ICH publishes New Draft Guideline on Genotoxic Impurities

The ICH has published a draft guideline for comment on the determination and the control of DNA reactive (mutagenic) impurities in medicinal products. The guideline is entitled: "M7: Assessment and Control of DNA Reactive (Mutagenic) Impurities in Pharmaceuticals to Limit Potential Carcinogenic Risk".

Guidelines on genotoxic impurities already exist. For example:

Unfortunately, all these regulations are inconsistent. They partly describe different approaches to the assessment of the genotoxic potential of impurities, or only give unprecise recommendations. There exists no regulation of the topic in the Japanese economic area.

Facing this unsatisfactory situation, the ICH has elaborated a guideline which should provide support and concrete specifications, and - among other things - should clarifiy the following points:

  • The assessment of the structure-activity relationship (SAR) of molecules delivers information about its carcinogenic potential. The question is which methods should be used in which cases to assess a SAR?
  • Impurities with similar hazard potential also have similar chemical properties (e.g. DNA-reactivity) and similiar chemical reaction mechanisms. How should one consider and estimate these substances for the calculation of the threshold of toxicologigal concern (TTC)?
  • How far can the TTC value change with regard to different exposures and should be thus respectively recalculated?
  • To what extent must already existing medicinal products be reassessed if they are to be marketed in a new formulation (i.e. as a combination product)?

The draft guideline deals with these questions and gives recommendations to them. The topic of changes with regard to the API, the finished product and the clinical applications after post approval changes is mainly discussed. A detailed discussion about control strategies in the context of life-cycle management is also precisely described.

The scope of this guideline covers new APIs and medicinal products during their clinical development. In cases of post approval submissions the guideline can only be used where:

  • Changes to the drug substance synthesis result in new impurities or increased acceptance criteria for existing impurities,
  • Changes in the formulation, composition or manufacturing process result in new degradants or increased acceptance criteria for existing degradants,
  • Changes in indication or dosing regimen are made which significantly affect the acceptable cancer risk level.

The guideline doesn't apply to:

  • Biological or biotechnologically manufactured medicinal products
  • Peptides
  • Oligonucleotides
  • Radiopharmaceuticals
  • Fermentation products
  • Herbal products
  • Crude products of animal or plant origin

The draft of the "M7" Guideline was published for comment on 7 February 2013 on the ICH website as a "Step 2 Document". No consultation deadline has been determined yet.


Click here to access the guideline.

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