(555d) The Use of a Morphological Population Balance to Develop a Quality By Digital Design Approach for Crystallisation Processes

In this presentation, UCB’s roadmap for the development of a Quality by Digital Design (QbDD) approach is described, in the context of a therapeutic project. This trip includes the development of a strategy of the calibration of a morphological population balance, in the context of process-specific considerations related with the solubility curve, nucleation and attrition. Based on this, a model-driven QbD approach for crystallisation process design was created. The analysis conducted to determine the relevant sweet-spot regions and operating windows was quite informative, regarding the process robustness. It provided useful conclusions on the nucleation control and seeding strategies required for the development of crystallisation processes reconciling particle properties (size, morphology, span) simultaneously, while ensuring process yield and cycle time.

The results are quite revealing. Even for growth dominated processes, reconciling all the particle properties requires very high seed loadings, as the control space is really tight. Otherwise, the system will move out of this tight space, leading to sub-optimum product quality control. Considering the high seed loading, undesired for process industrialisation, it becomes evident that a transition to control nucleation strategies is key for the development of crystallisations, tightly controlling particle properties.

This is a pioneering study, demonstrating, for the first time, a systematic calibration strategy for morphological population balances. Furthermore, it describes a workflow for the utilisation of such a population balance, for the development of QbD approaches. Finally, interesting conclusions for future research directions are extracted.