(495a) The Path from Batch to Continuous Manufacturing: An Industrial Application to a Diastereomeric Crystallization

Pharmaceutical continuous manufacturing paradigm has been transforming the mindset in drug substance process development and optimization for synthesis route scouting, separation, and purification, etc. [1]. For example, advantages and performance improvement in continuous crystallization have been widely acknowledged, while, with limited open industrial applications reported in a holistic view for the development of a continuous manufacturing process of drug substances [2]. In this work, a diastereomeric crystallization, which is one of the bedrock unit operations in optimizing a four-step batch-wise synthesis route into a two-step continuous flow synthesis, was re-designed and transferred from batch to continuous operation in a two-stage cascaded MSMPR crystallization, involving neutralization of API crude salt to its free base and antisolvent addition. Challenges and strategies in (1) pH control in neutralization to avoid the further protonation of API free base and (2) antisolvent composition control to mitigate the crystallization of a diastereomeric impurity (NMT 1.6 wt%) will be discussed. Product and process understanding combined with active process control was highlighted in this work [3], wherein mathematical models were deployed to balance the yield and diastereomeric purity, as well as to de-risk variations in API crude salt purity. Additionally, a Dynochem salt dissociation model was also employed to estimate the pKa values of the API and key acidic impurities. Furthermore, a gPROMS flowsheet simulation of the continuous crystallization process was also developed to predict the dynamic response of the integrated continuous manufacturing process, such as the variations in diastereomeric impurity level of API crude salt. Finally, the thought-process in consolidating the crystallization process design and scale in an integrated continuous manufacturing line will be discussed and concluded.

References

[1] US Food and Drug Administration. Q13 Continuous manufacturing of Drug Substances and Drug Product. Guidance for Industry. March 2023.

[2] Eren A, Civati F, Ma W, Gamekkanda JC, Myerson AS, Continuous crystallization and its potential use in drug substance Manufacture: A review. Journal of Crystal Growth. 2023; 601:126958.

[3] Su Q, Ganesh S, Moreno M, Bommireddy Y, Gonzalez M, Reklaitis GV, Nagy ZK. A perspective on Quality-by-Control (QbC) in pharmaceutical continuous manufacturing. Computers & Chemical Engineering. 2019; 125: 216-231.