Biomedical Engineering Reference
In-Depth Information
Conductivity
Bacteria
Fungi
Endotoxin
Viral clearance
Viral clearance
pH
Nucleic acids
Host cell proteins
Protein concentration
Figure
8.2. Conceptualized multidimensional process design space within which all contami-
nants and impurities are effectively cleared.
effectiveness. Presumably, similar knowledge will have been generated to define a space
within which all of the biological, chemical, and physical CQAs will be met (Fig. 8.2).
The final design space would combine the knowledge gained from all of these studies,
thus ensuring that all CQAs are reproducibly achieved. The design space would then be
proposed, through regulatory submission, as representing the boundaries within which
one would manufacture a biopharmaceutical product.
When describing a design space, one should account not only for manufacturing
process parameters, but for ancillary operations as well. As an example, consider
cleaning of a chromatography column. Changes to the cleaning frequency or cleaning
reagent concentration in manufacturing may alter the virus clearance profile (virus
capacity, separation from the protein peak, etc.) of the unit operation. One should also
assess fermentation process windows. It has been observed, for example, that when the
metabolic state of the cells or rates of protein expression change, retrovirus synthesismay
increase up to 2 log
10
[25].
A design space is described as a multidimensional window of operation that is
sufficiently well characterized to allow processing anywhere within that window.
Anticipating that comprehensive virus clearance DOE designs may be prohibitively
resource intensive, it is possible that initial viral clearance design spaces may comprise
relatively few dimensions. Nevertheless, these initial efforts will represent important
advances in the industry's collective efforts to adopt QbD.
8.6 STAYING IN THE DESIGN SPACE
A basic outcome of the QbD and design space approach is greater flexibility to document
and execute postapproval changes. With added flexibility will come the added care to
ensure that proposed change is justifiably represented by the existing design space.
Changes that fall outside the design space must be avoided.
One should consider with caution the addition of viral clearance steps after a process
has been designed. While augmenting virus safety, the added stepmay compromise other
product or process CQAs. Conversely, process changes apparently unrelated to virus
clearance may have a direct and unintended impact on virus clearance.
