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Biopharmaceutical Development
by Amber Ratcliff and Carol PreisigMonday, April 1, 2013 9:00 am
Todays
biomanufacturing
operations
require
constant
management
of
biopharmaceutical process attributes throughout process development and production.
Continuous online measurements of pH, dissolved oxygen (DO), oxidationreduction
potential (ORP), and conductivity (Figure 1) allow real-time industrial process monitoring
and adjustment. These functions are crucial to process improvement studies and
accurate, reliable manufacturing of high-quality products.
Figure 1: ()
LEVEL: BASIC
Accuracy, repeatability, response time, and detection limits are important, and so are
easy installation, calibration, and maintenance. Until the past few years, sensor
technology was not keeping pace with improvements in cell engineering processes,
which have been scaled up and modernized considerably. But three recent advances
optical DO sensor technology, smart sensors, and wireless technology are
improving data quality and the ease with which information is obtained and managed.
Here we describe those advances and present two examples of wireless smart sensors
in use: at an innovative, large-scale biopharmaceutical manufacturing plant and a
scaled-down simulator for studying the impact of industrial-scale inhomogeneities on
microbial cultures in a laboratory setting.
sensor triggered an oxygen-level alarm several times during the study, whereas the
three flow-dependent optical sensors provided consistent readings.
Figure 2: ()
Figure 3: ()
Figure 4: ()
Wireless adapters for sensors are available for a broad range of pH, DO, ORP, and
conductivity measurement applications. Wireless sensors feature a built-in
microprocessor that communicates with analog (420 mA) and digital Modbus
interfaces. (Modbus is a standard serial communications protocol commonly used in
connecting industrial electronic devices. It was developed with industrial applications in
mind.) Direct connectivity eliminates the need to send information through costly
transmitters, and the wireless signals are more robust and reliable than the low currents
produced in traditional measurement systems. Arc sensors contain smart sensor
technology and can be precalibrated and configured by the vendor. In addition, on- and
offline sensor management delivers extended sensor life and increases process
accuracy in challenging bioproduction environments.
In the Hamilton system, an Arc Wi sensor adapter and an Arc View handheld unit
enable wireless management and calibration of multiple sensors using one device. The
handheld unit (Figure 5) provides a local display configured with Arc Wi wireless
communication, which enables users to move around a facility and monitor data from
multiple sensors, communicating with up to 31 of them simultaneously. Figure 6 shows
a manufacturing plant installation with an Arc sensor unit in active transmission mode.
Figure 5: ()
Figure 6: ()
Improving Data Quality with Wireless Sensor Technology: In addition to the more
obvious benefits of monitoring data from multiple sensors using a handheld device,
wireless sensor technology also provides a marked improvement in data quality.
Wireless capability eliminates not only the fixed transmitter and connective cabling
between it and the sensors, but also other hardware that can cause signal interference.
Figure 7: ()
Case Studies
A Modern, 750-L Fermentation Plant Including a Cross-Flow Unit: When planning a
modern, 750-L fermentation plant including a cross-flow unit, a biopharmaceutical
manufacturer needed the best available measurement technology to meet its regulatory
requirements. After testing Hamiltons new smart Arc system, the plant engineer found
that it met the companys needs for efficiency, compactness, reliability, and precise
process controls (Figure 8).
Figure 8: ()
Figure 9: ()
Figure 10a: ()
Figure
10b: ()
Figure
11: ()
Operators also monitored pH in both the PFR and the STR (Figure 12). In that study,
the pH measurement along the PFR module did not indicate acid release. Monitoring
pH is especially useful when acids are formed in a PFR reactor for example,
in Escherichia coli cultivation.
Figure 12: ()
Looking Forward
The introduction of optical DO sensor
technology, intelligent sensors, and
wireless technology enables more reliable
biopharmaceutical
production
and
improved plant performance. Biomanufacturers will face challenges as they strive for
continuous improvement. In sensor technology, industry experts such as Lam would like
to see more measurement innovations, such as a reliable method for measuring
glucose online.
From a broader perspective, Leveen considers single-use technology to be the next
major trend in biopharmaceutical manufacturing. An early adopter of disposables for
biopharmaceutical production, he says, Because FDA regulation of therapeutics begins
with clinical trial material, the introduction of single-use bioprocess technology will begin
at this stage in therapeutic development.
Both industry suppliers and pharmaceutical company experts concur. Lam and others
insist that cost will be a driving factor in the decision-making process for years to come.
To succeed in the future biomanufacturing market, newly introduced technologies must
cost no more than current technology.
Acknowledgments
The authors are grateful to Stefan Junne, Arne Klingner, Dirk Itzeck, and Peter
Neubauer of the bioprocess engineering laboratory in the department of biotechnology
at the Technische Universitt Berlin for contributed content from the novel plug-flow
reactor case study as well as data and photos for Figures 10, 11, and 12.
The authors thank the following industry experts for helpful conversations: Dr. L. Harry
Lam, PhD, is a bioprocess engineer who has spent his career in biochemical
Author
Details
Corresponding author Amber Ratcliff is market segment manager for analytical
sensors at Hamilton Company, 4970 Energy Way, Reno, NV 89502; 1-800-648-5950. A
consultant with GeneCom Group, Carol Preisig, PhD, MBA, provides scientific writing
and industry research assistance to the company. Arc, Polilyte, and Arc VisiFerm are
registered trademarks of Hamilton Company.
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