New Downstream Processing Technology for Monoclonal Antibodies

The global market for monoclonal antibody drugs is estimated at expected to reach nearly 140 billion USD within the next 7 years. To keep up with market demand many big biopharma companies have invested in large production plants operating standardized platform processes, but with the passing of time the need to reduce costs incurred in production becomes more pressing, driven by rising markets for personalised medicines, growing adoption of single use disposable technologies, competition from smaller, leaner and more flexible production facilities, and the certain knowledge that new bioseparation technologies with the potential to significantly boost productivity are emerging.

Against the above, this collaborative PhD project between the University of Birmingham (Prof O.R.T. Thomas), Karlsruhe’s Institute of Technology (Prof M. Franzreb) and University College London (Prof D.G. Bracewell) concerns the advance of two powerful separation techniques for the capture and purification of mAbs, namely high-gradient magnetic fishing (HGMF) and continuous travelling heating zone reactor (THZR) chromatography, each promising substantial improvements in productivity over current bench marks methods, but addressing quite different bioprocess challenges.

HGMF, the more advanced of the two in terms of technical readiness, is a scaleable technique affording fast and efficient isolation of protein products from complex dirty (i.e. unclarified) bioprocess feedstocks and facile integration in fermentation processes for in situ product removal (ISPR). The process of HGMF combines rapid initial adsorption of a product of interest on to customised magnetic particles, with subsequent retrieval and processing of the product-laden magnetic support by means of high-gradient magnetic separation (HGMS) technology. HGMF has advanced to point where: established vendors of chromatography materials are now able to supply large quantities of high-capacity magnetic media for trialling HGMF; and automated ‘state-of-the-art’ ‘rotor-stator’ high-gradient magnetic separators for bioprocessing are now commercially available in cGMP compliant form.

There is strong interest in employing continuous chromatography for monoclonal antibody capture and purification. Though impressive cost and productivity savings have been reported ‘core problems’ persist, namely the use of large volumes of buffer for equilibrating, washing, eluting and cleaning of columns, generating as a consequence excessive quantities of waste. Moreover, the harsh low pH elution conditions typically employed to desorb mAb from Protein A/ G affinity columns can significant impair mAb structure and functionality and induce binding polyreactivity to foreign antigens. Effective solutions to these significant problems have not yet been forthcoming, but would clearly make for leaner, greener and more sustainable manufacturing of mAbs and other valuable bioproducts. In this context we recently introduced a new scaleable continuous chromatography format ‘Travelling Cooling/Heating Zone Reactor (TCZR/THZR) Chromatography’ employing a single column operated isocratically. In TCZR/THZR chromatography discrete ‘local’ changes in temperature are used to control adsorption–desorption equilibria; this is achieved through combined use of thermoresponsive chromatographic supports and a novel device that permits continuous thermally mediated desorption from the support

In this project the researcher shall focus his/her effort on:
(i) evaluating HGMF for initial capture and purification of mAb from unclarified high titre CHO culture broths employing high-capacity rProtein A linked magnetic adsorbents and a rotor-stator magnetic separator; and
(ii) exploring continuous THZR chromatography for the purification of mAbs from clarified CHO culture supernatants using a commercially available thermoresponsive rProtein A chromatography matrix.

The ideal candidate combines a deep interest in the separation challenges facing the manufacture of emerging biopharmaceuticals, willingness to learn all aspects of the project, possesses good communication, numeracy and team working skills, and an ability to write clearly and succinctly.