EMA rolls out implementation plan to address nitrosamine impurities

Regulatory NewsRegulatory News | 28 October 2020 |  By 

The European Medicines Agency (EMA) has rolled out its full plan to implement recommendations to reduce the risk that medicines will be contaminated with nitrosamine impurities, identifying short-, medium- and long-range priorities. The agency has also made templates available for marketing authorization holders to perform risk assessment and confirmatory testing.
The implementation plan builds out a framework for putting in place the specific recommendations of a June 2020 “lessons learned” report from the European Medicines Regulatory Network on the problem of pharmaceutical contamination with nitrosamine impurities.
The new plan, which runs 16 pages long, breaks out 40 separate recommendations and corresponding actions from the June report; for each recommendation, the report assigns a lead agency, identifies other involved parties, and assigns a timeline. (RELATED: EMA addresses risk evaluation, mitigation for nitrosamines, Regulatory Focus 06 August 2020)
Steps in the plan range from clarifying responsibilities of manufacturers of finished products and active pharmaceutical ingredients (APIs), to requiring impurity reporting in dossiers, to ensuring that marketing authorization holders (MAHs) and other stakeholders “are subject to effective, proportionate and dissuasive penalties…if product quality is not appropriately ensured.”
The plan also assigns the European Medicines Regulatory Network the task of publishing detailed information about potential sources for nitrosamine impurities. The network is also tasked with considering a revision of European Union (EU) guidelines on the chemistry of active substances to include detailed information about how to handle and report all used materials, including reagents, processing aids and quenchers. The document should also be revised to include the systematic approach to mutagenic impurities suggested in the International Council on Harmonization (ICH) M7 document: “Currently, applicants use an outdated approach to identify the large structures in many cases,” according to the plan.
In the plan, ICH is given the goal of working on the ICH Q7 and Q9 guidelines to restrict the use of reagents and recovery processes that may themselves be a source of impurities or contain amines from which nitrosamine impurities can be formed, and to clarify exactly how risk assessments should be carried out. “Due to uncertainties and gaps that became apparent during the implementation of the risk assessment for a high number of submissions, additional guidance on what constitutes a risk assessment and how it should be performed is considered necessary,” said the plan authors.
Revision of ICH Q7 and updating EU chemistry guidelines are both seen as longer-range tasks to be completed in 3-5 years, but the plan has the ICH Q9 updates happening within 1-3 years. Other long-range tasks include involvement of the European Directorate for the Quality of Medicines & HealthCare in central management of testing and reference material sourcing, as well as implementing a stronger communication plan about the problem of nitrosamine impurities in pharmaceutical products.

In the short term, meaning within the next 12 months, EMA wants to see a strategic group convened immediately after a major incident comes to light, as has occurred with angiotensin II receptor blockers (the “sartans”) and the diabetes drug metformin. China and India – major exporters of APIs and finished drugs – are members of the International Coalition of Medicines Regulatory Authorities (ICMRA), so ICMRA should update its global crisis management procedures as well, according to the plan. (RELATED: CHMP: Test all metformin for nitrosamines before release, Regulatory Focus 19 October 2020)
Another short-term goal is bringing EMA together with international partners by including them in plenary meetings addressing major incidents of nitrosamine contamination, and to make sure all relevant parties are notified and involved in incident management, by means of establishing a unified Eudranet mailbox.
Over the next year, the plan also recommends training for assessors to make sure that recommendations for controlling impurities are taken into account in the review of authorization or variation applications.
A detailed question-and-answer document is forthcoming within the next 12 months to provide information about potential sources of nitrosamine impurities, as well as other substances within the cohort of concern.
Implementation plan
Reporting templates


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