arousing fierce pushback from the supplement industry over what constitutes an NDI and which substances cannot be dietary ingredients at all.

The guidance's stance that synthetic copies of botanical constituents are not dietary ingredients is representative of industry's broader concerns. Many manufacturers consider synthetics and other technological advances largely safe and see them already prevalent in the food supply.

FDA published the draft guidance document in the Federal Register July 5 - on schedule as dictated by the recent Food Safety Modernization Act but after years of delay since agency officials first promised it.

Public comments on the draft guidance are due to FDA by Oct. 3.

Singling Out Synthetics

According to the guidance, a synthetic copy of a constituent of a botanical "was never part of the botanical and thus cannot be a 'constituent' of the botanical that qualifies as a dietary ingredient."

Some in industry argue this position makes little sense, given that synthetics often are more chemically stable than their naturally derived botanical counterparts.

"Synthetics, in my mind, usually lend to the safety of an ingredient as opposed to detracting from it," said food and drug attorney Claudia Lewis-Eng.

Lewis-Eng, a partner with Venable in Washington, said under the guidance, a synthetic botanical component still could pass muster as an NDI if it qualifies as another type of nutrient, such as a vitamin, mineral or amino acid.

Should that fail, a synthetic ingredient could reach market by going through the food additive approval process or being affirmed generally recognized as safe - both considered challenging paths to commercialization.

"I see that as a potential barrier to improving a product even though it would be substantially chemically equivalent to its natural counterpart," Lewis-Eng said.

Ephedra Rule Wording Resurfaces Writ Large

In deciding synthetic botanical constituents cannot be dietary ingredients, FDA cites its 2004 final rule banning ephedrine alkaloids, which stated that ephedrine hydrochloride and other synthetic sources of ephedrine do not qualify as dietary ingredients.

According to Steve Mister, president and CEO of the Council for Responsible Nutrition, the industry at the time prioritized removing ephedrine alkaloids from the market and did not focus on the implications of a broad application of the synthetics wording.

"With hindsight, perhaps we should have addressed that more at the time," he said. "It's troubling now to see the FDA citing that to say, 'Well, there's our precedent that you can't market a synthetic and call it a dietary ingredient.'"

Ovos Case Suggests Practicalities Of Synthetics

More recently, the agency ruled the homotaurine in Ovos Natural Health's Vivimind supplement is not a dietary ingredient because, for one, it does not qualify as an amino acid, and secondly, it is made synthetically rather than extracted from seaweed.

As in Ovos' case, commercial realities often force manufacturers to use synthetically derived ingredients rather than scarce and costly botanical substances.

"They use a synthetic because there's not enough kelp in the ocean," said Ovos' attorney Marc Ullman, who filed a citizen petition asking FDA to allow the marketing of homotaurine, a failed investigational new drug, as a supplement.

The partner with Ullman, Shapiro & Ullman added the synthetics provision is "certainly one of the more anti-innovative sections" of FDA's guidance.

CRN asserts FDA's position on synthetics is contrary to congressional intent as shown in the Dietary Supplement Health & Education Act of 1994.

In a June 29 letter to FDA, the trade group says the Ovos decision could lead to "environmentally detrimental or unsustainable" practices by the supplement industry if synthetic bioequivalent compounds are not allowed to substitute for botanical constituents.

A History Of Enforcement

FDA has based enforcement activity on its synthetics position; in July 2009, it warned American Cellular Labs that the synthetic steroids in its bodybuilding products are not dietary ingredients.

At the time, that tack elicited concern from industry that FDA would apply its view of synthetics to other supplement ingredients.

"I don't think FDA can argue from a safety standpoint that a nature-identical compound, a synthetic compound, is any way, shape or form different from a naturally sourced" one, former Natural Products Association executive Daniel Fabricant told "The Tan Sheet" in 2009.

Now director of the Division of Dietary Supplement Programs in FDA's food center, Fabricant defends the synthetics position in the NDI guidance as rooted in the ephedra rule and homotaurine decision precedents.

Regulate Like It's 1994

Aside from its synthetics language, the guidance is behind the times in other ways, CRN says.

FDA "basically seems like it's trying to freeze the world for supplements as it was in 1994 and doesn't allow for any of the natural advances in manufacturing and technology since then," said Mister.

Changes in the manufacturing process for an old dietary ingredient could trigger the need for a new safety profile submission to FDA, as could a supplement product that initiates a chemical change by combining dietary ingredients.

The document's position on microbial ingredients, which says "bacteria that have never been consumed as food are unlikely to be dietary ingredients," could have negative implications for probiotics in supplements. Lewis-Eng suggested new strains might be forced to go through the drug approval process if the NDI route were to become unavailable to them.

FDA accounts for the emerging role of nanotechnology in dietary ingredient development, saying nano-sized ingredients should go through the NDI submission process to account for altered chemical properties.

The agency's cautious approach toward nano-sized ingredients in the NDI guidance echoes the June draft guidance on nanotechnology in regulated products. In both, companies are encouraged to consult with FDA on the chemical and regulatory implications of nanoscale components.

-Dan Schiff ([email protected])

[Editor's note: This story appears courtesy of the editorial staff of 'The Tan Sheet,' your source for coverage of nonprescription pharmaceuticals and nutritionals. For a sample copy, call customer service at 800-332-2181.]