The Choice of Suitable Online Analytical Techniques and Data Processing for Monitoring of Bioprocesses - Measurement, Monitoring, Modelling, and Control of Bioprocesses - page 258

2.1.5 Custom Bioreactors—The Future Biocalorimeters?
Recently, conversion of industrial-scale bioreactors into biocalorimeters is
attracting interest due to the ease of measurement, the non-invasive nature of the
measurement and cost-effectiveness. The move from bench-scale to industrial-scale
biocalorimeters results in a decrease in surface area-to-volume ratio. This facilitates
heat measurements by reducing the heat transfer surface, resulting in better signal
quality [ 33 ]. Voisard et al. first converted a pilot-scale (300-L) fermenter into a
calorimeter and successfully monitored the growth of B. sphaericus [ 32 ]. An
approach for conversion of bioreactors, irrespective of size, to biocalorimeters by
integrating suitable calorimetric measurement principles has been proposed [ 34 ,
39 ]. However, a power compensation technique for heat flow rate measurements
was employed, and this is not feasible in industrial-scale bioreactors, which are
usually jacketed vessels in which the reactor temperature is controlled using
cooling fluid circulating through the jacket. Moreover, the measured heat signal
sensitivity was 50 mW L -1 , signal stability was of the order of 0.2 mW L -1 and the
response time was in the range of 1-2 min. Technical-scale calorimetric monitoring
demands a high-sensitivity heat flow rate signal (short-term noise\0.003 mW L -1 )
and dynamic temperature sensors (time constant \10 s). Current progress in tem-
perature sensor instrumentation and data acquisition (DAQ) tools may render the
conversion of large-scale bioreactors into high-sensitivity biocalorimeters.
Integration of a heat flow biocalorimeter into a PAT platform would provide the
end-user with insight into metabolic changes encountered in an ongoing bioprocess
and ensure a robust process control leading to high-titre product yield.
2.2 Dielectric Spectroscopy
Dielectric spectroscopy exploits the complex electrical properties of viable cells.
Any such complex, passive, electrical system can be defined by two characteris-
tics: capacitance measured in farads (F) and conductance measured in siemens (S).
Dielectric spectroscopy can provide information on the total and viable cell vol-
ume, since only cells with intact membranes act like capacitors when placed in an
electrical field. Obtaining information about the viable cell volume is important,
since monitoring the growth of the organism of interest can be crucial to the
process, for instance to determine the appropriate time for induction of recombi-
nant protein production. In addition, some interesting products are growth related
and may be indirectly monitored using dielectric spectroscopy. The measurement
of the evolution of the viable cell volume may identify the specific product for-
mation rate. In order to design control strategies to maintain a particular specific
growth rate or act on the product formation rate, it is crucial to make in situ
measurements of biomass or bioactivity. As highlighted in Chap. 1, such mea-
surements should be in real time, a feature which is possible with dielectric
spectroscopy.