Module 3 - Strategic case studies in practice

manufacturing practice, is considered principally avoidable by eliminating nitrocellulose as the responsible nitrosating agent in the lidding foil. This case demonstrates once again the need for thorough risk assessment on impurities such as CoC compounds within pharmaceutical process development. Overall, the interactions between starting materials, intermediates, drug substances, solvents, reagents and catalysts should be thoroughly investigated during manufacturing process development, taking into account relevant ICH Guidance (Q3A, Q3C, Q3D, Q7, Q9, Q11, M7) and the EMA Guideline on the Chemistry of Active Substances. 7 Based on the above considerations and the feedback from QWP and the Ad-hoc expert group, the following strategies to mitigate the presence of N -nitrosamines in human medicinal products should be considered: • Strive for designing / adapting manufacturing processes to prevent the formation of or contamination with N- nitrosamines. • Risk assessment of route of synthesis, starting materials, intermediates, raw materials (solvents, reagents, catalysts, etc.) and finished product manufacturing process (raw materials, packaging etc.) in consideration of the potential and confirmed root causes for the formation and contamination of N- nitrosamines in API synthesis and in finished product as detailed in 2.2.2 and 2.2.3 above. • In case of identification and confirmation of any risk for the presence of N-nitrosamine through testing, a change of manufacturing process, starting materials and intermediates, raw materials or primary packaging in order to avoid use of nitrosating agents should be considered. • If combination of nitrosating agents with solvents, reagent and catalysts have been justified to be unavoidable in the entire process, adequate control measures should be implemented. This must be reflected in the control strategy of the API and finished product as appropriate. • The control point for nitrosamines should be selected in such a way that it will give assurance of presence of the impurity below the acceptable limit in the finished product. • ICH M7(R1) provides the option for skip testing, which can be applied also in the case of a single nitrosamine impurities, as long as it can be shown that levels of the single mutagenic impurity in the drug substance are consistently less than 30% of the ICHM7(R1) limit for the respective N-nitrosamine, and provided the root cause of a detected nitrosamine is well-known and well-controlled as advised by QWP. • CHMP further agreed with the 2 nd QWP response that to justify omission from the specification, it has to be demonstrated that the level of the respective single nitrosamine is consistently at or below 10 % of the ICH M7(R1) limit, and the LOQ will need to be set at least this level. (Of note, levels below 10% of the limit would translate into a theoretical excess life time cancer risk of less than 1:1,000,000)

7 https://www.ema.europa.eu/en/chemistry-active-substances-chemistry-new-active-substances

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