Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

In Situ Product Removal as a Tool for Bioprocessing

Abstract

In situ product removal (ISPR) is the fast removal of product from a producing cell thereby preventing its subsequent interference with cellular or medium components. Over the past 10 years ISPR techniques have developed substantially and its feasibility (with improvements in yield or productivity) for several processes demonstrated. Assessment of progress, however, compared to the potential benefits inherent in the ISPR approach to bioprocessing reveals that these are far from being exploited fully. Here we indicate future directions including application of the ISPR approach to a wider range of product groups and the development of novel, more specific ISPR methodologies, applicable under sterile conditions in the immediate vicinity of the producing cells. General guidelines for adaptation of an appropriate ISPR approach for a given product are also provided.

This is a preview of subscription content, access via your institution

Access options

Buy this article

Prices may be subject to local taxes which are calculated during checkout

Similar content being viewed by others

References

  1. Mattiasson, B. and Hoist, O. (Eds.). 1991. Extractive Bioconversions. Marcel Dekker Inc. N.Y.

  2. Roffler, S.R., Blanch, H.W. and Wilke, C.R. 1984. In situ recovery of fermentation products. Trends Biotechnol. 2: 129–36.

    CAS  Google Scholar 

  3. Mattiasson, B. and Larsson, M. 1985. Extractive bioconversions with emphasis on solvent production. Biotechnology and Genetic Engineering Reviews 3: 137–174.

    CAS  Google Scholar 

  4. Daugulis, A.J. 1988. Integrated reaction and product recovery in bioreactor systems. Biotechnol. Prog. 4: 113–122.

    CAS  Google Scholar 

  5. Szathmary, S. and Grandics, P. 1990. Bioreactor integration with downstream processing. Bio/Technology 8: 924–925.

    CAS  PubMed  Google Scholar 

  6. Wecker, M.S. and Zall, R.R. 1987. Fermentation strategies: acetaldehyde or ethanol? Process Biochem. 22: 135–138.

    CAS  Google Scholar 

  7. Nishri, Y. and Freeman, A. 1992. Continuous production of acetaldehyde by immobilized yeast with in situ product trapping: comparison of alcohol dehy-drogenase and alcohol oxidase routes. Appl. Biochem. Biotechnol. In press.

  8. Swartz, R.W. 1985. Penicillins, p. 8–47. In: Comprehensive Biotechnology, Vol. 3. Moo-Young, M. (Ed.). Pergamon, Oxford, UK.

    Google Scholar 

  9. Ingram, L.O. and Buttke, T.M. 1984. Effect of alcohols on microorganisms. Adv. Microb. Physiol. 25: 254–300.

    Google Scholar 

  10. Morcira, A.R., Ulmer, D.C. and Linden, J.C. 1981. Butanol toxicity in the butyric fermentation. Biotechnol. Bioeng. Symp. 11: 567–579, Wiley, N.Y.

    Google Scholar 

  11. Silbiger, E. and Freeman, A. 1991. Continuous 1-hydrocortisone dehydrogenation with in situ product recovery. Enzyme Microb. Technol. 13: 869–872.

    CAS  PubMed  Google Scholar 

  12. Nienow, A.W. 1990. Agitators for mycelial fermentations. Trends Biotechnol. 8: 224–233.

    CAS  Google Scholar 

  13. Lewis, V.P. and Yang, S.T. 1992. A novel extractive fermentation process for propionic acid production from whey lactose. Biotechnol. Prog. 8: 104–110.

    CAS  Google Scholar 

  14. Laane, C., Boeren, S., Hilhorst, R. and Veeger, C. 1987. Optimization of biocatalysis in organic media, p. 65–84. In: Biocatalysis in Organic Media. Laane, C, Tramper, J. and Lilly, M. D. (Eds.). Elsevier, Amsterdam.

    Google Scholar 

  15. Sandquist, J., Blanch, H.W. and Wilke, C.R. 1991. Vacuum fermentation, p. 237–258. In: Extractive Bioconversions. Mattiasson, B. and Hoist, O. (Eds.). Marcel Dekker, N.Y.

    Google Scholar 

  16. Groot, W.J., van der Lans, R.G.J.M. and Luyben, K.Ch.A.M. 1992. Technologies for butanol recovery integrated with fermentations. Process Biochem. 27: 61–75.

    CAS  Google Scholar 

  17. Strathmann, H. and Gudernatsch, W. 1991. Continuous removal of ethanol from bioreactor by pervaporation, p. 67–89. Ibid

  18. Roffler, S.R., Randolph, T.W., Miller, D.A., Blanch, H.W. and Prausnitz, J.M. 1991. Extractive bioconversions with nonaqueous solvents, p. 133–172. Ibid

  19. Kaul, R. and Mattiasson, B. 1991. Extractive bioconversions in aqueous two phase systems, p. 173–188. Ibid

  20. Belfort, G. 1989. Membranes and bioreactors: A technical challenge in biotechnology. Biotechnol. Bioeng. 33: 1047–1066.

    CAS  PubMed  Google Scholar 

  21. Chang, H.N. 1987. Membrane bioreactors. Biotech. Adv. 5: 129–145.

    CAS  Google Scholar 

  22. Holst, O. and Mattiasson, B. 1991. Cultivation using membrane filtration and cell recycling, p. 11–26. In: Extractive Bioconversions. op. it.

    Google Scholar 

  23. Linardos, T.I., Kalogerakis, N. and Behie, L.A. 1992. Monoclonal antibody production in dialyzed continuous suspension culture. Biotechnol. Bioeng. 39: 504–510

    CAS  PubMed  Google Scholar 

  24. Duff, S.J.B. and Murray, W.D. 1988. Production of flavor aldehydes using nongrowing whole cells of Pichia pastoris . Annal. N.Y. Acad. Sci. 542: 428–433.

    CAS  Google Scholar 

  25. Fujii, M. and Taniguchi, M. 1991. Application of reversibly soluble polymers in bioprocessing. Trends Biotechnol. 9: 191–196.

    CAS  PubMed  Google Scholar 

  26. Shity, H. and Bar, R. 1992. New approach for selective separation of dilute products from simulated Clostridial fermentation broths using cyclodextrins. Biotechnol. Bioeng. 39: 462–466.

    CAS  PubMed  Google Scholar 

  27. Hoist, O. and Mattiasson, B. 1991. Solid sorbents used in extractive bioconversion processes, p. 189–205. Extractive Bioconversions. op. cit.

    Google Scholar 

  28. Wang, H.Y. 1983. Integrating biochemical separation and purification steps in fermentation processes. Annal. N.Y. Acad. Sci. 413: 313–321.

    CAS  Google Scholar 

  29. Wang, H.Y., Palanki, S. and Hyatt, G.S. 1989. Application of affinity adsorption in thienamycin fermentation. App. Microbiol Biotechnol. 30: 115–119

    CAS  Google Scholar 

  30. Mitsuda, S., Matsuda Y., Kobayashi, N., Suzuki, A., Itagaki, Y., Kumazawa, E., Highashio, K. and Kawanishi, G. 1991. Tissue plasminogen activator (t-PA) production by human fibroblasts using a bioreactor with t-PA adsorption column. Bioprocess Eng. 7: 137–140

    CAS  Google Scholar 

  31. Matsumura, M. 1991. Perstraction, p. 91–131. In: Extractive Bioconversions. op. it.

    Google Scholar 

  32. Seevaratnam, S., Hoist, O., Hjöleifsdottir, S. and Mattiasson, B. Extractive bioconversion for lactic acid production using solid sorbent and organic solvent. Bioprocess Eng. 6: 35–41

  33. Shabtai Y., Chaimovitz, S., Freeman, A., Katchalski-Katzir, E., Linder, C., Nemas, M., Perry, M. and Kedem, O. 1991. Continuous ethanol production by immobilized yeast reactor coupled with membrane pervaporation unit. Biotechnol. Bioeng. 38: 869–876

    CAS  PubMed  Google Scholar 

  34. Yabannavar, V.M. and Wang, D.I.C. 1991. Strategies for reducing solvent toxicity in extractive fermentation. Biotechnol. Bioeng. 37: 716–722

    CAS  PubMed  Google Scholar 

  35. Friedl, A., Qureshi, N. and Maddox, I.S. 1991. Continous acetone-butanol-ethanol (ABE) fermentation using immobilized cells of Clostridium aceto-butylicum in a packed bed reactor and integration with product removal by pervaporation. Biotechnol. Bioeng. 38: 518–527

    CAS  PubMed  Google Scholar 

  36. Groot, W.J., Den Reyer, M.C.H., Baart de la Faille, T., van der Lans, R.G.J.M. and Luyben, K.Ch.A.M. 1991. Integration of pervaporation and continuous butanol fermentation with immobilized cells. Chem. Eng. J. 46: B1–B10.

    CAS  Google Scholar 

  37. Davison, B.H. and Scott, C.D. 1992. A proposed biparticle fluidized-bed for lactic acid fermentation and simultaneous adsorption. Biotechnol. Bioeng. 39: 365–368.

    CAS  PubMed  Google Scholar 

  38. Kobayashi, T. 1991. Integration of reaction with product recovery in bioreactor systems. Annal. N.Y. Acad. Sci. 613: 248–254

    Google Scholar 

  39. Roffler, S.R., Wilke, C.R. and Blanch, H.W. 1988. Design and mathematical description of differential contactors used in extractive fermentations. Biotechnol. Bioeng. 32: 192–204

    CAS  PubMed  Google Scholar 

  40. Park, C.H., Okos, M.R. and Wankat, P. 1991. Acetone butanol ethanol (ABE) fermentation and simultaneous separation in a trickled bed reactor. Biotechnol. Prog. 7: 185–194

    Google Scholar 

  41. Ennis, B.M., Quershi, N. and Maddox, I.S. 1987. In line toxic product removal during solvent production by continuous fermentation using immobilized Clostridium acetobutylicum . Enzyme Microb. Technol. 9: 672–675.

    CAS  Google Scholar 

  42. Matsumura, M., Takehara, S. and Kataoka, H. 1992. Continuous butanol/isopropanol fermentation in down-flow column reactor coupled with pervaporation using supported liquid membrane. Biotechnol. Bioeng. 39: 148–156

    CAS  PubMed  Google Scholar 

  43. Lopez, J.L., Matson, S.L., Stanley, T.J. and Quinn, J. 1991. Liquid-liquid extractive membrane reactors, p. 27–66. In: Extractive Bioconversions. op. it.

    Google Scholar 

  44. Shukla, R., Kang, W. and Sirkar, K.K. 1989. Acetone-butanol-ethanol (ABE) production in a novel hollow fiber fermentor-extractor. Biotechnol. Bioeng. 34: 1158–1166.

    CAS  PubMed  Google Scholar 

  45. Marques, P.S.S., Passarinho, P.C.L.V., Cabral, J.M.S., Novais, J.M. and Kennedy, J.F. 1989. Extractive fermentation of ethanol using entrapped and adsorbed Saccharomyces bayanus cells. Int. Ind. Biotechnol. 9: 20–24.

    CAS  Google Scholar 

  46. Busche, R.M. 1991. Extractive fermentation of acetic acid. App. Biochem Biotechnol. 28/29: 605–622.

    Google Scholar 

  47. Yabannavar, V.M. and Wang, D.I.C. 1991. Extractive fermentation for lactic acid production. Biotechnol. Bioeng. 37: 1095–1100.

    CAS  PubMed  Google Scholar 

  48. Leay, L., Eberhardt, J.J., Allen, B.R., Scott, C.D. and Davison, B.H. 1990. Improved production of ethanol and N-butanol in immobilized cell bioreactors, p. 539–543. In: Physiology of Immobilized Cells, de Bont, J. A. M., Visser, J., Mattiasson, B. and Tramper, J. (Eds.). Elsevier, Amsterdam.

    Google Scholar 

  49. Diaz, M. 1988. Three phase extractive fermentation. Trends Biotechnol. 6: 126–130.

    Google Scholar 

  50. Persson, I., Stalbrand, H., Tjreld, F. and Hahn-Hagerdal, B. 1991. Semicontinous production of cellulytic enzymes with Trichoderma reesei Rutgers C30 in an aqueous two phase system. Appl. Biochem. Biotechnol. 27: 37–43.

    Google Scholar 

  51. Kang, W., Shukla, R. and Sirkar, K.K. 1990. Ethanol production in a microporous hollow-fiber-based extractive fermentor with immobilized yeast. Biotechnol. Bioeng. 36: 826–833.

    CAS  PubMed  Google Scholar 

  52. Minier, M., Frateloup, R., Blanc-Ferras, E. and Goma, G. 1990. Extractive acetonobutylic fermentation by coupling ultrafiltration and distillation. Biotechnol. Bioeng. 35: 861–869.

    CAS  PubMed  Google Scholar 

  53. Nomura, Y., Iwahara, M. and Kongo, M. 1987. Acetic acid production by an electrodialysis fermentation method with a computerized control system. Appl. Environ. Microbiol. 54: 137–142.

    Google Scholar 

  54. Payne, G.F. and Wang, H.Y. 1989. The effect of feedback regulation and in situ product removal on the conversion of sugar to cycloheximide by Streptomyces griseus . Arch. Microbiol. 151: 331–335.

    CAS  Google Scholar 

  55. Groot, W.J. and Luyben, K., Ch, A.M. 1986. In situ product recovery by adsorption in the butanol/isopropanol batch fermentation. Appl. Microbiol. Biotechnol. 25: 29–31.

    CAS  Google Scholar 

  56. Asada, M. and Shuler, M.L. 1989. Stimulation of ajmalicine production and excretion from Cathamntus roseus: effects of adsorption in situ, elicitons and alginate immobilization. App. Microbiol. Biotechnol. 30: 475–481.

    CAS  Google Scholar 

  57. Takamatsu, S. and Ryu, D.D.Y. 1988. Recirculating bioreactor-separator system for simultaneous biotransformation and recovery of product: Immobilized L-aspartate β-decarboxylase reactor system. Biotechnol. Bioeng. 32: 184–191.

    CAS  PubMed  Google Scholar 

  58. Dykstra, K.H., Li, X.-M. and Wang, H.Y. 1988. Computer modeling of antibiotic fermentation with on-line product removal. Biotechnol. Bioeng. 32: 356–362.

    CAS  PubMed  Google Scholar 

  59. VanderWielen, L.A.M., Porters, J.J.M., Straathof, A.J.J. and Luyben, K.Ch.A.M. 1990. Integration of bioconversion and continuous product separation by means of countercurrent adsorption. Chem. Eng. Sci. 45: 2397–2404.

    CAS  Google Scholar 

  60. Davison, B.H. and Thompson, J.E. 1992. Simultaneous fermentation and separation of lactic acid in a biparticle fluidized-bed bioreactor. Appl. Biochem. Biotechnol. 34/35: 431–439.

    Google Scholar 

  61. Reschke, M. and Schugerl, K. 1986. Simulation of the continuous reactive extraction of penicillin G in a Karr column. Chem. Eng. J. 32: B1–B5.

    CAS  Google Scholar 

  62. Hecht, V., Vorlop, J., Kalbitz, H., Gerth, K. and Lehmann, J. 1987. Vortex chamber for in situ recovery of the antibiotic Myxovirescin A in continuous cultivation. Biotech. Bioeng. 24: 222–227.

    Google Scholar 

  63. Traeger, M., Buse, R., Mueller, U. and Onken, U. 1989. Non ionic surfactants as in situ extraction solvents for hydrophobic fermentation products. Dechema Biotechnol. Conf. 3(B): 1093–1096

    CAS  Google Scholar 

  64. Eiki, H., Gushima, H., Saito, T., Ishida, H., Oka, Y. and Osono, T. 1988. Product inhibition and its removal on josamycin fermentation by Streptomyces narbonensis var. josamyaticus . J. Ferment. Technol. 66: 559–565

    CAS  Google Scholar 

  65. Harvis, T.A.J., Reuben, B.G., Cox, D.J., Vaid, A.K. and Carvell, J. 1988. The cross flow filtration of an unstable beta lactam antibiotic fermentation broth. J. Chem. Technol. Biotechnol. 42: 19–30.

    Google Scholar 

  66. Holst, O., Kaul, R., Larsson, M. and Mattiasson, B. 1987. Integration of bioconversions and downstream processing: some model studies. Annal. N.Y. Acad. Sci. 506: 468–477.

    CAS  Google Scholar 

  67. Payne, G.F., Payne, N.N., Shuler, M.L. and Asada, M. 1988. In situ adsorption for enhanced alkaloid production by Catharanthus roseus. Biotechnol. Lett. 10: 187–192.

    CAS  Google Scholar 

  68. Robins, R.J., Parr, A.J. and Rhodes, J.C. 1988. The use of continuous product removal to influence the distribution and net production of alkaloids by cell cultures. Biochem. Soc. Trans. 16: 67–71.

    CAS  Google Scholar 

  69. Janssens, L., De Pooler, H.L., Schamp, N.M. and Vandamme, E.J. 1992. Production of flavours by microorganisms. Process Biochem. 27: 192–215.

    Google Scholar 

  70. Vandamme, E.J. 1992. Production of vitamins, coenzymes and related bio-chemicals by biotechnological processes. J. Chem. Tech. Biotechnol. 53: 313–327.

    CAS  Google Scholar 

  71. Belin, J.M., Bensoussan, M. and Serrano-Carreon, L. 1992. Microbial biosynthesis for the production of food flavours. Trends in Food Science and Technology 3: 11–14.

    CAS  Google Scholar 

  72. Schindler, J. 1982. Terpenoids by microbial fermentation. Ind. Eng. Chem. Prod. Res. Dev. 21: 537–539.

    CAS  Google Scholar 

  73. Charlwood, B.V., Charlwood, K.A. and Brown, J.T. 1987. The effect of product removal on the accumulation of monoterpenes in pelargonium cultures. Proc. 4th European Congress on Biotechnology 2: 444.

    Google Scholar 

  74. Maume, K.A. and Cheetham, P.S.J. 1991. The production of g-decalactone by fermentation of castor oil. Biocatalysis 5: 79–97.

    CAS  Google Scholar 

  75. De Wulf, O. and Thomart, P. 1989. Bioconversion of vanillin to vanillyl alcohol in a two phase reactor. App. Biochem. Biotechnol. 20/21: 165–180.

    Google Scholar 

  76. Evans, P.J. and Wang, H.Y. 1984. Pigment production from immobilized Monascus sp. utilising polymeric resin adsorption. Appl. Environ. Microbiol. 47: 1323–1326.

    CAS  PubMed  PubMed Central  Google Scholar 

  77. Robins, R.J. and Rhodes, M.J.C. 1986. The stimulation of anthraquinone production by Cinchona ledgeriana cultures with polymeric adsorbents. Appl. Microbiol. Biotechnol. 24: 35–41.

    CAS  Google Scholar 

  78. Andersson, E., Johansson, A.C. and Hahn-Hagerdal, B. 1985. α-Amylase production in aqueous two phase systems with Bacillus subtilis . Enzyme Microb. Technol. 7: 333–338.

    CAS  Google Scholar 

  79. Park, K.M. and Wang, N.S. 1991. Alpha amylase fennentation with Bacillus amyloliquefaciens in aqueous two phase system. Biotechnol. Prog. 7: 439–444.

    CAS  Google Scholar 

  80. Persson, I., Tjerneld, F. and Hahn-Hagerdal, B. 1984. Semicontinuous cellulase production in an aqueous two-phase system with Trichoderma reesei Rutgers C30. Enzyme Microb. Technol. 6: 415–418.

    CAS  Google Scholar 

  81. Hu, W.S., Scholz, M.T., Favre, E. and Seamens, T.C. 1991. A new look at animal cell bioreactor development, p. 370–378. In: Production of Biologicals from Animal Cells in Culture. Spier, R., Griffiths, J. B. and Meignier, B (Eds.). Butterworth, Oxford

    Google Scholar 

  82. Propst, C.L., Von Wedel, R.J. and Lubiniecki, A.S. 1989. Using mammalian cells to produce products, p. 221–276. In: Fermentation Process Development of Industrial Organisms. Neway, J. O. (Ed.). Marcel Dekker, N.Y.

    Google Scholar 

  83. Ehnstrom, L., Frisenfelt, J. and Danielsson, M. 1991. The biostil process, p. 303–321. In: Extractive Bioconversions. op. it.

    Google Scholar 

  84. Woodley, J.M. and Lilly, M.D. 1992. Process engineering of two-liquid phase biocatalysist, p. 147–154. In: Biocatalysis in Non-conventional Media. Tramper, J., Vermue, M. H., Beeftink, H. H. and von Stockar, U. (Eds.). Elsevier, Amsterdam.

    Google Scholar 

  85. Harrop, A.J., Woodley, J.M. and Lilly, M.D. 1992. Production of naphthalene-cis-glycol by Pseudomonas putida in the presence of organic solvents. Enzyme Microb. Technol. 14: 725–730.

    CAS  Google Scholar 

  86. Bruce, L.J. and Daugulis, A.J. 1991. Solvent selection strategies for extractive biocatalysis. Biotechnol. Prog. 7: 116–124.

    CAS  PubMed  Google Scholar 

  87. Honda, H., Mano, T., Taya, M., Shimizu, K., Matsubara, M. and Kobayashi, T. 1987. A general framework for the assessment of extractive fermentations. Chem. Eng. Sci. 42: 493–498.

    CAS  Google Scholar 

  88. Daugulis, A.J., Axford, D.B. and McLellan, P.J. 1991. The economics of ethanol production by extractive fermentation. Canad. J. Chem. Eng. 69: 488–497.

    CAS  Google Scholar 

  89. Roffler, S., Blanch, H.W. and Wilke, C.R. 1987. Extractive fermentation of acetone and butanol: process design and economic evaluation. Biotechnol. Prog. 3: 131–140.

    CAS  Google Scholar 

  90. Woodley, J.M. and Lilly, M.D. 1990. Extractive biocatalysis: the use of two-liquid phase biocatalytic reactors to assist product recovery. Chem. Eng. Sci. 45: 2391–2396.

    CAS  Google Scholar 

  91. Eckert, F. and Schugerl, K. 1987. Continuous acetone butanol fermentation with direct product removal. Chem. Eng. Tech. 59: 958–959.

    Google Scholar 

  92. Hustedt, H., Menge, U. and Kula, M.R. 1985. Protein recovery using two phase systems. Trends in Biotechnol. 3: 139–144.

    CAS  Google Scholar 

  93. Mattiasson, B. and Ling, T.G.I. 1987. Extraction in aqueous two-phase systems for biotechnology, p. 270–292. In: Separations for Biotechnology. Verrall, M. S. and Hudson, M. J. (Eds.). Ellis Horwood, Chichester.

    Google Scholar 

  94. Belfort, G. 1987. Membrane separation technology: An overview, p. 239–297. In: Advanced biochemical engineering. Bungay, H. R. and Belfort, G. (Eds.). Wiley, N.Y.

    Google Scholar 

  95. Taya, M., Ishic, S. and Kobayashi, T. 1985. Monitoring and control for extractive fermentation of Clostridium acetobutylicum . J. Ferment. Technol. 63: 181–187.

    CAS  Google Scholar 

  96. Kita, A., Tone, H., Ishikura, T. and Ozaki, A. 1968. Microbiol production of salicylic acid from naphthalene. II. Product inhibitory kinetics and effects of product removal on the fermentation. J. Ferment. Technol. 46: 442–451.

    Google Scholar 

  97. Groot, W.J., van der Lans, R.G.J.M. and Luyben, K.Ch.A.M. 1989. Batch and continuous butanol fermentations with free cells: integration with product recovery by gas stripping. App. Microbiol. Biotechnol. 32: 305–308.

    CAS  Google Scholar 

  98. Drawert, F. and Barton, H. 1978. Biosynthesis of flavour compounds by microorganisms. III. Production of monoterpenes by the yeast Kluyveromyces lactis . J. Agric. Food Chem. 26: 765–766.

    CAS  Google Scholar 

  99. Hock, R., Benda, I. and Schreier, P. 1984. Formation of terpenes by yeast during alcoholic fermentation. Z. Lebens. Unter. Fors. 179: 450–452.

    CAS  Google Scholar 

  100. Jourdain, N., Goli, T., Jallageas, J.C., Crouzet, C., Ghommidh Ch Navarro, J.M. and Crouzet, J. 1985. Aroma components production by immobilized cells, p. 427–441. In: Topics in Bioflavor Research. Berger, R. G., Nitz, S. and Schreier, P. (Eds.). Eichorn, Marzling, F. R. G.

    Google Scholar 

  101. Georgiou, G., Lin, S.C. and Sharma, M.M. 1992. Surface-active compounds from microorganisms. Bio/Technology 10: 60–65.

    CAS  PubMed  Google Scholar 

  102. Arnold, F.H. 1991. Metal affinity separations: a new dimension in protein processing. Bio/Technology 9: 151–156.

    CAS  PubMed  Google Scholar 

  103. Szlag, D.C., Giuliano, K.A. and Snyder, S.M. 1990. A low cost aqueous two phase system for affinity extraction. ACS Symp. Ser. 419: 71–86.

    Google Scholar 

  104. Dall-Bauman, L. and Ivory, C.F. 1990. Protein separation via affinity-mediated membrane transport. ACS Symp. Ser. 419: 188–211.

    Google Scholar 

  105. Whitesides, G. 1983. Magnetic separation in biotechnology. Trends Biotechnol. 1: 144–148.

    Google Scholar 

  106. Ekberg, B. and Mosbach, K. 1989. Molecular imprinting: a technique for producing specific separation materials. Trends Biotechnol. 7: 92–96.

    CAS  Google Scholar 

  107. Yarmush, M.L., Antonsen, K.P., Sundaram, S. and Yarmush, D.M. 1992. Immunoadsorption: Strategies for antigen elution and production of reusable adsorbents. Biotechnol. Prog. 8: 168–178.

    CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Freeman, A., Woodley, J. & Lilly, M. In Situ Product Removal as a Tool for Bioprocessing. Nat Biotechnol 11, 1007–1012 (1993). https://doi.org/10.1038/nbt0993-1007

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nbt0993-1007

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing