Nitrosamine measures might disrupt anesthetic supply, Dr. Eric Tichy says
Hospitals should start conserving supply of short-term anesthetics as drug manufacturers become more conservative with nitrosamine measures, according to Eric Tichy, PharmD.
In 2021, the FDA issued a guidance for drugmakers on controlling impurities of nitrosamine, a probable carcinogen. The guidance recommended pharmaceutical companies to fully comply by October 2023.
Dr. Tichy, the division chair of the End Drug Shortages Alliance, told Becker’s drugmakers “are taking a very conservative approach” to nitrosamine contamination, “so we’re worried that’s a result of shortages for critical hospital medications in the next couple of months.”
He said the medication supplies hospital leaders should be watching include etomidate, ketamine and midazolam, which are anesthetics used for surgical procedures.
“There’s potential they would have to change their manufacturing processes to meet this requirement, and there’s a risk of recalls,” Dr. Tichy said. “A lot of times, you’ll see recalls are voluntary recalls, but the reason they volunteer is because they don’t want to take the risk, basically.”
In anticipation of these anesthetics falling into short supply, he recommends hospitals and health systems start conserving supply, such as avoiding excessive doses and being aware of alternative products.
That’s then an interesting selection in the context of NDSRIs, with only one of them bearing a secondary amine per se - and that category 5! Are there process impurities in the others, or I suppose for midazolam one could imagine the imine being reduced then nitrosated?
Impurities corresponding to a reduction of the imine in the ring are indeed known, also linked to synthesis you can have amine intermediates (prior to the formation of the last ring system):
E.g.
Midazolam EP impurity A = (6RS)-8-chloro-6-(2-fluorophenyl)-1-methyl-5,6-dihydro-4Himidazo[1,5-a][1,4]benzodiazepine
Midazolam EP impurity E
Midazolam EP impurity J = 8-chloro-6-(2-fluorophenyl)-1-methyl-3a,4,5,6-tetrahydro-3Himidazo[1,5-a][1,4]benzodiazepine
For etomidate it probably concerns acyclic secondary amines prior to ring formation stages.
Based on the context I assume the potential problems threatening supply are oriented at API level.
For investigating compounds and related impurities, I suggest not relying on commercial catalogs. Please refer to the Global Substance Registration System (GSRS). This database is free to access, and it’s part of the FDA’s Global Substance Registration System.
