FDA continuing to drill down to provenance of ingredients

06-Jul-2017 - Last updated on 03-Nov-2017 at 15:22 GMT

Recent warning letters show the Food and Drug Administration continues to hone in on the provenance of ingredients, and demonstrate that the tempo of enforcement remains unchanged despite the moves by the Trump Administration to roll back regulations in other areas.

The two recent warnings, sent to the companies Xcel Sports Nutrition and Hardcore Formulations, also show the emphasis on sports nutrition products as a source of concern for the inclusion of what the agency views as questionable ingredients. Those include botanical ingredients that FDA considers to be New Dietary Ingredients but that have no NDI notification on file, and pro-hormone ingredients that mimic the effects of steroids.

Acacia rigidula, picamilon and BMPEA

In the letter to Xcel, FDA took the company to task for a host of ingredients found in the company’s products. These included Acacia rigidula, picamilon and BMPEA (which some formulators have claimed is a constituent of A. rigidula but which was called out separately on the Xcel labels).

Interest in A. rigidula-containing supplements goes back several years and is linked to the controversial compound BMPEA (beta-methylphenylethylamine). The plant has been cited as a natural source of BMPEA, but a 2014 study by FDA scientists (Journal of Pharmaceutical and Biomedical Analysis, Vol. 88, pp. 457-466) concluded that phenylethamine, a related, amphetamine-like chemical, could be found in Acacia ridigula, but only in negligible, trace amounts. “Given the low natural abundance of PEA in the plant materials, it appears nearly impossible to achieve the amounts of PEA found in the dietary supplements by formulating them with plant material or extracts of A. rigidula. PEA, a positional isomer of AMP, was found in 9 of 21 dietary supplements analyzed at levels ranging from 963 to 60,500 micrograms per gram. We found no safety data on the biological effects of this isomer in humans.” They went on to say that there was no evidence that linked BMPEA to Acacia rigidula, and went so far as to call it "a non natural compound."

This was followed by a paper in Drug Testing and Analysis by Dr Pieter Cohen et al. which found BMPEA in varying quantities in 11 of 21 dietary supplements tested whose formulations were listed as being based on Acacia rigidula extracts.

Following Cohen’s paper US Senators Dick Durbin, D-IL and Richard Blumenthal, D-CT and well as US Sen. Chuck Schumer, D-NY, called on FDA to ban BMPEA.

In the letter to Xcel, FDA stated that A. rigidula is a New Dietary Ingredient, noting that, “To the best of FDA’s knowledge, there is no information demonstrating that A. rigidula was lawfully marketed as a dietary ingredient in the United States before October 15, 1994, nor is there information demonstrating that this ingredient has been present in the food supply as an article used for human food in a form in which the food has not been chemically altered. “

As far as picamilon is concerned, the letter states that, “It is a unique chemical entity synthesized from the dietary ingredients niacin and gamma-aminobutyric acid.” But a legal dietary ingredient it is not, nor is BMPEA, in the agency’s eyes. “Because picamilon and BMPEA do not fit in any of the dietary ingredient categories under section 201(ff)(1) of the Act, they are not dietary ingredients as defined in the Act,” the letter goes on to state.

Pro-hormone exclusion

In the letter to Hardcore Formulations, the agency took the company to task for its inclusion of two prohormone ingredients: Methylstenbolone (2,17a-Dimethyl-17b-hydroxy-5a-androst-1-en-3-one) and Dymethazine (17b-hydroxy-2a, 17b-dimethyl-5a-androstan-3-one-azine) that the agency said do not qualify as dietary ingredients. In a recall notice in 2015, the agency said, “prohormones are synthetic steroids that bear a similarity to anabolic steroids. It is FDA's position that the ingredients . . . are not properly dietary ingredients that may be present in dietary supplements.”

Risk posed by ingredients

“I see these warning letters representing much more than what is written on the pages. Despite the change in administrations, and the fact that the revised New Dietary Ingredient guidance has not been finalized, these warning letters show that FDA has not stopped enforcement,” said attorney Ivan Wasserman, head of the Washington, DC office of the firm Amin Talati Upadhye.

Wasserman said it’s a reminder that formulation questions have to be based on a more rigorous analysis than what’s cool, trending, or cheap. Each ingredient bears with it a certain amount of risk that ought to be considered.

“Companies that do not sell products with these particular ingredients should not just breathe a sigh of relief. Every dietary supplement company must understand and have a position on the regulatory status of every ingredient in every product. It must be in a position to defend its position that an ingredient is a dietary ingredient, and that a new dietary ingredient notification is not needed (unless it has submitted one). The ingredient may be grandfathered, may be GRAS, may be present in the food supply or whatever, but a company that is first trying to formulate its position on these key issues when it receives a warning letter from FDA is way behind the 8 ball,” he said.