The Choice of Suitable Online Analytical Techniques and Data Processing for Monitoring of Bioprocesses - Measurement, Monitoring, Modelling, and Control of Bioprocesses - page 253

the development of a calorimetric technique that could be readily integrated into a
bench-scale bioreactor, known as 'heat-flow calorimetry' [ 11 ]. Ciba-Geigy AG
(Basel, Switzerland) developed a new bench-scale calorimeter based on the heat
flow calorimetric technique, commercialised by Mettler Instruments AG (Swit-
zerland) as a 'reaction calorimeter, RC1' suitable for monitoring chemical reac-
tions [ 14 ]. The advent of bench-scale reaction calorimetry in the 1980s paved the
way for biocalorimetrists all over world to make advances in calorimetric science
[ 15 ]. A high-resolution version of the reaction calorimeter suitable for monitoring
biochemical reactions was developed by Marison et al. [ 16 ], and it caused a
paradigm shift in biocalorimetric research and demonstrated the usefulness of
heat-flow biocalorimeters in bioprocess monitoring. Further studies illustrated that
heat-flow biocalorimeters are high-performing (bio)reactors suitable for all kinds
of bioprocess applications, viz. cultivation of different cell lines, quantitative
studies including process monitoring and control [ 17 ] and biothermodyanamic
studies [ 5 ]. Due to their versatile nature, heat-flow biocalorimeters are widely
employed nowadays for bioprocess monitoring and control applications. More-
over, the decreasing surface-to-volume ratio in large-scale bioreactors results in a
good-quality heat flow signal. Hence huge scope exists for deploying heat-flow
calorimetry in industrial-scale bioreactors in the near future. Though several
research works employing bench-scale biocalorimeters have been reported, their
real potential is yet to be realised in the industrial biotechnology sector.
2.1.3 High-Resolution Heat Flow Rate Signal
The successful application of calorimetric techniques to bioprocess monitoring is
inherently related to the sensitivity of the instrument and the signal noise [ 16 ].
García-Payo et al. improved the resolution to 4-12 mW L -1 , and this is regarded
as a significant milestone in heat-flow biocalorimetric research [ 18 ], paving the
way for employing heat-flow calorimetry to monitor weakly exothermic reactions,
viz. anaerobic and animal cell growth processes. However, long-term signal noise
during calorimetric measurements is still an issue. Long-term noise disturbances in
measured calorimetric signals are attributed to ambient temperature fluctuations
and could be minimised by effectively thermostatting both the reactor housing and
its head plate. Such signal noise becomes less important with large-scale reactors
since the heat balances around the reactor would compensate for these.
2.1.4 Scope for Bench- and Large-Scale Biocalorimetry in General as a PAT
Process Analyser
Direct measurement of the metabolic activity of organisms is desirable, and this
may be achieved by quantitative measurement of metabolic activity via heat flow
rate measurements. Table 1 chronologically summarises the significant progress
achieved in biocalorimetry in real-time monitoring and control applications for a