LYOPHILIZATION

BASICS
What is lyophilization ?

❚ Lyophilization is defined as a process

of making a product lyophilic i.e.
water loving.
❚ Material that has been lyophilized
has been described as bone dry.
❚ Freeze drying or lyophilization is a
process of drying in which water is
sublimated from the product after it
is frozen.
FREEZE DRYING PROCESS

F R E E Z E D R Y IN G

F R E E Z IN G P R IM A R Y D R Y IN G S E C O N D A R Y D R Y IN G
O R IC E S U B L IM A T IO N O R W A T E R D E S O R P T IO N
Evolution of freeze drying.
During Tremondous requirement of dried
world war II blood plasma and serum as a blood
substitute for military.used in
canada,USA & ENGLAND

American red cross in honululu collected large amount of plasma

they could not store all of the liquid plasma. Hence they looked
forward for a method for drying it.

The freeze drying process came as the alternative method for drying
and saved the valualbel plasma and saved the life of many soilders.
 Evolution of freeze drying.

Thus the frozen dried plasma gave the frist graphic account of utility
of
freeze drying in the unexpected Pearl harbour attack.

Large quantities of liquid plasma were prevented from being

spoiled by conversion into dry plasma.

This could be transported over long distance and at extremes of

temperature and merely by addition of sterile water the plasm could
be regenerated and given intravenously.
Important terms

❚ Phase : a phase is defined as a any homogenous and

physical part of system which is bounded by surface
and is mechanicallly seperated from the other parts
of the system.
❚ Triple point : it is a point were 3 phases namely
liquid,solid and vapour coexist at particular
temperature and pressure.
❚ Eutetic point : the components are completely
missible with one another in the liquid state.they do
not from any compound and on solidification they
give rise merely to an intimate eutetic mixture and
the temperature this process occur known as eutetic
point.
❚ Eutetic temperature : temperature at which all the
areas of concentrated solutes are frozen.
Important terms
❚ Latent heat of fusion : it is the amount of heat
necessary to convert a unit mass of substance form
solid state to liquid state at temperature .the
pressure being to allow the coexistence of the two
phases.
❚ Latent of sublimation : it is the amount of heat
necessary a unit mass of substance from solid state
to gaseous state at same temperature . The
pressure being to allow the coexistence of the two
phases.
Why lyophilization ?

❚ Ease of processing a liquid ,hence

easy aseptic handling.
❚ Increase stability of a dry powder.
❚ Rapid and easy dissolution of dry
powder.
❚ Enhanced product stability in a dry
state.
Disadvantages of lyophilization

❚ Increased handling and processing

time.
❚ Need for sterile diluent upon
reconstitution.
❚ Cost and complexity of equipment.
 Structure of freeze dryer

FREEZE DRYER

D R Y IN G CONDENSOR VACCUM R E F R I G E R A TI O N C O N TR O L
CHAMBER PUMP S Y S TE M F A C IL IT IE S
Drying chamber

❚ The drying chamber of freeze dryer

consist of a vaccum tight unit
containing loading door and one or
more inspection window. Each
chamber contains a set of shelves
that has hydrolic stoppering
mechanism and gas bleed system.
Heat is applied directly through
electrical resistance coills or by
circulating hotwater, silicon or glycol.
Condenser

❚ The condenser in the freeze dryer is

a vacuum tight unit seperated from
chamber by a vacuum valve. They
contained a set of cooling plates
refrigerated by refrigeration system.
Condenser is supplied with hot water
defrosting system. It was a cold trap
used to collect the moisture.
Vacuum pump

❚ Each freeze dryer was equiped with

a two stage rotary gas ballast
vacuum pump.vacuum pump was an
essential component of the freeze
dryer and is required for evacuated
envouriment around the product.
Vacuum pump kept the chamber and
condensor sufficiently free from the
residual gases, water vapour stream
to be able to flow from the drying
Refrigeration system

❚ The freeze dryer is provided with

twin independent direct
expansion,single or multi-component
refrigeration plant. The commonly
used refrigerant is Freon R-
502 gas.
Control facilities

❚ The freeze dryer is instrumented to

control and operate the various plant
components like shelf staking
mechanism,hydraulic stoppering
device & chamber condensor valve.
❚ Instrumentation is also available to
measure and record the various
process variables like chamber
pressure,shelf temperature, product
temperature and condenser
 Typical lyophilization process
Component preparation
Washing
Filling Freeze drying
Sterilization Filling Freezing
Depyrogenation Partial Sublimation
Compounding stoppering
Solvent Desorption
Tray loading
Excipients Full stoppering

Active

Sterile filteration
Operation of freezedryer
❚ The freezing stage involves the solution to
a temperature well below its lowest
eutetic temperature untill it is completely
frozen. Freezing of the solution is most
conventially accompalised in the chamber
to be employed for drying, by placing the
filled vials on the shelf that is cooled by
the circulating refrigerant.
❚ Primary drying stage involves the
sublimation of ice from the product. This is
usually accomplaised by a reduction of the
pressure of the drying chamberand by the
Operation of freezedryer
❚ Secondary drying stage involves the
removal of adsorbed water from the
frozen product . This is the water which
did not as a ice during freezing and so did
not sublime. To accomplish the removal of
this water the product temperature is
usually raised and the chamber pressure
reduced further. The product is usually
processed until there is less than 1%
moisture left in the dried product.
Factors affecting process rate.

❚ 1) Depth of product in container : the

greater the depth of the product in
the container the longer will be the
drying process.
❚ 2) vapour pressure differential: the
actual driving force for the process is
the vapour pressure differential
between the vapour at the surface
where drying of the product is
occuring and that at the surface of
Factors affecting process rate.

❚ 3) amount of solid in the product,

their particle size & their thermal
conductance : the amount of solids
in the product ,their thermal
conductance will affect the rate of
drying. The more solid present,the
more impedment will be provided to
the escape of the water vapour.
❚ The smaller the ice crystal size
,faster the drying rate.
Factors affecting process rate.

❚ The poor the thermal conducting

properties of the solids in the
product , the slower will be the rate
of heat transfer through the frozen
material to the drying boundary.
Factors affecting formulation

❚ The active constituent of many

pharmaceutical products is present
in such a small quantity that if freeze
dryed alone its prescence will be
hard to detect visually. Therefore
excipents often are added to
increase the amount of solids.
❚ The solids contents of original
products must be between approx 5
to 25%. Therefore mannitol or
Lyophilization cycles- facts
❚ Eutectic determination is very
essential for optimizing the drying
cycle.
❚ For a cycle it is necessary to go
atleast 10°c below eutectic point.
Any further reduction in the
temperature will ultimately increase
the cycle time.Also this reduces the
drying cycle time by 50%.
❚ By proper freezing the ultimate cycle
time can be reduced.
Lyophilization cycles- facts

❚ In drying the condenser temperature

must be atleast 15°c below the
drying temperature.
❚ During cycle breakage of vials at
final stoppering stage is seen which
is upto 0.25%.this can be reduced
using siliconized rubber stoppers.
❚ Cake drying if observed is a result of
fast drying.
Lyophilization cycles- facts

❚ Greater product thickness in vials

will cause more time to freeze dry
the product.
❚ Thumb rule for fill volume versus vial
capacity is 2ml for 10ml. But you can
go max. upto 50%. But not more
than 50%.
❚ The lyophilizer is sterilized after each
product change.
Lyophilization cycles- facts

❚ For SIP cycle, it is not necessary to

defrost the condenser chamber. And
similarly for CIP cycle.
❚ Lyophilizers can be run on less load
also, it is not required to take
dummy loads.
❚ Cracks in cake come due to thermal
changes ,slow middle steps of drying
can remove this.
lyophilizer

SENSOR IN PRODUCT
VIAL
PRODUCT TEMP
SET POINT
CHAMBER

PRODUCT SHELF

SHELF TEMP. SENSOR

COOLER
BELOW HEATER
ABOVE SET POINT SET POINT
SHELF HEAT CONTROL
AND INDICATION

CENTRIFUGAL PUMP

HEAT TRANSFER FLUID

SIGNAL FOR CUTTING
PUMP OFF ABOVE SET POINT
Validation of lyophilizer
❚ Validation of filling and stoppering
process using media fill.
❚ Validation of filling volume into
containers.
❚ Validation of sterilization of
lyophilizer.
❚ Validation of handling of partially
stoppered vials.
❚ Validation of lyophilization cycle
using media fill.
Validation of lyophilizers

❚ Product validation in lyophilizer costs

150% of the total cost of lyophilizer.
❚ It is not necessary to use
thermocouples in production runs.
❚ Direct correlation between the
thermocouples and the shelf
temperature should be established
and then remove the thermocouples.
Validation of lyophilizers

❚ Any minor change in the formula

demands complete validation of the
cycle and stability study of the
product.
❚ Probe placement in the vials should
always be in the center very close to
bottom.
❚ It is always recommended to use
thermocouples than R.T.D’s.(PT100).
Validation of lyophilizers

❚ Power failures in validation studies

should be included and then stability
study should be carried out.
❚ For cycle development always use
the product probes.
❚ Hydraulic system validation include
checking of stoppered vials
manually.
Finished product testing of
lyophilized products.

❚ Dose uniformity - content uniformity

and weight variation.
❚ Sterility testing
❚ Stability testing - done since some
amount of moisture is still present in
the product.
Finished product inspection

❚ Melt back - generally the lyophilized

drug is in form of cake but the cake
may collapse due to change from
solid to liquid state because of
incomplete sublimation.
❚ Poor solubility - this may decrease
the potency of the drug.