Downstream Processing Technologies/Capturing and Final Purification

Opportunities for Innovation, Change, and Improvement. A Review of Downstream Processing Developments in Protein Purification
  • Nripen SinghEmail author
  • Sibylle Herzer
Part of the Advances in Biochemical Engineering/Biotechnology book series (ABE, volume 165)


Increased pressure on upstream processes to maximize productivity has been crowned with great success, although at the cost of shifting the bottleneck to purification. As drivers were economical, focus is on now on debottlenecking downstream processes as the main drivers of high manufacturing cost. Devising a holistically efficient and economical process remains a key challenge. Traditional and emerging protein purification strategies with particular emphasis on methodologies implemented for the production of recombinant proteins of biopharmaceutical importance are reviewed. The breadth of innovation is addressed, as well as the challenges the industry faces today, with an eye to remaining impartial, fair, and balanced. In addition, the scope encompasses both chromatographic and non-chromatographic separations directed at the purification of proteins, with a strong emphasis on antibodies. Complete solutions such as integrated USP/DSP strategies (i.e., continuous processing) are discussed as well as gains in data quantity and quality arising from automation and high-throughput screening (HTS). Best practices and advantages through design of experiments (DOE) to access a complex design space such as multi-modal chromatography are reviewed with an outlook on potential future trends. A discussion of single-use technology, its impact and opportunities for further growth, and the exciting developments in modeling and simulation of DSP rounds out the overview. Lastly, emerging trends such as 3D printing and nanotechnology are covered.

Graphical Abstract

Workflow of high-throughput screening, design of experiments, and high-throughput analytics to understand design space and design space boundaries quickly. (Reproduced with permission from Gregory Barker, Process Development, Bristol-Myers Squibb)


Bioprocessing Downstream High-throughput processing Modeling Process improvements Purification 



The authors would like to thank Yan Yao, Ph.D., Associate Director, Bristol-Myers Squibb, and Gregory Barker, Ph.D., Senior Engineer, Bristol-Myers Squibb for their critical review and feedback. The authors would also like to thank Professor Giorgio Carta, Ph.D., School of Engineering and Applied Sciences, University of Virginia, Arch Creasy, graduate student at the School of Engineering and Applied Sciences, University of Virginia, and aforementioned colleagues Gregory Barker and Yan Yao for the generous permission to reproduce Fig. 6, and Gregory Barker for the generous provision of Fig. 4.


  1. 1.
    Wilson ID, Allard ER, Cooke M, Poole CF (2000) Encyclopedia of separation science. Academic, San DiegoGoogle Scholar
  2. 2.
    Cohn EJ (1947) The separation of blood into fractions of therapeutic value. Ann Int Med 26:341–352PubMedGoogle Scholar
  3. 3.
    Constantino P (2002) Basel, Switzerland Patent No 20050106181 A1Google Scholar
  4. 4.
    Hagen AJ, Oliver CN, Sitrin R (1997) Optimization and scale-up of solvent extraction in purification of hepatitis A virus (VAQTA™). Biotechnol Bioeng 56:83–88PubMedGoogle Scholar
  5. 5.
    Kniskern PJ, Miller WJ, Hagopian A, Charlotte C, Hennessey J, John P et al (1998) US Patent No 5,847,112Google Scholar
  6. 6.
    Merieux I (1980) Belgium Patent No B74899Google Scholar
  7. 7.
    Yavordios D, Cousin M (1983) France Patent No. 0071515A1Google Scholar
  8. 8.
    Stern SA, Noble RD (1995) Membrane separations technology. Principles and applications. Elsevier, AmsterdamGoogle Scholar
  9. 9.
    Peterson EA, Sober HA (1954) Chromatography of proteins. I Cellulose ion-exchange; adsorbents. J Am Chem Soc 78(4):751–755Google Scholar
  10. 10.
    Porath J, Flodin P (1959) Gel filtration: a method for desalting and group separation. Nature 183:1657PubMedGoogle Scholar
  11. 11.
    Lea DJ, Sehon AH (1961) Preparation of synthetic gels for chromatography of macromolecules. Can J Chem 40:159Google Scholar
  12. 12.
    Vaughan MF (1960) Fractionation of polystyrene by gel filtration. Nature 188:55Google Scholar
  13. 13.
    Hjerten S (1961) Agarose as an anticonvection agent in zone electrophoresis. Biochim Biophys Acta 53(3):514–517PubMedGoogle Scholar
  14. 14.
    Hjerten S (1964) The preparation of agarose spheres for the chromatography of molecules and particles. Biochim Biophys Acta 79:393–398PubMedGoogle Scholar
  15. 15.
    March SC, Parikh I, Cuatrecasas P (1974) Affinity chromatography — old problems and new approaches- in immobilized biochemicals and affinity chromatography- part of the series Advances in Experimental Medicine and Biology (Vol. 42): SpringerGoogle Scholar
  16. 16.
    Williams KW, Smith RC (1975) Recent advances in column chromatography. Prog Med Chem 12:105–158PubMedGoogle Scholar
  17. 17.
    Hofstee BH (1973) Protein binding by agarose carrying hydrophobic groups in conjunction with charges. Biochem Biophys Res Commun 50(3):751–757PubMedGoogle Scholar
  18. 18.
    Er-El Z, Zaidenzaig Y, Shaltiel S (1972) Hydrocarbon-coated sepharoses. Use in the purification of glycogen phosphorylase. Biochem Biophys Res Commun 49(2):383–390PubMedGoogle Scholar
  19. 19.
    Hjerten S (1973) Some general aspects of hydrophobic interaction chromatography. J Chromatogr A:325–331Google Scholar
  20. 20.
    Yon RJ (1972) Chromatography of lipophilic proteins on adsorbents containing mixed hydrophobic and ionic groups. Biochem J 126(3):765–767PubMedPubMedCentralGoogle Scholar
  21. 21.
    Gagnon P (2012) Technology trends in antibody purification. J Chromatogr A 1221:57–70PubMedGoogle Scholar
  22. 22.
    Gottschalk U (2011) The future of downstream processing. Retrieved from
  23. 23.
    Jon HC, Zarbis-Papastoitsis G (2011) Advances in the production and downstream processing of antibodies. N Biotechnol 28(5)Google Scholar
  24. 24.
    Low D, O’Leary R, Pujar NS (2007) Future of antibody purification. J Chromatogr B 848:48–63Google Scholar
  25. 25.
    Marichal-Gallardo PA, Alvarez MM (2012) State-of-the-art in downstream processing of monoclonal antibodies: process trends in design and validation. Biotechnol Prog 28(4):899–916PubMedGoogle Scholar
  26. 26.
    Zhou JX, Tressel T, Yang X, Seewoester T (2008) Implementation of advanced technologies in commercial monoclonal antibody production. Biotechnol J 3:1185–1200PubMedGoogle Scholar
  27. 27.
    Kelley B (2007) Very large scale monoclonal antibody purification: the case for conventional unit operations. Biotechnol Prog 23(5):995–1008. doi: 10.1021/bp070117sCrossRefPubMedGoogle Scholar
  28. 28.
    Shukla AA, Thoemmes J (2010) Recent advances in large-scale production of monoclonal antibodies and related proteins. Trends Biotechnol 28(5):253–261PubMedPubMedCentralGoogle Scholar
  29. 29.
    Banholzer WF, Vosejpka LJ (2011) Risk taking and effective R&D management. Annu Rev Chem Biomol Eng 2:173–188PubMedGoogle Scholar
  30. 30.
    Hueske A-K, Endrikat J, Guenther E (2015) External environment, the innovating organization, and its individuals: a multilevel model for identifying innovation barriers accounting for social uncertainties. J Eng Technol Manage 35:45–70Google Scholar
  31. 31.
    Rogers M (2012) Energy = Innovation: 10 disruptive technologies. Sustainability & Resource Productivity SummerGoogle Scholar
  32. 32.
    Saunila M, Ukko J (2014) Intangible aspects of innovation capability in SMEs: impacts of size and industry. J Eng Technol Manage 33:32–46Google Scholar
  33. 33.
    Story VM, Daniels K, Zolkiewski J, Daintyd AJ (2014) The barriers and consequences of radical innovations: introduction to the issue. Ind Mark Manag 24:1271–1277Google Scholar
  34. 34.
    Weiss JC, Dale BC (1998) Diffusing against mature technology: Issues and Strategy. Ind Mark Manag 27:293–304Google Scholar
  35. 35.
    Tswett M (1903) O novoy kategorii adsorbtsionnykh yavleny i o primenenii ikh k biokkhimicheskomu analizu (A new category of adsorption phenomena and their use in biochemical analysis). Trudy Varhavskago Obshchestva estevoispytatelei Otd B 14:20–39Google Scholar
  36. 36.
    Curling J (2007) Process chromatography: five decades of innovation. BioPharm Int 13–18:48Google Scholar
  37. 37.
    Guiochon G, Felinger A, Shirazi DG, Katti AM (2006) Introduction. In: Fundamentals of preparative and nonlinear chromatography. AcademicGoogle Scholar
  38. 38.
    Grace JR, Leckner B, Zhu J, Cheng Y (2005) Fluidized beds. In: Multiphase flow handbook. CRC PressGoogle Scholar
  39. 39.
    Bartels CR, Kleiman G, Irish DB, Korzun JN (1957) United States/New York Patent No. US 2786831 AGoogle Scholar
  40. 40.
    Buiis A, Wesselingh JA (1980) Batch fluidized ion-exchange columns for streams containing suspended particles. J Chromatogr 201:319–327Google Scholar
  41. 41.
    Burns MA, Graves DJ (1985) Continuous affinity chromatography using a magnetically stabilized fluidized bed. Biotechnol Prog 1:95–103PubMedGoogle Scholar
  42. 42.
    Draeger MN, Chase HA (1990) Liquid fluidized beds for protein purification. Chem Eng Symp Ser No, 1, 12.11–12.12Google Scholar
  43. 43.
    Nixon L, Koval CA, Xu L, Noble RD, Slaff GS (1991) The effects of magnetic stabilization on the structure and performance of fluidized beds. Bioseparations 2:217–230Google Scholar
  44. 44.
    Hjorth R (1997) Expanded-bed adsorption in industrial bioprocessing: recent developments. Trends Biotechnol 15:230–235PubMedGoogle Scholar
  45. 45.
    Noppe W, Van Damme U, Gent N, Geeraerts F, Vanhoorelbeke K, Deckmyn H (2003) Biology and life sciences. In: Downstream: EBA '02 abstracts: Extended reports from the 4th international conference on expanded bed adsorption, St Petersburg, 2002. Amersham Biosciences, UppsalaGoogle Scholar
  46. 46.
    Flickinger MC (2013) Downstream industrial biotechnology: recovery and purification. WileyGoogle Scholar
  47. 47.
    Silver N (2012) The signal and the noise. The Penguin Press, New YorkGoogle Scholar
  48. 48.
    Fee CJ, Nawada S, Dimartino S (2014) 3D printed porous media columns with fine control of column packing geometry. J Chromatogr A 1333:18–24PubMedGoogle Scholar
  49. 49.
    Rathore AV, Velayudhan A (2003) In: Cazes J (ed) Scale-up and optimization in preparative chromatography. Marcel Dekker, IncGoogle Scholar
  50. 50.
    Allmendinger R, Simaria AS, Turner R, Farid SS (2014) Closed-loop optimization of chromatography column sizing strategies in biopharmaceutical manufacture. J Chem Technol Biotechnol 89(10):1481–1490. doi: 10.1002/jctb.4267CrossRefPubMedGoogle Scholar
  51. 51.
    Farid SS (2007) Process economics of industrial monoclonal antibody manufacture. J Chromatogr B Analyt Technol Biomed Life Sci 848(1):8–18. doi: 10.1016/j.jchromb.2006.07.037CrossRefPubMedGoogle Scholar
  52. 52.
    Hammerschmidt N, Tscheliessnig A, Sommer R, Helk B, Jungbauer A (2014) Economics of recombinant antibody production processes at various scales: industry-standard compared to continuous precipitation. Biotechnol J 9(6):766–775. doi: 10.1002/biot.201300480CrossRefPubMedGoogle Scholar
  53. 53.
    Liu S, Simaria AS, Farid SS, Papageorgiou LG (2013) Designing cost-effective biopharmaceutical facilities using mixed-integer optimization. Biotechnol Prog 29(6):1472–1483. doi: 10.1002/btpr.1795CrossRefPubMedGoogle Scholar
  54. 54.
    Schugerl K, Hubbuch J (2005) Integrated bioprocesses. Curr Opin Microbiol 8(3):294–300. doi: 10.1016/j.mib.2005.01.002CrossRefPubMedGoogle Scholar
  55. 55.
    Kelley B (2009) Industrialization of mAb production technology: the bioprocessing industry at a crossroads. MAbs 1(5):443–452PubMedPubMedCentralGoogle Scholar
  56. 56.
    Werner RG (2004) Economic aspects of commercial manufacture of biopharmaceuticals. J Biotechnol 113(1-3):171–182. doi: 10.1016/j.jbiotec.2004.04.036CrossRefPubMedGoogle Scholar
  57. 57.
    Liu HF, Ma J, Winter C, Bayer R (2010) Recovery and purification process development for monoclonal antibody production. MAbs 2(5):480–499PubMedPubMedCentralGoogle Scholar
  58. 58.
    Lu Y, Williamson B, Gillespie R (2009) Recent advancement in application of hydrophobic interaction chromatography for aggregate removal in industrial purification process. Curr Pharm Biotechnol 10(4):427–433PubMedGoogle Scholar
  59. 59.
    Nfor BK, Verhaert PD, van der Wielen LA, Hubbuch J, Ottens M (2009) Rational and systematic protein purification process development: the next generation. Trends Biotechnol 27(12):673–679. doi: 10.1016/j.tibtech.2009.09.002CrossRefPubMedGoogle Scholar
  60. 60.
    Shukla AA, Hubbard B, Tressel T, Guhan S, Low D (2007) Downstream processing of monoclonal antibodies--application of platform approaches. J Chromatogr B Analyt Technol Biomed Life Sci 848(1):28–39. doi: 10.1016/j.jchromb.2006.09.026CrossRefPubMedGoogle Scholar
  61. 61.
    Singh N, Arunkumar A, Chollangi S, Tan ZG, Borys M, Li ZJ (2015) Clarification technologies for monoclonal antibody manufacturing processes: current state and future perspectives. Biotechnol Bioeng. doi: 10.1002/bit.25810PubMedGoogle Scholar
  62. 62.
    Tao Y, Ibraheem A, Conley L, Cecchini D, Ghose S (2014) Evaluation of high-capacity cation exchange chromatography for direct capture of monoclonal antibodies from high-titer cell culture processes. Biotechnol Bioeng 111(7):1354–1364. doi: 10.1002/bit.25192CrossRefPubMedGoogle Scholar
  63. 63.
    Wang F, Yan X, Song L, Wang P, Lu D, Feng J, et al. (2013) A novel ‘pipeline’ system for downstream preparation of therapeutic monoclonal antibodies. Biotechnol Lett 35(9):1411–1418. doi: 10.1007/s10529-013-1234-2CrossRefPubMedGoogle Scholar
  64. 64.
    Aaberg PM, Houshmand H, Ljungloef A, Van AJ (2005) A method for chromatographic purification, US20,070,213,513 A1Google Scholar
  65. 65.
    Agner E (2003) Method for displacement chromatography, US6,576,134 B1Google Scholar
  66. 66.
    Cramer SM, Moore JA, Kundu A, Li Y, Jayaraman G (1995) Displacement chromatography of proteins using low molecular weight displacers, US5,478,924 AGoogle Scholar
  67. 67.
    Cramer SM, Shukla AA, Sunasara KM (2001) Low molecular weight displacers for protein purification in hydrophobic interaction and reversed phase chromatographic systems, US6,239,262 B1Google Scholar
  68. 68.
    Eriksson K, Johansson HJ, Olsson U (2007) Method of separating monomeric protein(s), US20,090,264,630 A1Google Scholar
  69. 69.
    Godavarti R, Iskra T (2006) Methods of purifying fc region containing proteins, US20,070,082,367 A1Google Scholar
  70. 70.
    Poll DJ, Harding DRK, Hancock WS (1986) High performance liquid chromatography mobile phase, US4,909,941 AGoogle Scholar
  71. 71.
    Shujun S (2013) Arginine wash in protein purification using affinity chromatography. US Patents No. 8,350,013 B2Google Scholar
  72. 72.
    Staby A (2000) Ion exchange chromatography of proteins and peptides with an organic modifier in the elution step, US6,451,987 B1Google Scholar
  73. 73.
    Sun S, Gallo C (2011) Arginine derivative wash in protein purification using affinity chromatography. US Patent No. 7,714,111Google Scholar
  74. 74.
    Sundberg R, Hopfer R (2004) Removal of bacterial endotoxin in a protein solution by immobilized metal affinity chromatography, US20,040,112,832 A1Google Scholar
  75. 75.
    Gillespie R, Vunnum S, Nguyen T, Macneil S (2012). J Chromatogr A 1251:101–110PubMedGoogle Scholar
  76. 76.
    Van Alstine J, Houshmand H, Ljunglof A, Aberg PM (2007) Method for chromatographic purification, US20,070,213,513 A1Google Scholar
  77. 77.
    Wang C, Coppola G, Chumsae C (2015) Protein purification using displacement chromatography: Google PatentsGoogle Scholar
  78. 78.
    Satzer P, Tscheließnigg A, Sommer R, Jungbauer A (2014) Separation of recombinant antibodies from DNA using divalent cations. Eng Life Sci 14(5)Google Scholar
  79. 79.
    Tsumoto K, Ejima D, Senczuk AM, Kita Y, Arakawa T (2007) Effects of salts on protein–surface interactions: applications for column chromatography. J Pharm Sci 96(7):1677–1690. doi: 10.1002/jps.20821CrossRefPubMedGoogle Scholar
  80. 80.
    Johansson K, Frederiksen SS, Degerman M, Breil MP, Mollerup JM, Nilsson B (2015) Combined effects of potassium chloride and ethanol as mobile phase modulators on hydrophobic interaction and reversed-phase chromatography of three insulin variants. J Chromatogr A 1381:64–73. doi: 10.1016/j.chroma.2014.12.081CrossRefPubMedGoogle Scholar
  81. 81.
    Ngo TT, Narinesingh D (2008) Kosmotropes enhance the yield of antibody purified by affinity chromatography using immobilized bacterial immunoglobulin binding proteins. J Immunoassay Immunochem 29(1):105–115. doi: 10.1080/15321810701735203CrossRefPubMedGoogle Scholar
  82. 82.
    Arakawa T, Tsumoto K, Nagase K, Ejima D (2007) The effects of arginine on protein binding and elution in hydrophobic interaction and ion-exchange chromatography. Protein Expr Purif 54(1):110–116. doi: 10.1016/j.pep.2007.02.010CrossRefPubMedGoogle Scholar
  83. 83.
    Cochet S, Hasnaoui MH, Debbia M, Kroviarski Y, Lambin P, Cartron JP, Bertrand O (1994) Chromatography of human immunoglobulin G on immobilized drimarene rubine R/K-5BL. Study of mild, efficient elution procedures. J Chromatogr A 663(2):175–186PubMedGoogle Scholar
  84. 84.
    Lin M-F, Williams C, Murray MV, Ropp PA (2005) Removal of lipopolysaccharides from protein–lipopolysaccharide complexes by nonflammable solvents. J Chromatogr B 816(1–2):167–174. doi: 10.1016/j.jchromb.2004.11.029CrossRefGoogle Scholar
  85. 85.
    Hou Y, Cramer SM (2011) Evaluation of selectivity in multimodal anion exchange systems: a priori prediction of protein retention and examination of mobile phase modifier effects. J Chromatogr A 1218(43):7813–7820. doi: 10.1016/j.chroma.2011.08.080CrossRefPubMedGoogle Scholar
  86. 86.
    Hirano A, Arakawa T, Kameda T (2014) Interaction of arginine with Capto MMC in multimodal chromatography. J Chromatogr A 1338:58–66. doi: 10.1016/j.chroma.2014.02.053CrossRefPubMedGoogle Scholar
  87. 87.
    Hirano A, Maruyama T, Shiraki K, Arakawa T, Kameda T (2014) Mechanism of protein desorption from 4-mercaptoethylpyridine resins by arginine solutions. J Chromatogr A 1373:141–148. doi: 10.1016/j.chroma.2014.11.032CrossRefPubMedGoogle Scholar
  88. 88.
    Holstein MA, Parimal S, McCallum SA, Cramer SM (2012) Mobile phase modifier effects in multimodal cation exchange chromatography. Biotechnol Bioeng 109(1):176–186. doi: 10.1002/bit.23318CrossRefPubMedGoogle Scholar
  89. 89.
    Herzer S, Bhangale A, Barker G, Chowdhary I, Conover M, O’Mara BW, et al. (2015) Development and scale-up of the recovery and purification of a domain antibody Fc fusion protein-comparison of a two and three-step approach. Biotechnol Bioeng 112(7):1417–1428. doi: 10.1002/bit.25561CrossRefPubMedGoogle Scholar
  90. 90.
    Liu Z, Gurgel PV, Carbonell RG (2012) Purification of human immunoglobulins A, G and M from Cohn fraction II/III by small peptide affinity chromatography. J Chromatogr A 1262:169–179. doi: 10.1016/j.chroma.2012.09.026CrossRefPubMedGoogle Scholar
  91. 91.
    Ishihara T, Hosono M (2015) Improving impurities clearance by amino acids addition to buffer solutions for chromatographic purifications of monoclonal antibodies. J Chromatogr B Analyt Technol Biomed Life Sci 995-996:107–114. doi: 10.1016/j.jchromb.2015.05.018CrossRefPubMedGoogle Scholar
  92. 92.
    Bolton GR, Boesch AW, Basha J, Lacasse DP, Kelley BD, Acharya H (2011) Effect of protein and solution properties on the Donnan effect during the ultrafiltration of proteins. Biotechnol Prog 27(1):140–152. doi: 10.1002/btpr.523CrossRefPubMedGoogle Scholar
  93. 93.
    Miao F, Velayudhan A, DiBella E, Shervin J, Felo M, Teeters M, Alred P (2009) Theoretical analysis of excipient concentrations during the final ultrafiltration/diafiltration step of therapeutic antibody. Biotechnol Prog 25(4):964–972. doi: 10.1002/btpr.168CrossRefPubMedGoogle Scholar
  94. 94.
    Stoner MR, Fischer N, Nixon L, Buckel S, Benke M, Austin F, et al. (2004) Protein-solute interactions affect the outcome of ultrafiltration/diafiltration operations. J Pharm Sci 93(9):2332–2342. doi: 10.1002/jps.20145CrossRefPubMedGoogle Scholar
  95. 95.
    Shukla D, Zamolo L, Cavallotti C, Trout BL (2011) Understanding the role of arginine as an eluent in affinity chromatography via molecular computations. J Phys Chem B 115(11):2645–2654. doi: 10.1021/jp111156zCrossRefPubMedGoogle Scholar
  96. 96.
    Bolton GR, Selvitelli KR, Iliescu I, Cecchini DJ (2015) Inactivation of viruses using novel protein A wash buffers. Biotechnol Prog 31(2):406–413. doi: 10.1002/btpr.2024CrossRefPubMedGoogle Scholar
  97. 97.
    Chollangi S, Parker R, Singh N, Li Y, Borys M, Li Z (2015) Development of robust antibody purification by optimizing protein-A chromatography in combination with precipitation methodologies. Biotechnol Bioeng 112(11):2292–2304. doi: 10.1002/bit.25639CrossRefPubMedGoogle Scholar
  98. 98.
    Frauenschuh A, Bill K (2011) Wash solution and method for affinity chromatography, US20,120,283,416 A1Google Scholar
  99. 99.
    Gillespie R, Vunnum S, Nguyen T, Macneil S (2012) Protein purification, US20,120,149,878 A1Google Scholar
  100. 100.
    Srajer Gajdosik M, Clifton J, Josic D (2012) Sample displacement chromatography as a method for purification of proteins and peptides from complex mixtures. J Chromatogr A 1239:1–9. doi: 10.1016/j.chroma.2012.03.046CrossRefPubMedGoogle Scholar
  101. 101.
    Huang B, Liu FF, Dong XY, Sun Y (2011) Molecular mechanism of the affinity interactions between protein A and human immunoglobulin G1 revealed by molecular simulations. J Phys Chem B 115(14):4168–4176. doi: 10.1021/jp111216gCrossRefPubMedGoogle Scholar
  102. 102.
    Schuler G, Reinacher M (1991) Development and optimization of a single-step procedure using protein A affinity chromatography to isolate murine IgG1 monoclonal antibodies from hybridoma supernatants. J Chromatogr 587(1):61–70PubMedGoogle Scholar
  103. 103.
    Lund LN, Christensen T, Toone E, Houen G, Staby A, St Hilaire PM (2011) Exploring variation in binding of protein A and protein G to immunoglobulin type G by isothermal titration calorimetry. J Mol Recognit 24(6):945–952. doi: 10.1002/jmr.1140CrossRefPubMedGoogle Scholar
  104. 104.
    Baumgartner K, Oelmeier SA, Hubbuch J (2015) The influence of mixed salts on the capacity of hic adsorbers: a predictive correlation to the surface tension and the aggregation temperature. Biotechnol Prog. doi: 10.1002/btpr.2166PubMedGoogle Scholar
  105. 105.
    Werner A, Hasse H (2013) Experimental study and modeling of the influence of mixed electrolytes on adsorption of macromolecules on a hydrophobic resin. J Chromatogr A 1315:135–144. doi: 10.1016/j.chroma.2013.09.071CrossRefPubMedGoogle Scholar
  106. 106.
    Wolfe LS, Barringer CP, Mostafa SS, Shukla AA (2014) Multimodal chromatography: characterization of protein binding and selectivity enhancement through mobile phase modulators. J Chromatogr A 1340:151–156. doi: 10.1016/j.chroma.2014.02.086CrossRefPubMedGoogle Scholar
  107. 107.
    Sipple et al., in preparationGoogle Scholar
  108. 108.
    Duhamel RC, Schur PH, Brendel K, Meezan E (1979) pH gradient elution of human IgG1, IgG2 and IgG4 from protein A-sepharose. J Immunol Methods 31(3-4):211–217PubMedGoogle Scholar
  109. 109.
    Gaza-Bulseco G, Hickman K, Sinicropi-Yao S, Hurkmans K, Chumsae C, Liu H (2009) Effect of the conserved oligosaccharides of recombinant monoclonal antibodies on the separation by protein A and protein G chromatography. J Chromatogr A 1216(12):2382–2387. doi: 10.1016/j.chroma.2009.01.014CrossRefPubMedGoogle Scholar
  110. 110.
    Ejima D, Yumioka R, Tsumoto K, Arakawa T (2005) Effective elution of antibodies by arginine and arginine derivatives in affinity column chromatography. Anal Biochem 345(2):250–257. doi: 10.1016/j.ab.2005.07.004CrossRefPubMedGoogle Scholar
  111. 111.
    Roben PW, Salem AN, Silverman GJ (1995) VH3 family antibodies bind domain D of staphylococcal protein A. J Immunol 154(12):6437–6445PubMedGoogle Scholar
  112. 112.
    Hogwood CE, Ahmad SS, Tarrant RD, Bracewell DG, Smales CM (2015) An ultra scale-down approach identifies host cell protein differences across a panel of mAb producing CHO cell line variants. Biotechnol J. doi: 10.1002/biot.201500010PubMedGoogle Scholar
  113. 113.
    Levy NE, Valente KN, Choe LH, Lee KH, Lenhoff AM (2014) Identification and characterization of host cell protein product-associated impurities in monoclonal antibody bioprocessing. Biotechnol Bioeng 111(5):904–912. doi: 10.1002/bit.25158CrossRefPubMedGoogle Scholar
  114. 114.
    Levy NE, Valente KN, Lee KH, Lenhoff AM (2015) Host cell protein impurities in chromatographic polishing steps for monoclonal antibody purification. Biotechnol Bioeng. doi: 10.1002/bit.25882PubMedGoogle Scholar
  115. 115.
    Lewus RA, Levy NE, Lenhoff AM, Sandler SI (2015) A comparative study of monoclonal antibodies. 1. Phase behavior and protein-protein interactions. Biotechnol Prog 31(1):268–276. doi: 10.1002/btpr.2011CrossRefPubMedGoogle Scholar
  116. 116.
    Tarrant RD, Velez-Suberbie ML, Tait AS, Smales CM, Bracewell DG (2012) Host cell protein adsorption characteristics during protein A chromatography. Biotechnol Prog 28(4):1037–1044. doi: 10.1002/btpr.1581CrossRefPubMedGoogle Scholar
  117. 117.
    Zhang S, Daniels W, Salm J, Glynn J, Martin J, Gallo C, et al. (2016) Nature of foulants and fouling mechanism in the protein A MabSelect resin cycled in a monoclonal antibody purification process. Biotechnol Bioeng 113(1):141–149. doi: 10.1002/bit.25706CrossRefPubMedGoogle Scholar
  118. 118.
    Liu Z, Mostafa SS, Shukla AA (2015) A comparison of protein A chromatographic stationary phases: performance characteristics for monoclonal antibody purification. Biotechnol Appl Biochem 62(1):37–47. doi: 10.1002/bab.1243CrossRefPubMedGoogle Scholar
  119. 119.
    Swinnen K, Krul A, Van Goidsenhoven I, Van Tichelt N, Roosen A, Van Houdt K (2007) Performance comparison of protein A affinity resins for the purification of monoclonal antibodies. J Chromatogr B Analyt Technol Biomed Life Sci 848(1):97–107. doi: 10.1016/j.jchromb.2006.04.050CrossRefPubMedGoogle Scholar
  120. 120.
    McCaw TR, Koepf EK, Conley L (2014) Evaluation of a novel methacrylate-based protein A resin for the purification of immunoglobulins and Fc-fusion proteins. Biotechnol Prog 30(5):1125–1136. doi: 10.1002/btpr.1951CrossRefPubMedPubMedCentralGoogle Scholar
  121. 121.
    Meininger DP, Rance M, Starovasnik MA, Fairbrother WJ, Skelton NJ (2000) Characterization of the binding interface between the E-domain of Staphylococcal protein A and an antibody Fv-fragment. Biochemistry 39(1):26–36PubMedGoogle Scholar
  122. 122.
    Moks T, Abrahmsen L, Nilsson B, Hellman U, Sjoquist J, Uhlen M (1986) Staphylococcal protein A consists of five IgG-binding domains. Eur J Biochem 156(3):637–643PubMedGoogle Scholar
  123. 123.
    Ghose S, Hubbard B, Cramer SM (2007) Binding capacity differences for antibodies and Fc-fusion proteins on protein A chromatographic materials. Biotechnol Bioeng 96(4):768–779. doi: 10.1002/bit.21044CrossRefPubMedGoogle Scholar
  124. 124.
    Sjoquist J, Wadso II (1971) A thermochemical study of the reaction between protein A from S. aureus and fragment Fc from immunoglobulin G. FEBS Lett 14(4):254–256PubMedGoogle Scholar
  125. 125.
    Yang L, Biswas ME, Chen P (2003) Study of binding between protein A and immunoglobulin G using a surface tension probe. Biophys J 84(1):509–522. doi: 10.1016/s0006-3495(03)74870-xCrossRefPubMedPubMedCentralGoogle Scholar
  126. 126.
    Muller E, Vajda J (2016) Routes to improve binding capacities of affinity resins demonstrated for protein A chromatography. J Chromatogr B Analyt Technol Biomed Life Sci. doi: 10.1016/j.jchromb.2016.01.036Google Scholar
  127. 127.
    LIfesciences G Application note (AA ed., Vol. 29190587). GE Lifesciences, PiscatawayGoogle Scholar
  128. 128.
    Ghose S, Zhang J, Conley L, Caple R, Williams KP, Cecchini D (2014) Maximizing binding capacity for protein A chromatography. Biotechnol Prog 30(6):1335–1340. doi: 10.1002/btpr.1980CrossRefPubMedGoogle Scholar
  129. 129.
    Gonzalez-Valdez J, Yoshikawa A, Weinberg J, Benavides J, Rito-Palomares M, Przybycien TM (2014) Toward improving selectivity in affinity chromatography with PEGylated affinity ligands: the performance of PEGylated protein A. Biotechnol Prog 30(6):1364–1379. doi: 10.1002/btpr.1994CrossRefPubMedGoogle Scholar
  130. 130.
    Gulich S, Uhlen M, Hober S (2000) Protein engineering of an IgG-binding domain allows milder elution conditions during affinity chromatography. J Biotechnol 76(2-3):233–244PubMedGoogle Scholar
  131. 131.
    Pabst TM, Palmgren R, Forss A, Vasic J, Fonseca M, Thompson C, et al. (2014) Engineering of novel Staphylococcal protein A ligands to enable milder elution pH and high dynamic binding capacity. J Chromatogr A 1362:180–185. doi: 10.1016/j.chroma.2014.08.046CrossRefPubMedGoogle Scholar
  132. 132.
    Watanabe H, Matsumaru H, Ooishi A, Honda S (2013) Structure-based histidine substitution for optimizing pH-sensitive Staphylococcus protein A. J Chromatogr B Analyt Technol Biomed Life Sci 929:155–160. doi: 10.1016/j.jchromb.2013.04.029CrossRefPubMedGoogle Scholar
  133. 133.
    Xia HF, Liang ZD, Wang SL, Wu PQ, Jin XH (2014) Molecular modification of protein A to improve the elution pH and alkali resistance in affinity chromatography. Appl Biochem Biotechnol 172(8):4002–4012. doi: 10.1007/s12010-014-0818-1CrossRefPubMedGoogle Scholar
  134. 134.
    Gagnon P, Nian R (2016) Conformational plasticity of IgG during protein A affinity chromatography. J Chromatogr A 1433:98–105. doi: 10.1016/j.chroma.2016.01.022CrossRefPubMedGoogle Scholar
  135. 135.
    Gagnon P, Nian R, Leong D, Hoi A (2015) Transient conformational modification of immunoglobulin G during purification by protein A affinity chromatography. J Chromatogr A 1395:136–142. doi: 10.1016/j.chroma.2015.03.080CrossRefPubMedGoogle Scholar
  136. 136.
    Mazzer AR, Perraud X, Halley J, O’Hara J, Bracewell DG (2015) Protein A chromatography increases monoclonal antibody aggregation rate during subsequent low pH virus inactivation hold. J Chromatogr A 1415:83–90. doi: 10.1016/j.chroma.2015.08.068CrossRefPubMedPubMedCentralGoogle Scholar
  137. 137.
    Shukla AA, Gupta P, Han X (2007) Protein aggregation kinetics during protein A chromatography. Case study for an Fc fusion protein. J Chromatogr A 1171(1-2):22–28. doi: 10.1016/j.chroma.2007.09.040CrossRefPubMedGoogle Scholar
  138. 138.
    Zhang S, Xu K, Daniels W, Salm J, Glynn J, Martin J, et al. (2016) Structural and functional characteristics of virgin and fouled Protein A MabSelect resin cycled in a monoclonal antibody purification process. Biotechnol Bioeng 113(2):367–375. doi: 10.1002/bit.25708CrossRefPubMedGoogle Scholar
  139. 139.
    Boulet-Audet M, Byrne B, Kazarian SG (2015) Cleaning-in-place of immunoaffinity resins monitored by in situ ATR-FTIR spectroscopy. Anal Bioanal Chem 407(23):7111–7122. doi: 10.1007/s00216-015-8871-3CrossRefPubMedPubMedCentralGoogle Scholar
  140. 140.
    Rogers M, Hiraoka-Sutow M, Mak P, Mann F, Lebreton B (2009) Development of a rapid sanitization solution for silica-based protein A affinity adsorbents. J Chromatogr A 1216(21):4589–4596. doi: 10.1016/j.chroma.2009.03.065CrossRefPubMedGoogle Scholar
  141. 141.
    Wang L, Dembecki J, Jaffe NE, O’Mara BW, Cai H, Sparks CN, et al. (2013) A safe, effective, and facility compatible cleaning in place procedure for affinity resin in large-scale monoclonal antibody purification. J Chromatogr A 1308:86–95. doi: 10.1016/j.chroma.2013.07.096CrossRefPubMedGoogle Scholar
  142. 142.
    Gronberg A, Eriksson M, Ersoy M, Johansson HJ (2011) A tool for increasing the lifetime of chromatography resins. MAbs 3(2):192–202PubMedPubMedCentralGoogle Scholar
  143. 143.
    Yang L, Harding JD, Ivanov AV, Ramasubramanyan N, Dong DD (2015) Effect of cleaning agents and additives on protein A ligand degradation and chromatography performance. J Chromatogr A 1385:63–68. doi: 10.1016/j.chroma.2015.01.068CrossRefPubMedGoogle Scholar
  144. 144.
    Saraswat M, Musante L, Ravida A, Shortt B, Byrne B, Holthofer H (2013) Preparative purification of recombinant proteins: current status and future trends. Biomed Res Int 2013:312709. doi: 10.1155/2013/312709CrossRefPubMedPubMedCentralGoogle Scholar
  145. 145.
    Stonier A, Simaria AS, Smith M, Farid SS (2012) Decisional tool to assess current and future process robustness in an antibody purification facility. Biotechnol Prog 28(4):1019–1028. doi: 10.1002/btpr.1569CrossRefPubMedGoogle Scholar
  146. 146.
    Liu HF, McCooey B, Duarte T, Myers DE, Hudson T, Amanullah A, et al. (2011) Exploration of overloaded cation exchange chromatography for monoclonal antibody purification. J Chromatogr A 1218(39):6943–6952. doi: 10.1016/j.chroma.2011.08.008CrossRefPubMedGoogle Scholar
  147. 147.
    Iskra T, Sacramo A, Gallo C, Godavarti R, Chen S, Lute S, Brorson K (2015) Development of a modular virus clearance package for anion exchange chromatography operated in weak partitioning mode. Biotechnol Prog 31(3):750–757. doi: 10.1002/btpr.2080CrossRefPubMedGoogle Scholar
  148. 148.
    Kelley BD, Jakubik J, Vicik S (2008) Viral clearance studies on new and used chromatography resins: critical review of a large dataset. Biologicals 36(2):88–98. doi: 10.1016/j.biologicals.2007.08.001CrossRefPubMedGoogle Scholar
  149. 149.
    Miesegaes GR, Lute SC, Read EK, Brorson KA (2014) Viral clearance by flow-through mode ion exchange columns and membrane adsorbers. Biotechnol Prog 30(1):124–131. doi: 10.1002/btpr.1832CrossRefPubMedGoogle Scholar
  150. 150.
    Norling L, Lute S, Emery R, Khuu W, Voisard M, Xu Y, et al. (2005) Impact of multiple re-use of anion-exchange chromatography media on virus removal. J Chromatogr A 1069(1):79–89PubMedGoogle Scholar
  151. 151.
    Roush D (2014) Viral clearance using traditional, well-understood unit operations (session I): anion exchange chromatography (AEX). PDA J Pharm Sci Technol 68(1):23–29. doi: 10.5731/pdajpst.2014.00963CrossRefPubMedGoogle Scholar
  152. 152.
    Roush D (2015) Viral clearance using traditional, well-understood unit operations: session 1.2. Anion exchange chromatography; and session 1.3. Protein a chromatography. PDA J Pharm Sci Technol 69(1):154–162. doi: 10.5731/pdajpst.2015.01039CrossRefPubMedGoogle Scholar
  153. 153.
    Strauss DM, Cano T, Cai N, Delucchi H, Plancarte M, Coleman D, et al. (2010) Strategies for developing design spaces for viral clearance by anion exchange chromatography during monoclonal antibody production. Biotechnol Prog 26(3):750–755. doi: 10.1002/btpr.385CrossRefPubMedGoogle Scholar
  154. 154.
    Strauss DM, Gorrell J, Plancarte M, Blank GS, Chen Q, Yang B (2009) Anion exchange chromatography provides a robust, predictable process to ensure viral safety of biotechnology products. Biotechnol Bioeng 102(1):168–175. doi: 10.1002/bit.22051CrossRefPubMedGoogle Scholar
  155. 155.
    Zhou JX, Solamo F, Hong T, Shearer M, Tressel T (2008) Viral clearance using disposable systems in monoclonal antibody commercial downstream processing. Biotechnol Bioeng 100(3):488–496. doi: 10.1002/bit.21781CrossRefGoogle Scholar
  156. 156.
    Yao Y, Lenhoff AM (2006) Pore size distributions of ion exchangers and relation to protein binding capacity. J Chromatogr A 1126(1-2):107–119. doi: 10.1016/j.chroma.2006.06.057CrossRefPubMedGoogle Scholar
  157. 157.
    DePhillips P, Lenhoff AM (2000) Pore size distributions of cation-exchange adsorbents determined by inverse size-exclusion chromatography. J Chromatogr A 883(1-2):39–54Google Scholar
  158. 158.
    Tao Y, Carta G (2008) Rapid monoclonal antibody adsorption on dextran-grafted agarose media for ion-exchange chromatography. J Chromatogr A 1211(1-2):70–79. doi: 10.1016/j.chroma.2008.09.096CrossRefGoogle Scholar
  159. 159.
    Bowes BD, Lenhoff AM (2011) Protein adsorption and transport in dextran-modified ion-exchange media. II Intraparticle uptake and column breakthrough. J Chromatogr A 1218(29):4698–4708. doi: 10.1016/j.chroma.2011.05.054CrossRefGoogle Scholar
  160. 160.
    Lenhoff AM (2011) Protein adsorption and transport in polymer-functionalized ion-exchangers. J Chromatogr A 1218(49):8748–8759. doi: 10.1016/j.chroma.2011.06.061CrossRefPubMedPubMedCentralGoogle Scholar
  161. 161.
    Perez Almodovar EX, Glatz B, Carta G (2012) Counterion effects on protein adsorption equilibrium and kinetics in polymer-grafted cation exchangers. J Chromatogr A 1253:83–93. doi: 10.1016/j.chroma.2012.06.100CrossRefPubMedPubMedCentralGoogle Scholar
  162. 162.
    Perez-Almodovar EX, Wu Y, Carta G (2012) Multicomponent adsorption of monoclonal antibodies on macroporous and polymer grafted cation exchangers. J Chromatogr A 1264:48–56. doi: 10.1016/j.chroma.2012.09.064CrossRefPubMedPubMedCentralGoogle Scholar
  163. 163.
    Xu Z, Li J, Zhou JX (2012) Process development for robust removal of aggregates using cation exchange chromatography in monoclonal antibody purification with implementation of quality by design. Prep Biochem Biotechnol 42(2):183–202. doi: 10.1080/10826068.2012.654572CrossRefPubMedPubMedCentralGoogle Scholar
  164. 164.
    Riordan WT, Heilmann SM, Brorson K, Seshadri K, Etzel MR (2009) Salt tolerant membrane adsorbers for robust impurity clearance. Biotechnol Prog 25(6):1695–1702. doi: 10.1002/btpr.256CrossRefPubMedGoogle Scholar
  165. 165.
    Yoshimoto N, Itoh D, Isakari Y, Podgornik A, Yamamoto S (2015) Salt tolerant chromatography provides salt tolerance and a better selectivity for protein monomer separations. Biotechnol J 10(12):1929–1934. doi: 10.1002/biot.201400550CrossRefPubMedGoogle Scholar
  166. 166.
    Gu F, Chodavarapu K, McCreary D, Plitt TA, Tamoria E, Ni M, et al. (2015) Silica-based strong anion exchange media for protein purification. J Chromatogr A 1376:53–63. doi: 10.1016/j.chroma.2014.11.082CrossRefPubMedGoogle Scholar
  167. 167.
    Fang F, Aguilar MI, Hearn MT (1996) Influence of temperature on the retention behaviour of proteins in cation-exchange chromatography. J Chromatogr A 729(1-2):49–66PubMedGoogle Scholar
  168. 168.
    Guo J, Carta G (2014) Unfolding and aggregation of a glycosylated monoclonal antibody on a cation exchange column. Part II. Protein structure effects by hydrogen deuterium exchange mass spectrometry. J Chromatogr A 1356:129–137. doi: 10.1016/j.chroma.2014.06.038CrossRefPubMedGoogle Scholar
  169. 169.
    Guo J, Carta G (2015) Unfolding and aggregation of monoclonal antibodies on cation exchange columns: effects of resin type, load buffer, and protein stability. J Chromatogr A 1388:184–194. doi: 10.1016/j.chroma.2015.02.047CrossRefPubMedGoogle Scholar
  170. 170.
    Gospodarek AM, Hiser DE, O’Connell JP, Fernandez EJ (2014) Unfolding of a model protein on ion exchange and mixed mode chromatography surfaces. J Chromatogr A 1355:238–252. doi: 10.1016/j.chroma.2014.06.024CrossRefPubMedGoogle Scholar
  171. 171.
    Bracewell DG, Boychyn M, Baldascini H, Storey SA, Bulmer M, More J, Hoare M (2008) Impact of clarification strategy on chromatographic separations: pre-processing of cell homogenates. Biotechnol Bioeng 100(5):941–949. doi: 10.1002/bit.21823CrossRefPubMedGoogle Scholar
  172. 172.
    Kramarczyk JF, Kelley BD, Coffman JL (2008) High-throughput screening of chromatographic separations: II. Hydrophobic interaction. Biotechnol Bioeng 100(4):707–720. doi: 10.1002/bit.21907CrossRefPubMedGoogle Scholar
  173. 173.
    McCue JT (2009) Theory and use of hydrophobic interaction chromatography in protein purification applications. Methods Enzymol 463:405–414. doi: 10.1016/s0076-6879(09)63025-1CrossRefPubMedGoogle Scholar
  174. 174.
    McCue JT, Engel P, Ng A, Macniven R, Thommes J (2008) Modeling of protein monomer/aggregate purification and separation using hydrophobic interaction chromatography. Bioprocess Biosyst Eng 31(3):261–275. doi: 10.1007/s00449-008-0200-1CrossRefPubMedGoogle Scholar
  175. 175.
    Deitcher RW, O’Connell JP, Fernandez EJ (2010) Changes in solvent exposure reveal the kinetics and equilibria of adsorbed protein unfolding in hydrophobic interaction chromatography. J Chromatogr A 1217(35):5571–5583. doi: 10.1016/j.chroma.2010.06.051CrossRefPubMedPubMedCentralGoogle Scholar
  176. 176.
    Deitcher RW, Xiao Y, O’Connell JP, Fernandez EJ (2009) Protein instability during HIC: evidence of unfolding reversibility, and apparent adsorption strength of disulfide bond-reduced alpha-lactalbumin variants. Biotechnol Bioeng 102(5):1416–1427. doi: 10.1002/bit.22171CrossRefPubMedGoogle Scholar
  177. 177.
    Gospodarek AM, Smatlak ME, O’Connell JP, Fernandez EJ (2011) Protein stability and structure in HIC: hydrogen exchange experiments and COREX calculations. Langmuir 27(1):286–295. doi: 10.1021/la103793rCrossRefPubMedGoogle Scholar
  178. 178.
    Muca R, Marek W, Piatkowski W, Antos D (2010) Influence of the sample-solvent on protein retention, mass transfer and unfolding kinetics in hydrophobic interaction chromatography. J Chromatogr A 1217(17):2812–2820. doi: 10.1016/j.chroma.2010.02.043CrossRefPubMedGoogle Scholar
  179. 179.
    Ueberbacher R, Rodler A, Hahn R, Jungbauer A (2010) Hydrophobic interaction chromatography of proteins: thermodynamic analysis of conformational changes. J Chromatogr A 1217(2):184–190. doi: 10.1016/j.chroma.2009.05.033CrossRefPubMedGoogle Scholar
  180. 180.
    Eriksson KO, Belew M (2011) Hydrophobic interaction chromatography. Methods Biochem Anal 54:165–181PubMedGoogle Scholar
  181. 181.
    To BC, Lenhoff AM (2007) Hydrophobic interaction chromatography of proteins. I The effects of protein and adsorbent properties on retention and recovery. J Chromatogr A 1141(2):191–205. doi: 10.1016/j.chroma.2006.12.020CrossRefPubMedGoogle Scholar
  182. 182.
    To BC, Lenhoff AM (2007) Hydrophobic interaction chromatography of proteins. II Solution thermodynamic properties as a determinant of retention. J Chromatogr A 1141(2):235–243. doi: 10.1016/j.chroma.2006.12.022CrossRefPubMedGoogle Scholar
  183. 183.
    To BC, Lenhoff AM (2008) Hydrophobic interaction chromatography of proteins III. Transport and kinetic parameters in isocratic elution. J Chromatogr A 1205(1-2):46–59. doi: 10.1016/j.chroma.2008.07.079CrossRefPubMedGoogle Scholar
  184. 184.
    To BC, Lenhoff AM (2011) Hydrophobic interaction chromatography of proteins. IV Protein adsorption capacity and transport in preparative mode. J Chromatogr A 1218(3):427–440. doi: 10.1016/j.chroma.2010.11.051CrossRefPubMedGoogle Scholar
  185. 185.
    Mirani MR, Rahimpour F (2015) Thermodynamic modelling of hydrophobic interaction chromatography of biomolecules in the presence of salt. J Chromatogr A 1422:170–177. doi: 10.1016/j.chroma.2015.10.019CrossRefPubMedGoogle Scholar
  186. 186.
    Nfor BK, Zuluaga DS, Verheijen PJ, Verhaert PD, van der Wielen LA, Ottens M (2011) Model-based rational strategy for chromatographic resin selection. Biotechnol Prog 27(6):1629–1643PubMedGoogle Scholar
  187. 187.
    Lemmens R, Olsson U, Nyhammar T, Stadler J (2003) Supercoiled plasmid DNA: selective purification by thiophilic/aromatic adsorption. J Chromatogr B Analyt Technol Biomed Life Sci 784(2):291–300PubMedGoogle Scholar
  188. 188.
    Senczuk AM, Klinke R, Arakawa T, Vedantham G, Yigzaw Y (2009) Hydrophobic interaction chromatography in dual salt system increases protein binding capacity. Biotechnol Bioeng 103(5):930–935. doi: 10.1002/bit.22313CrossRefPubMedGoogle Scholar
  189. 189.
    Melander W, Horvath C (1977) Salt effect on hydrophobic interactions in precipitation and chromatography of proteins: an interpretation of the lyotropic series. Arch Biochem Biophys 183(1):200–215PubMedGoogle Scholar
  190. 190.
    Kelley et al (2008) Weak partitioning chromatography for anion exchange purification of monoclonal antibodies. Biotechnol Bioeng 101:553–566Google Scholar
  191. 191.
    Johansson B-L, Belew M, Eriksson S, Glad G, Lind O, Maloisel J-L, Norrman N (2003) Preparation and characterization of prototypes for multi-modal separation aimed for capture of positively charged biomolecules at high-salt conditions. J Chromatogr A 1016(1):35–49. doi: 10.1016/S0021-9673(03)01141-5CrossRefPubMedGoogle Scholar
  192. 192.
    Yang T, Malmquist G, Johansson B-L, Maloisel J-L, Cramer S (2007) Evaluation of multi-modal high salt binding ion exchange materials. J Chromatogr A 1157(1–2):171–177. doi: 10.1016/j.chroma.2007.04.070CrossRefPubMedGoogle Scholar
  193. 193.
    Chen J, Tetrault J, Zhang Y, Wasserman A, Conley G, Dileo M, et al. (2010) The distinctive separation attributes of mixed-mode resins and their application in monoclonal antibody downstream purification process. J Chromatogr A 1217(2):216–224. doi: 10.1016/j.chroma.2009.09.047CrossRefPubMedGoogle Scholar
  194. 194.
    Kaleas KA, Tripodi M, Revelli S, Sharma V, Pizarro SA (2014) Evaluation of a multimodal resin for selective capture of CHO-derived monoclonal antibodies directly from harvested cell culture fluid. J Chromatogr B Analyt Technol Biomed Life Sci 969:256–263. doi: 10.1016/j.jchromb.2014.08.026CrossRefPubMedGoogle Scholar
  195. 195.
    Pezzini J, Joucla G, Gantier R, Toueille M, Lomenech A-M, Le Sénéchal C, et al. (2011) Antibody capture by mixed-mode chromatography: a comprehensive study from determination of optimal purification conditions to identification of contaminating host cell proteins. J Chromatogr A 1218(45):8197–8208. doi: 10.1016/j.chroma.2011.09.036CrossRefPubMedGoogle Scholar
  196. 196.
    Pete G (2009) IgG aggregate removal by charged-hydrophobic mixed mode chromatography. Curr Pharm Biotechnol 10(4):434–439. doi: 10.2174/138920109788488888CrossRefGoogle Scholar
  197. 197.
    Li P, Xiu G, Mata VG, Grande CA, Rodrigues AE (2006) Expanded bed adsorption/desorption of proteins with Streamline Direct CST I adsorbent. Biotechnol Bioeng 94(6):1155–1163. doi: 10.1002/bit.20952CrossRefPubMedGoogle Scholar
  198. 198.
    Mollerup JM, Hansen TB, Kidal S, Staby A (2008) Quality by design—thermodynamic modelling of chromatographic separation of proteins. J Chromatogr A 1177(2):200–206. doi: 10.1016/j.chroma.2007.08.059CrossRefPubMedGoogle Scholar
  199. 199.
    Nfor BK, Noverraz M, Chilamkurthi S, Verhaert PDEM, van der Wielen LAM, Ottens M (2010) High-throughput isotherm determination and thermodynamic modeling of protein adsorption on mixed mode adsorbents. J Chromatogr A 1217(44):6829–6850. doi: 10.1016/j.chroma.2010.07.069CrossRefPubMedGoogle Scholar
  200. 200.
    Pitiot O, Folley L, Vijayalakshmi MA (2001) Protein adsorption on histidyl-aminohexyl-sepharose 4B: I. Study of the mechanistic aspects of adsorption for the separation of human serum albumin from its non-enzymatic glycated isoforms (advanced glycosylated end products). J Chromatogr B Biomed Sci Appl 758(2):163–172. doi: 10.1016/S0378-4347(01)00176-1CrossRefPubMedGoogle Scholar
  201. 201.
    Wang J, Jenkins EW, Robinson JR, Wilson A, Husson SM (2015) A new multimodal membrane adsorber for monoclonal antibody purifications. J Membr Sci 492:137–146. doi: 10.1016/j.memsci.2015.05.013CrossRefGoogle Scholar
  202. 202.
    Follman DK, Fahrner RL (2004) Factorial screening of antibody purification processes using three chromatography steps without protein A. J Chromatogr A 1024(1-2):79–85PubMedGoogle Scholar
  203. 203.
    Komkova EN, Honeyman CH (2014) Mixed-mode chromatography membranes, US20,sss140,238,935 A1Google Scholar
  204. 204.
    Wang J, Sproul RT, Anderson LS, Husson SM (2014) Development of multimodal membrane adsorbers for antibody purification using atom transfer radical polymerization. Polymer 55(6):1404–1411. doi: 10.1016/j.polymer.2013.12.023CrossRefGoogle Scholar
  205. 205.
    Stone MT, Kozlov M (2014) Separating proteins with activated carbon. Langmuir 30(27):8046–8055. doi: 10.1021/la501005sCrossRefPubMedGoogle Scholar
  206. 206.
    Amara J, Boyle J, Yavorsky D, Cacace B (2016) High surface area fiber media with nano-fibrillated surface features, WO2,016,036,508 A1Google Scholar
  207. 207.
    Amara J, Cacace B, Yavorsky D, Boyle J (2014) Chromatography media for purifying vaccines and viruses, US20,150,352,465 A1Google Scholar
  208. 208.
    Yavorsky D, Amara J, Umana J, Cataldo W, Kozlov M, Stone M (2015) Chromatography media and method, US20,120,029,176 A1Google Scholar
  209. 209.
    Hardick O, Dods S, Stevens B, Bracewell DG (2015) Nanofiber adsorbents for high productivity continuous downstream processing. J Biotechnol 213:74–82. doi: 10.1016/j.jbiotec.2015.01.031CrossRefPubMedGoogle Scholar
  210. 210.
    Baur D, Angarita M, Muller-Spath T, Steinebach F, Morbidelli M (2016) Comparison of batch and continuous multi-column protein A capture processes by optimal design. Biotechnol J. doi: 10.1002/biot.201500481PubMedGoogle Scholar
  211. 211.
    Konstantinov KB, Cooney CL (2015) White paper on continuous bioprocessing, May 20–21, 2014, Continuous manufacturing symposium. J Pharm Sci 104(3):813–820. doi: 10.1002/jps.24268PubMedGoogle Scholar
  212. 212.
    Muller-Spath T, Aumann L, Strohlein G, Kornmann H, Valax P, Delegrange L, et al. (2010) Two step capture and purification of IgG2 using multicolumn countercurrent solvent gradient purification (MCSGP). Biotechnol Bioeng 107(6):974–984. doi: 10.1002/bit.22887CrossRefPubMedGoogle Scholar
  213. 213.
    Warikoo V, Godawat R, Brower K, Jain S, Cummings D, Simons E, et al. (2012) Integrated continuous production of recombinant therapeutic proteins. Biotechnol Bioeng 109(12):3018–3029. doi: 10.1002/bit.24584CrossRefPubMedGoogle Scholar
  214. 214.
    Anderson NG (2001) Practical use of continuous processing in developing and scaling up laboratory processes. Org Process Res Dev 5(6):613–621. doi: 10.1021/op0100605CrossRefGoogle Scholar
  215. 215.
    Fletcher N (2010) Turn batch to continuous processing. Manufacturing Chemist PharmaGoogle Scholar
  216. 216.
    Laird T (2007) Continuous processes in small-scale manufacture. Org Process Res Dev 11(6):927–927. doi: 10.1021/op700233eCrossRefGoogle Scholar
  217. 217.
    Laird T (2014) Process intensification: engineering for efficiency, sustainability and flexibility. Org Process Res Dev 18(1):276–276. doi: 10.1021/op400341eCrossRefGoogle Scholar
  218. 218.
    Mazumdar S, Ray SK (2001) Solidification control in continuous casting of steel. Sadhana 26(1):179–198. doi: 10.1007/bf02728485CrossRefGoogle Scholar
  219. 219.
    Reay DA, Ramshaw C, Harvey A (2013) Process intensification engineering for efficiency, sustainability and flexibility. Retrieved from
  220. 220.
  221. 221.
    Ruthven DM, Ching CB (1989) Counter-current and simulated counter-current adsorption separation processes. Chem Eng Sci 44(5):1011–1038. doi: 10.1016/0009-2509(89)87002-2CrossRefGoogle Scholar
  222. 222.
    Godawat R, Brower K, Jain S, Konstantinov K, Riske F, Warikoo V (2012) Periodic counter-current chromatography -- design and operational considerations for integrated and continuous purification of proteins. Biotechnol J 7(12):1496–1508. doi: 10.1002/biot.201200068CrossRefPubMedGoogle Scholar
  223. 223.
    Gjoka X, Rogler K, Martino RA, Gantier R, Schofield M (2015) A straightforward methodology for designing continuous monoclonal antibody capture multi-column chromatography processes. J Chromatogr A 1416:38–46. doi: 10.1016/j.chroma.2015.09.005CrossRefPubMedGoogle Scholar
  224. 224.
    Dutta AK, Tran T, Napadensky B, Teella A, Brookhart G, Ropp PA, et al. (2015) Purification of monoclonal antibodies from clarified cell culture fluid using protein A capture continuous countercurrent tangential chromatography. J Biotechnol 213:54–64. doi: 10.1016/j.jbiotec.2015.02.026CrossRefPubMedPubMedCentralGoogle Scholar
  225. 225.
    Napadensky B, Shinkazh O, Teella A, Zydney AL (2013) Continuous countercurrent tangential chromatography for monoclonal antibody purification. Sep Sci Technol 48(9):1289–1297. doi: 10.1080/01496395.2013.767837CrossRefGoogle Scholar
  226. 226.
    Shinkazh O, Kanani D, Barth M, Long M, Hussain D, Zydney AL (2011) Countercurrent tangential chromatography for large-scale protein purification. Biotechnol Bioeng 108(3):582–591. doi: 10.1002/bit.22960CrossRefPubMedGoogle Scholar
  227. 227.
    Casey C, Gallos T, Alekseev Y, Ayturk E, Pearl S (2011) Protein concentration with single-pass tangential flow filtration (SPTFF). J Membr Sci 384(1–2):82–88. doi: 10.1016/j.memsci.2011.09.004CrossRefGoogle Scholar
  228. 228.
    Dizon-Maspat J, Bourret J, D’Agostini A, Li F (2012) Single pass tangential flow filtration to debottleneck downstream processing for therapeutic antibody production. Biotechnol Bioeng 109(4):962–970. doi: 10.1002/bit.24377CrossRefPubMedGoogle Scholar
  229. 229.
    Chenette HCS, Robinson JR, Hobley E, Husson SM (2012) Development of high-productivity, strong cation-exchange adsorbers for protein capture by graft polymerization from membranes with different pore sizes. J Membr Sci 432-424:43–52. doi: 10.1016/j.memsci.2012.07.040CrossRefGoogle Scholar
  230. 230.
    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.201000292CrossRefPubMedGoogle Scholar
  231. 231.
    Orr V, Zhong L, Moo-Young M, Chou CP (2013) Recent advances in bioprocessing application of membrane chromatography. Biotechnol Adv 31(4):450–465. doi: 10.1016/j.biotechadv.2013.01.007CrossRefPubMedGoogle Scholar
  232. 232.
    Klutz S, Lobedann M, Bramsiepe C, Schembecker G (2016) Continuous viral inactivation at low pH value in antibody manufacturing. Chem Eng Process Process Intensification 102:88–101. doi: 10.1016/j.cep.2016.01.002CrossRefGoogle Scholar
  233. 233.
    Klutz S, Magnus J, Lobedann M, Schwan P, Maiser B, Niklas J, et al. (2015) Developing the biofacility of the future based on continuous processing and single-use technology. J Biotechnol 213:120–130. doi: 10.1016/j.jbiotec.2015.06.388CrossRefPubMedGoogle Scholar
  234. 234.
    Pollock J, Bolton G, Coffman J, Ho SV, Bracewell DG, Farid SS (2013) Optimising the design and operation of semi-continuous affinity chromatography for clinical and commercial manufacture. J Chromatogr A 1284:17–27. doi: 10.1016/j.chroma.2013.01.082CrossRefPubMedGoogle Scholar
  235. 235.
    Dutta AK, Tan J, Napadensky B, Zydney AL, Shinkazh O (2016) Performance optimization of continuous countercurrent tangential chromatography for antibody capture. Biotechnol Prog 32(2):430–439. doi: 10.1002/btpr.2250CrossRefPubMedGoogle Scholar
  236. 236.
    Brower KP, Ryakala VK, Bird R, Godawat R, Riske FJ, Konstantinov K, et al. (2014) Single-step affinity purification of enzyme biotherapeutics: a platform methodology for accelerated process development. Biotechnol Prog 30(3):708–717. doi: 10.1002/btpr.1870CrossRefPubMedGoogle Scholar
  237. 237.
    Read EK, Park JT, Shah RB, Riley BS, Brorson KA, Rathore AS (2010) Process analytical technology (PAT) for biopharmaceutical products: Part I. Concepts and applications. Biotechnol Bioeng 105(2):276–284. doi: 10.1002/bit.22528CrossRefPubMedGoogle Scholar
  238. 238.
    Tharmalingam T, Wu CH, Callahan S, T Goudar C (2015) A framework for real-time glycosylation monitoring (RT-GM) in mammalian cell culture. Biotechnol Bioeng 112(6):1146–1154. doi: 10.1002/bit.25520CrossRefPubMedGoogle Scholar
  239. 239.
    Box GEP, Hunter JS, Hunter WG (2005) Statistics for experimenters: design, innovation, and discovery. Wiley-InterscienceGoogle Scholar
  240. 240.
    Montgomery DC (2012) Design and analysis of experiments. WileyGoogle Scholar
  241. 241.
    Begley CG (2013) An unappreciated challenge to oncology drug discovery: pitfalls in preclinical research. Am Soc Clin Oncol Educ Book, 466–468. doi: 10.1200/EdBook_AM.2013.33.466Google Scholar
  242. 242.
    Cook DA, Beckman TJ, Bordage G (2007) Quality of reporting of experimental studies in medical education: a systematic review. Med Educ 41(8):737–745. doi: 10.1111/j.1365-2923.2007.02777.xCrossRefPubMedGoogle Scholar
  243. 243.
    Deming SN (1986) Chemometrics: an overview. Clin Chem 32(9):1702–1706PubMedGoogle Scholar
  244. 244.
    Ilzarbe L, Álvarez MJ, Viles E, Tanco M (2008) Practical applications of design of experiments in the field of engineering: a bibliographical review. Qual Reliab Eng Int 24(4):417–428. doi: 10.1002/qre.909CrossRefGoogle Scholar
  245. 245.
    Tanco M, Viles E, Ilzarbe L, Alvarez MJ (2007) Manufacturing industries need design of experiments (DoE). Proceedings of the World Congress on Engineering, IIGoogle Scholar
  246. 246.
    Nfor BK, Ripic J, van der Padt A, Jacobs M, Ottens M (2012) Model-based high-throughput process development for chromatographic whey proteins separation. Biotechnol J 7(10):1221–1232. doi: 10.1002/biot.201200191CrossRefPubMedGoogle Scholar
  247. 247.
    Welsh J (2015) Pushing the limits of high-throughput chromatography process development: current state and future directions. Pharm Bioprocess 3(1):1–3Google Scholar
  248. 248.
    Hussain M (2015) A direct qPCR method for residual DNA quantification in monoclonal antibody drugs produced in CHO cells. J Pharm Biomed Anal 115:603–606. doi: 10.1016/j.jpba.2015.03.005CrossRefPubMedGoogle Scholar
  249. 249.
    Nissom PM (2007) Specific detection of residual CHO host cell DNA by real-time PCR. Biologicals 35(3):211–215. doi: 10.1016/j.biologicals.2006.09.001CrossRefPubMedGoogle Scholar
  250. 250.
    Diederich P, Hoffmann M, Hubbuch J (2015) High-throughput process development of purification alternatives for the protein avidin. Biotechnol Prog 31(4):957–973. doi: 10.1002/btpr.2104CrossRefPubMedGoogle Scholar
  251. 251.
    Van Cleave VH (2003) Validation of immunoassays for anti-drug antibodies. Dev Biol (Basel) 112:107–112Google Scholar
  252. 252.
    Antony J (2003) 2 – Fundamentals of design of experiments. In: Design of experiments for engineers and scientists (pp. 6–16). Butterworth-Heinemann, OxfordGoogle Scholar
  253. 253.
    Tye H (2004) Application of statistical ‘design of experiments’ methods in drug discovery. Drug Discov Today 9(11):485–491. doi: 10.1016/S1359-6446(04)03086-7CrossRefPubMedGoogle Scholar
  254. 254.
    Donev AN (2004) Design of experiments in the presence of errors in factor levels. J Stat Plann Inference 126(2):569–585. doi: 10.1016/j.jspi.2003.09.002CrossRefGoogle Scholar
  255. 255.
    Franceschini G, Macchietto S (2008) Model-based design of experiments for parameter precision: state of the art. Chem Eng Sci 63(19):4846–4872. doi: 10.1016/j.ces.2007.11.034CrossRefGoogle Scholar
  256. 256.
    Rathore AS, Mittal S, Pathak M, Arora A (2014) Guidance for performing multivariate data analysis of bioprocessing data: pitfalls and recommendations. Biotechnol Prog 30(4):967–973. doi: 10.1002/btpr.1922CrossRefPubMedGoogle Scholar
  257. 257.
    Shen X, Huang H-C (2006) Optimal model assessment, selection, and combination. J Am Stat Assoc 101(474):554–568. doi: 10.1198/016214505000001078CrossRefGoogle Scholar
  258. 258.
    Shen X, Ye J (2002) Adaptive model selection. J Am Stat Assoc 97(457):210–221. doi: 10.1198/016214502753479356CrossRefGoogle Scholar
  259. 259.
    Zhang B, Shen X, Mumford SL (2012) Generalized degrees of freedom and adaptive model selection in linear mixed-effects models. Comput Stat Data Anal 56(3):574–586. doi: 10.1016/j.csda.2011.09.001CrossRefPubMedPubMedCentralGoogle Scholar
  260. 260.
    Cortina JM (1993) Interaction, nonlinearity, and multicollinearity: implications for multiple regression. J Manag 19(4):915–922. doi: 10.1177/014920639301900411CrossRefGoogle Scholar
  261. 261.
    Strobl C, Malley J, Tutz G (2009) An introduction to recursive partitioning: rationale, application and characteristics of classification and regression trees, bagging and random forests. Psychol Methods 14(4):323–348. doi: 10.1037/a0016973CrossRefPubMedPubMedCentralGoogle Scholar
  262. 262.
    Luo L, Yao Y, Gao F (2015) Bayesian improved model migration methodology for fast process modeling by incorporating prior information. Chem Eng Sci 134:23–35. doi: 10.1016/j.ces.2015.04.045CrossRefGoogle Scholar
  263. 263.
    Sainani KL (2013) Multivariate regression: the pitfalls of automated variable selection. PM R 5(9):791–794. doi: 10.1016/j.pmrj.2013.07.007CrossRefPubMedGoogle Scholar
  264. 264.
    Berry EM, Coustere-Yakir C, Grover NB (1998) The significance of non-significance. QJM 91(9):647–653PubMedGoogle Scholar
  265. 265.
    Gerss J (2006) Not significant--what now? Zentralbl Gynakol 128(6):307–310. doi: 10.1055/s-2006-942088CrossRefPubMedGoogle Scholar
  266. 266.
    Yan W, Hu S, Yang Y, Gao F, Chen T (2011) Bayesian migration of Gaussian process regression for rapid process modeling and optimization. Chem Eng J 166(3):1095–1103. doi: 10.1016/j.cej.2010.11.097CrossRefGoogle Scholar
  267. 267.
    Barker GA, Calzada J, Herzer S, Rieble S (2015) Adaptation to high throughput batch chromatography enhances multivariate screening. Biotechnol J 10(9):1493–1498. doi: 10.1002/biot.201400671CrossRefPubMedGoogle Scholar
  268. 268.
    Ryan TP (2006) Modern experimental design. Wiley-InterscienceGoogle Scholar
  269. 269.
    Eriksson L (2008) Design of experiments: principles and applications. UmetricsGoogle Scholar
  270. 270.
    Harring JR, Weiss BA, Li M (2015) Assessing spurious interaction effects in structural equation modeling: a cautionary note. Educ Psychol Meas 75(5):721–738. doi: 10.1177/0013164414565007CrossRefPubMedGoogle Scholar
  271. 271.
    Bedeian AG, Mossholder KW (1994) Simple question, not so simple answer: interpreting interaction terms in moderated multiple regression. J Manag 20(1):159–165Google Scholar
  272. 272.
    Myers RH, Montgomery DC, Anderson-Cook CM (2016) Response surface methodology: process and product optimization using designed experiments, 3rd edn. WileyGoogle Scholar
  273. 273.
    Dougherty S, Simpson JR, Hill RR, Pignatiello JJ, White ED (2014) Augmentation of definitive screening designs (DSD+). Int J Exp Des Process Optimisation 4(2):91–115. doi: 10.1504/IJEDPO.2014.066465CrossRefGoogle Scholar
  274. 274.
    Hecht ES, McCord JP, Muddiman DC (2015) Definitive screening design optimization of mass spectrometry parameters for sensitive comparison of filter and solid phase extraction purified, INLIGHT plasma N-glycans. Anal Chem 87(14):7305–7312. doi: 10.1021/acs.analchem.5b01609CrossRefPubMedPubMedCentralGoogle Scholar
  275. 275.
    Tai M, Ly A, Leung I, Nayar G (2015) Efficient high-throughput biological process characterization: definitive screening design with the Ambr250 bioreactor system. Biotechnol Prog 31(5):1388–1395. doi: 10.1002/btpr.2142CrossRefPubMedGoogle Scholar
  276. 276.
    Yang Y-P, D’Amore T (2014) Protein subunit vaccine purification. In: Wen EP, Ellis R, Pujar NS (eds) Vaccine development and manufacturing1st edn. Wiley, HobokenGoogle Scholar
  277. 277.
    Goos P (2002) The optimal design of blocked and split-plot experiments. SpringerGoogle Scholar
  278. 278.
    Barker TB (2005) Quality by experimental design, 3rd edn. CRC PressGoogle Scholar
  279. 279.
    Fisher RA (1966) The design of experiments8th edn. Oliver and Boyd, EdinburghGoogle Scholar
  280. 280.
    Lau CY, Zahidi AAA, Liew OW, Ng TW (2015) A direct heating model to overcome the edge effect in microplates. J Pharm Biomed Anal 102:199–202. doi: 10.1016/j.jpba.2014.09.021CrossRefGoogle Scholar
  281. 281.
    Close EJ, Salm JR, Bracewell DG, Sorensen E (2014) Modelling of industrial biopharmaceutical multicomponent chromatography. Chem Eng Res Des 92(7):1304–1314. doi: 10.1016/j.cherd.2013.10.022CrossRefGoogle Scholar
  282. 282.
    Chhatre S, Bracewell DG, Titchener-Hooker NJ (2009) A microscale approach for predicting the performance of chromatography columns used to recover therapeutic polyclonal antibodies. J Chromatogr A 1216(45):7806–7815. doi: 10.1016/j.chroma.2009.09.038CrossRefPubMedPubMedCentralGoogle Scholar
  283. 283.
    Hutchinson N, Chhatre S, Baldascini H, Davies JL, Bracewell DG, Hoare M (2009) Ultra scale-down approach to correct dispersive and retentive effects in small-scale columns when predicting larger scale elution profiles. Biotechnol Prog 25(4):1103–1110. doi: 10.1002/btpr.172CrossRefPubMedPubMedCentralGoogle Scholar
  284. 284.
    Lacki KM (2012) High throughput process development of chromatography steps: advantages and limitations of different formats used. Biotechnol J 7(10):1192–1202PubMedPubMedCentralGoogle Scholar
  285. 285.
    Kelley BD, Switzer M, Bastek P, Kramarczyk JF, Molnar K, Yu T, Coffman J (2008) High-throughput screening of chromatographic separations: IV. Ion-exchange. Biotechnol Bioeng 100(5):950–963. doi: 10.1002/bit.21905CrossRefPubMedGoogle Scholar
  286. 286.
    Creasy A, Barker G, Yao Y, Carta G (2015) Systematic interpolation method predicts protein chromatographic elution from batch isotherm data without a detailed mechanistic isotherm model. Biotechnol J 10:1400–1411PubMedPubMedCentralGoogle Scholar
  287. 287.
    Coffman JL, Kramarczyk JF, Kelley BD (2008) High-throughput screening of chromatographic separations: I. Method development and column modeling. Biotechnol Bioeng 100(4):605–618. doi: 10.1002/bit.21904CrossRefPubMedGoogle Scholar
  288. 288.
    Boning DS, Mozumder PK (1994) DOE/Opt: a system for design of experiments, response surface modeling, and optimization using process and device simulation. IEEE Trans Semiconductor Manuf 7(2):233–244. doi: 10.1109/66.286858CrossRefGoogle Scholar
  289. 289.
    Wu JCW, Hamada MS (2009) Experiments: planning, analysis, and optimization, 2nd edn. WileyGoogle Scholar
  290. 290.
    Ladd Effio C, Baumann P, Weigel C, Vormittag P, Middelberg A, Hubbuch J (2016) High-throughput process development of an alternative platform for the production of virus-like particles in Escherichia coli. J Biotechnol 219:7–19. doi: 10.1016/j.jbiotec.2015.12.018CrossRefPubMedGoogle Scholar
  291. 291.
    Staby A, Jensen RH, Bensch M, Hubbuch J, Dunweber DL, Krarup J, et al. (2007) Comparison of chromatographic ion-exchange resins VI. Weak anion-exchange resins. J Chromatogr A 1164(1-2):82–94. doi: 10.1016/j.chroma.2007.06.048CrossRefPubMedGoogle Scholar
  292. 292.
    Wensel DL, Kelley BD, Coffman JL (2008) High-throughput screening of chromatographic separations: III. Monoclonal antibodies on ceramic hydroxyapatite. Biotechnol Bioeng 100(5):839–854. doi: 10.1002/bit.21906CrossRefPubMedGoogle Scholar
  293. 293.
    Traylor SJ, Xu X, Li Y, Jin M, Li ZJ (2014) Adaptation of the pore diffusion model to describe multi-addition batch uptake high-throughput screening experiments. J Chromatogr A 1368:100–106. doi: 10.1016/j.chroma.2014.09.058CrossRefPubMedGoogle Scholar
  294. 294.
    Carta G (2012) Predicting protein dynamic binding capacity from batch adsorption tests. Biotechnol J 7(10):1216–1220. doi: 10.1002/biot.201200136CrossRefPubMedGoogle Scholar
  295. 295.
    Luo H, Cao M, Newell K, Afdahl C, Wang J, Wang WK, Li Y (2015) Double-peak elution profile of a monoclonal antibody in cation exchange chromatography is caused by histidine-protonation-based charge variants. J Chromatogr A 1424:92–101. doi: 10.1016/j.chroma.2015.11.008CrossRefPubMedGoogle Scholar
  296. 296.
    Ho SV, McLaughlin JM, Cue BW, Dunn PJ (2010) Environmental considerations in biologics manufacturing. Green Chem 12(5):755–766. doi: 10.1039/B927443JCrossRefGoogle Scholar
  297. 297.
    Lopes AG (2015) Single-use in the biopharmaceutical industry: a review of current technology impact, challenges and limitations. Food Bioprod Process 93:98–114Google Scholar
  298. 298.
    Shukla AA, Gottschalk U (2013) Single-use disposable technologies for biopharmaceutical manufacturing. Trends Biotechnol 31(3):147–154. doi: 10.1016/j.tibtech.2012.10.004CrossRefPubMedPubMedCentralGoogle Scholar
  299. 299.
    Langer ES, Rader R (2015) Future proofing biopharmaceutical manufacturing: the industry seeks a leaner version of itself. Pharm Bioprocess 1(5):415–418Google Scholar
  300. 300.
    McNerney T, Thomas A, Senczuk A, Petty K, Zhao X, Piper R, et al. (2015) PDADMAC flocculation of Chinese hamster ovary cells: enabling a centrifuge-less harvest process for monoclonal antibodies. MAbs 7(2):413–428. doi: 10.1080/19420862.2015.1007824CrossRefPubMedPubMedCentralGoogle Scholar
  301. 301.
    Weaver J, Husson SM, Murphy L, Wickramasinghe SR (2013) Anion exchange membrane adsorbers for flow-through polishing steps: Part I. Clearance of minute virus of mice. Biotechnol Bioeng 110(2):491–499. doi: 10.1002/bit.24720CrossRefPubMedGoogle Scholar
  302. 302.
    Weaver J, Husson SM, Murphy L, Wickramasinghe SR (2013) Anion exchange membrane adsorbers for flow-through polishing steps: Part II. Virus, host cell protein, DNA clearance, and antibody recovery. Biotechnol Bioeng 110(2):500–510. doi: 10.1002/bit.24724CrossRefPubMedGoogle Scholar
  303. 303.
    Smrekar V, Smrekar F, Strancar A, Podgornik A (2013) Single step plasmid DNA purification using methacrylate monolith bearing combination of ion-exchange and hydrophobic groups. J Chromatogr A 1276:58–64. doi: 10.1016/j.chroma.2012.12.029CrossRefPubMedGoogle Scholar
  304. 304.
    Sousa A, Almeida AM, Cernigoj U, Sousa F, Queiroz JA (2014) Histamine monolith versatility to purify supercoiled plasmid deoxyribonucleic acid from Escherichia coli lysate. J Chromatogr A 1355:125–133. doi: 10.1016/j.chroma.2014.06.003CrossRefPubMedGoogle Scholar
  305. 305.
    Teeters MA, Conrardy SE, Thomas BL, Root TW, Lightfoot EN (2003) Adsorptive membrane chromatography for purification of plasmid DNA. J Chromatogr A 989(1):165–173PubMedGoogle Scholar
  306. 306.
    Ladd Effio C, Hahn T, Seiler J, Oelmeier SA, Asen I, Silberer C, et al. (2016) Modeling and simulation of anion-exchange membrane chromatography for purification of Sf9 insect cell-derived virus-like particles. J Chromatogr A 1429:142–154. doi: 10.1016/j.chroma.2015.12.006CrossRefPubMedGoogle Scholar
  307. 307.
    Nestola P, Peixoto C, Villain L, Alves PM, Carrondo MJ, Mota JP (2015) Rational development of two flowthrough purification strategies for adenovirus type 5 and retro virus-like particles. J Chromatogr A 1426:91–101. doi: 10.1016/j.chroma.2015.11.037CrossRefPubMedGoogle Scholar
  308. 308.
    Banjac M, Roethl E, Gelhart F, Kramberger P, Jarc BL, Jarc M, Peterka M (2014) Purification of Vero cell derived live replication deficient influenza A and B virus by ion exchange monolith chromatography. Vaccine 32(21):2487–2492. doi: 10.1016/j.vaccine.2014.02.086CrossRefPubMedGoogle Scholar
  309. 309.
    Mundle ST, Giel-Moloney M, Kleanthous H, Pugachev KV, Anderson SF (2015) Preparation of pure, high titer, pseudoinfectious Flavivirus particles by hollow fiber tangential flow filtration and anion exchange chromatography. Vaccine 33(35):4255–4260. doi: 10.1016/j.vaccine.2014.09.074CrossRefPubMedGoogle Scholar
  310. 310.
    Thömmes J, Kula MR (1995) Membrane chromatography—an integrative concept in the downstream processing of proteins. Biotechnol Prog 11(4):357–367. doi: 10.1021/bp00034a001CrossRefGoogle Scholar
  311. 311.
    Francis P, von Lieres E, Haynes CA (2011) Zonal rate model for stacked membrane chromatography. I. Characterizing solute dispersion under flow-through conditions. J Chromatogr A 1218(31):5071–5078. doi: 10.1016/j.chroma.2011.05.017CrossRefPubMedGoogle Scholar
  312. 312.
    Zhou JX, Tressel T, Gottschalk U, Solamo F, Pastor A, Dermawan S, et al. (2006) New Q membrane scale-down model for process-scale antibody purification. J Chromatogr A 1134(1-2):66–73. doi: 10.1016/j.chroma.2006.08.064CrossRefPubMedGoogle Scholar
  313. 313.
    Ghosh P, Vahedipour K, Leuthold M, von Lieres E (2014) Model-based analysis and quantitative prediction of membrane chromatography: extreme scale-up from 0.08 ml to 1200 ml. J Chromatogr A 1332:8–13. doi: 10.1016/j.chroma.2014.01.047CrossRefPubMedGoogle Scholar
  314. 314.
    Tatarova I, Faber R, Denoyel R, Polakovic M (2009) Characterization of pore structure of a strong anion-exchange membrane adsorbent under different buffer and salt concentration conditions. J Chromatogr A 1216(6):941–947. doi: 10.1016/j.chroma.2008.12.018CrossRefPubMedGoogle Scholar
  315. 315.
    Borsoi-Ribeiro M, Bresolin IT, Vijayalakshmi M, Bueno SM (2013) Behavior of human immunoglobulin G adsorption onto immobilized Cu(II) affinity hollow-fiber membranes. J Mol Recognit 26(10):514–520. doi: 10.1002/jmr.2296CrossRefPubMedGoogle Scholar
  316. 316.
    Yavuz H, Bereli N, Yilmaz F, Armutcu C, Denizli A (2015) Antibody purification from human plasma by metal-chelated affinity membranes. Methods Mol Biol 1286:43–46. doi: 10.1007/978-1-4939-2447-9_4CrossRefPubMedGoogle Scholar
  317. 317.
    Francis P, Haynes CA (2009) Scale-up of controlled-shear affinity filtration using computational fluid dynamics. Biotechnol J 4(5):665–673. doi: 10.1002/biot.200800331CrossRefPubMedGoogle Scholar
  318. 318.
    Francis P, Martinez DM, Taghipour F, Bowen BD, Haynes CA (2006) Optimizing the rotor design for controlled-shear affinity filtration using computational fluid dynamics. Biotechnol Bioeng 95(6):1207–1217. doi: 10.1002/bit.21090CrossRefPubMedGoogle Scholar
  319. 319.
    Hou Y, Brower M, Pollard D, Kanani D, Jacquemart R, Kachuik B, Stout J (2015) Advective hydrogel membrane chromatography for monoclonal antibody purification in bioprocessing. Biotechnol Prog 31(4):974–982. doi: 10.1002/btpr.2113CrossRefPubMedGoogle Scholar
  320. 320.
    Nachman M, Azad AR, Bailon P (1992) Efficient recovery of recombinant proteins using membrane-based immunoaffinity chromatography (MIC). Biotechnol Bioeng 40(5):564–571. doi: 10.1002/bit.260400503CrossRefPubMedGoogle Scholar
  321. 321.
    Kuczewski M, Fraud N, Faber R, Zarbis-Papastoitsis G (2010) Development of a polishing step using a hydrophobic interaction membrane adsorber with a PER.C6-derived recombinant antibody. Biotechnol Bioeng 105(2):296–305. doi: 10.1002/bit.22538CrossRefPubMedGoogle Scholar
  322. 322.
    Kanavova N, Kosior A, Antosova M, Faber R, Polakovic M (2012) Application of a micromembrane chromatography module to the examination of protein adsorption equilibrium. J Sep Sci 35(22):3177–3183. doi: 10.1002/jssc.201200396CrossRefPubMedGoogle Scholar
  323. 323.
    Rathore AS, Muthukumar S (2014) High-throughput process development: II. Membrane chromatography. Methods Mol Biol 1129:39–44. doi: 10.1007/978-1-62703-977-2_4CrossRefPubMedGoogle Scholar
  324. 324.
    Close EJ, Salm JR, Iskra T, Sorensen E, Bracewell DG (2013) Fouling of an anion exchange chromatography operation in a monoclonal antibody process: visualization and kinetic studies. Biotechnol Bioeng 110(9):2425–2435. doi: 10.1002/bit.24898CrossRefPubMedPubMedCentralGoogle Scholar
  325. 325.
    Corbett R, Carta G, Iskra T, Gallo C, Godavarti R, Salm JR (2013) Structure and protein adsorption mechanisms of clean and fouled tentacle-type anion exchangers used in a monoclonal antibody polishing step. J Chromatogr A 1278:116–125. doi: 10.1016/j.chroma.2013.01.006CrossRefPubMedGoogle Scholar
  326. 326.
    Cheong WJ, Yang SH, Ali F (2013) Molecular imprinted polymers for separation science: a review of reviews. J Sep Sci 36(3):609–628. doi: 10.1002/jssc.201200784CrossRefPubMedGoogle Scholar
  327. 327.
    Bhut BV, Christensen KA, Husson SM (2010) Membrane chromatography: protein purification from E. coli lysate using newly designed and commercial anion-exchange stationary phases. J Chromatogr A 1217(30):4946–4957. doi: 10.1016/j.chroma.2010.05.049CrossRefPubMedGoogle Scholar
  328. 328.
    Boi C (2007) Membrane adsorbers as purification tools for monoclonal antibody purification. J Chromatogr B Analyt Technol Biomed Life Sci 848(1):19–27. doi: 10.1016/j.jchromb.2006.08.044CrossRefPubMedGoogle Scholar
  329. 329.
    Herigstad MO, Gurgel PV, Carbonell RG (2011) Transport and binding characterization of a novel hybrid particle impregnated membrane material for bioseparations. Biotechnol Prog 27(1):129–139. doi: 10.1002/btpr.502CrossRefPubMedGoogle Scholar
  330. 330.
    Nestola P, Villain L, Peixoto C, Martins DL, Alves PM, Carrondo MJ, Mota JP (2014) Impact of grafting on the design of new membrane adsorbers for adenovirus purification. J Biotechnol 181:1–11. doi: 10.1016/j.jbiotec.2014.04.003CrossRefPubMedGoogle Scholar
  331. 331.
    Sum CH, Chong JY, Wettig S, Slavcev RA (2014) Separation and purification of linear covalently closed deoxyribonucleic acid by Q-anion exchange membrane chromatography. J Chromatogr A 1339:214–218. doi: 10.1016/j.chroma.2014.03.016CrossRefPubMedGoogle Scholar
  332. 332.
    Zhong L, Scharer J, Moo-Young M, Fenner D, Crossley L, Honeyman CH, et al. (2011) Potential application of hydrogel-based strong anion-exchange membrane for plasmid DNA purification. J Chromatogr B Analyt Technol Biomed Life Sci 879(9-10):564–572. doi: 10.1016/j.jchromb.2011.01.017CrossRefPubMedGoogle Scholar
  333. 333.
    Mould DL, Synge RLM (1952) Electrokinetic ultrafiltration analysis of polysaccharides. A new approach to the chromatography of large molecules. Analyst 77(921):964–969. doi: 10.1039/AN9527700964CrossRefGoogle Scholar
  334. 334.
    Hahn R, Jungbauer A (2001) Control method for integrity of continuous beds. J Chromatogr A 908(1-2):179–184PubMedGoogle Scholar
  335. 335.
    Xie S, Allington RW, Frechet JM, Svec F (2002) Porous polymer monoliths: an alternative to classical beads. Adv Biochem Eng Biotechnol 76:87–125PubMedGoogle Scholar
  336. 336.
    Barroso T, Hussain A, Roque AC, Aguiar-Ricardo A (2013) Functional monolithic platforms: chromatographic tools for antibody purification. Biotechnol J 8(6):671–681. doi: 10.1002/biot.201200328CrossRefPubMedGoogle Scholar
  337. 337.
    Rajamanickam V, Herwig C, Spadiut O (2015) Monoliths in bioprocess technology. Chromatography 2(2):195–212Google Scholar
  338. 338.
    Trilisky EI, Lenhoff AM (2009) Flow-dependent entrapment of large bioparticles in porous process media. Biotechnol Bioeng 104(1):127–133. doi: 10.1002/bit.22370CrossRefPubMedPubMedCentralGoogle Scholar
  339. 339.
    Trilisky EI, Lenhoff AM (2010) Effect of bioparticle size on dispersion and retention in monolithic and perfusive beds. J Chromatogr A 1217(47):7372–7384. doi: 10.1016/j.chroma.2010.09.040CrossRefPubMedPubMedCentralGoogle Scholar
  340. 340.
    Herigstad MO, Dimartino S, Boi C, Sarti GC (2015) Experimental characterization of the transport phenomena, adsorption, and elution in a protein A affinity monolithic medium. J Chromatogr A 1407:130–138. doi: 10.1016/j.chroma.2015.06.045CrossRefPubMedGoogle Scholar
  341. 341.
    Barroso T, Branco RJ, Aguiar-Ricardo A, Roque AC (2014) Structural evaluation of an alternative Protein A biomimetic ligand for antibody purification. J Comput Aided Mol Des 28(1):25–34. doi: 10.1007/s10822-013-9703-1CrossRefPubMedGoogle Scholar
  342. 342.
    Dean PD, Watson DH (1979) J Chromatogr 165:301–319Google Scholar
  343. 343.
    Regnault V, Rivat C, Vallar L, Geschier C, Stolz JF (1992) Purification of biologically active human plasma transthyretin by dye-affinity chromatography: studies on dye leakage and possibility of heat treatment for virus inactivation. J Chromatogr 584(1):93–99PubMedGoogle Scholar
  344. 344.
    Ongkudon CM, Kansil T, Wong C (2014) Challenges and strategies in the preparation of large-volume polymer-based monolithic chromatography adsorbents. J Sep Sci 37(5):455–464. doi: 10.1002/jssc.201300995CrossRefPubMedGoogle Scholar
  345. 345.
    Arrua RD, Haddad PR, Hilder EF (2013) Monolithic cryopolymers with embedded nanoparticles. II Capillary liquid chromatography of proteins using charged embedded nanoparticles. J Chromatogr A 1311:121–126. doi: 10.1016/j.chroma.2013.08.077CrossRefPubMedGoogle Scholar
  346. 346.
    Guo SZ, Yang X, Heuzey MC, Therriault D (2015) 3D printing of a multifunctional nanocomposite helical liquid sensor. Nanoscale 7(15):6451–6456. doi: 10.1039/c5nr00278hCrossRefPubMedGoogle Scholar
  347. 347.
    Krejcova L, Nejdl L, Rodrigo MA, Zurek M, Matousek M, Hynek D, et al. (2014) 3D printed chip for electrochemical detection of influenza virus labeled with CdS quantum dots. Biosens Bioelectron 54:421–427. doi: 10.1016/j.bios.2013.10.031CrossRefPubMedGoogle Scholar
  348. 348.
    Lee W, Kwon D, Choi W, Jung GY, Jeon S (2015) 3D-printed microfluidic device for the detection of pathogenic bacteria using size-based separation in helical channel with trapezoid cross-section. Sci Rep 5:7717. doi: 10.1038/srep07717CrossRefPubMedPubMedCentralGoogle Scholar
  349. 349.
    Xu L, Gutbrod SR, Bonifas AP, Su Y, Sulkin MS, Lu N, et al. (2014) 3D multifunctional integumentary membranes for spatiotemporal cardiac measurements and stimulation across the entire epicardium. Nat Commun 5:3329. doi: 10.1038/ncomms4329CrossRefPubMedPubMedCentralGoogle Scholar
  350. 350.
    Guo SZ, Heuzey MC, Therriault D (2014) Properties of polylactide inks for solvent-cast printing of three-dimensional freeform microstructures. Langmuir 30(4):1142–1150. doi: 10.1021/la4036425CrossRefPubMedGoogle Scholar
  351. 351.
    Liu W, Li Y, Feng S, Ning J, Wang J, Gou M, et al. (2014) Magnetically controllable 3D microtissues based on magnetic microcryogels. Lab Chip 14(15):2614–2625. doi: 10.1039/c4lc00081aCrossRefPubMedGoogle Scholar
  352. 352.
    Wang X, Schroder HC, Feng Q, Draenert F, Muller WE (2013) The deep-sea natural products, biogenic polyphosphate (Bio-PolyP) and biogenic silica (Bio-Silica), as biomimetic scaffolds for bone tissue engineering: fabrication of a morphogenetically-active polymer. Mar Drugs 11(3):718–746. doi: 10.3390/md11030718CrossRefPubMedPubMedCentralGoogle Scholar
  353. 353.
    Wang X, Schroder HC, Grebenjuk V, Diehl-Seifert B, Mailander V, Steffen R, et al. (2014) The marine sponge-derived inorganic polymers, biosilica and polyphosphate, as morphogenetically active matrices/scaffolds for the differentiation of human multipotent stromal cells: potential application in 3D printing and distraction osteogenesis. Mar Drugs 12(2):1131–1147. doi: 10.3390/md12021131CrossRefPubMedPubMedCentralGoogle Scholar
  354. 354.
    Yao Q, Wei B, Liu N, Li C, Guo Y, Shamie AN, et al. (2015) Chondrogenic regeneration using bone marrow clots and a porous polycaprolactone-hydroxyapatite scaffold by three-dimensional printing. Tissue Eng Part A 21(7-8):1388–1397. doi: 10.1089/ten.TEA.2014.0280CrossRefPubMedPubMedCentralGoogle Scholar
  355. 355.
    Farahani RD, Chizari K, Therriault D (2014) Three-dimensional printing of freeform helical microstructures: a review. Nanoscale 6(18):10470–10485. doi: 10.1039/c4nr02041cCrossRefPubMedGoogle Scholar
  356. 356.
    Guo SZ, Gosselin F, Guerin N, Lanouette AM, Heuzey MC, Therriault D (2013) Solvent-cast three-dimensional printing of multifunctional microsystems. Small 9(24):4118–4122. doi: 10.1002/smll.201300975CrossRefPubMedGoogle Scholar
  357. 357.
    Lee H, Fang NX (2012) Micro 3D printing using a digital projector and its application in the study of soft materials mechanics. J Vis Exp 69:e4457. doi: 10.3791/4457CrossRefGoogle Scholar
  358. 358.
    Qin Z, Compton BG, Lewis JA, Buehler MJ (2015) Structural optimization of 3D-printed synthetic spider webs for high strength. Nat Commun 6:7038. doi: 10.1038/ncomms8038CrossRefPubMedPubMedCentralGoogle Scholar
  359. 359.
    Shin D, Kim J, Yoo DS, Kim K (2015) Design of 3D isotropic metamaterial device using smart transformation optics. Opt Express 23(17):21892–21898. doi: 10.1364/oe.23.021892CrossRefPubMedGoogle Scholar
  360. 360.
    Amor-Coarasa A, Kelly JM, Babich JW (2015) Synthesis of [11C]palmitic acid for PET imaging using a single molecular sieve 13X cartridge for reagent trapping, radiolabeling and selective purification. Nucl Med Biol 42(8):685–690. doi: 10.1016/j.nucmedbio.2015.03.008CrossRefPubMedGoogle Scholar
  361. 361.
    Gross BC, Anderson KB, Meisel JE, McNitt MI, Spence DM (2015) Polymer coatings in 3D-printed fluidic device channels for improved cellular adherence prior to electrical lysis. Anal Chem 87(12):6335–6341. doi: 10.1021/acs.analchem.5b01202CrossRefPubMedPubMedCentralGoogle Scholar
  362. 362.
    Liu X, Lei Z, Liu F, Liu D, Wang Z (2014) Fabricating three-dimensional carbohydrate hydrogel microarray for lectin-mediated bacterium capturing. Biosens Bioelectron 58:92–100. doi: 10.1016/j.bios.2014.02.056CrossRefPubMedGoogle Scholar
  363. 363.
    Chae MP, Rozen WM, McMenamin PG, Findlay MW, Spychal RT, Hunter-Smith DJ (2015) Emerging applications of bedside 3D printing in plastic surgery. Front Surg 2:25. doi: 10.3389/fsurg.2015.00025CrossRefPubMedPubMedCentralGoogle Scholar
  364. 364.
    Truskett VN, Watts MP (2006) Trends in imprint lithography for biological applications. Trends Biotechnol 24(7):312–317. doi: 10.1016/j.tibtech.2006.05.005CrossRefPubMedGoogle Scholar
  365. 365.
    Tseng P, Murray C, Kim D, Di Carlo D (2014) Research highlights: printing the future of microfabrication. Lab Chip 14(9):1491–1495. doi: 10.1039/c4lc90023eCrossRefPubMedGoogle Scholar
  366. 366.
    Cheong WJ, Ali F, Kim YS, Lee JW (2013) Comprehensive overview of recent preparation and application trends of various open tubular capillary columns in separation science. J Chromatogr A 1308:1–24. doi: 10.1016/j.chroma.2013.07.107CrossRefPubMedGoogle Scholar
  367. 367.
    Thayer JR, Flook KJ, Woodruff A, Rao S, Pohl CA (2010) New monolith technology for automated anion-exchange purification of nucleic acids. J Chromatogr B Analyt Technol Biomed Life Sci 878(13-14):933–941. doi: 10.1016/j.jchromb.2010.01.030CrossRefPubMedGoogle Scholar
  368. 368.
    Dinh NP, Cam QM, Nguyen AM, Shchukarev A, Irgum K (2009) Functionalization of epoxy-based monoliths for ion exchange chromatography of proteins. J Sep Sci 32(15-16):2556–2564. doi: 10.1002/jssc.200900243CrossRefPubMedGoogle Scholar
  369. 369.
    Du K (2014) Peptide immobilized monolith containing tentacle-type functionalized polymer chains for high-capacity binding of immunoglobulin G. J Chromatogr A 1374:164–170. doi: 10.1016/j.chroma.2014.11.060CrossRefPubMedGoogle Scholar
  370. 370.
    Hanora A, Savina I, Plieva FM, Izumrudov VA, Mattiasson B, Galaev IY (2006) Direct capture of plasmid DNA from non-clarified bacterial lysate using polycation-grafted monoliths. J Biotechnol 123(3):343–355. doi: 10.1016/j.jbiotec.2005.11.017CrossRefPubMedGoogle Scholar
  371. 371.
    Savina IN, Galaev IY, Mattiasson B (2006) Ion-exchange macroporous hydrophilic gel monolith with grafted polymer brushes. J Mol Recognit 19(4):313–321. doi: 10.1002/jmr.774CrossRefPubMedGoogle Scholar
  372. 372.
    Singh NK, Dsouza RN, Grasselli M, Fernandez-Lahore M (2014) High capacity cryogel-type adsorbents for protein purification. J Chromatogr A 1355:143–148. doi: 10.1016/j.chroma.2014.06.008CrossRefPubMedGoogle Scholar
  373. 373.
    Tao SP, Zheng J, Sun Y (2015) Grafting zwitterionic polymer onto cryogel surface enhances protein retention in steric exclusion chromatography on cryogel monolith. J Chromatogr A 1389:104–111. doi: 10.1016/j.chroma.2015.02.051CrossRefPubMedGoogle Scholar
  374. 374.
    Gagnon P (2010) Monoliths open the door to key growth sectors. Bioprocess IntGoogle Scholar
  375. 375.
    Martin C, Coyne J, Carta G (2005) Properties and performance of novel high-resolution/highpermeability ion-exchange media for protein chromatography. J Chromatogr A 1069(1):43–52PubMedGoogle Scholar
  376. 376.
    Hoshino Y, Kodama T, Okahata Y, Shea KJ (2008) Peptide imprinted polymer nanoparticles: a plastic antibody. J Am Chem Soc 130:15242–15243PubMedGoogle Scholar
  377. 377.
    Hoshino Y, Urakami T, Kodama T, Koide H, Oku N, Okahata Y, Shea KJ (2009) Design of synthetic polymer nanoparticles that capture and neutralize a toxic peptide. Small 5(13):1562–1568PubMedPubMedCentralGoogle Scholar
  378. 378.
    Zeng Z, Hoshino Y, Rodriguez A, Yoo H, Shea KJ (2010) Synthetic polymer nanoparticles with antibody-like affinity for a hydrophilic peptide. ACS Nano 4(1):199–204PubMedPubMedCentralGoogle Scholar
  379. 379.
    Wong G (2009) Biotech scientists bank on big pharma’s biologics push. Nat Biotechnol 27(3):293–295. doi: 10.1038/nbt0309-293CrossRefGoogle Scholar
  380. 380.
    Dinon F, Salvalaglio M, Gallotta A, Beneduce L, Pengo P, Cavallotti C, Fassina G (2011) Structural refinement of protein A mimetic peptide. J Mol Recognit 24(6):1087–1094. doi: 10.1002/jmr.1157CrossRefPubMedGoogle Scholar
  381. 381.
    Thompson AD, Dugan A, Gestwicki JE, Mapp AK (2012) Fine-tuning multiprotein complexes using small molecules. ACS Chem Biol 7(8):1311–1320. doi: 10.1021/cb300255pCrossRefPubMedPubMedCentralGoogle Scholar
  382. 382.
    Ulucan O, Eyrisch S, Helms V (2012) Druggability of dynamic protein-protein interfaces. Curr Pharm Des 18(30):4599–4606PubMedGoogle Scholar
  383. 383.
    Lee S-H, Hoshino Y, Randall AJ, Zeng Z, Baldi PJ, Doong R-a, Shea KJ (2012) Engineered synthetic polymer nanoparticles as IgG affinity ligands. J Am Chem Soc 134(38):15765–15772PubMedPubMedCentralGoogle Scholar
  384. 384.
    Hoshino Y, Arata Y, Yonamine Y, Lee S-H, Yamasaki A, Tsuhara R, et al. (2015) Preparation of nanogel-immobilized porous gel beads for affinity separation of proteins: fusion of nano and micro gel materials. Polym J 47(2):220–225. doi: 10.1038/pj.2014.101CrossRefGoogle Scholar
  385. 385.
    Box GEP (1976) Science and statistics. J Am Stat Assoc 71(356):791–799Google Scholar
  386. 386.
    Whitehead AN, Russell B (1963) Principia mathematica, vol III. 2nd edn. Cambridge University Press, New YorkGoogle Scholar
  387. 387.
    Hillestad M, Nesvik GO (1994) A comparison of deductive and inductive models for product quality estimation. In: Bonvin D (ed) IFAC advanced control of chemical processes. Pergamon, Kyoto, pp 327–332Google Scholar
  388. 388.
    Hurford A (2012) Mechanistic models: what is the value of understanding? Just simple enough: the art of mathematical modelling, vol 2016Google Scholar
  389. 389.
    Burden F, Winkler D (2008) Bayesian regularization of neural networks. Methods Mol Biol 458:25–44PubMedGoogle Scholar
  390. 390.
    Insaidoo FK, Rauscher MA, Smithline SJ, Kaarsholm NC, Feuston BP, Ortigosa AD, et al. (2015) Targeted purification development enabled by computational biophysical modeling. Biotechnol Prog 31(1):154–164. doi: 10.1002/btpr.2023CrossRefPubMedGoogle Scholar
  391. 391.
    Kayala MA, Azencott CA, Chen JH, Baldi P (2011) Learning to predict chemical reactions. J Chem Inf Model 51(9):2209–2222. doi: 10.1021/ci200207yCrossRefPubMedPubMedCentralGoogle Scholar
  392. 392.
    Kayala MA, Baldi P (2012) ReactionPredictor: prediction of complex chemical reactions at the mechanistic level using machine learning. J Chem Inf Model 52(10):2526–2540. doi: 10.1021/ci3003039CrossRefPubMedGoogle Scholar
  393. 393.
    Osberghaus A, Hepbildikler S, Nath S, Haindl M, von Lieres E, Hubbuch J (2012) Optimizing a chromatographic three component separation: a comparison of mechanistic and empiric modeling approaches. J Chromatogr A 1237:86–95. doi: 10.1016/j.chroma.2012.03.029CrossRefPubMedGoogle Scholar
  394. 394.
    Hanke AT, Ottens M (2014) Purifying biopharmaceuticals: knowledge-based chromatographic process development. Trends Biotechnol 32(4):210–220. doi: 10.1016/j.tibtech.2014.02.001CrossRefPubMedGoogle Scholar
  395. 395.
    Heinonen J, Kukkonen S, Sainio T (2014) Evolutionary multi-objective optimization based comparison of multi-column chromatographic separation processes for a ternary separation. J Chromatogr A 1358:181–191. doi: 10.1016/j.chroma.2014.07.004CrossRefPubMedGoogle Scholar
  396. 396.
    Korifi R, Le Dreau Y, Dupuy N (2014) Comparative study of the alignment method on experimental and simulated chromatographic data. J Sep Sci 37(22):3276–3291. doi: 10.1002/jssc.201400700CrossRefGoogle Scholar
  397. 397.
    Marks RE, Schnabl H (1999) Genetic algorithms and neural networks: a comparison based on the repeated prisoners dilemma. In: Brenner T (ed) Computational techniques for modelling learning in economics, vol 11. Springer, pp 197–219Google Scholar
  398. 398.
    Brooks CA, Cramer SM (1992) Steric mass-action ion exchange: displacement profiles and induced salt gradients. AIChE J 38(12):1969–1978. doi: 10.1002/aic.690381212CrossRefGoogle Scholar
  399. 399.
    Jungbauer A, Carta G (2010) Protein chromatography: process development and scale-up, 1st edn. WileyGoogle Scholar
  400. 400.
    Guiochon GF, Felinger A, Shirazi DG (2006) Fundamentals of preparative and nonlinear chromatography, 2nd edn. AcademicGoogle Scholar
  401. 401.
    Guiochon GL, Lin B (2003) Modeling for preparative chromatography, 1st edn. AcademicGoogle Scholar
  402. 402.
    Lopez ZK, Tejeda A, Montesinos RM, Magana I, Guzman R (1997) Modeling column regeneration effects on ion-exchange chromatography. J Chromatogr A 791(1-2):99–107PubMedGoogle Scholar
  403. 403.
    Karlsson D, Jakobsson N, Axelsson A, Nilsson B (2004) Model-based optimization of a preparative ion-exchange step for antibody purification. J Chromatogr A 1055(1-2):29–39PubMedGoogle Scholar
  404. 404.
    Edwards-Parton S, Thornhill NF, Bracewell DG, Liddell JM, Titchener-Hooker NJ (2008) Principal component score modeling for the rapid description of chromatographic separations. Biotechnol Prog 24(1):202–208. doi: 10.1021/bp070240jCrossRefPubMedGoogle Scholar
  405. 405.
    Susanto A, Herrmann T, von Lieres E, Hubbuch J (2007) Investigation of pore diffusion hindrance of monoclonal antibody in hydrophobic interaction chromatography using confocal laser scanning microscopy. J Chromatogr A 1149(2):178–188. doi: 10.1016/j.chroma.2007.03.002CrossRefPubMedGoogle Scholar
  406. 406.
    Ishihara T, Kadoya T, Endo N, Yamamoto S (2006) Optimization of elution salt concentration in stepwise elution of protein chromatography using linear gradient elution data. Reducing residual protein A by cation-exchange chromatography in monoclonal antibody purification. J Chromatogr A 1114(1):97–101. doi: 10.1016/j.chroma.2006.02.042CrossRefPubMedGoogle Scholar
  407. 407.
    Ishihara T, Kadoya T, Yamamoto S (2007) Application of a chromatography model with linear gradient elution experimental data to the rapid scale-up in ion-exchange process chromatography of proteins. J Chromatogr A 1162(1):34–40. doi: 10.1016/j.chroma.2007.03.016CrossRefPubMedGoogle Scholar
  408. 408.
    Ishihara T, Yamamotob S (2005) Optimization of monoclonal antibody purification by ion-exchange chromatography. Application of simple methods with linear gradient elution experimental data. J Chromatogr A 1069(1):99–106PubMedGoogle Scholar
  409. 409.
    Muller-Spath T, Strohlein G, Aumann L, Kornmann H, Valax P, Delegrange L, et al. (2011) Model simulation and experimental verification of a cation-exchange IgG capture step in batch and continuous chromatography. J Chromatogr A 1218(31):5195–5204. doi: 10.1016/j.chroma.2011.05.103CrossRefPubMedGoogle Scholar
  410. 410.
    Osberghaus A, Hepbildikler S, Nath S, Haindl M, von Lieres E, Hubbuch J (2012) Determination of parameters for the steric mass action model--a comparison between two approaches. J Chromatogr A 1233:54–65. doi: 10.1016/j.chroma.2012.02.004CrossRefPubMedGoogle Scholar
  411. 411.
    Westerberg K, Broberg-Hansen E, Sejergaard L, Nilsson B (2013) Model-based risk analysis of coupled process steps. Biotechnol Bioeng 110(9):2462–2470. doi: 10.1002/bit.24909CrossRefPubMedGoogle Scholar
  412. 412.
    Lapelosa M, Patapoff TW, Zarraga IE (2015) Modeling of protein-anion exchange resin interaction for the human growth hormone charge variants. Biophys Chem 207:1–6. doi: 10.1016/j.bpc.2015.07.004CrossRefPubMedGoogle Scholar
  413. 413.
    Kluters S, Wittkopp F, Johnck M, Frech C (2015) Application of linear pH gradients for the modeling of ion exchange chromatography: separation of monoclonal antibody monomer from aggregates. J Sep Sci. doi: 10.1002/jssc.201500994PubMedGoogle Scholar
  414. 414.
    Mazumder J, Zhu J, Bassi AS, Ray AK (2009) Modeling and simulation of liquid-solid circulating fluidized bed ion exchange system for continuous protein recovery. Biotechnol Bioeng 104(1):111–126. doi: 10.1002/bit.22368CrossRefPubMedGoogle Scholar
  415. 415.
    Xenopoulos A (2015) A new, integrated, continuous purification process template for monoclonal antibodies: process modeling and cost of goods studies. J Biotechnol 213:42–53. doi: 10.1016/j.jbiotec.2015.04.020PubMedGoogle Scholar
  416. 416.
    Teeters M, Benner T, Bezila D, Shen H, Velayudhan A, Alred P (2009) Predictive chromatographic simulations for the optimization of recovery and aggregate clearance during the capture of monoclonal antibodies. J Chromatogr A 1216(33):6134–6140. doi: 10.1016/j.chroma.2009.06.066CrossRefPubMedGoogle Scholar
  417. 417.
    Ladiwala A, Rege K, Breneman CM, Cramer SM (2005) A priori prediction of adsorption isotherm parameters and chromatographic behavior in ion-exchange systems. Proc Natl Acad Sci U S A 102(33):11710–11715. doi: 10.1073/pnas.0408769102CrossRefPubMedPubMedCentralGoogle Scholar
  418. 418.
    Guelat B, Strohlein G, Lattuada M, Delegrange L, Valax P, Morbidelli M (2012) Simulation model for overloaded monoclonal antibody variants separations in ion-exchange chromatography. J Chromatogr A 1253:32–43. doi: 10.1016/j.chroma.2012.06.081CrossRefPubMedGoogle Scholar
  419. 419.
    Sarangapani PS, Hudson SD, Jones RL, Douglas JF, Pathak JA (2015) Critical examination of the colloidal particle model of globular proteins. Biophys J 108(3):724–737. doi: 10.1016/j.bpj.2014.11.3483CrossRefPubMedPubMedCentralGoogle Scholar
  420. 420.
    Lang KM, Kittelmann J, Durr C, Osberghaus A, Hubbuch J (2015) A comprehensive molecular dynamics approach to protein retention modeling in ion exchange chromatography. J Chromatogr A 1381:184–193. doi: 10.1016/j.chroma.2015.01.018CrossRefPubMedGoogle Scholar
  421. 421.
    Paloni M, Cavallotti C (2015) Molecular modeling of the affinity chromatography of monoclonal antibodies. Methods Mol Biol 1286:321–335. doi: 10.1007/978-1-4939-2447-9_25CrossRefPubMedGoogle Scholar
  422. 422.
    Kisley L, Chen J, Mansur AP, Dominguez-Medina S, Kulla E, Kang MK, et al. (2014) High ionic strength narrows the population of sites participating in protein ion-exchange adsorption: a single-molecule study. J Chromatogr A 1343:135–142. doi: 10.1016/j.chroma.2014.03.075CrossRefPubMedPubMedCentralGoogle Scholar
  423. 423.
    Kisley L, Poongavanam M-V, Kourentzi K, Willson RC, Landes CF (2015) pH-dependence of single-protein adsorption and diffusion at a liquid chromatographic interface. J Separation Sci. doi: 10.1002/jssc.201500809PubMedGoogle Scholar
  424. 424.
    Marek W, Muca R, Wos S, Piatkowski W, Antos D (2013) Isolation of monoclonal antibody from a Chinese hamster ovary supernatant. II: Dynamics of the integrated separation on ion exchange and hydrophobic interaction chromatography media. J Chromatogr A 1305:64–75. doi: 10.1016/j.chroma.2013.06.076CrossRefPubMedGoogle Scholar
  425. 425.
    Baumann P, Hahn T, Hubbuch J (2015) High-throughput micro-scale cultivations and chromatography modeling: powerful tools for integrated process development. Biotechnol Bioeng 112(10):2123–2133. doi: 10.1002/bit.25630CrossRefPubMedGoogle Scholar
  426. 426.
    Huuk TC, Hahn T, Osberghaus A, Hubbuch J (2014) Model-based integrated optimization and evaluation of a multi-step ion exchange chromatography. Separation and Purification Technology 136:207–222. doi: 10.1016/j.seppur.2014.09.012CrossRefGoogle Scholar
  427. 427.
    Sharma C, Malhotra D, Rathore AS (2011) Review of computational fluid dynamics applications in biotechnology processes. Biotechnol Prog 27(6):1497–1510PubMedGoogle Scholar
  428. 428.
    Joshi V, Shivach T, Kumar V, Yadav N, Rathore A (2014) Avoiding antibody aggregation during processing: establishing hold times. Biotechnol J 9(9):1195–1205. doi: 10.1002/biot.201400052CrossRefPubMedGoogle Scholar
  429. 429.
    Lapelosa M, Patapoff TW, Zarraga IE (2014) Molecular simulations of the pairwise interaction of monoclonal antibodies. J Phys Chem B 118(46):13132–13141. doi: 10.1021/jp508729zCrossRefPubMedGoogle Scholar
  430. 430.
    Helling C, Borrmann C, Strube J (2012) Optimal integration of directly combined hydrophobic interaction and ion exchange chromatography purification processes. Chem Eng Technol 35(10):1786–1796. doi: 10.1002/ceat.201200043CrossRefGoogle Scholar
  431. 431.
    Buyel JF, Woo JA, Cramer SM, Fischer R (2013) The use of quantitative structure–activity relationship models to develop optimized processes for the removal of tobacco host cell proteins during biopharmaceutical production. J Chromatogr A 1322:18–28. doi: 10.1016/j.chroma.2013.10.076CrossRefPubMedGoogle Scholar
  432. 432.
    Kruhlak NL, Benz RD, Zhou H, Colatsky TJ (2012) (Q)SAR modeling and safety assessment in regulatory review. Clin Pharmacol Ther 91(3):529–534. doi: 10.1038/clpt.2011.300CrossRefPubMedGoogle Scholar

Copyright information

© Springer International Publishing AG 2017

Authors and Affiliations

  1. 1.Bristol-Myers Squibb, Global Manufacturing and SupplyDevensUSA
  2. 2.Bristol-Myers Squibb, Global Manufacturing and SupplyHopewellUSA

Personalised recommendations