Rajeev Ram, Ph.D.
The transition to continuous manufacturing of biologics requires a transformation of the supporting technologies which have become critical for manufacturing. Two technologies that have recently transformed biopharmaceutical manufacturing are process analytics for rapid on-line monitoring of critical quality attributes (CQA) and tools for high-throughput process development.
Here, I consider the challenges associated with measuring several of CQA for therapeutic proteins in a continuous manufacturing process. Such tools are essential for bringing Quality by Design (QbD) protocols to the continuous manufacturing of therapeutic proteins. Some aspects of process analysis are considerably easier as process samples are generated continuously and sample volume constraints can be relaxed. However, real-time process controls require continuous measurements of product quality data – which is incompatible with the workflow of several conventional product characterization tools (eg. HPAEC-PAD).
We will consider several novel approaches to analysis including optical assays developed in our lab, nanofluidics developed by the Han Lab, and nanoparticle based sensors developed in the Strano Lab. These technologies together offer the potential for comprehensive measurement of CQA in real-time.
For continuous perfusion bioprocessing, a lack of scale-down technology is a major barrier to process development. Recently,a microfluidics based bioreactor system was developed for continuous and perfusion processes. This microbioreactor’s smaller 1-2 mL volume enables long term continuous experiments with neglibile media usage. On line cell density and precise flow-rate control enabled controlled genetic switching of Pichia pastoris in a perfusion microbioreactor. Commercial perfusion microbioreactors are now available for high-density CHO cell cultue. A mature perfusion microbioreactor platform has the potential to fill a critical need in the evolving landscape of continuous biomanufacturing.