Abstract
Mutagenic impurities (MIs) are of serious concern for pharmaceutical industry, regulatory agencies and public health. The first guideline addressing the control of genotoxic impurities (GTIs) dates back to 2006. Since then there have been several updates and refinements, which eventually resulted in the guideline, published by the International Conference on Harmonisation (ICH) in June 2014. The ICH M7 guideline, compared to previous ones, offers greater flexibility in terms of control strategies for GTIs in drug substances. More specifically, it describes a control strategy that relies on process controls in lieu of analytical testing which is based on understanding the process chemistry and process parameters that impact the levels of GTIs. This principle is adopted in the theoretical purge factor determination tool proposed by Teasdale et al. Several case studies applying the proposed theoretical purge factor determination tool were published in recent years. The results confirm the tool's good predictability of the extent to which the impurity is removed by the process. Hopefully, this approach will soon be released as an in-silico tool, generally accepted by the regulatory agencies.
Highlights
The need to investigate the potential genotoxicity of drugs resulted from several incidents in the past and is nowadays a serious matter of concern for pharmaceutical industry
It describes a control strategy that relies on process controls in lieu of analytical testing which is based on understanding the process chemistry and process parameters that impact the levels of genotoxic impurities (GTIs)
According to the definition given in the International Conference on Harmonisation (ICH) M7 guideline,[1] genotoxicity refers to any deleterious change in the genetic material regardless of the mechanism by which the change is induced, whereas the term mutagen refers to a substance that induces mutation which is a heritable change in cells or organisms.[2]
Summary
The need to investigate the potential genotoxicity of drugs resulted from several incidents in the past and is nowadays a serious matter of concern for pharmaceutical industry. Genotoxic impurities (GTIs) in drug substances are mainly the consequence of using electrophilic reagents for building up the molecular structure If they don’t react completely, they can persist in the reaction mixture and may be carried onward in the synthesis. Due to their high reactivity they can react with the DNA and potentially induce genetic mutations. For this reason regulatory agencies established standards which assure that unavoidable impurities are limited to have no or acceptable levels of risk.[3] Identification and control of potential mutagenic/genotoxic impurities in drug substances or drug products is still a challenging task for pharmaceutical companies. Lines will be presented in this review article, together with identification and control strategies, especially the theoretical purge factor determination approach and its practical application
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