Module 3 - Strategic case studies in practice

reduce nitrosamines) are susceptible to frequent changes.

• Implementation of a

harmonized approach across the EU not feasible as based on subjective criteria. • Time- and resource consuming with difference in theoretical excess cancer risk versus ICH M7 approach being negligible • The overall probability of being exposed to two or more nitrosamine-contaminated products at the same time is not possible to estimate, as well as the average level of contamination • Additional factor would be arbitrary and not evidence- based and scientifically justified • In products especially with short treatment durations and high daily doses, LTL-adjusted limits may be many-fold higher than limits calculated for lifetime exposure and may acutely overwhelm the repair capacity of human DNA. • Relies on strict linearity of the

Factor to address Polypharmacy

• Additional factor could ensure excess cancer risk to remain < 1:100.000) in case of exposure to multiple products contaminated with nitrosamines • Lowers the risk for patients potentially more vulnerable • Keeps excess lifetime cancer risk 1:100.000 proportionate to the treatment duration • Consistent with ICH M7 (R1) as it is based on the theory underlying the linear extrapolation calculations used for AI estimates.

Less than lifetime (LTL)

dose response even in the higher dose ranges, which is unproven.

Taking into account all arguments above , CHMP agreed that implementation of limits for N- nitrosamines in medicinal products based on ICH M7 principles for substances of the “cohort of concern” and calculated considering a lifetime daily exposure would provide the most appropriate and science-based approach that would also be consistent with the general handling of mutagenic impurities according to ICH M7(R1) and would also allow for the protection of public health. Indeed, this approach is considered sufficiently conservative to protect public health, especially with the additional safe-guard of not allowing a less-than-lifetime approach that could theoretically lead to high acute exposure to nitrosamines from medicinal products used for only short periods of time.

EMA/369136/2020

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