Skip to main content
SpringerLink
Log in

Bioreactor Design and Scale-Up

  • Chapter
Book cover Cell and Tissue Reaction Engineering

Part of the book series: Principles and Practice ((PRINCIPLES))

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.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 89.00
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 119.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

Abbreviations

C o2 :

oxygen concentration

d R :

stirrer diameter

D R :

vessel diameter

n R :

stirrer speed

P/V :

mean power input per volume

Re:

Reynolds number

Θ m :

mixing time

k La:

mass transfer coefficient

U s :

superficial gas velocity

A :

active membrane area

Δci :

transmembrane concentration difference of component i

P i :

permeability coefficient of a single component i

r p :

particle radius

S i :

transport of a certain component i through the membrane

U p :

particle velocity in the gravitational field

η fl :

fluid viscosity

ρ fl :

fluid density

g :

gravitational force

A :

cross-sectional area of the fluidized bed vessel

D FB :

diameter of the bed of the fluidized bed or fixed bed

H FB :

height of the fluidized bed or fixed bed

K :

constant depending on particle shape and surface properties

k aV :

decay constant of retrovirus vector

q O2 :

cell specific oxygen consumption rate

q FB * :

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

S v :

surface area per unit volume of particles

U fl :

fluid velocity

V FB :

volume of fluidized bed or fixed bed

X :

number of immobilized cells

Δp :

pressure drop

ε:

void fraction

ρ fl :

fluid density

ρ s :

solids apparent density

a :

solute equivalent spherical radius (m)

C = X 2/X 1 :

cell concentration factor

D s :

unhindered solute diffusion coefficient (m2 s−1)

D M :

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

D R = Q F/V :

dilution rate (s−1)

D R,crit :

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

J s :

solute flux (gmol s−1 m−1)

J v :

solvent flux (m s−1)

k :

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

k c :

kinetic constant of substrate utilization (s−1)

K :

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

K s :

Michaelis constant for substrate utilization (gmol m−3)

L :

active fibre length (m)

L p :

membrane hydraulic permeability (m2 s kg−1)

MW:

molecular weight

N A = 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

P M :

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

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

local wall Peclet number

Q F :

feed flow rate (m3 s−1)

Q R :

recycle flow rate (m3 s−1)

Q 1 :

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

R i :

inner membrane radius (m)

R K :

radius of Krogh cylinder (m)

R M :

membrane resistance to diffusive transport (s m−1)

R o :

outer membrane radius (m)

R R = QR/QF :

recycle ratio

R u = 8.314 × 107 :

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

S :

membrane sieving coefficient towards the solute

S F :

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

S 1 :

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

T :

temperature (K)

u o :

fiber lumen inlet axial velocity (m s−1)

V :

bioreactor volume

v w :

transmembrane wall velocity (m s−1)

X :

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

X gell :

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

X o :

initial cell concentration in the bioreactor (cells/m3)

X 1 :

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

X 2 :

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

Y X/S :

cell yield coefficient

Z :

axial coordinate (m)

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

fiber Pressure modules

δ :

membrane wall thickness (m)

η fl :

bulk solution viscosity (kg m−1 s−1)

μ :

specific cell growth rate (s−1)

μ max :

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

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

k La:

gas-liquid mass transfer coefficient

References

  • Akiyama I, Tomiyama K, Sakaguchi M, Takaishi M, Mori M, Hosokawa M, Nagamori S, Shimizu N, Huh NH, Miyazaki M (2004) Expression of CYP3A4 by an immortalized human hepatocyte line in a three-dimensional culture using a radial-flow bioreactor. Int J Mol Med 14: 663–668

    PubMed  Google Scholar 

  • Amanullah A, Burden E, Jug-Dujakovic M, Mikola M, Pearre C, Herber W (2004) Development of a large-scale cell bank in cryobags for the production of biologics. http://www.wavebiotech. com/pdfs/literature/Merck_Cancun_2004.pdf. Cited January 3, 2008

  • Apelblat A, Katzir-Katchalsky A, Silberberg A (1974) A mathematical analysis of capillary tissue fluid exchange. Biorheol 11: 1–49

    Google Scholar 

  • Belfort G (1989) Membrane and bioreactors: A technical challenge in biotechnology. Biotechnol Bioeng 33: 1047–1066

    PubMed  Google Scholar 

  • Biotechnology by open learning: Bioreactor design and product yield (1992) Butterworth-Heinemann, London

    Google Scholar 

  • Bohmann A, Pörtner R, Märkl H (1995) Performance of a membrane dialysis bioreactor with radial-flow fixed bed for the cultivation of a hybridoma cell line. Appl Microbiol Biotechnol 43: 772–780

    PubMed  Google Scholar 

  • Bohmann A, Pörtner R, Schmieding J, Kasche V, Märkl H (1992) Integrated membrane dialysis bioreactor with radial-flow fixed bed — a new approach for continuous cultivation of animal cells. Cytotechnol 9: 51–57

    Google Scholar 

  • Born C, Biselli M, Wandrey C (1995) Production of monoclonal antibodies in a pilot scale fluidized bed bioreactor. In: Beuvery EC et al. (eds) Animal Cell Technology: Developments Towards the 21st Century, pp. 683–686. Kluwer, The Netherlands

    Google Scholar 

  • Brecht R (2007) Disposable bioreactor technology: Challenges and trends in cGMP manufacturing. BioProduction 2007, Berlin, Germany (presentation)

    Google Scholar 

  • Breman BB, Beenackers AACM, Bouma MJ, Van der Werf MH (1996) Axial liquid mixing and a gas—liquid multi-stage agitated contactor (MAC). Chem Eng Res Des 74: 669–678

    Google Scholar 

  • Brotherton JD, Chau PC (1996) Modeling of axial-flow hollow fiber cell culture bioreactors. Biotechnol Prog 12: 575–590

    Google Scholar 

  • Burger C, Carrondo MJ, Cruz P, Cuffe M, Dias E, Griffiths JB, Hayes K, Hauser H, Looby D, Mielke C, Moreira JL, Rieke E, Savage AV, Stacey GN, Welge T (1999) An integrated strategy for the process development of a recombinant antibody-cytokine fusion protein expressed in BHK cells. Appl Microbiol Biotechnol 52: 345–353

    PubMed  Google Scholar 

  • Butler M (2004) Animal Cell Culture Technology — The Basics, 2nd ed. Oxford University Press, New York

    Google Scholar 

  • Card C (2007) Large scale, animal free production of human monoclonal antibody using PERC.6™ cells in a disposable, stirred-tank bioreactor. 20th ESACT meeting 2007, Dresden, Germany (poster)

    Google Scholar 

  • Card C, Smith T (2006) Application report draft — SUB05601

    Google Scholar 

  • Celonic (2007) http://www.celonic.de (27.05.2007)

  • Cheryan M, Mehaia MA (1983) A high performance membrane bioreactor for continuous fermentation of lactose to ethanol. Biotechnol Lett 5: 519–524

    Google Scholar 

  • Chisti MY, Moo-Young M (1987) Airlift reactors: characteristics, applications and design considerations. Chem Eng Sci 43: 451–457

    Google Scholar 

  • Chisti Y (2000) Animal-cell damage in sparged bioreactors. Trends Biotechnol 10: 420–432

    Google Scholar 

  • Chmiel H (2006) Bioprozesstechnik. Spektrum Akademischer Verlag. München

    Google Scholar 

  • Chu L, Robinson DK (2003) Industrial choices for protein production by large-scale cell culture. Biochemical Eng 10: 180–187

    Google Scholar 

  • Cong C, Chang Y, Deng J, Xiao C, Su Z (2001) A novel scale-up method for mammalian cell culture in packed-bed bioreactor. Biotechnol Lett 23: 881–885

    Google Scholar 

  • Cronin CN, Lim KB, Rogers J (2007) Production of selenomethionyl-derivatized proteins in baculovirus-infected insect cells. Protein Sci 16: 2023–2029

    PubMed  Google Scholar 

  • Dean RC, Karkare SB, Ray NG, Runstadler PW, Venkatasubramanian K (1987) Large-scale culture of hybridoma and mammalian cells in fluidized bed bioreactors. Ann NY Acad Sci 506: 129–146

    PubMed  Google Scholar 

  • Deng J, Yang Q, Cheng X, Li L, Zhou J (1997) Production of rhEPO with a serum-free medium in the packed bed bioreactor. Chin J Biotechnol 13: 247–252

    PubMed  Google Scholar 

  • Dewar V, Voet P, Denamur F, Smal J (2008) Industrial implementation of in vitro production of monoclonal antibodies. ILAR J 46

    Google Scholar 

  • Doran PM (2006) Bioprocess Engineering Principles. Academic Press, London

    Google Scholar 

  • Ducommun P, Bolzonella I, Rhiel M, Pugeaud P, von Stockar U, Marison IW (2001) On-line determination of animal cell concentration. Biotechnol Bioeng 72: 515–522

    PubMed  Google Scholar 

  • Ducommun P, Rueux PA, Kadouri A, von Stockar U, Marison IW (2002) Monitoring of temperature effects on animal cell metabolism in a packed bed process. Biotechnol Bioeng 77: 838–842

    PubMed  Google Scholar 

  • Dwyer JL (1984) Scale-up of bioproduct separation with high performance liquid chromatography. Bio/Technology 2: 957

    Google Scholar 

  • Eibl D (2006) Engineering aspects of the BioWave reactor. BioWave training course at UAS Wädenswil, Switzerland (presentation)

    Google Scholar 

  • Eibl R, Eibl D (2006) Design and use of the Wave Bioreactor for plant cell culture. In: Dutta Gupta S, Ibaraki Y (eds) Plant Tissue Culture Engineering, Series: Focus on Biotechnology, vol 6, pp 203–227. Springer, Dordrecht

    Google Scholar 

  • Eibl R, Eibl D (2007) Disposable bioreactors for cell culture based-bioprocessing, Achema Worldwide News: 8–10

    Google Scholar 

  • Eibl R, Eibl D (2008) Application of disposable bag-bioreactor in tissue engineering and for the production of therapeutic agents. In: Scheper T (ed) Advances in Biochemical Engineering/ Biotechnology. Springer, Berlin Heidelberg New York, in press.

    Google Scholar 

  • Eibl R, Eibl D, Pechmann G, Ducommun C, Lisica L, Lisica S, Blum P, Schär M, Wolfram L, Rhiel M, Emmerling M, Röll M, Lettenbauer C, Rothmaier M, Flükiger M (2003) Produktion pharmazeutischer Wirkstoffe in disposable Systemen bis zum 100L Massstab, Teil 1. KTI-Projekt 5844.2 FHS, Final Report, University of Applied Sciences Wädenswil, Switzerland

    Google Scholar 

  • Fassnacht D (2001) Fixed-Bed Bioreactors for the Cultivation of Animal Cells. VDI Verlag GmbH, Düsseldorf

    Google Scholar 

  • Fassnacht D, Pörtner R (1999) Experimental and theoretical considerations on oxygen supply for animal cell growth in fixed bed bioreactors. J Biotechnol 72: 169–184

    PubMed  Google Scholar 

  • Fassnacht D, Reimann I, Pörtner R, Märkl H (2001) Scale-up von Festbettreaktoren zur Kultivierung tierischer Zellen. Chem Ing Tech 73: 1075–1079

    Google Scholar 

  • Fassnacht D, Rössing S, Singh R, Al-Rubeai M, Pörtner R (1999) Influence of BCL-2 Expression on antibody productivity in high cell density hybridoma culture systems. Cytotechnol 30: 95–105

    Google Scholar 

  • Fassnacht D, Rössing S, Stange J, Pörtner R (1998) Long-term cultivation of immortalised mouse hepatocytes in a high cell density fixed bed bioreactor. Biotechnol Technol 12: 25–30

    Google Scholar 

  • Fenge Ch, Lüllau E (2006) Cell culture bioreactors. In: Ozturk SS, Hu WS (eds) Cell Culture Technology for Pharmaceutical and Cell-Based Therapies. Taylor & Francis, New York

    Google Scholar 

  • Forestell SP, Dando JS, Chen J, de Vries P, Bohnlein E, Rigg RJ (1997) Novel retroviral packaging cell lines: complementary tropisms and improved vector production for efficient gene transfer. Gene Ther 4: 600–610

    PubMed  Google Scholar 

  • Frahm B, Lane P, Märkl H, Pörtner R (2003) Improvement of a mammalian cell culture process by adaptive, model-based dialysis fed-batch cultivation and suppression of apoptosis. Bioproc Biosyst Eng 26: 1–10

    Google Scholar 

  • Fries S, Glazomitsky K, Woods A, Forrest G, Hsu A, Olewinski R, Robinson D, Chartrain M (2005) Evaluation of disposable bioreactors. BioProcess Int 10(Supplement): 36–44

    Google Scholar 

  • Fussenegger M, Fassnacht D, Schwartz R, Zanghi JA, Graf M, Bailey JE, Pörtner R (2000) Regulated overexpression of the survival factor bcl-2 in CHO cells increases viable cell density in batch culture and decreases DNA release in extended fixed-bed cultivation. Cytotechnol 32: 45–61

    Google Scholar 

  • Galliher P (2007) Case study: Scale up to 1,000L perfusion in a disposable stirred tank bioreactor. BioProduction 2007, Berlin, Germany (presentation)

    Google Scholar 

  • Genzel Y, Olmer RM, Schaefer B, Reichl U (2006) Wave microcarrier cultivation of MDCK cells for influenza virus production in serum containing and serum-free media. Vaccine 24: 6074–6087

    PubMed  Google Scholar 

  • Gion T, Shimada M, Shirabe K, Nakazawa K, Ijima H, Matsushita T, Funatsu K, Sugimachi K (1999) Evaluation of a hybrid artificial liver using a polyurethane foam packed-Bed culture system in dogs. J Surg Res 82: 131–136

    PubMed  Google Scholar 

  • Glacken MW, Fleishaker RJ, Sinskey AJ (1983) Large-scale production of mammalian cells and their products: engineering principles and barriers to scale-up. Ann NY Acad Sci 413: 355–372

    PubMed  Google Scholar 

  • Golmakany N, Rasaee MJ, Furouzandeh M, Shojaosadati SA, Kashanian S, Omidfar K (2005) Continuous production of monoclonal antibody in a packed-bed bioreactor. Biotechnol Appl Biochem 41: 273–278

    PubMed  Google Scholar 

  • Gramer MJ, Poeschl DM (2000) Comparison of cell growth in T-flasks, in micro hollow fiber bioreactors, and in an industrial scale hollow fiber bioreactor system. Cytotechnol 34: 111–119

    Google Scholar 

  • Hambach B, Biselli M, Runstadler PW, Wandrey C (1992) Development of a reactor-integrated aeration system for cultivation of animal cells in fluidized beds. In: Spier RR, Griffiths JB, MacDonald C (eds) Animal Cell Technology: Developments, Process and Products, pp 381–385. Oxford, Butterworth-Heinemann

    Google Scholar 

  • Hami LS, Green C, Leshinsky N, Markham E, Miller K, Craig S (2004) GMP production and testing of Xcellerated T Cells™ for the treatment of patients with CLL. Cytotherapy 6: 554–562

    PubMed  Google Scholar 

  • Heidemann R, Riese U, Lütkemeyer D, Büntemeyer H, Lehmann J (1994) The Super-Spinner: a low cost animal cell culture bioreactor for the CO2 -incubator. Cytotechnol 14: 1–9

    Google Scholar 

  • Himmelfarb P, Thayer PS, Martin KE (1969) Spin filter culture: The propagation of mammalian cells in suspension. Science 164: 555–557

    PubMed  Google Scholar 

  • Hongo T, Kajikawa M, Ishida S, Ozawa S, Ohno Y, Sawada J, Umezawa A, Ishikawa Y, Kobayashi T, Honda H (2005) Three-dimensional high-density culture of HepG2 cells in a 5-ml radial-flow bioreactor for construction of artificial liver. J Biosci Bioeng 99: 237–244

    PubMed  Google Scholar 

  • Hu YC, Kaufman J, Cho MW, Golding H, Shiloach J (2000) Production of HIV-1 gp120 in packed-bed bioreactor using the vaccinia virus/T7 expression system. Biotechnol Prog 16: 744–750

    PubMed  Google Scholar 

  • Hundt B, Best C, Schlawin N, Kassner H, Genzel Y, Reichl U (2007) Establishment of a mink enteritis vaccine production process in stirred-tank reactor and Wave® Bioreactor microcarrier culture in 1–10L scale. Vaccine 25: 3987–3995 IBS Integra BioScience Website — January 31, 2008

    PubMed  Google Scholar 

  • Ijima H, Nakazawa K, Mizumoto H, Matsushita T, Funatsu K (1998) Formation of a spherical multicellular aggregate (spheroid) of animal cells in the pores of polyurethane foam as a cell culture substratum and its application to a hybrid artificial liver. J Biomater Sci Polym 9: 765–778

    Google Scholar 

  • Iwahori T, Matsuno N, Johjima Y, Konno O, Akashi I, Nakamura Y, Hama K, Iwamoto H, Uchiyama M, Ashizawa T, Nagao T (2005) Radial flow bioreactor for the creation of bioartificial liver and kidney. Transplant Proc 37: 212–214

    PubMed  Google Scholar 

  • Jockwer A, Medronho RA, Wagner R, Anspach FB, Deckwer W-D (2001) The use of hydrocyclones for mammalian cell retention in perfusion bioreactors. In: Lindner-Olsson E, Chatzissavidou N, Lüllau E (eds) Animal Cell Technology: From Target to Market, pp 301–305. Kluwer, Dordrecht

    Google Scholar 

  • Kaiser K (2006) Current Trends in Downstream Processing. 3rd Annual Biologicals Manufacturing, 8–9 March 2006, London, UK

    Google Scholar 

  • Kataoka K, Nagao Y, Nukui T, Akiyama I, Tsuru K, Hayakawa S, Osaka A, Huh NH (2005) An organic-inorganic hybrid scaffold for the culture of HepG2 cells in a bioreactor. Biomat 26: 2509–2516

    Google Scholar 

  • Kawada M, Nagamori S, Aizaki H, Fukaya K, Niiya M, Matsuura T, Sujino H, Hasumura S, Yashida H, Mizutani S, Ikenaga H (1998) Massive culture of human liver cancer cells in a newly developed radial flow bioreactor system: ultrafine structure of functionally enhanced hepatocarcinoma cell lines. In Vitro Cell Dev Biol Anim 34: 109–115

    PubMed  Google Scholar 

  • Kelsey LJ, Pillarella MR, Zydney AL (1990) Heoretical analysis of convective flow profiles in a hollow-fiber membrane bioreactor. Chem Eng Sci 45: 3211–3220

    Google Scholar 

  • Knazek RA, Gullino PM, Frankel DS, Dedrick RL (1972) Cell culture on artificial capillaries: an approach to tissue growth in vitro. Science 178: 65–67

    PubMed  Google Scholar 

  • Kompala DS, Ozturk SS (2006) Optimization of high cell density perfusion bioreactors. In: Ozturk SS, Hu WS (eds) Cell Culture Technology For Pharmaceutical and Cell-Based Therapies. Taylor & Francis, New York

    Google Scholar 

  • Kossen NWF (1994) Scale-up. In: Galindo E, Ramirez OT (eds) Advances in Bioprocess Engineering, pp 53–65. Kluwer, Dordrecht

    Google Scholar 

  • Krahe M (2003) Biochemical Engineering. Ullmann&s Encyclopedia of Industrial Chemistry. http://www.mrw.interscience.wiley.com/ueic/articles/b04_381/frame.html

  • Kunas KT, Keating J (2005) Stirred tank single-use bioreactor: Comparison to traditional stirred bioreactor. bioLOGIC Europe 2005, Geneva, Switzerland (presentation)

    Google Scholar 

  • Kurosawa H, Yasumoto K, Kimura T (2000) Polyurethane membrane as an efficient immobilization carrier for high-density culture of rat hepatocytes in the fixed-bed bioreactor. Biotechnol Bioeng 70: 160–166

    PubMed  Google Scholar 

  • Kwon MS, Kato T, Dojima T, Park EY (2005) Application of a radial-flow bioreactor in the production of beta1,3-N-acetylglucosaminyltransferase-2 fused with GFPuv using stably transformed insect cell lines. Biotechnol Appl Biochem 42: 41–46

    PubMed  Google Scholar 

  • Kyung KH, Gerhardt P (1984) Biotechnol Bioeng 26: 252–256

    PubMed  Google Scholar 

  • Levine B (2007) Making waves in cell therapy: the wave bioreactor for the generation of adherent and non-adherent cells for clinical use. http://www.wavebiotech.com/pdf/literature/ISCT_2007_Levine_Final.pdf.Cited January 3, 2008

  • Lipman NS, Jackson LR (1998) Hollow fibre bioreactors: an alternative to murine ascites for small scale (<1 gram) monoclonal antibody production. Research Immunol 149: 571–576

    Google Scholar 

  • Lisica S (2004) Energieeintrag in Wave-Bioreaktoren. Modelling Approaches, University of Applied Sciences Wädenswil, Switzerland, unpublished

    Google Scholar 

  • Looby D, Racher AJ, Griffiths JB, Dowsett AB (1990) The immobilization of animal cells in fixed bed and fluidized porous glass sphere bioreactors. In: de Bont JAM, Visser J, Mattiasson B, Tramper J (eds) Physiology of Immobilized Cells. (Elsevier Science B.V, pp 255–264. Amsterdam, Netherlands

    Google Scholar 

  • Lu JT, Chung YC, Chan ZR, Hu YC (2005) A novel oscillating bioreactor BelloCell: implications for insect cell culture and recombinant protein production. Biotechnol Lett 27: 1059–1065

    PubMed  Google Scholar 

  • Lüdemann I, Pörtner R, Schaefer C, Schick K, Šrámková K, Reher K, Neumaier M, Franék F, Märkl H (1996) Improvement of the culture stability of non-anchorage-dependent animal cells grown in serum-free media through immobilization. Cytotechnol 19: 111–124

    Google Scholar 

  • Lundgren B, Bliiml G (1998) Microcarriers in cell culture production. In: Subramanian G (ed) Bioseparation and Bioprocessing — A Handbook. Wiley-VCH, New York

    Google Scholar 

  • Ma N, Mollet M, Chalmers JJ (2006) Aeration, mixing and hydrodynamics. In: Ozturk SS, Hu WS (eds) Cell Culture Technology for Pharmaceutical and Cell-Based Therapies. Taylor & Francis, New York

    Google Scholar 

  • Märkl H (1989) Folien und Membranen als neue Elemente im Fermenterbau. Forum Mikrobiologie 5: 234–237

    Google Scholar 

  • Manual “Cytopilot” (2007) GE Healthcare. http://www1.gelifesciences.com

  • Matsushita T, Ketayama M, Kamihata K, Funatsu K (1990) Anchorage-dependent mammalian cell culture using polyurethane foam as a new substratum for cell attachment. Appl Microbiol Biotechnol 33: 287–290

    PubMed  Google Scholar 

  • McDonogh RM, Bauser H, Stroh N, Chmiel H (1992) Separation efficiency of membranes in biotechnology: an experimental and mathematical study of flux control. Eng Sci 47: 271–279

    Google Scholar 

  • McTaggart S, Al-Rubeai M (2000) Effects of culture parameters on the production of retroviral vectors by a human packaging cell line. Biotechnol Prog 16: 859–865

    PubMed  Google Scholar 

  • Mehaia MA, Cheryan M (1984) Hollow fiber bioreactor for ethanol production: Application to the conversion of lactose by Kluyveromyces fragilis. Enzyme Microb Technol 6: 117–120

    Google Scholar 

  • Merten OW, Cruz PE, Rochette C, Geny-Fiamma C, Bouquet C, Goncalves D, Danos O, Carrondo MJT (2001) Comparison of different bioreactor systems for the production of high titer retroviral vectors. Biotechnol Prog 17: 326–335

    PubMed  Google Scholar 

  • Meuwly F, Ruffieux PA, Kadouri A, von Stockar U (2007) Packed-bed bioreactors for mammalian cell culture: Bioprocess and biomedical applications. Biotechnol Adv 25: 45–56

    PubMed  Google Scholar 

  • Mishra VP, Joshi JB (1994) Flow generated by a disc turbine. 4. Multiple-impellers. Chem Eng Res Des 73: 657–668

    Google Scholar 

  • Miyoshi H, Yanagi K, Fukuda H, Ohshima N (1994) Long-term continuous culture of hepatocytes in a packed-bed bioreactor utilizing porous resin. Biotechnol Bioeng 43: 635–644

    PubMed  Google Scholar 

  • Moro AM, Rodrigues MT, Gouvea MN, Silvestri ML, Kalil JE, Raw I (1994) Multiparametric analyses of hybridoma growth on glass cylinders in a packed-bed bioreactor system with internal aeration. Serum-supplemented and serum-free media comparison for MAb production. J Immunol Meth 176: 67–77

    Google Scholar 

  • Moser A (1985) Special cultivation techniques. In: Rehm HJ, Reed G (eds) Biotechnology, vol. 2, pp 311–347. VCH, Weinheim

    Google Scholar 

  • Mulder M (1990) Basic Principles of Membrane Technology. Kluwer, Dordrecht, The Netherlands

    Google Scholar 

  • Nagata S (1975) Mixing: Principles and Applications. Kodansha, Tokyo

    Google Scholar 

  • Nehring D, Gonzalez R, Pörtner R, Czermak P (2006) Experimental and modelling study of different process modes for retroviral production in a fixed bed bioreactor. J Biotechnol 122: 239–253

    PubMed  Google Scholar 

  • Nienow AW (1990) Gas dispersion performance in fermeter operation. Chem Eng Prog 86: 61–71

    Google Scholar 

  • Nienow AW, Langheinrich C, Stevenson NC, Emery AN, Clayton TM, Slater NKH (1996) Homogenisation and oxygen transfer rates in large agitated and sparged animal cell bioreactors: Some implications for growth and production. Cytotechnol 22: 87–94

    Google Scholar 

  • Noll TBM, Wandrey C (1997) On-line biomass monitoring of immobilised hybridoma cells by dielectrical measurements. In: Carrondo MJT, Griffiths JB, Moreira JLP (eds) Animal Cell Technology: from Vaccine to Genetic Medicine, pp 289–294. Kluwer, Dordrecht

    Google Scholar 

  • Ong CP, Pörtner R, Märkl H, Yamazaki Y, Yasuda K, Matsumura M (1994) High density cultivation of hybridoma in charged porous carriers. J Biotechnol 34: 259–268

    PubMed  Google Scholar 

  • Ozturk SS (2007) Comparison of product quality: Disposable and stainless steel bioreactor. BioProduction 2007, Berlin, Germany (presentation)

    Google Scholar 

  • Park S, Stephanopoulos G (1993) Packed bed bioreactor with porous ceramic beads for animal cell culture. Biotechnol Bioeng 41: 25–34

    PubMed  Google Scholar 

  • Porter MC, Michaels AS (1970) Membrane ultrafiltration. Chem Tech 1: 56–61

    Google Scholar 

  • Pörtner R (1998) Reaktionstechnik der Kultur tierischer Zellen. Shaker Verlag, Aachen

    Google Scholar 

  • Pörtner R (ed) (2007) Animal Cell Biotechnology — Methods and Protocols. Humana Press, Clifton, UK

    Google Scholar 

  • Pörtner R, Lüdemann I, Märkl H (1997) Dialysis cultures with immobilized hybridoma cells for effective production of monoclonal antibodies. Cytotechnol 23: 39–45

    Google Scholar 

  • Pörtner R, Lüdemann I, Reher K, Neumaier M, Märkl H (1998) Fixed-bed dialysis culture of a transfectoma cell line producing chimeric Fab-fragments with “nutrient-splif”-feeding strategy. Biotechnol Technol 12: 501–505

    Google Scholar 

  • Pörtner R, Märkl H (1998) Dialysis cultures. Appl Microbiol Biotechnol 50: 403–414

    PubMed  Google Scholar 

  • Pörtner R, Märkl H, Fassnacht D (1999) Immobilization of Mammalian Cells in Fixed Bed Bioreactors. Bioforum. Bioresearch plus Biotechnology. G.I.T. Verlag, Darmstadt, Germany

    Google Scholar 

  • Pörtner R, Platas Barradas OBJ (2007) Cultivation of mammalian cells in fixed bed reactors. In: Pörtner R (ed) Animal Cell Biotechnology — Methods and Protocols. Humana Press, Clifton, UK

    Google Scholar 

  • Pörtner R, Platas OB, Fassnacht D, Nehring D, Czermak P, Märkl H (2007) Fixed bed reactors for the cultivation of mammalian cells: design, performance and scale-up. Open Biotechnol J 1: 41–46

    Google Scholar 

  • Ray NG, Karkare SB, Runstadler PW (1989) Cultivation of hybridoma cells in continuous cultures: Kinetics of growth and product formation. Biotechnol Bioeng 33: 724–730

    PubMed  Google Scholar 

  • Ray NG, Tung AS, Hayman EG, Vorunakis JN, Rundstadler PW (1990) Continuous cell cultures in fluidized-bed bioreactors — cultivation of hybridomas and recombinant chines hamster ovary cells immobilized in collagen micropheres. Ann NY Sci 589: 443–457

    Google Scholar 

  • Reiter M, Blüml G, Gaida T, Zach N, Doblhoff-Dier O, Unterluggauer F, Noe M, Plail R, Huss S, Katinger H (1991) Modular Integrated Fluidized Bed Bioreactor Technology. Bio/Technology 9:1100–1102

    PubMed  Google Scholar 

  • Schlegel HG, Doelle HW, Fiechter A, Yamada H, Shimizu S, Becker Th, Breithaupt D, Kasper C, Liese A, Lütz St, Pörtner R, Sell D, Stahl F, Suck K, Ulber R, Wegener J, Würges K, Zorn H (2007) Biotechnology. In: Ullmann’s Encyclopedia of Industrial Chemistry

    Google Scholar 

  • Schonberg JA, Beifort G (1987) Enhanced nutrient transport in hollow fiber perfusion bioreactors: a theoretical analysis. Biotechnol Prog 3: 80–89

    Google Scholar 

  • Sendresen C, Fassnacht D, Benati C, Pörtner R (2001) Possible strategies for the production of viral vector: the role of the engineering design. In: Lindner-Olsson E, Chatzissavidou N, Lüllau E (eds) Animal Cell Technology: From Target to Market, pp 538–540. Kluwer, Dordrecht, Netherlands

    Google Scholar 

  • Simpson N, Milner A, Al-Rubeai M (1997) Prevention of hybridoma cell death by Bcl-2 during suboptimal culture conditions. Biotechnol Bioeng 54: 1–16

    PubMed  Google Scholar 

  • Slivac I, Sráek VG, Radoševic K, Kmetiá I, Kniavald Z (2006) Aujeszky’s disease virus production in disposable bioreactor. J Biosci 3: 363–368

    Google Scholar 

  • Spier RE, Griffiths B (1984) An examination of the data and concepts germane to the oxygenation of cultured animal cells. Dev Biol Stand 55: 81–92

    Google Scholar 

  • Starfing EH (1896) On the absorption of fluid from the convective tissue space. J Physiol 19: 312–326

    Google Scholar 

  • Strathmann H (1979) Trennung von molekularen Mischungen mit Hilfe synthetischer Membranen. Dr. Dietrich Steinkopf Verlag, Darmstadt

    Google Scholar 

  • Thelwall PE, Anthony ML, Fassnacht D, Pörtner R, Brindle KM (1998) Analysis of cell growth in a fixed bed bioreactor using magnetic resonance spectroscopy and imaging. In: Merten OW, Perrin P, Griffiths JB (eds) New Developments and New Applications in Animal Cell Technology, pp 627–633. Kluwer, The Netherlands

    Google Scholar 

  • Thermo Fisher Scientific (2007) Application note: AN003 Rev 1

    Google Scholar 

  • Varley J, Birch J (1999) Reactor design for large scale suspension animal cell culture. Cytotechnol 29:177–205

    Google Scholar 

  • Vick Roy TB, Mandel DK, Dea DK, Blanch HW, Wilke CR (1983) The application of recycle to continuous fermentative lactic acid production. Biotechnol Lett 5: 665–670

    Google Scholar 

  • Voisard D, Meuwly F, Ruffieux PA, Baer G, Kadouri A (2003) Potential of cell retention techniques for large-scale high-density perfusion culture of suspended mammalian cells. Biotechnol Bioeng 80: 751–765

    Google Scholar 

  • Wang G, Zhang W, Jackfin C, Freedman D, Eppstein L, Kadouri A (1992) Modified CelliGen-packed bed bioreactors for hybridoma cell cultures. Cytotechnol 9: 41–49

    Google Scholar 

  • Warnock JN, Bratch K, Al-Rubeai M (2005) Packed bed bioreactors. In: Chauduri J, Al-Rubeai M (eds) Bioreactors for Tissue Engineering. Springer, Dordrecht, The Netherlands

    Google Scholar 

  • Weber W, Weber E, Geisse S, Memmert K (2002) Optimization of protein expression and establishment of the wave bioreactor for baculovirus/insect cell culture. Cytotechnol 38: 77–85

    Google Scholar 

  • Wei J, Russ MB (1977) Convection and diffusion in tissues and tissue cultures. J Theor Biol 66: 775–787

    PubMed  Google Scholar 

  • Werther J (2007) Fluidized-bed bioreactors. In: Ullmann’s Encyclopedia of Industrial Chemistry, Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

    Google Scholar 

  • Yamashita Y, Shimada M, Tsujita E, Tanaka S, Ijima H, Nakazawa K, Sakiyama R, Fukuda J, Ueda T, Funatsu K, Sugimachi K (2001) Polyurethane foam/spheroid culture system using human hepatoblastoma cell line (Hep G2) as a possible new hybrid artificial liver. Cell Transplant 10: 717–722

    PubMed  Google Scholar 

  • Yang ST, Luo J, Chen C (2004) A fibrous-bed bioreactor for continuous production of monoclonal antibody by hybridoma. Adv Biochem Eng Biotechnol 87: 61–96

    PubMed  Google Scholar 

  • Yoshida H, Mizutani S, Ikenaga H (1993) Production of monoclonal antibodies with a radial-flow bioreactor. In: Kaminogawa S et al. (eds) Animal Cell Technology: Basic and Applied Aspects. Kluwer, Dordrecht, Boston, London, 5, 347–353

    Google Scholar 

  • Zambaux JP (2007) How synergy answers the biotech industry needs. BioProduction 2007, Berlin, Germany (presentation)

    Google Scholar 

  • Zijlstra G (2007) Scale-up of a PER.C6® fed-batch process in 50 and 250L Hyclone single bioreactors compared to 50L and 250L stainless steel bioreactors. 20th ESACT Meeting 2007, Dresden, Germany (poster)

    Google Scholar 

Complementary Reading

  • Biotechnology by Open Learning: Bioreactor Design and Product Yield (1992). Butterworth-Heinemann, London

    Google Scholar 

  • Butler M (2004) Animal Cell Culture Technology — The Basics, 2nd ed. Oxford University Press, New York

    Google Scholar 

  • Chisti Y (2000) Animal-cell damage in sparged bioreactors. Trends Biotechnol 10: 420–432

    Google Scholar 

  • Doran PM (2006) Bioprocess Engineering Principles. Academic Press, London

    Google Scholar 

  • Eibl R, Eibl D (2006) Design and use of the wave bioreactor for plant cell culture. In: Dutta Gupta S, Ibaraki Y (eds) Plant Tissue Culture Engineering, Series: Focus on Biotechnology, vol 6. Springer, Dordrecht, pp 203–227

    Google Scholar 

  • Eibl R, Eibl D (2008) Application of disposable bag-bioreactor in tissue engineering and for the production of therapeutic agents. In: Scheper T (ed) Advances in biochemical engineering/biotechnology. Springer, Berlin Heidelberg, in press.

    Google Scholar 

  • Krahe M (2003) Biochemical Engineering. Ullmann’s Encyclopedia of Industrial Chemistry. http://www.mrw.interscience.wiley.com/ueic/articles/b04_381/frame.html

  • Lundgren B, Blüml G (1998) Microcarriers in cell culture production. In: G. Subramanian: Bioseparation and Bioprocessing — A Handbook. Wiley-VCH, New York

    Google Scholar 

  • Meuwly F, Ruffieux PA, Kadouri A, von Stockar U (2007) Packed-bed bioreactors for mammalian cell culture: Bioprocess and biomedical applications. Biotechnol Adv 25: 45–56

    PubMed  Google Scholar 

  • Mulder M (1991) Basic principles of membrane technology. Kluwer, Dordrecht, The Netherlands

    Google Scholar 

  • Ozturk SS, Hu WS (eds) (2006) Cell Culture Technology For Pharmaceutical and Cell-Based Therapies. Taylor & Francis, New York

    Google Scholar 

  • Pörtner R (ed) (2007) Animal Cell Biotechnology — Methods and Protocols. Humana Press, Clifton, UK

    Google Scholar 

  • Shuler ML, Kargi F (2002) Bioprocess Engineering — Basic Concepts. Prentice Hall PTR, Englewood Cliffs, NJ

    Google Scholar 

  • Varley J, Birch J (1999) Reactor design for large scale suspension animal cell culture. Cytotechnol 29:177–205

    Google Scholar 

  • Voisard D, Meuwly F, Ruffieux PA, Baer G, Kadouri A (2003) Potential of cell retention techniques for large-scale high-density perfusion culture of suspended mammalian cells. Biotechnol Bioeng 80: 751–765

    Google Scholar 

  • Werther J (2007) Fluidized-bed bioreactors. In: Ullmann’s Encyclopedia of Industrial Chemistry. Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Chemical Engineering and Materials, University of Calabria, I-87030, Rende (CS), Italy

    G. Catapano

  2. Institute of Biopharmaceutical Technology, University of Applied Sciences Giessen-Friedberg, Giessen, Germany

    P. Czermak

  3. Department of Chemical Engineering, Kansas State University, Durland Hall 105, KS, 66506-5102, Manhattan, USA

    P. Czermak

  4. Department of Life Sciences and Facility Management, Institute of Biotechnology, Zurich University of Applied Sciences, Wädenswil, Switzerland

    R. Eibl & D. Eibl

  5. Institute of Bioprocess and Biosystems Engineering, Hamburg University of Technology (TUHH), Denickestr. 15, D-21073, Hamburg, Germany

    R. Pörtner

Authors
  1. G. Catapano
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. P. Czermak
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. R. Eibl
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. D. Eibl
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. R. Pörtner
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

Copyright information

© 2009 Springer-Verlag Berlin Heidelberg

About this chapter

Cite this chapter

Catapano, G., Czermak, P., Eibl, R., Eibl, D., Pörtner, R. (2009). Bioreactor Design and Scale-Up. In: Cell and Tissue Reaction Engineering. Principles and Practice. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-540-68182-3_5

Download citation

Publish with us

Policies and ethics

Search

Navigation