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Are Current Genotoxic Impurity (GTI) Regulations Too Weak?

Genotoxic impurities were around long before humans first began boiling bark.  Our attempts to quantify, understand and control GTI formation, however, is a much more recent phenomena. It’s also a work in progress, and our knowledge of their potential impact continues to multiply.

When it comes to GTIs, the various teams working here at Neuland keep their ears to the ground. It’s an area in which we’re fairly experienced, and it’s also an area – as a complex chemistry synthesis provider – that stimulates both considerable discussion and some concern.

GTIs are broadly regulated by a variety of regulations and industry guidance including:

In the industry, a great deal of confusion has surfaced regarding contradictory standards and lack of clear guidance on emerging issues. Granted, genotoxic impurities have been the subject of furious research over the last ten years, so rapid change in guidance is to be expected as our understanding of GTI formation and clearance continues to expand and regulatory frameworks adjust and adapt to the growing body of knowledge.

Here are some of the thoughts and concerns that I’ve heard regarding the existing standards.

  • Consensus seems to be that the Threshold of Toxicological Concern (TTC) concept is strong, but concerns have also been expressed that the maximum daily exposure of 1.5 µg may be overly conservative.
  • Current guidelines don’t provide any clear guidance on GTIs found in clinical/investigational medicines, an area where some guidance would be helpful.
  • One particular circumstance that requires clarity: if more than a single potential genotoxic impurity is equally likely to be present, which should be used as the control?
  • Currently, there is no specific guidance on natural product-derived and herbal medicines.
  • Additional guidance on TTC limits for oncology products should be considered since typical lifetime exposure limits can be exceeded.
  • It was noted that manufacturing process changes made to existing and novel excipients could result in potentially higher risks.
  • No clear GTI analytical methodologies have been established for compound-specific genotoxicity and carcinogenicity.
  • There remain “causes for concern” for existing medicinal products or existing monographs.
  • The emergence of in-silico techniques for identifying structural alerts (versus the tradtional Ames test) is a testimony to the power of computing, but risk factors can arise with dataset reliability and accuracy.

Do you have any thoughts on how genotoxic impurity regulatory standards should be tightened? Share them in the comments.


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