Brief analysis of the application of freeze-drying technology in the field of bio-pharmaceutical

Brief analysis of the application of freeze-drying technology in the field of bio-pharmaceutical
Biotechnology plays an important role in the development of science and technology in the 21st century. The field of biotechnology has also become the fastest-growing field in today's high-tech, and the commanding heights of gun battles in the development of science and technology in various countries. The application of freeze dryer in biopharmaceuticals can greatly solve the chemical, physical and biological instability of biochemical drugs and biological agents. Due to the sublimation of tiny ice crystals, the solid material tends to maintain its volume before freezing after being lyophilized, and is easily dissolved and restored after adding water. The quality of the substance needs to meet certain conditions during the sublimation process. From the viewpoint of the temperature of the biological drug product, it is generally possible to maintain a low temperature state lower than -25 ° C, and it is preferable to dry heat-labile substances such as enzymes, hormones, nucleic acids, blood, and immunological products. After the biological drug product is dried, 95% to 99% of the water can be removed, and the drying process needs to be carried out under vacuum conditions, so that the obtained product is not easily oxidized, so the technique is suitable for long-term preservation of the product. With the rapid development of biopharmaceuticals, freeze-drying technology has been proved to be a very effective technology by pharmaceutical production practice, and will increasingly show its superiority in the process of continuous development of the pharmaceutical industry.

I. Introduction to freeze-drying technology
Vacuum freeze-drying technology is referred to as freeze-drying. It is a high-tech drying technology that integrates various technologies such as vacuum, refrigeration and drying. Not only that, lyophilization technology also involves expertise in multidisciplinary fields such as heat and mass transfer, fluid mechanics, automatic control, food nutrition, bioengineering, and materials science. Freeze-drying technology has become the preferred dry preservation method for medical biological products because it realizes dehydration and drying of products under vacuum and low temperature conditions. At the beginning of the twentieth century, lyophilization technology has been widely used by scholars from all over the world after Shakel's freeze-dried preservation of biological products.

In the 1940s, after the preservation of penicillin and plasma, it was used in commercial production for the dry preservation of freeze-dried strains, culture media, hormones, vitamins, human plasma and pharmaceuticals. In the mid-twentieth century, lyophilization technology was continuously improved due to the continuous introduction of various types of freeze-drying equipment. The rapid development of electronic technology provides multi-dimensional technical information and means to promote the gradual improvement of the vacuum freeze-drying equipment automatic control system. The drying process is fully automatic controlled by means of a microcomputer, and a plurality of equipments and various drying processes are provided. Self-selected group control method. China's freeze-drying technology was developed mainly after adapting to market demand in the 1980s. Equipment performance and product quality have gradually reached international standards, and its application range has gradually expanded from simple medical biological products to food, materials, Aviation and other aspects.

Freeze-drying techniques can be used to dry heat sensitive materials and substances that require biological activity. The process generally involves first freezing the dried liquid in a low temperature environment to condense the moisture, and then sublimating the solid moisture of the material in a vacuum environment to dry it. Freeze-drying technology not only minimizes the physical and chemical denaturation of materials during drying, but also reduces damage to living tissues and cell bodies and death of living cells and viruses. The lyophilization method can concentrate the liquid medicine without changing the color, and the state is loose, and it can be dissolved immediately after adding water, which not only has good stability, but also reduces the chance of being contaminated, so that the transportation is convenient and can be stored for a longer time, the medicine The quality has also improved.

If human plasma is lyophilized, its shelf life can be extended from the previous months to 5 to 10 years; after the freeze-dried live attenuated measles vaccine, the shelf life can be extended from the previous 3 months to 1 year. The disadvantage of lyophilization is the high cost of investment, maintenance and product. Many pharmaceutical companies in China now use freeze-drying technology to process biological drugs, such as antibiotics, vaccines, enzyme preparations, and plasma.

Second, the performance index of the freeze dryer
The performance of the freeze dryer is worthy of careful analysis. In addition to the most advanced freeze-drying technology, freeze dryer applications should have safety, reliability, suitability and economic performance.

*, the performance indicators of the freeze dryer including the area of ​​the partition, the spacing of the partitions, the amount of water captured by the condenser, etc. should match the production capacity of the freeze dryer;

Secondly, the separator of the freeze dryer should be flat and the temperature should be uniform. The temperature difference should be limited to ±1 °C. Under such conditions, the quality of the same batch produced can be guaranteed to be uniform;

Third, the water vapor condenser should be able to reduce the temperature to the required level within 2~5h, usually below 45°C;

Fourth, the vacuum of the empty box should be measured and should reach 2.66 Pa within 30 min. Because the cabinet, lamellar and condenser of the freeze dryer need to withstand the corresponding internal and external pressure, once it occurs in a vacuum environment Leakage can cause contamination of drugs. Therefore, it is necessary to carry out a rigorous vacuum test on the internal and external pressure parts of the freeze dryer to meet the specific specifications;

Fifth, the freeze-drying box generally adopts a large rounded structure. The material of the freeze-drying case body should be made of high-quality stainless steel with high corrosion resistance, and the design should be reasonable and easy to clean. All the boxes and plates that are in direct or indirect contact with the drug. Layers, hoses, condensers, valves and other components should be made of low-carbon stainless steel with good corrosion resistance. The components such as the box body, the laminar layer and the condenser are easy to clean, and the internal structure design should be as simple as possible, and there is no dead angle structure that is difficult to clean. When cleaning, ultra-filtered water of 50~65°C must be used and cannot be reused. Parts of the freeze dryer should be easily disassembled for easy maintenance. The surface of the freeze-dried case and the layer is mirror-polished to reduce vacuum venting and easy cleaning.

Third, the freeze-drying process
The whole process of vacuum freeze drying includes three stages of pre-freezing, sublimation drying and analytical drying. Each stage has requirements for each stage, and the requirements for different materials are not the same. The quality of the freeze-dried product, the concentration of the product, the thickness of the can, the shape, capacity, caliber and thermal conductivity of the container, are directly related to the process design and control methods at each stage.

*, pre-freezing stage. Pre-freezing first freezes the material and quickly lowers its temperature below the eutectic point (the eutectic point is the temperature at which the different components contained in the material freeze together), laying the foundation for the sublimation stage. The pre-freezing stage is mainly controlled by the freezing temperature and freezing speed. The temperature should drop below the freezing point of the material, and the freezing point will vary from material to material. The freezing rate directly affects the size of the ice crystal particles of the material, and the structure and sublimation speed of the solid material depend on the size of the ice crystal particles. It is usually required that the material freeze is completed within 1~3h, and then enter the sublimation drying stage;

Second, sublimate the drying stage. The main process of lyophilization is sublimation drying. The purpose of sublimation drying is to sublimate the ice in the material. Ice is not allowed to dissolve during the sublimation process. Once the ice melts, the entire freeze-drying process is declared unsuccessful. Sublimation must ensure that the ice is insoluble and the water vapor around the ice is below the two basic conditions of the saturated vapor pressure at the freezing point of the material. In the sublimation drying stage, the water vapor is continuously removed, the water vapor pressure is lower than the saturated vapor pressure, and the drying speed is increased to ensure uninterrupted supply of all the heat required for the sublimation process. This requires the optimization of water vapor. Pressure and heating temperature control enables sublimation drying to achieve fast, low energy consumption. The sublimation drying stage varies in length depending on the product;

Third, analyze the drying stage. After sublimation drying, all the ice crystals in the material are removed, which will leave a lot of holes in the material, but about 10% of the unfrozen water will remain in the matrix of the material. The analytical drying is to reduce the residual unfrozen water. The mass fraction is reduced to about 2%, and the finished product is completely dried.

Fourth, summary
The development of human high-tech in the 21st century will be marked by major developments in the fields of biology, materials, electronics, and information science. The application of vacuum freeze-drying technology in the biopharmaceutical process will provide technical support for medical development and cure human diseases. To protect people's physical health will play a more active role.