This document is intended for applicants as a guide for compiling a dossier that is suitable for evaluation for a Certificate of Suitability (CEP) for chemical purity and microbiological quality. It applies to all substances described in the Ph. Eur. and that are within the scope of the Certification Procedure, for assessment of their quality.
Mutagenic impurities
In line with ICH M7 guideline, a specific discussion on potential mutagenic impurities should be provided as part of the overall discussion on impurities. It is expected that potential mutagenic impurities arising from the synthesis of the final substance and its starting material(s) as well as degradation products are listed and classified (class 1 to class 5) in the dossier as per ICH M7. Toxicological data in support of this classification should be provided, as needed. If a mutagenic impurity is liable to be present in the substance a control strategy in line with ICH M7 should be proposed. Only demonstrating absence of concerned impurities may not be sufficient to support compliance to ICH M7. In addition, the applicant is requested to provide in section 3.2.S.3.2 a comprehensive risk assessment to address possible formation of N-nitrosamine impurities in substances for human use. If a risk is identified, a suitable control strategy should be introduced. The risk evaluation should not only address risks related to the manufacturing process, but also those deriving from the introduction of materials used in themanufacturing process and other potential sources of contamination (e.g. starting materials, reagents, solvents, recovery of materials, equipment, degradation). Any risk concerning formation and carry-over of N- nitrosamines should be addressed taking into account the EMA Q&A document(EMA/409815/2020). In regard the substances for veterinary use only, the discussion on mutagenic impurities should be given in a similar way following the recommendations established in the Guideline on assessment and control of DNA reactive (mutagenic) impurities in veterinary medicinal products(EMA/CVMP/SWP/377245/2016).