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Lyophilisation
Lyophilisation is a low-temperature dehydration process that involves freezing the product, reducing the pressure, and then removing the ice by sublimation. Freeze-drying leads to a higher quality product due to lower temperatures in processing. The original shape of the product is maintained and the quality of the rehydrated product is excellent. Primary applications of freeze drying are biological (e.g., bacteria and yeast), biomedical (e.g., surgical implants), food processing (e.g., coffee) and preservation.

Principle
•	Lyophilization is carried out using a simple principle of physics sublimation. Sublimation is the transition of a substance from the solid to the vapour state, without first passing through an intermediate liquid phase.

•	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 concentration gradient of water vapour between the drying front and condenser is the driving force for removal of water during lyophilization.

Objectives
•	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.

History of freeze-drying
Freeze-drying may seem like the food preservation technology of the future, and the technology we use today is more advanced, with the concept of preserving food with pressure and temperature having a long, interesting history. Freeze-drying does not include sugar, sulfite or other preservatives in the diet, but it still makes delicious shelf-stable products. And it has been used for many years.

Early technology
Freeze-drying developed separately in early societies in the Americas, East Asia, and Northern Europe. Peru was the first place where indigenous peoples stored beets and potatoes on top of the Andes Mountains. He set his frozen items in the summer sun, causing the snow to evaporate. "Chuño" is a staple in their diet, and these preserved potatoes are finely ground. It is mainly used in cooking and baking. This method fed the local communities throughout the year, with food that was safely preserved, which also gave them good taste. Hundreds of years ago, Japanese monks south of Osaka on Mount Koya developed a similar process for tofu preservation. To make "koyadofu", bean yogurt is packed on an icy hill where low temperatures and atmospheric pressure. Then at the high altitude the water is quickly evaporated from the tofu. The Vikings in northern Europe used similar techniques to preserve codfish, which only built triangular wooden racks that could produce large amounts of preserved food. This early method of freeze-drying in fish preserved for two years - an incredible invention for this early population. Freeze drying was introduced in the 1890s by Richard Altman, who devised a method for freezing dried tissues (either plants or animals), but this was not discovered until the 1930s. In 1909, Schekel independently created a vacuum chamber using an electric pump. No freeze drying information was reported until 1927, and in 1934 Elzer patented the freeze drying system with improvements in the freezing and condenser stages.

Innovation in Science
These early attempts at freeze-drying were much less advanced and less stable than the advanced freeze-drying methods used today. In fact, the freeze-drying technique was not used successfully in the laboratory until 1890, when the tissue was completely dried and first rehydrated. However, it took decades for science to be ready for widespread use. During World War II, freeze-drying was used to transport plasma from hospitals in Europe. Freeze-drying safely protects blood plasma, which makes travel significantly easier and easier to reactivate without deteriorating in quality. After a while, this technique was proven and used as a method for the protection and transportation of vaccines - a method that is still used today.

Many food brands have already struggled to develop new food products with freeze-drying technology. In 1965, Nestle released the Nescafe Gold Blend, the first freeze-dried instant coffee. In the following years, freeze-drying produced a whole new set of foods, most of which (including freeze-dry ice cream) were launched into space in Gemini in 1965 and Apollo 7 in 1968.

The lyophilisation process
Lyophilization is a process of drying under low temperature and vacuum. The water in the sample is first solidified and then removed directly by evaporating the ice. This is done under vacuum and without going into the liquid phase. The special purpose of freeze drying is to keep the samples at a low temperature and freeze them during the entire drying process, preserving thermo-labeled components (protein, flavor, color), maintaining the dried product in all original shapes and sizes long-term composition (i.e. enzymatic, genetic) or microbial. All this can be stored without falling, which is made possible by the lack of water.

In other words, freeze drying is a dehydration technique. The essence of the freeze drying process is that, unlike other dehydration methods, dehydration takes place, the product is in a frozen state and in a vacuum. These conditions stabilize the product and reduce the effects of oxidation and other degradation processes. Freeze drying has become an accepted method for processing heat sensitive products that require long-term storage at freezing temperatures.

Freeze drying process step
There are 4 basic steps that require understanding-

•Pre-treatment- correcting the product before freezing. changes such as product concentration, product thinning, addition of components to increase stability and / or improve processing, reducing high vapor pressure solvent or increasing surface area

•Freezing - Freezing the product solution to a temperature below its eutectic point. The rate of crystallization define the freezing process and efficiency of primary drying.

•Primary drying (ice sublimation) - heat is introduced from the shelf to the product under graded control by electrical resistance coils or circulating silicons. Removal of moisture upto 99%.

•Secondary drying (moisture desorption)- the temperature is raised and bound water is removed, rate of drying is low.

•Process monitoring and verification after drying the vaccum is replaced by filtered air or nitrogen and the bottles or vials are sealed.

Things to consider for freeze drying process
	Choice of Equipment for Temperature Test

	Choice of Equipment for Vacuum Test

	Temperature Sensor Designs

	Live Data Option

	Long Process Duration

	Data Analysis, Data Integrity and FDA Compliance

	Sensor Contact to Shelves

	Calibration

	Regular Monitoring of the Process Online

	Sensor Interchangeability

Freeze dryer design
Essential components

Chamber
it is a vaccum light box which is called the lyophillization chamber or cabinet. The chamber contains shelves for processing the product. It can also fit with the stoppering system. The door locking arrangement is made by hydraulic or electric motor.

Shelves
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.

Process condenser
The process condensers sometimes referred as just the condenser or the cold trap. It Is designed to trap the solvent, which is usually water, during the dyeing process. The process condenser will consist of coils or sometimes plates which are refrigerated to low temperature. These refrigerated color plates may be in a vessel separate to the chamber, or they cold be located within the same chamber as the shelves. Hence there is designation "external condenser" 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 an internal condenser the refrigerator coils or plates are placed beneath the shelves on smaller machines, and behind the shelves on lager machines but again there is no performance constraint, only the geometry of the chamber.

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.

Refrigeration system
The product to be freeze dried is either frozen before into the dryer or frozen whilst on the shelves. 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.

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 100 bar. To achieve such a low vacuum, a two- stage rotary vacuum pump is used. For large chambers, multiple pumps may be used.

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.

Manifold method
In the manifold method, flasks ampoules or vials are individually attached to the ports of a drying chamber. The product either frozen in a freezer, by direct submersion in a low temperature bath, or by shell freezing, depending on the nature of the product and the volume to be freeze dried. The prefrozen product is quickly attached to the drying chamber or manifold to prevent warming. The vacuum must be created in the product container quickly and the operator relies on evaporative cooling to maintain the low temperature the product. This procedure can only be used for relatively small volumes and product with high eutectic and collapse temperature.

Batch method
In a batch drying, large numbers of similar sized vessels containing like product are placed together in tray dryer. The product is usually prefrozen on the shelf of the tray dryer. Precise control of the product temperature and the amount heat applied to the product during drying can be maintained. Slight difference in heat different areas. input from the shelf can be expressed Batch drying is used to prepare large numbers of ampoules or vials of one product and is commonly used in the pharmaceutical industry.

Bulk method
Bulk drying is generally carried out in a tray dryer like batch drying. However, the product is poured into a bulk pan and dried as a single unit. Although the product is spread throughout the entire surface area of the shelf and may be the same thickness as product in vials, the lack of empty spaces within the product mass changes the rate of heat input. The heat input is limited primarily to that provided by contact with the shelf.

Advantages
•	Chemical composition is minimized

•	Removal of water without excessive heating

•	Enhanced product stability in a dry state

•	Ease of processing a liquid, simplifies aseptic handling

•	More compatible with sterile operations than dry power filling

Disadvantages
•	Increased handling and processing time

•	Volatile compounds may be removed by vaccum

•	Need for sterile diluents upon reconstruction

•	Long time process

•	The product is prone to oxidation

•	Cost may be an issue depending upon the product.

Applications
Pharmaceutical and biotechnology :-

1.the companies use this to increase shelf-life of products, vaccines and other injectables.

2.By removing water, the material can be easily stored, shipped, and reconstituted to its original form for injection.

Food industry Freeze-dried foods are close in composition and chemistry to their natural structure, retaining essential vitamins and nutrients. The freeze-drying process is widely used by NASA to make freeze-dry ice cream, a popular astronaut food. It is widely used to add aroma or flavor to food.

Technological industry in bio seperations, freeze drying can be used as a late stage production purification cause it removes solvents more efficiently

Others faura and fauna preservations, recovery of water damaged documents and many more