Abstract
ABSTRACTIn the production of biopharmaceuticals disk‐stack centrifugation is widely used as a harvest step for the removal of cells and cellular debris. Depth filters followed by sterile filters are often then employed to remove residual solids remaining in the centrate. Process development of centrifugation is usually conducted at pilot‐scale so as to mimic the commercial scale equipment but this method requires large quantities of cell culture and significant levels of effort for successful characterization. A scale‐down approach based upon the use of a shear device and a bench‐top centrifuge has been extended in this work towards a preparative methodology that successfully predicts the performance of the continuous centrifuge and polishing filters. The use of this methodology allows the effects of cell culture conditions and large‐scale centrifugal process parameters on subsequent filtration performance to be assessed at an early stage of process development where material availability is limited. Biotechnol. Bioeng. 2016;113: 1934–1941. © 2016 The Authors. Biotechnology and Bioengineering Published by Wiley Periodicals, Inc.
Highlights
Quality by Design (QbD) regulatory initiatives over the last decade have required that biopharmaceutical manufacturers develop a thorough understanding of a product’s quality attributes and manufacturing process through the generation of design spaces (Rathore, 2009)
Extensive work has been published on the use of the Rotating shear device (RSD) to understand the consequence of shear stress placed on cell culture materials and predicting the impact of similar levels of exposure prevailing in the feed zones of pilot-scale centrifuges
The need to prepare large quantities of sheared material so as to satisfy the feed requirements for subsequent filtration experiments was met by use of a Capillary shear device (CSD)
Summary
Quality by Design (QbD) regulatory initiatives over the last decade have required that biopharmaceutical manufacturers develop a thorough understanding of a product’s quality attributes and manufacturing process through the generation of design spaces (Rathore, 2009). High throughput scale-down techniques enable the rapid generation of extensive experimental data representative of large-scale performance, both in the upstream and downstream manufacturing process. One of the disadvantages of disk-stack centrifugation is that in many designs the cells enter the centrifuge through a feed zone in which high levels of shear are present. This shear can damage shear-sensitive mammalian cells resulting in the generation of submicron particles which are carried over to the centrate (Jain et al, 2005). A typical process sequence for a mammalian cell culture process might begin with the removal of cells and cell debris achieved through a combination of a centrifugal step followed by a depth filtration step (Shukla and Kandula, 2008)
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