Module 3 - Strategic case studies in practice

manufacturing of medicinal products would further substantially vary between operators, leading to different limits for each medicinal product and for the same product across the EU that would not be acceptable from a public health point of view. As the numerator of this ratio differs for each product of each MAH, harmonisation of the limits defined based on this approach cannot be achieved. Lastly, this ratio depends on economic factors that by nature are very volatile and may therefore lead to frequent changes in limits, which would create a substantial unpredictability in the limits fixed. Furthermore, no clear benefit is expected as the difference in theoretical excess cancer risk between the ALARA/ALARP vs. the approach defined in sections 2.5.1 and 2.5.2 is considered to be negligible, owing to the little numerical difference between the limits set by these two approaches. For all these reasons, CHMP decided to recommend the approach defined in sections 2.5.1 and 2.5.2 for setting limits for nitrosamines, i.e. based on toxicological considerations as outlined in the internationally agreed ICH Guideline M7(R1) on mutagenic impurities. This approach is considered sufficiently conservative from the safety point of view. Of note, the ICH M7(R1) allows for additional risk management approaches where appropriate. Assessment of human risk stemming from potent nitrosamines such as NDMA and NDEA (classified as probable human carcinogens) is very difficult because exposure levels are far below those than can be experimentally tested and verified in animal studies and available field studies (e.g. epidemiological studies) are inconclusive. There is no empirical way to determine the actual risk from nitrosamine impurities in pharmaceuticals in relation to the background nitrosamine exposure levels (neither for specific nitrosamines such as NDMA or the total sum of nitrosamines) and to quantify the difference in risk when using ALARP approach vs. approach defined in sections 2.5.1 and 2.5.2. There has been some support for using ALARP approach, including from QWP, SWP, ad-hoc expert group, in this referral procedure based on a precautionary principle approach to reduce as much as possible the amount of nitrosamines in medicines. Having considered that applying the ALARP approach for manufacturing of medicinal products for setting limits may in particular not lead to sufficiently clear and predictable limits, and the absence of clear benefit of this approach in terms of risk reduction, the CHMP concluded that this approach is not adequate for setting limits for N-nitrosamines in medicinal products and that the approach as per ICH M7(R1)for CoC substances is sufficiently conservative to ensure patient safety and allows the setting of clear and predictable limits.

2.5.4. Comparison of different options for setting limits

The advantages and disadvantages of the various options for setting limits of N-nitrosamines as considered by CHMP are summarized in the table 2.5.4-1 below. Table 2.5.4-1 Advantages and disadvantages of different regulatory approaches for setting nitrosamine limits:

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