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Dynamic Single-Use Bioreactors Used in Modern Liter- and m3- Scale Biotechnological Processes: Engineering Characteristics and Scaling Up

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Book cover Disposable Bioreactors II

Part of the book series: Advances in Biochemical Engineering/Biotechnology ((ABE,volume 138))

Abstract

During the past 10 years, single-use bioreactors have been well accepted in modern biopharmaceutical production processes targeting high-value products. Up to now, such processes have mainly been small- or medium-scale mammalian cell culture-based seed inoculum, vaccine or antibody productions. However, recently first attempts have been made to modify existing single-use bioreactors for the cultivation of plant cells and tissue cultures, and microorganisms. This has even led to the development of new single-use bioreactor types. Moreover, due to safety issues it has become clear that single-use bioreactors are the “must have” for expanding human stem cells delivering cell therapeutics, the biopharmaceuticals of the next generation. So it comes as no surprise that numerous different dynamic single-use bioreactor types, which are suitable for a wide range of applications, already dominate the market today. Bioreactor working principles, main applications, and bioengineering data are presented in this review, based on a current overview of greater than milliliter-scale, commercially available, dynamic single-use bioreactors. The focus is on stirred versions, which are omnipresent in R&D and manufacturing, and in particular Sartorius Stedim’s BIOSTAT family. Finally, we examine development trends for single-use bioreactors, after discussing proven approaches for fast scaling-up processes.

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Abbreviations

1-D:

1-dimensional

2-D:

2-dimensional

3-D:

3-dimensional

Ao,G :

Interfacial area of gas bubbles

a :

Specific interfacial area

B :

Width of the bag

Bo:

Bond number

c m :

Dimensionless mixing number

c o2 :

Actual concentration of the oxygen in the liquid

c *o2 :

Saturation concentration of the oxygen in the liquid

c s :

Distance between stirrers

c s /d s :

Ratio of stirrer distance to stirrer diameter

cv:

Culture volume

C :

Correlation factor

CFD:

Computational fluid dynamics

CHO:

Chinese hamster ovary cells

d 0 :

Shaking diameter

d 32 :

Sauter diameter

d B :

Bubble diameter

d m,SF :

Maximal shake flask diameter

d s :

Stirrer diameter

d s /D :

Ratio of the stirrer and bioreactor diameter

d SF :

Diameter shake flask

d x :

Cell diameter

D :

Vessel diameter

D I :

Inner diameter of the container

DO:

Dissolved oxygen

Do2 :

Diffusion coefficient of oxygen

FDA:

Food and Drug Administration

Fr :

Froude number

FVM:

Finite volume method

hMSC:

Human mesenchymal stem cells

h :

Stirrer height

h/D :

Ratio of stirrer height and bioreactor diameter

h/H :

Ratio of stirrer and liquid height

H :

Height of the liquid

Ha :

Hatta number

HCD:

High cell density

H/D :

Ratio of liquid height and bioreactor diameter

HTS:

High-throughput screening

k :

Rocking rate

k H :

Henry coefficient

k L :

Mass transfer coefficient

k a L :

Volumetric mass transfer coefficient

k n :

Reaction coefficient

L :

Length of the bag

LBM:

Lattice–Boltzmann method

LDA:

Laser–Doppler anemometry

m :

Slope in (26)

M :

Torque

M d :

Dead weight torque (measured without liquid, representing only the bearing torque)

n :

Reaction order

Ne :

Newton number

N S :

Rotation frequency

OD:

Optical density

OTR:

Oxygen transfer rate

OUR:

Oxygen uptake rate

P :

Power input

P/V :

Specific power input

PIV:

Particle image velocimetry

PMP:

Plant-made protein

p O2 :

Oxygen partial pressure

PTV:

Particle tracking velocimetry

q 02 :

Specific oxygen uptake rate

Re :

Reynolds number

Recrit :

Critical Reynolds number

RT:

Rushton turbine

S.U.B.:

Single-use bioreactor from ThermoFisher scientific

SBI:

Segment blade impeller

Sc:

Schmidt number

t :

Time

u G :

Superficial gas velocity

u max :

Maximum velocity

u Tip :

Tip speed

V :

Working volume

WIM:

Wave-induced motion

X :

Living cell density

x :

Radial coordinate

x 1 and x 2 :

Empirical constants

XD:

Extreme density

α:

Volume fraction

β:

Coefficient

γNT :

Local shear gradients

γNT, m :

Mean local shear gradients

εT :

Local energy dissipation rate

η:

Viscosity

θm :

Mixing time

λ:

Kolmogorov length scale

ρ:

Density

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Acknowledgments

The results presented are part of a PhD thesis. The authors are grateful to Dipl.-Ing. Ute Husemann, Dr. Gerhard Greller, Dipl.-Ing. Jacqueline Herrman and Dr. Alexander Tappe, from Sartorius Stedim Biotech for providing geometric details for the bioreactors under investigation and experimental results for the BIOSTAT CultiBag STR, as well as for their participation in many helpful discussions.

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  1. School of Life Sciences and Facility Management, Institute of Biotechnology, Zurich University of Applied Sciences (ZHAW), 8820, Wädenswil, Switzerland

    Christian Löffelholz, Stephan C. Kaiser, Regine Eibl & Dieter Eibl

  2. Department Chemical and Process Engineering, Technische Universität Berlin, Straße des 17. Juni 135, 10623, Berlin, Germany

    Matthias Kraume

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Correspondence to Christian Löffelholz .

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  1. IBT Institut für Biotechnologie Bioverfahrenstechnik, Zürcher Hochschule für Angew.Wissensch Life Sciences und Facility Management, Wädenswil, Switzerland

    Dieter Eibl

  2. Hochschule Wädenswil, Wädenswil, Switzerland

    Regine Eibl

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Löffelholz, C., Kaiser, S.C., Kraume, M., Eibl, R., Eibl, D. (2013). Dynamic Single-Use Bioreactors Used in Modern Liter- and m3- Scale Biotechnological Processes: Engineering Characteristics and Scaling Up. In: Eibl, D., Eibl, R. (eds) Disposable Bioreactors II. Advances in Biochemical Engineering/Biotechnology, vol 138. Springer, Berlin, Heidelberg. https://doi.org/10.1007/10_2013_187

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