Identification of critical process parameters and quality attributes for bioreactor-based expansion of human MSCs

Frontiers in Bioengineering and Biotechnology, vol. 13, pp. 1608194

Abstract

Mesenchymal stem/stromal cells (MSCs) have been identified as a promising therapeutic option for osteoarthritis, graft vs. host disease and cardiovascular diseases, among others. For widespread application of these therapies, robust and scaled manufacturing processes are required that reliably yield high amounts of high quality MSCs. One of the primary challenges in MSC manufacturing is achieving robustness, due to the high donor-to-donor and batch-to-batch variability seen in MSC manufacturing. To achieve more consistent manufacturing, standardization of the manufacturing process and analytical methods to determine cell quality and control process parameters will be needed. Traditionally, MSCs are cultivated in two dimensional (2D) systems, such as flasks or plates. However, these systems are limited in their scalability. To enhance volumetric productivity, upscaling may be achieved using agitated bioreactors where the MSCs are grown on microcarriers or other types of scaffolds. In this article, we have reviewed existing publications on the manufacturing of MSCs in agitated bioreactor systems regarding the process conditions used and the quality parameters measured to define more clearly the most relevant cell quality and process parameters. Key cell quality parameters measured are cell number and viability, immunophenotype and differentiation potential, while key process parameters include the cultivation system (cell source, bioreactor type, media composition), physiochemical properties of the media such as pH and dissolved oxygen (DO), as well as nutrient supply. Defining these parameters more clearly will support the development of robust MSC manufacturing processes at scale using improved process control and facilitate the widespread clinical application of MSC-based cell therapies.

Authors 3

1. Laura Herbst corresponding Aachen Department Bio-Adaptive production Fraunhofer Institute for Production Technology

   Fraunhofer Institute for Production Technology IPT

   Affiliation as printed

   Department Bio-Adaptive production, Fraunhofer Institute for Production Technology (FHG), Aachen, Germany

2. Bastian Nießing Aachen Department Bio-Adaptive production Fraunhofer Institute for Production Technology

   Fraunhofer Institute for Production Technology IPT

   Affiliation as printed

   Department Bio-Adaptive production, Fraunhofer Institute for Production Technology (FHG), Aachen, Germany

3. Robert Heinrich Schmitt Aachen Department Bio-Adaptive production Fraunhofer Institute for Production Technology Chair of Intelligence in Quality Sensing Laboratory for Machine Tools and Production Engineering (WZL)

   RWTH Aachen University · Fraunhofer Institute for Production Technology IPT

   Affiliation as printed

   Department Bio-Adaptive production, Fraunhofer Institute for Production Technology (FHG), Aachen, Germany

   WZL RWTH Aachen, Chair of Intelligence in Quality Sensing, Laboratory for Machine Tools and Production Engineering, RWTH Aachen University, Aachen, Germany