FDA issues new Draft Guidance regarding "Genotoxic and Carcinogenic Impurities in Drug Substances and Products"

In December 2008 the US Food & Drug Administration (FDA) issued a new document with recommendations regarding limits for genotoxic and carcinogenic impurities in drug substances and products in clinical trials and after the authorisation was granted. This draft guidance contains precise proposals for the qualification of these impurities with respect to their carcinogenic risk. It is intended as an addition to the ICH guidelines Q3A, Q3B and Q3C comprising rather general requirements. The EMEA Guideline regarding genotoxic impurities, which was issued in 2006, also allows a maximum value of 1,5 µg genotoxic impurities per daily dose - without differentiating more in detail.

The FDA guidance draft refers to the threshold approach and basically suggests three ways for characterising and reducing genotoxic and carcinogenic impurities:

  • "Changing the synthetic and/or purification routes to minimize the formation and/or maximize the removal of the relevant impurity.
  • Allowing a maximum daily exposure target of 1.5 µg per day for the relevant impurity as a general target for marketed products, though higher levels may be acceptable during clinical development. Certain impurities with structural alerts suggesting particularly high genotoxic and carcinogenic potential would not be appropriate for this general threshold approach and would need to be evaluated on a case-by-case basis.
  • Further characterizing the genotoxic and carcinogenic risk via mechanism of action or weight-of-evidence approaches, or through additional studies to better support appropriate impurity specifications."

The following chapters of the guidance comprise

  • proposals for the duration of exposure to genotoxic and carcinogenic impurities in connection with different concentrations during a clinical trial
  • recommendations for the characterisation and reduction of impurities for the various development phases
  • a decision tree flow diagram for actions to take when genotoxic and carcinogenic impurities were found.

You can find the Draft Guidance for Industry here.

The handling of genotoxic impurities is also one of the issues discussed during the ECA Education Course "Impurities" in Prague, Czech Republic, from 13-15 May 2009.

Prepared by:
Dr Gerhard Becker
On behalf of the European Compliance Academy (ECA)

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