Modelling Approaches for Bio-Manufacturing Operations

Part of the Advances in Biochemical Engineering/Biotechnology book series (ABE, volume 132)


Fast and cost-effective methods are needed to reduce the time and money needed for drug commercialisation and to determine the risks involved in adopting specific manufacturing strategies. Simulations offer one such approach for exploring design spaces before significant process development is carried out and can be used from the very earliest development stages through to scale-up and optimisation of operating conditions and resource deployment patterns both before and after plant start-up. The advantages this brings in terms of financial savings can be considerable, but to achieve these requires a full appreciation of the complexities of processes and how best to represent them mathematically within the context of in silico software. This chapter provides a summary of some of the work that has been carried out in the areas of mathematical modelling and discrete event simulations for production, recovery and purification operations when designing bio-pharmaceutical processes, looking at both financial and technical modelling.

Graphical Abstract


CFD Modelling Sensitivity analysis Simulation Window of operation 


  1. 1.
    Ambler CM (1959) The theory of scaling up laboratory data for the sedimentation type centrifuge. J Biochem Microbiol Technol Eng 1:185–205CrossRefGoogle Scholar
  2. 2.
    Boulding N, Yim SSS, Keshavarz-Moore E, Ayazi Shamlou P, Berry M (2002) Ultra scaledown to predict filtering centrifugation of secreted antibody fragments from fungal broth. Biotechnol Bioeng 79:381–388CrossRefGoogle Scholar
  3. 3.
    Boushaba R, Baldascini H, Gerontas S, Titchener-Hooker NJ, Bracewell DG (2011) Demonstration of the use of windows of operation to visualize the effects of fouling on the performance of a chromatographic step. Biotechnol Progr 27:1009–1017CrossRefGoogle Scholar
  4. 4.
    Boychyn M, Yim SSS, Ayazi Shamlou P, Bulmer M, More J, Hoare M (2001) Characterization of flow intensity in continuous centrifuges for the development of laboratory mimics. Chem Eng Sci 56:4759–4770CrossRefGoogle Scholar
  5. 5.
    Boychyn M, Yim SSS, Bulmer M, More J, Bracewell DG, Hoare M (2004) Performance prediction of industrial centrifuges using scale-down models. Bioproc Biosyst Eng 26:385–391CrossRefGoogle Scholar
  6. 6.
    Chan SH, Kiang S, Brown MA (2003) One-dimensional centrifugation model. AIChE J 49:925–938CrossRefGoogle Scholar
  7. 7.
    Chowdhury BR, Chakraborty R, Chaudhuri UR (2003) Modelling and simulation of diffusional mass transfer of glucose during fermentative production of pediocin AcH from Pediococcus acidilactici H. Biochem Eng J 16:237–243CrossRefGoogle Scholar
  8. 8.
    Ernst S, Garro OA, Winkler S, Venkataraman G, Langer R, Cooney CL, Sasisekharan R (1997) Process simulation for recombinant protein production: cost estimation and sensitivity analysis for heparinase I expressed in Escherichia coli. Biotechnol Bioeng 53:575–582CrossRefGoogle Scholar
  9. 9.
    Farid S, Novais JL, Karri S, Washbrook J, Titchener-Hooker NJ (2000) A tool for modelling strategic decisions in cell culture manufacturing. Biotechnol Progr 16:829–836CrossRefGoogle Scholar
  10. 10.
    Farid SS, Washbrook J, Titchener-Hooker NJ (2005a) Combining multiple quantitative and qualitative goals when assessing biomanufacturing strategies under uncertainty. Biotechnol Progr 21:1183–1191CrossRefGoogle Scholar
  11. 11.
    Farid SS, Washbrook J, Titchener-Hooker NJ (2005b) Decision-support tool for assessing biomanufacturing strategies under uncertainty: stainless steel versus disposable equipment for clinical trial material preparation. Biotechnol Progr 21:486–497CrossRefGoogle Scholar
  12. 12.
    Fee CJ (2001) Economics of wash strategies for expanded bed adsorption of proteins from milk with buoyancy-induced mixing. Chem Eng Proc 40:329–334CrossRefGoogle Scholar
  13. 13.
    Gebicke KW, Johl H-J, Sternad W, Trösch W, Chmiel H (1993) Application of modelling and simulation for optimisation of a continuous fermentation process. Comp Chem Eng 17(supplement 1):177–182Google Scholar
  14. 14.
    Gerontas S, Asplund M, Hjorth R, Bracewell DG (2010) Integration of scale-down experimentation and general rate modelling to predict manufacturing scale chromatographic separations. J Chromatogr A 1217:6917–6926CrossRefGoogle Scholar
  15. 15.
    Giannasi F, Lovett P, Godwin AN (2001) Enhancing confidence in discrete event simulations. Comput Ind 44:141–157CrossRefGoogle Scholar
  16. 16.
    Groep ME, Gregory ME, Kershenbaum LS, Bogle IDL (2000) Performance modelling and simulation of biochemical process sequences with interacting unit operations. Biotechnol Bioeng 67:300–311CrossRefGoogle Scholar
  17. 17.
    Gu T, Hsu K-H, Syu M-J (2003) Scale-up of affinity chromatography for purification of enzymes and other proteins. Enzyme Microb Tech 33:430–437CrossRefGoogle Scholar
  18. 18.
    Hetherington PJ, Follows M, Dunnill P, Lilly MD (1971) Release of protein from bakers’ yeast (Saccharomyces cerevisiae) by disruption in an industrial homogeniser. Trans IChemE 49:142–148Google Scholar
  19. 19.
    Holford NHG, Kimko HC, Monteleone JPR, Peck CC (2000) Simulation of clinical trials. Annu Rev Pharmacol 40:209–234CrossRefGoogle Scholar
  20. 20.
    Jang JD, Barford JP (2000) An unstructured kinetic model of macromolecular metabolism in batch and fed-batch cultures of hybridoma cells producing monoclonal antibodies. Biochem Eng J 4:153–168CrossRefGoogle Scholar
  21. 21.
    Karri S, Davies E, Titchener-Hooker N, Washbrook J (2001) Biopharmaceutical process development: part III, a framework to assist decision making, Biopharm Europe, September, pp 76–82Google Scholar
  22. 22.
    King JMP, Griffiths P, Zhou Y, Titchener-Hooker NJ (2004) Visualising bioprocesses using, 3D-windows of operation. J Chem Technol Biotechnol 79:518–525CrossRefGoogle Scholar
  23. 23.
    King JMP, Titchener-Hooker NJ, Zhou Y (2007) Ranking bioprocess variables using global sensitivity analysis: a case study in centrifugation. Bioproc Biosyst Eng 30:123–134CrossRefGoogle Scholar
  24. 24.
    Li Z, Gu Y, Gu T (1998) Mathematical modelling and scale-up of size exclusion chromatography. Biochem Eng J 2:145–155CrossRefGoogle Scholar
  25. 25.
    Lim AC, Zhou Y, Washbrook J, Titchener-Hooker NJ, Farid S (2004) A decisional-support tool to model the impact of regulatory compliance activities in the biomanufacturing industry. Comput Chem Eng 28:727–735CrossRefGoogle Scholar
  26. 26.
    Lim AC, Zhou Y, Washbrook J, Sinclair A, Fish B, Francis R, Titchener-Hooker NJ, Farid SS (2005) Application of a decision-support tool to assess pooling strategies in perfusion culture processes under uncertainty. Biotechnol Prog 21:1231–1242CrossRefGoogle Scholar
  27. 27.
    Looby M, Ibarra N, Pierce JL, Buckley K, O’Donovan E, Heenan M, Moran E, Farid SS, Baganz F (2011) Application of quality by design principles to the development and technology transfer of a major process improvement for the manufacture of a recombinant protein. Biotechnol Prog, (in press;
  28. 28.
    Maybury JP, Mannweiler K, Titchener-Hooker NJ, Hoare M, Dunnill P (1998) The performance of a scaled down industrial disk stack centrifuge with a reduced feed material requirement. Bioprocess Eng 18:191–199CrossRefGoogle Scholar
  29. 29.
    Mustafa MA, Washbrook J, Lim AC, Zhou Y, Titchener–Hooker NJ, Morton P, Berezenko S, Farid, SS (2004) A software tool to assist business–process decision–making in the biopharmaceutical industry. Biotechnol Prog 20:1096–1102 [Correction: Biotechnol Prog (2005) 21:320]Google Scholar
  30. 30.
    Mustafa MA, Washbrook J, Titchener-Hooker NJ, Farid SS (2006) Retrofit decisions within the biopharmaceutical industry: an EBA case study. Food Bioprod Process 84 C1:84–89Google Scholar
  31. 31.
    Petrides D (1994) Biopro designer: an advanced computing environment for modelling and design of integrated biochemical processes. Comput Chem Eng 18(supplement):S621–S625CrossRefGoogle Scholar
  32. 32.
    Petrides D, Koulouris A, Siletti C (2002) Throughput analysis and debottlenecking of biomanufacturing facilities: a job for process simulators, BioPharm, August pp 2–7Google Scholar
  33. 33.
    Petrides D, Siletti C, Jiménez J, Psathas P, Mannion Y (2011) Optimizing the design and operation of fill-finish facilities using process simulation and scheduling tools. Pharmaceut Eng 31:1–10.
  34. 34.
    Pinto JM, Montagna JM, Vecchietti AR, Iribarren OA, Asenjo JA (2001) Process performance models in the optimization of multiproduct protein production plants. Biotechnol Bioeng 74:451–465CrossRefGoogle Scholar
  35. 35.
    Pisano G (1996) Learning-before-doing in the development of new process technology. Res Policy 25:1097–1119CrossRefGoogle Scholar
  36. 36.
    Reynolds T, Boychyn M, Sanderson T, Bulmer M, More J, Hoare M (2003) Scale-down of continuous filtration for rapid bioprocess design: recovery and dewatering of protein precipitate suspensions. Biotechnol Bioeng 83:454–464CrossRefGoogle Scholar
  37. 37.
    Shanklin T, Roper K, Yegneswaran PK, Marten MR (2001) Selection of bioprocess simulation software for industrial applications. Biotechnol Bioeng 72:483–489CrossRefGoogle Scholar
  38. 38.
    Siddiqi SF, Titchener-Hooker NJ, Ayazi Shamlou P (1996) Simulation of particle size distribution changes occurring during high-pressure disruption of bakers’ yeast. Biotechnol Bioeng 50:145–150CrossRefGoogle Scholar
  39. 39.
    Titchener-Hooker NJ, Zhou Y, Hoare M, Dunnill P (2001) Biopharmaceutical process development: part II methods of reducing development time, Biopharm Europe September, pp 68–74Google Scholar
  40. 40.
    Varadaraju H, Schneiderman S, Zhang L, Fong H, Menkhaus TJ (2011) Process and economic evaluation for monoclonal antibody purification using a membrane-only process. Biotechnol Progr 27:1297–1305CrossRefGoogle Scholar
  41. 41.
    Varga EG, Titchener–Hooker NJ, Dunnill P (2001) Prediction of the pilot-scale recovery of a recombinant yeast enzyme using integrated models. Biotechnol Bioeng 74:96–107CrossRefGoogle Scholar
  42. 42.
    Weaver LE, Carta G (1996) Protein adsorption on cation exchangers: comparison of macroporous and gel-composite media. Biotechnol Prog 12:342–355CrossRefGoogle Scholar
  43. 43.
    Williams HP (1999) Model building in mathematical programming, 4th edn. Wiley, ChichesterGoogle Scholar
  44. 44.
    Wong HH, O’Neill BK, Middelberg APJ (1997) A mathematical model for Escherichia coli debris size reduction during high pressure homogenisation based on grinding theory. Chem Eng Sci 52:2883–2890CrossRefGoogle Scholar
  45. 45.
    Woodley J, Titchener-Hooker NJ (1996) The use of windows of operation as a bioprocess design tool. Bioprocess Eng 14:263–268CrossRefGoogle Scholar
  46. 46.
    Workman RW (2000) Simulation of the drug development process: a case study from the pharmaceutical industry, proceedings of the winter simulation conferenceGoogle Scholar
  47. 47.
    Zhou YH, Titchener-Hooker NJ (1999) Visualising integrated bioprocess designs through, “windows of operation”. Biotechnol Bioeng 65:550–557CrossRefGoogle Scholar
  48. 48.
    Zhou YH, Holwill ILJ, Titchener-Hooker NJ (1997) A study of the use of computer simulations for the design of integrated downstream processes. Bioprocess Eng 16:367–374CrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2012

Authors and Affiliations

  1. 1.The Advanced Centre for Biochemical EngineeringUniversity College LondonLondonUK

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