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Lyophilization Technology
&Form Fill Seal Technology
 PREPARED BY:
 KISHAN RAM
 Dept. M.PHARM QA
 GUIDED BY:
 Mr. AJAY I. PATEL
 ASSISTANT-
PROFESSOR
 BKMGPC RAJKOT

TABLE OF CONTENT :
Lyophilization Technology
 History
 Objectives
 Principle
 Basic components of a Lyophilizer
 Lyophilization process
 Steps involved in Lyophilization
Form Fill Seal Technology
Processing of FFS technology

 LYOPHILIZATION TECHNOLOGY:
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 values that will
no longer support biological activity or chemical
reactions.

History
Freeze drying was first actively developed during WORLD WAR II
transport of serum.
The main aim was to store the products without refrigeration and to
remove moisture from thermolabile compounds.
 Atlas in 1961 built 6 production freeze drying cabinet for Nestle
group in Germany, Holland.

Objectives of Lyophilization process
•To preserve the biological activity of a product.
•To reduce the product weight to lower the transportation cost.
•To extend 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.

Principle
 Lyophilization is carried out using a simple principle of physics
sublimation.
 Lyophilization is performed at temperature and pressure conditions
below the triple point, to enable sublimation of ice.
 The entire process is performed at low temperature and pressure by
applying vacuum, hence is suited for drying of thermolabile
compounds.
 The driving force is vapor pressure difference between the
evaporating surface and the condenser.

Basic components of a Lyophilizer

PROCESSING
Fundamental process steps are:
1. Freezing: the product is frozen. This provides a necessary condition for low
temperature
2. 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.
3. Heat: Heat is applied to the frozen product to accelerate sublimation.
4. Condensation: Low-temperature condenser plates remove the vaporized
solvent from the vacuum chamber by converting it back to a solid. This
completes the process.

STEPS INVOLVED IN LYOPHILIZATION
FREEZING STAGE
PRIMARY DRYING STAGE
PACKING
SECONDARY DRYING STAGE

1.Freeze Drying
•Freezing the product solution to a temperature below its eutectic
temperature.
•Decrease the shelf temperature to -50oc.
•Low temperature and low atmospheric pressure are maintained.
•Freons are used as refrigerant.
•Formation of ice crystals occurs.
•The rate of ice crystallization define the freezing process and
efficiency of primary drying.

2.Primary Drying (Sublimation)
•Heat is introduced from 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 4.58mmHg.
•The driving force is vapor pressure difference between the
evaporating surface and the condenser.
•Easily removes moisture up to 98% to 99%.

3.Secondary Drying (Desorption)
•The temperature is raised to 50°C – 60°C and vacuum is lowered about
50mmHg.
•Bound water is removed.
•Rate of drying is low.
•It takes about 10-20 hrs.

4.Packing
• After drying the vacuum is replaced by filtered dry air or
nitrogen to establish atmospheric pressure
• Ampoules are sealed by either tip sealing or pull sealing
method
• Vials and bottles are sealed with rubber closures and
aluminum caps

Advantages of freeze drying over
conventional drying
Product quality Freeze drying Conventional drying
Form of wet material to be
dried
Whole, liquids
Pieces, powders
Pieces
Dry shape and form Maintained Shriveled
Appearance Nearly same Shriveled
color Maintained Faded
Rehydration Fast Slow
Heat exposure 0-150oC 200-300oC
Oxygen exposure Very low High
Retained volatiles Excellent Poor

Advantages of Lyophilization
Removal of water at low temperature
Thermolabile materials can be dried.
Compatible with aseptic operations
More precise fill weight control
Sterility can be maintained.
Reconstitution is easy

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

Common Lyophilized Products
Pharmaceuticals – large and small molecules
Bacteria
Viruses
Vaccines
Plasma
Fruit
Coffee
Flowers etc.

Form fill seal (FFS) technology is an automated computer
operated technology, to prepare sterile products.
The reason behind FFS technology is to reduce the
contamination during production in a closed sterile chamber
of a machine.
Thus there should be no personnel intervention so reduce the
chances of contamination during the manufacturing of sterile
products.
Form Fill Seal Technology

Processing of FFS
1. Pre-sterilization of machine: carried out in 2 different phases
◦ Programmed in sequence
◦ H2O2 sterilization cycle
2. Production in aseptic chamber: which involves 3 steps
◦ Formation of container
◦ Filling of container with content
◦ Sealing of container
3.Post-production cleaning

Advantages of FFS Technology
 Bags made on FFS are less expensive than pre-made bags = “pay back”
 Total automation - usually unattended, labour saving provides = “pay-back”
 Consistent packing rate
 Compact (especially the Vertical FFS)
 Fast - increased production rate, reduced no. of shifts = “pay back”
 Easy and quick to clean-out between production batches
 Fewer moving parts - especially Vertical FFS
 'Online‟ film printing provides readable bar code and product info

Disadvantages of FFS Technology
 Cannot handle paper.
 Cannot handle multi-ply packing materials.
 Not economical for packing low density, aerated powders
 Cannot remove „trapped air‟ very quickly or easily.

References
1. The science and practice of pharmacy by Remington, 21 edition, vol-
1. Pg 828-831.
2. The Theory And Practice of Industrial Pharmacy by Leon Lachmann,
Herbert.A.Lieberman and Joseph I. Kanig, 1991. Pg 62-64, 672-674.
3. Pharmaceutical engeenering by CVS subhramanym, page no. 400-402
4. World Journal of Pharmaceutical Sciences · January 2018 AN
OUTLOOK TO FORM FILL SEAL TECHNOLOGY by Pratik
Swarup Das and at all ,Volume 7, Issue 2, 290-295.

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