API Process Development and Scale-up challenges en route to Validation

Process development has been underway for a late stage small molecule drug substance (Active Pharmaceutical Ingredient (API)) program, not only to improve overall efficiency and yield but also to identify potential process risks such as mixing sensitivities, solid settling, and reaction stability at scale. In preparation for the program’s first commercial scale campaign, efforts to mitigate risk through process modeling and experimentation were carried out. True to form, unforeseen challenges arose during batch execution. For example, one issue was that heat transfer expectations from modeling did not agree with observed batch performance as processing parameters were outside of any stressed conditions tested, which threatened the batch purity. As the program moves toward validation, the technology transfer process to the commercialization site has introduced its own set of challenges that required further development to address differences in site environmental requirements and operating procedures.