Team Leader (DSP)

Prof. Dr. Michael Wolff
Prof. Dr. Michael Wolff

Profile

Universitätsplatz 2, Gebäude 25, 39106 Magdeburg, Germany

Team (DSP)

Pavel Marichal-Gallardo, M. Sc.
Pavel Marichal-Gallardo, M. Sc.
Phone: +49 391 67 546 79
Fax: +49 391 6110 500
Room: G25-118
Anja Bastian
Technical Assistant
Phone: +49 391 67 546 70
Room: G25-123

Additional Information

Collaborations with industry:

  • BIA Separations Inc.
  • EMC microcollections GmbH
  • IDT Biologika GmbH
  • Merckle Biotec GmbH
  • Novartis Vaccines and Diagnostics GmbH & Co. KG
  • Sartorius Stedim Biotech GmbH
  • Sentinext Therapeutics Sdn Bhd
  • Tosoh Bioscience LLC

Collaborations with academia:

  • Federal University of Rio de Janeiro, Rio de Janeiro, Brazil; Chemical Engineering Program Cell Culture Engineering Laboratory (Prof. Dr. Leda dos Reis Castilho)
  • Karlsruhe Institute of Technology, Karlsruhe; Biomolecular Separation Engineering (Prof. Dr. Jürgen Hubbuch)
  • Max Planck Institute for Dynamics of Complex Technical Systems, Magdeburg, Germany; Physical and Chemical Foundations of Process Engineering Group (Prof. Dr.-Ing. Andreas Seidel-Morgenstern)
  • Max Planck Institute for Dynamics of Complex Technical Systems, Magdeburg, Germany; Physical and Chemical Process Engineering Group (Prof. Dr.-Ing. Kai Sundmacher)

Downstream Processing

Header image 1377693701

Downstream Processing

Motivation

The production of recombinant proteins and vaccines is a rapidly growing field in biotechnological industry. Manufacturing of biologicals is a complex task ranging from strain development and upstream processing to the purification and formulation of the product. At the beginning of the biotechnology era, product concentrations in bioreactors were within the mg per liter range. Currently, yields of up to 10 g per liter of fermenter harvest are obtained in monoclonal antibody production. These achievements have been mainly accomplished by the use of high expression cell lines, media optimization, and an increase in cell numbers using appropriate cultivation conditions. However, while bioreactor yields were improved significantly, optimization of downstream processing was often neglected and now constitutes a bottleneck in various manufacturing processes.

Downstream processing often accounts for the major part of production costs of (bio)pharmaceuticals. This is mainly due to the high demands on purity, removal of contaminants, and product safety. In order to develop efficient downstream processes it is not only necessary to improve existing purification methods and to introduce new unit operations but also to reconsider complete downstream processing trains.

Currently, our research group focuses on the development of novel platform technologies for the purification of virus particles (influenza virus, vaccinia virus, flaviviruses), viral vectors, virus like particles and pharmaceutically relevant glycoproteins (e.g. erytropoetin, factor VIII). Furthermore, we investigate the aggregation behavior of macromolecular biological components and virus particles. An overview of the different activities is given below.

Fig.1. Current downstream processing activities at BPE Zoom Image
Fig.1. Current downstream processing activities at BPE

Example Influenza Vaccines

Our work on downstream processing of influenza virus aims at the exploration and development of a purification process for cell culture-derived vaccines. Unit operations like ultrafiltration, size-exclusion, ion-exchange, affinity, steric exclusion, and hydrophobic interaction chromatography are combined to an overall process train. To improve performance and productivity of the DSP we focus on the use of modern resins, membrane adsorbers, and monoliths as well as continuous methods like simulated moving bed chromatography.

Fig. 2 Options for downstream processing in influenza vaccine manufacturing Zoom Image
Fig. 2 Options for downstream processing in influenza vaccine manufacturing

References

1.
Fischer, L. M.; Wolff, M. W.; Reichl, U.: Purification of cell culture-derived influenza A virus via continuous anion exchange chromatography on monoliths. Vaccine 36 (22), pp. 3153 - 3160 (2018)
2.
Fortuna, A. R.; Taft, F.; Villain, L.; Wolff, M. W.; Reichl, U.: Optimization of cell culture-derived influenza A virus particles purification using sulfated cellulose membrane adsorbers. Engineering in Life Sciences 18 (1), pp. 29 - 39 (2018)
3.
Carvalho, S. B.; Fortuna, A. R.; Wolff, M. W.; Peixoto, C.; Alves, P. M.; Reichl, U.; Carrondo, M. J. T.: Purification of influenza virus-like particles using sulfated cellulose membrane adsorbers. Journal of Chemical Technology and Biotechnology 93 (7), pp. 1988 - 1996 (2018)
4.
Hämmerling, F.; Pieler, M.; Hennig, R.; Serve, A.; Rapp, E.; Wolff, M. W.; Reichl, U.; Hubbuch, J.: Influence of the production system on the surface properties of influenza A virus particles. Engineering in Life Sciences 17 (10), pp. 1071 - 1077 (2017)
5.
Marichal-Gallardo, P.; Pieler, M.; Wolff, M. W.; Reichl, U.: Steric exclusion chromatography for purification of cell culture-derived influenza A virus using regenerated cellulose membranes and polyethylene glycol. Journal of Chromatography A 1483 (3), pp. 110 - 119 (2017)
6.
Pieler, M.; Heyse, A.; Wolff, M. W.; Reichl, U.: Specific ion effects on the particle size distributions of cell culture–derived influenza A virus particles within the Hofmeister series. Engineering in Life Sciences 17 (5), pp. 470 - 478 (2017)
7.
Pieler, M.; Frentzel, S.; Bruder , D.; Wolff, M. W.; Reichl, U.: A cell culture-derived whole virus influenza A vaccine based on magnetic sulfated cellulose particles confers protection in mice against lethal influenza A virus infection. Vaccine 34 (50), pp. 6367 - 6374 (2016)
8.
Wang, W.; Voigt, A.; Wolff, M. W.; Reichl, U.; Sundmacher, K.: Binding kinetics and multi-bond: Finding correlations by synthesizing interactions between ligand-coated bionanoparticles and receptor surfaces. Analytical Biochemistry 505, pp. 8 - 17 (2016)
9.
Weigel, T.; Solomaier, T.; Wehmeyer, S.; Peuker, A.; Wolff, M. W.; Reichl, U.: A membrane-based purification process for cell culture-derived influenza A virus. Journal of Biotechnology 220, pp. 12 - 20 (2016)
10.
Wolff, M. W., Pieler, M. M., Marichal-Gallardo, P., Reichl, U.
Method for the separation of virus compositions including depletion and purification thereof.
11.
Serve, A.; Pieler, M.; Benndorf, D.; Rapp, E.; Wolff, M. W.; Reichl, U.: Comparison of Influenza Virus Particle Purification Using Magnetic Sulfated Cellulose Particles with an Established Centrifugation Method for Analytics. Analytical Chemistry 87 (21), pp. 10708 - 10711 (2015)
12.
Weigel, T.; Solomaier, T.; Peuker, A.; Pathapati, T.; Wolff, M. W.; Reichl, U.: A flow-through chromatography process for influenza A and B virus purification. Journal of Virological Methods 207, pp. 45 - 53 (2014)
13.
Kröber, T.; Wolff, M. W.; Hundt, B.; Seidel-Morgenstern, A.; Reichl, U.: Continuous purification of influenza virus using simulated moving bed chromatography. Journal of Chromatography A 1307, pp. 99 - 110 (2013)
14.
Wolff, M. W., Opitz, L., Reichl, U.
Method for the preparation of sulfated cellulose mebranes and sulfated cellulose membranes.
15.
Post-Hansen, S., Faber, R., Reichl, U., Wolff, M. W., Gram, A. P.
Purification of Vaccinia viruses using hydrophobic interaction chromatography.
16.
Wolff, M.; Siewert, C.; Hansen, S. P.; Faber, R.; Reichl, U.: Purification of cell culture-derived modified Vaccinia Ankara virus by pseudo-affinity membrane adsorbers and hydrophobic interaction chromatography. Biotechnology and Bioengineering 107 (2), pp. 312 - 320 (2010)
17.
Wolff, M.; Siewert, C.; Lehmann, S.; Hansen, S.P.; Djurup, R.; Faber, R.; Reichl, U.: Capturing of Cell Culture-Derived Modified Vaccinia Ankara Virus by Ion Exchange and Pseudo-Affinity Membrane Adsorbers. Biotechnology and Bioengineering 105 (4), pp. 761 - 769 (2010)

 
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