Biomedical Engineering Reference
In-Depth Information
Even with established and extensively tested cell lines, unexpected events can
endanger the marketing of a product. For example, squirrel monkey retrovirus (SMRV)
found in several cell lines was used to produce protein biotherapeutics [9]. This
contamination was detected fortuitously during expression analysis of recombinant cell
lines. A similar problem arose with the finding that MMV was introduced adventitiously
into a manufacturing process [10]. This led to more stringent requirements for clearance
of nonenveloped, resistant viruses.
Finally, during the 2002West Nile virus (WNV) epidemic in theUnited States, it was
learned that WNV could be transmitted via transfused blood. Plasma fractionators
reviewed their production processes and validation data for clearance of a model virus,
bovine viral diarrheal virus (BVDV), which is similar to WNV. It was confirmed that
existing virus validation data could support continued use of the plasma products within
the existing manufacturing space [11]. The manufacturing processes included inactiva-
tion steps such as pasteurization, solvent/detergent treatment, and vapor heating.
Eventually, WNV was isolated and used in spiking studies to confirm an appropriate
level of viral clearance.
8.5.3 Construct a Virus Clearance Knowledge Base
Over the last decade or so, considerable information on viral safety has been published in
the form of peer-reviewed articles, conference proceedings, regulatory guidance,
summary basis of approvals, and EPARs (European Public Assessment Reports).
[12,13] Contract testing laboratories are another useful source of information for
designing viral clearance into a process. These laboratories have valuable insights on
robustness and current acceptance of the various viral clearance techniques. Multiple
sources of information should be used to initiate and develop a viral clearance knowledge
base for inactivation and removal mechanisms. The following provides a sampling of the
kind of data and understanding that one may find in the public domain for various
established viral clearance technologies.
In one survey, data were compiled for several model viruses.
Parvovirus, reovirus, and hepatitis Awere selected as models for nonenveloped viruses.
Murine leukemia virus and pseudorabies virus were selected as models for enveloped
viruses [14]. Table 8.3 describes properties of these model viruses.
For the parvovirus models, irradiation was found to be very effective under
appropriate conditions, but heat-inactivation effectiveness varied with virus. Reovirus
was inactivated by heat treatments of
Inactivation.
60
C, UV radiation, and gamma radiation.
Hepatitis Awas inactivated by irradiation and by dry heat, although dry heat effectiveness
was affected by moisture content. Although several of the nonenveloped viruses
presented a significant inactivation challenge, the enveloped viruses were shown to
have a low resistance to physicochemical treatments. Heat and low pH have been
demonstrated as effective inactivation mechanisms for enveloped viruses.
Although effective treatments were identified for each specific model virus, viruses
exhibited significant differences in terms of their susceptibility to the various inactivation
methods. In addition to the virus classes, many other variables affect the outcome and
