Hold On! That Previously Acceptable Level of Nitrosamine in Your Product is No Longer Acceptable!

Yesterday, the Agency expressed confidence that manufacturers of varenicline tablets containing the N‑nitroso-varenicline impurity can meet the FDA’s original acceptable intake limit of 37 ng or less per day. Their statement read:  “FDA is now confident in manufacturers’ ability to supply patients with varenicline containing the N-nitroso-varenicline impurity at or below the agency’s acceptable intake limit of 37 ng per day. Any newly manufactured varenicline for the U.S. market should have levels of the N-nitroso-varenicline impurity at or below that limit.”

The FDA had previously exercised regulatory discretion and permitted an interim level of N‑nitroso-varenicline significantly above the FDA’s original acceptable intake limit (the interim limit was set at 185 ng or less per day) until the impurity could be eliminated or reduced to acceptable levels.  The Agency is now confident that manufacturers can meet the original lower limit and, thus, has removed its interim discretionary limit; it will no longer permit manufacturers to utilize the higher limit in any newly manufactured product. The announcement read:  “[i]n July 2021, FDA announced it would not object to certain manufacturers distributing varenicline tablets containing N-nitroso-varenicline above FDA’s acceptable intake limit, but below the interim acceptable intake limit of 185 ng per day, until the impurity could be eliminated or reduced to acceptable levels. The agency’s current assessment shows manufacturers can adequately supply the market with varenicline at or below the acceptable intake limit of 37 ng per day.”

The Agency notes that it permitted the interim limit because the dangers of smoking (this product is used for smoking cessation) outweigh the temporary higher limit of N‑nitroso-varenicline in varenicline tablets.  The full FDA announcement and previous warnings for n‑nitrosamine limits in varenicline tablets can be found here.  This likely means that the Agency has concluded that a sufficient number of manufacturers can meet the new limit and supply the market demand for the drug product without causing a shortage in the marketplace.