Lyphilization Cycle And Controls Of Lyophilizers

Lyphilization Cycle And Controls Of Lyophilizers

       After sterilization of the lyophilizer and aseptic loading, the initial step is freezing the solution. In some cycles, the shelves are at the temperature needed for freezing, while for other cycles, the product is loaded and then the shelves are taken to the freezing temperature necessary for product freeze. In those cycles in which the shelves are precooled prior to loading, there is concern for any ice formation on shelves prior to loading. Ice on shelves prior to loading can cause partial or complete stoppering of vials prior to lyophilization of the product. A recent field complaint of a product in solution and not lyophilized was attributed to preliminary stoppering of a few vials prior to exposure to the lyophilization cycle. Unfortunately, the firm's 100% vial inspection failed to identify the defective vial.

       Typically, the product is frozen at a temperature well below the eutectic point. 

       The scale-up and change of lyophilization cycles, including the freezing procedures, have presented some problems. Studies have shown the rate and manner of freezing may affect the quality of the lyophilized product. For example, slow freezing leads to the formation of larger ice crystals. This results in relatively large voids, which aid in the escape of water vapor during sublimation. On the other hand, slow freezing can increase concentration shifts of components. Also, the rate and manner of freezing has been shown to have an affect on the physical form (polymorph) of the drug substance. 

        It is desirable after freezing and during primary drying to hold the drying temperature (in the product) at least 4-5o below the eutectic point. Obviously, the manufacturer should know the eutectic point and have the necessary instrumentation to assure the uniformity of product temperatures. The lyophilizer should also have the necessary instrumentation to control and record the key process parameters. These include: shelf temperature, product temperature, condenser temperature, chamber pressure and condenser pressure. The manufacturing directions should provide for time, temperature and pressure limits necessary for a lyophilization cycle for a product. The monitoring of product temperature is particularly important for those cycles for which there are atypical operating procedures, such as power failures or equipment breakdown. 

        Electromechanical control of a lyophilization cycle has utilized cam-type recorder-controllers. However, newer units provide for microcomputer control of the freeze drying process. A very basic requirement for a computer controlled process is a flow chart or logic. Typically, operator involvement in a computer controlled lyophilization cycle primarily occurs at the beginning. It consists of loading thechamber, inserting temperature probes in product vials, and entering cycle parameters such as shelf temperature for freezing, product freeze temperature, freezing soak time, primary drying shelf temperature and cabinet pressure, product temperature for establishment of fill vacuum, secondary drying shelf temperature, and secondary drying time.

        In some cases, manufacturers have had to continuously make adjustments in cycles as they were being run. In these situations, the lyophilization process was found to be non-validated.

        Validation of the software program of a lyophilizer follows the same criteria as that for other processes. Basic concerns include software development, modifications and security. The Guide to Inspection of Computerized Systems in Drug Processing contains a discussion on potential problem areas relating to computer systems. A Guide to the Inspection of Software Development Activities is a reference that provides a more detailed review of software requirements. 

        Leakage into a lyophilizer may originate from various sources. As in any vacuum chamber, leakage can occur from the atmosphere into the vessel itself. Other sources are media employed within the system to perform the lyophilizing task. These would be the thermal fluid circulated through the shelves for product heating and cooling, the refrigerant employed inside the vapor condenser cooling surface and oil vapors that may migrate back from the vacuum pumping system. 

        Any one, or a combination of all, can contribute to the leakage of gases and vapors into the system. It is necessary to monitor the leak rate periodically to maintain the integrity of the system. It is also necessary, should the leak rate exceed specifiedlimits, to determine the actual leak site for purposes of repair. 

        Thus, it would be beneficial to perform a leak test at some time after sterilization, possibly at the beginning of the cycle or prior to stoppering. The time and frequency for performing the leak test will vary and will depend on the data developed during the cycle validation. The pressure rise found acceptable at validation should be used to determine the acceptable pressure rise during production. A limit and what action is to be taken if excessive leakage is found should be addressed in some type of operating document.  

        In order to minimize oil vapor migration, some lyophilizers are designed with a tortuous path between the vacuum pump and chamber. For example, one fabricator installed an oil trap in the line between the vacuum pump and chamber in a lyophilizer with an internal condenser. Leakage can also be identified by sampling surfaces in the chamber after lyophilization for contaminants. One could conclude that if contamination is found on a chamber surface after lyophilization, then dosage units in the chamber could also be contaminated. It is a good practice as part of the validation of cleaning of the lyophilization chamber to sample the surfaces both before and after cleaning. 

        Because of the lengthy cycle runs and strain on machinery, it is not unusual to see equipment malfunction or fail during a lyophilization cycle. There should be provisions in place for the corrective action to be taken when these atypical situations occur. In addition to documentation of the malfunction, there should be an evaluation of the possible effects on the product (e.g., partial or complete meltback. Refer to subsequent discussion). Merely testing samples after the lyophilization cycle is concluded may be insufficient to justify the release of the remaining units. For example, the leakage of chamber shelf fluid into the chamber or a break in sterility would be cause for rejection of the batch.

       The review of Preventive Maintenance Logs, as well as Quality Assurance Alert Notices, Discrepancy Reports, and Investigation Reports will help to identify problem batches when there are equipment malfunctions or power failures. It is recommended that these records be reviewed early in the inspection.