SCIENTIFIC FOUNDATION

Wagner, Michael R., et al. (2026)

together with: TU Graz, RCPE, Takeda

Mixing of miscible liquids is an essential process in multiple industrial settings, usually with the intent to homogenize the product. This seemingly simple process is in fact a complex hydrodynamic problem that has a direct impact on the product quality. In this study, numerical simulations of a stirred tank were performed with a 50/50 ratio of liquids and systematically varied the Reynolds and Richardson numbers. A positive correlation between the mixing time and the Richardson number was observed, as reported in the literature. The influence of the Reynolds number was not as pronounced and clear. Based on the Power, Froude and Richardson numbers, we were able to derive an exponential scaling for the dimensionless mixing time that collapsed all our data onto one master curve.

Wagner, Michael R., et al. (2026)

together with: TU Graz, RCPE, Takeda

The immortalized NK-92 cell line is widely used to study natural killer (NK) cell biology and develop immunotherapies. NK-92 cells exhibit strong cytotoxic activity against tumor and virus-infected cells and are often used as a functional surrogate for primary NK cells. Beyond research applications, NK-92 cells are currently being evaluated in clinical trials as an allogeneic, off-the-shelf cell therapy. NK cells are typically cultured in static systems, which limits scalability. For clinical and commercial applications, large-scale cell expansion requires scalable platforms, such as bioreactors. However, conventional bubble-aerated bioreactors generate shear stress and foam, which can impair proliferation during prolonged culture and compromise cell quality. To address these limitations, a membrane-based stirring and aeration system was compared to a conventional pitched-blade impeller with microsparger aeration in 2 L stirred-tank bioreactors. NK-92 cells were expanded from static pre-cultures into shake flasks and subsequently inoculated into each bioreactor with continuous feeding to maintain ideal nutrient supply. Both systems supported comparable growth, viability, and metabolic profiles. Cells showed comparable growth, viability and metabolism profile in both systems. However, cells expanded in the membrane-based system exhibited markedly higher cytotoxicity and cytotoxic capacity. Computational fluid dynamic simulations of both systems suggest that this observation is likely attributable to the more homogeneous shear distribution in the membrane-stirred setup compared to the pitched-blade configuration. Overall, this work presents a novel cultivation method to produce highly cytotoxic NK-92 cells in a well scalable stirred-tank bioreactor platform for allogeneic off-the-shelf cell therapy.

Brauneck, Gesa, et al. (2026)

together with: TBA

Filamentous microorganisms exhibit complex morphologies that influence product formation and are affected by various bioprocess parameters. Consistent morphology is therefore essential for comparable results during scale-up. This study investigates the scale-up of Streptomyces species (Streptomyces spp.) cultivations from shake flasks to stirred-tank reactors while maintaining comparable morphology. Shake flask cultivations demonstrated that variations in hydromechanical stress, quantified by the energy dissipation rate, strongly affect the morphology of Streptomyces spp., confirming its relevance for scale-up. A scale-up based on the average energy dissipation rate led to altered morphology. Alternatively, the maximum energy dissipation rate was investigated, as it reflects hydromechanical stress more accurately. Since prior determination or measurement is unfeasible, computational fluid dynamics (CFD) simulations were applied for systematic quantification. Scale-up based on these simulations resulted in improved morphological consistency across scales, suggesting a new scale-up parameter. To overcome oxygen limitations, pure oxygen aeration was implemented, further enhancing morphological comparability.

Bernauer, Sören, et al. (2022)

together with: TBA

In high-performance industrial fermentation processes, stirring and aeration may account for significant production costs. Compared to the widely applied Rushton impellers, axial-pumping impellers are known to yield a lower power draw and at the same time improve mixing. However, their lower gas dispersion capability requires stronger agitation, compromising these benefits. Diverse advanced impeller forms have been developed to cope with this challenge. We apply alternating radial and axial impellers and demonstrate strong gas dispersion and energy-efficient mixing for the first time in a large-scale (160 m3) bioreactor, based on experimental and computational fluid dynamics simulation data. For equal operating conditions (stirrer speed, aeration rate), this setup yielded similar gas hold-ups and better mixing times (35%) compared to a classical Rushton-only configuration. Hence, applying a radial impeller on an upper level for improving gas dispersion maintains the benefits of axial impellers in terms of reducing energy demand (up to 50%). We conclude that this effect is significant only at large-scale, when bubbles substantially expand due to the release of the hydrostatic pressure and have time to coalesce. The work thus extends current knowledge on mixing and aeration of large-scale reactors using classical impeller types.

Eibl, Philipp, et al. (2020)

together with: TU Graz, RCPE

Studying the hydrodynamics in industrial stirred tanks via Computational Fluid Dynamics has gained a lot of attention in recent years, since the increasing computational capacities allow for sophisticated numerical simulations for a lot of engineering applications. Modern graphic cards are extensively developed for parallel calculations for scientific purposes. As a highly parallelizable algorithm, the lattice Boltzmann method has been applied successfully for efficient calculation of single-phase, as well as multiphase simulations in various flavors. A Lagrangian approach for the calculation of the gas phase in industrial bioreactors, specifically stirred tanks, is presented on top of the standard lattice Boltzmann method with the BGK collision operator for single phase flow. Different fluid phase boundary conditions are compared to model the moving walls inside the bioreactor, e.g., the stirrer blades. Turbulence is modeled with the Large Eddy Simulation approach. Production scale reactors may range up to several hundred cubic meters with internal structures such as heat exchanger bundles inside the fluid domain, therefore the size of individual tubes can be significantly smaller than the vessel diameter. In order to resolve the exact fluid flow field around these tubes the resolution must be significantly higher than in the bulk of the fluid. Increasing the resolution in the whole domain makes the simulation unfeasible due to the higher computational cost. Alternatively, local grid refinement can be applied or, if the exact flow inside the tube bundle is of minor interest, a porous media model can be applied that recovers the correct flow around the tube bundles. In order to correctly predict the fluid flow field with the porous media approach the flow rate and pressure gradient through the modeled porous zone must be known prior to the full-scale simulation. Modeling the distribution of soluble species in the liquid phase is crucial for the simulation of mixing times in stirred tank reactors. Therefore, a mass conserving and stable LBM-approach, recently presented by Osmanlic and Körner (2016) is applied for the simulation of advective transport. This approach does not produce unphysical oscillations, only models advective transport and is therefore applied in the case of high Peclet numbers where diffusion is negligible. For the simulation of thermal energy distribution inside stirred tanks, the transport model of Osmanlic is adapted and studied extensively regarding numerical diffusion.

Witz, Christian, et al. (2016)

together with: TU Graz, RCPE, Sandoz GmbH

To date, the efficiency of industrial-size bioreactors has mainly been improved based on empirical knowledge. Computer simulation may help to understand the processes that occur inside the reactor and to develop new reactor designs. Euler-Lagrange simulations of the two-phase flow in large bioreactors, which could not be performed within a timeframe suitable for engineering purposes due to the limited computation resources, were made possible by the calculation power of graphic cards. The lattice Boltzmann method is well suited for parallelization which makes it ideal for calculating the fluid field inside a reactor driven by multiple Rushton turbines on graphic processing units. The bubble movements were captured via a Lagrangian approach by solving the Newton's equations of motion. A two-way coupling between the disperse and continuous phases was applied. Break up and coalescence of the bubbles were modeled via stochastic algorithms using the approach rate of small turbulent eddies and the comparison of the contact time and film breakage time, respectively. To gather experimental data, a conductivity sensor was used to measure the local gas holdup. The rate and the duration of current drops were recorded to estimate the bubble size and the void fraction around the sensor's tip position. The sensor was used in a 150l custom-built acrylic reactor. Several flow regimes with varying gas flow rates and stirrer speeds were investigated. The experimental results were in good agreement with the simulation data, especially at low stirring and low aeration rates. To prove the applicability of the code to large-scale problems, a 40 m3 reactor was simulated.