The use of these techniques allows for far more rapid development of appropriate freeze-drying conditions, and the widespread
availability of these two techniques in particular has revolutionized
how freeze-drying development is done in the commercial sector as
well as in academic research.
Powerful experimental design techniques such as Design of
Experiments (DoE) can be applied to the screening of freezedrying formulations [34] using data derived from thermal analysis
or FDM, and this can be used to design a freeze-drying cycle. This
type of information can be fed then into process analytical technology to scale-up and optimize freeze-drying cycles at medium- and
even large-scale using statistical principles and process
mapping [35].
4 Scale-Up Factors and PAT
The need to operate the freeze-dryer under low-pressure conditions to convert ice directly into water vapor (sublimation) adds to
the complexity and cost of dryers because the chamber holding the
product must withstand the differential pressure from vacuum to
atmosphere. Although a suitable vacuum pump is essential for
initially evacuating the chamber and eliminating air that may leak
into the dryer during operation, vacuum pumps are not capable of
continuously removing water vapor subliming from the product,
and a refrigerated trap (termed the process condenser) must be
placed between the product and the pump to condense the moisture migrating from the drying product. In reality, it is the condenser that comprises the “pumping force” of the system. Process
condensers may be incorporated into the drying chamber (referred
as an internal condenser) or located in a separate chamber between
the product chamber and pump (external condenser). Each geometry has advantages and disadvantages although either design may
be used. Stainless steel is typically used to fabricate research or
production dryers because this metal can be cleaned by a wide
range of sanitizers including steam. For GMP manufacture the
freeze-dryer is invariably sterilized by pressurized steam, and this
adds to the complexity and expense of the dryer because it must
conform to the requirements to operate under these conditions
(i.e., it must be a certified pressure vessel) as well as under the
sub-atmospheric pressure conditions to which it will be subjected
during the lyophilization process (i.e., as a vacuum vessel). Modern
freeze-dryers are also fitted with internal stoppering devices for
sealing vials at the end of the cycle, valves and monitoring devices
for assessing drying efficiency, and are typically computer or microprocessor controlled so that cycles can be reproduced and evaluated
for regulatory purposes. When freeze-drying vaccines, it may be
122
Kevin R. Ward and Paul Matejtschuk
availability of these two techniques in particular has revolutionized
how freeze-drying development is done in the commercial sector as
well as in academic research.
Powerful experimental design techniques such as Design of
Experiments (DoE) can be applied to the screening of freezedrying formulations [34] using data derived from thermal analysis
or FDM, and this can be used to design a freeze-drying cycle. This
type of information can be fed then into process analytical technology to scale-up and optimize freeze-drying cycles at medium- and
even large-scale using statistical principles and process
mapping [35].
4 Scale-Up Factors and PAT
The need to operate the freeze-dryer under low-pressure conditions to convert ice directly into water vapor (sublimation) adds to
the complexity and cost of dryers because the chamber holding the
product must withstand the differential pressure from vacuum to
atmosphere. Although a suitable vacuum pump is essential for
initially evacuating the chamber and eliminating air that may leak
into the dryer during operation, vacuum pumps are not capable of
continuously removing water vapor subliming from the product,
and a refrigerated trap (termed the process condenser) must be
placed between the product and the pump to condense the moisture migrating from the drying product. In reality, it is the condenser that comprises the “pumping force” of the system. Process
condensers may be incorporated into the drying chamber (referred
as an internal condenser) or located in a separate chamber between
the product chamber and pump (external condenser). Each geometry has advantages and disadvantages although either design may
be used. Stainless steel is typically used to fabricate research or
production dryers because this metal can be cleaned by a wide
range of sanitizers including steam. For GMP manufacture the
freeze-dryer is invariably sterilized by pressurized steam, and this
adds to the complexity and expense of the dryer because it must
conform to the requirements to operate under these conditions
(i.e., it must be a certified pressure vessel) as well as under the
sub-atmospheric pressure conditions to which it will be subjected
during the lyophilization process (i.e., as a vacuum vessel). Modern
freeze-dryers are also fitted with internal stoppering devices for
sealing vials at the end of the cycle, valves and monitoring devices
for assessing drying efficiency, and are typically computer or microprocessor controlled so that cycles can be reproduced and evaluated
for regulatory purposes. When freeze-drying vaccines, it may be
122
Kevin R. Ward and Paul Matejtschuk