Implementing Continuous Manufacturing for the Final Methylation Step in the AMG 397 Process to Deliver Key Quality Attributes

In this article, we describe the process development efforts to improve the final methylation step in the AMG 397 drug substance process, culminating in the execution of a Good Manufacturing Practice (GMP) continuous manufacturing process. During the development, batch kinetic studies and detailed NMR analysis of the final step identified that rapid base addition and the presence of stoichiometric water were critical to ensure consistent levels of reaction conversion and to obtain the desired active pharmaceutical ingredient (API) in high purity. As a result, a continuous process was developed to facilitate the rapid base addition and short deprotonation residence time, ensuring reliable process performance on a multi-kilogram scale. The AMG 397 GMP manufacture, comprised of the continuous reaction process and semi-batch isolation, delivered the final API in high purity (>99%) and yield (76%), exceeding the API specifications. The lessons learned from the manufacturing campaign, which include equipment clogging and loss of tubing integrity, are discussed and drove the development of a second-generation continuous process to improve reaction processing for future deliveries. The second-generation process has not encountered the challenges of the GMP campaign due tothe implementation of important equipment modifications, and the improved processhas been successfully demonstrated on a 100 g scale.