1 Introduction
Raw material medicine machinery and equipment is one of the 8 major categories of pharmaceutical equipment in China, including reaction equipment, tower equipment, crystallization equipment, separation equipment, filtration equipment, extraction equipment, distillation equipment, heat exchangers, evaporation equipment, drying equipment, screening Equipment, storage equipment and sterilization equipment. As we all know, China is a big country in the production of bulk drugs, but it is not a strong country in the production of bulk drugs. There are many reasons for this, but one of the most important reasons is that there is a certain gap between the production of APIs and the application of new technologies and the international high-end level. Therefore, in order to improve the quality level of China's API production, in addition to improving the control standards of production enterprises from hardware and software, we should also strengthen the application of new technologies for APIs in accordance with new changes in the global market, and truly integrate with the international market.
2. New technology application
2.1 Research on environmental protection and energy conservation
Among the 6066 key industrial pollution source monitoring enterprises announced by the State Environmental Protection Administration in March 2007, pharmaceutical companies accounted for 117, and most of the fermentation-based API manufacturers, some of which were suspended due to environmental problems. Therefore, tapping potential to reduce consumption and improve economic efficiency will become an important task for raw material drug manufacturers in the future. The following is a few practical examples to illustrate the development and application of APIs in environmental protection and energy conservation.
2.1.1 freeze-drying equipment
2.1.1.1 Liquid nitrogen vacuum freeze dryer
The lyophilizer's refrigeration system provides a cold source for the drying oven and vacuum condenser. Among them, it is more common to freeze the dryer with a compression mechanism, but the heart component compressor often causes many failures due to various factors and requires frequent maintenance. Today, the new liquid nitrogen vacuum freeze dryer solves this problem, which effectively reduces the probability of failure of the refrigeration system.
The liquid nitrogen lyophilizer is a lyophilizer that uses liquid nitrogen as a cold source to cool the system. Unlike a conventional lyophilizer, the cold source is liquid nitrogen. The air contains 78% of nitrogen. Therefore, the preparation of liquid nitrogen is very convenient and can be said to be an inexhaustible environmentally friendly energy source. In addition, due to the use of liquid nitrogen refrigeration, the compressor and water cooler are no longer used, so the noise is low, the operation is reliable, the maintenance of the heart parts is not required, the maintenance is simple, and the power consumption is reduced by more than 50%, which will bring the enterprise Come to the long-term economic benefits.
2.1.1.2 New sterilization of freeze-drying equipment - H2O2 disinfection at room temperature
In order to improve the sanitary condition of the production line and achieve certain disinfection conditions to avoid pollution, Vapovac Disinfection Equipment Co., Ltd. provides a new sterilization process for freeze-drying equipment [3] - under the action of the existing vacuum system, the gaseous state H2O2 is transported to the pipe of the lyophilizer for sterilization by hydrogen peroxide. The significant difference between this process and other disinfection processes is that the gaseous H2O2 sterilization process is carried out at room temperature and under vacuum, so it has the following characteristics: (1) Compared with other chemical disinfection methods, the manpower is reduced and the pressure is reduced. The equipment is at risk of contamination and does not produce carcinogenic or by-products that cause genetic mutations; (2) no need for overpressure explosion-proof containers, which reduces the cost of use; (3) disinfectants can be used well without the need for additional gas distribution equipment. Distributed in all corners of the dryer to achieve a full range of disinfection work (which is not achieved by ordinary steam sterilization); (4) reduce the cost of 20% in each sterilization cycle and 50 compared with steam sterilization % disinfection time.
2.1.2 Drying equipment
2.1.2.1 New spiral dryer - combination of drying and cooling
In order to realize the production process of "drying + cooling" of drugs in a small space, Heinen of Germany designed and produced a new type of screw dryer [4], as shown in Figure 2, it has two sets of independent and very good. Coordinated system: * The set is responsible for the drying process and the second set is responsible for the cooling process. This results in two completely different temperature zones in the equipment throughout the continuous production process. The entire drying process is carried out from the bottom up, and this bottom-up path is a spiral belt. After the drug completes the drying process, it enters the cooling zone at the top to begin cooling. The cooling process of the drug is carried out in a spiral from top to bottom under the control of the cooling system. In this way, the drug is dried from the bottom up and cooled from top to bottom, leaving the device and transported to the packaging line for packaging. In the dryer, most of the air used is used as circulating air in the whole process. This way, the exhaust gas emissions of the entire equipment are reduced to low, so that the energy is efficiently utilized. In addition, the system's complete air handling equipment, including filters, humidifiers, heat exchangers, blowers, automatic control valves and activated carbon filters, are operated in separate technical spaces, which reduces batch and purge Time means saving production costs.
2.1.2.2 Vertical automatic filter press - combination of filtration separation and drying
With the trend of shrinking product size, more and more pharmaceutical companies are using low-consumption and high-output processes. One of the main parts is the advanced nature of dehydration methods to reduce energy consumption and product waste and loss. Larox's fully automated solid-liquid separation solution in Finland significantly reduces energy, water, manpower and wastewater treatment costs and increases product recovery. The Larox vertical automatic filter press is completely different from other conventional dewatering methods. Instead of using centrifugal, vacuum, thermal or other similar methods, it combines hydraulic and inflatable diaphragms, as shown in Figure 3, to separate forces. The zui is enlarged, so that a more effective solid-liquid separation effect is obtained with a small energy consumption of zui. Compared with centrifuges, vacuum filters, etc., the Larox vertical filter press can greatly improve the processing capacity of existing dryers. For example, a 3% reduction in filter cake moisture can increase the throughput of the drying equipment by 16%. If you do not need to increase production, you can significantly reduce the unit drying energy consumption (cost / t products).
2.2 Research safety applications
In pharmaceutical manufacturing enterprises, many raw materials are in the form of powder or bulk materials before production and processing. The dust-containing mixture formed by mixing powdery substances with air is often a dangerous product that is easy to explode. In order to prevent accidents during the production process, materials with a risk of deflagration are not allowed to “flow†at will.
Due to the modular structure design, the vacuum negative pressure conveying system is very flexible and widely used. It can extract raw materials from cylindrical containers, or transport raw materials from various containers to various process equipment, for example, mixing equipment at the beginning of production, filtration equipment, filling equipment, and tableting and packaging equipment. .
Modular powder raw material vacuum and pressure transport system, which is a new system combining powder raw material transportation system and raw material barrel emptying system, which can completely separate the raw materials of the equipment from the surrounding environment. Unlike many other isolation systems that cannot withstand pressure shocks, this new “multiple solution†can be used in reactors that are subjected to temperature, pressure or vacuum negative pressure shocks. Even when used in a corrosive environment, it is only necessary to replace a corrosion-resistant output valve.
Features: (1) The system has no electrical parts at all, so it will never cause deflagration due to electric spark; (2) The system does not have any rotating parts, such as bearings, so there is no friction, so there is no heat caused by friction. Deflagration and detonation; (3) special inert gas (such as nitrogen) protection device may be added to meet the transportation equipment that is not suitable for standard vacuum negative pressure; (4) transport system and raw material tank emptying system combination (including CIP), The loading and unloading of raw materials is completely isolated from the surrounding environment; (5) The modular structure design of the loading system enables the user to select and achieve the desired configuration to prevent pollution and ensure safety. For example, different vacuum raw materials can be used to deliver different raw materials to the mixer.
2.3 Online Technology Application and Automation
The “online†in the pharmaceutical production process is inseparable from the real-time production. To be truly "online" (detection, control...), you must rely on automation technology and its applications to achieve real-time detection and process control.
2.3.1 Real online CIP, SIP
As the quality of pharmaceutical production is increasing, people pay more and more attention to the reliability of each process in the pharmaceutical production process and the content of pollutants in the final product of Zui. The most important process is equipment cleaning and sterilization. In-place cleaning (CIP) and in-situ sterilization (SIP) have put forward higher requirements for pharmaceutical production equipment. However, there are some misunderstandings or confusions between some devices that are called CIP or SIP, such as single cleaning nozzles or single steam inlets, but no system design; unreasonable design and no control procedures and control systems; Failure to do DQ file support according to URS (User Requirements Standard). In fact, these have no CIP/SIP meaning. The true online CIP/SIP should have control process, system design, design confirmation by URS, and design of simulation technology.
2.3.2 Accurately monitor the temperature of the sterilization process
In order to ensure the high quality of the automated production process, the production of pharmaceuticals must meet very stringent requirements, reducing the risk of microbial contamination to a small size. The key to preventing pollution is to regularly clean and sterilize the workshop and equipment. Through the online disinfection process, it is cleaned with steam at 121-135 °C for 15-30 minutes. However, temperature measurements must be hygienic and do not allow for the accumulation of contaminated buildup. Standard measuring instruments with plug-in sensors have precise measurement results, but there are also several important defects: (1) must be welded into the piping system, the welding must be polished, at most small solder joints The risk of contamination by tiny particles; (2) the flow of liquid in the pipeline; (3) the inconsistency of measured values. The ideal solution is to use a tube-clamped resistance thermometer, which is a special silver temperature sensor that is back-pressed by a continuous spring force and fitted to a plug-in measurement. The pipe clamp type resistance thermometer does not need to be welded, and the installation is simple; when measuring the pipe temperature, it does not affect the inside of the pipe, does not interfere with the production process, can accurately control the temperature, has high precision, the measurement result has high repeatability, and is easy to clean the dead angle, the cost low.
2.3.3 Online Corrosion Detection - Controllable Corrosion Control
Corrosion is a phenomenon that cannot be ignored in raw material medicine equipment. It will bring a lot of economic losses to enterprises every year. The total economic loss caused by corrosion in Germany alone is hundreds of billions of euros. But some of these corrosion losses can be avoided. Unfortunately, there has not been a clear and clear classification of corrosion levels before this, nor can it be measured directly like pressure or temperature, because the effective corrosion detection method has not been established. However, with the continuous development of microelectronic technology, the SmartCET corrosion sensor based on the principle of "current change due to corrosion - sensing electrode - detection", as shown in Figure 8, can solve the problem. The sensor is a patented product of InterCorr Corporation of the United States and is considered to be "an electronic component whose electrode has been corroded".
The corrosion sensor can perform the following functions: (1) Accurate dynamic calculation. Equipment pipeline corrosion is a dynamic process of change, the degree of corrosion is different, the system sensing parameters are different, so that dynamic measurement can be realized through accurate calculation; (2) the location of corrosion hole is determined to ensure the reliability of measurement. Porous corrosion is a manifestation that indicates a point of inhomogeneity in the localized homogeneous material. In the SmartCET corrosion sensing technology, the defect information of the corrosion point can be determined according to the feedback information measured at different points, thereby determining the position of the corrosion hole. It can be seen that the use of corrosion sensors can achieve the controllability of corrosion. Corrosion testing is no longer a theoretical science and technology, but will become a real part of the raw material drug equipment.
2.3.4 Condition diagnosis and monitoring
The downtime of the equipment not only increases the production cost, but also may cause the entire batch of products to be scrapped, causing serious losses to the enterprise. Therefore, the application of equipment condition diagnosis and monitoring technology in pharmaceutical industrial enterprises such as pharmaceuticals is increasing.
There are three levels of diagnostic analysis of the working conditions: simple monitoring (fault identification), positioning analysis (analysis and determination of fault location), and diagnostic analysis (defect definition). For example, monitoring the operating conditions of the regulating valve and the piping system of the equipment. (1) Use the sensor to monitor the pressure and flow; (2) Analyze and judge the equipment working parameters based on the * level, and explain the status notes; (3) All diagnostic information is uploaded and visually displayed for the operator Take maintenance measures purposefully.
Therefore, the fault diagnosis analysis system is not just a flashing LED diode system. The condition diagnosis and monitoring technology will become a practical technology for the raw material medicine equipment, which can continuously reduce the maintenance cost of the equipment throughout its life cycle. At the same time, it can also guarantee the high quality of the products, achieve fast and efficient maintenance and repair, and improve equipment utilization.
2.4 Design Method - Application Simulation Technology, Combination of Virtual and Real
In today's industrial design, CAD/CAM/CAE has become common, but the application of analog technology and virtual technology in the design and manufacture of APIs has yet to be further developed and deepened. In fact, the application of analog technology and virtual technology can make the planners and producers of API equipment solutions gain multiple benefits.
2.4.1 Virtual Model - At a glance, timely inspection
Air compressor products, virtual design air compressors, through interactive virtual reality, visual design process, make planning very easy to understand, improve the quality of planning and design. At the same time, when planning and designing, multiple programs can be compared, and the zui good solution can be selected. Through virtual prototypes and detailed modules, virtual assembly and timely inspection can be performed to check the size and assemblability of each component, to find problems early, to accurately define the range of possible problems, to consider alternatives early, and to correct errors in time. It is convenient for safety performance detection; through virtual prototypes, virtual tests can be performed without having to do more physical tests, which saves time and saves money. It can be seen that analog technology will gradually become the top priority of equipment planning and design.
2.4.2 Networked working methods - doing more with less
Simulation technology makes the process flow more intuitive and makes it easier to analyze the production process. Therefore, designers tend to use this “virtual reality scenario†to discuss with the user during the planning and design process. Moreover, in this virtual real world, the performance of future devices can also be tested and optimized to improve future equipment maintenance and repair time. The virtual reality intelligent design software enables multiple designers to participate in the planning and design of the project, exchange ideas, test equipment together, and find maintenance strategies.
In addition, object-oriented data models and modular design have become very effective overall design techniques, and integrated planning and design has quickly adapted to different application areas.
In short, the application of simulation technology and virtual technology makes the whole process of design-debugging faster and clearer, the project design modification is realized quickly, and the cost of new equipment design is significantly reduced. As a result, the design project design speed can be increased by 30%; Design costs can be reduced by 40%; project investment costs can be reduced by 30%.
2.5 structural design modularity
In the pharmaceutical industry, the demand for new equipment is often caused by several factors. First of all, the trend of centralization of production areas is becoming more and more obvious, and the necessary re-equipment of some production lines is followed. Secondly, new drugs with high active ingredients are constantly being introduced, which also requires upgrading old equipment to meet new production needs while meeting GMP and FDA regulations. The characteristics of pharmaceutical processes, GMP and new production needs have enabled pharmaceutical equipment products to evolve from simple mechatronics to systematic and modular solutions to adapt to changes in users and to update products.
2.5.1 Multi-functional modular combination
Modular design is an effective way to coordinate the diverse needs of customers, achieve rapid response and reduce product costs. The M5 multi-function system, which combines the grinding concepts commonly used in the pharmaceutical industry, can be converted into grinders with different functions in a matter of minutes.
The M5 multi-function system consists of standard components (metering unit, inlet and outlet unit, CIP unit, control unit, chassis structure) and functional units (spiral airflow mill, fluidized bed to jet mill, impact mill/grading wheel combination, ultrafine The classifier consists of a combination of standard components and different functional units to form a different function grinder. Such as the standard component + spiral jet mill can form a spiral jet mill combination, standard components + fluidized bed for jet mill can form a fluidized bed to jet mill combination, standard components + impact mill can form ultra-fine impact Mill combination.
It can be seen that the multifunctional modular combination structure is flexible and maneuverable, and the combination is fast, and can effectively isolate and save space.
2.5.2 Modularity combined with process
With the deepening of GMP implementation, pharmaceutical equipment products are also developing from simple mechatronics to modular devices combined with production process operations [15] to improve the technical level of their equipment.
· Raw material crystallization equipment, characterized in that the stirring form is developed by using modular method: different material types, different mixing forms, and then through the modular design, using fluid mechanics analysis and research, designing specially constructed blades to Ensure the formation and non-breaking of the crystal to ensure the rationality and optimization of the equipment.
Modular CIP workstations are modularly designed according to the CIP process. Its specifications range from a wide range of applications, from biological fermentation, Chinese herbal medicine extraction, raw material medicine production to blood product equipment, which can provide an effective guarantee for cleaning and verification of pharmaceutical enterprises.
·Pharmaceutical batching system integration module combines the processes of concentrated, diluted, filtered, sterilized and clean liquid in a modular device, which makes the system easy to operate, materials closed, reduce two-way pollution, and conforms to GMP. Claim.
·Multi-functional extraction and concentration modular device, which integrates dynamic/static water extraction, dynamic/static alcohol extraction, hot reflux extraction, Soxhlet extraction, percolation extraction and steam distillation extraction, and can complete various extraction processes. It is a combination of modern technology and traditional extraction methods.
In short, the modular design combined with the process enables the system or device to be combined according to the process requirements, the operation is simplified, the use is convenient, the closed operation, the prevention of pollution, and the environmental protection, energy saving, compliance with GMP requirements, etc., is the pharmaceutical equipment technology. The direction of innovation.
3. Conclusion
After China's accession to the WTO, the pharmaceutical machinery market has become more open, and the pharmaceutical equipment economy is producing profound, fundamental and bright future changes and innovations. As one of the main products of China's pharmaceutical equipment, raw material medicine equipment must achieve satisfactory development in this transformation and innovation. It must conform to the national environmental protection and energy conservation guiding policy, follow the safety application rules, and strive to develop automation technology and virtual technology. The application and modularization design can only realize the development of China's APIs from imitation to self-development to independent innovation, thus connecting with the international community and stepping into the ranks of the world's advanced technologies.
(Source: China Chemical Machinery Network Author: Sun Huai, Liao Yuehua)
Raw material medicine machinery and equipment is one of the 8 major categories of pharmaceutical equipment in China, including reaction equipment, tower equipment, crystallization equipment, separation equipment, filtration equipment, extraction equipment, distillation equipment, heat exchangers, evaporation equipment, drying equipment, screening Equipment, storage equipment and sterilization equipment. As we all know, China is a big country in the production of bulk drugs, but it is not a strong country in the production of bulk drugs. There are many reasons for this, but one of the most important reasons is that there is a certain gap between the production of APIs and the application of new technologies and the international high-end level. Therefore, in order to improve the quality level of China's API production, in addition to improving the control standards of production enterprises from hardware and software, we should also strengthen the application of new technologies for APIs in accordance with new changes in the global market, and truly integrate with the international market.
2. New technology application
2.1 Research on environmental protection and energy conservation
Among the 6066 key industrial pollution source monitoring enterprises announced by the State Environmental Protection Administration in March 2007, pharmaceutical companies accounted for 117, and most of the fermentation-based API manufacturers, some of which were suspended due to environmental problems. Therefore, tapping potential to reduce consumption and improve economic efficiency will become an important task for raw material drug manufacturers in the future. The following is a few practical examples to illustrate the development and application of APIs in environmental protection and energy conservation.
2.1.1 freeze-drying equipment
2.1.1.1 Liquid nitrogen vacuum freeze dryer
The lyophilizer's refrigeration system provides a cold source for the drying oven and vacuum condenser. Among them, it is more common to freeze the dryer with a compression mechanism, but the heart component compressor often causes many failures due to various factors and requires frequent maintenance. Today, the new liquid nitrogen vacuum freeze dryer solves this problem, which effectively reduces the probability of failure of the refrigeration system.
The liquid nitrogen lyophilizer is a lyophilizer that uses liquid nitrogen as a cold source to cool the system. Unlike a conventional lyophilizer, the cold source is liquid nitrogen. The air contains 78% of nitrogen. Therefore, the preparation of liquid nitrogen is very convenient and can be said to be an inexhaustible environmentally friendly energy source. In addition, due to the use of liquid nitrogen refrigeration, the compressor and water cooler are no longer used, so the noise is low, the operation is reliable, the maintenance of the heart parts is not required, the maintenance is simple, and the power consumption is reduced by more than 50%, which will bring the enterprise Come to the long-term economic benefits.
2.1.1.2 New sterilization of freeze-drying equipment - H2O2 disinfection at room temperature
In order to improve the sanitary condition of the production line and achieve certain disinfection conditions to avoid pollution, Vapovac Disinfection Equipment Co., Ltd. provides a new sterilization process for freeze-drying equipment [3] - under the action of the existing vacuum system, the gaseous state H2O2 is transported to the pipe of the lyophilizer for sterilization by hydrogen peroxide. The significant difference between this process and other disinfection processes is that the gaseous H2O2 sterilization process is carried out at room temperature and under vacuum, so it has the following characteristics: (1) Compared with other chemical disinfection methods, the manpower is reduced and the pressure is reduced. The equipment is at risk of contamination and does not produce carcinogenic or by-products that cause genetic mutations; (2) no need for overpressure explosion-proof containers, which reduces the cost of use; (3) disinfectants can be used well without the need for additional gas distribution equipment. Distributed in all corners of the dryer to achieve a full range of disinfection work (which is not achieved by ordinary steam sterilization); (4) reduce the cost of 20% in each sterilization cycle and 50 compared with steam sterilization % disinfection time.
2.1.2 Drying equipment
2.1.2.1 New spiral dryer - combination of drying and cooling
In order to realize the production process of "drying + cooling" of drugs in a small space, Heinen of Germany designed and produced a new type of screw dryer [4], as shown in Figure 2, it has two sets of independent and very good. Coordinated system: * The set is responsible for the drying process and the second set is responsible for the cooling process. This results in two completely different temperature zones in the equipment throughout the continuous production process. The entire drying process is carried out from the bottom up, and this bottom-up path is a spiral belt. After the drug completes the drying process, it enters the cooling zone at the top to begin cooling. The cooling process of the drug is carried out in a spiral from top to bottom under the control of the cooling system. In this way, the drug is dried from the bottom up and cooled from top to bottom, leaving the device and transported to the packaging line for packaging. In the dryer, most of the air used is used as circulating air in the whole process. This way, the exhaust gas emissions of the entire equipment are reduced to low, so that the energy is efficiently utilized. In addition, the system's complete air handling equipment, including filters, humidifiers, heat exchangers, blowers, automatic control valves and activated carbon filters, are operated in separate technical spaces, which reduces batch and purge Time means saving production costs.
2.1.2.2 Vertical automatic filter press - combination of filtration separation and drying
With the trend of shrinking product size, more and more pharmaceutical companies are using low-consumption and high-output processes. One of the main parts is the advanced nature of dehydration methods to reduce energy consumption and product waste and loss. Larox's fully automated solid-liquid separation solution in Finland significantly reduces energy, water, manpower and wastewater treatment costs and increases product recovery. The Larox vertical automatic filter press is completely different from other conventional dewatering methods. Instead of using centrifugal, vacuum, thermal or other similar methods, it combines hydraulic and inflatable diaphragms, as shown in Figure 3, to separate forces. The zui is enlarged, so that a more effective solid-liquid separation effect is obtained with a small energy consumption of zui. Compared with centrifuges, vacuum filters, etc., the Larox vertical filter press can greatly improve the processing capacity of existing dryers. For example, a 3% reduction in filter cake moisture can increase the throughput of the drying equipment by 16%. If you do not need to increase production, you can significantly reduce the unit drying energy consumption (cost / t products).
2.2 Research safety applications
In pharmaceutical manufacturing enterprises, many raw materials are in the form of powder or bulk materials before production and processing. The dust-containing mixture formed by mixing powdery substances with air is often a dangerous product that is easy to explode. In order to prevent accidents during the production process, materials with a risk of deflagration are not allowed to “flow†at will.
Due to the modular structure design, the vacuum negative pressure conveying system is very flexible and widely used. It can extract raw materials from cylindrical containers, or transport raw materials from various containers to various process equipment, for example, mixing equipment at the beginning of production, filtration equipment, filling equipment, and tableting and packaging equipment. .
Modular powder raw material vacuum and pressure transport system, which is a new system combining powder raw material transportation system and raw material barrel emptying system, which can completely separate the raw materials of the equipment from the surrounding environment. Unlike many other isolation systems that cannot withstand pressure shocks, this new “multiple solution†can be used in reactors that are subjected to temperature, pressure or vacuum negative pressure shocks. Even when used in a corrosive environment, it is only necessary to replace a corrosion-resistant output valve.
Features: (1) The system has no electrical parts at all, so it will never cause deflagration due to electric spark; (2) The system does not have any rotating parts, such as bearings, so there is no friction, so there is no heat caused by friction. Deflagration and detonation; (3) special inert gas (such as nitrogen) protection device may be added to meet the transportation equipment that is not suitable for standard vacuum negative pressure; (4) transport system and raw material tank emptying system combination (including CIP), The loading and unloading of raw materials is completely isolated from the surrounding environment; (5) The modular structure design of the loading system enables the user to select and achieve the desired configuration to prevent pollution and ensure safety. For example, different vacuum raw materials can be used to deliver different raw materials to the mixer.
2.3 Online Technology Application and Automation
The “online†in the pharmaceutical production process is inseparable from the real-time production. To be truly "online" (detection, control...), you must rely on automation technology and its applications to achieve real-time detection and process control.
2.3.1 Real online CIP, SIP
As the quality of pharmaceutical production is increasing, people pay more and more attention to the reliability of each process in the pharmaceutical production process and the content of pollutants in the final product of Zui. The most important process is equipment cleaning and sterilization. In-place cleaning (CIP) and in-situ sterilization (SIP) have put forward higher requirements for pharmaceutical production equipment. However, there are some misunderstandings or confusions between some devices that are called CIP or SIP, such as single cleaning nozzles or single steam inlets, but no system design; unreasonable design and no control procedures and control systems; Failure to do DQ file support according to URS (User Requirements Standard). In fact, these have no CIP/SIP meaning. The true online CIP/SIP should have control process, system design, design confirmation by URS, and design of simulation technology.
2.3.2 Accurately monitor the temperature of the sterilization process
In order to ensure the high quality of the automated production process, the production of pharmaceuticals must meet very stringent requirements, reducing the risk of microbial contamination to a small size. The key to preventing pollution is to regularly clean and sterilize the workshop and equipment. Through the online disinfection process, it is cleaned with steam at 121-135 °C for 15-30 minutes. However, temperature measurements must be hygienic and do not allow for the accumulation of contaminated buildup. Standard measuring instruments with plug-in sensors have precise measurement results, but there are also several important defects: (1) must be welded into the piping system, the welding must be polished, at most small solder joints The risk of contamination by tiny particles; (2) the flow of liquid in the pipeline; (3) the inconsistency of measured values. The ideal solution is to use a tube-clamped resistance thermometer, which is a special silver temperature sensor that is back-pressed by a continuous spring force and fitted to a plug-in measurement. The pipe clamp type resistance thermometer does not need to be welded, and the installation is simple; when measuring the pipe temperature, it does not affect the inside of the pipe, does not interfere with the production process, can accurately control the temperature, has high precision, the measurement result has high repeatability, and is easy to clean the dead angle, the cost low.
2.3.3 Online Corrosion Detection - Controllable Corrosion Control
Corrosion is a phenomenon that cannot be ignored in raw material medicine equipment. It will bring a lot of economic losses to enterprises every year. The total economic loss caused by corrosion in Germany alone is hundreds of billions of euros. But some of these corrosion losses can be avoided. Unfortunately, there has not been a clear and clear classification of corrosion levels before this, nor can it be measured directly like pressure or temperature, because the effective corrosion detection method has not been established. However, with the continuous development of microelectronic technology, the SmartCET corrosion sensor based on the principle of "current change due to corrosion - sensing electrode - detection", as shown in Figure 8, can solve the problem. The sensor is a patented product of InterCorr Corporation of the United States and is considered to be "an electronic component whose electrode has been corroded".
The corrosion sensor can perform the following functions: (1) Accurate dynamic calculation. Equipment pipeline corrosion is a dynamic process of change, the degree of corrosion is different, the system sensing parameters are different, so that dynamic measurement can be realized through accurate calculation; (2) the location of corrosion hole is determined to ensure the reliability of measurement. Porous corrosion is a manifestation that indicates a point of inhomogeneity in the localized homogeneous material. In the SmartCET corrosion sensing technology, the defect information of the corrosion point can be determined according to the feedback information measured at different points, thereby determining the position of the corrosion hole. It can be seen that the use of corrosion sensors can achieve the controllability of corrosion. Corrosion testing is no longer a theoretical science and technology, but will become a real part of the raw material drug equipment.
2.3.4 Condition diagnosis and monitoring
The downtime of the equipment not only increases the production cost, but also may cause the entire batch of products to be scrapped, causing serious losses to the enterprise. Therefore, the application of equipment condition diagnosis and monitoring technology in pharmaceutical industrial enterprises such as pharmaceuticals is increasing.
There are three levels of diagnostic analysis of the working conditions: simple monitoring (fault identification), positioning analysis (analysis and determination of fault location), and diagnostic analysis (defect definition). For example, monitoring the operating conditions of the regulating valve and the piping system of the equipment. (1) Use the sensor to monitor the pressure and flow; (2) Analyze and judge the equipment working parameters based on the * level, and explain the status notes; (3) All diagnostic information is uploaded and visually displayed for the operator Take maintenance measures purposefully.
Therefore, the fault diagnosis analysis system is not just a flashing LED diode system. The condition diagnosis and monitoring technology will become a practical technology for the raw material medicine equipment, which can continuously reduce the maintenance cost of the equipment throughout its life cycle. At the same time, it can also guarantee the high quality of the products, achieve fast and efficient maintenance and repair, and improve equipment utilization.
2.4 Design Method - Application Simulation Technology, Combination of Virtual and Real
In today's industrial design, CAD/CAM/CAE has become common, but the application of analog technology and virtual technology in the design and manufacture of APIs has yet to be further developed and deepened. In fact, the application of analog technology and virtual technology can make the planners and producers of API equipment solutions gain multiple benefits.
2.4.1 Virtual Model - At a glance, timely inspection
Air compressor products, virtual design air compressors, through interactive virtual reality, visual design process, make planning very easy to understand, improve the quality of planning and design. At the same time, when planning and designing, multiple programs can be compared, and the zui good solution can be selected. Through virtual prototypes and detailed modules, virtual assembly and timely inspection can be performed to check the size and assemblability of each component, to find problems early, to accurately define the range of possible problems, to consider alternatives early, and to correct errors in time. It is convenient for safety performance detection; through virtual prototypes, virtual tests can be performed without having to do more physical tests, which saves time and saves money. It can be seen that analog technology will gradually become the top priority of equipment planning and design.
2.4.2 Networked working methods - doing more with less
Simulation technology makes the process flow more intuitive and makes it easier to analyze the production process. Therefore, designers tend to use this “virtual reality scenario†to discuss with the user during the planning and design process. Moreover, in this virtual real world, the performance of future devices can also be tested and optimized to improve future equipment maintenance and repair time. The virtual reality intelligent design software enables multiple designers to participate in the planning and design of the project, exchange ideas, test equipment together, and find maintenance strategies.
In addition, object-oriented data models and modular design have become very effective overall design techniques, and integrated planning and design has quickly adapted to different application areas.
In short, the application of simulation technology and virtual technology makes the whole process of design-debugging faster and clearer, the project design modification is realized quickly, and the cost of new equipment design is significantly reduced. As a result, the design project design speed can be increased by 30%; Design costs can be reduced by 40%; project investment costs can be reduced by 30%.
2.5 structural design modularity
In the pharmaceutical industry, the demand for new equipment is often caused by several factors. First of all, the trend of centralization of production areas is becoming more and more obvious, and the necessary re-equipment of some production lines is followed. Secondly, new drugs with high active ingredients are constantly being introduced, which also requires upgrading old equipment to meet new production needs while meeting GMP and FDA regulations. The characteristics of pharmaceutical processes, GMP and new production needs have enabled pharmaceutical equipment products to evolve from simple mechatronics to systematic and modular solutions to adapt to changes in users and to update products.
2.5.1 Multi-functional modular combination
Modular design is an effective way to coordinate the diverse needs of customers, achieve rapid response and reduce product costs. The M5 multi-function system, which combines the grinding concepts commonly used in the pharmaceutical industry, can be converted into grinders with different functions in a matter of minutes.
The M5 multi-function system consists of standard components (metering unit, inlet and outlet unit, CIP unit, control unit, chassis structure) and functional units (spiral airflow mill, fluidized bed to jet mill, impact mill/grading wheel combination, ultrafine The classifier consists of a combination of standard components and different functional units to form a different function grinder. Such as the standard component + spiral jet mill can form a spiral jet mill combination, standard components + fluidized bed for jet mill can form a fluidized bed to jet mill combination, standard components + impact mill can form ultra-fine impact Mill combination.
It can be seen that the multifunctional modular combination structure is flexible and maneuverable, and the combination is fast, and can effectively isolate and save space.
2.5.2 Modularity combined with process
With the deepening of GMP implementation, pharmaceutical equipment products are also developing from simple mechatronics to modular devices combined with production process operations [15] to improve the technical level of their equipment.
· Raw material crystallization equipment, characterized in that the stirring form is developed by using modular method: different material types, different mixing forms, and then through the modular design, using fluid mechanics analysis and research, designing specially constructed blades to Ensure the formation and non-breaking of the crystal to ensure the rationality and optimization of the equipment.
Modular CIP workstations are modularly designed according to the CIP process. Its specifications range from a wide range of applications, from biological fermentation, Chinese herbal medicine extraction, raw material medicine production to blood product equipment, which can provide an effective guarantee for cleaning and verification of pharmaceutical enterprises.
·Pharmaceutical batching system integration module combines the processes of concentrated, diluted, filtered, sterilized and clean liquid in a modular device, which makes the system easy to operate, materials closed, reduce two-way pollution, and conforms to GMP. Claim.
·Multi-functional extraction and concentration modular device, which integrates dynamic/static water extraction, dynamic/static alcohol extraction, hot reflux extraction, Soxhlet extraction, percolation extraction and steam distillation extraction, and can complete various extraction processes. It is a combination of modern technology and traditional extraction methods.
In short, the modular design combined with the process enables the system or device to be combined according to the process requirements, the operation is simplified, the use is convenient, the closed operation, the prevention of pollution, and the environmental protection, energy saving, compliance with GMP requirements, etc., is the pharmaceutical equipment technology. The direction of innovation.
3. Conclusion
After China's accession to the WTO, the pharmaceutical machinery market has become more open, and the pharmaceutical equipment economy is producing profound, fundamental and bright future changes and innovations. As one of the main products of China's pharmaceutical equipment, raw material medicine equipment must achieve satisfactory development in this transformation and innovation. It must conform to the national environmental protection and energy conservation guiding policy, follow the safety application rules, and strive to develop automation technology and virtual technology. The application and modularization design can only realize the development of China's APIs from imitation to self-development to independent innovation, thus connecting with the international community and stepping into the ranks of the world's advanced technologies.
(Source: China Chemical Machinery Network Author: Sun Huai, Liao Yuehua)
Henan Qianli Machinery CO. Ltd is a profession manufacture of Farm Tractor, rice machine, Reaper Machine, Power Tiller, garden machine and other farm implements. Our factory was established in 1987 and has more than 30 years of production and sales experience. We focus on providing customers with high-quality products and excellent services.
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