New paradigm of scalable manufacturing for allogeneic cell therapy products
January 15-19, 2017
Two dimensional (2-D) cell culture technologies have proven inadequate for large scale manufacturing to meet the anticipated commercial demands for cell therapy products. Growing cells on microcarriers suspended in bioreactors is considered a viable option for scaling up the manufacturing process. However, the commonly used cylindrical bioreactors with horizontal impellers require relatively high agitation power in order to fully suspend microcarriers, which can cause hydrodynamic stress to the cells in the culture fluid. Anchorage dependent cells grown on microcarriers are known to be more sensitive to hydrodynamic shear stress than suspended single cell cultures. In addition, the cells respond to their growth environment in ways that may affect product quality and potency. Combination of these facts makes it more challenging to identify the acceptable range of agitation rates to achieve satisfactory cell growth and quality attributes, and this problem becomes worse as the size of bioreactor increases. A single-use bioreactor system using an innovative Vertical-Wheel technology is recently introduced which promotes efficient, homogenous liquid mixing and uniform microcarrier suspension with low power input. Physical measurement of the minimum power levels required for homogeneous suspension of microcarriers and computational fluid dynamic analysis, indicate that the vertical mixing mechanism not only requires very low power input to fully suspend microcarriers, but also the low shear environment remains constant across the full range of vessel sizes from 0.5 to 50 liters. This unique characteristic of the vertical mixing mechanism offers unparalleled scalability to achieve a consistent and robust manufacturing process for shear sensitive cellular therapy products. The Vertical-Wheel single-use bioreactors have been evaluated with several different cell types including human bone marrow-derived mesenchymal stem cells (BM-MSC), human Chondrocytes, embryonic and induced pluripotent stem cells (PSC’s). The results of physical measurements of Kolmogorov scales, the growth of various types of cells, and the differentiation kinetics of PSC’s in various sizes of Vertical-Wheel bioreactors will be discussed.
Brian Lee, Yas Hashimura, Seda Karamil, Francisco Rosello, Kenny Cruz, Nathan Starkweather, Robin Wesselschmidt, and Mattew Croughan, "New paradigm of scalable manufacturing for allogeneic cell therapy products" in "Scale-up and Manufacturing of Cell-based Therapies V", Tom Brieva, Celgene Cellular Therapeutics William Miller, Northwestern University Chris Mason, University College London Eds, ECI Symposium Series, (2017). http://dc.engconfintl.org/cellbasedtherapies_v/62