Biomedical Engineering Reference
In-Depth Information
TABL E 7.1. Recommended Sequence of Activities for the Development of Design Space
Stage
Activity
Outcome
Determine acceptable
ranges for product
quality attributes
Identify critical product
attributes and acceptable
variation
Product attribute responses to
be measured during process
characterization (e.g., levels
of CHO host-cell proteins,
levels, aggregate levels,
potency)
Risk analysis
Evaluate process risks with
respect to product and process
consistency and operational
flexibility
Subset of unit operations to be
explored for expanded design
space
Parameter screening
Use existing process knowledge
and previous experience with
similar processes to eliminate
nonkey parameters.
Identification of key and critical
operational parameters for
modeling DOE.
Resolution III or IV screening
DOE
Modeling DOE
ResolutionVor response surface
DOE to detect curvature
(nonlinear responses)
Identification of interactions
between variables
Predictive small-scale model
Failure limits
Proposed limits for design space
Scale-down model
verification
Comparison of modeling DOE
predictions to manufacturing
scale operation
Verified relevance of
small-scale models to
manufacturing scale process.
Satellite runs
previous clinical exposure of the product, nonclinical (animal) studies, in vitro biological
activity assays, an understanding of the molecule's mechanism of action, and
manufacturing capability. Ultimately, it is the relationship between the variation in
operational parameters (i.e., process inputs) and the variation in critical quality attributes,
which determines the boundaries of the process design space. Next, process characteri-
zation (robustness) studies can be used to explore the operating ranges and establish
acceptable ranges for the operational parameters. Once established, operating within
these limits, the combination of which defines the design space, provides the “assurance
of quality.” It should be mentioned that for products produced in mammalian cell culture,
the assurance of quality must include the demonstration of adequate viral clearance.
Thus, the evaluation of process changes within the design space must include an
assessment of how these changes affect the level of viral clearance. In cases where the
factors controlling viral clearance for a particular step are not well understood, additional
viral clearance studies would be required to justify the proposed design space.
The terms space and multidimensional combination in the ICHQ8 definition of
design space imply the need for extensive use of design of experiments (DOE) to map
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