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physical structure integrity of the cake), the
freeze-drying product viscosity is lowered and an irreversible
reeze-drying, a leading drying technology,
process from a is widely used in the biopharmaceutical melting may occur.
glass bottle to industry to stabilize products.1 Although Such a collapse can result in the rejection of
a freeze-drying it is predominantly used for the storage a partial or total batch.
of active ingredients before reconstitution into Initial freezing of the product involves two
tray. steps: ice nucleation followed by ice crystal
a final formulation, it also may be useful for
some stages of intermediate production, such growth. Once the solidification temperature is
as Active Pharmaceutical Ingredient (API) reached, all other elements of the formulation
operations. are typically rendered an amorphous solid.
A freeze-drying cycle may be divided into The sublimation phase is an endothermic
three stages.2,3 First, the product is frozen at a process which is controlled predominantly by
sufficiently low temperature to reach a vitreous shelf temperature and chamber pressure. Nu-
state where pure water has crystallized and merous other factors (such as container heat
the amorphous content remains in the inter- transfer coefficient, container geometry, stopper
W. L. Gore & Associates, Inc.
stitial region. In the second stage, the product design, freeze-dryer geometry, freezing behavior,
401 Airport Road
undergoes sublimation at a temperature below fill depth, formulation type and concentration,
P.O. Box 1550
the glass transition or collapse temperatures and the robustness of the filling process) also are
Elkton, MD 21922-1550
and crystallized water is sublimed. Finally, important and together contribute to the product
USA
secondary drying is undertaken at a higher temperature at the interface where the water
Phone: 410.392.4440 (US)
temperature to remove sorbed water from the crystals sublimate. The product temperature is
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interstitial region. kept below collapse temperature with a safety
Email: lyoguard@wlgore.com
Maintenance of correct temperatures margin during the whole cycle. At the end of
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throughout the whole process is essential. In- this stage, products with conforming visual
deed, if the product temperature rises above the aspect and homogeneous moisture content are
collapse temperature1 (maximum temperature obtained. The high number of parameters influ-
allowed during the freeze-drying process to keep encing this process explains why it is so difficult
Figure 1. Product
weight profile during
freeze-drying using a
microbalance, at the end
of primary drying (48
hours), moisture content
is 12%, at the end of
secondary drying (60
hours), moisture content
is 1.3%.
Figure 5. Lyophilization Cycle A - in blue, the temperature cycle, Figure 6. Lyophilization Cycle B - in blue, the temperature cycle, in
in pink, pressure cycle. pink, pressure cycle.
radiation may induce a temperature gradient from chamber container validation was a time consuming process, taking
center to its periphery, which may ultimately cause water and over 200 working hours.
organic solvent content heterogeneity within the lyophilized
cake. In order to test for homogeneity, samples from a single Lyophilization Cycles
batch were removed from membrane trays placed on the lowest Cycle A
and middle shelves of the lyophilization chamber (i.e., closest As seen from the temperature recordings, at the end of the
to the condenser at the coolest part and at the warmest part primary drying phase (after 42 hours), the cake temperature
of the chamber, respectively - Figure 7. did not reach a plateau approximating to shelf temperature
- Figure 10.
Freezing Conditions
The effects of rapid and slow freezing were compared on the
same bulk by loading parts of the lot on freeze-dryer shelves at
two different temperatures (0°C and ‑45°C). The end products
were analyzed with respect to organic solvent content, using
a moisture testing device, and product particle size.
Results
Non-Optimized Process Evaluation
Freezing Time
The freezing process in large bottles on pre-cooled shelves
was long; taking two and six hours to reach ‑40°C and ‑45°C,
respectively - Figure 8.
This extended freezing time was predominantly due to Figure 10. Lyophilization cycles (a). In pink, shelf temperature; in
bottle geometry, which results in a poor capacity for the first yellow and blue, the measured sample temperature (at the middle
ice layer to dissipate the water crystallization exotherm. and at the top of the cake); in dark blue, the measured pressure, in
brown, the measured condenser temperature. During lyophilization
cycles illustrated in A, sample temperature hardly reached a
Primary Drying Cycle Length plateau value after 42 hours, indicating that lyophilization was not
The freeze-drying cycle time using glass bottles was 160 completely finished (primary drying: OK, secondary drying: absent).
hours - Figure 9. The product temperature from the vial bot- During the lyophilization cycle illustrated in 14b, real pressure value
tom reached positive temperature after 140 hours indicating was higher than the set value. This indicates an excessive vapor
the end of the sublimation endoderm. flux, at least during the first 10 hours of the primary drying.
Glass Integrity – Lensing In addition, there was a discrepancy between the target cham-
When a product is freeze-dried in large bottles, there is a ber pressure and the effective pressure, indicative of excessive
tendency for the bottle bottom to weaken as a result of freez- vapor flux at the beginning of the sublimation process.
ing and subsequent ice expansion, resulting in a lens shaped
fracture. During stoppering, the fragile glass released tension Cycle B
by cracking or fully breaking in a lens shape. As seen in Figure 11, the sample temperature reached a
plateau before the end of the primary drying sequence, indi-
New Process Evaluation cating that the ice had been completely sublimated out of the
Membrane Trays sample before the secondary drying sequence commenced. In
An analysis of the leachable and extractables studies done addition, there was no discrepancy between the set-up and
following the USP and EP guidelines showed that the trays real chamber pressure measurements. No membrane tray
were suitable for this application. This portion of the new inflation was observed using this cycle.
Published in Pharmaceutical Engineering, March/April 2009; Copyright 2008. All rights reserved. This file is for web posting only;
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