The Development of Antibody Purification Technologies

Process Scale Purification of Antibodies

Volumn , Issue , 2008, Pages 25-52

  Curling, John ^a  

^a John Curling Consulting AB   (Sweden)

Author keywords

Antibody purification technologies; Chromatographic purification of antibodies; Purification of fully humanized monoclonal antibodies from in vitro cell culture

Indexed keywords

EID: 84890627431     PISSN: None     EISSN: None     Source Type: Book    
DOI: 10.1002/9780470444894.ch2     Document Type: Chapter

References (131)

1. Hofmeister, F. (1888). Zur Lehre von der Wirkung der Salze. II. Archiv Experi- mentelle Pathologie und Pharmakologie 24, 247-260
2. Brieger, L., Ehrlich, P. (1893). Beiträge zur Kenntis der Milch immunisierter Thiere. Zeitschrift für Hygiene und Infektions -Krankheiten 13, 336
3. Heide, K., Schwick, H.G. (1973). Salt fractionation of immunoglobulins. In: Her- zenberg, L.A., Weir, W.M., Herzenberg, L.A., Blackwell, C. (eds) Weir's Handbook of Experimental Immunology, Vol. 2, Blackwell Scientific Publishers, Oxford, pp. 6.1-6.11
4. Rader, R.A. (2004). Biopharma. Biopharmaceutical Products in the U.S. Market. Biotechnology Information Institute, Rockville, MD, pp. 299-301
5. Manil, L., Motté, P., Pernas, P.,Troalen,E, Bohuon, C., Bellet, D. (1986). Evaluation of protocols for purification of mouse monoclonal antibodies. Journal of Immu- nological Methods 90, 25-37
6. Newcombe, A.R., Cresswell, C., Davies, S., Watson, K., Harris, G., O'Donovan, K., Francisa, R. (2005). Optimized affinity purification of polyclonal antibodies from hyper-immunized ovine serum using a synthetic Protein A adsorbent, MAbsor- bent ® A2P Journal of Chromatography B 814, 209-215
7. Francis, R. (2007). Development of a MEP Hypercel IgG purification process for a commercial antibody product. Presentation at the Mixed -mode Chromatogra phy Meeting, SCI, London, 2007
8. Thillaivinayagalingam, P., O'Donovan, K., Newcombe, A.R., Keshavarz-Moore, E. (2007). Characterisation of an industrial affinity process used in the manufacturing of digoxin -specific polyclonal Fab fragments. Journal of Chromatography B 848, 88-96
9. Cohn, E.J., Strong, L.E., Hughes, W.L., Mulford, D.J., Asworth, J.N., Melin, M., Taylor, H.L. (1946). Preparation and properties of serum and plasma proteins. IV. A system for the separation into fractions of the protein and lipoprotein com ponents of biological tissues and fl uids. Journal of the American Chemical Society 62,45975
10. Oncley, J.L., Melin, M., Richert, D.A., Cameron, J.W., Gross, P.M., Jr. (1949). The separation of the antibodies, isoagglutinins, prothrombin, plasminogen, and β1- lipoprotein into subfractions of human plasma. Journal of the American Chemical Society 71, 541-550
11. Nitschmann, H., Kistler, P., Lergier, W. (1954). A simplified method for obtaining albumin and gamma -globulin from blood plasma by alcohol precipitation. Hel vetica Chimica Acta 37, 866-873
12. Nitschmann, H., Kistler, P. (1962). Large scale production of human plasma frac tions. Vox Sanguinis 7, 41424
13. Curling, J.M., Bryant, C. (2005).The plasma fractionation industry. New opportuni ties to move forward. BioProcess International 3,18-27
14. Chanutin, A., Curnish, R.R. (1960). The precipitation of plasma proteins by short chain fatty acids. Archives of Biochemistry and Biophysics 89, 218-220
15. Steinbuch, M., Audran, R. (1969). Isolation of IgG immunoglobulin from human plasma using caprylic acid. Revue Française d'Etudes Cliniques et Biologiques 14, 1054-1058
16. Steinbuch, M. (1980). Protein fractionation by ammonium sulphate, Rivanol ® and caprylic acid precipitation. In Curling, J.M. (ed.) Methods of Plasma Protein Frac tionation, Academic Press, London, pp. 33-56
17. Lebing, W., Remington, K.M., Schreiner, C., Paul, H.-I. (2003). Properties of a new intravenous immunoglobulin (IGIV-C, 10%) produced by virus inactivation with caprylate and column chromatography. Vox Sanguinis 84,193-201
18. Parkkinen, J., Rahola, A., von Bonsdorff, L., Tölö, H., Törmä, E. (2006). A modified caprylic acid method for manufacturing immunoglobulin G from human plasma with high yield and efficient virus clearance. Vox Sanguinis 90, 97-104
19. Lundblad, J.L., Seng, R.L. (1991). Inactivation of lipid -enveloped viruses in pro teins by caprylate. Vox Sanguinis 60, 75-81
20. Russo, C., Callegaro, L., Lanza, E., Ferrone, S. (1983). Purification of IgG mono clonal antibody by caprylic acid precipitation. Journal of Immunological Methods 65, 269-271
21. McKinney, M.M., Parkinson, A. (1987). A simple, non-chromatographic procedure to purify immunoglobulins from serum and ascites fl uid. Journal of Immunological Methods 96, 271-278
22. Temponi, M., Kageshita, T., Perosa, E, Ono, R., Okada, H., Ferrone, S. (1989). Purification of murine IgG monoclonal antibodies by precipitation with caprylic acid: comparison with other methods of purification. Hybridoma 8, 85-95
23. Mohanty, J.G., Elazhary, Y. (1989). Purification of IgG from serum with caprylic acid and ammonium sulphate precipitation is not superior to ammonium sulphate alone. Comparative Immunology, Microbiology and Infectious Diseases 12, 153-160
24. Reik, L.M., Maines, S.L., Ryan, D.E., Levin, W., Bandiera, S., Thomas, P.E. (1987). A simple, non-chromatographic purification procedure for monoclonal antibodies. Journal of Immunological Methods 100,123-130
25. Tiselius, A. (1948). Nobel lecture. http://nobelprize.org, accessed June 2008
26. Tiselius, A. (1952). Presentation speech. http://nobelprize.org, accessed June 2008
27. Ettre, L.S. (2003). M. S. Tswett and the invention of chromatography. LCGC Magazine. http://chromatographyonline.findpharma.com/lcgc/data/ articlestandard/lcgc/2022003/56954/article.pdf. Accessed January 2008
28. Ettre, L.S. (2006). The Centenary of Chromatography. LCGC Magazine http:// chromatographyonline.findpharma.com/lcgc/Column%3A+Milestones+in+Chro matography/The -Centenary-of -Chromatography/ ArticleStandard/ Article/ detail/358293. Accessed January 2008
29. Peterson, E.A., Sober, H.A. (1956). Chromatography of proteins. I. Cellulose ion - exchange adsorbents. Journal of the American Chemical Society 78, 751-755
30. Porath, J., Flodin P. (1959). Gel filtration: A method for desalting and group sepa ration. Nature 183,1657
31. Hjertén, S. (1961). Agarose as an anti -convection agent in zone electrophoresis. Biochimica et Biophysica Acta 53, 514-517
32. Hjertén, S. (1964).The preparation of agarose spheres for the chromatography of molecules and particles. Biochimica et Biophysica Acta 79, 393-398
33. Billaudelle, H., Lundblad, G., Falksweden, L.-G., Ullberg-Olsson, K. (1966). Frac- tionation of human immune serum anti tetanus by gel filtration. Zeitschrift Immu- nitätsforsch 131,170-183
34. Gelotte, B., Flodin, P., Killander J. (1962). Fractionation of human plasma proteins by gel filtration and zone electrophoresis or ion -exchange chromatography. Archives of Biochemistry and Biophysics 106 (suppl. 1), 319-326
35. Baumstark, J.S., Laffin, R.J., Bardawil, W.A. (1964). A preparative method for the separation of 7S gamma globulin from human serum. Archives of Biochemistry and Biophysics 108, 514-522
36. Hoppe, H.H. Krebs, H.-J., Mester, Th., Hennig, W. (1967). Herstellung von Anti- Rh-Gammaglobulin zur Immunisierings -Prophylaxe. Münchner Medizinische Wochenschrift 109,1749-1752
37. Hoppe, H.H., Mester, T., Hennig, W., Krebs, H.-J. (1973). Prevention of Rh - immunization. Modified production of IgG anti -Rh for intravenous application by ion-exchange chromatography (IEC). Vox Sanguinis 25, 308-316
38. Friesen A.D., Bowman, J.M., Bees, W.C.H. (1983). Column ion exchange chro- matographic production of human immune globulins and albumin. In Curling, J.M. (ed.) Separation of Plasma Proteins, Pharmacia Fine Chemicals, Uppsala, pp. 117-130
39. Friesen A.D. (1986). Chromatographic methods of fractionation. Development of Biological Standards 67, 3-13
40. Joustra, J., Lundgren, H. (1969). Preparation of freeze -dried, monomeric, immu- nochemically pure IgG by a rapid and reproducible chromatographic technique. Proceedings of the 17th Colloquium, Bruges. Pergamon Press, Oxford, pp. 511-515
41. Björling, H. (1972). Plasma fractionation methods used in Sweden. Vox Sanguinis 23,18-25
42. Curling, J.M., Berglöf, I, Lindquist, L.-O., Eriksson, S. (1977). A chromatographic procedure for the purification of human plasma albumin. Vox Sanguinis 33, 97-107
43. Suomela, H. (1980). An ion exchange method for immunoglobulin production. In Curling, J.M. (ed.) Methods of Plasma Protein Fractionation, Academic Press, London, pp. 107-116
44. Bertolini, J. (1999). Chromatographic purification of immunoglobulins. Down stream 31, 20-21
45. Teschner, W., Butterweck, H.A., Auer, W., Muchitsch, E.-M., Weber, A., Liu, S.-L., Wah, P.-S., Schwarz, H.-P. (2007). A new liquid, intravenous immunoglobulin product (IGIV 10%) highly purified by a state-of-the-art process. Vox Sanguinis 92, 42-55
46. Rousell, R.H., McCue, J.P. (1991). Antibody purification from plasma. In Harris, J.R. (ed.) Blood Separation and Plasma Fractionation, Wiley-Liss, New York, NY, pp. 307-340
47. Buchacher, A, Iberer, G. (2006). Purification of intravenous immunoglobulin G from human plasma- Aspects of yield and virus safety. Biotechnology Journal 2, 148-163
48. Price, H., Bees, W.L., Soluk, L., Griffiths, A. (2005). Production of virally safe, despeciated equine botulinum antitoxin. Downstream - PPB '05 Abstracts, GE Healthcare, pp. 25-26
49. 74
50. Tiselius, A., Hjertén, S., Levin, Ö. (1956). Protein chromatography on calcium phosphate columns. Archives of Biochemistry and Biophysics 65,132-155
51. Stanker, L.H., Vanderlaan, M., Juarez-Salinas, H. (1985). One-step purification of mouse monoclonal antibodies from ascites fl uid by hydroxylapatite chromatogra phy. Journal of Immunological Methods 76,157-169
52. Pavlu, B., Johansson, U. (1986). Rapid purification of monoclonal antibodies by high-performance liquid chromatography. Journal of Chromatography 359, 44960
53. Gagnon, P., He, J., Ng, P., Zhen, I, Aberin, C., Mekosh, H. (2006). Practical issues in the industrial use of hydroxyapatite for purification of monoclonal antibodies. Presentation at the 232nd ACS National Meeting, San Francisco, CA, 2006
54. Gagnon, P., He, I, Ng, P., Zhen, J., Aberin, C., Mekosh, H. (2006). The practical task of monoclonal IgG purification with CHT ™ ceramic hydroxyapatite. Presen tation at the 11th Annual Waterside Conference, Chicago, IL, 2006
55. Gagnon, He, I, Ng, P., Zhen, I, Aberin, C., Mekosh, H. (2006). A tale of two plat forms: 2-step purification of monoclonal IgG with protein A and CHT ™ ceramic hydroxyapatite. Presentation at IBC production and Purification of Monoclonal Antibodies, Carlsbad, CA, 2006
56. Cuatrecasas, P., Wilchek, M., Anfinsen, C.B. (1968). Selective enzyme purification by affinity chromatography. Proceedings of the National Academy of Sciences of the United States of America 61, 636-643
57. Axén, R., Porath, J., Ernback, S. (1967). Chemical coupling of peptides and pro teins to polysaccharides by means of cyanogen halides. Nature 214,1302-1304
58. Jensen, K. (1958). A normally occurring staphylococcal antibody in human serum. Acta Pathologica et Microbiologica Scandinavica 44, 421
59. Grov, A., Myklestad, B., Oeding, P. (1964). Immunochemical studies on antigen preparations from Staphylococcus aureus. 1. Isolation and chemical characteriza tion of Antigen A. Acta Pathologica et Microbiologica Scandinavica 61, 588-596
60. Julianelle, L.A., Wieghard, C.W. (1935). The immunological specificity of staphy- lococci. Journal of Experimental Medicine 62,11,12
61. Forsgren, A., Sjöquist, J. (1966). Protein A from S. aureus. I. Pseudo-immune reaction with human gamma -globulin. Journal of Immunology 97, 822-827
62. Hjelm, H., Hjelm, K., Sjöquist, J. (1972). Protein A from Staphylococcus aureus. Its isolation by affinity chromatography and its use as an immunosorbent for isola tion of immunoglobulins. FEBS Letters 28, 73-76
63. Kronvall, G. (1973). A surface component in group A, C, and G streptococci with non-immune reactivity for immunoglobulin G. Journal of Immunology 111, 1401-1406
64. Björk, L., Kronvall G. (1984). Purification and some properties of streptococcal Protein G, a novel IgG binding reagent. Journal of Immunology 133, 969-974
65. Åkerström B., Björk, L. (1985). A physicochemical study of Protein G, a molecule with unique immunoglobulin G -binding properties. Journal of Biological Chem istry 261,10240-10247
66. Gagnon, P. (1996). Purification Tools for Monoclonal Antibodies. Validated Bio- systems, Inc., Tucson, AZ, p. 155
67. Björk, I., Petersson, B.A., Sjöquist, J. (1972). Some physicochemical properties of protein A from Staphylococcus aureus. European Journal of Biochemistry 29, 579-584
68. Sjödahl, J. (1977). Repetitive sequences in protein A from Staphylococcus aureus. Arrangement of five regions within the protein, four being highly homologous and Fc-binding. European Journal of Biochemistry 73, 343-351
69. Sjödahl, J. (1977). Structural studies on the four repetitive units Fc -binding regions in protein A from Staphylococcus aureus. European Journal of Biochemistry 78, 47190
70. Löfdahl, S., Guss, B., Uhlén, M., Philipson, L., Lindberg, M. (1983). Gene for staphylococaal protein A. Proceedings of the National Academy of Sciences of the United States of America 80, 697-701
71. Guss, B., Uhlén,M., Nilsson, B.,Lindberg,M.,Sjöquist,J.,Sjödahl, J. (1984). Region X, the cell-wall-attachment part of staphylococcal protein A. European Journal of Biochemistry 138,41320
72. Uhlén, M., Guss, B., Nilsson, B., Gatenbeck, S., Philipson, L., Lindberg, M. (1984). Complete sequence of the staphylococcal gene encoding Protein A. Journal of Biological Chemistry 259,1695-1702
73. Moks, T., Abrahmsén, L., Nilsson, B., Hellman, U., Sjöquist, J., Uhlén, M. (1986). Staphylococcal protein A consists of five IgG -binding domains. European Journal of Biochemistry 156, 637-643
74. Nilsson, B., Moks, T., Jansson, B., Abrahmsén, L., Elmblad, A., Holmgren, E., Henrichson, C., Jones, T.A., Uhlén, M. (1987). A synthetic IgG -binding domain based on staphylococcal protein A. Protein Engineering 1,107-113
75. Linhult, M., Gûlich, S., Gräslund, T., Simon, A., Karlsson, M., Sjöberg, A., Nord, K., Hober, S. (2004). Improving the tolerance of a Protein A analogue to repeated alkaline exposures using a bypass mutagenesis approach. Proteins 55, 407-416
76. Hober, S., Linhult, M., Gülich, S., Sjöberg, A., Nord, K., Ståhl, S. (2002). Stabiliza tion of protein domains towards alkaline conditions. Downstream - Gab'02 Abstracts, pp. 32-34
77. Hober, S., Nord, K., Linhult, M. (2007). Protein A chromatography for antibody purification. Journal of Chromatography B 848,407
78. Starovasnik, M.A., O'Connell, M.P., Fairbrother, W.J., Kelley, R.F. (1999). Antibody variable region binding by staphylococcal protein A: Thermodynamic analysis and location of the Fv binding site on E -domain. Protein Science 8, 1423-1431
79. Ghose, S., Allen, M., Hubbard, B., Brooks, C., Cramer, S.M. (2005). Antibody vari able region interactions with Protein A: implications for the development of generic purification processes. Biotechnology and Bioengineering 92, 665-673
80. Repligen Corp. (2007). Annual Report 2007. http://www.repligen.com/uploads/ 2007RGENAnnualReport_F.pdf, accessed June 2008
81. Hahn, R., Schlegel, R., Jungbauer, A. (2003). Comparison of protein A adsorbents. Journal of Chromatography B 790, 35-51
82. Jagschies, G. (2007). Flexible manufacturing. Mab scenarios from 100 to 1,000 kg. Presentation at the Bioprocess International Conference, Boston, MA, 2007
83. Farid, S.S. (2007). Process economics of industrial monoclonal antibody manufac ture. Journal of Chromatography B 848, 8-18
84. Shukla, A.A., Hubbard, B., Tressel, T., Guhan, S., Low, D. (2007). Downstream processing of monoclonal antibodies- Application of platform approaches. Journal of Chromatography B 848, 28-39
85. Riske, E, Smith, M., Menon, M, Goetschalck, S., Goidsenhoven, I.V., Krul, A., Pimpaneau, V., Renaers, I., Van Tichelt, N., Van Houdt, K., Hayes, M., Lawrence, C., Bigelow, R., Schroeder, J. (2007). A potential generic downstream process using Cibacron Blue resin at very high loading capacity produces a highly purified monoclonal antibody preparation from cell culture harvest. Journal of Chroma tography B 848,108-115
86. Johansson, H.J., Ljunglöf, A., Eriksoon, K., Brekan, E., Rodrigo, G., Björkman, T. (2007). A novel multimodal anion exchanger designed for monoclonal antibody purification. Presentation at IBC 's 18th International Antibody Development & Production Conference, Carsbad, CA, 2007
87. GE Healthcare (2007). Application Note 28 -9087-92 AA. Two-step purification of monoclonal IgG1 from CHO cell culture supernatant. http://www1.gelifesciences. com, accessed June 2008
88. Sommerfeld, S., Strube, J. (2005). Challenges in biotechnology production- Generic processes and process optimization for monoclonal antibodies. Chemical Engineering and Processing 44,1123-1137
89. Follman, D.K., Fahrner, R.L. (2004). Factorial screening of antibody purification processes using three chromatography steps without Protein A. Journal of Chro matography A 1024, 79-85
90. Arunakumari, A., Wang, J., Ferreira, G. (2007). Improved downstream process design for human monoclonal antibody production. BioPharm International 20 (Suppl.: Advances in Process Chromatography), 360
91. Van Reis, R., Lébréton, B., Fontes, N., Lin, A. P., Banerjee, B, Mehta, A. (2006). Future trends in bioseparations. Presentation at Recovery of Biological Products XII, Litchfield, AZ, 2006
92. Zhou, J.X.,Tressel,T. (2006). Basic concepts in Q membrane chromatography for large-scale antibody production. Biotechnology Progress 22, 341-349
93. Mitchell, H.K., Gordon, M., Haskins, F.A. (1949). Separation of enzymes on the filter paper chromatopile. Journal of Biological Chemistry 180,1071-1076
94. Brandt, S., Goffe, R.A., Kessler, S.B., O'Connor, J.L., Zale, S. (1988). Membrane- based affinity technology for commercial scale purifications. Bio/Technology 6, 779-782
95. Gebauer, K.H., Thömmes, J., Kula, M-R. (1997). Plasma protein fractionation with advanced membrane adsorbents. Biotechnology and Bioengineering 54,181-189
96. Plaigin, M., Lacoste-Bourgeacq, J.F., Mandaro, R., Lemay, C. (1989). Purification of plasma proteins by radial fl ow chromatography cartridges. Biotechnology of plasma proteins. Editions INSERM, Paris 175, pp. 169-175
97. Jungbauer, A., Unterluggauer, F., Steindl, F, Rtiker, F., Katinger, H. (1987). Combination of Zetaprep mass ion -exchange media and high performance cation-exchange chromatography for the purification of high-purity monoclonal antibodies. Journal of Chromatography 397, 313-320
98. Jungbauer, A., Unterluggauer, E, Uhl, K., Buchacher, A., Steindl, F. (1988). Scale up of monoclonal antibody purification using radial streaming ion exchange chro- matography. Biotechnology and Bioengineering 32, 326-333
99. Porath, J., Maisano, F., Belew, M. (1985). Thiophilic adsorption- a new method for protein fractionation. FEBS Letters 185, 306-310
100. Finger, U.,Thömmes, I, Kinzelt, D., Kula, M-R. (1995). Application of thiophilic membranes for the purification of monoclonal antibodies from cell culture. Journal of Chromatography B 664, 69-78
101. Cabanne, C., Raedts, M., Zavadsky, E., Santarelli, X. (2007). Evaluation of radial chromatography versus axial chromatography, practical approach. Journal of Chromatography B 845,191-199
102. Tingley, S. (2007). BioSC - sequential multi-column chromatography. Relieving the downstream bottleneck. Improving productivity and enabling continuous processing. Presentation at the Bioprocess International Conference, Boston, MA, 2007
103. Bisschops, M., Frick, L., Ransohoff, T., de la Fuente, R., Pennings, M. (2007). Scaled-down MAb capture in a disposable format. Continuous multicolumn chro matography process. Presentation at the Bioprocess International Conference, Boston, MA, 2007
104. Przybycien, T.M., Pujar, N.S., Steele, L.M. (2004). Alternative bioseparations: life beyond packed bed chromatography. Current Opinion in Biotechnology 15, 46978
105. Thömmes, J., Etzel, M. (2007). Alternatives to chromatographic separations. Bio technology Progress 23, 425
106. Low, D. (2007). The future of antibody purification. Presentation at the Bioprocess International Conference, Paris, France, 2007
107. Ramanan, S., Stenson, R. (2006). Large-scale antibody purification using non - chromatographic methods. Presentation at the 234th ACS National Meeting, Boston, MA, 2007
108. Farrugia, A., Robert, P. (2006). Plasma protein therapies: current and future per spectives. Best Practice and Research in Clinical Haematology 19, 243-258
109. FFF Enterprises (2007). http://www.fffenterprises.com/Email/BioSupply- Trends/2007-08-01.html, accessed June 2008
110. Curling, J.M., Bryant, C., Chen, T., Ethier, J., Gurgel, P., Weiss, J. (2006). Process modelling and simulation are essential decision tools- Cohn and chromatography compared. Presentation at Recovery of Biological Products XII, Litchfield, AZ, 2006
111. Kelley, B. (2007). Very large scale monoclonal antibody purification: the case for conventional unit operations. Biotechnology Progress 23, 995-1008
112. Ransohoff, T.C., Levine, H.L. (1991). Purification of monoclonal antibodies. In Seetharam, R., Sharma, S.K. (eds) Purification and Analysis of Recombinant Pro teins, Marcel Dekker, Inc., NY, pp. 213-235
113. Birch, J.R., Bonnerjea, J., Flatman, S., Vranch, S. (1995). The production of mono clonal antibodies. In Birch, J.R., Lennox, E.S. (eds) Monoclonal Antibodies: Prin ciples and Applications, Wiley -Liss, Inc., NY, pp. 231-265
114. Wurm, F.M. (2004). Production of recombinant protein therapeutics in cultivated mammalian cells. Nature Biotechnology 22,1393-1398
115. Langer, E., Ranck, J. (2006). Capacity bottleneck squeezed by downstream pro cesses. BioProcess International 4,14-18
116. Rader, R.A. (2007). Biopharmaceutical Products in the U.S. and European Markets, 6th ed, BioPlan Associates, Inc., Rockville, MD, p. 658
117. Sofer G.K., Chirica, L.C. (2006). Improving productivity in downstream process ing. BioPharm International 19,48-55
118. Low, D., O'Leary, R., Pujar, N.S. (2007). Future of antibody purification. Journal of Chromatography B 848, 48-63
119. Farid, S.S. (2006). Established bioprocesses for producing antibodies as a basis for future planning. Advances in Biochemical Engineering, Biotechnology 101,12
120. Rader, R.A. (2007). Biopharmaceutical Products in the U.S. and European Markets. Sixth Edition. BioPlan Associates, Inc., Rockville, MD
121. EMEA (2007). European Public Assessment Reports. http://www.emea.europa. eu/htms/human/epar/a.htm, accessed June 2008
122. FDA (2007). Center for Drugs Evaluation and Research. http://www.fda.gov/cder/, accessed June 2008
123. Staby, A., Jensen, I.H., Mollerup,I. (2000). I. Strong anion -exchange resins. Journal of Chromatography A 897, 99-111
124. Staby, A., Jensen, I.H. (2001) I. More strong anion -exchange resins. Journal of Chromatography A 908,149-161
125. Staby, A., Sand, M.B., Hansen, R.G., Jacobsen, J.H., Andersen, L.A., Gerstenberg, M.,Bruus, U.K., Jensen, I.H. (2004). Comparison of chromatographic ion -exchange resins. III. Strong cation -exchange resins. Journal of Chromatography A 1034, 85-97
126. Staby, A., Sand, M.B., Hansen, R.G., Jacobsen, J.H., Andersen, L.A., Gerstenberg, M., Bruus, U.K., Jensen, I.H. (2005). Comparison of chromatographic ion -exchange resins. IV. Strong and weak cation -exchange resins and heparin resins. Journal of Chromatography A 1034, 85-97
127. Staby, A., Jacobsen, J.H., Hansen, R.G., Bruus, U.K., Jensen, I.H. (2006). Compari son of chromatographic ion -exchange resins. V. Strong and weak cation -exchange resins. Journal of Chromatography A 1118,168-179
128. Staby, A., Jensen, R.H., Bensch, M., Hubbuch, J., Dünweber, D.L., Krarup, J. Nielsen, J., Lund, M., Kidal, S., Hansen, T.B., Jensen, I.H. (2007). Comparison of chromatographic ion -exchange resins. VI. Weak anion-exchange resins. Journal of Chromatography A 1164, 82-94
129. Coffman, J., Kelley, B., Kramarczyk, J. (2003) High-throughput screening of resins and excipients for optimization of selectivity. Presentation at Recovery of Biologi cal Products XI, Banff, Canada, 2003
130. Kohler G., Milstein, C. (1975). Continuous cultures of fused cells secreting anti body of predefined specificity. Nature 256,49597
131. Jagschies, G., O'Hara, A. (2007). Debunking downstream bottleneck myth. Genetic Engineering News 27,14