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The following examples present several case studies (among many of
them), presented in the pharmaceutical literature, from screening studies,
through analysis of factor effects, to the optimization of formulation and/
or pharmaceutical processes.
Example
1
DoE was applied to evaluate infl uence of the granulation processing
parameters on the granule properties and dissolution characteristics
of a modifi ed release drug (Ring et al., 2011). This work accentuated
that understanding the relationship between high shear wet
granulation processing parameters and the characteristics of
intermediate and fi nal products is crucial in the ability to apply QbD
and process analytical technologies (PAT) to secondary
pharmaceutical processes. The objective of the work was to map
the knowledge domain for a high shear granulation/tableting
process, by analyzing the relationship between critical granulation
processing parameters and critical quality attributes (CQA) of the
intermediate and fi nal products. The following critical controlled
parameters (CCP) were investigated: impeller speed, wetting rate,
granulation time, and jacket temperature, with additional control of
granule particle size by two different milling techniques. A Taguchi
L-9 orthogonal design methodology was chosen for the study, and
in addition to determining the dissolution of the resulting tablets
after 2 and 4 h, a comprehensive range of granule and tablet
characteristics were monitored. Four factors were varied on 3
levels in 36 experiments, which were further split into 2 separate
18 experimental runs by using 2 different milling techniques. The
three-level Taguchi designs require relatively few data points and
assume that all two-way interactions are negligible. The
consequence is that some of the unexplained variance can be due
to the effect of interactions that are not negligible, thus increasing
the possible sources of error. The overall data analysis was
performed by the ANOVA test and
p
-values were used to relate CQA
of the system to CPP. It was demonstrated that with respect to
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