Metric-Driven Process Development of a Late Stage Drug Substance

Batch chemical manufacture of a pharmaceutical intermediate typically includes three common elements: reaction, work-up, and isolation. At the start of development, resources are often divided among these elements to enable work in parallel. While such practice allows investigations to proceed quickly, there is a risk that choices made for each element are not necessarily optimal for processing nor environmentally sound when examining the process in its entirety. This occurs because the criterion for a successful reaction differs for work-up and isolation. For example, consider solvent selection. It is often desirable to choose a solvent system that affords homogenous reaction conditions, becomes immiscible during work-up to remove water-soluble waste, and ultimately proves insoluble for the product yet highly soluble for impurities. This presentation will contextualize these challenges and share experimental practices through a case study of a process to synthesize a late-stage active pharmaceutical ingredient (API). The process described was constrained to deliver a specific crystal form and of course meet the general criteria of high impurity purge and high yield. Material properties of the API – a BCS Class I material – as well as of the reagents further challenged development by requiring a thorough understanding of the impact of both pH and the presence of water. A combination of automated and manual experiments streamlined work and serves as a platform for future development. Several metrics such as greenness, cost, overall cycle time, and process mass intensity were used to evaluate the options and guide development decisions.