A Look At Perfusion: The Upstream Continuous Process

Although implementation of continuous manufacturing for biopharmaceuticals is in the early stages, continuous cell culture technology has been around for close to thirty years. Perfusion was initially developed in the late 1980s as a means for increasing protein titers (1). However, high costs driven by media consumption limited widespread commercial adoption. In the same time frame, advances in cell line engineering, media composition, and bioreactor design led to 10-fold increases in titers for batch and fed-batch modes, eliminating the first driver for adoption of perfusion technology. As a result, over the next 20 years or so, perfusion processes were largely used only for production of toxic or unstable proteins that degrade if exposed to culture conditions for typical batch/fed-batch residence times. Recently, however, growing recognition in the industry that there is a need for alternative manufacturing strategies that can boost efficiency and productivity while reducing costs has led to renewed interest in perfusion technology.

What Is Perfusion Cell Culture?
A perfusion cell culture process involves the constant feeding of fresh media and removal of spent media and product while retaining high numbers of viable cells (Figure 1). Removing spent media while keeping cells in culture can be done using alternating tangential-flow (ATF) and standard tangential-flow filtration (TFF). Another option is to retain the cells by binding them to a substrate (capillary fibers, membranes, microcarriers in fixed bed, and so on) in the bioreactor. Other methods include use of centrifuges. Lately, a revival of methods using acoustic waves has been seen (2).

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