Development and new technology of API

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 applications

2.1 Research on environmental protection and energy conservation In March 2007, the State Environmental Protection Administration announced 6 066 key industrial pollution source monitoring enterprises, pharmaceutical companies accounted for 117, mostly fermented API manufacturers, some of which were suspended due to environmental issues [ 1]. 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 refrigeration system of the freeze dryer can provide 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, as shown in Figure 1, which effectively reduces the failure probability 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% [2], which will Bring long-term economic benefits to the company.

2.1.1.2 New sterilization of freeze-drying equipment - H2O2 disinfection at room temperature

In order to improve the hygienic condition of the production line and achieve certain disinfection conditions to avoid pollution, Vapovac disinfection equipment company 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 – a 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 - the combination of filtration separation and drying As the product size continues to shrink, more and more pharmaceutical companies are using low-consumption, high-output processes, one of the main parts It is the advanced nature of the dehydration method to reduce the level of energy consumption and product waste and loss. Larox's fully automated solid-liquid separation solution [5] 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.
Figure 4 shows the vacuum negative pressure conveying system [6]. Due to the modular structure design, it 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. .



Figure 5 shows the modular vacuum raw material vacuum and pressure transport system. It is a new system that combines the powder raw material transportation system and the raw material tank emptying system to 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” and production real-time in the pharmaceutical production process are inseparable. 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, at present, some devices are called CIP or SIP, which is misunderstood or confusing [7-8], such as cleaning nozzles or steam inlets alone, without system design; unreasonable design and no control Program, control system; failed 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 the drug must meet very strict requirements, and the risk caused by microbial contamination is reduced to small. 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. The standard measuring instrument with plug-in sensor shown in Figure 6 has accurate measurement results, but there are also several important defects: (1) must be welded into the piping system, the welding must be polished, in most small welding There is a risk of contamination of the tiny particles at the point; (2) it will hinder the flow of the pipe liquid; (3) it will lead to inconsistencies in the measured values. The ideal solution is to use the tube-clamping resistance thermometer shown in Figure 7, 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 [9].

2.3.3 Online Corrosion Detection - Controlled Corrosion of Corrosion is a phenomenon that cannot be ignored in raw material medicine equipment. It will bring a lot of economic losses to the company every year. The total economic loss caused by corrosion in Germany alone is as high as Hundreds of billions of euros [10]. 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" [10].



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 Fault Diagnosis and Monitoring Equipment failures not only increase production costs, 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 (fault definition) [11]. For example, monitor the operating conditions of the regulating valve and the piping system of the equipment, as shown in Figure 9. (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, Virtual Reality Combination 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 deepening. 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 Figure 10(a) shows the air compressor product and Figure 10(b) shows the virtual design air compressor [12]. Through interactive virtual reality and visual design process, the planning is very easy to understand and improves 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 mode - The multiplier simulation technology makes the process flow more intuitive and can more easily analyze the production process. Therefore, designers tend to use this "virtual" in the planning and design process. The real-life scenario is discussed with the user, as shown in Figure 11 [13]. 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% [13].


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 diversified needs of customers, achieve rapid response and reduce product cost. Figure 12 shows the M5 multi-function system, which combines the grinding concept commonly used in the pharmaceutical industry, and can be converted into grinders with different functions in a few minutes [14].



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, as shown in Figure 13; standard components + fluidized bed to jet mill can form a fluidized bed to jet mill combination, as shown in Figure 14. The standard component + impact mill can form a superfine impact mill combination, as shown in Figure 15.


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 their equipment. Technical grade.

Figure 16 shows the raw material crystallization equipment, which is characterized by the fact that the agitation form is developed in a modular way: different material types, different agitation forms, and then through the modular design, using fluid mechanics analysis to design a special structure The blade is used to ensure the formation and non-breaking of the crystal to ensure the rationality and optimization of the equipment.



Figure 17 shows a modular CIP workstation that is a modular design based on the CIP process flow. 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.

Figure 18 is a pharmaceutical ingredient system integration module, which combines the processes of concentrated, diluted, filtered, sterilized, and clean liquid transportation on a modular device to make the system easy to operate, the materials are closed, and the two-way pollution is reduced. Meet GMP requirements.

Figure 19 is a 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 to complete various methods of extraction. The process is a combination of modern process 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. <孙怀远廖磊华>

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