Freeze driers come in all sizes from units that fit on a bench top and have limited (if any) shelf temperature control, to units for which the process can be carefully monitored and controlled and that can have in excess of 50 m2 of shelving. In addition to scale and complexity of operation, if the freeze drier is to be used to process material for therapeutic application, issues of Good Manufacturing Practice (GMP) will also apply (Cameron & Murgatroyd 1997). The intended use of a freeze drier must be known before the unit is designed, as retrofitting for a therapeutic application will probably not be practical. The cost of a GMP production-scale freeze drier is a sizeable component for any project budget and so it is vital that the system is planned to fit its intended use. A system for large-scale production of therapeutics with its associated filling equipment and controlled dispensing environment will be a multimillion pound project.
A schematic of a production-scale freeze drier is given in Figure 20.6. The same basic components are common to all large freeze driers. There is a sample chamber with temperature-controlled
shelves, along with a mechanism for stoppering of the containers in situ. This chamber is connected via a closable valve to the condenser chamber (although in some models the condenser can be integral with the main chamber). The water vapour sublimed from the product collects on the cooled condenser coils. Connected to the coolant pathway are compressors that provide cooling and warming to the shelves and condenser coils, and vacuum pumps that deliver the required vacuum. Internal pressure is monitored by pressure gauges and shelf temperature by thermocouples or resistance thermometers. The chamber can be flushed with inert gas and often there are means for the condenser coils to be rapidly thawed. On modern systems all of these items are controlled by a programmable Logic controller (PLC) and this interfaces to PC-based software, so that all of the operations are computer controlled and the parameter data collected and stored.
For therapeutic applications there will be basic requirements, irrespective of scale and whether filling is to be an automated or manual process. All parts in atmospheric contact with the product should be of 316-grade stainless steel. At least steam-in-place (SIP) and possibly chemical clean-in-place (CIP) systems should be built into the system to allow decontamination and sterilization between runs. The filling environment must be assured by use of downwards flow laminar air for loading and unloading operations. Suitable safety measures to prevent contamination from the operators (protective clothing/equipment) and equipment used (dedicated, sanitizable, pyrogen free) must be used. Vacuum Leak rate testing and filter integrity testing must be performed and meet specification. Operations should be well planned and controlled by standard operating procedures. Validation of the processes and equipment will be required. Validation should be of the freeze drier itself, its operating parameters, consistency of operation and limits of variability. Also, the cycle being used for any given product should be validated (including the acceptable range of variation permissible within individual containers of product in a single batch) and the limits set in terms of the variation in operating parameters that can occur at any given cycle step. In addition, the limit of variation in critical parameters must be determined for at least three and preferably more batches so that consistency of the freeze-dried product can be demonstrated. The temperature variation within a freeze drier will need to be determined by temperature mapping using calibrated thermocouples, across the shelves and between shelves. The coldest points within a freeze drier will need to be identified and used during validation of the steam sterilization cycles. The validation required for a pharmaceutical freeze drier has been outlined in a number of publications (Parenteral Society 1997; Bindschaedler 2004). Other useful information on GMP lyophilization applications is available on the FDA website (FDA 1998).
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