Crystallization of 204 kg of final active pharmaceutical ingredient was accomplished continuously using a cascade of mixed suspension mixed product removal crystallizers in cGMP manufacturing. This article describes the journey taken to transform a set of technical to final batch crystallizations into a continuous, combined cooling and antisolvent crystallization using three stirred tank crystallizers in series. Conversion of the batch process to a continuous process was beneficial to kinetically purge a key impurity. The conversion also allowed for the direct integration of the crystallization process with upstream continuous chemistry sections. A robust control strategy was developed from early Research Article scale all the way to cGMP manufacturing. The authors will share the tools, techniques, modeling, and equipment used and challenges overcome to ensure a safe and reliable manufacturing process. A new intermittent flow technique transferred hot solution from a continuous evaporator into the first crystallizer with no solids bearding at the end of the inlet tubing. The continuous distillation, crystallization, and slurry-off filters were a key part of a broader continuous process and new building that won an International Society for Pharmaceutical Engineering 2019 Facility of the Year Award for Innovation.

• Eli Lilly & Co
• Eli Lilly Kinsale
• D&M Continuous Solutions LLC

• API
• Modeling

1. API
2. cGMP manufacturing
3. Continuous crystallization
4. continuous distillation
5. Control strategy
6. cooling and antisolvent
7. encrustation
8. form control
9. kinetic impurity rejection
10. kinetics modeling
11. microscopy
12. modeling
13. MSMPR
14. particle size distribution
15. population balance
16. Research Article
17. residence time distribution
18. Scale-up
19. solids fouling
20. startup and shutdown
21. Supersaturation