Biomedical Engineering Reference
In-Depth Information
TABL E 8.5. An Outline Viral Clearance Design Space for Inactivation of Type C Retrovirus
Attribute
Setting
pH
3.8
Incubation time
30min
14
C
Incubation temperature
Buffer system
Citrate or acetate
Total protein concentration
40mg/mL
NaCl concentration
500mM
pI of protein
3-9
Process intermediate
Cell-free intermediate after initial
capture chromatography step
Product
Monoclonal antibody (not retrovirus targeted)
provided the conditions in Table 8.5 were met [23]. Although not discussed in QbD
terminology by the authors, this study has in effect outlined a viral clearance (in this case
inactivation) design space for a specific virus particle. Because processes are evaluated
on a case-by-case basis, regulatory agencies to date have not yet accepted this generic
bracketing concept for either clinical materials or for license applications.
Mammalian virus clearance studies run under GLP are currently required to validate
viral clearance into a specific process. The cost of these studies is high, so it is not feasible
to construct a full design space with this kind of study. To manage this issue, several
strategiesmaybe employed. First, onemay consider use of nonhazardous, nonmammalian
virus models (i.e., bacteriophages) as a means of generating a large amount of clearance
data with relative speed and cost-effectiveness. Second, one may generate preliminary
mammalian virus clearance data under non-GLP conditions. One biopharmaceutical
company has described the use of non-GLP facilities to perform a comparison of new and
classical viral clearance methods [24]. Others rely on contract testing organizations that
canperformpreliminary studieswithout the rigors ofGMPcompliance toprovidevaluable
process design information. Third, onemust account for the possibility that future process
changes will lead to the need for new studies. This is especially the case for early phase
studies, for which most companies opt for using center-point-only study design.
Finally, planning is essential. Awell-characterized scale-down clearance model must
be developed before the virus testing may begin. Experimental issues related to, for
example, virus viability and virus assays during virus clearance studies should be
anticipated and discussed with the test facility. Product shipping studies should be
executed to assure that the product arrives at the test facility free of excessive aggregation
or denaturation: aggregates may lead to over- or underestimation of viral clearance,
depending on the clearancemechanism. Planning canmitigate risks of project delays or of
finding out too late that the manufacturing process provides insufficient viral clearance.
8.5.6 Create a Design Space Proposal for the Unit Operation
From the experimental data derived above and learning from the scientific literature, one
derives knowledge about the impact of critical process variables on viral clearance
