Towards advanced understanding of scale-up: From computational fluid dynamics to systems biotechnology approaches

Conference Dates

May 6-11, 2018


Scale-up of mammalian cell culture processes from development scale to commercial manufacturing scale is routinely performed in biopharmaceutical process development. For this purpose, well established biochemical engineering principles, empirical formula and scale-up criteria were developed. Considering well characterized equipment as well as company specific process and platform knowledge, scale-up typically is successfully achieved. Yet, improved understanding of scale-up phenomena is desirable for various reasons.

Since miniaturized systems are increasingly used in biopharmaceutical process development and, at the same time, efforts with respect to resources and timelines to achieve final manufacturing scale are to be minimized, scale-up steps need to cope with larger bioreactor volume changes in the future. From a process science perspective, an integrated analysis of scale-up phenomena considering both the biochemical engineering aspects (e.g. power input, kLa) as well as cell-level data is needed.

In order to gain more profound understanding of scale-up, comprehensive characterization of our cultivation systems using computational fluid dynamics (CFD) was achieved (Figure 1). To further improve and integrate the understanding of an antibody producing CHO cell in a bioreactor environment across scales, we performed thorough analysis of metabolic rates and fluxes in different cultivation scales. In addition, gene expression data using NGS were obtained (Figure 2).

We designed a new method for preparation of liquid marbles by using hydrophilic particles [1] (Fig.1). Salt-hydrogel marbles were prepared by atomising droplets of hydrogel solution in a cold air column followed by rolling of the collected hydrogel microbeads in a bed of micrometre size salt particles. Evaporation of the water from the resulting salt marbles with a hydrogel core yielded hollow-shell salt microcapsules. The method is not limited to hydrophilic particles and could potentially be also applied to other materials, such as graphite, carbon, silica and others. The structure and morphology of the salt-hydrogel marbles were analysed with SEM and their particle size distributions were measured. We also tested the dissolution times of the dried salt marbles compared them to these for table salt samples at the same conditions. The high accessible surface area of the shell of salt microcrystals allows a faster initial release of salt from the hollow-shell salt capsules upon their dissolution in water than from the same amount of table salt. The results suggest that such hollow-shell particles could find applications as a table salt substitute in dry food products and salt seasoning formulations with reduced salt content without the loss of saltiness.

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