Nitrosamine: MAHs have only six months of time remaining

Since contamination with nitrosamines caused recalls of yet another substance class a few days ago, the EMA has been concerned as to how far the range of nitrosamine-contaminated medicinal products extends and which products could still be susceptible to such contamination. It intends to obtain an assurance from every Marketing Authorisation Holder (MAH) that no nitrosamines are contained in finished products. MAHs should perform a risk assessment for all of their products within the next six months.

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.

Risk assessment required for all 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:

  • Evaluate possibility of nitrosamines being present in every concerned medicine within 6 months
  • Prioritise evaluations, starting with medicines more likely to be at risk of containing nitrosamines
  • Take into account findings from CHMP’s review of sartans
  • Notify authorities of outcome of risk evaluations
  • Test products at risk of containing any nitrosamines
  • Immediately report detection of nitrosamines to authorities
  • Apply for necessary changes to marketing authorisations to address nitrosamine risk
  • Complete all steps within 3 years, prioritising high risk products

EMA has given a tight time period for the evaluation and implementation

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!



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