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Cell Culture Process Operations for Recombinant Protein Production

Part of the Advances in Biochemical Engineering/Biotechnology book series (ABE,volume 139)

Keywords

  • Batch
  • Cell culture
  • Continuous processing
  • Data analysis
  • Fed-batch
  • Lactate metabolism
  • Perfusion

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  • DOI: 10.1007/10_2013_252
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References

  1. Heidemann R, Lunse S, Tran D, Zhang C (2010) Characterization of cell-banking parameters for the cryopreservation of mammalian cell lines in 100-mL cryobags. Biotechnol Prog 26(4):1154–1163. doi:10.1002/btpr.427

    CAS  Google Scholar 

  2. 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

    CAS  CrossRef  Google Scholar 

  3. Yuk IH, Baskar D, Duffy PH, Hsiung J, Leung S, Lin AA (2011) Overcoming challenges in WAVE Bioreactors without feedback controls for pH and dissolved oxygen. Biotechnol Prog 27(5):1397–1406. doi:10.1002/btpr.659

    CAS  CrossRef  Google Scholar 

  4. Wlaschin KF, Hu WS (2006) Fedbatch culture and dynamic nutrient feeding. Adv Biochem Eng Biotechnol 101:43–74. doi:10.1007/10_015

    CAS  Google Scholar 

  5. Boedeker BG (2001) Production processes of licensed recombinant factor VIII preparations. Semin Thromb Hemost 27(4):385–394. doi:10.1055/s-2001-16891

    CAS  CrossRef  Google Scholar 

  6. Sen A, Kallos MS, Behie LA (2002) Passaging protocols for mammalian neural stem cells in suspension bioreactors. Biotechnol Prog 18(2):337–345. doi:10.1021/bp010150t

    CAS  CrossRef  Google Scholar 

  7. Freyer JP, Sutherland RM (1986) Regulation of growth saturation and development of necrosis in EMT6/Ro multicellular spheroids by the glucose and oxygen supply. Cancer Res 46(7):3504–3512

    CAS  Google Scholar 

  8. Moreira JL, Feliciano AS, Santana PC, Cruz PE, Aunins JG, Carrondo MJT (1994) Repeated-batch cultures of baby hamster kidney cell aggregates in stirred vessels. Cytotechnology 15(1–3):337–349. doi:10.1007/BF00762409

    CAS  CrossRef  Google Scholar 

  9. Moreira JL, Alves PM, Aunins JG, Carrondo MJT (1995) Hydrodynamic effects on BHK cells grown as suspended natural aggregates. Biotechnol Bioeng 46(4):351–360

    CAS  CrossRef  Google Scholar 

  10. Moreira JL, Santana PC, Feliciano AS, Cruz PE, Racher AJ, Griffiths JB, Carrondo MJT (1995) Effect of viscosity upon hydrodynamically controlled natural aggregates of animal cells grown in stirred vessels. Biotechnol Prog 11(5):575–583

    CAS  CrossRef  Google Scholar 

  11. Sen A, Kallos MS, Behie LA (2001) Effects of hydrodynamics on cultures of mammalian neural stem cell aggregates in suspension bioreactors. Ind Eng Chem Res 40(23):5350–5357

    CAS  CrossRef  Google Scholar 

  12. Kehoe DE, Lock LT, Parikh A, Tzanakakis ES (2008) Propagation of embryonic stem cells in stirred suspension without serum. Biotechnol Prog 24(6):1342–1352. doi:10.1002/btpr.57

    CAS  CrossRef  Google Scholar 

  13. Luo J, Vijayasankaran N, Autsen J, Santuray R, Hudson T, Amanullah A, Li F (2012) Comparative metabolite analysis to understand lactate metabolism shift in Chinese hamster ovary cell culture process. Biotechnol Bioeng 109(1):146–156. doi:10.1002/bit.23291

    CAS  CrossRef  Google Scholar 

  14. Ljunggren J, Häggström L (1992) Glutamine limited fed-batch culture reduces the overflow metabolism of amino acids in myeloma cells. Cytotechnology 8(1):45–56. doi:10.1007/BF02540029

    CAS  CrossRef  Google Scholar 

  15. Lim AC, Washbrook J, Titchener-Hooker NJ, Farid SS (2006) A computer-aided approach to compare the production economics of fed-batch and perfusion culture under uncertainty. Biotechnol Bioeng 93(4):687–697. doi:10.1002/bit.20757

    CAS  CrossRef  Google Scholar 

  16. Kelley B (2009) Industrialization of mAb production technology: the bioprocessing industry at a crossroads. MAbs 1(5):443–452

    CrossRef  Google Scholar 

  17. Krishnan R, Chen H (2012) A comprehensive strategy to evaluate single-use bioreactors for pilot-scale cell culture production. Am Pharm Rev

    Google Scholar 

  18. Vicki G (2005) Disposable bioreactors become standard fare. Gen Eng News 25(14):80

    Google Scholar 

  19. Whitford WG (2006) Fed-batch mammalian cell culture in bioproduction. BioProcess Intern 4:30–40

    CAS  Google Scholar 

  20. Chee Furng Wong D, Tin Kam Wong K, Tang Goh L, Kiat Heng C, Gek Sim Yap M (2005) Impact of dynamic online fed-batch strategies on metabolism, productivity and N-glycosylation quality in CHO cell cultures. Biotechnol Bioeng 89(2):164–177. doi:10.1002/bit.20317

    CrossRef  Google Scholar 

  21. Lavric V, Ofiteru ID, Woinaroschy A (2005) A sensitivity analysis of the fed-batch animal-cell bioreactor with respect to some control parameters. Biotechnol Appl Biochem 41(Pt 1):29–35

    CAS  Google Scholar 

  22. Zhou W, Rehm J, Europa A, Hu WS (1997) Alteration of mammalian cell metabolism by dynamic nutrient feeding. Cytotechnology 24(2):99–108

    CAS  CrossRef  Google Scholar 

  23. Zhou W, Rehm J, Hu W-S (1995) High viable cell concentration fed-batch cultures of hybridoma cells through on-line nutrient feeding. Biotechnol Bioeng 46(6):579–587. doi:10.1002/bit.260460611

    CAS  CrossRef  Google Scholar 

  24. Castro PM, Hayter PM, Ison AP, Bull AT (1992) Application of a statistical design to the optimization of culture medium for recombinant interferon-gamma production by Chinese hamster ovary cells. Appl Microbiol Biotechnol 38(1):84–90

    CAS  CrossRef  Google Scholar 

  25. Xie L, Wang DI (1996) High cell density and high monoclonal antibody production through medium design and rational control in a bioreactor. Biotechnol Bioeng 51(6):725–729

    CAS  CrossRef  Google Scholar 

  26. Zhang L, Shen H, Zhang Y (2004) Fed-batch culture of hybridoma cells in serum-free medium using an optimized feeding strategy. J Chem Technol Biotechnol 79(2):171–181. doi:10.1002/jctb.940

    CAS  CrossRef  Google Scholar 

  27. Gong X, Li D, Li X, Fang Q, Han X, Wu Y, Yang S, Shen BQ (2006) Fed-batch culture optimization of a growth-associated hybridoma cell line in chemically defined protein-free media. Cytotechnology 52(1):25–38. doi:10.1007/s10616-006-9026-3

    CAS  CrossRef  Google Scholar 

  28. Kuwae S, Ohda T, Tamashima H, Miki H, Kobayashi K (2005) Development of a fed-batch culture process for enhanced production of recombinant human antithrombin by Chinese hamster ovary cells. Journal of Bioscience and Bioengineering 100(5):502–510. doi: http://dx.doi.org/10.1263/jbb.100.502

    Google Scholar 

  29. Sauer PW, Burky JE, Wesson MC, Sternard HD, Qu L (2000) A high-yielding, generic fed-batch cell culture process for production of recombinant antibodies. Biotechnol Bioeng 67(5):585–597. doi:10.1002/(SICI)1097-0290(20000305)67:5<585::AID-BIT9>3.0.CO;2-H

    CAS  CrossRef  Google Scholar 

  30. Xie L, Wang DIC (1994) Fed-batch cultivation of animal cells using different medium design concepts and feeding strategies. Biotechnol Bioen 43(11):1175–1189. doi:10.1002/bit.260431123

    CAS  CrossRef  Google Scholar 

  31. Xie L, Wang DIC (1994) Applications of improved stoichiometric model in medium design and fed-batch cultivation of animal cells in bioreactor. Cytotechnology 15(1–3):17–29. doi:10.1007/BF00762376

    CAS  CrossRef  Google Scholar 

  32. Zhou W, Hu WS (1994) On-line characterization of a hybridoma cell culture process. Biotechnol Bioeng 44(2):170–177. doi:10.1002/bit.260440205

    CAS  CrossRef  Google Scholar 

  33. Korke R, Gatti MdL, Lau ALY, Lim JWE, Seow TK, Chung MCM, Hu W-S (2004) Large scale gene expression profiling of metabolic shift of mammalian cells in culture. Journal of Biotechnology 107(1):1–17. doi: http://dx.doi.org/10.1016/j.jbiotec.2003.09.007

  34. Mulukutla BC, Gramer M, Hu W-S (2012) On metabolic shift to lactate consumption in fed-batch culture of mammalian cells. Metabolic Engineering 14(2):138–149. doi: http://dx.doi.org/10.1016/j.ymben.2011.12.006

  35. Lao M-S, Toth D (1997) Effects of ammonium and lactate on growth and metabolism of a recombinant Chinese hamster ovary cell culture. Biotechnol Prog 13(5):688–691. doi:10.1021/bp9602360

    CAS  CrossRef  Google Scholar 

  36. Ozturk SS, Riley MR, Palsson BO (1992) Effects of ammonia and lactate on hybridoma growth, metabolism, and antibody production. Biotechnol Bioeng 39(4):418–431. doi:10.1002/bit.260390408

    CAS  CrossRef  Google Scholar 

  37. Xing Z, Li Z, Chow V, Lee SS (2008) Identifying inhibitory threshold values of repressing metabolites in CHO cell culture using multivariate analysis methods. Biotechnol Prog 24(3):675–683. doi:10.1021/bp070466m

    CAS  CrossRef  Google Scholar 

  38. Warburg O (1956) On the origin of cancer cells. Science 123(3191):309–314

    CAS  CrossRef  Google Scholar 

  39. Altamirano C, Paredes C, Cairó JJ, Gòdia F (2000) Improvement of CHO cell culture medium formulation: simultaneous substitution of glucose and glutamine. Biotechnol Prog 16(1):69–75. doi:10.1021/bp990124j

    CAS  CrossRef  Google Scholar 

  40. Altamirano C, Paredes C, Illanes A, Cairó JJ, Gòdia F (2004) Strategies for fed-batch cultivation of t-PA producing CHO cells: substitution of glucose and glutamine and rational design of culture medium. J Biotechnol 110 (2):171–179. doi:http://dx.doi.org/10.1016/j.jbiotec.2004.02.004

  41. Berrios J, Altamirano C, Osses N, Gonzalez R (2011) Continuous CHO cell cultures with improved recombinant protein productivity by using mannose as carbon source: Metabolic analysis and scale-up simulation. Chem Eng Sci 66(11):2431–2439. doi: http://dx.doi.org/10.1016/j.ces.2011.03.011

  42. Huang Y-M, Hu W, Rustandi E, Chang K, Yusuf-Makagiansar H, Ryll T (2010) Maximizing productivity of CHO cell-based fed-batch culture using chemically defined media conditions and typical manufacturing equipment. Biotechnol Prog 26(5):1400–1410. doi:10.1002/btpr.436

    CAS  CrossRef  Google Scholar 

  43. Ma N, Ellet J, Okediadi C, Hermes P, McCormick E, Casnocha S (2009) A single nutrient feed supports both chemically defined NS0 and CHO fed-batch processes: Improved productivity and lactate metabolism. Biotechnol Prog 25(5):1353–1363. doi:10.1002/btpr.238

    CrossRef  Google Scholar 

  44. Xing Z, Kenty B, Koyrakh I, Borys M, Pan S-H, Li ZJ (2011) Optimizing amino acid composition of CHO cell culture media for a fusion protein production. Process Biochem 46 (7):1423–1429. doi: http://dx.doi.org/10.1016/j.procbio.2011.03.014

    Google Scholar 

  45. Burky JE, Wesson MC, Young A, Farnsworth S, Dionne B, Zhu Y, Hartman TE, Qu L, Zhou W, Sauer PW (2007) Protein-free fed-batch culture of non-GS NS0 cell lines for production of recombinant antibodies. Biotechnol Bioeng 96(2):281–293. doi:10.1002/bit.21060

    CAS  CrossRef  Google Scholar 

  46. Qian Y, Khattak SF, Xing Z, He A, Kayne PS, Qian NX, Pan SH, Li ZJ (2011) Cell culture and gene transcription effects of copper sulfate on Chinese hamster ovary cells. Biotechnol Prog 27(4):1190–1194

    CAS  CrossRef  Google Scholar 

  47. deZengotita VM, Miller WM, Aunins JG, Zhou W (2000) Phosphate feeding improves high-cell-concentration NS0 myeloma culture performance for monoclonal antibody production. Biotechnol Bioeng 69(5):566–576. doi:10.1002/1097-0290(20000905)69:5<566::AID-BIT11>3.0.CO;2-4

    CAS  CrossRef  Google Scholar 

  48. Glacken MW, Fleischaker RJ, Sinskey AJ (1986) Reduction of waste product excretion via nutrient control: Possible strategies for maximizing product and cell yields on serum in cultures of mammalian cells. Biotechnol Bioeng 28(9):1376–1389. doi:10.1002/bit.260280912

    CAS  CrossRef  Google Scholar 

  49. Xie L, Wang DIC (1996) Material balance studies on animal cell metabolism using a stoichiometrically based reaction network. Biotechnol Bioeng 52(5):579–590. doi:10.1002/(SICI)1097-0290(19961205)52:5<579::AID-BIT5>3.0.CO;2-G

    CAS  CrossRef  Google Scholar 

  50. Gagnon M, Hiller G, Luan Y-T, Kittredge A, DeFelice J, Drapeau D (2011) High-End pH-controlled delivery of glucose effectively suppresses lactate accumulation in CHO Fed-batch cultures. Biotechnol Bioeng 108(6):1328–1337. doi:10.1002/bit.23072

    CAS  CrossRef  Google Scholar 

  51. Li J, Wong CL, Vijayasankaran N, Hudson T, Amanullah A (2012) Feeding lactate for CHO cell culture processes: Impact on culture metabolism and performance. Biotechnol Bioeng 109(5):1173–1186. doi:10.1002/bit.24389

    CAS  CrossRef  Google Scholar 

  52. Wilkens C, Altamirano C, Gerdtzen Z (2011) Comparative metabolic analysis of lactate for CHO cells in glucose and galactose. Biotechnol Bioproc E 16(4):714–724. doi:10.1007/s12257-010-0409-0

    CAS  CrossRef  Google Scholar 

  53. Zagari F, Jordan M, Stettler M, Broly H, Wurm FM (2013) Lactate metabolism shift in CHO cell culture: the role of mitochondrial oxidative activity. New Biotechnol 30(2):238–245. doi: http://dx.doi.org/10.1016/j.nbt.2012.05.021

  54. Dean J, Reddy P (2013) Metabolic analysis of antibody producing CHO cells in fed-batch production. Biotechnol Bioeng 110(6):1735–1747. doi:10.1002/bit.24826

    CAS  CrossRef  Google Scholar 

  55. Yoon SK, Choi SL, Song JY, Lee GM (2005) Effect of culture pH on erythropoietin production by Chinese hamster ovary cells grown in suspension at 32.5 and 37.0°C. Biotechnol Bioeng 89(3):345–356. doi:10.1002/bit.20353

    CAS  CrossRef  Google Scholar 

  56. Tsao YS, Cardoso AG, Condon RGG, Voloch M, Lio P, Lagos JC, Kearns BG, Liu Z (2005) Monitoring Chinese hamster ovary cell culture by the analysis of glucose and lactate metabolism. J Biotechnol 118(3):316–327. doi: http://dx.doi.org/10.1016/j.jbiotec.2005.05.016

    Google Scholar 

  57. Miller WM, Wilke CR, Blanch HW (1987) Effects of dissolved oxygen concentration on hybridoma growth and metabolism in continuous culture. J Cell Physiol 132(3):524–530. doi:10.1002/jcp.1041320315

    CAS  CrossRef  Google Scholar 

  58. Heidemann R, Lütkemeyer D, Büntemeyer H, Lehmann J (1998) Effects of dissolved oxygen levels and the role of extra- and intracellular amino acid concentrations upon the metabolism of mammalian cell lines during batch and continuous cultures. Cytotechnology 26(3):185–197. doi:10.1023/a:1007917409455

    CAS  CrossRef  Google Scholar 

  59. Mulukutla BC, Khan S, Lange A, Hu W-S (2010) Glucose metabolism in mammalian cell culture: new insights for tweaking vintage pathways. Trends Biotechnol 28(9):476–484. doi: http://dx.doi.org/10.1016/j.tibtech.2010.06.005

    Google Scholar 

  60. Chen K, Liu Q, Xie L, Sharp PA, Wang DIC (2001) Engineering of a mammalian cell line for reduction of lactate formation and high monoclonal antibody production. Biotechnol Bioeng 72(1):55–61. doi:10.1002/1097-0290(20010105)72:1<55::AID-BIT8>3.0.CO;2-4

    CAS  CrossRef  Google Scholar 

  61. Jeon M, Yu D, Lee G (2011) Combinatorial engineering of ldh-a and bcl-2 for reducing lactate production and improving cell growth in dihydrofolate reductase-deficient Chinese hamster ovary cells. Appl Microbiol Biotechnol 92(4):779–790. doi:10.1007/s00253-011-3475-0

    CAS  CrossRef  Google Scholar 

  62. Kim S, Lee G (2007) Down-regulation of lactate dehydrogenase-A by siRNAs for reduced lactic acid formation of Chinese hamster ovary cells producing thrombopoietin. Appl Microbiol Biotechnol 74(1):152–159. doi:10.1007/s00253-006-0654-5

    CAS  CrossRef  Google Scholar 

  63. Zhou M, Crawford Y, Ng D, Tung J, Pynn AFJ, Meier A, Yuk IH, Vijayasankaran N, Leach K, Joly J, Snedecor B, Shen A (2011) Decreasing lactate level and increasing antibody production in Chinese Hamster Ovary cells (CHO) by reducing the expression of lactate dehydrogenase and pyruvate dehydrogenase kinases. J Biotechnol 153(1–2):27–34. doi: http://dx.doi.org/10.1016/j.jbiotec.2011.03.003

  64. Dorai H, Kyung YS, Ellis D, Kinney C, Lin C, Jan D, Moore G, Betenbaugh MJ (2009) Expression of anti-apoptosis genes alters lactate metabolism of Chinese hamster ovary cells in culture. Biotechnol Bioeng 103(3):592–608. doi:10.1002/bit.22269

    CAS  CrossRef  Google Scholar 

  65. Fogolín MB, Wagner R, Etcheverrigaray M, Kratje R (2004) Impact of temperature reduction and expression of yeast pyruvate carboxylase on hGM-CSF-producing CHO cells. J Biotechnol 109(1–2):179–191. doi: http://dx.doi.org/10.1016/j.jbiotec.2003.10.035

    Google Scholar 

  66. Irani N, Wirth M, van den Heuvel J, Wagner R (1999) Improvement of the primary metabolism of cell cultures by introducing a new cytoplasmic pyruvate carboxylase reaction. Biotechnol Bioeng 66(4):238–246. doi: 10.1002/(SICI)1097-0290(1999)66:4<238::AID-BIT5>3.0.CO;2-6

    CAS  CrossRef  Google Scholar 

  67. Kim S, Lee G (2007) Functional expression of human pyruvate carboxylase for reduced lactic acid formation of Chinese hamster ovary cells (DG44). Appl Microbiol Biotechnol 76(3):659–665. doi:10.1007/s00253-007-1041-6

    CAS  CrossRef  Google Scholar 

  68. D-w Jeong, Cho I, Kim T, Bae G, Kim I-H, Kim I (2006) Effects of lactate dehydrogenase suppression and glycerol-3-phosphate dehydrogenase overexpression on cellular metabolism. Mol Cell Biochem 284(1–2):1–8. doi:10.1007/s11010-005-9004-7

    Google Scholar 

  69. Yang J-D, Lu C, Stasny B, Henley J, Guinto W, Gonzalez C, Gleason J, Fung M, Collopy B, Benjamino M, Gangi J, Hanson M, Ille E (2007) Fed-batch bioreactor process scale-up from 3-L to 2,500-L scale for monoclonal antibody production from cell culture. Biotechnol Bioeng 98(1):141–154. doi:10.1002/bit.21413

    CAS  CrossRef  Google Scholar 

  70. Smelko J, Wiltberger K, Hickman E, Morris B, Blackburn T, Ryll T (2011) Performance of high intensity fed-batch mammalian cell cultures in disposable bioreactor systems. Biotechnol Prog 27(5):1358–1364

    CAS  CrossRef  Google Scholar 

  71. Gramer MJ, Ogorzalek T (2007) A semi-empirical mathematical model useful for describing the relationship between carbon dioxide, pH, lactate and base in a bicarbonate-buffered cell-culture process. Biotechnol Appl Biochem 047(4):197–204. doi:10.1042/ba20070001

    CAS  CrossRef  Google Scholar 

  72. Le H, Kabbur S, Pollastrini L, Sun Z, Mills K, Johnson K, Karypis G, Hu W-S (2012) Multivariate analysis of cell culture bioprocess data—Lactate consumption as process indicator. J Biotechnol 162(2–3):210–223. doi: http://dx.doi.org/10.1016/j.jbiotec.2012.08.021

    Google Scholar 

  73. Schmelzer AE, Miller WM (2002) Effects of osmoprotectant compounds on NCAM polysialylation under hyperosmotic stress and elevated pCO2. Biotechnol Bioeng 77(4):359–368. doi:10.1002/bit.10175

    CAS  CrossRef  Google Scholar 

  74. Zhu MM, Goyal A, Rank DL, Gupta SK, Boom TV, Lee SS (2005) Effects of elevated pCO2 and osmolality on growth of CHO Cells and production of antibody-fusion protein B1: A case study. Biotechnol Prog 21(1):70–77. doi:10.1021/bp049815s

    CrossRef  Google Scholar 

  75. Zhao L, Fan L, Wang J, Niu H, Tan W-S (2009) Responses of GS-NS0 Myeloma cells to osmolality: cell growth, intracellular mass metabolism, energy metabolism, and antibody production. Biotechnol Bioproc E 14(5):625–632. doi:10.1007/s12257-008-0223-0

    CAS  CrossRef  Google Scholar 

  76. Takuma S, Hirashima C, Piret JM (2007) Dependence on glucose limitation of the pCO2 influences on CHO cell growth, metabolism and IgG production. Biotechnol Bioeng 97(6):1479–1488. doi:10.1002/bit.21376

    CAS  CrossRef  Google Scholar 

  77. Ray NG, Rivera R, Rajeew G, Dale M (1997) Large-scale production of humanized monoclonal antibody expressed in a GS-NS0 cell line. In: Carrondo MJT, Griffiths B, Moreira JLP (eds) Animal cell technology. Kluwer Academic Publishers, Dordrecht, pp 235–241

    CrossRef  Google Scholar 

  78. Bonham-Carter J, Shevitz J (2011) A brief history of perfusion biomanufacturing. BioProc Int 9(9):24–31

    Google Scholar 

  79. 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

    Google Scholar 

  80. MacDonald HL, Neway JO (1990) Effects of medium quality on the expression of human interleukin-2 at high cell density in fermentor cultures of Escherichia coli K-12. Appl Environ Microbiol 56(3):640–645

    CAS  Google Scholar 

  81. Tang X, Tan Y, Zhu H, Zhao K, Shen W (2009) Microbial conversion of glycerol to 1,3-propanediol by an engineered strain of Escherichia coli. Appl Environ Microbiol 75(6):1628–1634. doi:10.1128/aem.02376-08

    CAS  CrossRef  Google Scholar 

  82. Singh V (2003) Disposable perfusion bioreactor for cell culture. United States Patent 6544788

    Google Scholar 

  83. Pierce LN, Shabram PW (2004) Scalability of a disposable bioreactor from 25 L-500 L run in perfusion mode with a CHO-based cell line: A tech review. BioProcess J 3(4):51–56

    Google Scholar 

  84. Laustsen M (2011) A method for producing a biopolymer (e.g. polypeptide) in a continuous fermentation process. EP 2171034 A1 Patent

    Google Scholar 

  85. Catapano G, Czermak P, Eibl R, Eibl D, Pörtner R (2009) Bioreactor Design and Scale-Up In: Eibl R, Eibl D, Pörtner R, Catapano G, Czermak P (eds) Cell and tissue reaction engineering. Springer

    Google Scholar 

  86. Davis JM (2007) Hollow fiber cell culture. In: Pörtner R (ed) Animal cell biotechnology: methods and protocols. Humana Press, Totowa

    Google Scholar 

  87. Pörtner R, Barradas OBJP (2007) Cultivation of mammalian cells in fixed-bed reactors. In: Pörtner R (ed) Animal cell biotechnology: methods and protocols. Humana Press, Totowa

    Google Scholar 

  88. Blüml G (2007) Microcarrier cell culture technology. In: Pörtner R (ed) Animal cell biotechnology: methods and protocols. Humana Press, Totowa

    Google Scholar 

  89. 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

    CAS  CrossRef  Google Scholar 

  90. Shackel I, Bass A, Brewer A, Brown P, Tsao M, Chang L (2007) Comparison of manufacture techniques for RAV12 monoclonal antibody in production medium containing no animal derived proteins. In: Smith R (ed) Cell technology for cell products. Springer

    Google Scholar 

  91. Pui PW, Trampler F, Sonderhoff SA, Groeschl M, Kilburn DG, Piret JM (1995) Batch and semicontinuous aggregation and sedimentation of hybridoma cells by acoustic resonance fields. Biotechnol Prog 11(2):146–152. doi:10.1021/bp00032a005

    CAS  CrossRef  Google Scholar 

  92. 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

    CAS  Google Scholar 

  93. 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

    CAS  CrossRef  Google Scholar 

  94. Sergeant D, Moser M, Carvell JP (2007) Measurement and control of viable cell density in a mammalian cell bioprocessing facility: validation of the software. In: Noll T (ed) 20th ESACT meeting, dresden, Springer, Germany, pp 379–384

    Google Scholar 

  95. Fernandez D, Femenia J, Cheung D, Nadeau I, Tescione L, Monroe B, Michaels J, Gorfien S (2006) Scale-down perfusion process for recombinant protein expression. In: Sanetaka Shirahata KI, Masaya Nagao (ed) Animal cell technology: basic and applied aspects: proceedings of the 19th annual meeting of the Japanese association for animal cell technology (JAACT), Springer, Kyoto, pp 59–65

    Google Scholar 

  96. 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

    CAS  CrossRef  Google Scholar 

  97. 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

    CAS  CrossRef  Google Scholar 

  98. Mattes RA, Root D, Chang D, Malony M, Ong M (2007) In situ monitoring of CHO cell culture medium USING near-infrared spectroscopy. BioProc Int (Supplement. January 2007.)

    Google Scholar 

  99. Abu-Absi NR, Kenty BM, Cuellar ME, Borys MC, Sakhamuri S, Strachan DJ, Hausladen MC, Li ZJ (2011) Real time monitoring of multiple parameters in mammalian cell culture bioreactors using an in-line Raman spectroscopy probe. Biotechnol Bioeng 108(5):1215–1221. doi:10.1002/bit.23023

    CAS  CrossRef  Google Scholar 

  100. OSIsoft, LLC (2010) PI ProcessBook, PI DataLink. PI WebParts Course, OSIsoft, LLC

    Google Scholar 

  101. Aegis. http://aegiscorp.com/products/on-demand-data-mapping-platform–nexus-.html

  102. SAP http://www54.sap.com/lob/manufacturing/software/integration-and-intelligence/index.html

  103. Chaudhuri UR, Chadhuri UR (2013) Fundamentals of automatic process control. CRC Press, Boca Raton

    Google Scholar 

  104. Emerson (2013) http://www2.emersonprocess.com/en-us/brands/deltav/Pages/index.aspx.

  105. Kourti T, MacGregor JF (1995) Process analysis, monitoring and diagnosis, using multivariate projection methods. Chemomet Intell Lab Syst 28(1):3–21

    CAS  Google Scholar 

  106. Westerhuis JA, Kourti T, MacGregor JF (1999) Comparing alternative approaches for multivariate statistical analysis of batch process data. J Chemomet 13(3–4):397–413

    CAS  CrossRef  Google Scholar 

  107. Gabrielsson J, Lindberg N-O, Lundstedt T (2002) Multivariate methods in pharmaceutical applications. J Chemom 16(3):141–160

    CAS  CrossRef  Google Scholar 

  108. Johnson R, Yu O, Kirdar AO, Annamalai A, Ahuja S, Ram K, Rathore AS (2007) Application of multivariate analysis in biotech processing. BioPharm Int 20(10):130–144

    CAS  Google Scholar 

  109. Gunther JC, Conner JS, Seborg DE (2007) Fault detection and diagnosis in an industrial fed-batch cell culture process. Biotechnol Prog 23(4):851–857

    CAS  Google Scholar 

  110. Kirdar AO, Conner JS, Baclaski J, Rathore AS (2007) Application of multivariate analysis toward biotech processes: case study of a cell-culture unit operation. Biotechnol Prog 23(1):61–67

    CAS  CrossRef  Google Scholar 

  111. Bhushan N, Hadpe S, Rathore AS (2012) Chemometrics applications in biotech processes: assessing process comparability. Biotechnol Prog 28(1):121–128

    CAS  CrossRef  Google Scholar 

  112. Kirdar AO, Green KD, Rathore AS (2008) Application of multivariate data analysis for identification and successful resolution of a root cause for a bioprocessing application. Biotechnol Prog 24(3):720–726

    CAS  CrossRef  Google Scholar 

  113. Undey C, Ertunc S, Cinar A (2003) Online batch/fed-batch process perfomance monitoring, quality prediction, and variable-contribution analysis for diagnosis. Ind Eng Chem Res 42(20):4645–4658

    CrossRef  Google Scholar 

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Abu-Absi, S., Xu, S., Graham, H., Dalal, N., Boyer, M., Dave, K. (2013). Cell Culture Process Operations for Recombinant Protein Production. In: Zhou, W., Kantardjieff, A. (eds) Mammalian Cell Cultures for Biologics Manufacturing. Advances in Biochemical Engineering/Biotechnology, vol 139. Springer, Berlin, Heidelberg. https://doi.org/10.1007/10_2013_252

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