Module 3 - Strategic case studies in practice

The technical long-term limit for NDMA and NDEA in the API set for sartans was considered feasible by CHMP since the source of N -nitrosamine impurities was identified in the active substance manufacturing process and thought to be avoidable by introducing reasonable changes. Having considered the knowledge acquired on the presence of nitrosamines in medicinal products since the sartans referral and taking into account the data assessed within the current review, in particular related to the root causes where it became clear that the root causes can be numerous, concomitant, at any stage of the production or storage of the medicinal product and cannot always be characterised, the CHMP considered that the outcome of the sartan referral should be reconsidered in light of the outcome of this Art. 5(3) referral. However, it is not within the competence of the CHMP to make changes to a legally binding decision. Instead CHMP invites the European Medicines Agency to inform the European Commission about these considerations. 3. Expert consultations The ad-hoc expert group meeting took place on Feb 27 th and 28 th 2020 at the EMA. An extensive list of questions regarding the five topics most important for pharmaceutical quality, control of pharmaceutical quality, exposure to N-nitrosamines, cancer risk and risk assessment of nitrosamines was issued to the experts several weeks before the meeting. A summary of the conclusions of the expert group to the topics is provided here. The full meeting minutes with all questions and detailed answers is provided as Annex 1. Chemistry The experts consider the root-causes identified and confirmed so far plausible but emphasize that it would be beneficial to have more details from companies in general, outlining the rationale for their conclusions. Additional potential root causes for N-nitrosamine contamination of API and drug product have been proposed by the experts. Most of the additional root-causes are based on theoretical considerations and might affect either drug substance or drug product. The experts confirmed that polar aprotic solvents such as Dimethylformamide (DMF), Dimethylacetamide (DMAc) and N-Methyl-2-pyrrolidone (NMP) bear a risk of nitrosamine formation and they recommend avoiding these, if possible. Nitroalkanes such as Nitromethane are also known nitrosating agents. Furthermore, appropriate measures are recommended in case these solvents/reagents are used and unavoidable. Furthermore, experts considered how nitrosamine impurities can form in solid oral dosage forms when all components are ostensibly in the solid state. It was suggested that grinding surfaces together during e.g. granulation or compression could lead to reactions on surfaces. This could be investigated by applying pressure and can be followed by IR or x-ray crystallography. Alternatively, adding a small amount of water to a granulation process could result in relatively high local concentrations of nitrites which are highly soluble, thus leading to rapid reactions with nitrosatable amines, if present. It was also highlighted that exposure of the drug product to heat during e.g. formulation, storage and shipping might play a role in nitrosamine formation. 3.1. Ad-hoc expert group

EMA/369136/2020

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