EMA issues recommendations on impurities in medicines

The European Medicines Agency (EMA) has published recommendations on impurities in medicines, based on lessons learnt from the discovery of carcinogenic nitrosamine impurities in angiotensin type 1 receptor antagonists (sartans).

The June 2020 recommendations clarify the roles and responsibilities of drug companies, amend guidance on controlling impurities and good manufacturing practice, and detail the management of impurities once detected including communication with patients and healthcare professionals, and cooperation with other international regulatory authorities.

The EMA launched an Article 5(3) procedure in September 2019 to provide additional guidance to companies that manufacter and market medicines in the EU. Recommendations based on the lessons learnt will complement the outcome of the Article 5(3) procedure, and provide key scientific opinion on nitrosamine impurities in medicines containing chemically synthesised active substances.

Marketing authorisation holders should review their manufacturing processes to identify and, if necessary, mitigate the risk of presence of nitrosamine impurities in three steps. Although the deadline to complete step 1 (risk evaluation) has been extended until 1 October 2020 because of restrictions due to the COVID-19 pandemic, the EMA encourages marketing authorisation holders to submit the outcome of this step earlier if they have completed the risk evaluation or identified any risk in their products. They should notify the national competent authorities as soon as possible if tests confirm the presence of nitrosamine, irrespective of the amount detected, and should assess the immediate risk to patients and take appropriate action to minimise exposure to nitrosamines.

If a risk for an active substance is identified, marketing authorisation holders should submit the step 1 response template and proceed with step 2 confirmatory testing of the finished product (if no risk is identified, they should conduct a risk evaluation of the finished product and submit the outcome of step 1 after they reach final conclusion on the active substance and finished product). In step 2, marketing authorisation holders should perform confirmatory testing on the products identified to be at risk of nitrosamine formation or contamination and report any confirmed presence of nitrosamines as soon as possible. In step 3, they should apply for any necessary changes to the manufacturing process resulting from this review using established regulatory procedures.

The EMA plans to complete their review of manufacturing processes by 26 September 2022.