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Review
. 2020 Nov 26:8:599674.
doi: 10.3389/fbioe.2020.599674. eCollection 2020.

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

Suman C Nath  1   2 , Lane Harper  1 , Derrick E Rancourt  1   2
Affiliations
Review

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

Suman C Nath et al. Front Bioeng Biotechnol. .

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.

Keywords: biologics manufacturing; bioreactor; cGMP; cell-based therapy; genetic engineering; integrated bioprocessing.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
Schematic illustration of current multi-step cell manufacturing strategies in planar culture for cell therapy applications.
FIGURE 2
FIGURE 2
Schematic illustrations of integrated single-step cell manufacturing strategies in bioreactor culture for cell therapy applications. Cells are isolated from patient’s (a) blood or (b) bone-marrow, or (c) skin and genetically modified. After expansion, cells are stored in a master cell bank or differentiated directly in bioreactor. After performing characterization, quality assurance and screening for safety and efficacy, cells are delivered to hospital or stored in cell bank for future use.
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