Understanding the EMA Advice on Nitrosamine Presence

  • October 18, 2019

On September 26, 2019, the European Medicines Agency (EMA) released an advice to Marketing Authorization Holders (MAH) of human medicines to review their drug products on possible presence of nitrosamines.

Why was this advice released?

In 2018, a nitrosamine impurity was detected in a batch of valsartan for the EU market, originating from a Chinese manufacturer. Valsartan is an active pharmaceutical ingredient (API) regulating blood pressure, which is processed further to a drug product for human use. The nitrosamine impurity found was N-nitroasaminedimethylamine (NDMA).

Nitrosamines are potential carcinogenic substances. Long-term exposure above certain levels might increase the risk on cancer. Nitrosamines are not expected to form during the manufacture of the vast majority of medicines containing chemically synthesized active substances and they are present in small amounts in drinking water and some food products.

Consequential investigations revealed detectable amounts of nitrosamines in other ‘sartans’ as well. A root cause was identified in the synthesis process of those sartans containing a tetrazole ring only. These findings resulted in product recalls and strict regulations to the manufacturing of these specific products.

As the investigation progressed, nitrosamine impurities were also detected in drug products outside the sartan classes. As such, the scope on the investigation to nitrosamines impurities has been widened to all medicinal products intended for human use.

What are the next steps?

A definite root cause has not yet been identified on the presence of nitrosamine impurities in medicinal products for human use, which therefore could be introduced by either the API synthesis route, by carry-over effects in the (API) production, introduced by any starting materials or formed during drug product manufacturing.

As consequence, EMA has requested all marketing authorization holders to review their human medicinal drug products containing chemically synthesized API’s on potential risk to containing nitrosamines impurities. The risk assessments will need to be completed by March 26 (within 6 months from the release of the EMA advice).

Products identified of being at risk of containing nitrosamine impurities must be immediately tested using validated analytical test methods to confirm nitrosamine presence, and authorities must be kept informed at all times. Adjustments in the manufacturing process to eliminate nitrosamine impurities and/or product specifications might be required. Within 3 years after the publication of the EMA advice, the required changes to the drug product should be submitted and concluded.