Cell-Based Therapy Manufacturing in Stirred Suspension Bioreactor: Thoughts for cGMP Compliance

Abstract

Cell-based therapy (CBT) is attracting much attention to treat incurable diseases. In recent years, several clinical trials have been conducted using human pluripotent stem cells (hPSCs), and other potential therapeutic cells. Various private- and government-funded organizations are investing in finding permanent cures for diseases that are difficult or expensive to treat over a lifespan, such as age-related macular degeneration, Parkinson’s disease, or diabetes, etc. Clinical-grade cell manufacturing requiring current good manufacturing practices (cGMP) has therefore become an important issue to make safe and effective CBT products. Current cell production practices are adopted from conventional antibody or protein production in the pharmaceutical industry, wherein cells are used as a vector to produce the desired products. With CBT, however, the “cells are the final products” and sensitive to physico- chemical parameters and storage conditions anywhere between isolation and patient administration. In addition, the manufacturing of cellular products involves multi-stage processing, including cell isolation, genetic modification, PSC derivation, expansion, differentiation, purification, characterization, cryopreservation, etc. Posing a high risk of product contamination, these can be time- and cost- prohibitive due to maintenance of cGMP. The growing demand of CBT needs integrated manufacturing systems that can provide a more simple and cost-effective platform. Here, we discuss the current methods and limitations of CBT, based upon experience with biologics production. We review current cell manufacturing integration, automation and provide an overview of some important considerations and best cGMP practices. Finally, we propose how multi-stage cell processing can be integrated into a single bioreactor, in order to develop streamlined cGMP-compliant cell processing systems.

Comparison of 2,3,5,4′-tetrahydroxystilbene-2-O-b-D-glucoside-induced proliferation and differentiation of dental pulp stem cells in 2D and 3D culture systems—gene analysis

“…Researchers have reported that 3D bioreactors differentiate DPSCs into different cell types, including neural progenitor cells and adipose-like structures. 32 , 33 , 34 In our results, 2D and 3D cultures treated with THSG induced neurogenic ( Fig. 6 ) and adipogenic ( Fig.…”

“…Additionally, several studies have reported the osteogenic, adipogenic, and pluripotent differentiation of MSCs in 3D bioreactors. 32 Although 3D culture improved the differentiation and dedifferentiation in MSCs, prolonged in vitro expansion causes various types of damage, such as rapid aging and stemless loss. 28 Our previous studies have demonstrated that THSG improves self-renewal and osteogenic differentiation in DPSCs.…”

Cellular Nanosponges for Biological Neutralization

“…In this perspective, biomanufacturing technologies based on 3D-bioreactors for large and ultra-large scale-up of cell production are beneficial. [115,116] In addition, processes for large-scale cell membrane derivation, efficient nanoparticle coating, and reliable quality control methods are also required. Overall, with continuous research and development, we expect the cellular nanosponge technology will reveal and demonstrate more unique strengths towards biological neutralization applications, which will benefit various patient populations.…”

Translating stem cell research into development of cellular drugs—a perspective from manufacture of stem cell products and CMC considerations

“… 12 Methods and tools (such as bioreactors) that work well at bench‐scale may be difficult to reproduce at scale particularly if they are prone to contamination or yielding variable culture batches. 13 Thus, it is important to allow sufficient development time to demonstrate proficiency and reliability of the proposed scale‐up mechanism.…”