Following up on the work that led to the cohort of concern arguments within Lhasa Limited’s Nexus platform, and material that I’ve repeatedly presented (first presented at the USP-LATAM workshop at the end of 2021, actually), we now have a paper just released in OPRD formalising the edges; which compounds are definitely not CoC?
This isn’t to say that everything that remains in the cohort is still potent; the SAR derisking of Thomas et al and Cross and Ponting is still critical, but those nitroso compounds that can’t form diazonium ions really shouldn’t be in the cohort…
the acceptable limits for nitrosamines translate into parts per billion in the drug products and their ingredients
the secondary amines present in the drug products are a levels vastly greater than ppb
the amount of nitrite (or other nitrosating agent) needed to exceed the acceptable limits is then also in the ppb range (especially for excipients which can be present in vastly larger quantities than the drug substance)
It follows that standard GMP practices cannot be successful in reducing the risks from nitrosating agents in excipients. At best GMP practices may control to ppm or just sub ppm levels.
And thus alternative practices will have to be found to reduce the overall risk to an acceptable level.