Biomedical Engineering Reference
In-Depth Information
level of virus safety [3]. The complementary means of achieving this end point include
the following:
.
Identification of potential sources of viral contamination from, for example, cell
banks or adventitious contamination during processing.
.
Cell line qualification with respect to virus contamination.
.
Testing of unprocessed bulk solutions and suspensions, for example, cell harvest
pools and spent cell culture media.
.
Assessment of specific unit operations within the manufacturing process for
capability to effect virus clearance.
In this framework, it is common for a purely empirical understanding of process
capability to be derived and therefore presented in a regulatory submission. Especially
focusing on the assessment of virus clearance capabilities, it is typical for such
characterization to be limited to a relatively small set of experiments (often three) in
which scale-down models of a given unit operation are evaluated at nominal midpoint
conditions or obvious worst-case settings of the clearance mechanism (e.g., lower
temperature limit in a heat inactivation step or high pH limit in a low pH inactivation
step). Data derived from these studies are used to support the claim that the process
provides adequate virus clearance. The benefits of this approach are that regulators
accept it and the costs to implement are relatively low.
The current approach is conceptually juxtaposed with a design space approach, a
more holistic approach to characterizing the virus clearance capabilities of a unit
operation and a process. A design space is conceptualized as a multidimensional
window of operation that is sufficiently well characterized to allow processing
anywhere within that window. The design space approach combines existing knowl-
edge from the literature, one's technical understanding, and a stronger experimental
design to achieve deeper knowledge of process capabilities. A brief comparison of
current and design space approaches is found in Table 8.1. In this table, an
intermediate milestone between the current state and the future end state is described
to acknowledge that progress toward the end state should be viewed as a continuum
and not as a step function.
8.3 BENEFITS OF APPLYING DESIGN SPACE PRINCIPLES
TO VIRUS CLEARANCE
Although the benefits of QbD have been described by regulatory and industry repre-
sentatives, the extent to which the industry and regulators will adopt QbD principles is
not yet certain. The following brief discussion presumes that the adoption of QbDwill be
transformative in the industry.
The creation of a design space for a virus clearance unit operation requires that the
manufacturer acquire in-depth knowledge of the unit operation technology in general and
how that technology performs for the specific application. Regulators who agree that a
