Biomedical Engineering Reference
In-Depth Information
mechanistic or first-principle models. These models could provide additional confidence
regarding unimportant variables and facilitate scaling. For tablets, there is a long
history of mechanistic or semimechanistic models for manufacturing unit operations
such as roller compaction [45] and for tablet characteristics [46] that may impact
performance. There are models for chromatography steps, but not all aspects may be
covered (e.g., channeling through cracks, column behavior at the interface with the
housing). Chromatography also depends on a variety of product-specific attributes [47].
Despite potential limitations, the presence of a relevant mechanistic model can increase
confidence in a design space.
Pharmaceutical products can be placed along a continuum of complexity. Similarly,
pharmaceutical manufacturing processes can also have differing levels of complexity.
Biotechnology products tend to have both product attribute complexity and process
complexity. Currently, there are only limited mechanistic models for either product
attributes or complex process steps. Although biological characterization and knowledge
of product mechanism(s) of action can improve the understanding of product attributes,
there will still be uncertainty. Complexmanufacturing steps may have many quantitative
and qualitative factors and the potential for hidden interactions. Thus, creating design
spaces for biotechnology products requires risk-based approaches to eliminate large
numbers of variables. Even with advances in risk management, there is likely to be
greater uncertainty for biotechnology product design spaces. There are approaches to
deal with this uncertainty. In Fig. 2.10, a conservative design space is proposed. It may be
prudent not to extend the design space to limits of failure when there is uncertainty
regarding the design space. In addition, the quality system can be tailored to fit the
complexity of the process [43, 44] and provide for appropriate risk management within
design spaces. Although movement within a design space always needs be justified by
the quality system, a design space with greater uncertainty may benefit from inclusion of
a well-defined protocol to verify that movement within the design space does not have
unintended effects on product quality. Protocols could focus directly on a risk-based
verification that deals with areas of uncertainty. Inspections by regulators could check for
the appropriate use of such protocols in managing significant movement within the
design space. Minor changes to operating parameters and the ongoing verification of the
initial design space should also be part of the sponsor's quality system. Verification at
scale can be an important part of initial and ongoing process validation. The use of a
multivariate approach to monitoring is likely to provide useful information over the
product life cycle.
2.7 FUTURE HORIZONS
In the discussion of design space, we have used parameters such as protein load, pH,
and conductivity. There are many more parameters that can be altered in a chromatog-
raphy process step such as linear flow rate, buffer ions, washes, equilibration, and
cycle number. All these parameters can be considered in developing the design space.
For simplicity, all these are squeezed into the two-dimensional space in the lower left
corner of Fig. 2.11. There are still manymore dimensions for changes to this process step.
