Questions and Answers on the 'Guideline on the Limits of Genotoxic Impurities'

The Euopean Medicine Agency published a questions and answers document on the Guideline on the limits of genotoxic impurities. The document was adopted by the CHMP on September 23, 2010.

The aim of this question-and-answer document is to provide clarification and harmonisation of the 'Guideline on the limits of genotoxic impurities' (EMEA/CHMP/QWP/251344/2006), published in 2006. In total 8 Questions will be answered in the Q and A document.

In the following you will find two question and answers taken from the document:

Question 1. The guideline does not need to be applied retrospectively to authorised products unless there is a specific cause for concern. What might constitute "a cause-for-concern" in terms of application to currently marketed products?

If a manufacturing procedure for API remains essentially unchanged a re-evaluation with respect to the presence of potentially genotoxic impurities is generally not needed. However, new knowledge may indicate a previously unknown cause for concern. One example is the mesylate salt drug substances for which a few years ago, a concern regarding the potential for formation of genotoxic alkyl mesylates was raised. This concern resulted in the "Production Statement" requesting a specific evaluation of the potential for formation of these highly toxic products now included as part of the PhEur monographs for all the mesylates salts.

Question 4. What would be an appropriate strategy to qualify a new impurity that arises during Phase III or with a commercial product? For example, would it be acceptable that a new unidentified impurity, discovered at the 0.05-0.09% range requires no action to be taken? Would an impurity discovered in the 0.10 to 0.15%, even if it triggers a structural alert, be fully qualified by testing the active ingredient containing this impurity in an Ames test?

In line with the ICH guideline, no action is generally required for a new unidentified impurity found at levels below the ICH identification threshold. When an impurity is found above the ICH identification threshold, but below the qualification threshold, and the structure gives rise to a structural alert, this can be negated by carrying out an Ames test on the active ingredient containing the impurity as long as the impurity is present at a minimum concentration of 250 ?g/plate (estimated detection limit for most relevant mutagens in Ames test, see Kenyon et al., Reg Tox & Pharm, 2007, 75-86). If the structure cannot be elucidated, then no action is generally required. Above the ICH qualification threshold, then the ICH guidance should be followed.

Here you can read all question and answers on the 'Guideline on the limits of genotoxic impurities'

Source: EMA Webpage

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