Batch processing has traditionally been employed in the pharmaceutical industry for the purification of monoclonal antibodies (mAbs). However, in recent years, integrated continuous biomanufacturing (ICB) technologies have been increasingly developed and adopted within these purification processes due to their advantages such as process intensification, smaller footprint, and more homogenous product quality. Nevertheless, implementation of end-to-end ICB still requires (1) additional development for post-chromatography unit operations, including diafiltration and (2) a high-fidelity continuous control strategy systematically integrating all the unit operations. This presentation addresses both considerations, as described below:<br/><br/>Most prior ICB efforts have focused primarily on the chromatography operations in the protein purification process. Diafiltration, which occurs towards the end of the process train for buffer exchange, also has the potential for continuous operation. Operating DF in a continuous format requires precise control over the process parameters such that the exiting protein concentration remains well-controlled and the target buffer exchange is achieved, regardless of the fluctuations in the feed stream. In this work, a control framework for continuous diafiltration (cDF) was designed to address the stated requirements. Experiments were conducted to develop semi-empirical process models relating the key parameters governing the DF operation. The models were subsequently coupled with simulations to determine the optimal design and operating space, which were then adopted to develop the control. The control strategy was evaluated for its robustness in conjunction with other unit operations. Our automated cDF will not only be useful in developing an integrated workflow but will also provide guidelines for improved design of cDF filters.<br/><br/>In summary, the development of an integrated continuous control strategy is critical for end-to-end success, but challenging, as it would have to ideally identify all real-time process disturbances and minimize their subsequent effects on the critical quality attributes of the drug substance. Our unified experimental and modeling approach, as demonstrated for diafiltration operation, can be leveraged towards the development and implementation of a successful continuous control strategy essential for end-to-end ICB.

Development of a robust control strategy for continuous diafiltration

ACS Spring 2022

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