On October 10th, 2022, European Medicines Agency (EMA) published revised document Questions and answers for marketing authorisation holders/applicants on the CHMP Opinion for the Article 5(3) of Regulation (EC) No 726/2004 referral on nitrosamine impurities in human medicinal products (EMA/409815/2020, revision 12).
The assessment report of the CHMP’s Article 5(3) of Regulation (EC) No 726/2004 opinion on nitrosamine impurities in human medicinal products provides general guidance and recommendations on mitigating and preventing the presence of nitrosamines in human medicinal products. In this context all MAHs/Applicants of human medicinal products should work with the manufacturers of their active pharmaceutical ingredients (APIs) and finished products (FPs) to ensure that the presence of nitrosamine impurities in their medicinal products is mitigated as much as possible and controlled at or below a limit defined based on ICH guideline M7(R1) principles (Guideline on assessment and control of DNA reactive (mutagenic) impurities in pharmaceuticals to limit potential carcinogenic risk) for substances of the “cohort of concern” reflected in this guideline and calculated considering a lifetime daily exposure and kept as low as possible and that appropriate risk mitigating measures are taken.
The updated version of Q&A document covers the following questions:
- which limits apply for nitrosamines in medicinal products
ICH M7(R1) guideline defines N-nitrosamines as substances of the “cohort of concern” for which limits in medicinal products refer to the so-called substance-specific acceptable intake (AI) (the threshold of toxicological concern (TTC), value of 1.5 ug/day cannot be applied) which is associated with a negligible risk (theoretical excess cancer risk of < 1 in 100,000 over a lifetime of exposure). The calculation of AI assumes a lifelong daily administration of the maximum daily dose of the medicinal product and is based on the approach outlined in the ICH M7(R1) guideline as well as the principles described in relation to the toxicological evaluation in the assessment report of the CHMP’s Article 5 opinion on nitrosamine impurities in human medicinal products. The ‘less than lifetime’ (LTL) approach should not be applied in calculating the limits as described above. For products intended for advanced cancer only as defined in the scope of the ICH S9 guideline, N- nitrosamine impurities should be controlled according to ICH Q3A(R2) (Impurities in new drug substances) and ICH Q3B(R2) (Impurities in new drug products) guidelines, as specified in the Q&A document to ICH S9 guideline (nonclinical evaluation for anticancer pharmaceuticals – questions and answers). If the active substance itself is mutagenic or clastogenic at therapeutic concentrations, N-nitrosamine impurities should be controlled at limits for non-mutagenic impurities according to ICH M7(R1).
- what is the approach to control the presence of nitrosamines until a substance specific AI is established
If N-nitrosamines are identified without sufficient #carcinogenicity data to derive a substance-specific limit for lifetime exposure as recommended in ICH M7(R1) guideline, and the class specific TTC for nitrosamines of 18 ng/day is not used for controlling the levels of the nitrosamine in the finished product. To protect public health, to inform decisions on required market actions while ensuring at the same time availability of medicines while a formal AI is established, a temporary AI (t-AI) of 178 ng/day (total nitrosamines) can be adopted by the relevant authorities for marketed medicines identified to contain one or more nitrosamines exceeding the TTC of 18 ng/day. It is expected that the t-AI would be used for a period of less than 12 months, as an exposure over this period is not expected to increase the theoretical overall lifetime risk above 1:100,000.