Extreme Scale-Down Approaches for Rapid Chromatography Column Design and Scale-Up During Bioprocess Development - Measurement, Monitoring, Modelling, and Control of Bioprocesses - page 114

3.1.2 Feed Material
Ideally, the feed material used to conduct any form of scale-down chromatography
should be as representative of the process-scale product and impurity profile as
possible. This implies that the scale of the upstream process should be consistent
with the quantities needed to conduct the scale-down chromatographic step. Fur-
thermore, the feed consumed per test condition should be minimised to cover as
much of the search space as possible.
3.1.3 Mechanistic Modelling
Chromatography models can help to increase process understanding when used in
conjunction with extreme scale-down devices, but require the use of mechanistic
equations to represent mass transport, diffusion, dispersion and equilibrium
properties accurately [ 29 ]. Models that account for every one of these effects can
be quite complex and may require advanced mathematical understanding. Fortu-
nately, however, not all mass transport effects are critical in a given separation, and
this can enable model simplification. Some mass transport terms can be combined
together while still reflecting the necessary chromatographic properties. After a
model has been chosen, the remaining unknown parameters need to be determined
experimentally in order to calibrate the model. These can be obtained more
quickly and cheaply using extreme scale-down devices than at conventional col-
umn scale. An example of mechanistic scale-up modelling is given later.
3.1.4 Graphical Representations
Beyond providing mechanistic outputs, an added requirement of in silico
approaches is their facile representation in order that the consequence of process
choices can be visualised easily. User interfaces can be constructed to portray
likely windows of operation and thus enable the determination of specific com-
binations of process parameters that satisfy performance targets. Fractionation
diagrams may also be useful in this context [ 21 ].
3.1.5 Techniques for Visualising Adsorption
Techniques for labelling proteins and visualising their adsorption onto resin beads
can be a useful way of gathering intra-particle diffusion data [ 12 ]. These can give
both qualitative and quantitative information about uptake rates and the maximum
extent of adsorption to support scale-down studies; For example, confocal scan-
ning laser microscopy can be used to track product uptake onto resin beads [ 32 ]or
for fouling studies [ 28 ], determining the effectiveness of cleaning procedures and
so column lifetimes.