Biomedical Engineering Reference
In-Depth Information
well-designed strategy to manage the numerous variables associated with cell-culture
media, cell-culture development could be rate limiting and/or result in poor process
capability once in the manufacturing plant.
11.3 CURRENT PRACTICE FOR RAW MATERIALS
Current practice for raw material analysis is described in ICH guide Q7: Good
Manufacturing Practice Guide for active pharmaceutical ingredients (API). Materials
used to prepare active pharmaceutical ingredients (both small molecules and biologics)
need to have the identity of each batch confirmed on receipt and a Certificate of Analysis
(C of A) provided from the supplier. In addition, the supplier must be qualified as suitable
based on audits of their facility, their analytical results must be confirmed to be reliable,
and a sampling plan is needed for each incoming material.
Even though these guidelines are followed, there remains a possibility that changes
in raw materials will occur during the life cycle of a product and that some of these
changes will not be measured in the analytical tests reported on the C of A. Examples of
unanticipated raw material changes that have an impact on production come from both
big pharmaceutical companies and biologic manufacturers. These include subtle
changes in the level of impurities ranging from hydrogen peroxide affecting protein
stability to particle size variations affecting dissolution rates. The incoming specifica-
tions and tests used to accept a raw material for use are based on the results from
development studies. Once a process is inmanufacturing, quality systems are put in place
to ensure consistent practices, creating a momentum to maintain the status quo.
Additional effort is needed to change a process once it is in manufacturing even in
response to new information.
11.4 QbD IN DEVELOPMENT
DOE is applied extensively during the small-scale development stage of a process and
then, to a lesser extent, through clinical drug manufacturing and into early commercial
manufacturing. In a similar way, QbD for raw materials would ideally start during the
development phase of a process by identifying which variables in a raw material will
affect product yield or quality. Development experiments identify these key factors so
that they can be controlled. At this stage, QbD for raw materials might be indistinguish-
able from QbD applied to develop a cell-culture process.
In contrast, while DOE is a key tool used for QbD in the development stage of a
process, DOE is not normally incorporated into a manufacturing process itself. DOE is
not part of the standard design practice for pharmaceutical or biopharmaceutical
processes [1]. Since DOE is not planned into manufacturing processes, it cannot be
used as a tool to detect or learn from future variation in rawmaterial composition. While
simplifying the manufacturing operation in the short term, this strategy does reduce the
opportunity to continue to develop a resilient manufacturing process, one designed for
ongoing learning. It is assumed that major sources of variation in raw materials are
