Biomedical Engineering Reference
In-Depth Information
7
Controls
The goal of PAT is to understand and control the manufacturing process,
which is consistent with our current drug quality system:
quality cannot be
tested into products; it should be built-in or should be by design
.
Food and Drug Administration, 2009
According to the Food and Drug Administration (FDA) Guidance for Industry,
process analytical technology (PAT) is intended to support innovation and
efficiency in pharmaceutical development. PAT is a system for designing,
analyzing, and controlling manufacturing through timely measurements
(i.e., during processing) of critical quality and performance attributes of raw
and in-process materials and processes with the goal of ensuring final prod-
uct quality. It is important to note that the term
analytical
in PAT is viewed
broadly to include chemical, physical, microbiological, mathematical, and
risk analyses conducted in an integrated manner.
To fulfill process requirements, single-use sensors, which are either inte-
grated in the single-use bioreactor or included in the cover and are disposed
of with the bioreactor, are required. They provide a continuous signal and
allow information about the status of the cell culture to be gathered at any
time. The traditional batch analysis such as high-pressure liquid chroma-
tography (HPLC), electrochemistry, and wet chemical analysis in place of
disposable sensors increases the risk of contamination.
Since disposable bioreactors are new to the industry, the first attempt to
monitor the product in the bioreactor was to use the traditional biosensors
used in hard-walled systems to measure bioreactor temperature, dissolved
oxygen (DO), pH, conductivity, and osmolality. These probes must first be
sterilized (via autoclaving) and then attached to penetration adapter fit-
tings that are welded into bioreactor bags. Not surprisingly, this is a labor-
intensive and time-consuming process that has the potential to compromise
the integrity and sterility of single-use bioreactor bags, and has been largely
discarded in favor of truly disposable sensors. Critical process parameters
that are often monitored include pressure, pH, DO, conductivity, UV absor-
bance, flow, and turbidity. The packages that contain the traditional tech-
nologies for monitoring these parameters are not usually compatible with
or effective when integrated into single-use assemblies for many reasons:
cost, cross-contamination, inability to maintain a closed system, and system
incompatibility with gamma irradiation.
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