2.1 Operational
Principles
A freeze-dryer (lyophilizer) will comprise a number of fundamental
component parts, including a product chamber (which may house a
number of temperature-controlled shelves), a process condenser
(also known as a cold trap), and a vacuum pump (typically a rotary
vane pump). Other features may vary, depending on the size and
operational requirements of the system and the chosen approaches
employed by equipment manufacturers, each of whom tend to have
slightly different designs and engineering solutions to achieve the
same ultimate goal. For example, shelf temperature control is
almost invariably achieved by the use of a circulating thermal
medium such as low-viscosity silicone oil, which is cooled via a
heat exchanger and warmed using an electrical heater, both of
which are part of the refrigeration circuit. The flow pattern of the
fluid, its viscosity, and the speed at which it is pumped through the
shelves may vary from manufacturer to manufacturer, but the ultimate aim will be to achieve effective heat transfer into or out of the
product on the shelves. On smaller dryers, a single refrigeration
compressor may be employed to cool both the shelves and the
process condenser, while on an industrial dryer, there may be
several compressors and/or separate systems dedicated to different
cooling functions within the one dryer.
There are also differences in the devices used for process monitoring: some examples of process analytical technologies (PAT) are
given later in this chapter, but even at the most basic level, a small
research laboratory dryer may have a Pirani gauge to measure
pressure (vacuum), while nowadays, an industrial dryer is more
likely to have a capacitance manometer (CM gauge)—these work
in very different ways and will typically provide very different readouts even under identical conditions, even when each gauge is
working well and has been perfectly calibrated. Control systems
work in different ways, with those on smaller dryers usually offering
the operator the flexibility to change set points of temperature,
pressure, and time at any time during the process; while at
manufacturing scale, such changes are typically (and understandably) not possible, and, therefore, the lyophilization cycle should be
demonstrated to be sufficiently robust by the time it is employed at
this scale. All of these factors must be considered as part of the
scale-up process.
Freeze-drying is a complex process during which drying may
proceed more or less rapidly within individual samples throughout
the process batch, such that parts of the product will be frozen,
whereas other areas are drying or will have dried depending on the
nature of the product and stage in the cycle. The precise freezing
and drying behavior will be determined by the interrelationship
between the product and shelf temperature, system pressure, extent
of product dryness, and variations in drying conditions throughout
the cycle.
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Kevin R. Ward and Paul Matejtschuk
Principles
A freeze-dryer (lyophilizer) will comprise a number of fundamental
component parts, including a product chamber (which may house a
number of temperature-controlled shelves), a process condenser
(also known as a cold trap), and a vacuum pump (typically a rotary
vane pump). Other features may vary, depending on the size and
operational requirements of the system and the chosen approaches
employed by equipment manufacturers, each of whom tend to have
slightly different designs and engineering solutions to achieve the
same ultimate goal. For example, shelf temperature control is
almost invariably achieved by the use of a circulating thermal
medium such as low-viscosity silicone oil, which is cooled via a
heat exchanger and warmed using an electrical heater, both of
which are part of the refrigeration circuit. The flow pattern of the
fluid, its viscosity, and the speed at which it is pumped through the
shelves may vary from manufacturer to manufacturer, but the ultimate aim will be to achieve effective heat transfer into or out of the
product on the shelves. On smaller dryers, a single refrigeration
compressor may be employed to cool both the shelves and the
process condenser, while on an industrial dryer, there may be
several compressors and/or separate systems dedicated to different
cooling functions within the one dryer.
There are also differences in the devices used for process monitoring: some examples of process analytical technologies (PAT) are
given later in this chapter, but even at the most basic level, a small
research laboratory dryer may have a Pirani gauge to measure
pressure (vacuum), while nowadays, an industrial dryer is more
likely to have a capacitance manometer (CM gauge)—these work
in very different ways and will typically provide very different readouts even under identical conditions, even when each gauge is
working well and has been perfectly calibrated. Control systems
work in different ways, with those on smaller dryers usually offering
the operator the flexibility to change set points of temperature,
pressure, and time at any time during the process; while at
manufacturing scale, such changes are typically (and understandably) not possible, and, therefore, the lyophilization cycle should be
demonstrated to be sufficiently robust by the time it is employed at
this scale. All of these factors must be considered as part of the
scale-up process.
Freeze-drying is a complex process during which drying may
proceed more or less rapidly within individual samples throughout
the process batch, such that parts of the product will be frozen,
whereas other areas are drying or will have dried depending on the
nature of the product and stage in the cycle. The precise freezing
and drying behavior will be determined by the interrelationship
between the product and shelf temperature, system pressure, extent
of product dryness, and variations in drying conditions throughout
the cycle.
102
Kevin R. Ward and Paul Matejtschuk