Abstract
The interest for perfusion is increasing nowadays. This new focus has emerged from a synergy of a demand for disposable equipment and the availability of robust cell separation device, as well as the need for higher flexibility and lower investment cost. The cell separation devices mostly used today are based on filtration, i.e. alternating flow filtration, tangential flow filtration, spin-filter, or acceleration/gravity, i.e. inclined settler, centrifuge, acoustic settler. This paper gives an introduction to the basic concepts of perfusion and its practical implementation. It reviews the actual cell separation devices and describes the approaches used in the field to develop and optimize the perfusion processes.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Adams T, Noack U, Frick T, Greller G, Fenge C (2011) Increasing efficiency in protein and cell production by combining single-use bioreactor technology and perfusion. BioPharm Int Suppl 24(5):4–11
Ahn WS, Jeon JJ, Jeong YR, Lee SJ, Yoon SK (2008) Effect of culture temperature on erythropoietin production and glycosylation in a perfusion culture of recombinant CHO cells. Biotechnol Bioeng 101(6):1234–1244. doi:10.1002/bit.22006
Amos B, Al-Rubeai M, Emery AN (1994) Hybridoma growth and monoclonal antibody production in a dialysis perfusion system. Enzym Microb Technol 16(8):688–695
Angepat S, Gorenflo VM, Piret JM (2005) Accelerating perfusion process optimization by scanning non-steady-state responses. Biotechnol Bioeng 92(4):472–478. doi:10.1002/bit.20635
Apelman S (1992) Separation of animal cells in continuous cell culture systems. In: Murakami H, Shirahata S, Tachibana H (eds) Animal cell technology: basic & applied aspects. Kluwer, Dordrecht, pp 149–154
Apelman S, Bjorling T (1991) New centrifugal separator. Biotech Forum Eur 8:356–358
Avgerinos GC, Drapeau D, Socolow JS, Mao JI, Hsiao K, Broeze RJ (1990) Spin filter perfusion system for high density cell culture: production of recombinant urinary type plasminogen activator in CHO cells. Biotechnology (N Y) 8(1):54–58
Batt BC, Davis RH, Kompala DS (1990) Inclined sedimentation for selective retention of viable hybridomas in a continuous suspension bioreactor. Biotechnol Prog 6(6):458–464. doi:10.1021/bp00006a600
Bleckwenn NA, Golding H, Bentley WE, Shiloach J (2005) Production of recombinant proteins by vaccinia virus in a microcarrier based mammalian cell perfusion bioreactor. Biotechnol Bioeng 90(6):663–674. doi:10.1002/bit.20423
Bollin F, Dechavanne V, Chevalet L (2011) Design of experiment in CHO and HEK transient transfection condition optimization. Protein Expr Purif 78(1):61–68. doi:10.1016/j.pep.2011.02.008
Boycott AE (1920) Sedimentation of blood corpuscles. Nature 104:532–538
Caron A, Tom R, Kamen A, Massie B (1994) Baculovirus expression system scaleup by perfusion of high-density Sf-9 cell cultures. Biotechnol Bioeng 43(9):881–891
Carvell JP, Dowd JE (2006) On-line measurements and control of viable cell density in cell culture manufacturing processes using radio-frequency impedance. Cytotechnology 50(1–3):35–48. doi:10.1007/s10616-005-3974-x
Castilho LR, Medronho RA (2002) Cell retention devices for suspended-cell perfusion cultures. Adv Biochem Eng Biotechnol 74:129–169
Chatzisavido N, Bjorling T, Fenge C, Boork S, Lindner-Olsson E, Apelman S (1993) A continuous cell centrifuge for lab scale perfusion processes of mammalian cells. In: Kobayashi T, Kitagawa Y, Okumura K (eds) Animal cell technology: basic and applied aspects. Kluwer, Dordrecht, pp 463–468
Chen ZL, Wu BC, Liu H, Liu XM, Huang PT (2004) Temperature shift as a process optimization step for the production of pro-urokinase by a recombinant Chinese hamster ovary cell line in high-density perfusion culture. J Biosci Bioeng 97(4):239–243. doi:10.1016/S1389-1723(04)70198-X
Choo CY, Tian Y, Kim WS, Blatter E, Conary J, Brady CP (2007) High-level production of a monoclonal antibody in murine myeloma cells by perfusion culture using a gravity settler. Biotechnol Prog 23(1):225–231. doi:10.1021/bp060231v
Chotteau V, Björling T, Boork S, Brink-Nilsson H, Chatzissavidou N, Fenge C, Lindner-Olsson E, Olofsson M, Rosenquist J, Sandberg H, Smeds A-L, Drapeau D (2001) Development of a large scale process for the production of recombinant truncated factor VIII in CHO cells under cell growth arrest conditions. In: L-Oecnl E (ed) From target to market, Proceedings of the 17th ESACT meeting, Kluwer, Tylösand, 10–14 June 2001, pp 287–292
Chotteau V, Bjorling T, Gretander A, Tuvesson O, Dudel U (2002) Evaluation of cell separation devices for the perfusion of animal cell culture in biopharmaceutical processes. In: Cell culture engineering VII, Snowmass Village, 1–6 Apr 2002
Chotteau V, Clincke M-F, Zhang Y, Thoring L (2013) Achievement of extreme cell densities in different perfusion systems and impact of the cell density In: Integrated continuous biomanufacturing, ECI conference, Castelldefels, 20–24 Oct 2013
Chotteau V, Zhang Y, Clincke MF (2014a) Very high cell density in perfusion of CHO cells by ATF, TFF, Wave bioreactor and/or CellTank technologies – impact of cell density and applications. In: Subramanian G (ed) Continuous processing in biopharmaceutical manufacturing. Wiley-VCH Weinheim (to appear)
Chotteau V, Zhang Y, Thoring L (2014b) Extreme cell densities of CHO cells in perfused stirred tank bioreactor. In: Cell culture engineering XIV, Quebec City, 4–9 May 2014
Chu L, Robinson DK (2001) Industrial choices for protein production by large-scale cell culture. Curr Opin Biotechnol 12(2):180–187
Chuppa S, Tsai YS, Yoon S, Shackleford S, Rozales C, Bhat R, Tsay G, Matanguihan C, Konstantinov K, Naveh D (1997) Fermentor temperature as a tool for control of high-density perfusion cultures of mammalian cells. Biotechnol Bioeng 55(2):328–338. doi:10.1002/(SICI)1097-0290(19970720)55:2<328::AID-BIT10>3.0.CO;2-D
Clincke MF, Molleryd C, Zhang Y, Lindskog E, Walsh K, Chotteau V (2011) Study of a recombinant CHO cell line producing a monoclonal antibody by ATF or TFF external filter perfusion in a WAVE Bioreactor. BMC Proc 5(Suppl 8):P105. doi:10.1186/1753-6561-5-S8-P105
Clincke MF, Molleryd C, Samani PK, Lindskog E, Faldt E, Walsh K, Chotteau V (2013a) Very high density of Chinese hamster ovary cells in perfusion by alternating tangential flow or tangential flow filtration in WAVE Bioreactor-part II: applications for antibody production and cryopreservation. Biotechnol Prog 29(3):768–777. doi:10.1002/btpr.1703
Clincke MF, Molleryd C, Zhang Y, Lindskog E, Walsh K, Chotteau V (2013b) Very high density of CHO cells in perfusion by ATF or TFF in WAVE bioreactor. Part I. Effect of the cell density on the process. Biotechnol Prog 29(3):754–767. doi:10.1002/btpr.1704
Cortin V, Thibault J, Jacob D, Garnier A (2004) High-titer adenovirus vector production in 293S cell perfusion culture. Biotechnol Prog 20(3):858–863
Dalm MC, Cuijten SM, van Grunsven WM, Tramper J, Martens DE (2004) Effect of feed and bleed rate on hybridoma cells in an acoustic perfusion bioreactor: part I. Cell density, viability, and cell-cycle distribution. Biotechnol Bioeng 88(5):547–557. doi:10.1002/bit.20287
Dalm MC, Jansen M, Keijzer TM, van Grunsven WM, Oudshoorn A, Tramper J, Martens DE (2005) Stable hybridoma cultivation in a pilot-scale acoustic perfusion system: long-term process performance and effect of recirculation rate. Biotechnol Bioeng 91(7):894–900. doi:10.1002/bit.20552
de la Broise D, Noiseux M, Lemieux R, Massie B (1991) Long-term perfusion culture of hybridoma: a “grow or die” cell cycle system. Biotechnol Bioeng 38:781–787
Deo YM, Mahadevan MD, Fuchs R (1996) Practical considerations in operation and scale-up of spin-filter based bioreactors for monoclonal antibody production. Biotechnol Prog 12(1):57–64. doi:10.1021/bp950079p
Dowd JE, Kwok KE, Piret JM (2001) Glucose-based optimization of CHO-cell perfusion cultures. Biotechnol Bioeng 75(2):252–256
Dowd JE, Jubb A, Kwok KE, Piret JM (2003) Optimization and control of perfusion cultures using a viable cell probe and cell specific perfusion rates. Cytotechnology 42(1):35–45. doi:10.1023/A:1026192228471
Ducommun P, Bolzonella I, Rhiel M, Pugeaud P, von Stockar U, Marison IW (2001) On-line determination of animal cell concentration. Biotechnol Bioeng 72(5):515–522
Ducommun P, Kadouri A, von Stockar U, Marison IW (2002a) On-line determination of animal cell concentration in two industrial high-density culture processes by dielectric spectroscopy. Biotechnol Bioeng 77(3):316–323
Ducommun P, Ruffieux P, Kadouri A, von Stockar U, Marison IW (2002b) Monitoring of temperature effects on animal cell metabolism in a packed bed process. Biotechnol Bioeng 77(7):838–842
Elsayed EA, Wagner R (2011) Application of hydrocyclones for continuous cultivation of SP-2/0 cells in perfusion bioreactors: effect of hydrocyclone operating pressure. BMC Proc 5(Suppl 8):P65. doi:10.1186/1753-6561-5-S8-P65
Emery AN, Jan DC, Al-Rubeai M (1995) Oxygenation of intensive cell-culture system. Appl Microbiol Biotechnol 43(6):1028–1033
Esclade LRJ, Carrel S, Peringer P (1991) Influence of the screen material on the fouling of spin filters. Biotechnol Bioeng 38(2):159–168
Figueredo-Cardero A, Chico E, Castilho LR, Medronho RA (2009) CFD simulation of an internal spin-filter: evidence of lateral migration and exchange flow through the mesh. Cytotechnology 61(1–2):55–64. doi:10.1007/s10616-009-9242-8
Galvez J, Lecina M, Sola C, Cairo JJ, Godia F (2012) Optimization of HEK-293S cell cultures for the production of adenoviral vectors in bioreactors using on-line OUR measurements. J Biotechnol 157(1):214–222. doi:10.1016/j.jbiotec.2011.11.007
Genzel Y, Vogel T, Buck J, Behrendt I, Ramirez DV, Schiedner G, Jordan I, Reichl U (2014) High cell density cultivations by alternating tangential flow (ATF) perfusion for influenza A virus production using suspension cells. Vaccine. doi:10.1016/j.vaccine.2014.02.016
Goh JS, Liu Y, Liu H, Chan KF, Wan C, Teo G, Zhou X, Xie F, Zhang P, Zhang Y, Song Z (2014) Highly sialylated recombinant human erythropoietin production in large-scale perfusion bioreactor utilizing CHO-gmt4 (JW152) with restored GnT I function. Biotechnol J 9(1):100–109. doi:10.1002/biot.201300301
Goldman MH, James DC, Rendall M, Ison AP, Hoare M, Bull AT (1998) Monitoring recombinant human interferon-gamma N-glycosylation during perfused fluidized-bed and stirred-tank batch culture of CHO cells. Biotechnol Bioeng 60(5):596–607
Gorenflo VM, Smith L, Dedinsky B, Persson B, Piret JM (2002) Scale-up and optimization of an acoustic filter for 200 L/day perfusion of a CHO cell culture. Biotechnol Bioeng 80(4):438–444. doi:10.1002/bit.10386
Gorenflo VM, Angepat S, Bowen BD, Piret JM (2003) Optimization of an acoustic cell filter with a novel air-backflush system. Biotechnol Prog 19(1):30–36. doi:10.1021/bp025625a
Gorenflo VM, Pfeifer TA, Lesnicki G, Kwan EM, Grigliatti TA, Kilburn DG, Piret JM (2004) Production of a self-activating CBM-factor X fusion protein in a stable transformed Sf9 insect cell line using high cell density perfusion culture. Cytotechnology 44(3):93–102. doi:10.1007/s10616-005-0703-4
Gorenflo VM, Chow VS, Chou C, Piret JM (2005a) Optical analysis of perfusion bioreactor cell concentration in an acoustic separator. Biotechnol Bioeng 92(4):514–518. doi:10.1002/bit.20693
Gorenflo VM, Ritter JB, Aeschliman DS, Drouin H, Bowen BD, Piret JM (2005b) Characterization and optimization of acoustic filter performance by experimental design methodology. Biotechnol Bioeng 90(6):746–753. doi:10.1002/bit.20476
Grandics P, Szathmary S, Szathmary Z, O’Neill T (1991) Integration of cell culture with continuous, on-line sterile downstream processing. Ann N Y Acad Sci 646:322–333
Griffiths B (2001) Scale-up of suspension and anchorage-dependent animal cells. Mol Biotechnol 17(3):225–238. doi:10.1385/MB:17:3:225
Griffiths JP, Pirt SJ (1967) The uptake of amino acids by mouse cells (strain LS) during growth in batch culture and chemostat culture: the influence of cell growth rate. Proc R Soc Lond Sers B Contain Pap Biol Character R Soc 168(1013):421–438
Handa-Corrigan A, Nikolay S, Jeffery D, Heffernan B, Young A (1992) Controlling and predicting monoclonal antibody production in hollow-fiber bioreactors. Enzym Microb Technol 14(1):58–63
Hecht V, Duvar S, Ziehr H, Burg J, Jockwer A (2014) Efficiency improvement of an antibody production process by increasing the inoculum density. Biotechnol Prog. doi:10.1002/btpr.1887
Heidemann R, Zhang C, Qi H, Larrick Rule J, Rozales C, Park S, Chuppa S, Ray M, Michaels J, Konstantinov K, Naveh D (2000) The use of peptones as medium additives for the production of a recombinant therapeutic protein in high density perfusion cultures of mammalian cells. Cytotechnology 32(2):157–167. doi:10.1023/A:1008196521213
Henry O, Kwok E, Piret JM (2008) Simpler noninstrumented batch and semicontinuous cultures provide mammalian cell kinetic data comparable to continuous and perfusion cultures. Biotechnol Prog 24(4):921–931. doi:10.1002/btpr.17
Hiller GW, Clark DS, Blanch HW (1993) Cell retention-chemostat studies of hybridoma cells-analysis of hybridoma growth and metabolism in continuous suspension culture in serum-free medium. Biotechnol Bioeng 42(2):185–195. doi:10.1002/bit.260420206
Hiller GW, Clark DS, Blanch HW (1994) Transient responses of hybridoma cells in continuous culture to step changes in amino acid and vitamin concentrations. Biotechnol Bioeng 44(3):303–321. doi:10.1002/bit.260440308
Himmelfarb P, Thayer PS, Martin HE (1969) Spin filter culture: the propagation of mammalian cells in suspension. Science 164(3879):555–557
Jardin BA, Montes J, Lanthier S, Tran R, Elias C (2007) High cell density fed batch and perfusion processes for stable non-viral expression of secreted alkaline phosphatase (SEAP) using insect cells: comparison to a batch Sf-9-BEV system. Biotechnol Bioeng 97(2):332–345. doi:10.1002/bit.21224
Jockwer A, Medronho RA, Wagner R, Anspach FB, Deckwer W-D (2001) The use of hydrocyclones for mammalian cell retention in perfusion bioreactors. In: Linder-Olsson E, Chatzissavidou N, Lüllau E (eds) Animal cell technology: from target to market. Kluwer, Dordrecht, pp 301–305
Johnson M, Lanthier S, Massie B, Lefebvre G, Kamen AA (1996) Use of the Centritech Lab centrifuge for perfusion culture of hybridoma cells in protein-free medium. Biotechnol Prog 12(6):855–864. doi:10.1021/bp960072n
Kawahara H, Mitsuda S, Kumazawa E, Takeshita Y (1994) High-density culture of FM-3A cells using a bioreactor with an external tangential-flow filtration device. Cytotechnology 14(1):61–66
Kim JS, Ahn BC, Lim BP, Choi YD, Jo EC (2004) High-level scu-PA production by butyrate-treated serum-free culture of recombinant CHO cell line. Biotechnol Prog 20(6):1788–1796. doi:10.1021/bp025536y
Kim BJ, Chang HN, Oh DJ (2007) Application of a cell-once-through perfusion strategy for production of recombinant antibody from rCHO cells in a Centritech Lab II centrifuge system. Biotechnol Prog 23(5):1186–1197. doi:10.1021/bp0700861
Kim BJ, Oh DJ, Chang HN (2008) Limited use of Centritech Lab II centrifuge in perfusion culture of rCHO cells for the production of recombinant antibody. Biotechnol Prog 24(1):166–174. doi:10.1021/bp070235f
Kinosita K (1949) Sedimentation in tilted vessels. J Colloid Interface Sci 4:166–176
Kompala DS, Ozturk SS (2005) Optimization of high cell density perfusion bioreactors. In: Ozturk SS, Hu W-S (eds) Cell culture technology for pharmaceutical and cell-based therapies. Taylor & Francis, Boca Raton, FL
Konstantinov K, Goudar C, Ng M, Meneses R, Thrift J, Chuppa S, Matanguihan C, Michaels J, Naveh D (2006) The “push-to-low” approach for optimization of high-density perfusion cultures of animal cells. Adv Biochem Eng/Biotechnol 101:75–98
Kuczewski M, Schirmer E, Lain B, Zarbis-Papastoitsis G (2011) A single-use purification process for the production of a monoclonal antibody produced in a PER.C6 human cell line. Biotechnol J 6(1):56–65. doi:10.1002/biot.201000292
Kumar A, Bansal V, Nandakumar KS, Galaev IY, Roychoudhury PK, Holmdahl R, Mattiasson B (2006) Integrated bioprocess for the production and isolation of urokinase from animal cell culture using supermacroporous cryogel matrices. Biotechnol Bioeng 93(4):636–646. doi:10.1002/bit.20719
Kurosawa H, Markl H, Niebuhrredder C, Matsumura M (1991) Dialysis bioreactor with radial-flow fixed-bed for animal-cell culture. J Ferment Bioeng 72(1):41–45
Kyung YS, Peshwa MV, Gryte DM, Hu WS (1994) High density culture of mammalian cells with dynamic perfusion based on on-line oxygen uptake rate measurements. Cytotechnology 14(3):183–190
Lipscomb ML, Mowry MC, Kompala DS (2004) Production of a secreted glycoprotein from an inducible promoter system in a perfusion bioreactor. Biotechnol Prog 20(5):1402–1407. doi:10.1021/bp049973j
Maiorella B, Dorin G, Carion A, Harano D (1991) Crossflow microfiltration of animal cells. Biotechnol Bioeng 37(2):121–126. doi:10.1002/bit.260370205
Mercille S, Johnson M, Lemieux R, Massie B (1994) Filtration-based perfusion of hybridoma cultures in protein-free medium: reduction of membrane fouling by medium supplementation with DNase I. Biotechnol Bioeng 43(9):833–846. doi:10.1002/bit.260430902
Mercille S, Johnson M, Lanthier S, Kamen AA, Massie B (2000) Understanding factors that limit the productivity of suspension-based perfusion cultures operated at high medium renewal rates. Biotechnol Bioeng 67(4):435–450
Meuwly F, von Stockar U, Kadouri A (2004) Optimization of the medium perfusion rate in a packed-bed bioreactor charged with CHO cells. Cytotechnology 46(1):37–47. doi:10.1007/s10616-005-2105-z
Meuwly F, Papp F, Ruffieux PA, Bernard AR, Kadouri A, von Stockar U (2006) Use of glucose consumption rate (GCR) as a tool to monitor and control animal cell production processes in packed-bed bioreactors. J Biotechnol 122(1):122–129. doi:10.1016/j.jbiotec.2005.08.005
Meuwly F, Ruffieux PA, Kadouri A, von Stockar U (2007) Packed-bed bioreactors for mammalian cell culture: bioprocess and biomedical applications. Biotechnol Adv 25(1):45–56. doi:10.1016/j.biotechadv.2006.08.004
Miller WM, Blanch HW, Wilke CR (1988) A kinetic analysis of hybridoma growth and metabolism in batch and continuous suspension culture: effect of nutrient concentration, dilution rate, and pH. Biotechnol Bioeng 32(8):947–965. doi:10.1002/bit.260320803
Nivitchanyong T, Martinez A, Ishaque A, Murphy JE, Konstantinov K, Betenbaugh MJ, Thrift J (2007) Anti-apoptotic genes Aven and E1B-19 K enhance performance of BHK cells engineered to express recombinant factor VIII in batch and low perfusion cell culture. Biotechnol Bioeng 98(4):825–841. doi:10.1002/bit.21479
Noll T, Biselli M (1998) Dielectric spectroscopy in the cultivation of suspended and immobilized hybridoma cells. J Biotechnol 63(3):187–198
Oh HK, So MK, Yang J, Yoon HC, Ahn JS, Lee JM, Kim JT, Yoo JU, Byun TH (2005) Effect of N-Acetylcystein on butyrate-treated Chinese hamster ovary cells to improve the production of recombinant human interferon-beta-1a. Biotechnol Prog 21(4):1154–1164. doi:10.1021/bp050057v
Ozturk SS (1996) Engineering challenges in high density cell culture systems. Cytotechnology 22(1–3):3–16. doi:10.1007/BF00353919
Padawer I, Ling WL, Bai Y (2013) Case study: an accelerated 8-day monoclonal antibody production process based on high seeding densities. Biotechnol Prog 29(3):829–832. doi:10.1002/btpr.1719
Pinto RC, Medronho RA, Castilho LR (2008) Separation of CHO cells using hydrocyclones. Cytotechnology 56(1):57–67. doi:10.1007/s10616-007-9108-x
Pohlscheidt M, Jacobs M, Wolf S, Thiele J, Jockwer A, Gabelsberger J, Jenzsch M, Tebbe H, Burg J (2013) Optimizing capacity utilization by large scale 3000 L perfusion in seed train bioreactors. Biotechnol Prog 29(1):222–229. doi:10.1002/btpr.1672
Rodrigues CA, Fernandes TG, Diogo MM, da Silva CL, Cabral JM (2011) Stem cell cultivation in bioreactors. Biotechnol Adv 29(6):815–829. doi:10.1016/j.biotechadv.2011.06.009
Rodriguez J, Spearman M, Tharmalingam T, Sunley K, Lodewyks C, Huzel N, Butler M (2010) High productivity of human recombinant beta-interferon from a low-temperature perfusion culture. J Biotechnol 150(4):509–518. doi:10.1016/j.jbiotec.2010.09.959
Runstadler PW (1992) The importance of cell physiology to the performance of animal cell bioreactors. Ann N Y Acad Sci 665:380–390
Ryll T, Dutina G, Reyes A, Gunson J, Krummen L, Etcheverry T (2000) Performance of small-scale CHO perfusion cultures using an acoustic cell filtration device for cell retention: characterization of separation efficiency and impact of perfusion on product quality. Biotechnol Bioeng 69(4):440–449
Sandberg H, Lutkemeyer D, Kuprin S, Wrangel M, Almstedt A, Persson P, Ek V, Mikaelsson M (2006) Mapping and partial characterization of proteases expressed by a CHO production cell line. Biotechnol Bioeng 95(5):961–971. doi:10.1002/bit.21057
Schmid G, Wilke CR, Blanch HW (1992) Continuous hybridoma suspension cultures with and without cell retention: kinetics of growth, metabolism and product formation. J Biotechnol 22(1–2):31–40
Searles JA, Todd P, Kompala DS (1994) Viable cell recycle with an inclined settler in the perfusion culture of suspended recombinant Chinese hamster ovary cells. Biotechnol Prog 10(2):198–206. doi:10.1021/bp00026a600
Serra M, Brito C, Correia C, Alves PM (2012) Process engineering of human pluripotent stem cells for clinical application. Trends Biotechnol 30(6):350–359. doi:10.1016/j.tibtech.2012.03.003
Seth G, Hamilton RW, Stapp TR, Zheng L, Meier A, Petty K, Leung S, Chary S (2013) Development of a new bioprocess scheme using frozen seed train intermediates to initiate CHO cell culture manufacturing campaigns. Biotechnol Bioeng 110(5):1376–1385. doi:10.1002/bit.24808
Shen Y, Yanagimachi K (2011) CFD-aided cell settler design optimization and scale-up: effect of geometric design and operational variables on separation performance. Biotechnol Prog 27(5):1282–1296. doi:10.1002/btpr.636
Shevitz J (2000) Fluid filtration system. US Patent 6,544,424
Shirgaonkar IZ, Lanthier S, Kamen A (2004) Acoustic cell filter: a proven cell retention technology for perfusion of animal cell cultures. Biotechnol Adv 22(6):433–444. doi:10.1016/j.biotechadv.2004.03.003
Smith CG, Guillaume J-M, Greenfield PF, Randerson DH (1991) Experience in scale-up of homogeneous perfusion culture for hybridomas. Bioprocess Eng 6(5):213–219
Tang YJ, Ohashi R, Hamel JF (2007) Perfusion culture of hybridoma cells for hyperproduction of IgG(2a) monoclonal antibody in a wave bioreactor-perfusion culture system. Biotechnol Prog 23(1):255–264. doi:10.1021/bp060299a
Tao Y, Shih J, Sinacore M, Ryll T, Yusuf-Makagiansar H (2011) Development and implementation of a perfusion-based high cell density cell banking process. Biotechnol Prog 27(3):824–829. doi:10.1002/btpr.599
Tolbert WR, Feder J, Kimes RC (1981) Large-scale rotating filter perfusion system for high-density growth of mammalian suspension cultures. In Vitro 17(10):885–890
Vallez-Chetreanu F, Fraisse Ferreira LG, Rabe R, von Stockar U, Marison IW (2007) An on-line method for the reduction of fouling of spin-filters for animal cell perfusion cultures. J Biotechnol 130(3):265–273. doi:10.1016/j.jbiotec.2007.04.007
Velez D, Miller L, Macmillan JD (1989) Use of tangential flow filtration in perfusion propagation of hybridoma cells for production of monoclonal-antibodies. Biotechnol Bioeng 33(7):938–940
Vernardis SI, Goudar CT, Klapa MI (2013) Metabolic profiling reveals that time related physiological changes in mammalian cell perfusion cultures are bioreactor scale independent. Metab Eng 19:1–9. doi:10.1016/j.ymben.2013.04.005
Vogel JH, Nguyen H, Giovannini R, Ignowski J, Garger S, Salgotra A, Tom J (2012) A new large-scale manufacturing platform for complex biopharmaceuticals. Biotechnol Bioeng 109(12):3049–3058. doi:10.1002/bit.24578
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 82(7):751–765. doi:10.1002/bit.10629
Wang MD, Yang M, Huzel N, Butler M (2002) Erythropoietin production from CHO cells grown by continuous culture in a fluidized-bed bioreactor. Biotechnol Bioeng 77(2):194–203
Warikoo V, Godawat R, Brower K, Jain S, Cummings D, Simons E, Johnson T, Walther J, Yu M, Wright B, McLarty J, Karey KP, Hwang C, Zhou W, Riske F, Konstantinov K (2012) Integrated continuous production of recombinant therapeutic proteins. Biotechnol Bioeng 109(12):3018–3029. doi:10.1002/bit.24584
Warnock JN, Al-Rubeai M (2006) Bioreactor systems for the production of biopharmaceuticals from animal cells. Biotechnol Appl Biochem 45(Pt 1):1–12. doi:10.1042/BA20050233
Woodside SM, Bowen BD, Piret JM (1998) Mammalian cell retention devices for stirred perfusion bioreactors. Cytotechnology 28(1–3):163–175
Wu P, Ozturk SS, Blackie JD, Thrift JC, Figueroa C, Naveh D (1995) Evaluation and applications of optical cell density probes in mammalian cell bioreactors. Biotechnol Bioeng 45(6):495–502. doi:10.1002/bit.260450606
Xu Z-J, Michaelides EE (2005) A numerical simulation of the Boycott effect. Chem Eng Commun 192:532–549
Yabannavar VM, Singh V, Connelly NV (1992) Mammalian cell retention in a spinfilter perfusion bioreactor. Biotechnol Bioeng 40(8):925–933. doi:10.1002/bit.260400809
Yang WC, Lu J, Kwiatkowski C, Yuan H, Kshirsagar R, Ryll T, Huang YM (2014) Perfusion seed cultures improve biopharmaceutical fed-batch production capacity and product quality. Biotechnol Prog. doi:10.1002/btpr.1884
Yuk IH, Olsen MM, Geyer S, Forestell SP (2004) Perfusion cultures of human tumor cells: a scalable production platform for oncolytic adenoviral vectors. Biotechnol Bioeng 86(6):637–642. doi:10.1002/bit.20158
Zhang S, Handa-Corrigan A, Spier RE (1993) A comparison of oxygenation methods fro high-density perfusion culture of animal cells. Biotechnol Bioeng 41(7):685–692. doi:10.1002/bit.260410702
Zhang J, Collins A, Chen M, Knyazev I, Gentz R (1998) High-density perfusion culture of insect cells with a biosep ultrasonic filter. Biotechnol Bioeng 59(3):351–359
Zhang Y, Stobbe P, Orrego CS, Chotteau V (2014a) Perfusion at very high cell density of CHO cells anchored in a non-woven matrix based bioreactor, manuscript in preparation
Zhang Y, Thoring L, Chotteau V (2014b) A method to optimize the cell specific perfusion rate in perfusion process. In: Cell culture engineering XIV, Quebec City, 4–9 May 2014
Zijlstra G, Hof R, Schilder J (2008) Improved process for the culturing of cells. The Netherlands Patent WO 2008/006494 A1, 17 Jan 2008
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2015 Springer International Publishing Switzerland
About this chapter
Cite this chapter
Chotteau, V. (2015). Perfusion Processes. In: Al-Rubeai, M. (eds) Animal Cell Culture. Cell Engineering, vol 9. Springer, Cham. https://doi.org/10.1007/978-3-319-10320-4_13
Download citation
DOI: https://doi.org/10.1007/978-3-319-10320-4_13
Published:
Publisher Name: Springer, Cham
Print ISBN: 978-3-319-10319-8
Online ISBN: 978-3-319-10320-4
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)