Economic Drivers and Trade-Offs in Antibody Purification Processes - The future of therapeutic MAbs lies in the development of economically feasable downstream processes. - BioPharm International


Economic Drivers and Trade-Offs in Antibody Purification Processes
The future of therapeutic MAbs lies in the development of economically feasable downstream processes.

BioPharm International Supplements

Alternatives to Chromatography

Research into alternatives for column chromatography focuses on methods that have the potential to effectively handle increased amounts of both the product and impurities (e.g., host cell proteins and antibody aggregates or isomers). Ideally, these alternatives should achieve a separation power equal to that of column chromatography while reducing the COG/g.33 When assessing the cost-effectiveness of these alternatives, it is important to consider not only the equipment sizes and resource consumption, but also the development and validation costs required.

Table 1. Example of downstream process economic trade-offs
Membrane chromatography operating in flow-through mode is emerging as a popular alternative to anion-exchange chromatography steps in MAb purification,11,26,34–36 because of its rapid operation, ease of scale-up, and cost savings (Table 1). The dominant component in the distribution of raw material costs shifts from buffer costs in packed-bed chromatography to membrane costs; a membrane suitable for processing a batch of several thousand liters can cost several thousands of dollars and is disposable and not reusable. The key process economic trade-offs for anion-exchange applications therefore depends on whether the savings in buffer, labor, and overheads outweigh the high cost of the membranes. Critical variables that will affect the outcome of this cost comparison are the relative differences in the handling capacities assumed between anion-exchange membranes and resins, which dictate the sizes required, and the assumed WFI and buffer costs; higher values of these variables increase the economic attractiveness of membrane chromatography.26 The pace at which resin and membrane capacities improve will contribute to which operation secures its place in future platform processes. In cases where packed-bed and membrane chromatography offer similar COG/g, the real cost advantages may be in the development and validation costs that are significantly reduced with membrane chromatography because there is no column packing or cleaning validation.26

Summary and Outlook

As demand and titers continue to increase for MAbs, the DSP costs will become an increasingly dominant proportion of the COG/g with the DSP handling capacity representing a potential bottleneck that could reduce productivity. These factors have encouraged a shift in development efforts towards new DSP solutions that improve the process economics and alleviate bottlenecks. Consequently, the industry is taking advantage of improvements that affect the critical process economic drivers by looking to: improve the overall DSP yield and reduce the batch duration using platform processes based on two chromatography operations without intermediate buffer exchange steps; increase DSP capacity by taking advantage of improvements in chromatography resins that allow increased throughput over shorter times; and lower buffer demands and validation costs using new technologies such as membrane chromatography.

These improvements will be important for facilities that already have large bioreactor capacities installed, and also for newer facilities that will probably be built with smaller capacities with flexibility in mind to allow rapid turnaround between campaigns for multiple products. Furthermore, if cheaper and faster expression technologies, such as glycoengineered Pichia pastoris, become more widespread, there will be an even greater spotlight on DSP costs. Although new DSP approaches may present complex and challenging problems to tackle, it is anticipated that this line of enquiry will dominate studies in the near future so that more cost-effective MAb platform technologies can evolve. However, with each of these new approaches there are trade-offs and potential risks that need to be evaluated to assess the impact on process economics. The capacity to cost such alternatives provides a common basis for such decision-making and will prove a vital tool for bioprocess designs in the future. Process economics can also be dramatically improved if the potency of MAbs is increased; recent efforts in this area are an encouraging sign for the future. BP

This is an excerpt from the chapter entitled "Process Economic Drivers in Industrial Monoclonal Antibody Manufacture" in the forthcoming John Wiley and Sons book Process Scale Purification of Antibodies edited by Uwe Gottschalk.

SUZANNE S. FARID, PhD, is a lecturer (assistant professor) at the Advanced Centre for Biochemical Engineering, Department of Biochemical Engineering, University College London, London, UK, +44 20 7679 4415,


1. Reichert JM, Rosensweig CJ, Faden LB, Dewitz MC. Monoclonal antibodies successes in the clinic. Nat Biotechnol. 2005;23:1073–1078.

2. Gottschalk U. The renaissance of protein purification. Supplement to BioPharm Int. 2006 June.

3. Datar RV, Cartwright, T., Rosen, C. Process economics of animal cell and bacterial fermentations: a case study analysis of tPA. Bio/Technol. 1993;11:349–357.

4. Sadana A, Beelaram AM. Efficiency and economics of bioseparation: some case studies. Bioseparation. 1994;4:221–235.

5. Clemento A. New and integrated approaches to successful accelerated drug development. Drug Information J. 1999;33:699–710.

6. Mitchell P. Next-generation monoclonals less profitable than trailblazers? Nature Biotechnol. 2005;23:906.

7. Farid SS, Washbrook J, Titchener-Hooker NJ. Decision-support tool for assessing bio-manufacturing strategies under uncertainty: stainless steel versus disposable equipment for clinical trial material preparation. Biotechnol Progress. 2005;21(2),486–497.

8. Kamarck ME. Building biomanufacturing capacity—the chapter and verse Nat Biotechnol. 2006;24:503–505.

9. Sommerfeld S, Strube J. Challenges in biotechnology production—generic processes and process optimization for monoclonal antibodies. Chem Eng Proc. 2005;44(10):1123–1137.

10. Werner RG. Economic aspects of commercial manufacture of biopharmaceuticals. J Biotechnol. 2004;113:171–182.

11. Li F, Zhou JX, Yang X, Tressel T, Lee B. Current therapeutic antibody production and process optimization. BioProcessing J. 2005 Sept/Oct;1–8.

12. Wheelwright SM. Protein purification: design and scale-up of downstream processing. New York: Hanser; 1991. chapter 1.

13. Dowd C, van Reis R. Cost reduction strategies in recovery process design. Proceedings of IBC's 4th International Conference on Production and Economics of Biopharmaceuticals; 2001 Nov 14–15. San Diego, CA.

14. Ultee ME, Rea DW. Antibody purification. In: Flickinger MC, Drew SW, editors. Encyclopedia of bioprocess technology: fermentation, biocatalysis, and bioseparation. New York: Wiley; 1999. vol 1.

15. Carson KL. Flexibility—the guiding principle for antibody manufacturing. Nat Biotechnol. 2005;23:1054-1058.

16. Kelley B. Very large scale monoclonal antibody purification: the case for conventional unit operations. Biotechnol Prog. 2007;23(5):995–1008.

17. Farid S. A decision-support tool for simulating the process and business perspectives of biopharmaceutical manufacture [PhD thesis]. London (UK): University of London; 2001.

18. Farid SS, Washbrook J, Titchener-Hooker NJ. Combining multiple quantitative and qualitative goals when assessing biomanufacturing strategies under uncertainty. Biotechnol Prog. 2005;21(4):1183–1191.

19. Hodge G. Disposable components enable a new approach to biopharmaceutical manufacturing. BioPharm Int. 2004;17(3):38–49.

20. Watler PK. Cost and capacity comparison of transgenics and cell culture production systems. Proceedings of IBC's 4th International Conference on Production and Economics of Biopharmaceuticals; 2001 Nov 14–15. San Diego, CA.

21. Lewis-Sandy D. Optimizing consumables reuse for therapeutic protein production. Proceedings of IBC's 4th International Conference on Production and Economics of Biopharmaceuticals; 2001 Nov 14–15. San Diego, CA.

22. Rathore AS, Latham P, Levine H, Curling J, Kaltenbrunner O. Costing issues in the production of biopharmaceuticals. BioPharm Int. 2004 Feb.

23. Blank GS, Zapata G, Fahrner R, Milton M, Yedinak C, Knudsen H, Schmelzer C. Expanded bed adsorption in the purification of monoclonal antibodies: a comparison of process alternatives. Bioseparation. 2001;10:65–71.

24. Jagschies G, Grönberg A, Björkman T, Lacki K, Johansson HJ. Technical and economical evaluation of downstream processing options for monoclonal antibody (MAb) production. BioPharm Int. 2006 June.

25. Aldington S, Bonnerjea J. Scale-up of monoclonal antibody purification processes. J Chromatogr B. 2007;848:64–78.

26. Zhou J, Tressel T. Basic concepts in Q membrane chromatography for large-scale antibody production. Biotechnol Progr. 2006;22:341-349.

27. Warner WM, Nochumson S. Rethinking the economics of chromatography. BioPharm Int. 2003 Jan; 58–60.

28. Jagschies G, O'Hara A. Debunking downstream bottleneck myth. Gen Eng News. 2007 Aug;27(14).

29. Thiel KA. Biomanufacturing, from bust to boom... to bubble? Nat Biotechnol. 2004;22:1365–1372.

30. Smith M. An evaluation of Protein A and non-Protein A methods for the recovery of monoclonal antibodies and considerations for process scale-up. Proceedings of scaling-up of biopharmaceutical products. 2004 Jan 26–27; Amsterdam.

31. Sofer G, Chirica LC. Improving productivity in downstream processing, Pharm Tech Eur. 2007 Apr.

32. Davies J, Smith, M, Bonnerjea J. The influence of scale of operation on purification process design. Proceedings of 154th Society for General Microbiology Meeting, 2004 29 March–2 April, Bath, UK.

33. Thömmes J, Etzel M. Alternatives to chromatographic separations. Biotechnol Progr. 2007;23(1):42–45.

34. Knudsen H, Fahrner R, Xu Y, Norling L, Blank G. Membrane ion-exchange chromatography for process-scale antibody purification. J Chromatogr A. 2001;907:145–154.

35. Boi C. Membrane adsorbers as purification tools for monoclonal antibody purification. J Chromatogr B. 2007;848:19–27.

36. Lim JAC, Sinclair A, Kim DS, Gottschalk U. Economic benefits of single use membrane chromatography in polishing: A cost of goods model. BioProcess Int. 2007;5(2):60–64.

blog comments powered by Disqus



FDA Approves Pfizer's Trumenba for the Prevention of Meningitis B
October 30, 2014
EMA: Extrapolation Across Indications for Biosimilars a Possibility
October 30, 2014
Bristol-Myers Squibb Announces Agreement to Acquire HER2-Targeted Cancer Treatment
October 29, 2014
Contract Research and Manufacturing Organization Paragon Bioservices Raises $13 Million
October 28, 2014
Yale and Gilead Extend Sequencing Initiative
October 28, 2014
Author Guidelines
Source: BioPharm International Supplements,
Click here