Challenges and opportunities in the manufacture and expansion of cells for therapy

Abstract

Laboratory-based ex vivo cell culture methods are largely manual in their manufacturing processes. This makes it extremely difficult to meet regulatory requirements for process validation, quality control and reproducibility. Cell culture concepts with a translational focus need to embrace a more automated approach where cell yields are able to meet the quantitative production demands, the correct cell lineage and phenotype is readily confirmed and reagent usage has been optimized. Areas covered: This article discusses the obstacles inherent in classical laboratory-based methods, their concomitant impact on cost-of-goods and that a technology step change is required to facilitate translation from bed-to-bedside. Expert opinion: While traditional bioreactors have demonstrated limited success where adherent cells are used in combination with microcarriers, further process optimization will be required to find solutions for commercial-scale therapies. New cell culture technologies based on 3D-printed cell culture lattices with favourable surface to volume ratios have the potential to change the paradigm in industry. An integrated Quality-by-Design /System engineering approach will be essential to facilitate the scaled-up translation from proof-of-principle to clinical validation.

Large-Scale Microcarrier Culture of Chinese Perch Brain Cell for Viral Vaccine Production in a Stirred Bioreactor

“…Microcarrier technology, providing a large surface area for cell growth, has become a popular platform for cell production [ 14 , 15 , 21 , 22 , 23 , 24 ]. However, few reports have referred to cells of aquatic animals [ 25 , 26 , 27 , 28 ].…”

Large-scale microcarrier culture of HEK293T cells and Vero cells in single-use bioreactors

“…Using this production mode, maybe the virus yields meet the demand when the project is in clinical phase or just goes into market. However, as the number of patients receiving gene therapy increases every year, the production of a large quantities of viruses will become a limiting factor (Maartens et al 2017). The objective of the present work was to develop microcarriers bead-to-bead transfer processes and establish the scale-up cultivation processes for HEK293T cells and Vero cells in 50–200 l single-use XDR bioreactors.…”

“…The microcarriers provide attachment surface for adherent cells growth. Compared to multilayer flasks, microcarriers can significantly reduce process complexity and labor intensity even in large-scale culture process (Maartens et al 2017). The product contact portion of single-use bioreactor is composed of a single-use sterile plastic bag assembly which is used in place of traditional stainless steel tank.…”

Tolerising cellular therapies: what is their promise for autoimmune disease?

“…In recent years, investigators have turned their attention to the ex-vivo expansion or differentiation of ‘tolerogenic’ immune cells, followed by their adoptive transfer, as a potential route to therapeutic tolerance induction. To a large degree, these strategies have been catalysed by advances in bio-manufacturing in general, with robust and scalable processes leading to the efficient manufacture of advanced cellular therapies 6. To date, three main types of tolerogenic cell have been the focus of therapeutic strategies in humans.…”