SpringerLink
Log in

Downstream Processing

  • Chapter
  • First Online:
Microbial Biomass Process Technologies and Management

Abstract

Generally, the cost of biopharmaceuticals or biologics depends on the downstream processing. This refers to the recovery and purification of biosynthetic products generated during the upstream stage into finished products such as whole cells, organic acids, amino acids, solvents, antibiotics, industrial enzymes, therapeutic proteins, vaccines, and gums. The downstream stage also includes the sale of that product to other businesses, governments, or private individuals. The type of end user varies according to the finished product. Regardless of the industry involved, the downstream process involves direct contact with customers through the finished product. The third chapter is therefore dedicated to the complexity of downstream processing techniques. These include the establishment of platform technologies and high-throughput methods optimized using experimental approaches based on quality by design and design of experiment. Additionally, the authors explain how integration of modeling, simulation of unit operations, and the use of miniplant facilities are linked to process development.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution

Subscribe and save

Springer+ Basic
EUR 32.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or Ebook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free ship** worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free ship** worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Shukla AA, Thömmes J (2010) Recent advances in large-scale production of monoclonal antibodies and related proteins. Trends Biotechnol 28:253–261

    Article  CAS  PubMed  Google Scholar 

  2. Bhambure R et al (2011) High-throughput process development for biopharmaceutical drug substances. Trends Biotechnol 29:127–135

    Article  CAS  PubMed  Google Scholar 

  3. Del Va IJ et al (2010) Towards the implementation of quality by design to the production of therapeutic monoclonal antibodies with desired glycosylation patterns. Biotechnol Prog 26:1505–1527

    Article  Google Scholar 

  4. Chon JH, Zarbis-Papastoitsis G (2011) Advances in the production and downstream processing of antibodies. New Biotechnol 28:458–463

    Article  CAS  Google Scholar 

  5. Kelley B (2009) Industrialization of mAb production technology: the bioprocessing industry at a crossroads. MAbs 1:443–452

    Article  PubMed  PubMed Central  Google Scholar 

  6. Strube J, Grote F, Ditz R (2012) Bioprocess design and production technology for the future. In: Subramanian G (ed) Biopharmaceutical production technology, vol 2, 1st edn. Wiley-VCH, Weinheim

    Google Scholar 

  7. Low D et al (2997) Future of antibody purification. J Chromatogr B 848:48–63

    Article  Google Scholar 

  8. Singh RP, Heldman DR (1993) Introduction to food engineering, 2nd edn. Academic Press, Harcourt Brace & Company, San Diego, CA

    Google Scholar 

  9. Wesner J (2008) Reduction of host-cell DNA in mammalian cell culture using charged filters at protein-A capture for monoclonal antibodies. BPI, Korea. www.bioprocessintl.com

    Google Scholar 

  10. Zhou JX, Gottschalk U (2008) Orthogonal virus clearance applications in monoclonal antibody production. Wiley, Boca Raton, FL, pp 169–189

    Google Scholar 

  11. Zhou JX (2008) Viral clearance using disposable system in MAb commercial downstream process. Biotechnol Bioeng 100:488–496

    Article  CAS  PubMed  Google Scholar 

  12. Cheremisinoff NP et al (1993) Filtration equipment for wastewater treatment. Prentice-Hall, Englewood Cliffs

    Google Scholar 

  13. Halberthal J (2016) Nutsche filter. Engineering aspects in solid-liquid separation. www.solidliquid-separation.com

  14. Koichi I, Dennis R (2016) Industrial gas filtration. Filtration: principles and practices. encyclopedia.che.engin.umich.edu

  15. Loff Lawrence G (1990) Filter media, filter rating. In: Svarovsky L (ed) Solid-liquid separation, 3rd edn. Butterworth & Co., London

    Google Scholar 

  16. Maas Joseph H (1988) Gas-solid separations. In: Schweitzer PA (ed) Handbook of separation techniques for chemical engineers, 2nd edn. McGraw-Hill, New York

    Google Scholar 

  17. Osborne DG, Pierson HG (1999) Vacuum filtration. In: Svarovsky L (ed) Solid-liquid separation, 3rd edn. Butterworth & Co., London

    Google Scholar 

  18. Perry Robert H, Don WG (1997) Perry’s chemical engineers’ handbook, 7th edn. McGraw Hill, New York

    Google Scholar 

  19. Phelan M (2008) Focus on filtration. Chem Eng 8:53–54

    Google Scholar 

  20. Svarovsky L (1992) Pressure filtration. In: Svarovsky L (ed) Solid-liquid separation, 3rd edn. Butterworth & Co., London

    Google Scholar 

  21. Watson JHP (1990) High gradient magnetic separation. In: Svarovsky L (ed) Solid-liquid separation, 3rd edn. Butterworth & Co., London, pp 661–662

    Chapter  Google Scholar 

  22. Zievers JF (1998) Batch filtration. In: Schweitzer PA (ed) Handbook of separation techniques for chemical engineers, 2nd edn. McGraw-Hill, New York

    Google Scholar 

  23. Hill P et al (2007) Cell harvesting. Wiley, Boca Raton, FL, pp 305–330

    Google Scholar 

  24. Yigzaw (2006) Exploitation of the adsorptive properties of depth filters for host-cell protein removal during monoclonal antibody purification. Biotechnol Progr 22:288–296

    Article  CAS  Google Scholar 

  25. Susan R et al (2004) Bioanalytical chemistry, Ch. 13. In: Centrifugation methods. Wiley, Hoboken, NJ, pp 247–267

    Google Scholar 

  26. Basel RM et al (1983) Monitoring to use the present Method to distinguish between Live and microbial number in food by density centrifugation. Appl Environ Microbiol 45:1156–1159

    Google Scholar 

  27. Leung WW-F (1998) Industrial centrifugation technology. McGraw-Hill Education, New York. ISBN-13: 9780070371910

    Google Scholar 

  28. Ford TC, Graham JM (1991) An introduction to centrifugation. BIOS Scientific, Oxford. ISBN: 1 872748 40 6

    Google Scholar 

  29. Baldwin C, Robinson CW (1990) Disruption of Saccharomyces cerevisiae using enzymatic lysis combined with high-pressure homogenization. Biotechnol Tech 4:329–334

    Google Scholar 

  30. Kleinig AR, Middelberg APJ (1998) On the mechanism of microbial cell disruption in high-pressure homogenisation. Chem Eng Sci 53:891–898

    Article  CAS  Google Scholar 

  31. Dunnill P (1982) Biosafety in the large-scale isolation of intracellular microbial enzymes. Chem Ind 22:877–879

    Google Scholar 

  32. Cameron P, Hambleton P, Melling J. et al. (1987) Assessing the microbiological integrity of biotechnology equipment. In: Verrall MS, Hudson MJ. (Eds.): Separations for biotechnology, 490–496. Chichester: Ellis Horwood.

    Google Scholar 

  33. Engler CR, Robinson CW (1979) New method of measuring cell-wall rupture. Biotechnol Bioeng 21:1861–1869

    Article  CAS  Google Scholar 

  34. Middelberg APJ (1995) Process-scale disruption of microorganisms. Biotechnol Adv 13:491–551

    Article  CAS  PubMed  Google Scholar 

  35. Kleinig AR et al (1995) Influence of broth dilution on the disruption of Escherichia coli. Biotechnol Tech 9:759–762

    Article  CAS  Google Scholar 

  36. Hetherington PJ et al (1971) Release of protein from baker’s yeast (Saccharomyces cerevisiae) by disruption in an industrial homogeniser. Trans Instn Chem Engrs 49:142–148

    CAS  Google Scholar 

  37. Bailey JE, Ollis DF (1987) Biochemical engineering fundamentals, 2nd edn. McGraw-Hill, New York, NY

    Google Scholar 

  38. Naglak TJ et al (1990) Chemical permeabilization of cells for intracellular product release. In: Separation processes in biotechnology. Marcel Dekker, New York

    Google Scholar 

  39. Bulock J, Christiansen B (1989) Basic biotechnology. Academic Press, Cambridge, MA

    Google Scholar 

  40. Brookman J (1974) Mechanism of cell integration in high pressure homogenizer. Biotechnol Bioeng 16:371–383

    Article  Google Scholar 

  41. Felix H (1982) Cell disruption. Anal Biochem 107:207–214

    Google Scholar 

  42. Felix H (1982) Permeabilized cells. Anal Biochem 120:234

    Article  Google Scholar 

  43. Follows M et al (1971) Release of enzymes from Baker’s yeast by disruption in an industrial homogenizer. Biotechnol Bioeng 13:549–560

    Article  CAS  PubMed  Google Scholar 

  44. Ayazi Shamlou P et al (1995) A physical model of high-pressure disruption of Bakers’ yeast cells. Chem Eng Sci 13:83–1391

    Google Scholar 

  45. Wuytack EY et al (2002) Bacterial inactivation by high-pressure homogenisation and high hydrostatic pressure. Int J Food Microbiol 77:205–212

    Article  CAS  PubMed  Google Scholar 

  46. Stang M et al (2001) Emulsification in high-pressure homogenizers. Eng Life Sci 1:151–157

    Article  CAS  Google Scholar 

  47. Floury J et al (2003) Effect of high pressure homogenisation on methylcellulose as food emulsifier. J Food Eng 58:227–238

    Article  Google Scholar 

  48. Sanguansri P, Augustin MA (2006) Nanoscale materials development – a food industry perspective. Trends Food Sci Technol 17:547–556

    Article  CAS  Google Scholar 

  49. Cortés-Muñoz M et al (2009) Characteristics of submicron emulsions prepared by ultra-high pressure homogenisation: effect of chilled or frozen storage. Food Hydrocolloids 23:640–654

    Article  Google Scholar 

  50. Halim R et al (2012) Microalgal cell disruption for biofuel development. Appl Energy 91:116–121

    Article  CAS  Google Scholar 

  51. Marie P et al (2002) Influence of major parameters in emulsification mechanisms using a high-pressure jet. J Food Eng 53:43–51

    Article  Google Scholar 

  52. Cushen M et al (2011) Nanotechnologies in the food industry – recent developments, risks and regulation. Trends Food Sci Technol 24:30–46

    Article  Google Scholar 

  53. Ji Y et al (2011) Effect of heat treatments and homogenisation pressure on the acid gelation properties of recombined whole milk. Food Chem 129:463–471

    Article  CAS  Google Scholar 

  54. Masson LMP et al (2011) Effect of ultra-high pressure homogenization on viscosity and shear stress of fermented dairy beverage. LWT-Food Sci Technol 44:495–501

    Article  CAS  Google Scholar 

  55. Ciron CIE et al (2012) Modifying the microstructure of low-fat yoghurt by microfluidisation of milk at different pressures to enhance rheological and sensory properties. Food Chem 130:510–519

    Article  CAS  Google Scholar 

  56. Biasuttia M et al (2010) Rheological properties of model dairy emulsions as affected by high pressure homogenization. IFSET 11:580–586

    Google Scholar 

  57. Innocente N et al (2009) Effect of high-pressure homogenization on droplet size distribution and rheological properties of ice cream mixes. J Dairy Sci 92:1864–1875

    Article  CAS  PubMed  Google Scholar 

  58. Heffernan SP (2011) Efficiency of a range of homogenisation technologies in the emulsification and stabilization of cream liqueurs. Innov Food Sci Emerg Technol 12:628–634

    Article  CAS  Google Scholar 

  59. Schultz S et al (2004) High-pressure homogenization as a process for emulsion formation. Chem Eng Technol 27:361–368

    Article  CAS  Google Scholar 

  60. Naganagouda K, Mulimani VH (2008) Aqueous two-phase extraction (ATPE): an attractive and economically viable technology for downstream processing of Aspergillus oryzae [alpha]-galactosidase. Process Biochem 43:1293–1299

    Article  CAS  Google Scholar 

  61. Walter H, Johansson G (1995) Aqueous two-phase systems. Methods in enzymology, vol 24. Academic Press, New York

    Google Scholar 

  62. Veide A et al (1983) A process for large scale isolation of b-galactosidase from E. coli in an aqueous two-phase system. Biotechnol Bioeng 25:1789–1800

    Article  CAS  PubMed  Google Scholar 

  63. Van Berlo M (1998) Poly(ethylene glycol)-salt aqueous two-phase systems with easily recyclable volatile salts. J Chromatogr B Biomed Sci Appl 711:61–68

    Article  PubMed  Google Scholar 

  64. Belter PA et al (1988) Bioseparations: downstream processing for biotechnology. Wiley, New York

    Google Scholar 

  65. Ladisch MR (2001) Bioseparations engineering: principles, practice and economics. Wiley, New York

    Google Scholar 

  66. Klein E (1991) Affinity membranes: their chemistry and performance in adsorptive separation processes. Wiley, New York

    Google Scholar 

  67. Azarkan ME et al (2003) Fractionation and purification of the enzymes stored in the latex of Carica papaya. J Chromatogr B 790:229–238

    Article  CAS  Google Scholar 

  68. Benavides J, Rito-Palomares M (2008) Practical experiences from the development of aqueous two-phase processes for the recovery of high value biological products. J Chem Technol Biotechnol 83:133–142

    Article  CAS  Google Scholar 

  69. Cleland JL et al (1992) Polyethylene glycol enhanced refolding of bovine carbonic anhydrase B. Reaction stoichiometry and refolding model. J Biol Chem 267:13327–13334

    CAS  PubMed  Google Scholar 

  70. Nitsawang S et al (2006) Purification of papain from Carica papaya latex: aqueous two-phase extraction versus two-step salt precipitation. Enzyme Microbial Technol 39:1103–1107

    Article  CAS  Google Scholar 

  71. Vernau J, Kula MR (1990) Extraction of protein from biological raw material using aqueous (polyethylene) glycol-citrate. Biotechnol Appl Biochem 12:397–404

    CAS  Google Scholar 

  72. Adam F et al (2012) “Solvent-free” ultrasound-assisted extraction of lipids from fresh microalgae cells: a green, clean and scalable process. Bioresource Technology 114:457–465

    Article  CAS  PubMed  Google Scholar 

  73. Azmir J et al (2013) Techniques for extraction of bioactive compounds from plant materials: a review. J Food Eng 117:426–436

    Article  CAS  Google Scholar 

  74. Chavan Y, Singhal RS (2013) Ultrasound-assisted extraction (UAE) of bioactives from arecanut (Areca catechu L.) and optimization study using response surface methodology. Innov Food Sci Emerg Technol 17:106–113

    Article  CAS  Google Scholar 

  75. Herrero M et al (2013) Compressed fluids for the extraction of bioactive compounds. Trends Anal Chem 43:67–83

    Article  CAS  Google Scholar 

  76. Hidalgo D et al (2014) Integrated and sustainable system for multi-waste valorization. Environ Eng Manage J 13:2467–2475

    CAS  Google Scholar 

  77. Roseiro LB et al (2013) Supercritical, ultrasound and conventional extracts from carob (Ceratonia siliqua L.) biomass: effect on the phenolic profile and antiproliferative activity. Indus Crops Prod 47:132–138

    Article  CAS  Google Scholar 

  78. Li Y et al (2013) Solvent-free microwave extraction of bioactive compounds. Trends Anal Chem 47:1–11

    Article  Google Scholar 

  79. Mulder M (2012) Basic principles of membrane technology. Kluwer, Dordrecht

    Google Scholar 

  80. Jornitz MW (2006) Sterile filtration. Springer, Berlin. ISBN-10: 354028625X; ISBN-13: 9783540286257

  81. Van Reis R, Zydney A (2007) Bioprocess membrane technology. J Mem Sci 297:16–50

    Article  Google Scholar 

  82. Ripperger S, Schulz G (1986) Microporous membranes in biotechnical applications. Bioprocess Eng 1:43–49

    Article  CAS  Google Scholar 

  83. Melin T, Rautenbach R (2007) Membranverfahren. Springer, Berlin. ISBN 3-540-00071-2

    Google Scholar 

  84. Hostettmann K et al (1998) Preparative chromatography techniques applications in natural product isolation, 2nd edn. Springer, Berlin, p 50

    Book  Google Scholar 

  85. Ettre LS, Sakodynskii KI (1993) Discovery of chromatography II: Completion of the development of chromatography (1903–1910). Chromatographia 5–6:329–338

    Article  Google Scholar 

  86. Still WC et al (1978) Rapid chromatographic technique for preparative separations with moderate resolution. J Org Chem 43(14):2923–2925

    Google Scholar 

  87. Ettre LS (1993) Nomenclature for chromatography (IUPAC Recommendations 1993). Pure Appl Chem (4):819–872

    Google Scholar 

  88. Harwood Laurence M, Moody Christopher J (1989) Experimental organic chemistry: principles and practice (Illustrated edn). Wiley-Blackwell, Oxford, pp 180–185

    Google Scholar 

  89. Anfinsen Christian B, Tileston EJ, Middlebrook RF (eds) (1976) Advances in protein chemistry. pp 6–7

    Google Scholar 

  90. Paper chromatography. www.chemguide.co.uk

  91. Edwin H (2007) Vegetable tannins – lessons of a phytochemical lifetime. Phytochemistry 68:2713–2721

    Article  Google Scholar 

  92. Laurence M, Moody Christopher J (1989) Experimental organic chemistry: principles and practice (Illustrated edn). Wiley-Blackwell, Oxford, pp 180–185

    Google Scholar 

  93. Fair JD, Kormos CM (2008) Flash column chromatograms estimated from thin-layer chromatography data. J Chromatogr A 1211:49–54

    Article  CAS  PubMed  Google Scholar 

  94. Harrison RG et al (2003) Bioseparations science and engineering. Oxford University Press, New York, NY

    Google Scholar 

  95. Hage DS (1999) Affinity chromatography: a review of clinical applications. Clin Chem 45:593–615

    CAS  PubMed  Google Scholar 

  96. Lilly MD (1992) Biochemical engineering research: its contribution to the biological industries. Trans IchemE 70(C):3–7

    CAS  Google Scholar 

  97. Buckton G et al (2002) The effect of spray-drying feed temperature and subsequent crystallization conditions on the physical form of lactose. AAPS PharmSciTech 3:1–6

    Article  PubMed Central  Google Scholar 

  98. Gharsallaoui A et al (2007) Applications of spray-drying in microencapsulation of food ingredients: an overview. Food Res Int 40:1107–1121

    Article  CAS  Google Scholar 

  99. Gonnissen Y et al (2008) Coprocessing via spray drying as a formulation platform to improve the compactability of various drugs. Eur J Pharm Biopharm 69:320–334

    Article  CAS  PubMed  Google Scholar 

  100. Hanrahan FP, Webb BH (1961) USDA develops foam-spray drying. Food Eng 33:37–38

    Google Scholar 

  101. Jorge MCP, Filipe G (2004) Spray drying technology for better API crystals. Process Dev:38–39. www.sp2.uk.com

Download references

Author information

Authors and Affiliations

  1. Amity Institute of Microbial Technology, Amity University Uttar Pradesh, Noida, Uttar Pradesh, India

    Basanta Kumara Behera & Ajit Varma

Authors
  1. Basanta Kumara Behera
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ajit Varma
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

Copyright information

© 2017 Springer International Publishing AG

About this chapter

Cite this chapter

Kumara Behera, B., Varma, A. (2017). Downstream Processing. In: Microbial Biomass Process Technologies and Management. Springer, Cham. https://doi.org/10.1007/978-3-319-53913-3_3

Download citation

Publish with us

Policies and ethics

Search

Navigation