Extreme Scale-Down Approaches for Rapid Chromatography Column Design and Scale-Up During Bioprocess Development - Measurement, Monitoring, Modelling, and Control of Bioprocesses - page 111

Consequently, very few manufacturing options may be studied in practice [ 19 ],
and instead column design may be driven more by prior experience or heuristics
when selecting a resin or buffer composition. This can result in sub-optimal pro-
cesses that overlook superior operating conditions in order to accelerate com-
mercialisation [ 30 ]. Techniques developed recently in the extreme scale-down
field can alleviate some of these problems by evaluating feed, resin and mobile
phase properties more systematically and at lower resource cost to try and identify
operating strategies for economic and robust column separations. Extreme scale-
down enables the collection of large amounts of empirical knowledge that can
improve process understanding and manufacturing flexibility. Although such
studies do not eliminate larger laboratory or pilot column studies, they focus
efforts upon what is most feasible upon scale-up. The scale-down data restrict
larger column experiments to verifying, refining or fine-tuning scale-down pre-
dictions (Fig. 1 ), and if operated in a way that can represent column hydrody-
namics, the data can assist ultimately in specifying an optimal column operating
protocol [ 37 ]. There are a number of extreme scale-down devices, including small
columns of around 1 mL in volume, batch incubation methods, miniature columns
and chromatography pipette tips which use up to a few hundred microlitres of
resin, and microfluidic devices (with a few microlitres of resin). Such methods are
consistent with the limited feed quantities available in early development and thus
can cover a larger number of conditions in parallel and thus in a shorter period of
time than might otherwise be the case in a conventional laboratory column. This
makes development faster and cheaper and provides better focus for larger trials
[ 15 , 16 , 33 ]. By mapping chromatographic design spaces, extreme scale-down can
help ultimately in the design and control of processes that deliver the required
product specification consistently. Nevertheless, extreme scale-down requires
consideration of many factors, including which device is the most suitable and
how easily it can be operated to deliver the required information. This chapter
includes some of the general considerations for extreme scale-down process
development and presents a summary of the different types of devices. It also
provides an overview of selected case studies involving these devices. Allied
issues of analysis and experimental design are also discussed.
2 General Considerations for Extreme Scale-Down
In extreme scale-down devices, the physical layout of matrix may be quite dif-
ferent from that of a normal packed column owing to the difference in geometries
of the methods at the two scales. Thus, if extreme scale-down data are gathered
early in development in the form of high-throughput screening (HTS), these dif-
ferences may allow the acquisition of only qualitative trends in the search space,
rather than quantitatively predictive information about scale-up outcomes.
Although these qualitative data in themselves do not constitute a design space,
they provide an approximate idea about the location of an operating area and can