BASIC PRINCIPLES, OPERATION

AND VALIDATION OF FREEZE

DRYER
BY: Dhaval Surti

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Basic Principles of Freeze Dryer
 What is Lyophilization (Freeze Drying) ?
 Lyophilization is the process of removal of ice or
other frozen solvents from a material through the
process of sublimation and the removal of bound
water molecules through the process of
desorption.
 This process, called sublimation, transforms the
ice directly into water vapor, without first passing
through the liquid state. The water vapor given off
by the product in the sublimation phase
condenses as ice on a collection trap, known as
condenser.

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Sublimation Process-Eutectic Temperature

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Structure of Freeze Dryer

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Basic Principles of Freeze Dryer
 The steps required to lyophilize a product in
a batch process are summarized as follows:
 Pretreatment/Formulation
 Loading in Freeze Dryer (vials or ampoules)
 Freezing (Thermal Treatment) at atmospheric Pressure below
eutectic temperature
 Primary Drying (Sublimation) under Vacuum
 Secondary Drying (Desorption) under Vacuum
 Pre-aeration and Stoppering (For Product in Vials) under
Partial Vacuum followed by aeration
 Removal of Dried product from Freeze Dryer

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Why Lyophilization?
 The product which is stable only in powder
form but is unstable at high temperature. Hence
to convert such product in dry powder form
without exposing to heat, the product is first
made in solution form, frozen to make it solid
ice and dried by applying very high vacuum
which vaporizes frozen water without going
through the liquid state.
 To be considered stable, a lyophilized product
should contain acceptable limits moisture
content and is properly sealed.
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Basic Principles of Freeze Dryer
 RECIPE FOR FREEZE DRYING
 Lyophilization in a freeze dryer requires a working
process or cycle which is sometimes referred to as a
‘Recipe’. Typically there are multiple steps involved in
both freezing and drying of the product.
 Individual temperature, pressure and time are specified
for each step.
 Each specific product or formulation that is lyophilized
requires the ‘Development of Freeze Drying Process’
that is based on unique characteristics of the product,
the amount of the product filled in container and the
size of container (Vial/Ampoule).
 There is no universal ‘Safe’ recipe that will work with
every product.

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Basic Principles of Freeze Dryer
 Common Steps of Freeze Drying Recipe
1. Freezing
2. Evacuation
3. Primary Drying (Sublimation)
4. Secondary Drying (Desorption)
5. Partial Aeration (with partial vacuum in
Vials)
6. Full Stoppering of the vials
7. Aeration to Atmospheric Pressure

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Structure of Freeze Dryer
 Refrigeration System
 Vacuum System
 Control System
 Product Chamber or Manifold
 Condenser

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Steps of Freeze Drying
 Loading of Freeze Dryer
Here the filled and Half Stoppered Vials are loaded in
freeze dryer. The fill volume, container size and
temperature during loading will be according to the
product.

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Structure of Chamber showing
shelves and open Door

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Half Stoppered Vials on their way to
Freeze Dryer Loading

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Vials loading in Small Freeze Dryer

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Vials loaded in Freeze Dryer

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Steps of Freeze Drying
 Freezing
 Here the liquid product filled in vials/ampoules is
completely frozen.
 Freezing is important as unfrozen product may expand
outside of the container when placed under a vacuum.
 Shelf freeze dryer allows the precise control of cooling
rates which affects product freezing rates and crystal
size. Larger ice crystals improves the speed of the
freeze drying process because of the larger vapor
pathways left behind in the dried portion of the product
as the ice crystals are sublimated.

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Steps of Freeze Drying
 Evacuation
 Here, first the condenser is being cooled to
temperature less than -40°C so as to facilitate the
condensation of the vapor generated from the
frozen product during drying steps.
 After condenser cooling, vacuum pumps are
started, vacuum valve is opened and the main
valve separating chamber and condenser is being
opened so as to apply vacuum in chamber.
 Vacuum valve is provided on condenser hence
any vapor generated from chamber will travel
through main valve to condenser and will
condense on condenser coils in form of ice.
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Picture of Condenser Coil

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Steps of Freeze Drying
 Primary Drying
 The bulk water removed from the product
during freeze drying is via sublimation of all
of the free ice crystals during the primary
drying step. Organic solvents are also
removed during primary drying.
 Primary drying is a slow process conducted
at cooler temperatures, safely below the
product’s critical collapse temperature. All
methods of heat transfer- conduction,
convection and radiation are employed
during primary drying.
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Steps of Freeze Drying
 Secondary Drying
 In addition to the free ice that is sublimated during
primary drying, there remains a substantial amount of
water molecules that are bound to the product. This
water is removed by desorption in secondary drying.
 Secondary drying is done at increased temperature
because all of the free ice has been removed during
primary drying hence there are no chances of melting
or product collapse.
 Some freeze dryer have the facility to remove the
samples for moisture content determination in
secondary drying step based on which the drying step
can be terminated.

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Steps of Freeze Drying
 Partial Aeration (Pre-Aeration)
 Once the secondary drying step is completed, partial
aeration-also called pre-aeration is being performed usually
using inert gas like nitrogen so as to leave some vacuum
inside the vials
 Full Stoppering
 Once the Partial Aeration is completed, the vials are full
stoppered by lowering the freeze dryer shelves one by one.
This can be automatic step in the freeze dryer recipe or can
be performed in manual mode by pushing the button.
 Once the full stoppering is completed, shelf position is
restored to original position.

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Steps of Freeze Drying
 Aeration
 Final aeration is done usually with compressed
air to bring the chamber to the atmospheric
pressure.
 Condenser aeration is done after chamber
aeration.
 Door of the freeze dryer is opened at aseptic
area side to unload vials.
 The vials are then sent to capping machine.
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Picture of shelves before and after
stoppering (Empty Shelve
Demonstration)

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Vials After Full Stoppering in Freeze
Dryer

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Half stoppered vials before Freeze
Drying and Full Stoppered vials
After Freeze Drying

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Vials After Freeze Drying

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Examples of Good and Rejected
Freeze Dried Vials

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Advantages of Freeze Drying
1. To dry thermo labile and water-unstable materials.

2. To get accurate, sterile dosing into the final product

container.

3. To extend the shelf life or stability

4. To preserve the biological activity of a product.

5. To eliminate the need for refrigerated storage.

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Disadvantages of Freeze Drying
1. Very complex process requires high degree of
automation and process control and men power with
special skills and training for routine operation.
2. Capital cost of the Freeze Dryer equipment is very
high.
3. Operating cost, regular maintenance, utilities and spare
parts cost of the freeze dryer is very high resulting in
higher cost of end product.
4. Freeze Drying is very long process running for several
hours to days.
5. A least scope of saving the product in condition of
equipment failure during running process.
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Validation of Lyophilizer
Two Parts
Equipment Qualification and Process Qualification
1. Equipment Qualification
 URS
 DQ
 FAT
 SAT
 Installation Qualification
 Operational Qualification
 Performance Qualification

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Validation of Lyophilizer
Equipment Qualification
 Shelf Temperature Performance Verification
Ultimate shelf heating and cooling rates (+20°C to -40°C in ≤ 60 minutes)
Ultimate high and low temperatures (minimum temp below -55°C after 30 min cooling
and max temp above +80°C)
 Condenser Cooling Verification
Maximum condenser cooling rate (Ambient to -40°C in ≤30 minutes)
Ultimate condenser cooling test (Temperature ≤ -75°C after 60 minutes of cooling)
 Vacuum Performance Verification
Time to achieve 100 µbar should be less than 40 minutes
Ultimate vacuum of 5 µbar

 Main Valve Leak Rate Test (0.01 mbar  Liter / Sec)

Main valve leak rate of 2 µbar in 30 minutes,
Allowable rise = 0.05x1800 seconds /4360 liters = 0.0021 mbar
 Shelf Temperature Set point Control at -40°C, 0°C and +40°C ± 2°C
 Shelf Temperature Uniformity Verification -40°C, 0°C and +40°C ± 2°C
 Vacuum Set point Control at 500, 100 and 50 µbar ± 5 µbar
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Validation of Lyophilizer
 CIP Coverage Verification (Riboflavin Test)
 SIP Effectiveness Verification (Sterilization and cooling)

 System Leak Rate Test (0.01 mbar  Liter / Sec)

Allowable rise = 0.01x3600 seconds /8140 liters = 0.0044 mbar
 Shelf Ram Bellows Integrity Test
Verify the pressure rise test of the bellows was performed to confirm the leak tight to
0.01 mbar  Liter / Sec. Record the pump down time to 10 μbar here as the pass
criteria. In our case it is 13 minutes.

 Main Valve Bellows Integrity Test

Verify the pressure rise test of the bellows was performed to confirm the leak tight to
0.01 mbar  Liter / Sec. Record the pump down time to 10 μbar here as the pass
criteria. In our case it is 06 minutes.

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Validation of Lyophilizer
 Condenser Capacity Verification

 Condenser Defrosting Test

 Freeze Drying Cycle with Placebo

 CIP and SIP

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Validation of Lyophilizer
Process Qualification
 Finished Product Attributes
 Physical Appearances
 Residual Moisture

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Hope this has been of
some help to you…

Thanks to All of You

for Your time and
Attention
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