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Evaluating Functional Equivalency as a Lyophilization Cycle Transfer Tool
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:
Rationale of methodology
Comparability of relevant technical characteristics of the lyophilizer units. As long as the critical process parameters such as shelf temperature, chamber pressure, condenser temperature, and duration of various cycle steps are held within a specified range, the drying profile as well as the quality of the final product will remain consistent from batch-to-batch, irrespective of the lyophilizer unit used. The majority of commercial lyophilization cycles in use today are very conservative with respect to equipment capacity. That is, the maximum operating capacities of various systems such as refrigeration, vacuum system, shelf-temperature control, load of water to be sublimed versus condenser capacity, and so forth are not challenged during the course of routine production cycles. This fact enhances the reliability of production and allows for a successful cycle transfer between apparently dissimilar units. In such case, as long as the selected cycle parameters are within the performance envelope of a given lyophilizer, the cycle can be reliably executed within narrow process limits. However, in some instances, not only good control of the lyophilization parameters (including the chamber pressure, shelf temperature, duration, and so forth) are necessary for scale up, but also there must be comparability of the lyophilizer unit dependent factors such as shelf area, finish of the shelf material (e.g., thickness of the shelf wall), and the heat-transfer rate (e.g., ice sublimation rate in primary drying).
There are, however, several equipment characteristics that may have a pronounced effect upon the course of the typical lyophilization cycle. These characteristics include the type of vacuum instrumentation (e.g., capacitance manometer or thermocouple gauge), method of pressure control (e.g., bleed gas or vacuum valve stifling), shelf-temperature uniformity, and range of shelf-temperature thermo regulation. These technical characteristics are easily evaluated by surveying the equipment and equipment specifications and reviewing data generated during the initial and subsequent routine qualifications (11). The authors reviewed selected technical characteristics of three production-scale lyophilizers (labeled A420FT, B420FT, and C220FT).
Comparison of sublimation rate studies using mannitol solution. Each of the three consecutive stages in lyophilization cycle (i.e., freezing, primary drying, and secondary drying) must be fully executed to yield a dry product with consistently low residual moisture. Although the final moisture level throughout the lot reaches a constant low value at the end of terminal drying, the drying rates of individual vials during earlier stages of the cycle may be different in the load such that some vials may dry faster than others. As the drying progresses, the remaining vials eventually catch up and the entire lot is fully dry and attains a low uniform residual moisture level after a sufficiently long period of drying. Such intermediate non-uniformity of drying rate generally occurs because of vial-related factors (e.g., differences in vials, freezing-time differences, location of vials, variability in stopper placement) or equipment-related factors (e.g., shelf temperature gradients during temperature ramps, radiant heat from the chamber walls and door).
In experiments performed in the laboratory using a pilot-scale lyophilizer (25 ft2, 40-L condenser capacity), the drying rate profiles during the early part of sublimation (primary drying) were within ±10% of each other in three separate but identical runs. The runs were performed using trays of vials filled with 62-mL mannitol solutions in 100-cm3 glass vials.
Because a given lyophilizer unit is, by definition, functionally equivalent to itself, application of this same limit to a comparison of drying rates between different lyophilizer units provides a rational approach for functional equivalence. Thus, the limit of ±10% variability within different units was selected as the acceptance criteria for functional equivalence.
For the direct comparison of lyophilizer units A420FT (420-ft2 shelf surface area), B420FT (same model as A420FT but has longer vapor path between the condenser and vacuum pumps), and C220FT (220-ft2 shelf surface area), vials containing mannitol solutions were used and the initial rate of sublimation drying was studied in Type I borosilicate glass vials of 100-cm3 capacity. The concentration of mannitol was kept at 5.82% w/v in water for injection (which corresponded to the percent solid composition of a solution for lyophilization of a commercial product). After completion of the freezing process, sublimation drying was conducted for as long as 16 h at the first shelf-temperature regimen of primary drying. The cycle was interrupted and the amount of water lost because of sublimation was calculated by the difference in weights. The drying rates of trays of corresponding locations among three lyophilizer units were compared.
Cycle parameters for these trials were selected on the basis of existing production cycles executed in the units under study. The rationale for conducting only a partial cycle was to magnify the profiles of drying-rate kinetics, which is highly variable among individual vials during the early part of primary drying of a lyophilization cycle. If the cycle was allowed to proceed to completion, then all the vials would be equally dry to a very low level of residual moisture and comparison of the kinetics of drying would not reveal any meaningful differences.
Comparison of process parameters during cycles. The drying-rate studies were conducted in full and partially loaded conditions. Data from these cycles were used for comparison. Under full-load conditions (210 trays), a large amount of solution (~800 kg) is subjected to the lyophilization process. Such a large load of water to be sublimed represents the worst-case scenario in which the aspect ratio of the load versus the condenser capacity was close to 90%, when normally, only 60–70% range is recommended by the equipment manufacturers. Under such conditions, the system capabilities are fully challenged. Hence, the flawless execution of the lyophilization cycles (i.e., maintaining all the independent and dependent parameters within narrow limits) confirms that these units are indeed capable of the performance according to the set parameters and that the profiles generated are comparable to each other.
Materials and methods
Comparison of process parameters during cycles. Shelf-temperature, condenser-temperature, and chamber-pressure profiles during the lyophilization runs were compared in lyophilizers under partial-load and full-load conditions, and the process parameter data were analyzed following the runs to determine the extent of agreement from unit to unit.
All of the critical hardware and the process control and monitoring mechanisms among the lyophilization units studied were comparable to each other. This similarity supports the hypothesis that the programmable cycle parameters such as shelf temperature, chamber pressure, and time duration of various stages will be executed identically in these units. Even during the early period of drying (when the greatest variability in the sublimation dry rate is expected), the observed rates of sublimation drying were quite close to each other, i.e., 1.79% and 3.21% in fully loaded and partially loaded conditions, respectively. Even under fully loaded conditions and relatively aggressive cycle conditions of the shelf temperature regimen, the lyophilization cycles were executed smoothly as seen by the maintenance of all the independent and dependent parameters (as reflected by the mean product temperatures) within the narrow limits of specifications confirming functional equivalency of these units. In a follow-up study, a set of four commercial large-scale lyophilizers (420-ft2 shelf area) were evaluated for functional equivalency. The validation matrix to use these multiple lyophilizer units for a commercial product was minimized, thereby saving resources and time.
These results provide the basis to establish functional equivalence among different lyophilizers. Once established, functional equivalence can facilitate successful implementation of scale-up and transfer of lyophilization cycles. Such equivalency procedures are desirable in large manufacturing operations, where multiple lyophilizers are used for processing a common lyophilized product, and reduced validation campaigns based upon a matrixing approach can save considerable resources and time.
Amol Mungikar, PhD, is a research investigator; Miron Ludzinski is a senior research scientist, and Madhav Kamat, PhD, RPh,* is a senior principal scientist at Biopharmaceutics R&D, Drug Product Processing and Packaging Technologies, Bristol-Myers
Squibb Company, One Squibb Drive, New Brunswick, NJ 08993, Madhav.email@example.com
*To whom all correspondence should be addressed.
Submitted: Mar. 17, 2008. Accepted: Apr. 24, 2009.
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