Manufacturing Development and Genotoxic Impurity Control Strategy of the Hedgehog Pathway Inhibitor Vismodegib

The development work toward the robust and efficient manufacturing process to vismodegib, the active pharmaceutical ingredient (API) in Erivedge, is described. The optimization of the four-stage manufacturing process was designed to produce the API with the required critical quality attributes: (1) the selective catalytic hydrogenation reduction of the nitro compound 3 to the corresponding aniline 4 while minimizing the formation of potential genotoxic (mutagenic) impurities; (2) the control of the polymorphic phase and multipoint specification for particle size distribution.