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

Article
Continuous flow
Drug substance
Process development

In this article, we describe our work with Amgen on 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 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. To solve for these challenges, we developed a continuous process to facilitate the rapid base addition and short deprotonation residence time, ensuring reliable process performance on a multi-kilogram scale.

As a result, 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. In addition, we discuss lessons learned from the manufacturing campaign, which include equipment clogging and loss of tubing integrity, which drove the development of a second-generation continuous process to improve reaction processing for future deliveries. The second-generation process has not encountered the same challenges of the GMP campaign due to the implementation of important equipment modifications, and the improved process has been successfully demonstrated on a 100g scale.

Read the entire article, “Implementing Continuous Manufacturing for the Final Methylation Step in the AMG 397 Process to Deliver Key Quality Attributes,” to learn how our team helped Amgen deliver high yield and purity of AMG 397 using a continuous manufacturing process.

View the full article (via ACS Publications)