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George Johnson1, Angela White2, Julia Kenny2, and Jim Harvey2
1Institute of Life Science, Swansea University Medical School, SA2 8PP
2GSK R&D, Park Road, Ware, Hertfordshire, SG12 0DP, United Kingdom
The international committee on harmonisation (ICH) have produced the M7 guideline for how genotoxic impurities should be tested and assessed. If during these assessments, a ‘positive’ response is detected and the threshold for toxicological concern (TTC) exceeded, then there is an option to define a permitted daily exposure (PDE). This is carried out by defining a point of departure (PoD) from the in vivo dose response data. The recommendation is to use the no observed effect level (NOEL) as the PoD, however, there is potential to do this using the benchmark dose approach instead. Through a series of case studies, the BMD approach will be shown to perform well on various data sets, and in numerous different scenarios with the advantages discussed.
Potential Genotoxic impurities (PGTIs) in pharmaceuticals at trace levels are of increasing concerns to both pharmaceutical industries and regulatory body due to their potentials for human carcinogenesis. Determination of these genotoxic impurities at ppm or ppt levels requires highly sensitive analytical methodologies, which poses tremendous challenges on analytical communities in pharmaceutical Research and development. Practical guidance with respect to the analytical determination of diverse classes of PGTIs is currently lacking in the literature.