Control systems, freeze-drying

Velardi, S. A., Barresi, A. A., 2008b. Method and system for controlling a freeze drying process. International Publication No. WO/ 2008/034855, World Intellectual Property Organization. 

In pharmaceutical systems, both heat and mass transfer are involved whenever a phase change occurs. Lyophilization (freeze-drying) depends on the solid-vapor phase transition of water induced by the addition of thermal energy to a frozen sample in a controlled manner. Lyophilization is described in detail in Chapter 16. Similarly, the adsorption of water vapor by pharmaceutical solids liberates the heat of condensation, as discussed in Chapter 17. 

Fig. 1.69. Course of a freeze drying process during which Tke has not been kept constant at -26.8 °C. To avoid the declining temperature, either Tsh could have been increased after 2 h (difficult to control, the inertia of the heating system is substantial) or pc increased until Tkt is constant at -26,8 °C. 1, pch (TM) 2, pch (CA) 3, Tpt (RTD) 4, Tke (BTM) 5, end of pressure control.

The control system of a freeze drying plant should allow to program the following data independently from each other during manual operation ... 

In modern freeze-drying systems, the filter integrity test is carried out automatically. All the relevant process parameters are documented by the control system of the unit. The important thing is to make sure that after every integrity test, the filter and the entire piping system are perfectly dry. This is effected by means of the installed liquid ring pump. 

The control system of the freeze-drying unit provides control, monitoring and documentation of the process. Such a system must be reliable and comply with GM P and GAMP (Good Automation Manufacturing Practice) demands with respect to computer validation. It should be SCADA (Supervisory Control and Data Acquisition) compatible. A possible hardware architecture is shown in Figure 2.55.1. 

Peak levels of the drug were observed at 4-6 h postadministration in the cases of the solid dispersion systems. In the case of dicumarol crystal powder, peak levels were observed at 2 to 12 hours postadministration. Average AUC values (0 8 h) of dicumarol following the administration of the dicumarol-PVP solid dispersion systems were 3.31 times (coevaporation method) and 1.54 times (freeze-drying method) that of control. The corresponding numbers for p-cyclodextrin dispersions were 2.18 and 1.72. 

Buffers are often added to control pH, but caution must be exercised when buffers are used in a formulation to be freeze dried. As discussed earlier, crystallization of either buffer component (acid or base) during freezing may cause a significant pH shift during freezing, thereby causing greater pH variation than would have been obtained in an unbuffered system. 

Risbud, M.V. Hardikar, A.A. Bhat, S.V. Bhonde, R.R. pH-sensitive freeze-dried chitosan-polyvinyl pyrrohdone hydrogels as controlled release system for antibiotic delivery. J. Control. Release 2000, 68, 23-30. 

Unlike manifold-based or batch drying, bulk drying allows no control of the conditions to which the product is exposed. Usually, the product is removed from the freeze-drying system prior to closure and then packaged in air-tight containers. Bulk drying is usually restricted to stable products scarcely vulnerable to oxygen and moisture. 

The dryer should possess temperature sensors to measure the shelf and product temperatures throughout the freeze-drying process. Most freeze-dryers can be equipped with a computer system to control the pressure in the chamber and the shelf temperature as a function of time. The product temperature allows one to confirm that the shelf temperature and chamber pressure are within their preset limits. 

During freeze-drying, the condenser temperature creates a low-pressure zone in the dryer for vapour to migrate. Such a zone should therefore be maintained at a preset, low level. If such a level is exceeded, then a pressure rise in the system can cause the product to melt down. Freezer-dryers equipped with condenser overload controls automatically cool the shelves until the emergency is solved. 

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