General Principles of
Freeze Drying (The Lyophilization Process)
For example, if a machine is equipped with an
ice condenser for which the lowest temperature limit is –40°
C (Fig 4), it would be impossible to lower the pressure below
the vapor pressure corresponding to –40° C, i.e. 10-1
torr.
This value is irrespective to the type or design
of the vacuum pump. A failure in the refrigeration system leads
to a chain reaction:
- A rise in condenser temperature.
- A rise in chamber pressure.
- A rise in product temperature.
- An irreversible eutectic melting and the boiling
of liquid fractions.
- Product failure.
Because of the importance of the refrigeration system, a freeze
dryer must be equipped with a condenser designed and constructed
with the ability to:
- Condense all vapors from the product.
- Provide a vapor route of minimum distance to
avoid hindering vapor flow.
- Permit easy defrosting after the run.
- Prevent vapors from contaminating the oil in
the vacuum pump.
- Provide a simple cleaning operation.
- Provide the necessary BTU output under load
to condense vapor at a maximum rate without disturbing the
product’s selected primary sublimation temperature.
- Insure the necessary low temperature (saturated
suction) during the secondary drying to deliver the lower
vacuum levels needed for this phase.
- Provide a high degree of reliability.
Heating Control in the
Freeze Drying Process:
The transmission of energy to the product needs
to be carefully controlled for three important considerations:
- To avoid transferring too much heat and passing
the safe primary drying temperature.
- To avoid supplying insufficient heat, hence
prolonging the sublimation period.
- To achieve a homogeneous temperature in the
total batch, as the lyophilization cycle will be determined
by the temperature of the “coldest” product area.
- The higher the sublimation temperature, the
faster the drying cycle. The conditions of low temperature
and high vacuum, can have, if they are unnecessarily prolonged,
an effect on living organisms, which form the great bulk of
freeze dried products.
Production Application:
In industrial freeze drying applications it is
essential to reproduce indentical drying protocols for a wide
range of products. To accomplish this goal, it is vital to insure
the same parameters for each operation. The essential criteria
are:
- The temperature of the product.
- The duration of the primary and secondary drying
phases.
- Heat input.
- Chamber pressure.
By a series of reproducible runs on a scaleable
the optimum cycle can be established. If the process is automated
it is essential that:
- Cycle is performed with a guarantee of functional
security.
- Validation is simple.
- Allows maximum flexibility for a variety of
product drying protocols.
- In the pilot development phase, it is critical
that the favorable conditions for freezing and the optimum
parameters of primary and secondary drying be established.
Secondary Drying:
At the end of the sublimation phase (primary drying),
all the ice will have disappeared. The product will begin to
rise in temperature, and will tend to approach the control temperature
of the shelf. However, at this stage the product is not sufficiently
dry for long term storage. For most products, the residual moisture
is in the region of 5% to 7%.
The product now enters the desorption phase, during
which the last traces of water vapor are removed, along with
traces of the “bound” water within the product matrix.
This phase is identified as secondary drying. The aim of this
final phase is to reduce the product to the acceptable moisture
levels needed for long term storage (3% to 1%).
The reasons for drying the product to these levels
are desirable for several benefits:
- When the water content is higher than these
levels, the product will denature.
- When the residual moisture is forced
lower than these levels, many products may undergo chemical
or enzymatic changes.
Residual moisture in the product is generally
dependent on four factors:
- The product matrix (both in frozen and sublimation
mode.)
- The vacuum in the drying chamber.
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