Biomedical Engineering Reference
In-Depth Information
concerns agencies may have when looking at parameters such as step yield, which have
historically been viewed as critical process parameters. Well-defined data sets and risk
analysis should be able to justify replacing “historical” process parameters with ones
based on end point analysis or product quality attribute decisions. These types of
decisions will need to be addressed in the appropriate sections of regulatory filings as
well as other company documentation such as batch records and SOPs.
12.10 FUTURE PAT TOOLS
PAT tools are taking longer than some practitioners would like, but it is becoming
more ingrained in corporate philosophies and operational excellence thinking. Many
practitioners strugglewith the lack of availability of the appropriate analytical tools to get
the information needed to obtain the desired “window” into the process.Many companies
struggle with issues of intellectual property and funding collaborations with instrument
manufacturers who are willing to custom fabricate tools to fit their manufacturing
processes. In spite of these types of barriers, the need to learn more about biological
manufacturing processes is still driving innovations in academic, research institutes and
industry geared to arriving at new and improved tools for monitoring and controlling the
processes.
Enabling tools and technologies that may provide newways of looking at biological
processes in the future may include techniques such as ultrasonic detection, nanofluidics
and SPR arrays, automatedmicroimaging techniques, automated flow injection analysis,
calorimetry, and rugged spectroscopic techniques to address loss on filtration and loss on
drying for monitoring critical quality attributes in cell culture fluid. Further refinement
and ruggedness testing is needed in the instrument development arena end to address ease
of use and ease of implementation in a manufacturing environment.
Ultrasonic detection of protein aggregates in cell culture broth may allow improved
strategies and controls to be developed for harvest steps and will certainly help properly
load columns for initial purification steps. Since the technology does not rely on light
scatter to quantify process changes, it allows implementation of the tool to evaluate
opaque solutions. In fact, ultrasonic reflectometry is already being used to assess
membrane integrity in microfiltration and ultrafiltration skids [55]. This technology
could also be used to assess slurry uniformity prior to column pouring and packing. As
the ultrasound technology becomes better understood and data deconvolution algorithms
improve, this may become a key window into our processes that does not exist today.
Sound waves are also being used to generate equipment performance process signatures
for applications such as granulation [71, 72] and fluidized bed coating processes [73] that
allow engineers to proactively perform preventive maintenance before an event occurs
that could potentially result in a lost batch upon failure. Clearly, soundwave technologies
are destined to be one of the tools in the PAT toolbox of the future.
Online monitoring bioreactor monitoring by calorimetry [56] may be another PAT
tool in the future that scientist and engineers will begin to rely upon to make process
decisions. The simple fact that heat production in combination with the material flows
correlated withmetabolicmaps may allow finer control of cellular metabolic processes is
