EMA Identifies Potential Sources Of Nitrosamine Contamination

As companies evaluate scores of products for the possible presence of nitrosamine impurities, the EU regulator has listed potential sources of contamination identified to date to help sponsors develop a risk-based approach for their evaluations.

Source: Shutterstock

Companies Are Evaluating Drugs For Possible Presence Of Nitrosamines

The European Medicines Agency has listed potential sources of nitrosamine contamination in medicines to help sponsors comply with its recent request for them to evaluate their products for the possible presence of the cancer-causing impurity.

Companies making medicines containing chemically synthesised active substances – including generics and over-the counter products – were asked by the EMA last month to start evaluating their products after an online pharmacy in the US found that Sanofi's antacid medicine Zantac (ranitidine) and generic versions of the product contained dangerous levels of nitrosamine.

Considering the large number of medicines that must be checked, the agency has suggested that sponsors should use a risk-based approach to prioritize their evaluations and to undertake confirmatory testing.

In newly updated guidance on nitrosamines for marketing authorization holders (MAHs), the EMA has listed potential sources of contamination in medicines identified to date. These include, among other things: degradation processes of starting materials, intermediates and drug substances; the use of contaminated starting materials and intermediates supplied by vendors that use processes or raw materials that may allow nitrosamine formation; and the use of certain packaging materials

The EMA said the updated guidance, published on 18 October, can help companies with the ongoing review of their manufacturing processes and help identify products at greater risk. For example, regarding certain packaging materials, the agency explained that in one case nitrosamine contamination had been observed in a finished product stored in blister. In this case, the MAH had hypothesized that the lidding foil containing nitrocellulose printing primer may have reacted with amines in printing ink to generate nitrosamines, which could be transferred to the product under certain packaging process conditions.

While regulators in the EU and the US are conducting their respective inquiries on nitrosamine contamination, there have been certain company-led recalls of ranitidine. On 18 October, for example, Sanofi announced plans to voluntarily recall Zantac OTC in the US and Canada, “due to inconsistencies in preliminary test results of the active ingredient” used in the US and Canadian products. The company clarified that it was not recalling ranitidine products in other jurisdictions as the active ingredients used in products outside of the US and Canada are sourced from different suppliers. (Also see "OTC Zantac Recall: Sanofi Heeds To Potential Ranitidine Contaminant" - HBW Insight, 18 Oct, 2019.)

A senior EMA official had earlier stated that the nitrosamine episode was indicative of wider problems and could result in a paradigm shift in quality.  (Also see "Nitrosamine Episode Could Lead To Paradigm Shift In Quality" - Pink Sheet, 10 Oct, 2019.)