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.