Biomedical Engineering Reference
In-Depth Information
2.6 UNCERTAINTY AND COMPLEXITY
A design space has regulatory implications. Movement within a design space is not
considered a change [3]. Such movement can occur without a regulatory submission.
However, movement within a design space does not remove responsibility from the
sponsor's quality system [43, 44] to ensure product quality.
There can be many different spaces in a manufacturing unit operation (Fig. 2.10).
The knowledge space is the space explored by small-scale DOE. The design space is the
space explored by DOE that leads to acceptable product. A section of the design space
may have been used to successfully manufacture pilot and full-scale lots. A smaller
operating space will generally be used for initial manufacturing based on pilot and
full-scale experience.
There are many possible sources of uncertainty in a design space generated by DOE.
DOE is based on a model, and predictions of results within the design space are only as
good as the model. The experiments are done at laboratory scale, and extrapolation to
full-scale manufacturing should be justified. The generation of a design space can miss
important factors at a number of levels. Variables can be overlooked in the initial fishbone
diagram. Screening studies may discard variables that have important interactions if they
do not have a significant main effect. An example of this would be the chromatography
variables, cycle number, and regeneration buffer pH. Over the tested ranges, each of these
variables may not impact product quality and could be disregarded based on screening
experiments. However, together they may have significant impact.
If only a small number of variables are removed based on prior knowledge and
screening experiments, the uncertainty is low. In addition, some process steps may have
Figure 2.10. In developing a design space, there are many spaces to consider. The knowledge
space represents the space explored by experimentation and may include areas of failures,
indicated above in gray. The area labeled as design space includes the area modeled to produce
acceptableproduct in small-scaleexperiments. A smaller operating spacemay limit experienceat
pilot or full-scale manufacturing. Uncertainty in risk assessments, scaling, modeling, and so on
may limit confidence in the DOE defined space, and a more conservative design space may be
appropriate in such situations.
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