Upstream continuous processing: recent advances in production of biopharmaceuticals and challenges in manufacturing.

Upstream continuous processing, or most commonly perfusion processing, for biopharmaceutical production, is emerging as a feasible and viable manufacturing approach. Development in production of recombinant therapeutic proteins as well as viral vectors, vaccines, and cell therapy products, has numerous research publications that came out in previous years. Recent research areas are in perfusion-operation strategies maximizing and controlling bioreactor cell density, adding feed solution designed to supplement basal medium feed stream, combining cell line engineering with bioreactor conditions such as hypoxia, and implementing online process monitoring of cell density by capacitance sensor and metabolites by Raman spectroscopy. Perfusion applications are not limited to production process alone but include other upstream areas where high cell density process is essential such as in cell bank preparation, N-1 seed bioreactor, and combination with intensified fed-batch production process. This review covers recent advances in continuous processing over the last two years for biopharmaceutical production.