Lyophilization technology for freeze drying

1. Lyophilization technology
(freeze drying)
Presented by:
Mr. Roshan Khetade
(M Pharm 2nd year Quality
Assurance Department)

2. Content
 Definition
 Principle
 Objective of lyophilization process
 Processing
 Freeze dry product characteristics
 Advantages of lyophilization
 Disadvantages of lyophilization
 Application
 Lyophilization Equipment
 Freeze Drying Methods
 References

3. Definition
 A stabilizing process in which a substance is first frozen and then
the quantity of the solvent is reduced first by sublimation
(primary drying stage) and then desorption (secondary drying
stage) to value that will longer support biological activity or
chemical reaction.

4. Principle
 Lyophilization is carried out using a simple principle of physics
sublimation .
 Sublimation is the transition of substance from the solid to
vapour state without first passing through an intermediate phase
 Lyophilization is performed at temperature and pressure
condition below the triple point to enable sublimation of ice.
 The entire process is performed at low temperature and pressure
by applying of thermolabile compounds.
 The concentration gradient of water vapour between the drying
front and condenser is the driving force for removed of water
during lyophilization.

5. Objective of lyophilization
 To pressure the biological activity of a product.
 To reduce the product weight to lower the transportation cost.
 To extent the shelf life or stability.
 To dry thermolabile materials.
 To eliminate the need for refrigerated storage.
 To get accurate sterile dosing into the final product container.

6. Steps involved in lyophilization
 Freezing stage
 Primary drying stage
 Secondary drying stage
 Packaging

7. Processing
 Freezing: The product is frozen this provides a recessing
condition for low temperature.
 Vacuum: after freezing the product is placed under vacuum this
enables the frozen solvent in the product to vaporize without
passing through liquid phase a process known as sublimation.
 Heat: Heat is applied to the frozen product to accelerate
sublimation.
 Condenser: Low temperature condenser plates remove the
vaporized form the vacuum chamber by converting it back to a
solid.

8. Freeze drying
 Freezing the product solution to a temperature below its entotic
temperature.
 Decrease shelf temperature to -50’C.
 Low temperature and low atmosphere pressure are maintained.
 Freon are used as refrigerant.
 Formation of ice crystals occurs.
 The rate of ice crystallization define the freezing process and
efficiency of primary drying.

9. Primary drying
 Heat is introduced form shelf to the product under graded control
by electrical resistance coils or circulating silicone.
 The temperature and pressure should be below the triple point of
water i.e. 0.0098’C and 4.58 mmHg.
 The driving force is vapour pressure difference between the
evaporating surface and the condenser.
 Easily removes moisture up to 98% to 99%.

10. Secondary drying
 The temperature is raised to 50 to 60’c and vacuum is lowered
about 50mmHg.
 Bound water is removed.
 Rate of drying is low.
 It takes about 10 to 20 hrs.

11. Packaging
 After drying the vacuum is replaced by filtered dry air on
nitrogen to established atmosphere pressure.
 Ampoules are sealed by either tip sealed or pull sealing method.
 Vials and bottles are sealed with rubber closure and aluminum
caps

12. Freeze dry product characteristics
 Sufficient strength
 Uniform colour
 Sufficient dry
 Sufficient porous
 Sterile
 Free of pyrogen and particulates.
 Chemically stable both in dry state and reconstitution.

13. Advantages of lyophilization
 Removed of water at low temperature.
 Thermolabile materials can be dried.
 Compatible with aseptic operation.
 More precise fill weight control.
 Sterility can be maintained.
 Reconstitution is easy.

14. Disadvantages of lyophilization
 Many biological molecules are damaged by the stress associated
with a freezing ,freeze drying or both.
 The product is prone to oxidation due to high parasite and large
surface area. Therefore the product should be packed in vacuum
or using inert gas or in container impervious to gas.
 Cost may be an issue depending on the product.

15. Application
 Pharmaceutical and biological: to increase the shelf life to
product such as vaccine and other injectables.
 Food industry:
 Technical industries:
 Others:

16. Lyophilization Equipment
1.There are essentially three categories of freeze dryers: the manifold
freeze-dryer, the rotary freeze dryer and the tray style freeze-dryer.
Two components are common to all types of freeze dryers: a
vacuum pump to reduce the ambient gas pressure in a vessel
containing the substance to be dried and a condenser to remove the
moisture by condensation on a surface cooled to −40 to −80°C (−40
to −112°F).
2.The manifold, rotary and tray type freeze-dryers differ in the method
by which the dried substance is interfaced with a condenser. In
manifold freeze-dryers a short usually circular tube is used to
connect multiple containers with the dried product to a condenser.
3.The rotary and tray freeze-dryers have a single large reservoir for the
dried substance. Rotary freeze-dryers are usually used for drying
pellets, cubes and other pourable substances.

17. Lyophilization Equipment
 The rotary dryers have a cylindrical reservoir that is rotated
during drying to achieve a more uniform drying throughout the
substance.
 A manifold dryer used in a laboratory setting when drying liquid
substances in small containers and when the product will be used
in a short period of time.
 A manifold dryer will dry the product to less than 5% moisture
content.
 Tray style freeze dryer usually have rectangular reservoir with
shelves on which products, such as pharmaceutical solutions and
tissue extracts, can be placed in trays, vials and other containers.

18. Lyophilization container requirements
 The container in which a substance is lyophilized must permit
thermal conductivity, be capable of being tightly sealed at the end
of the lyophilization cycle, and minimize the amount of moisture
to permeate its walls and seal.
 The enclosed reagents can only remain properly lyophilized if
the container in which they are processed meets these
requirements.

19. Lyophilization Heat Transfer
 Successful lyophilization is heavily dependent on good thermal
conductivity. For this, containers used in the lyophilization
process must be capable of meeting a number of heat-transfer
requirements.
 Should provide good thermal contact with the lyophilizer shelf,
which is the source of heat during processing; and should have a
minimum of insulation separating the source of heat from the
product requiring heating.
 Poor thermal conductivity often results from the use of containers
made of materials with low coefficients of heat transfer. It can
also be caused by the shape, size, or quality of the container.

20. Freeze Dryer Design

21. Essential Components Chamber
 This is the vacuum tight box, sometimes called the lyophilization
chamber or cabinet.
 The chamber contains shelf or shelves for processing product.
 The chamber can also fit with a stoppering system. It is typically
made of stainless steel and usually highly polished on the inside
and insulated and clad on the outside.
 The door locking arrangement by a hydraulic or electric motor.

22. Shelves
 A small research freeze dryer may have only one shelf but all
others will have several.
 The shelf design is made more complicated because of the
several functions it has to perform.
 The shelf act as a heat exchanger, removing energy from the
product during freezing, and supplying energy to the product
during the primary and secondary drying segments of the freeze
drying cycle.
 The shelves will be connected to the silicone oil system through
either fixed or flexible hoses. Shelves can be manufactured in
sizes up to 4 m2 in area.

23. Process Condenser
 The process condenser is sometimes referred as just the condenser or
the cold trap. It is designed to trap the solvent, which is usually water,
during the drying process.
 The process condenser will consist of coils or sometimes plates which
are refrigerated to allow temperature. These refrigerated coils or plates
may be in a vessel separate to the chamber, or they could be located
within the same chamber as the shelves.external and internal condenser.
 Physically, the external condenser is traditionally placed behind the
chamber, but it may be at the side, below or above.
 The position of the condenser does not affect trapping performance. For
internal condenser the refrigerated coils or plates are placed beneath the
shelves on smaller machines, behind the shelves on larger machines.

24. Shelf fluid system
 The freeze-drying process requires that the product is first frozen
and then energy in the form of heat is applied throughout the
drying phases of the cycle.
 This energy exchange is traditionally done by circulating a fluid
through the shelves at a desired temperature.
 The temperature is set in an external heat exchange system
consisting of cooling heat exchangers and an electrical heater.
 The fluid circulated is normally silicone oil. This will be pumped
around the circuit at a low pressure in a sealed circuit by means
of a pump.

25. Refrigeration system
 The product to be freeze dried is either frozen before into the
dryer or frozen whilst on the shelves.
 A considerable amount of energy is needed to this duty.
Compressors or sometimes-liquid nitrogen supplies the cooling
energy.
 Most often multiply compressors are needed and the compressor
may perform two duties, one to cool the shelves and the second to
cool the process condenser.

26. Vacuum system
 To remove solvent in a reasonable time, vacuum must be applied
during the drying process.
 The vacuum level required will be typically in the range of 50 to
100μ bar.
 To achieve such a low vacuum, a two stage rotary vacuum pump
is used. For large chambers, multiple pumps may be used.

27. Control system
 Control may be entirely or usually fully automatic for production
machines.
 The control elements required are as mentioned above, shelf
temperature, pressure and time.
 A control program will set up these values as required by the
product or the process. The time may vary from a few hours to
several days.
 Other data such as a product temperatures and process condenser
temperatures can also be recorded.

28. Freeze Drying Methods
 Three methods of freeze drying are commonly used:
 1. Manifold drying.
 2. Batch drying, and
 3. Bulk drying.

29. References
 Lippincolt, Williams K. Remington, The Science & practice of
pharmacy, Parenteral Preparation, 20th ed, ISE publication,
Phelabelphia. 2000; 1: 804-819.
 Akers MJ, Remington: The science and practice of pharmacy,
Lippincott Williams & wilkins publisher, 2000; 21: 525.
 Chien & Yiew W. Pharmaceutical Dosage forms: Parenteral
Medications. Indian Journal of pharmaceutical science and
technology, 1981; 35: 106-118.
 Liberman HA, Lachman L and Schwartz BJ. Pharmaceutical
dosage form: Parenterals, Marcel Dekker publisher, 1989; 1.
 21. Wang W. Lyophilization and development of solid protein
pharmaceuticals. International Journal of pharmaceutics, 2000;
52: 1-60.