Biomedical Engineering Reference
In-Depth Information
On the other end of the spectrum are monoclonal antibodies, the most common
example of a product category for whichmanymanufacturers have adopted a manufactur-
ing platform approach. A platformmanufacturing process is a standardized process that a
manufacturer establishes for all products of a like product category, for example,
monoclonal antibodies. The established platform will have proven virus clearance
capabilities. It is important, however, to ensure that the efficiency of the platform for
viral clearance is confirmed for each specific product. The EU draft guideline on
monoclonal antibodies states “The 'platform manufacturing' process will never be
identical for each monoclonal antibody and interference by the product cannot be
excluded beforehand. Therefore each process should be separately validated for its ability
to remove viruses. However, for a new product, the manufacturer may partly rely on viral
validation data obtained with other products manufactured with the same 'platform
manufacturing' process. Such data may be considered supportive but the manufacturer
will need to justify the relevance of the data and demonstrate that virus validation data
obtained from the new product is comparable to data obtained for other products” [21].
Biopharmaceutical products vary in the extent to which they can tolerate virus
clearance conditions. At the extreme, viral therapeutics are intrinsically difficult to
handle, and virus safety assurance relies on complementary mechanisms that include
extensive testing of raw materials and cell substrate and even end-product testing. Most
biopharmaceuticals are susceptible to denaturation or aggregation, so one must assess
product or process-intermediate stability, especially during exposure to harsh inactiva-
tion conditions. On the contrary, process impurities may actually protect a virus from
inactivation. Preliminary scoping studies may reveal stability issues caused by either
inactivation or removal steps. Purity and impurity profiles, potency, and product yield are
some relevant measurable parameters.
When designing in a viral clearance strategy, a cost analysis is warranted. For typical
biopharmaceutical processes, virus clearance steps are strategically placed to minimize
costs. Consider, for example, the cost of a virus filter step or a low-pH inactivation step.
Since the area of the virus filter is determined by the volume to be processed, one might
want to place the filter into the process where the volume is reduced. Likewise, handing
large volumes of low-pH inactivation and subsequent neutralization solutions can be
costly. It has been observed that a reduction in buffer consumption by one-third can
reduce downstream process costs by approximately 6% [22]. Although strategic,
cost-conscious placement of viral clearance steps is appropriate, risks associated with
product source and segregation of pre- and postviral clearance steps may dictate a less
cost-effective placement in the process flow scheme.
8.5.5 Perform Characterization/Robustness Studies
After evaluating the viral clearance options and constructing a process strategy, viral
clearance studies are needed to confirm that the clearance options are effective. Over
the last decade, there have been more requests from regulatory agencies to test
“worst-case” conditions for one or more independent variables. In some situations,
“worst case” is clear. For example, as dwell time is an important factor for successful
inactivation, inactivation kinetics are generally evaluated as part of a viral clearance
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