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.

Robust on-line sampling and analysis during long-term perfusion cultivation of mammalian cells.

In an attempt to support robust automated sampling and analysis of mammalian cell bioreactors, an integrated platform, BaychroMA®, was developed which includes an innovative sterile sampling device, automated sample transport, a sample preparation module, online analyzers, and communication interfaces to process automation systems. The robustness of this platform was verified by applying it to a laboratory-scale perfusion bioreactor that was operated for over 100 days. Both manual and automated samples were collected over the course of the run and a comparison was made for cell density, viability, glucose, and lactate concentrations.

The "push-to-low" approach for optimization of high-density perfusion cultures of animal cells.

High product titer is considered a strategic advantage of fed-batch over perfusion cultivation mode. The titer difference has been experimentally demonstrated and reported in the literature. However, the related theoretical aspects and strategies for optimization of perfusion processes with respect to their fed-batch counterparts have not been thoroughly explored.