Nitrosamine impurities have been in the regulatory spotlight since they were discovered in several blood pressure medicines leading to product recalls across the EU and the US
Nitrosamine impurities have been in the regulatory spotlight since they were discovered in several blood pressure medicines known as sartans back in June 2018. N-nitrosodimethylamine (NDMA) and N‑nitrosodiethylamine (NDEA) have both been detected in several batches of sartans which has led to product recalls across the EU and the US.
Nitrosamines refer to any molecule containing the nitroso functional group. These molecules are of concern because nitrosamine impurities are probable human carcinogens.
Nitrosamines impurities can be derived from several potential sources which include but is not limited to:
The EMA has recently released a publication instructing Marketing Authorisation Holders (MAH) to take precautionary measures to mitigate the risk of nitrosamine formation or presences during the manufacture of all medicines containing chemically synthesised active substances.
The publication also serves as a reminder of the responsibilities of the MAH as laid down in Directive 2001/83/EC. While the MAH can delegate activities such as API manufacturing, they cannot delegate responsibility for ensuring the quality, safety and efficacy of the finished product for the patient.
The EMA have also published a Questions and Answers document to further assist MAHs.
Nitrosamines refer to any molecule containing the nitroso functional group
The MAH together with API and finished product manufacturers should perform a risk evaluation using Quality Risk Management Principles that are set out in ICH Q9 of their medicinal products containing chemically synthesised API. The risk assessment should consist of the identification of hazards and the analysis and evaluation of risks associated with the arrangements for preventing nitrosamine formation as well as contamination or cross-contamination.
This risk evaluation for all products should be complete at the latest by 19 March 2020.
Key questions to consider during the risk assessment are:
Should the risk evaluation lead to the identification of nitrosamines confirmatory testing should be performed using appropriately validated and sensitive testing methods. Following that, updates to the MAH may be required.
PharmaLex says it can provide assessments of products for nitrosamine impurities.