Biomedical Engineering Reference
In-Depth Information
during process development has evolved from test-tubes using millilitre-scale
quantities through to micro-well-plate-based development and now into chip-
based applications.
• Automation: This encourages fast, accurate and reliable process development
and requires liquid handling systems capable of transferring microlitre- to
millilitre-scale sample volumes. At these scales it is important to control phe-
nomena such as hold-up loss, evaporation and surface tension effects to enable
fast, accurate and precise dispensing. Automation reduces operator burden,
enabling that person to conduct other activities while routine operations are
carried out.
• Parallelisation: Running multiple conditions simultaneously brings clear
throughput benefits and also enables more replicates to be run, increasing
confidence in the data. Additionally, this reduces down-time when samples
would otherwise have to be stored to await processing. Storage can be prob-
lematic with conventional serial column operations if one is dealing with crude
feed material and unstable products, owing to the deleterious effects of phe-
nomena such as enzymatic breakdown, aggregation or precipitation.
• Data transformation: For quantitative scale-up, empirical correlations may be
needed to account for scale differences where these cannot be compensated fully
by experimental means. Alternatively, mathematical models can use the scale-
down data to simulate performance at larger scales. Regime analysis and
computational fluid dynamics can be useful in providing the mechanistic
framework for scale-up. The output results can then be displayed through dia-
grams such as windows of operation.
Implementing these extreme scale-down principles permits the generation of
information-rich response surfaces [ 34 ] when searching for robust operating
regions. Some of these principles are more applicable to microlitre operations than
millilitre scale-down. The following sections of this chapter summarise the devices
available, discuss key considerations and look at published examples of their
application.
3 Millilitre Scale-Down
3.1 General Considerations
3.1.1 Scale of Operation
Millilitre-scale approaches use columns containing only one or a few millilitres of
resin. First-principles or experimental correlations may be applied to the output
data to correct for differences from larger columns. In comparison with standard
laboratory beds, millilitre-scale columns reduce feedstock requirements consid-
erably by using very small bed heights and diameters.
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