(52b) Product Quality Control of Monoclonal Antibodies By Integrated Continuous Manufacturing

The recent improvements of continuous up- and downstream processes in the production of therapeutic proteins suggest their final integration to a single process stream. The physical integration on the upstream production with a downstream capture has previously been reported¹. Besides general benefits of continuous manufacturing, such as reduced equipment size, enhanced cost efficiency and high volumetric productivity, the steady state operation favors constant or even improved product quality.

The primary modulation of quality attributes is dependent on the culture conditions of the production bioreactor². The persistent removal of waste metabolites in continuous culture supports the consistent product glycosylation as well as charge variances, affecting the therapeutic efficacy of secreted antibodies. Attaching previously in-group developed (semi-)continuous chromatography steps, utilizing both capture and purification are able to further narrow or modify the product homogeneity.

In the development towards an integrated process, a perfusion culture has been set up employing two different filter-based cell retention devices, namely tangential flow filtration (TFF) and alternating tangential flow filtration (ATF), to achieve stable cultivation of mammalian cells. Operating conditions are set according to a thorough characterization in terms of key process parameters and aiming at the connection to the subsequent capture and purification step.

In contrast to previous work, the product quality data from different continuous production setups is compared, including the impact of different operation parameters. Contrary to batch and fed-batch processes, product quality is resolved in time. The control and monitoring of the perfusion culture as well as the adaption of subsequent downstream processes will be shown.

Literature:

1.   V. Warikoo et al., Biotechnology and bioengineering 109, 3018–29 (2012).

2.   P. Hossler, S. F. Khattak, Z. J. Li, Glycobiology 19, 936–49 (2009).