with high system pressures designed to optimize heat conduction
from shelf into product. Removing the product when sublimation
has been judged as complete will provide a product which appears
dry but which displays a high-moisture content that is invariably
too high (e.g., 10%) to provide long-term storage stability, and the
drying cycle is extended to remove additional moisture by desorption during secondary drying.
2.3.2 Secondary Drying
In contrast to primary drying, which is a dynamic process associated
with high vapor flow rates, secondary drying is much less efficient
with secondary drying times typically representing between 10%
and 25% of the total process time but only removing a small fraction
of the total water initially present in the liquid formulation. Under
secondary drying conditions, the product approaches steady-state
conditions where moisture is desorbed or absorbed from or into
the product in response to relative humidity and shelf temperatures.
Desorption is favored by increasing shelf temperature, using highvacuum conditions in the chamber, thereby reducing the system
vapor pressure or relative humidity. Conversely, when the shelf
temperature is reduced and the vapor pressure in the system
increased by warming the condenser, dried products will reabsorb
moisture and exhibit an increase in moisture content. Although
product collapse during secondary drying is generally less likely
than collapse during primary drying, it is possible to induce collapse
in the dried matrix by exposing the product to temperatures above
its glass transition temperature (T g ).
2.4 Stoppering
the Product
A freeze-dried product will generally be very hygroscopic and have
a very high-specific surface area (typically in the order of 1–10 m
2
per g, depending primarily on solute density and freezing conditions). Consequently, exposing the dried product to atmospheric
conditions will result in reabsorption of atmospheric moisture into
the product. Both water and air are damaging to a dried product,
causing degradative changes resulting in poor stability; it is therefore prudent to stopper the product within the freeze-dryer prior to
removal. It may also be necessary to dry stoppers prior to use or
ensure appropriate low-moisture stoppers are used to prevent damage by moisture ingress from the stopper during the shelf life of the
product post-lyophilization; the significance of this will be dependent on the amount and properties of the product. Stoppering
under a full vacuum (low pressure) provides ideal conditions for
ensuring product stability because reactive atmospheric gases are
reduced to a minimum. However, injecting water into a product in
a fully evacuated vial can induce foaming, which can be reduced by
back filling vials with an inert gas, such as nitrogen, before stoppering. Maintaining a certain level of vacuum, e.g., 0.5–0.9 Atmospheres, can help ensure a good stopper/vial seal is achieved while
preventing foaming during rehydration.
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Kevin R. Ward and Paul Matejtschuk
from shelf into product. Removing the product when sublimation
has been judged as complete will provide a product which appears
dry but which displays a high-moisture content that is invariably
too high (e.g., 10%) to provide long-term storage stability, and the
drying cycle is extended to remove additional moisture by desorption during secondary drying.
2.3.2 Secondary Drying
In contrast to primary drying, which is a dynamic process associated
with high vapor flow rates, secondary drying is much less efficient
with secondary drying times typically representing between 10%
and 25% of the total process time but only removing a small fraction
of the total water initially present in the liquid formulation. Under
secondary drying conditions, the product approaches steady-state
conditions where moisture is desorbed or absorbed from or into
the product in response to relative humidity and shelf temperatures.
Desorption is favored by increasing shelf temperature, using highvacuum conditions in the chamber, thereby reducing the system
vapor pressure or relative humidity. Conversely, when the shelf
temperature is reduced and the vapor pressure in the system
increased by warming the condenser, dried products will reabsorb
moisture and exhibit an increase in moisture content. Although
product collapse during secondary drying is generally less likely
than collapse during primary drying, it is possible to induce collapse
in the dried matrix by exposing the product to temperatures above
its glass transition temperature (T g ).
2.4 Stoppering
the Product
A freeze-dried product will generally be very hygroscopic and have
a very high-specific surface area (typically in the order of 1–10 m
2
per g, depending primarily on solute density and freezing conditions). Consequently, exposing the dried product to atmospheric
conditions will result in reabsorption of atmospheric moisture into
the product. Both water and air are damaging to a dried product,
causing degradative changes resulting in poor stability; it is therefore prudent to stopper the product within the freeze-dryer prior to
removal. It may also be necessary to dry stoppers prior to use or
ensure appropriate low-moisture stoppers are used to prevent damage by moisture ingress from the stopper during the shelf life of the
product post-lyophilization; the significance of this will be dependent on the amount and properties of the product. Stoppering
under a full vacuum (low pressure) provides ideal conditions for
ensuring product stability because reactive atmospheric gases are
reduced to a minimum. However, injecting water into a product in
a fully evacuated vial can induce foaming, which can be reduced by
back filling vials with an inert gas, such as nitrogen, before stoppering. Maintaining a certain level of vacuum, e.g., 0.5–0.9 Atmospheres, can help ensure a good stopper/vial seal is achieved while
preventing foaming during rehydration.
116
Kevin R. Ward and Paul Matejtschuk