Module 3 - Strategic case studies in practice

Regulatory Approach

Pros

Cons

Limit based on analytical capability

Does not take into account toxicological data, only based on analytical capability Analytical limits may be different for different nitrosamines Leads to different actual exposures depending on the daily dose of the medicinal product. For high daily doses, the technical limit could be above the limit based on ICH M7(R1) approach. If strictly applied, it may lead to unnecessary drug shortage creating public health issues for critical products whereas the difference in theoretical excess cancer risk versus ICH M7 (R1) approach is negligible. Limit may not be sufficiently predictable, as state-of-the art methodologies evolve and lower analytical limits for a given API/product may be achieved. Limits based on ICH M7 (R1) are usually higher than analytical limits (unless a medicinal product has a large maximum daily dose).

• Leads to lowest technically possible limit (and usually

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lower than those based on ICH M7 (R1) approach, depending on the maximum daily dose)

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• Enables classification of nitrosamines as non-

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acceptable impurities to be avoided unless justified sufficiently, similar to the ICH Q3C approach. In addition, future classification of other cohort of concern compounds as acceptable impurities in medicinal products is prevented.

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Limit based on ICH M7(R1) methodology

Based on toxicology data with limits corresponding to the same

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level of theoretical risk. • Based on a lifetime of

exposure estimate (70 years).

• conservative linear risk

extrapolation and potency handled by compound specific thresholds based on carcinogenicity data & adequate extrapolation to humans • Allows to take into account the actual exposure (daily amount

EMA/369136/2020

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