Challenges and opportunities in biopharmaceutical manufacturing control

The total sales of biopharmaceuticals have been steadily increasing for decades with growing approval of new drug products, especially for monoclonal antibodies. This trend motivates the development of deeper understanding and advancement of biopharmaceutical manufacturing operations. This article describes opportunities, needs, and challenges in process control and operations for biopharmaceutical manufacturing associated with continuous operations, process data analytics, and novel bioseparations. Challenges and opportunities in continuous operations are described for (1) microscale technologies for high-speed continuous process development, (2) the design of plug-and-play modular unit operations with integrated process monitoring and control systems to facilitate straightforward deployment in the laboratory, (3) dynamic models for unit operations and entire biopharmaceutical manufacturing plants to support process development and plant-wide control, and (4) easy-to-use model-based control technologies for optimizing startup, changeover, and shutdown aided with real-time process analytical technology (PAT). A challenge is the derivation of process monitoring and control techniques that are able to simultaneously address the uncertainties, nonlinearities, time delays, nonminimum phase behavior, constraints, spatial distributions, and mixed continuous-discrete operations that arise in biopharmaceutical operations. New process data analytics and grey-box modeling methods are needed to deal with the heterogeneity and tensorial dimensionality of much of the most promising PAT for the measurement of biopharmaceutical data. Novel bioseparations as discussed as a potential cost-effective unit operation, with a detailed discussion of challenges for the widespread application of crystallization to therapeutic proteins.