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EU: Regulators propose 40 actions to cut risk of medicine impurities

2020/06/26  EMA

In mid-2018, the European medicines regulatory network became aware of the presence of Nnitrosamines in sartan active pharmaceutical ingredients (APIs) and instituted regulatory actions across the EU, including recalls of some medicines from pharmacies and measures to prohibit the use of APIs from certain manufacturers.

A subsequent review of sartans by the European Medicines Agency (EMA) found that the risk from the N-nitrosamine impurities (which are classified as probable human carcinogens) was low. In the vast majority of sartan medicines, N-nitrosamines were either not found or were present at very low levels. Given the greater risk to patients from stopping their treatments, regulators advised patients not to stop their sartan treatments without speaking with their healthcare professional.

As for the source of the impurities, EMA’s review concluded that the use of the solvent dimethylformamide together with sodium nitrite in the presence of an acid led to the formation of Nnitrosamines during the manufacture of sartan APIs. There was also a potential for contamination from other sources, including solvents, reagents and manufacturing equipment already contaminated with N-nitrosamines. Taking these root causes into account, the review set out new requirements for marketing authorisation holders (MAHs) of sartan medicines, including the requirement to test their products for N-nitrosamines and make necessary changes to their API manufacturing processes.

The sartans case and the subsequent review of sartans in the EU raised a number of important issues. First, it had become clear that the potential for N-nitrosamine formation had not been recognised during the development or evaluation of sartan medicines. Second, although the risk to patients was considered low, some API batches contained levels of impurities that necessitated regulatory actions, such as recalls. Third, the incident caused significant concern among patients and the general public with possible implications on adherence to treatments.

In May 2019, the network embarked on a lessons learnt exercise to consider ways to prevent unexpected impurities such as N-nitrosamines from being present in human medicines and to better manage such cases should they occur in the future. Drawing on the experience from the sartans incident, the lessons learnt group made recommendations covering prevention, incident management, market surveillance, communication and international cooperation.

The recommendations from this exercise are those of regulators in the European regulatory network. Other stakeholders, such as the pharmaceutical industry, are encouraged to conduct their own exercises and consider what additional actions they should take.

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