Safety genotoxic impurities

A final challenge for early screening is the detection of genotoxic impurities and synthetic intermediates which can create occupational/manufacturing as well as patient safety issues. This again is a complex issue because the material screened from a library might be synthesized and purified by different routes to a drug that enters the clinic. These issues are addressed in a later section. 

CHMP (2008). CHMP Safety Working Party (SWP) Question Answers on the CHMP Guideline on limits of genotoxic impurities. London, 26 June 2008, Doc. Ref. EMEA/CHMP/SWP/431994/2007 Revision 1, http //www.emea.europa.eu/pdfs/human/swp/43199407en.pdf, 1-3. 

PhRMA published a draft position paper proposing a classification system for genotoxic impurities and associated limits during each phase of development based on the level of risk these impurities may pose on the safety of subjects participating in clinical trials. This staged TTC concept was also recommended for establishing limits for conunercial products. 

Concerns over the safety of tiny amounts of potential genotoxic impurities in APIs were driven by major advances in analytical instrumentation that allow detection of these impurities at parts per million levels. 

The issue of potential genotoxic impurities (PGIs) in active pharmaceutical ingredients (APIs) and drug products continues to receive considerable attention. Alkyl halides are well-known to be potentially genotoxic and are, hence, a safety concern in medicinal chemistry. ... 

ICH guideline to ensure the safety of the product. See the Chapter 4 by Parsons and Miller for further discussion on the subject of genotoxic impurities. 

Results of acute, short-term and long-term toxicity studies, reproduction studies, developmental studies, genotoxicity studies, and studies of the toxicity of metabolites and impurities, and other adverse effects. Data on human toxicology, the no observable effect level, acceptable daily intake, and proposed and safety directions... 

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