In‐Line Monitoring and Advanced Control Strategies in Downstream Bioprocessing of Biologics

Downstream processing is essential to the manufacture of biologics and directly impacts the product quality, safety and process efficiency. As biopharmaceuticals become increasingly complex and new requirements involving sterile manufacturing and highly compliant and scalable manufacturing systems take precedence, in-line monitoring and advanced control strategies have also proved to be an effective way of reshaping the field. This chapter explores the philosophy behind the techniques and technologies and practical realization of real-time analytical applications and control systems of downstream bioprocessing. It discusses Process Analytical Technology (PAT), spectroscopy-based-sensors (e.g., NIR, Raman, UV-Vis), and soft-sensor models to ensure that processing conditions get controlled to monitor critical quality attribute (CQA) in purification, filtration, and formulation. Model predictive control (MPC), feedback/feedforward models and adaptive control routines are given particular attention to be able to optimize process parameters in real-time. The paper also covers the cases studied in the industry with increased productivity, decreased failure in a batch, and the possibility of the attainment of regulations with Quality by Design (QbD) systems. The issues of sensor calibration, data integration and process validation are discussed, and the way forward with machine learning and digital twins. In-line monitoring supports the next generation of downstream biomanufacturing of biologics and biopharmaceuticals that is both intelligent, efficient, and quality-centric due to data-driven decision-making and process control in real-time.