End-to-End Continuous Small-Scale Drug Substance Manufacturing: From a Continuous In Situ Nucleator to Free-Flowing Crystalline Particles

In the evolving landscape of pharmaceutical manufacturing, a comprehensive continuous production process is being crafted for the small-scale production of active pharmaceutical ingredients. This study focuses on continuous crystallization with separate nucleation and crystal growth units, as well as continuous downstream processing, encompassing filtration, washing, and drying until the formation of free-flowing particles. We introduce a novel continuous nucleator designed based on solubility data and produced via 3D printing, enabling the fast and precise small-scale manufacturing of a nucleator meeting the requirements for nucleation and further growth processes. The nucleator is evaluated with regard to its suitability for continuous long-term operation across various coupled crystallizers. As a practical application example, it is connected to a slug flow crystallizer to enable high-quality continuous crystallization. Additionally, the full integration of downstream processes using a continuous vacuum screw filter to achieve free-flowing product particles is realized. Even under non-optimized process conditions, with the help of the in situ generation of nuclei, free-flowing product particles are successfully obtained. This is particularly useful during drug development when no material is available for seed addition and to quickly obtain products for further characterization.