IMPORTANCE

OF
FREEZE DRYING

PRESENTED BY:-
RAMESHWAR MADHARIA
PE/2013/313

1
Content

 Introduction
 Basic Concepts
 Freeze-Drying Steps
 Why & when Freeze-Dry?
 Desired Freeze Dried Product Characteristics
 Advantages & Dis-advantages of Lyophilization
 Common Lyophilized Products
 Main Challenges of Lyophilization
 Why does Freeze-Drying takes so long???
 Importance of Freeze-Drying
 Conclusion
 References
Introduction 3

Freeze-Drying

Also called lyophilisation, it is a drying process where the wet

product is first frozen to a solid phase and subsequently dried to
vapour phase through sublimation, that is, without passing
through the liquid phase, by exposing it to a low partial pressure
of water vapour.

Lyo = Solvent Philo = Friend

The lyophilisation process makes the dried product “solvent

loving”.

V.Lavakumar et al.; Lyophilization/Freeze Drying - A Review; IJNTPS; Volume 3 | number 4 |

oct | 2013
 4
Basic Concepts (1/3): Phase Diagram

Below the triple point co-ordinates,

Solid ice can sublimate to vapour:

1. Liquid is frozen at atmospheric

pressure.

2. Pressure is reduced.

3. Temperature is raised to promote

sublimation from ice to vapour.

4. Vapour travels to the ice

condenser where it is trapped as
ice.

5. When drying is finished, trapped

ice is melted and drained.
Shukla S.; Freeze drying process: a review; IJPSR, 2011; Vol. 2(12): 3061-3068
Basic Concepts (2/3): Vacuum 5

Vacuum: an enclosed region of space in which the pressure has

been reduced (below normal atmospheric pressure)-

Atmospheric pressure: 1.013 mbar

Rough vacuum: 1.013 mbar - 1 mbar

Medium vacuum: 1 mbar - 10-3 mbar

High vacuum: 10-3 mbar - 10-7 mbar

Ultra-high vacuum < 10-7 mbar

Lyophilisation is normally performed at medium vacuum.

Shukla S.; Freeze drying process: a review; IJPSR, 2011; Vol. 2(12): 3061-3068
 6
Basic Concepts (3/3):Vapour Pressure

The vapour pressure of a liquid is the pressure exerted by its

vapour when the liquid and vapour are in dynamic equilibrium.

If a substance is placed in an evacuated, closed container, some

of it would vaporise. The pressure in the space above the liquid
would increase from zero and eventually stabilise at a constant
value: the vapour pressure.

This equilibrium pressure is a function of the temperature of the

substance
 7
Freeze-Drying Steps

Freezing
Primary Drying
Secondary Drying

Ancillary operations:

• Loading / unloading the product

• Venting (re-establishing atmospheric pressure) / Backfilling
• Defrosting
• Cleaning of the unit (CIP)
• Sterilisation of the unit (SIP)
• HEPA filter integrity testing
• Leak test of the unit

A guide to freeze drying for the laboratory; An Industry Service Publication ; Labconco
corporation.
 8
Freezing

PURPOSE: Cool (freeze) the product achieving a temperature

below the eutectic point, getting a crystalline solid (glass state
in case of amorphous materials).

An immobilisation of the product is also achieved, avoiding:

• Frothing under vacuum

• Material shrinkage
• Solvent migration
• Concentration during drying
• Temperature dependent reactions, speciallythose

leading to loss of activity.

A guide to freeze drying for the laboratory; An Industry Service Publication ; Labconco
corporation.
 9
Freezing Rate

It is important to have the

correct freezing rate to allow
the growth of DENDRITIC ICE
CRYSTALS.

When sublimated, there are

funnels, allowing vapour to
escape.

A guide to freeze drying for the laboratory; An Industry Service Publication ; Labconco
corporation.
 10
Primary Drying
PURPOSE: remove the ice from the product with:

· Minimum damage to the product

· Retention of shape

After the product is frozen at a temperature T1, the chamber is

pumped down to a pressure Pc lower than the product saturation
vapour pressure Pp.

Sublimation is an endothermic process, latent heat must be

provided.

Primary drying is complete when all the ice has sublimed.

Moisture still remains bound to the product.

A guide to freeze drying for the laboratory; An Industry Service Publication ; Labconco
corporation.
 11
Switching from Primary Drying to
Secondary Drying

Primary drying is complete when:

- The interface disappears at the vial base

- Product and shelf temperature are identical
- Chamber and condenser pressure are identical

A guide to freeze drying for the laboratory; An Industry Service Publication ; Labconco
corporation.
 12
Secondary Drying

PURPOSE: to remove residual and bound moisture (typically from

10% to less than 2%). Water in the product isn’t crystalline but
adsorbed.

Residual water is removed by desorption. Secondary drying time

is governed by the water desorption rate from the solid.

This process is temperature dependant and not time dependant.

When equilibrium is reached increasing the time is useless.

Product temperature is raised as much as possible without

having denaturalisation. Condenser pressure (and so its
temperature) must be as low as possible.

A guide to freeze drying for the laboratory; An Industry Service Publication ; Labconco
corporation.
 13
Simplified P&ID of a Freeze Dryer

C ham ber + S helves

Ice C ondenser

V acuum P um pset
S helf C ooling / H eating
S ystem

R efrigerating
S ystem
Why Freeze-Dry? 14

Minimum damage / loss of activity

Low final moisture

Long shelf life

Ease of reconstitution

Possibility of sterile manufacturing

Accurate dosing.
 15
When to Freeze-Dry?

Labile products

High value products

Sterile drying

Accurate dosing

Reconstitution is difficult

Long shelf life is required

Retention of form.
 Desired Freeze Dried Product 16

Characteristics
 Intact cake
 Sufficient strength
 Uniform color
 Sufficiently dry
 Sufficiently porous
 Sterile
 Free of pyrogens
 Free of particulates
 Chemically stable—both in dry
state and after reconstitution

Pharmaceutical dosage forms: Manufacturing and Compounding; Remington: Essentials of Pharmaceutics; pg.
no.525-528.
 17
Advantages of Lyophilization

 Removal of water at low temperature

 Ease of reconstitution

 Compatible with aseptic operations

 More precise fill weight control

 Done properly, the freeze-dried solid has

relatively high specific surface area,
which promotes rapid, complete
reconstitution.

Pharmaceutical dosage forms: Manufacturing and Compounding; Remington: Essentials of Pharmaceutics; pg.
no.525-528.
 18
Dis-advantages of Lyophilization

 The drug may not be stable as a freeze-

dried solid
 Many biological molecules are damaged
by the stresses associated with freezing,
freeze-drying, or both
 Not all solutes can be freeze-dried to
form a pharmaceutically acceptable cake
 Cost may be an issue, depending on the
product.

Pharmaceutical dosage forms: Manufacturing and Compounding; Remington: Essentials of Pharmaceutics; pg.
no.525-528.
 19
Common Lyophilized Products

 Pharmaceuticals – large and small molecules

 Bacteria
 Viruses
 Vaccines
 Plasma
 Small Zoological Specimens (Taxidermy)
 Fruit
 Coffee
 Flowers
 Water-Damaged Documents.

Shukla S.; Freeze drying process: a review; IJPSR, 2011; Vol. 2(12):
3061-3068
 Main Challenges of Lyophilization 20

 Development of formulation that meets all the necessary critical

product attribute requirements (quality appearance, potency,
stability, recon time, etc)
 Establishment of temperature, pressure, and time cycle settings
that can achieve best product quality in shortest possible time
 Transfer and scale-up of lab-developed process to production
scale process
 Keep all the equipment running smoothly
 Special challenges in product development of lyophilized biologic
formulations and cycles.
 21
Why does Freeze-Drying takes so long???

 Sometimes, the properties of the

formulation require that the
temperature be very low, often
below –30oC. This decreases the
driving force
 The heat required is very high, and
heat transfer in freeze drying is
very inefficient
 Huge batch sizes,takes time to
complete the 3 stages of
lyophilization.
Importance of Freeze-Drying 22

Freeze drying is used for more than 30 categories of substances

or materials. The most important markets are the pharmaceutical
industry and biotechnology as well as the food industry.
The process finds a wide range of applications:

 Preserving product characteristics of the initial substances

(e. g. pharmaceutical products, milk)
 Preserving the original form (e. g. taxidermy, archaeological finds,
flowers)
 Conditioning materials (e. g. freeze dried fruit in yoghurt)
 Chemical analysis (e. g. analysis of foodstuffs, slurry, soil)
 More recent applications relate to drying nanoparticles, where
capillary forces or surface tension are unlikely to have any
effects.

Smart Freeze Drying;Basic principles, optimum procedures and applications; Martin Christ
Gefriertrocknungsanlagen GmbH; January 2010.
 23
Freeze-Drying Applications

Antibiotics Pathological samples

Antitoxins Pharmaceuticals
Bacteria / Viruses Plasma
Blood coagulants Reagents
Enzymes Standards
Fine chemicals Tissues
Hormones / Growth Vaccines
factors
Media
etc...

Smart Freeze Drying;Basic principles, optimum procedures and applications; Martin Christ
Gefriertrocknungsanlagen GmbH; January 2010.
Conclusion

• Roughly 50% of all commercial biologic (therapeutic

protein products) are lyophilized.

• Lyophilization technology and the expertise to use it

are vital to the ability of the biopharmaceutical
industry to prepare and market life-saving injectable
medicines.

• Lyophilization is the most challenging (and most

expensive) of all sterile product manufacturing unit
operations.
 25

References:-

 Shukla S.; Freeze drying process: a review; IJPSR, 2011; Vol.

2(12): 3061-3068
 V.Lavakumar et al.; Lyophilization/Freeze Drying - A Review;
IJNTPS; Volume 3 | number 4 | oct | 2013
 A guide to freeze drying for the laboratory; An Industry Service
Publication ; Labconco corporation.
 Smart Freeze Drying;Basic principles, optimum procedures and
applications; Martin Christ Gefriertrocknungsanlagen GmbH;
January 2010.
 Pharmaceutical dosage forms: Manufacturing and Compounding;
Remington: Essentials of Pharmaceutics; pg. no.525-528.
 Guide to inspections of lyophilization of parenterals; 1 von 17;
23.11.98 18:19
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THANK
YOU....