Lyophilization or freeze drying of injectable pharmaceuticals is a well-established and extensively practiced process (1–3). Although used for several conventional and biotechnology-based drug products, the process remains complex, time consuming, and cost intensive. For successful lyophilization, each of the three stages (i.e., freezing, primary drying, and secondary drying) must be fully executed before the cycle proceeds to the next stage. Furthermore, various mechanical and control systems of the lyophilization unit must maintain process conditions within narrow limits to ensure uniform quality and dryness throughout the entire batch. For production-scale batch sizes on the order of 10,000–100,000 vials, the importance of tight process control is evident, even more so when expensive products such as biotechnology-based drugs are processed.
The lyophilization cycle recipes in current use can be broadly classified into two groups: those based on product-temperature cycles and those based on shelf-temperature time cycles. In the first, product temperatures are monitored continuously throughout the cycle by means of temperature probes that are inserted into representative vials within the load. The cycle conditions required to advance to the next portion of the cycle are product temperature–based or progress of the cycle is controlled by product temperatures. For example,
In cycles based on shelf-temperature time, product-temperature probes are often used to help evaluate the effect of cycle deviations on product quality. By definition, the probes are not used to control the progress of a cycle. In practice, the distinction between these two methods of process control is important because measurement of product temperature(s) during routine production operation tends to vary because of the number of factors such as inconsistency in manual placement of the probes, differences in geometry of the probes, location of the probe tips, and so forth. Moreover, with modern lyophilizer units where loading and unloading of the vials is performed using an automated system through a partial door ("pizza door"), placement of temperature probes has become almost impossible. In cycles based on product temperature, variability in the length of various segments of the cycle may occur because of the dependence on product-temperature probes. Cycles based on shelf-temperature time, by comparison, are highly reproducible and vary relatively little with respect to the length of the individual cycle segments, or the length of the overall cycle. Other methods for monitoring the progress of lyophilization cycles have been reported such as barometric, manometric, and pressure-rise measurement (4–6). These methods, however, need retrofitting to the existing equipment with new hardware and/or more extensive process qualification and validations.Lyophilization cycles are frequently transferred from one lyophilizer unit to another because of a number of factors such as change of site of manufacture, a change of scale, or to allow flexibility within a plant to accommodate scheduling, maintenance, or repair. The approach required for a successful transfer will depend to some extent on the type of cycle being transferred. Cycles based on product temperature are less affected by differences in the lyophilization equipment used because the effect of these differences on product temperatures is automatically compensated for by the method of cycle step control. For shelf-temperature-time–based cycles, functional equivalence of the equipment used is required for consistent product-cycle transfer. The transfer of product cycles between units that are not functionally equivalent may require modifications to the cycle recipe and considerable revalidation effort. Currently, there exist reports on lyophilization process qualifications and transfer of cycles (7–9), but there are no specific industry procedures or regulatory guidelines available that can be used for the transfer of lyophilization cycles across lyophilizers. A recent general report describes some of the factors that must be considered during such a transfer process (10).
In this article, the authors develop a comprehensive methodology to establish functional equivalence between different lyophilizers. Once functional equivalence between units is established, test requirement and validation protocols may be optimized, resulting in considerable savings of time, resources, and capital. Such a procedure is extremely desirable in large manufacturing operations, where multiple lyophilizer units are used within or across the plants. The following approach was used: