Introduction Freeze-Drying- Freeze- drying or lyophilisation is commonly used in the pharmaceutical industry to improve the stability and long-term storage of liable drugs and has taken on added importance in light of the growth of pharmaceutical biotechnology. It is an effective manufacturing process for drugs that are unstable in solution. The molecular structure of a product is preserved by freeze-drying and attain 100% dryness at the same time. Freeze-drying provides easy shipping and storage of the product. The process is designed such that the maximum temperature during the drying operation is maintained low enough so that the product does not break down.It is a time and energy consuming intensive process that could take days or even weeks to finish in the freeze-drying cycle. In all the pharmaceutical unit operations, the drying operation is the most expensive, largely as a result of the high heat of vaporisation of water. Among the most common drying operations, freeze-drying is the most expensive, not only in terms of operating cost but also in terms of capital investment.Freeze-drying is done in three steps- freezing, primary drying and secondary drying. During the freezing stage, the shelf temperature is lowered to at least -40 degrees which converts most of the water into ice. Then the system is evacuated through the vacuum pump, at the same time shelf temperature is increased slowly to carry out ice sublimation in the primary drying step. Shelf temperature and chamber pressure are settled such that the product temperature remains below its collapse temperature. The remaining moisture which is not removed during the primary drying is removed by the desorption during the secondary drying stage at an elevated shelf temperature.During Primary Step- The rate of water vapour from the vails is governed by three barriers or resistances. The resistance of the dried product layer, the resistance of the vail and the resistance of the chamber to the condenser pathway.In the freeze-dryers, product temperature is not controlled directly instead shelf temperature and chamber pressure is controlled. The pressure is usually controlled by introducing a non-condensable gas such as Nitrogen in the chamber with vails. The gas and water vapour flow from the chamber to the condenser reservoir driven by the pressure and concentration gradients. There is a duct connecting the chamber to the condenser reservoir and it can be several meters long.Components of Freeze-Dryers –The Product Chamber- In this chamber there are sets of vertically adjustable shelves. The vails or ice slabs are placed on the shelves whose temperature is controlled. Often by a heat transfer fluid, pumped through the system. There are single or multiple inlet ports available on the chamber walls which allows inflow if nitrogen or air to control the pressure.The product chamber is connected through a duct to the condenser chamber.The Chamber to Condenser Duct- The duct is a critical component of the equipment. Though the functionality of duct is simple, choosing the right dimensions is critical for the overall performance of the dryer. The duct also includes the isolation valve that controls the flow to the condenser. The flow of water vapour and gas can significantly affect the dryer performance.The Condenser Chamber- The condenser chamber contains an arrangement of coils or other surfaces that are maintained below the saturation temperature of water. Typically, the condenser coils temperature is from -90 degrees to -40 degrees. There is a vacuum pump in the condenser chamber for the removal of noncondensable gases. The gases flow through the vacuum pump but water vapours condense on the coils forming ice layer on coils. The condenser performance is the single most critical factor affecting the efficiency of a freeze-dryer.The efficiency of freeze-dryers is studied by using CFD techniques.Computational Fluid Dynamics- CFD is a branch of fluid mechanics that applies numerical methods for the solution of physical problems involving fluid flows. It is now recognised to be an important part of the computer-based engineering design tools and it is extensively used today in many industries. CFD methods can be used to analyze the various design and process parameters, where at the same time reducing the involved experimental work and associated costs. In the pharmaceutical sciences, flow problems involving dispersion phenomena and optimal design selection are frequently encountered. Computational methods have been used to characterise a particular design by its close concentration, dispersion, particle loss characteristics and associate them with potential design improvements. CFD modelling has been found useful in the study of the various pharmaceutical unit operations, for instance, mixing and dissolution, CFD is making a significant impact in pharmaceutical sciences and technology. The finite element analysis of unsteady heat and mass transfer in a vail was developed and applied for in-process product temperature and vapour content analysis. Effect of vapour flow in a freeze dryer chamber on the uniformity of drying rates within a batch of vails can be studied using CFD simulations.Literature ReviewFreeze-Drying- Freeze-Drying or Lyophilisation is a process to make the product more stable and easier for handling. Freeze-drying freezes the molecular structure of the product and makes it stable for a long period of time, freeze-drying is mostly used in the pharmaceutical industry. During the freeze-drying, all the moisture from the product is evaporated or sublimed and 100% dryness is attained so the product doesn’t contaminate as it is stored for a long time. It is a long and expensive process, it can last up to days or even weeks. Industrial freeze-dryers are not only expensive to run but also expensive to implement. Because of these expenses, the freeze-dried drugs can be expensive also [1].Freeze-dryer- It is a component which is mostly used in the pharmaceutical industry, it is used to attain 100% dryness of the products, so the medicines or drugs can be stored for longer period of time and can be easily handled easily, without causing any problems or loss of the product. It works on the principle of freezing and drying. Freeze-dryer holds the molecular structure of a product that keeps it away from contamination and stable for a long period of time.Freeze-dryer is used to get rid of moisture available in the product, it is used for the drugs which are unstable in the availability of moisture. It helps to stabilise, store or increase the shelf life of a drug product and other biological products [1,2]. Freeze-drying works in three steps-  Freezing- The most important step in lyophilization is freezing as it defines the texture of the frozen material, ice sublimation rates are strongly related with ice crystal morphology, textural and structural parameters of material are mostly fixed during the freezing step.Freezing is carried out in three processes, first of all, is nucleation followed by the crystallization of the freeze concentration and then the last one is maximal freeze concentrate [3].Primary drying-The removal of water in bulk quantity from the product during the freeze-drying is via sublimation of all the ice crystals during the primary step which was produced in freezing step. Organic solvents are also removed during the primary drying. It is a slow process conducted at colder temperatures, being aware of the products collapse temperature. Heat energy is required for sublimation to go from the solid phase to the gas phase. All three heat transfer techniques are considered during freeze-drying of a product. The three heat transfer techniques are- conduction, convection and radiation.The primary ways of heat transfer to the product are through convection and radiation from the surrounding environment. While working with the products with low collapse temperatures, it can be necessary to wrap or insulate the product to slow down the rate of heat transfer and to avoid the collapse of the product. In Pharmaceutical shelf freeze dryers, most of the amount of heat is transferred into the product through the conduction and it is important to maximize the surface contact of the product with the shelf, effects of radiation and convection are also important for the product uniformity and process control purposes. Because of the radiant heat from the inside walls of the product chamber will help product on the corners of the shelf to dry more quickly than the product placed in the centre of the shelf. Uneven contact to the shelf, convective heat transfer help to promote uniform product drying. Pressures from 100 mTorr to 300 mTorr range will usually promote an adequate amount of convection. It is very important to keep the product temperature below the critical temperature during the process to avoid collapse, otherwise, the whole batch will fail a can cause a loss in big amount. The product temperature depends on the vapour pressure at the ice interface and in turn, the vapour pressure is dependent on the rate of heat transfer and the system vacuum level set point. During this process, the system pressure and the shelf temperature are set and controlled in combination to yield the appropriate product temperature [3].Secondary Drying- After the primary drying step, there still remains a substantial amount of water molecules that are bound to the product. These water molecules are removed by secondary drying (desorption). All the ice has been evaporated during the primary step, the product temperature can now be increased without any fear of melting or collapse of the product. The last step starts during the primary drying, but at a higher temperature (from 30oC to 50oC), desorption proceeds much faster. Secondary drying rates depend on the product temperature, the system vacuum can be continued at the same level used during the primary step, lower vacuum level will not improve secondary drying times. It will be continued until the product has acceptable moisture content for longer period storage, moisture content in fully dried products is usually 0.5% to 0.3%. In some cases, the drier the product, the longer the shelf life will be. Secondary drying process should be controlled accordingly for some complex biological products which may actually become too dry for optimum storage results [3].Components of freeze-dryer –Product Chamber- The product vacuum tight box, also called the lyophilization chamber or cabinet. The product chamber contains several numbers of shelves for processing product. It is made of stainless steel and highly polished on the inside and insulated and covered on the outside. The door is locked by a hydraulic or electric motor [3].Shelves- Industrial freeze-dryers contains a large number of shelves, Shelf is designed in such a complicated way because of the functions it has to perform. The shelf act as a heat exchanger, exchanging heat energy from the product and freezing the product during the freezing step. Followed by supplying the heat energy during the primary and secondary drying steps to the product. The shelves are connected to the silicone oil system through fixed or flexible hoses [4]. Condenser Chamber- The condenser chamber contains an arrangement of coils or other surfaces that are maintained below the saturation temperature of water. Typically, the condenser coils temperature is from -90 degrees to -40 degrees. There is a vacuum pump in the condenser chamber for the removal of non-condensable gases. The gases flow through the vacuum pump but water vapours condense on the coils forming ice layer on coils.Shelf Fluid System- During the freeze-drying process the product first must freeze and then heat energy is transferred throughout the drying phase of the process. This freezing and heating of the product are done by circulation of a fluid present in the shelves at the desired temperature. The temperature of a fluid is set in an external heat exchange system consisting of cooling heat exchangers and an electrical heater. The fluid circulated through the shelves is usually silicone oil, which is pumped around the circuit at a low pressure by the pump [4].Refrigeration System- The product which has to be freeze dried is either frozen before into the dryer or frozen on the shelves, a considerable amount of energy is needed to this work. The cooling energy is supplied by the compressors or by use of liquid nitrogen. Most often multiple compressors are used during the process, one compressor is used to cool down the shelves at the desired temperature and the other one is used to cool the condenser for the sublimation of water vapour [4].Vacuum System- Vacuum is produced in the chambers during the drying processes to remove the solvent in a reasonable time. The vacuum level can be in the range of 50 to 100? bar. Multiple vacuum pumps can be used to achieve this low level of vacuum [4].Control Systems- Control systems can be fully automatic for freeze-drying machines, which controls the shelf temperatures, pressure in the chambers, the processing time of each stage. This system set up the values according to products or according to the processes. The time can vary from days to weeks for the production processes, so the controls systems help to maintain the required pressure, temperature [4].Different types of freezers- Pilot Freeze-Dryers – These are the small size of freeze-dryers used for the research in laboratories and Universities. They are made in a small size, so they can be moved, and their capacity of storage is small.Industrial Freeze-Dryers- These types of freezers are huge in size, they have capacity of containing hundreds of shelves at once, they are used in big industries producing medicines, vaccines or drugs. They have a separate chamber for condenser connected through a duct. The condenser can have a capacity to trap ice up to 1500 kg.Computational Fluid Dynamics- CFD is the analyse fluid flows governed by the using partial differential equations which represent conversation laws for the mass, momentum and energy. It is used to solve complex problems involving fluid-solid or fluid-gas interaction. CFD analyses are frequently used in aerodynamics, hydrodynamics and even in freeze-drying industries. CFD solvers transform partial differential equations into algebraical equations and solve these equations numerically [5].CFD analysis works on three phases-Pre-processing- in this phase, the problem is transformed into an idealized and discretized computer model. Type of flow is modelled as assumed (viscous/inviscid, compressible/incompressible, steady/non-steady). Mesh generation and applying boundary conditions are also other processes of CFD analysis [5].Solving- All the computations are done in this phase, performed by the solver. There are multiple solvers varying in efficiency and capability of solving physical phenomena [5].Post-processing- final results are obtained are visualized and analysed in the post-processing phase. The results and conclusions can be drawn based on the obtained results. Example of obtained results can be static or moving pictures, graphs or tables [5].References:Varma, N. (2014). Computational Fluid Dynamics Analysis of Freeze Drying Process and Equipment. Master of Science in Aeronautics & Astronautics. Purdue University West Lafayette, Indiana.Tang, X. and Pikal, M. (2004). Pharmaceutical Research. Design of Freeze-Drying Processes for Pharmaceuticals: Practical Advice, [online] 21(2), p.10. Available at: https://link.springer.com/content/pdf/10.1023%2FB%3APHAM.0000016234.73023.75.pdf [Accessed 11 Oct. 2018].Barley, J. (2018). Freeze Drying / Lyophilization Information: Basic Principles. [online] Spscientific.com. Available at: https://www.spscientific.com/freeze-drying-lyophilization-basics/ [Accessed 19 Nov. 2018].World Journal of Pharmaceutical Research. (2015). LYOPHILIZATION / FREEZE DRYING – A REVIEW, 4(8), pp.516-543.Femto Engineering. (2017). An introduction to CFD: what, why and how. [online] Available at: https://www.femto.eu/stories/what-is-cfd/ [Accessed 4 Dec. 2018].Kuzmin, D. (2018). [online] Mathematik.uni-dortmund.de. Available at: http://www.mathematik.uni-dortmund.de/~kuzmin/cfdintro/lecture1.pdf [Accessed 1 Dec. 2018].