Kilogram-scale prexasertib monolactate monohydrate synthesis under continuous-flow CGMP conditions

Area of Science:

• Pharmaceutical Manufacturing
• Chemical Engineering
• Drug Development

Background:

• Pharmaceutical manufacturing is shifting from batch to continuous processing for potent and tailored therapeutics.
• Traditional batch processing presents challenges for manufacturing highly potent compounds.

Purpose of the Study:

• To develop and demonstrate a multistep continuous-flow current good manufacturing practices (CGMP) process for producing prexasertib monolactate monohydrate.
• To produce a sufficient quantity (24 kg) of the drug substance for human clinical trials.

Main Methods:

• Utilized eight continuous unit operations including reactors, extractors, evaporators, crystallizers, and filters.
• Operated the process in laboratory fume hoods at a rate of approximately 3 kg per day.
• Integrated advances in chemistry, engineering, analytical science, process modeling, and equipment design.

Main Results:

• Successfully produced 24 kilograms of prexasertib monolactate monohydrate suitable for clinical use.
• Achieved a production rate of approximately 3 kilograms per day.
• Demonstrated improved performance, safety, and containment compared to traditional batch processes.

Conclusions:

• A multistep continuous-flow CGMP process is feasible and effective for manufacturing potent pharmaceutical compounds like prexasertib.
• Continuous processing offers significant advantages in terms of efficiency, safety, and containment for drug manufacturing.
• The developed process supports the advancement of tailored therapeutics through scalable and safe manufacturing solutions.