Cell and Tissue Reaction Engineering pp 173-259

Part of the Principles and Practice book series (PRINCIPLES)

Bioreactor Design and Scale-Up

  • G. Catapano
  • P. Czermak
  • R. Eibl
  • D. Eibl
  • R. Pörtner

Abstract

Design and selection of cell culture bioreactors are affected by cell-specific demands, engineering aspects, as well as economic and regulatory considerations. Mainly, special demands such as gentle agitation and aeration without cell damage, a well controlled environment, low levels of toxic metabolites, high cell and product concentrations, optimized medium utilization, surface for adherent cells, and scalability have to be considered. This chapter comprises engineering aspects of bioreactor systems (design, operation, scale-up) developed or adapted for cultivation of mammalian cells, such as bioreactors for suspension culture (stirred-tank reactors, bubble columns, and air-lift reactors), fixed bed and fluidized bed reactors, hollow fiber and membrane reactors, and, finally, disposable bioreactors. Aspects relevant for selection of bioreactors are discussed. Finally, an example is given of how to grow mammalian suspension cells from cryopreserved vials to laboratory and pilot scale.

List of Symbols

Co2

oxygen concentration

dR

stirrer diameter

DR

vessel diameter

nR

stirrer speed

P/V

mean power input per volume

Re

Reynolds number

Θm

mixing time

kLa

mass transfer coefficient

Us

superficial gas velocity

A

active membrane area

Δci

transmembrane concentration difference of component i

Pi

permeability coefficient of a single component i

rp

particle radius

Si

transport of a certain component i through the membrane

Up

particle velocity in the gravitational field

ηfl

fluid viscosity

ρfl

fluid density

g

gravitational force

A

cross-sectional area of the fluidized bed vessel

DFB

diameter of the bed of the fluidized bed or fixed bed

HFB

height of the fluidized bed or fixed bed

K

constant depending on particle shape and surface properties

kaV

decay constant of retrovirus vector

qO2

cell specific oxygen consumption rate

qFB*

volume-specific uptake or production rate related to fixed bed volume

Sv

surface area per unit volume of particles

Ufl

fluid velocity

VFB

volume of fluidized bed or fixed bed

X

number of immobilized cells

Δp

pressure drop

ε

void fraction

ρfl

fluid density

ρs

solids apparent density

a

solute equivalent spherical radius (m)

C = X2/X1

cell concentration factor

Ds

unhindered solute diffusion coefficient (m2 s−1)

DM

solute diffusion coefficient in the membrane (m2 s−1)

DR = QF/V

dilution rate (s−1)

DR,crit

critical dilution rate at wash-out (s−1)

Js

solute flux (gmol s−1 m−1)

Jv

solvent flux (m s−1)

k

overall cell mass transport coefficient (m3 m−2 s−1)

kc

kinetic constant of substrate utilization (s−1)

K

partition coefficient of a solute between the membrane and the neighboring fluid

Ks

Michaelis constant for substrate utilization (gmol m−3)

L

active fibre length (m)

Lp

membrane hydraulic permeability (m2 s kg−1)

MW

molecular weight

NA = 6.023 × 1023

Avogadro’s number (molecules/mole)

P

pressure (kPa)

\(Pe_{ax} = {U_0 L \over D_s}\big({R_i \over L}\big)\)

reduced axial Peclet number

PM

solute diffusive permeability in the membrane (m s−1)

\(Pe_{w}(Z) = {V_w (Z) R_i \over D_s}\)

local wall Peclet number

QF

feed flow rate (m3 s−1)

QR

recycle flow rate (m3 s−1)

Q1

flow rate of the stream leaving the bioreactor tank (m3 s−1)

R = (1 − S)

membrane rejection coefficient towards the solute

\({\rm Re}_{in} = {U_0 R_i \over \eta\pi}\)

inlet Reynolds number

Ri

inner membrane radius (m)

RK

radius of Krogh cylinder (m)

RM

membrane resistance to diffusive transport (s m−1)

Ro

outer membrane radius (m)

RR = QR/QF

recycle ratio

Ru = 8.314 × 107

universal gas constant, (dynes cm (mole K)−1)

S

membrane sieving coefficient towards the solute

SF

substrate concentration in the feed stream, (gmol m−3)

S1

substrate concentration in the stream leaving the bioreactor tank (gmol m−3)

T

temperature (K)

uo

fiber lumen inlet axial velocity (m s−1)

V

bioreactor volume

vw

transmembrane wall velocity (m s−1)

X

cell concentration in the permeate or removal stream (cells/m3)

Xgell

cell concentration in the gel/cake (cells/m3)

Xo

initial cell concentration in the bioreactor (cells/m3)

X1

cell concentration in the stream leaving the bioreactor tank (cells/m3)

X2

cell concentration in the stream leaving the membrane module (cells/m3)

YX/S

cell yield coefficient

Z

axial coordinate (m)

Greek Symbols

\(\alpha = L\big({16 \eta_{fi}L_P \over R_i^3} \big)^{1 \over 2}\)

fiber Pressure modules

δ

membrane wall thickness (m)

ηfl

bulk solution viscosity (kg m−1 s−1)

μ

specific cell growth rate (s−1)

μmax

maximal cell growth rate (s−1)

Π

osmotic pressure (kPa)

σ

Staverman reflection coefficient

\(\Phi^2 = {\pi_{{\rm max}}x_o \over y_{x/s} S_F D_S} (R_k - R_o)^2\)

towards the solute squared Thiele modulus

\(\Psi = {S_F Y_{X/S} \over X_o}\)

dimensionless yield coefficient

Superscripts and Subscripts

i

refers to device inlet

L

liquid phase

M

membrane phase

o

refers to device outlet

w

refers to the membrane interface with the liquid

BEV

Baculovirus expression vector CHO cells Chinese hamster ovary cells

PER.C6

cells human embryogenic retinoblast cells

kLa

gas-liquid mass transfer coefficient

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Copyright information

© Springer-Verlag Berlin Heidelberg 2009

Authors and Affiliations

  • G. Catapano
    • 1
  • P. Czermak
    • 2
    • 3
  • R. Eibl
    • 4
  • D. Eibl
    • 4
  • R. Pörtner
    • 5
  1. 1.Department of Chemical Engineering and MaterialsUniversity of CalabriaRende (CS)Italy
  2. 2.Institute of Biopharmaceutical TechnologyUniversity of Applied Sciences Giessen-FriedbergGiessenGermany
  3. 3.Department of Chemical EngineeringKansas State UniversityManhattanUSA
  4. 4.Department of Life Sciences and Facility ManagementInstitute of Biotechnology, Zurich University of Applied SciencesWädenswilSwitzerland
  5. 5.Institute of Bioprocess and Biosystems EngineeringHamburg University of Technology (TUHH)HamburgGermany

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