Innovations for Scalable Manufacturing of Allogeneic Cell Therapy Products
Allogeneic cell therapies are poised to become a new frontier for therapeutic medicines. However, reliable and scalable manufacturing technology is still needed, especially for large scale commercial production.
While allogeneic cell therapies have the potential to address much larger patient populations across a greater variety of diseases compared to autologous therapies, they are currently behind in terms of developmental and approval progress. One of the critical challenges for future commercialisation of allogeneic cell therapy products is finding a scalable technology that can reliably maintain product quality throughout the manufacturing process, from small scale R&D up to large scale manufacturing.
While lab-scale process development and clinical manufacturing of allogeneic cell therapy products have mostly been done using 2D planar platforms, these planar technologies are inadequate for commercial-scale production due to lack of scalability, intensive labour requirements, limited process control and monitoring and ultimately the high cost of goods. Alternatively, a bioreactor-based suspension cell culture platform is considered to be a scalable solution that can significantly reduce manufacturing costs.
However, most allogeneic cell therapy products are anchorage-dependent, mortal human cells with unique growth requirements and characteristics that are significantly different from traditional host cells used to produce recombinant proteins or monoclonal antibodies. For example, human primary cells and mesenchymal stromal cells (MSCs) are typically grown on the surface of microcarriers. Embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) naturally form spherical cell aggregates, which is critical not only for cell expansion but also for the subsequent directed differentiation into a target cell type.
Since microcarriers and cell aggregates are much larger than single cells, greater power input using higher agitation rates is necessary to fully suspend these bigger particles in a bioreactor. However, higher agitation rates in stirred-type bioreactors with horizontal impellers can lead to higher levels of damaging hydrodynamic shear stress. Furthermore, fluid zones where microcarriers or aggregates are not homogeneously suspended can occur due to an uneven distribution of turbulent energy dissipation rates. These critical issues of shear stress and uneven energy dissipation in a bioreactor’s microenvironment are exacerbated as vessel size and fluid volume increase in scale, which means that conventional stirred-type bioreactors may be unable to provide consistent cell growth and differentiation performance during scale-up. Innovations in technology and bioprocessing are now critical for the progression of allogeneic cell therapies.
Single-use bioreactors using the innovative Vertical-WheelTM mixing mechanism are one of the enabling technologies that can unlock scalable manufacturing of allogeneic cell therapy products. The Vertical-Wheel’s design, in conjunction with a distinct U-shaped single-use vessel, promotes homogeneous suspension of microcarriers and cell aggregates with low power input. Computational fluid dynamics analysis shows minimal shear stress levels as well as uniform distribution of turbulent energy dissipation rates. As such, Vertical-Wheel bioreactors provide a consistent microenvironment for cells and unparalleled scalability across a full range of vessel sizes, from research to clinical and even up to commercial scale.
Read the next edition in PBS Biotech’s blog series for ‘Maximising the Yield and Quality Of iPSC-Derived Therapeutic Products’, which provides working examples of how Vertical-Wheel bioreactors have been used to successfully scale-up manufacturing of different allogeneic cell therapy products.
ABOUT PBS BIOTECH
PBS Biotech, Inc. manufactures the most advanced single-use bioreactors for the rapidly emerging cell and gene therapy market. Innovative Vertical-WheelTM mixing technology provides the benefits of complete particle suspension with low power input, homogeneous dissipation energy distribution, and minimal hydrodynamic shear stress. With unparalleled scalability across a full range of vessel sizes, Vertical-Wheel bioreactors enable high-quality and efficient manufacturing of cell and gene therapy products, from research to clinical and commercial scale. PBS Biotech also offers industry-leading contract research and process development services for a variety of cell and gene therapy applications.