(158g) Integration of Continuous Filtration and Drying with a Material Attribute Control Strategy Enabling the Continuous Drying of a Monohydrate Product

The development of control strategy is one of the regulatory considerations when implementing continuous manufacturing in the pharmaceutical industry¹. Unlike batch processes, which allow for active in-process controls during paused steps, continuous manufacturing requires more robust control strategies through either fully validated process parameters and ranges, or through active process controls using Process Analytical Technology (PAT) monitoring and process instrumentation measurements. In this integration study, a control strategy utilizing density and temperature measurements along with a predictive model for feedback process control was implemented in a surge vessel between two continuously operated unit operations (i.e., the continuous filter² and the continuous dryer³). This implementation ensures a stabilized critical input material attribute (i.e., slurry solid loading) feeding into the continuous dryer, enabling the continuous production of the monohydrate form of the dried product (an intermediate).

The model system consists of a material preparation step in which the slurry composition is manually formulated to mimic the crystallization endpoint excluding the impurities and then passes through a cooling stage in a two-stage MSMPR. A continuous rotary filter processes the slurry mixture and outputs the wet cake into a surge tank. In the tank, the wet cake is re-suspended into a slurry to enable flowability into the continuous drum dryer. Prior feasibility studies were conducted to determine the appropriate process parameters and material attributes for each step. In particular, the dryer requires the input material attributes of slurry solid concentrations and solvent compositions to be defined and controlled. The key process parameters were then studied to ensure the output of the desired monohydrate form of the product and the complete removal of free solvents. At the surge tank, a recirculation pump actively circulates the re-suspended slurry through a density meter, where the temperature and density are measured to predict the solid loading (wt%) based on a regression model. This value is then used as the process variable in a PI feedback control loop to actively adjust the solvent feed rate, thereby stabilizing the solid loading. Using this developed control strategy, a fully integrated demonstration run was performed at an equivalent product throughput of approximately 120 g/h. This work showcased the practical implementation of a critical material attribute (CMA) control strategy using a surge vessel to enable end-to-end continuous pharmaceutical manufacturing. Additionally, its potential further implementation is discussed, including PAT-related quality attributes control strategy development and diversion strategy design using the intermediate surge vessel.

References

(1) International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use. Q13 Continuous Manufacturing of Drug Substances and Drug Products.

(2) Wu, W.; Sayin, R.; Shvedova, K.; Born, S. C.; Testa, C. J.; Yeole, S. S.; Censullo, A. S.; Srivastava, A. K.; Ramnath, A.; Hu, C.; Takizawa, B.; O’Connor, T. F.; Yang, X. B.; Ramanujam, S.; Mascia, S. A Continuous Rotary Filtration for the Separation and Purification of an Active Pharmaceutical Ingredient. Org Process Res Dev 2023. https://doi.org/10.1021/acs.oprd.3c00263.

(3) Testa, C. J.; Hu, C.; Shvedova, K.; Wu, W.; Sayin, R.; Casati, F.; Halkude, B. S.; Hermant, P.; Shen, D. E.; Ramnath, A.; Su, Q.; Born, S. C.; Takizawa, B.; Chattopadhyay, S.; O’Connor, T. F.; Yang, X.; Ramanujam, S.; Mascia, S. Design and Commercialization of an End-to-End Continuous Pharmaceutical Production Process: A Pilot Plant Case Study. Org Process Res Dev 2020, 24 (12), 2874–2889. https://doi.org/10.1021/acs.oprd.0c00383.