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,
- Cool shelves to –45 °C or below and hold until all product temperatures (or average of all product temperatures) are below
–40 °C. The cycle will not move to the next step until step requirement is met.
- Freeze all product at –40 °C or below for at least 3 h.
- Advance to next step.
- Alternatively, in a cycle based on shelf-temperature time, the conditions required to advance to the next step are independent
of the product temperatures. For example,
- Cool shelves to –40 °C or below
- Maintain shelf-fluid temperature at ≤ –40 °C for 4 h
- Advance to the next step.
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
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:
- Evaluate comparability of relevant technical characteristics of the lyophilizer units
- Compare sublimation rates using a model compound
- Compare lyophilization process parameters during the cycles (i.e., the ability of the units to properly maintain all independent
parameters within the narrow limits of specifications throughout the trials).