After the nitrosamines, which are classified as probably carcinogenic, were initially discovered in several sartan-containing antihypertensives in the last year, additional cases of N-nitrosodimethylamine (NDMA) and N-nitrosodiethylamine (NDEA) contamination have now come to light. Affected are not only products containing sartans, but also pioglitazone, a diabetes drug, and ranitidine, an active ingredient to prevent heartburn, which is used in OTC and Rx medicinal products.
What these three active ingredients have in common is that they are mass market medicines, which are taken by a large number of patients. But they neither originate from the same production plant, nor are they synthesised in a comparable manner. Therefore, it has not yet been conclusively determined for all cases how the contamination occurred. In addition to contaminated solvents, improper storage or transport may be possible causes that need to be looked at. The chemical instability of ranitidine in particular gives reason to suspect that environmental influences might cause nitrosamine precursors to form in the API.
In view of the many possible causes of contamination, the EMA now demands that all marketing authorisation holder perform risk-based assessments of their production processes with respect to a possible contamination with nitrosamines. This risk assessment is mandatory for all synthetic medicinal products - irrespective of their APIs and production processes. The Committee for Human Medical Products of the EMA (CHMP) specifically asks MAHs to:
Authorisation holders for human medical products only have 6 months left for the risk assessment - very little time for a task where new risk factors can turn up with each new case that comes to light. In parallel with this, the EMA is working on a guideline for the avoidance of nitrosamine contamination in chemically-synthesised active ingredients.
The result of the risk assessment will decide whether additional steps are necessary: intensified GMP audits of the supply chain, adaptations to laboratory analyses or even changes to the production process, including the related regulatory consequences. Do you want to find out more? Contact us!