Challenges and opportunities in biopharmaceutical manufacturing control

This article provides a perspective on control and operations for biopharmaceutical manufacturing. Challenges and opportunities are described for (1) microscale technologies for high-speed continuous processing, (2) plug-and-play modular unit operations with integrated monitoring and control systems, (3) dynamic modeling of unit operations and entire biopharmaceutical manufacturing plants to support process development and plant-wide control, and (4) model-based control technologies for optimizing startup, changeover, and shutdown. A challenge is the ability to simultaneously address the uncertainties, nonlinearities, time delays, non-minimum phase behavior, constraints, spatial distributions, and mixed continuous-discrete operations that arise in biopharmaceutical operations. The design of adaptive and hybrid control strategies is discussed. Process data analytics and grey-box modeling methods are needed to deal with the heterogeneity and tensorial dimensionality of biopharmaceutical data. Novel bioseparations as discussed as a potential cost-effective unit operation, with a discussion of challenges for the widespread application of crystallization to therapeutic proteins.