Final ICH M7 Guideline on Genotoxic Impurities published

On on 15 July 2014, the ICH issued the guideline M7 "Assessment and Control of DNA reactive (mutagenic) Impurities in Pharmaceuticals to limit Potential Carcinogenic Risk" as Step 4 document. in In the last step of the ICH process (Step 5) this guideline now has to be implemented in the national regulations in the three ICH regions Europe, United States and Japan. The final M7 Guideline was published exactly 17 months after the release of the draft consensus guideline (Step 2) in February 2013, where it could be commented in a 6-month period.

The guideline comprises information, how impurities in pharmaceutical products relative to their genotoxic potential have to be evaluated with the analysis of structure-activity relationships and how the critical toxicological threshold (threshold of toxicological concern TTC) has to be determined. In the individual chapters, some highly complex issues and scenarios are covered - as, for instance, the question why potentially genotoxic substances with similar molecular structure and probably the same mechanism of action should still not be combined for the calculation of the TTC. Another problem the Guideline tries to clarify is the different values of the TTC, depending on the duration of the use of the medicinal product.

The last section of the document contains a statement of the ICH, that due to its complexity the guideline has to be implemented in the respective national rules and regulations after 18 months only. However, the following exceptions apply to some requests:

  • For the implementation of Ames tests the specifications of M7 have to be applied immediately. However, the Ames tests carried out before release of M7 need not be repeated. 
  • The development programmes having started phase 2b/3 prior to publication of M7 can be continued. The requirements for the execution of two quantitative analyses of structure-activity relations (section 6), for impurity assessment (section 5) and for the documentation (section 9) do not have to be considered, though. 
  • For a new marketing authorisation application which does not include the phase 2b/3 clinical trials, compliance with the aforementioned points is expected until 36 months after the publication of M7. 

Compared to the previous Guideline version (Step 2) it now contains changes, clarifications and precisions in several parts. For a more detailed analysis of the new M7 Guideline please see one of our next newsletters.

The ECA will conduct the Impurities Forum 2014in Berlin, where a complete day will be dedicated to the implementation of Genotoxic Impurities ICH M7. On another day you will cover the implementation of Elemental Impurities ICH Q3D - whose finalisation is scheduled for September. The days can be booked separately or alternatively the entire 3 days of the Impurities Forum.

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