Since N-nitrosamine impurities were first detected in several high blood pressure medications, authorities have scrambled to remove the risk to patients. First, there was a recall of selected lots, then, in 2019, the European Medicines Agency announced that companies would be required to conduct a scientific evaluation on the presence of N-nitrosamine impurities in human medicines containing chemically synthesised active pharmaceutical ingredients (APIs).
Initially, the requirement was limited to chemical medicines, but the Committee for Medicinal Products for Human Use (CHMP) later widened the scope to include biologics. The procedure involves a three-step approach.
First, companies were required to carry out an evaluation to identify if APIs and/or finished products could be at risk of the presence of N-nitrosamines. The conclusions were to be reported to the authorities by no later than 31 March 2021 for chemically synthesised APIs, and by 1 July 2021 for products containing biological APIs.
If a risk is identified, step two requires companies to carry out confirmatory testing to confirm or refute the presence of N-nitrosamines. The agency has said MAHs should report the outcomes as soon as possible.
If the presence of N-nitrosamine(s) is confirmed, the third phase involves marketing authorisation holders (MAHs) informing authorities of their risk mitigation strategies and implementing effective risk mitigation controls through the submission of variations, or other regulatory pathways requested by the authority (for example, referrals). The third phase is to be completed no later than 26 September 2022 for products containing chemically synthesised APIs, and by 1 July 2023 for products containing biological APIs.