(138e) Process Development and Characterization of an Acutely Hazardous Reaction through Data Rich Experimentation

Nemtabrutinib is an oral small molecule reversible inhibitor of Bruton’s tyrosine kinase for the treatment of chronic lymphocytic leukemia (CLL) and Non-Hodgkin’s Lymphoma. A key reaction engineering challenge in the synthesis of the isolated penultimate involved a reduction via an acutely toxic gaseous reagent. This presentation will focus on the process development and scale-up of this reaction to control a key impurity that has low rejection downstream in the active pharmaceutical ingredient (API). The multi-phasic reaction required pressurized operation to limit the formation of the reaction impurity. This and the hazardous nature of the reaction created challenges in obtaining detailed process understanding around the highly non-linear reaction profile. Data rich experimentation (DRE) techniques were leveraged to avoid altering the reactor headspace during sampling and to avoid exposure to hazards. The multi-stage reaction was characterized through these methods to understand the various factors impacting the reaction and the impurity generation rates. Through this enhanced process understanding, a robust process was implemented at manufacturing scale to consistently produce over 200 kilograms of quality drug substance intermediate across multiple batches.