Development of a novel and efficient cell culture flocculation process using a stimulus responsive polymer to streamline antibody purification processes

Biotechnology and Bioengineering

Volumn 110, Issue 11, 2013, Pages 2928-2937

  Kang, Yun Kenneth ^a   Hamzik, James ^b   Felo, Michael ^c   Qi, Bo ^a   Lee, Julia ^a   Ng, Stanley ^a   Liebisch, Gregory ^a   Shanehsaz, Behnam ^a   Singh, Nripen ^b   Persaud, Kris ^a   Ludwig, Dale L ^a   Balderes, Paul ^a  

^a ELI LILLY AND COMPANY   (United States)

^b EMD Millipore   (United States)

^c Biomanufacturing Sciences Network   (United States)

Author keywords

Aggregates; Depth filtration; Flocculation; Harvest; HCP; HMW; Host DNA; Hydrophobic interaction; Impurity removal; Monoclonal antibody; Precipitation; Purification; Residual polymer; Salt tolerant; Smart polymer; Stimulus responsive polymer

Indexed keywords

DEPTH FILTRATION; HCP; HMW; HYDROPHOBIC INTERACTIONS; IMPURITY REMOVAL; RESIDUAL POLYMERS; RESPONSIVE POLYMER; SALT TOLERANT; SMART POLYMERS;

AGGREGATES; CELL CULTURE; CELLS; DEBRIS; DESIGN OF EXPERIMENTS; FLOCCULATION; HARVESTING; IMPURITIES; MONOCLONAL ANTIBODIES; ORGANIC POLYMERS; PRECIPITATION (CHEMICAL); PROTEINS; REMOVAL; SALT REMOVAL;

PURIFICATION;

ANTIBODY; CELL PROTEIN; DNA; POLYMER; PROTEIN A;

ANIMAL CELL; ARTICLE; CELL CULTURE; CELL DENSITY; CONTROLLED STUDY; DOWNSTREAM PROCESSING; FEMALE; FLOCCULATION; HIGH PERFORMANCE LIQUID CHROMATOGRAPHY; HOST CELL; NONHUMAN; PURIFICATION;

MAMMALIA;

AGGREGATES; DEPTH FILTRATION; FLOCCULATION; HARVEST; HCP; HMW; HOST DNA; HYDROPHOBIC INTERACTION; IMPURITY REMOVAL; MONOCLONAL ANTIBODY; PRECIPITATION; PURIFICATION; RESIDUAL POLYMER; SALT TOLERANT; SMART POLYMER; STIMULUS RESPONSIVE POLYMER;

ANIMALS; ANTIBODIES; BIOLOGICAL PRODUCTS; CELL CULTURE TECHNIQUES; CHEMICAL FRACTIONATION; CHO CELLS; CRICETINAE; CRICETULUS; FILTRATION; FLOCCULATION; HUMANS; RECOMBINANT PROTEINS; TECHNOLOGY, PHARMACEUTICAL;

EID: 84884531166     PISSN: 00063592     EISSN: 10970290     Source Type: Journal    
DOI: 10.1002/bit.24969     Document Type: Article

References (28)

1. Akeprathumchai S, Han B, Wickramasinghe SR, Carlson JO, Czermak P, Preibeta K. 2004. Murine leukemia virus clearance by flocculation and microfiltration. Biotechnol Bioeng 88(7):880-889.
2. Aunins JG, Wang DI. 1989. Induced flocculation of animal cells in suspension culture. Biotechnol Bioeng 34(5):629-638.
3. Coffman J, Shpritzer RI, Vicik SM. 2010. Separation methods. US patent 7855280.
4. Fischer D, Li Y, Ahlemeyer B, Krieglstein J, Kissel T. 2003. In vitro cytotoxicity testing of polycations: Influence of polymer structure on cell viability and hemolysis. Biomaterials 24(7):1121-1131.
5. Gagnon P. 2012. Technology trends in antibody purification. J Chromatogr A 1221:57-70.
6. Han B, Akeprathumchai S, Wickramasinghe SR, Qian X. 2003. Flocculation of biological cells: Experiment vs. theory. AIChE J 49(7):1687-1701.
7. Hove S, Cacace B, Felo M, Chefer K. 2010. Development of a robust clarification process for high density mammalian cell culture processes; August 1-5, 2010; Recovery of Biological Products XIV, Squaw Creek, Lake Tahoe.
8. Jaber J, Moya W, Hamzik J, Boudif A, Zhang Y, Soice N. 2011. Stimulus responsive polymers for the purification of biomolecules. US patent 2011/0313066 A1.
9. Kang Y, Ng S, Lee J, Adaelu J, Qi B, Persaud K, Ludwig D, Balderes P. 2012. Development of an alternative monoclonal antibody polishing step. Biopharm Int 25(5):34-45.
10. Kelley B, Blank G, Lee A. 2009. Downstream processing of monoclonal antibodies: Current practices and future opportunities. In: Gottschalk U, editor. Process scale purification of antibodies. Hoboken, NJ: John Wiley & Sons, Inc. p 23.
11. Kilander J, Blomström S, Rasmuson A. 2007. Scale-up behaviour in stirred square flocculation tanks. Chem Eng Sci 62:1606-1618.
12. Lutz H, Abbott I, Blanchard M, Parampalli A, Setiabudi G, Chiruvolu V, Noguchi M. 2009. Considerations for scaling-up depth filtration of harvested cell culture fluid. BioPharm Int 22(3): 58, 60-62, 64-66.
13. McNerney T, Thomas A, Senczuk A, Carvalho J, Chinniah S, Zhao X, Pallitto M, Piper R. 2011. PDADMAC flocculation of CHO cells: A centrifuge-less harvest process for mAbs; 241st ACS National Meeting & Exposition, Anaheim, CA. p BIOT-302.
14. Moghimi SM, Symonds P, Murray JC, Hunter AC, Debska G, Szewczyk A. 2005. A two-stage poly(ethylenimine)-mediated cytotoxicity: Implications for gene transfer/therapy. Mol Ther 11(6):990-995.
15. Peram T, McDonald P, Carter-Franklin J, Fahrner R. 2010. Monoclonal antibody purification using cationic polyelectrolytes: An alternative to column chromatography. Biotechnol Prog 26(5):1322-1331.
16. Pezzini J, Joucla G, Gantier R, Toueille M, Lomenech AM, Le Senechal C, Garbay B, Santarelli X, Cabanne C. 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.
17. Riske F, Schroeder J, Belliveau J, Kang X, Kutzko J, Menon MK. 2007. The use of chitosan as a flocculant in mammalian cell culture dramatically improves clarification throughput without adversely impacting monoclonal antibody recovery. J Biotechnol 128(4):813-823.
18. Romero J, Chrostowski J, De Vilmorin PG, Case JY. 2010. Method of isolating biomacromolecules using low pH and divalent cations. USA patent 2010/0145022 A1.
19. Roush DJ, Lu Y. 2008. Advances in primary recovery: Centrifugation and membrane technology. Biotechnol Prog 24(3):488-495.
20. Schirmer E, Kuczewski M, Golden K, Lain B, Bragg C, Chon J, Cacciuttolo M, Zarbis-Papastoitsis G. 2010. Primary clarification of very high-density cell culture harvests by enhanced cell settling. BioProcess Int 8(1):32-39.
21. Shan J, Xia J, Guo Y, Zhang X. 1996. Flocculation of cell, cell debris and soluble protein with methacryloyloxyethyl trimethylammonium chloride-Acrylonitrile copolymer. J Biotechnol 49:173-178.
22. Shpritzer R, Vicik S, Orlando S, Acharya H, Coffman JL. 2006. Calcium phosphate flocculation of antibody-producing mammalian cells at pilot scale; September 10-14, 2006; The 232nd ACS National Meeting; San Francisco, CA. p BIOT-80.
23. Shukla AA, Hinckley P. 2008. Host cell protein clearance during Protein A chromatography: Development of an improved column wash step. Biotechnol Prog 24(5):1115-1121.
24. 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.
25. Thommes J, Etzel M. 2007. Alternatives to chromatographic separations. Biotechnol Prog 23(1):42-45.
26. Wang J, Diehl T, Aguiar D, Dai X, Arunakumari A. 2009. Precipitation of process-derived impurities in non-Protein A purification schemes for antibodies. Biopharm Int 22(October, Suppl.):4-10, 32.
27. Yoo S, Ghosh R. 2012. Simultaneous removal of leached protein-A and aggregates from monoclonal antibody using hydrophobic interaction membrane chromatography. J Membr Sci 390-391:263-269.
28. Zhao X, Petty K, McNerney T, Thomas A, Ma J, Tressel T, Piper R. 2012. Developing recovery clarification processes for mammalian cell culture with high density and high solid content; 243rd ACS National Meeting & Exposition, San Diego, CA. p BIOT-160.