Two cases in point outline the parameters of the issue. One case is astaxanthin, the potent antioxidant carotenoid that has boomed in popularity in recent years. The other is PQQ, or pyrroloquinoline quinone, a dietary supplement and beverage ingredient that is far more obscure but seems poised for prime time because of promising science results.
PQQ—natural, or synthetic?
In the case of PQQ, Mitsubishi Gas Chemical filed a successful New Dietary Ingredient (NDI) notification with FDA on the compound, which it had under development in the early 2000s and markets under the brand name BioPQQ. Mitsubishi says derives its PQQ from a natural source. A competitor has brought what it says is a bioidentical ingredient to market that it admits is chemically synthesized by a Chinese partner. Beyond the issue of whether a separate notification should be required for truly identical NDIs is the issue of the specifications of Mitsubishi’s ingredient, which under the rules governing the submissions Mitsubishi was permitted to redact.
“If they don’t know the specifications, how can they possibly claim it is the same ingredient?” asked Marc Ullman, an attorney with the firm Ullman, Shapiro & Ullman who represents Mitsubishi.
In an open letter to industry, Mitsubishi lays out its position that the competing ingredient is noncompliant, and any finished products using the ingredients are treading on legally risky ground. A dietary supplement or other product containing an NDI for which no notification has been filed would be defined as adulterated, the letter said. (To read the full text of the letter, click here.)
“We believe that knowingly distributing adulterated material is not only unethical, but poses a liability risk to the manufacturers and the health of their customers,” the letter said.
"If a company is marketing a product with this ingredient in it, it is by law adulterated,” Ullman said. FDA has made it abundantly clear that the agency believes that you cannot have a synthetic botanical dietary ingredient, he said.
Individual obligation for filing
Jason Sapsin, a former FDA counsel now in private practice with the firm Fox Rothschild, echoed Ullman’s concerns, and said in his opinion it’s clear that new notifications are required for every instance of an NDI brought forth by ingredient manufacturers. It’s a commitment of each company to the safety of its particular ingredient, he said.
“The reason that you do that is you are expected to explain to the agency the basis on which you—you personally, your company—have concluded that the ingredient is reasonably expected to be safe,” Sapsin told NutraIngredients-USA.
“That’s an individual obligation that falls on any company that is marketing a New Dietary Ingredient,” he said.
Habitual risk takers
Yet it is common knowledge that there are ingredients out there that likely would be seen by FDA as NDIs that have no notifications on file. The issue extends far beyond the two ingredients under discussion here. Such ingredients either have tenuous lines of reasoning purporting to show they are grandfathered in under the Old Dietary Ingredient provision of DSHEA, or they skirt the issue altogether.
Why would a company choose to use an ingredient that might fall within this legally uncertain penumbra? It could be a question of company culture, Sapsin said.
“The question comes down in my view to the degree of risk that the manufacturer is prepared to take. I think in the current environment, which is generally pro enforcement, the safer course of action would be to submit the NDI for the synthetic,” Sapsin said.
In the case of astaxanthin, the question expands beyond the issue of treading on someone else’s NDI toes to include straight adulteration. As demand for astaxanthin has risen, suppliers, mainly in China, started flooding the market with offerings that contained naturally-derived astaxanthin and synthesized versions of the ingredient. The synthesized versions are meant for the aquaculture market, where they provide the red color in the flesh of farmed salmon and trout. While safe and approved for this use, these ingredients are not meant for or approved for direct human consumption as a dietary ingredient.
Astaxanthin in its natural form is derived from the algae species Haematococcus pluvialis, and responsible suppliers such as Valensa, Cyanotech, Fuji and Algatechnologies all have submitted NDI notifications on their ingredients.
“When we looked at the samples we had received from China it was obviously a mixture of natural astaxanthin and astaxanthin from the salmon feed industry,” said Rudi Moerck, PhD, CEO of Valensa. “You cannot tell the difference other than if you take the time to find out what the optical isomers are.”
“Knock-off versions should never be allowed without sufficient safety data and an NDI at minimum. They should really have GRAS before launching since this is a much more comprehensive safety review than an NDI,” said Bob Capelli, vice president of sales, marketing and materials management for Hawaii-based Cyanotech.
"If these shady operators are selling astaxanthin ingredients and promoting them as “identical” to astaxanthin sourced from Haematococcus pluvialis without having obtained an NDI, they are, in effect, selling adulterated and illegal products. They are in no way compliant with DSHEA," said Joe Kuncewitch, national sales manager for AstaReal, Inc.
(More on this adulteration issue in a separate article.)
A dietary ingredient, or not?
In the end, Moerck said that in his view the NDI draft guidance as it now stands would exclude any synthetic version of astaxanthin from qualifying as a dietary ingredient, so they couldn’t even get in the door with an NDI notification even if a company wanted to go that route. Other observers of the back-and-forth on the issue of the draft guidance as it relates to so-called synthetic botanicals aren’t so sure the issue is quite that set in stone. Yet the risk that FDA will reject the filing in this interregnum while the sticking points on the draft guidance are hammered out between FDA and industry stakeholders has to balanced against the risk of bringing to market a potentially noncompliant ingredient, Sapsin said.
“I don’t think that calculation is worth it. For me, tactically, I would rather have that fight (with FDA) sooner rather than later. I wouldn’t want to put my downstream customers in jeopardy,” he said.