Shelf primary-drying control

Searles, J.A., Carpenter, J.F., Randolph, T.W. The ice nucleation temperature determines the primary drying rate of lyophilization for samples frozen on a temperature-controlled shelf. PDAJ. Pharm. Sci. Technol. 90, 860-871, 2001... 

Primary drying Evacuate chamber, control at a target set point of 80 pHg ( 20 pHg). Ramp shelf to —10 C at an average controlled rate of 30°C/hr Control shelf at target set point of —10 C ( 5°) for 15 hr... 

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. 

A reliable control of the product temperature throughout the process is of the utmost importance, especially during the primary drying stage. In practice, such control can only be exercised through changes in the shelf... 

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. ... 

Typically, the drying process can be divided into primary and secondary phases. During the primary phase, the drug solution is filled into vials and then placed within a temperature-controlled drying chamber. There, the solution is frozen according to physiochemical principles as the shelf temperature is lowered to below freezing. The shelf temperature is... 

It has already been mentioned that there exists no absolute dividing line between primary and secondary drying. However, for practical purposes of process control and economy, it is important to establish the point of completion of sublimation, i.e. the removal of all ice from the product. The interested reader is directed to the literature, where available techniques have been described and compared in detail.The most direct indicator of ice removal is the chart recorder output of the product temperature. As sublimation nears completion, the product temperature rises, dually to reach the shelf temperature. A practical problem lies in the difficulty of measuring the temperature of the dried cake in a reliable manner, and in the atypical drying behaviour of any vial that carries a temperature probe. 

The risk of chemical instability can be assessed from the primary sequence of the protein. The sequence containing labile amino acids such as Asn-Gly and Met would be indicative of potential instability issues. The rate of chemical reactions that alter the primary sequence of the protein is higher in solution conditions and can limit the shelf-life of protein therapeutics. As the mobility of reactants is minimized in the solid state, freeze-drying is often attempted to improve the stability [16]. In such instances, physical instability is a major issue to be dealt with. Freezedrying, also termed as lyophilization, is a dessication process in which the solvent (usually water) is first frozen and then is removed by sublimation in a vacuum [17]. In other words, the protein in solution is frozen, producing discrete ice and solute crystals. The solid ice is sublimed. Controlled heating desorbs any of the tightly bound water. 

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