CRN sent a letter this week addressed to Douglas Stern, deputy director for regulatory affairs for the US Food and Drug Administration. In the letter, CRN alleges that FDA’s responses on the NAC issue have dodged a central legal question.
FDA first declared NAC as an illegal dietary ingredient via a series of warning letters to marketers of hangover cures that were posted in July 2020. Several of these products included NAC, which FDA, in a side note in the warning letters, said was not a legal dietary ingredient because of its prior use as a drug. It was the first time the Agency had made that kind of statement about the ingredient.
Ingredient on market for decades, without safety concerns
NAC, or N-acetyl-L-cysteine, is a derivative of the amino acid L-cysteine and is a precursor of the cellular antioxidant glutathione. The ingredient was first approved as a mucolytic drug sometime around 1963. It’s hard to say with certainty if that’s the right date because of imprecise documentation, which has been one of CRN’s objections.
It’s unclear how long it was marketed for that use, but it has not been used a prescription pharmaceutical in many decades. At present it is used in emergency rooms as a treatment in cases of acetaminophen poisoning to prevent severe liver damage. The ingredient has a long history of safety in that application where it is administered at a much higher dosage than what is found in dietary supplements, according to Rick Kingston, PharmD of the University of Minnesota (Kingston is also the president of regulatory and scientific affairs at Safety Call International).
Hundreds of NAC products on market
Despite its early use as a respiratory medication, the ingredient has been widely used for many years in finished dietary supplements, frequently as a standalone product. A recent search on Amazon produced more than 400 products for sale mentioning the ingredient, which is usually positioned as a ‘cellular antioxidant,’ or for liver support. Some major brand names in the industry were represented in that search. On the supply end, a search on Alibaba brings up more than 1,000 hits of bulk N-acetyl-L-cysteine (NAC) for sale, with the usual huge range of prices per kilogram that is typical for that portal.
At least one major supplement manufacturer claims to have solid proof that the ingredient was on the market as a supplement prior to the DSHEA grandfather date of Oct. 15, 1994.
CRN: Central legal issue still unaddressed
CRN had commented on FDA’s position in a letter dated June 1, 2021. The Agency responded in November of that year, but CRN said that response did not address the central legal issue, which according to trade organization is “whether the drug preclusion provision in section 201(ff)(3)(B)(i) properly precludes NAC from being marketed in dietary supplements.”
Rather, as this week’s letter to FDA states, the Agency veered off into a discussion of the ingredient’s safety record, which in CRN’s view is a non sequitur.
“Safety and current market evaluation are not relevant factors in the determination of whether section 201(ff)(3)(B)(i) is applicable to NAC and can be applied retroactively,” the letter states.
CRN also demands that its petition be handled separately from another filed by the Natural Products Association. FDA had proposed a combined response to both, but the CRN says that’s not appropriate as the two petitions seek different actions from the Agency.
The full text of CRN's letter is available here.