The industry is now at a turning point with the introduction of the PAT initiative by FDA, allowing organizations the freedom
to review current operating procedures, and introduce and apply new technology in the pursuit of greater process understanding.
The emphasis so far has been on final product testing, but the real benefits will only be realized with the introduction of
process monitoring systems early on in the product development life cycle. Providing detailed process knowledge in real-time
as early as possible optimizes the process, increases robustness and provides an opportunity for a 'right first time' approach.
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There is a vast array of monitoring technologies available. Most have been adapted and modified from existing laboratory techniques
and, while providing useful information, are highly susceptible to process changes — making multiple calibrations and complex
modelling the standard operating procedure. These techniques are typically more suited to the final production stages where
very few changes are likely to occur. Prior to this, the nature of the work involves at least some degree of change or optimization,
which makes retuning and inherently recalibration a daily occurrence.
Central to the strategies adopted by most organizations will be to utilize robust and flexible technologies to address the
industry's evolving needs. A number of novel or improved analytical techniques have been developed as we seek innovative
methods of monitoring the nature and behaviour of drugs, formulations and processes. These often involve a high degree of
sophistication not only in relation to the monitoring system and algorithms, but also in terms of the experience and training
required to interpret the data. The ideal scenario would include key parameter that could be simply and unambiguously monitored
and interpreted. One of the most fundamental parameters that has largely been forgotten is temperature.
Every process produces either an endothermic or exothermic change (or both). It is a direct measurement of change in any process,
and its control and monitoring is an area that should and could be exploited to dramatically improve the level of understanding
of a process — greatly reducing the time for scale-up. Calorimetry can address process issues across all areas of an API's life cycle from laboratory development through to the
full-scale manufacture. It is only the limitations in the existing technology that has held back its application as a universal
monitoring technique.
Reactor design and temperature control
Figure 1
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Reactor design. The majority of APIs are developed and manufactured using a constantly stirred batch reactor, which despite numerous step
changes still relies on the same approach for controlling the temperature that was developed more than 100 years ago. These
systems continue to provide sufficient quantities of all pharmaceutical products required by the market, but the efficiencies
and costs of these processes are less than optimum. One fundamental issue inherent in the design of these systems is the inability
to provide responsive temperature control (Figure 1). The two illustrations in Figure 2 show the basic configuration applied
to both the laboratory- and industrial-sized reactor.
Figure 2
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Temperature control. In terms of temperature control, the basic design and concept of a large reactor does not change significantly from the systems
used in the laboratory. The process temperature in the systems is controlled by varying both the temperature and flow rate
of the heat transfer fluid (HTF) surrounding the vessel.
The volume of HTF employed at such a large scale simply makes this level of control impossible, severely compromising the
carefully developed method from the laboratory. In addition, the surface to volume ratio of the larger vessels also places
the engineer at a severe disadvantage when trying to scale the data generated by a 1 L to 100 L reactor, requiring crude estimates.
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