MODEL SETUP
The key to a successful CFD analysis of a bioprocess is to choose correct models based on underlying physics and biochemistry.
These models also require the right boundary conditions and initial conditions.
Currently, there are two broadly categorized computational approaches for modeling the interaction between phases in multiphase
flows: the EulerLagrange approach^{8–11} and the EulerEuler approach.^{12–17} In the EulerLagrange approach, the fluid phase is treated as a continuum by solving the timeaveraged NavierStokes equations,
whereas the dispersed phase is solved by tracking a large number of particles through the calculated flow field. The EulerLagrange
approach typically deals with the dispersed second phase by occupying a low volume fraction, even though high mass loading
is acceptable. The particle trajectories are computed individually at specified intervals during the fluid phase calculation.
In the EulerEuler approach, the different phases are treated mathematically as interpenetrating continua. Because the volume
of a phase cannot be occupied by the other phases, the concept of phasic volume fraction is introduced. These volume fractions
are assumed to be continuous functions of space and time and their sum is equal to one. Conservation equations for each phase
are derived to obtain a set of equations that have similar structures for all phases. In both approaches, the continuum phase
and discrete phase momentum equations are coupled through the drag source and sink terms, and through the volume fraction
of the dispersed phase.
The flow in an agitated bioreactor typically is in a fully turbulent regime, although some emulsification processes may operate
in a laminar or transitional regime because of the high viscosity of the mixture. Two methods often used to model the turbulent
flow are the Reynoldsaveraged NavierStokes (RANS) models and the unsteady large eddy simulation (LES) models. The direct
numerical simulation (DNS) method is too computationally demanding for real applications.
RANSbased models have different variations, such as the standard kepsilon, the ChenKim, the renormalized group (RNG), the
realizable kepsilon, and the komega, which all assume isotropic turbulence and do not show superiority of one over another,^{18} and the Reynolds stress transport models (RSTM), which incorporate the anisotropy characteristics by solving transport equations
for Reynolds stress terms. However, the improvement on the accuracy of RSTM predictions over the k–e models is not conclusive.^{19–24} Based on the Kolmogorov theory, the LES models solve only for the large eddies explicitly, while the smallscale effects,
below the filter size with corresponding wave number lying in the inertial convective subrange of the energy spectrum, are
modeled using a subgrid scale model. Good agreement between experimental data and model predictions on mean velocities and
turbulence quantities in agitated tanks have been reported.^{22,25–33} LES requires less computational effort than direct numerical simulation (DNS), which is the most exact approach to model
turbulence and can resolve the smallest eddies, but uses significantly more effort than methods that solve RANS.^{34}
When modeling a rotating system such as in an agitated tank, the multiple reference frame (MRF) and the sliding mesh (SM)
model often are used. The MRF model performs a steadystate calculation with a rotating reference frame in the impeller region
and a stationary reference frame in the outer region. In this way, the effects of the impeller rotation are accounted for
by the frame of reference, allowing for explicit modeling of the impeller geometry. The SM model allows the impeller region
to slide relative to the outer region in discrete timesteps and performs timedependent calculations using implicit or explicit
interpolation of data at successive timesteps. The SM model is a more accurate representation of the actual phenomenon of
the impeller rotation, but unfortunately a computationally demanding one.
The predictive capabilities of all available CFD models when applied to agitated bioreactors equipped with various impellers
in up or downpumping mode are discussed in the reviews.^{23,24,36–38} In summary, all turbulent models can predict the mean flowfield and power number very well,^{23,30,31,39} and also can capture most of the key features of nearimpeller flows with sufficient accuracy, but provide various degrees
of agreement with experimental data on turbulent characteristics. The standard kepsilon turbulence model combined with the
MRF model, as commonly used in engineering CFD simulations of stirred tanks and often faulted for its assumption of isotropic
turbulence, can model the turbulent flow with adequate accuracy if fine enough grids coupled with higherorder discretization
schemes are used.^{38} The LES for modeling flow in stirred tanks has the advantage of capturing the instantaneous velocity field and vortex structures.^{22,25,28,30,31,40}
Figure 1

Cells growing in bioreactors take up nutrients from the culture medium and release products, byproducts, and waste metabolites.
Mixing and sparging greatly influence the mass transfer phenomena required for an adequate supply of nutrients and removal
of waste metabolites.^{35} Agitation is used to maintain cells in suspension, provide a homogeneous mix of nutrients, and prevent the accumulation
of toxic gases. Multiple tasks and numerous choices of impellers make process scaleup extremely challenging. Figure 1 illustrates
how CFD provides assistance in understanding the extracellular environment, optimizing the operation conditions, designing
hardware configuration, and implementing scaleup and scaledown strategies.
