Large‐Scale Synthesis

The capability to fulfill drug substance requirements to support the various elements of pharmaceutical development is an essential component of the overall drug development process. The preparation of bulk materials for toxicology, formulation development, and clinical supplies can represent a significant challenge, depending on such factors as the molecular complexity of the drug candidate, the quantities of materials required, and the state of development of the synthetic process. As a drug candidate proceeds through the various stages of drug development and into commercial launch, the challenge of process development is to ensure the uninterrupted supply of drug substance without compromising the ability to ultimately supply a commercially viable chemical process. This chapter provides a general overview of the issues and requirements associated with the development and scale-up of chemical processes for bulk active drug substances. An account of the nevirapine process development efforts at Boehringer Ingelheim is also provided as an example of the evolution of a chemical process from the initial efforts in medicinal chemistry to commercial-scale operations. Keywords: active pharmaceutical ingredients; drug development process; in-process controls; process chemist; process development