Abstract: Through the introduction and analysis of the "three-in-one" equipment for aseptic bulk drugs, combined with the new GMP and the characteristics of the production process, the selection of such equipment was expounded.
Key words: aseptic bulk drug; three-in-one device; application of problem 1 In recent years, due to the occurrence of various drug incidents, China's drug regulatory systems and production companies are paying more and more attention to the production of sterile drugs, especially the recent new edition. The GMP standard is basically the same as that of the European Union, and the requirements for production equipment are further improved. In general, the production of sterile bulk drugs is usually carried out by combining the final product refining and sterilizing processes in the production process as a one-step operation unit in the production process. Aseptic and insoluble particulate contamination is the two main characteristics distinguishing sterile raw materials from non-sterile bulk drugs, so the aseptic bulk drug “three-in-one†equipment (the function of the original multiple equipment is optimized to one device) The equipment that completes multiple work contents is directly related to the production process and quality of the product, and is the main equipment guarantee used in the production of aseptic bulk drugs. There are few introductions about this application, and there is a lack of reference materials for the actual production. In view of this situation, this paper analyzes and discusses the advantages and disadvantages of the “three-in-one†equipment for aseptic bulk drugs, combined with “three in oneâ€. "The development and application of some new technologies of the unit, as well as the ability to meet the new GMP requirements, explains how to comprehensively utilize the new technological advances of the "three-in-one" units to achieve a fully enclosed production process for aseptic bulk drugs. I hope that it will help you to choose equipment to improve the practical application to a higher level.
2 Aseptic raw material drug fully enclosed production system "three-in-one" equipment introduction Filtration, washing, dryer, commonly known as "three-in-one" equipment, is the key equipment commonly used in the production of bulk drugs, tank-type "three-in-one" The tank of the equipment is similar to a large suction filter. The chassis is made up of a metal sintered plate filter (with two main materials of stainless steel and titanium), a support plate and a heating plate. The can body has a jacket for heating and cooling. The tank has a stirrer that can move up and down. The stirrer has a hollow structure, and the medium is used for heating and cooling, and plays a main role in the drying stage. The container can be protected by inert gas, consisting of an "input/output" interface system, a working system, a sampling system, a CIP and a SIP system. FIG. 1 is a schematic structural view of a “three-in-one†device.
1—Rotary joint 2—lifting device 3—reducer 4—explosion-proof motor 5—mechanical seal 6—mixing shaft assembly 7—corrugated pipe assembly 8—upper tank 9—stirring paddle assembly 10—tank kalan 11—tank Lifting device 12 - filtrate outlet device 13 - tank bottom bracket 14 - discharge valve 15 - sampling valve 16 - tank base 17 - tank bottom leg 18 - catcher 19 - hood N1 - gas inlet N2 - venting port N3 - anti Blowing mouth N4—vacuum port/capture port N5—trap steam outlet N6—trap steam inlet N7—pressure sensor interface N8—upper thermometer interface N9—bursting plate interface N10—hand hole, view port N11—cleaning port N12 - Raw material import N13 - Pressure gauge interface N14 - Sampling port N15 - Discharge port N16 - Lower thermometer interface N17 - SIP interface N18 - View lamp port N19 - Bellows cleaning port N20 - Filtrate outlet N21 - Balance port N22 - Tank bottom steam Import N23 - tank bottom steam outlet N24 - tank steam inlet N25 - tank steam outlet N26 - head steam inlet N27 - head steam outlet N28 - paddle hot water inlet N29 - paddle hot water outlet N30 - discharge valve CIP port N31 - solvent import process can be briefly described as follows:
(1) Firstly seal the whole unit system, and fill it with sterile inert gas (such as N2 gas) to protect the crystal liquid to be treated from the crystallizer through the automatic valve to the “three-in-oneâ€. After reaching a certain volume, close the feed valve.
(2) Pressurizing with an inert gas to achieve solid-liquid separation of the crystallization liquid through a large metal filter plate at the bottom.
(3) After the solid solution separation of the crystallizing liquid, the filter cake is spray-washed.
(4) After the washing is finished, the stirring device is lowered by the hydraulic device to stir, and at the same time, the material layer is heated by the internal heating heating pipeline system, and the drying process temperature is strictly controlled, otherwise the degradation of the drug may be caused. The system is vacuumed while heating and drying, so that the solvent evaporates quickly, and the dust collector is automatically activated to ensure the normal ventilation of the vacuum system.
(5) After the material layer is dry (can be sampled or analyzed or analyzed by automatic process), the vacuum is stopped and the automatic discharge program is entered.
(6) Automatic discharging: lowering the stirring device, controlling the stirring speed and the falling speed of the stirring blade to carry out the scraping and feeding action, so that the powdery material quickly enters the silo through the discharge valve, and stops when stirring and scraping close to the metal filter plate layer. The agitation is lowered, and then the inert gas is injected instantaneously, and the bottom material is completely blown to the silo.
If a high-pressure sterile inert gas (such as N2 gas) is introduced near the discharge opening, the silo is connected and vacuumed at the same time, and the weighing can also realize the whole process of filtering, washing, drying and dispensing of the medicine.
3 Advantages and Disadvantages of “Three-in-One†Equipment in the Production of Sterile Bulk Drugs 3.1 Advantages of “Three-in-One†Equipment in the Production of Sterile Bulk Drugs How to ensure that the production system meets the cleanliness requirements before use in the production process of aseptic bulk drugs Maintaining sterility is a key issue in the production of sterile bulk drugs.
Aseptic manufacturing processes typically have more variables than the final sterilization process, such as air cleanliness in the production environment, temperature and humidity, operator's aseptic handling practices, packaging materials, and sterilization of sterile clothing. These factors add a lot of difficulty to the aseptic manufacturing process. In a non-closed production process, the material has several parts that are exposed outside the equipment and needs to be processed manually. Once pollution occurs, it is quite difficult to find and confirm which part is causing the pollution. Therefore, in the production process of aseptic bulk drugs, the use of fully enclosed equipment production mode is more effective than other non-closed production modes to avoid product environmental pollution. In theory, the “three-in-one†fully enclosed production system has no open door to the entire production system except raw material imports and finished product exports. Therefore, it has the following advantages:
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3.1.1 Reduce the probability of pollution, help to ensure the sterility of the product. Wash, filter, dry and other processes in a closed device to complete a number of operations, reducing the risk of contamination transfer between different devices, the device can also pass Protective gas such as N2, which is in contact with the external environment, greatly reduces the chance of product contamination and is beneficial to the sterility of the product.
3.1.2 Online CIP and SIP can be realized, easy to clean and sterilize or cleaned after disassembly. The current “three-in-one†device has changed the disadvantages of the original centrifugation, filtration or oven not suitable for online cleaning and sterilization; by installing spray ball By turning on pure steam and other methods, if necessary, adding cleaning solvent can automatically complete the cleaning and sterilization function without disassembling the equipment, and provide equipment guarantee for aseptic production. The “three-in-one†equipment that is packaged is currently able to do CIP and SIP in some foreign countries. Now it can't be done in China, and most of them are cleaned and sterilized after disassembly.
3.1.3 Non-polluting sampling can be achieved. Most of the “three-in-one†equipment is designed with a safe and pollution-free sampling valve device. When sampling, it is not necessary to open the equipment cover or the cabinet door to avoid the contamination of the sampling tool with impurities.
3.1.4 Improve production efficiency and save operating costs (1) Since the work done by multiple processes and multiple equipments becomes one device, the operation time is reduced and the production cycle is shortened; (2) The clean area is saved on site. Space, reduce construction costs; (3) also saves operating costs such as air conditioning and refrigeration, and has certain effectiveness in reducing costs, increasing efficiency, and saving energy.
3.1.5 Saving labor costs, also conducive to the stable quality of products, reducing the production process, improving the degree of automation, reducing labor, reducing the risk of errors and pollution in the operation of employees, and conducive to the uniformity of quality between batches of drugs. .
3.1.6 In line with the development trend of clean production in the world The fully enclosed production process in pharmaceutical production has always been the best production method pursued by pharmaceutical manufacturers. In this way, the pharmaceutical production process is free from external or artificial impurities, pollution, etc. The impact is the most effective way to ensure the quality of the drug, and the impact of production on the environment is minimal. This production method is in line with the development trend of clean production in the world.
3.2 Main defects of “three-in-one†equipment in the production of aseptic bulk drugs Domestic integrated equipment has solved many problems and has many advantages. However, there are some defects or not perfect in practical applications: (1) Inside the equipment Residue of materials, 5%~10% of materials in each batch of materials can not be automatically discharged from the equipment, that is, using air knife or barrel tilting, can not solve the problem, this is the biggest problem of this "three in one" . (2) It combines the functions of filtration and drying, but the efficiency of filtration and drying is lower than that of centrifuges and dryers, which is also a problem that cannot be overcome in China at present. According to relevant information, the US vibrating "three-in-one" equipment can solve the above problems.
4 Under the new GMP conditions, the functions of the “three-in-one†equipment for aseptic bulk drugs should be based on the requirements of Chapter 8 of the new GMP and the first chapter of the sterile drugs. The “three-in-one†equipment for aseptic bulk drugs should have the following basic skills:
(1) It is possible to perform multi-unit operation functions on an integrated device. For example, the “three-in-one†equipment for filtration, washing and drying introduced in this paper replaces the original filtering equipment, can complete the washing operation, and can realize the drying function; and the “three-in-one†equipment is disassembled and crushed. The continuous operation function of the sieve and weighing in the closed system fully reflects the practical significance of the “three-in-one†equipment.
(2) The “three-in-one†described in this paper is a closed system with a separate sampling system; the parts in contact with the drug are all made of 316 stainless steel, and the coolant and lubricant have their own independent operating system completely separated from the drug; Some mechanical seals have gas seals and particulate collection devices or introduce US-style lip seals. Prevents particles from entering the tank or contaminated equipment inside the container; effectively reducing the chance of contamination. The equipment is designed to reduce the occurrence of pollution, cross-contamination, confusion and errors; the material of the equipment, the lubricant used, the coolant and so on will not increase the pollution of the product; the incoming and outgoing materials, sampling, design and mechanical seal wear Particle prevention and other aspects, effectively prevent particles from entering the tank or container contaminated equipment; greatly reducing the probability of pollution.
(3) The equipment introduced in this paper is equipped with manual and automatic operation procedures, with touch operation screen, convenient operation, automatic diagnosis and fault diagnosis, and easy maintenance. The production process is relatively mature and stable, and can be considered for programming control, with pneumatic or Electric valve with one-button operation. Reducing complicated operation procedures may lead to erroneous operations, causing loss to production, and convenient operation for maintenance, which reduces the chance of equipment being contaminated during maintenance.
(4) The equipment should be easy to carry out CIP and SIP thoroughly, or the parts contacting the medicine should be able to be cleaned and sterilized after disassembly; and it is convenient for the batch to clear the boundary and prevent the batch of materials from the residual contamination of the batch, resulting in drug quality accidents. Now used in the production of aseptic bulk drugs, the "three-in-one" equipment has the in-place cleaning and sterilization of the tank, the removal and cleaning of the discharge valve and the sampling valve, and the in-situ sterilization function. The disassembly and cleaning can be steam sterilized together with the tank body, and the parts in contact with the direct medicine can be cleaned or removed in place, and steam sterilized in place after assembly.
(5) The parts of the "three-in-one" equipment used for aseptic production and the medicines are all made of 316L stainless steel, most of which use CNC machine tool cutting, automatic welding, machine polishing, cleaning passivation and other processes. The surface of the equipment is smooth, flat, easy to clean or disinfect, corrosion-resistant, does not chemically react with the drug or adsorbs the drug, or releases the substance into the drug, which affects the quality of the product and causes no harm to the drug.
In addition, equipment should also consider energy saving factors.
5 Conclusion The design and selection of “three-in-one†equipment mainly considers product characteristics, process route and GMP, etc. It is not the combined function as much as possible, in the condition of fully satisfying product quality and GMP requirements, in a closed container or pipeline. It is ideal to deliver or produce medicines. Therefore, in terms of how to select the integrated equipment according to the characteristics of the production process, it should also be noted that: in general, the product is not suitable for use when the product is sticky or smashed with heat and viscosity; the special crystal material cannot be used when it is not stirred. A machine with agitation; materials with heat sensitivity or low temperature requirements can be cooled or vacuumed to dry, in addition to basically can be used to improve product quality.
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