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Questions and Answers on Nitrosamine Impurities for Marketing Authorization

EMA Updates on nitrosamine impurities along with Questions and answers for marketing authorization holders/applicants. The update regards the following:

Which limits apply for nitrosamines in medicinal products? (updated)

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) and ICH Q3B(R2) guidelines, as specified in the Q&A document to ICH S9 guideline.

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? (new)

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 18ng/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 of time is not expected to increase the theoretical overall lifetime risk above 1:100,000.

Other Q&A on this topic include:

  • Should the risk of presence of nitrosamines be considered for all human medicinal products?
  • What is the ‘call for review’?
  • For the ‘call for review’ for chemically synthesised and biological medicinal products, when and how should MAHs report steps 1 and 2 to competent authorities?
  • What are the currently identified risk factors for presence of nitrosamines?
  • What factors should be considered in prioritising the risk evaluation?
  • How should the risk evaluation be performed?
  • What are the requirements of the analytical method(s)?
  • What should I do if a nitrosamine is detected in my medicinal product?
  • Which are the measures to mitigate the risk of presence of nitrosamines?

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