This concept paper addresses the need to review and update the guideline on the chemistry of active substances. This need was recognised in the report on “Lessons learnt from presence of N-nitrosamine impurities in sartan medicines” (LLE), which made recommendations to reduce the risk of N-nitrosamines being present in human medicines and to help the European medicines regulatory network be better prepared to manage future cases of unexpected impurities. While in the last few years, experience has predominantly been gained in the management and risk mitigation of N-nitrosamines, it is foreseen that (some of) the principles covered in revised guideline will apply to other ‘cohort of concern’ (CoC) impurities and also other potent toxins.
2. Problem statement
In 2018, the EU medicines regulatory network became aware of the presence of N-nitrosamine impurities in sartan active substances (APIs). Subsequently, N-nitrosamines have been detected in a significant number of other active substances. It appears that despite available guidance on how to assess and control mutagenic and potentially mutagenic impurities, the risk of formation of N-nitrosamine impurities was not adequately considered during development, manufacture and evaluation of active substances. The guideline ‘Chemistry of active substances’ has been identified in the LLE report as one of the most important guidelines to be revised to include further recommendations on prevention, risk mitigation and control of N-nitrosamines, other CoC impurities and also other potent toxins.
3. Discussion (on the problem statement)
The following aspects will be taken into account for the revision of the guideline on the chemistry of active substances to further define the requirements in regulatory submissions, with reference to the EMA/CMDh questions-and-answers document on N-nitrosamines and the LLE report:
The Quality Working Party (QWP) recommends revising the guideline on the chemistry of active substances taking into account the issues identified in the sartans LLE report as well as learnings from the ongoing ‘call for review’. The revision will clarify the requirements for all applications regarding active substances and will bring the guidance up to date with recent developments and knowledge gained on formation of N-nitrosamines and implementation of adequate risk mitigation measures. In addition to N-nitrosamines specifically, the updated guidance will be relevant also for other compounds belonging to the cohort of concern as well as other potent toxins more generally.
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