Biomedical Engineering Reference
In-Depth Information
TABL E 8.2. Examples of Virus Commonly Used for Clearance Studies
Virus Contaminant
Test Virus
RVLP (retrovirus-like particles)
X-MuLV
Adventitious RNA virus, nonenveloped
Reovirus 3, EMC
Adventitious RNA virus, enveloped
VSV, parainfluenza, Sindbis, BVDV, XMuLV
Adventitious DNA virus, nonenveloped
SV40, CPV, PPV, MVM
Adventitious DNA virus, enveloped
Pseudorabies
and application-specific interaction between the virus stock and the active ingredient or
impurities in the test article.
8.4.5 Scale-Down Model Systems
Scale-down model systems are commonly used in viral clearance evaluation and
validation studies. Commonly, it is the only time when a unit operation is actually
challenged with a virus load to assess clearance capabilities. It is therefore imperative
that the scale-down models accurately represent the performance of their cognate
full-scale unit operations. Issues related to heat transfer, mass transfer, and fluid flow
dynamics challenge one's ability to achieve fully parallel performance between small-
scale and full-scale unit operations. Therefore, translation of data into knowledge should
be done with a firm understanding of the limitations of the small-scale test system.
8.4.6 Inability to Confirm Manufacturing-Scale Effectiveness
Building from the small-scale processing knowledge, processes are scaled up incremen-
tally and the overall CQA profile of the product is assessed. Process adjustments during
scale-up are required often due to the imperfect relationship between small-scale and
full-scale unit operations. With most chemical, physical, and biochemical quality
attributes, the product may be assayed directly. With virus contaminants, assays of
in-process intermediate and final bulk are of limited value due to limits of detection, as
described subsequently. This places a heavier reliance on the scale-down model system.
8.4.7 Assay Limitations
There are three main categories of virus assays. The detection limit of each is relatively
low because each assay analyzes only a small fraction of the full product volume. Each
has major limitations with respect to one or more assay attributes:
Cell culture-based assays are performed by adding a small volume of test sample
(containing virus) to a tissue culture and quantifying the interaction between virus and
cells. This provides an indirect estimate of the number of virus particles in the original
sample. The precision of this kind of assay is generally accepted as being
0.5 log
10
[3], high enough to cause difficulty in the interpretation of DOE-based study results.
These assays also tend to be relatively slow and expensive.
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