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Process Design for Human Mesenchymal Stem Cell Products in Stirred-Tank Bioreactors

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Cell Culture Engineering and Technology

Part of the book series: Cell Engineering ((CEEN,volume 10))

Abstract

Mesenchymal stem cells (MSCs) and their extracellular vesicles (EVs) are gaining importance as so-called advanced therapy medicinal products. However, the manufacturing of such products is challenging due to their complexity and sensitivity to intrinsic and environmental parameters, which determine their therapeutic functionality. MSCs respond strongly to their microenvironment, which modulates cell behavior and induces the secretion of EVs. It is therefore necessary to mimic the physiological niche of MSCs in vitro in order to ensure therapeutic efficacy. In this chapter, we discuss the critical quality attributes of MSCs and EVs, and the critical process parameters during in vitro manufacturing. We consider the suitability of different bioreactor types, focusing on stirred-tank bioreactors that are typically used for MSC expansion. For EV production, we also consider hollow-fiber and fixed-bed reactors. We describe how the production of MSCs and EVs can be enhanced by process modifications, and identify topics that require further investigation.

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Abbreviations

ad:

Adipose tissue

APIs:

Active pharmaceutical ingredients

ATMPs:

Advanced therapy medicinal products

bm:

Bone marrow

CBMP:

Cell-based medicinal products

CD:

Cluster of differentiation

CPP:

Critical process parameter

CQA:

Critical quality attribute

DO:

Dissolved oxygen

ECM:

Extracellular matrix

EMA:

European medicines agency

EVs:

Extracellular vesicles

FBS:

Fetal bovine serum

FDA:

Food and drug administration

GMP:

Good manufacturing practice

hESC:

Human embryonic stem cell

IL:

Interleukin

INF:

Interferon

ISCT:

International society of cell therapy

MSCs:

Mesenchymal stem cells

PAT:

Process analytical technology

PX:

Passage number X

QbD:

Quality by design

QTPP:

Quality target product profile

R&D:

Research and development

sCTMP:

Somatic cell therapy medicinal products

STR:

Stirred-tank bioreactor

TNF:

tumor necrosis factor

uc:

Umbilical cord

Nc :

Critical agitation rate

dS :

Diameter of the stirrer

dT :

Diameter of the tank

hS :

Height of the stirrer

kLa:

Volumetric mass transfer coefficient

T:

Temperature

p:

Pressure

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  1. Institute of Bioprocess Engineering and Pharmaceutical Technology IBPT), University of Applied Sciences Mittelhessen (THM), Gießen, Germany

    Jan Barekzai, Florian Petry, Peter Czermak & Denise Salzig

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    Ralf Pörtner

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Barekzai, J., Petry, F., Czermak, P., Salzig, D. (2021). Process Design for Human Mesenchymal Stem Cell Products in Stirred-Tank Bioreactors. In: Pörtner, R. (eds) Cell Culture Engineering and Technology. Cell Engineering, vol 10. Springer, Cham. https://doi.org/10.1007/978-3-030-79871-0_10

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