A Continuous Process for Manufacturing Apremilast. Part II: Process Characterization to Establish a Parametric Control Strategy

This is Part II of a series on the development and characterization of an integrated continuous manufacturing (CM) process developed for the penultimate step in the synthesis of the drug substance Apremilast (Otezla). Part I gives the development history and highlights the achieved process intensification. Here, we describe the process characterization (PC) undertaken. In doing so, we point out aspects of characterization that are unique to an integrated CM process and give our strategy for navigating PC in this scenario. Moreover, we provide data that support a robust control strategy which relies on parametric control only (i.e., no in-process controls) followed by batch release of the produced Apremilast drug substance intermediate. Such a control strategy is advantageous as it minimizes divert-to-waste loss and operational costs.