Lyophilization

LYOPHILIZATION AND FFS TECHNOLOGY

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

2. TABLE OF CONTENT : Lyophilization Technology History Objectives Principle Basic components of a Lyophilizer Lyophilization process S teps involved in Lyophilization Form Fill Seal Technology Processing of FFS technology

3. 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.

4. 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.

5. 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.

6. 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 .

7. Basic components of a Lyophilizer

8. Lyophilization process

9. PROCESSING Fundamental process steps are: Freezing : the product is frozen. This provides a necessary 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. Condensation : Low-temperature condenser plates remove the vaporized solvent from the vacuum chamber by converting it back to a solid. This completes the process.

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

11. 1.Freeze Drying Freezing the product solution to a temperature below its eutectic temperature. Decrease the shelf temperature to -50 o c. 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.

12. 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%.

13. 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 .

14. 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

15. 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 0-150 o C 200-300 o C Oxygen exposure Very low High Retained volatiles Excellent Poor

16. 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

17. 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

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

19. 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

20. 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

21. 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

22. 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.

23. References The science and practice of pharmacy by Remington, 21 edition, vol-1. Pg 828-831. The Theory And Practice of Industrial Pharmacy by Leon Lachmann , Herbert.A.Lieberman and Joseph I. Kanig , 1991. Pg 62-64, 672-674. Pharmaceutical engeenering by CVS subhramanym , page no. 400-402 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.