Pressure primary-drying control

The chamber pressure during the sublimation step (i.e. the primary drying process) has been found to be related to the product and shelf-surface temperatures [8] however, determining the shelf temperature required is more difficult as it depends on the nature of the heat transfer fluid used to control the shelf temperature and also on the particular design of the freeze-dryer. 

For safety reasons, the pressure is set in such a way that the temperature is 5°C below the melting point of the product. On an hourly basis, the freeze-dryer automatically uses a drain valve to allow the pressure within the system to drop. A simultaneous fall in product temperature is indicative of the presence of frozen solvent that should thus be extracted during the sublimation or primary drying step. Detecting any residual solvent in this way avoids the risk of the product melting down. Before the desorption step is started, this pressure control cycle is repeated until no further drop in product temperature is observed. 

The co-solvent system that has been most extensively evaluated was the tert-butanol/water combination. The tert-butanol possesses a high vapor pressure, freezes completely in most commercial freeze-dryers, readily sublimes during primary drying, can increase sublimation rates, and has low toxicity. This co-solvent system is being used in the manufacture of a marketed injectable pharmaceutical product. When using this solvent system, both formulation and process control required optimization to maximize drying rates and to minimize residual solvent levels at the end of drying. 

The effects of pressure variations, as they occur when pressure is controlled independently via calibrated leaks, are more complicated [6-12]. In many cases, an increase in chamber pressure favors ice sublimation and is reflected in a shorter primary drying time because of the improved thermal exchanges and of the higher product temperature [6,10 12]. 

Compared to lyophilization under maximum vacuum, the implementation of calibrated leaks during primary drying offers a number of advantages. The primary drying of the product is shortened, and therefore a few hours can be saved on the overall cycle time. In the same equipment, the batch size can be varied within wide limits with minimal effects on cycle time and on product properties. The transposition of the cycle to another freeze-drier and the scale-up operations are facilitated, as the control of the pressure level minimizes the effects of conceptual differences among lyophilizers. Noteworthy differences in drying rate will be attenuated under constant pressure conditions. Technology transfers are also made easier. If the source... 

Fig. 5.9 Comparison of (a) product temperature as estimated by pressure rise test technique and (b) chamber pressure profiles during primary drying for , solid line) uncontrolled and (O, dashed line) controlled...

While the operator was away from the primary-side control station, the pressurizer PORV opened and closed twice without his knowledge. The pressure had increased because of the continued heatup of the reactor coolant system that resulted when both steam generators had essentially boiled dry. 

Gieseler et al. utilized tunable diode laser absorption spectroscopy to detect water vapor concentrations, gas velocities and mass flow during freeze-drying of pure water at different pressure and shelf temperature settings and of a 5%w/w mannitol solution. The analyzer was interfaced to the spool that connected the dryer chamber to the condenser. The reported method was advantageous in that primary and secondary drying end-point control based upon mass flow rate was independent of freeze-dryer size and configuration. ... 

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