Discussion on the implementation of GMP regulations in pharmaceutical machinery

China Pharmaceutical Equipment Industry Association clearly implements pharmaceutical manufacturing management standards (GMP) as the main task of industry management. This is an analysis of the development of pharmaceutical machinery in China. It aims to further highlight the characteristics of pharmaceutical machinery products and enhance domestic pharmaceutical equipment. The level of design innovation. Although the scale, variety and output of pharmaceutical machinery production have already reached considerable strength and level, it has become a large professional product industry in China. However, with the integration of economic trade and international standards and the internationalization of GMP regulations, pharmaceutical manufacturers are encouraged to The GMP concept of pharmaceutical equipment has been strengthened, and there is an urgent need for more perfect functions, making equipment GMP increasingly become a hotspot of technology and competition in domestic sales. According to the recent medical machine exhibitions, the production plants have increased year by year, many similar products and new products have been reduced. Many competitions of similar products in the same region tend to be obvious (such as: Nanjing hot air circulation oven, Jiangsu and Zhejiang rotary vibrating screen, etc.), to say In the past few years, the pharmaceutical industry pursued the revitalization of the scale of the variety, then it should be the pursuit of quality level of competition development. This time, the implementation of GMP in pharmaceutical machinery can be said that following the implementation of GMP in pharmaceutical companies in the 1980s, the national phase-out of 1Cr18Ni8Ti promoted the widespread use of low-carbon stainless steel in the raw materials of pharmaceutical machinery, and encouraged the introduction of advanced foreign technology to enable new products to emerge and actively adopt international standards. Another opportunity for development after the quality of pharmaceutical products has generally improved is to make the products of the “eight-nation coalition forces” of the pharmaceutical equipment industry unify and improve under the GMP regulations, and to create a development space for further improving the functions of the medicine machine. The article refers to “equipment GMP”, which explains the following: Equipment GMP is an important part of the pharmaceutical production management system, indicating that the pharmaceutical equipment itself implements GMP efforts, and can also be used as a special term in the industry implementation of GMP. The following article discusses the GMP essentials of pharmaceutical equipment in conjunction with the relevant requirements and understanding of the specification, and is for reference only. I. GMP Specification Overview and Equipment GMP Proposed GMP originated from the US FDA. Its guiding ideology lies in the control and management of the whole process of pharmaceutical production, in order to achieve that the drug is “safe” and “effective”. After implementation, a good society has emerged. The effect and rapid reference to the WHO and other countries, regions and pharmaceutical companies, the emergence of GMP internationalization trend, Switzerland, Britain, Japan, Germany, China and other dozens of countries have issued or government actions GMP regulations, or non-legal norms, but regardless of the nature of the GMP, are extremely comprehensive and strict, so far in the pharmaceutical industry has a strong authority and binding. As far as the scope of GMP control is concerned, it involves a wide range of aspects, including personnel, plant, equipment, facilities, production process, transmission, analysis, verification and library management. This shows that GMP is a very systematic norm, its management The details are no less than Total Quality Management (TQC). Although they have many similarities, GMP is a regulation in nature, and TQC is the difference between activities. Strict and strict is the outstanding feature of GMP. Pharmaceutical equipment is an important means of production and one of the factors that cannot be ignored. This is the consistent view of GMP on pharmaceutical equipment. The WHO and FDA's GMP, CGMP (API) and China's current GMP texts all use equipment as a separate chapter. Although not much is discussed, it covers design, manufacturing, installation, maintenance, use, etc., such as: requiring "total cleaning" "It can be understood as the external, internal, or a group of devices of the device, and its principle is very strong. In this understanding, GMP is mainly proposed from the perspective of drug administration and use. Therefore, it is considered to be a requirement for the use of equipment. In addition, there are industrial barriers to the production of pharmaceuticals and equipment, and the lack of details of equipment implementation. Therefore, equipment manufacturing has always been a call-to-action requirement, but failed to form a situation of main dynamics. From the analysis of the relationship between pharmaceutical equipment and pharmaceutical production, pharmaceutical equipment not only relates to the modernization of the pharmaceutical industry, but also the specifications, structure, materials and performance of the equipment have a great impact on the production of pharmaceuticals, such as: equipment specifications and production are not matched, In production, a batch of “paper batches” with multiple batches of production is produced, resulting in uncontrollable drug mixing; for example, manual, semi-automatic, single-function equipment makes the pharmaceutical process incapable of continuing to limit the pharmaceutical industry. The scale and modernization of these issues confirm the closeness of equipment and GMP. According to the industry data: Strictly speaking, pharmaceutical production can really meet the GMP regulations. Compared with hardware such as plant facilities and equipment, systems and management software, hardware seems to be more important. From the perspective of international GMP dynamics, in the future, pharmaceutical-specific equipment, containment devices, barrier facilities, automation, and microcomputer processing will enter GMP as new content, and Japan has taken the lead in engaging in "medical device GMP." Therefore, the issue of specifying the GMP content of pharmaceutical equipment has arisen, which will make it more easy to operate, and it is also the intention of the industry to engage in equipment GMP. With the increasing awareness of GMP, pharmaceutical manufacturers are more cautious about equipment selection. The functions are all prior to the single function, innovative before the old products, the appearance is simple and not before packaging... They think the price does not represent the product. The quality and quality of the product, the price is always considered after the Zui, the performance is not good (energy, pollution, etc.) its loss is long-term, may be much greater than the investment in equipment. What kind of equipment is considered to be GMP, and it can not be accurately judged by the current GMP. In this case, the equipment GMP is initially defined as follows: it has the necessary functions, functions such as hygiene and safety for the production of drugs (drugs), and equipment. The structure and the materials used, equipment that does not harbor, retain materials, pollute the processed materials, or pollute or affect the environment outside the production, and is easy to operate, repair, and clean. This is merely a conclusion that induction is not conclusive. With this initial definition, design can be promoted and GMP essentials can be infiltrated into the manufacture of products. Second, the implementation of the GMP essentials of pharmaceutical equipment combined with the definition of equipment GMP, then all pharmaceutical products can produce their own GMP control scope and GMP innovation concept space. The complexity of the pharmaceutical process determines the diversification of equipment functions. The pros and cons of the equipment are mainly reflected in the suitability of the application and the environment. Therefore, the applicability requirements of the pharmaceutical equipment under the specific conditions of pharmaceutical GMP are more than ordinary. Mechanical products. The following applicability requirements are briefly described in several main aspects: 1 Functional design and requirements Functionality refers to the electromechanical motion function and operation of the pharmaceutical machinery under certain conditions of use and environmental conditions to complete the basic process actions. Auxiliary functions such as being contaminated. With the development of new and high technology, the infiltration of new technologies in the cross-field, the application of advanced principles, mechanisms, control methods and testing methods, the functions of pharmaceutical machinery are continuously enriched and improved, but the requirements for equipment production are becoming more and more demanding. Conventional designs do not meet the requirements for cleanliness, cleaning, and non-contamination in pharmaceuticals, so improvements or additions to the functions required for pharmaceutical production must be considered. Only the main functions related to GMP are discussed below. (1) Purification function. Cleanliness is one of the main points of GMP. It means two meanings to the equipment, that is, the equipment itself does not pollute the production environment and does not pollute the drugs. In order to achieve this standard, it is necessary to design a purification function on the equipment in the processing of medicines, where the general cleanliness of the exposed areas of the medicines (drugs) and the general cleanliness of the room area are not possible or man-machine-contaminated. This type of function is not the same for equipment in different occasions, such as hot air circulation drying equipment, air pollution is obvious, its air purification; washing bottle, water injection machine cleanliness; crushing, granulation, Powder machinery such as coating and tableting, the control of the dust; the dustproof problem of the filling equipment needs to be solved by other purification methods and devices. As far as purification is concerned, the US FDA recommends in CGMP that in order to prevent accidental contamination, it should be considered as far as possible in the equipment to be implemented in a closed system, that is, "no sunlight". Of course, this is not easy to do, but it is not impossible. For example, the one-step granulator combines multiple processes of multiple equipment and open production into one closed-loop container device, creating a pharmaceutical principle. A precedent that combines with purification needs. There are many aspects of purification, such as: water, gas, dust, etc. The design of a multi-functional extraction tank adopts computer program control, which makes the whole process of feeding and discharging automatic, and achieves the separation of man-machines in operation and production, in addition to the automatic extrusion slagging function. (Residues can be burned and utilized), with unique innovations, showing strong competitive momentum among many similar products. Therefore, as long as the equipment design can meet the above points, it is reasonable and feasible, and the equipment has this function. (2) Cleaning function. At present, equipment cleaning is mostly in manual cleaning, and there are not many in-situ cleaning. Manual cleaning can easily lead to new pollution while overcoming cross-contamination between materials, and equipment structure factors make it difficult to clean, etc. More reflected in production. With the emphasis on the purity and effectiveness of pharmaceuticals, the in-place cleaning (CIP) function promoted by GMP will become the development aspect of cleaning technology. There are also some examples of CIP reports in China, such as the self-cleaning device designed for the vacuum exhaust pipe and the tank rotary seal of a double cone dryer; the high pressure water rushing mechanism designed by a large liquid container; the improvement of the mirror of a fermentation equipment Cleaning the structure, etc. For cleaning, in the past, the manufacturer did not necessarily understand the material change and the batch cleaning requirements in the use of the equipment, and often did not neglect the design of the function or unconsciously increased the difficulty of cleaning the equipment, such as the coil heating structure of the liquid heating vessel. Not only is it difficult to clean, but it also increases the possibility of contamination. In some pure water delivery systems that are considered to be free of contamination, the adhesions found in the pump body confirm the ubiquity of bacterial growth and pollution. Therefore, GMP attaches great importance to the cleaning and monitoring of intermediate equipment and intermediate links in pharmaceutical systems. As for where to clean, how to clean, how easy it is to clean, and how to clean it, we should consider the combination of CIP functions that need to be cleaned or not easy to clean. Such an outstanding CIP design will continue to emerge. (3) Online monitoring and control functions. It mainly refers to the equipment with analysis and processing system, which can automatically complete several work steps or process work functions, which is also the premise of equipment connection, linkage operation and control. GMP requires that the production of drugs should be continuous, and the time of process transfer is short. However, in the case of a large number of purely mechanical and functional single devices, it is difficult to achieve this requirement, and at the same time, it has the advantage of expanding this function. For these devices with low automation, decentralized operation, and experienced human-machine participation, how to reduce transmission, turnover, interval, reduce contact between humans and drugs, and shorten the exposure time of drugs should become equipment design and equipment. An important guiding ideology for improvement. Practice has also proved that in the pharmaceutical process, the coordinated connection and online control functions of the equipment are effective. The online function of the equipment depends on the application of the integrated technology of machine, electricity and instrument. With the design and application of industrial PC, metering, display and analytical instruments, multi-machine control, random monitoring, real-time analysis, data display, memory printing, program New features such as control and automatic alarms enable online technology to be promoted. For example, the man-machine dialogue control system of the washing and sealing group has made it possible to continuously operate the production. As long as it is fully studied, its scope will not only be limited to the production line equipment, but also multi-machine combination, multi-process combination, and multi-function. (4) Security protection function. Drugs have different properties such as heat sensitivity, moisture absorption, volatilization, and reaction. If you do not pay attention to these characteristics, it is easy to cause changes in drug quality. This is also a problem that should be paid attention to in equipment design. Therefore, protection functions such as dustproof, waterproof, anti-overheat, explosion-proof, anti-infiltration, anti-static, anti-overload, etc. are generated, and some have to be protected under abnormal conditions, such as "emergency braking" for high-speed operation equipment. "Safety valve" for high-pressure equipment; structure in which the powder moving shaft seal does not leak to the drug; and no bottle stop, automatic waste, jam stop, foreign object removal, etc. In the past product design, more attention was paid to the development of main functions, and the protection function was relatively weak. Now, in the case of many similar products and basically the same level, users need more perfect functions, so many pharmaceutical products have also been considered to turn to add new functions, or to improve or update products, such as: application instruments, instruments, Computer technology to achieve early warning, display, processing, etc. in the operation of equipment to replace manual and empirical operations, improve the automatic operation of the equipment, automatic protection functions, improve product orders, and carry out functional competition of the same type of products. 2 Structural design and requirements The structure of the equipment is considered to be invariant. The structure of the equipment (in whole or in part) is unreasonable and unsuitable. Once it is put into use, it is almost impossible to change it. For example, the structure of the jacketed heating type container equipment As the specification becomes larger, the uniformity of heat transfer and heat is found to be worse in use, and the regularity of the change of the normal curve is more obvious. Therefore, the positive double-cone structure of many large-scale equipment is improved to long double-cone, and the past is short and thick. The extraction can is improved to a mushroom shape. However, most of the pharmaceutical companies still have to replace the equipment when it is updated or scrapped, so the impact of the structure of the equipment on production is a prerequisite. (1) Structural elements are a major aspect of the structure associated with drugs and cleaning. Pharmaceutical equipment has almost direct and indirect contact with drugs (drugs), powder, liquid, granules, paste and other traits. In the preparation of drugs, the structure should generally facilitate the flow, displacement, reaction, exchange and cleaning of materials. . Practice has proved that the convexity and concave, groove, table and corner in the equipment are unfavorable materials to be cleaned and cleaned. Therefore, it is required that the structural elements of these parts should adopt large rounded corners, inclined surfaces, taper angles, etc. to avoid lanyards and block materials. This is extremely important for the good self-unloading and easy-cleaning of the holding and conveying mechanisms on the fixed and rotating containers and the medicine machine. In addition, on the inner surface of the equipment and the surface of the parts working on the equipment (such as: stirring paddles, etc.), it is not designed to have a platform or a groove as much as possible, and the structure of bolting is avoided, and the form of the countersunk head should not be used. The only reason is that it is easy to accumulate things, and the structure is often more complicated. Here we can only emphasize the implementation of this principle in design. At present, there are many design examples of sanitary structures, such as: conical containers, round angles in box-shaped equipment, round threads in easy-to-clean structures, and clamp-type quick-opening pipe fittings. (2) The design of some non-main part structures in pharmaceutical equipment is easy to be despised, which is precisely the part of equipment GMP implementation. For example, the structure of the hot air device of the sugar-coated sugar-coated machine is mostly under the wind and without filtration, which is easy to form gas pollution. Some air ducts are formed by wrinkles, and the appearance of the equipment is beautiful but the dust accumulation factor is not considered. Another example: a tunnel drying box imported into the Anzhen line, the structure does not consider the arrangement of glass shards, the four corners of the bottom of the rectangular box accumulate a large amount of glass swarf and the circulating airflow to form pollution, which must be removed by overhauling. Another example: the bottle is often polluted in the use of a tunnel dryer in China. After inspection, it is considered that: 1 The air filter is an overhead structure. Compared with the side, it has a large dust-collecting area, fast failure and inconvenient replacement, and the structure is not reasonable; 2 The filter material is made of felt cotton, which is easy to shed. When the filter is blocked, the laminar flow becomes a mixed flow, and dust floats. This shows that these seemingly insignificant parts have a significant impact on pharmaceutical production. At this spring exhibition, there is a hot air drying box equipment, and the door seal is improved to form a silica gel, which is heat-resistant, non-toxic and hygienic, and has attracted many users' attention in many similar products. Therefore, the rationality of the equipment structure does not only refer to the use, but also includes maintenance, installation and other aspects. (3) The components in contact with the drug should have a high degree of non-adhesive material, and the polishing treatment is an effective process. There are many parts in pharmaceutical machinery that are polished. With the application of single-sided and double-sided stainless steel polishing plates, the polished objects are mainly stainless steel thick plates, castings, weldments and so on. It is not uncommon to throw a bit in the manufacturing process. Therefore, when designing the parts such as paddles, rods, shifting forks and sheet metal forming that need to be polished, the external contour structure is required to be simple and concise, and it is easy to throw the position in the continuous rotation. . Secondly, we should pay attention to a problem with universality. In the polishing evaluation, light and light are two conclusions obtained by visual and touch inspection. Some bright surfaces are not necessarily high in roughness value, and the lanyard material is often only "light" on the surface. "It is not slippery." (4) Lubrication is undoubtedly necessary for mechanical movement. In particular, a considerable part of the medicine machine belongs to the movement of the table. The moving shaft is concentrated and the structure is complicated, and it is related to the production of medicines. In addition, the equipment has specific requirements for cleaning. GMP stipulates that no matter what the situation, lubricants and cleaning agents should not be in contact with the drug, including the possibility of falling in, infiltrating, etc., which imposes stringent requirements on the lubrication and sealing design of the equipment. There are two measures for how to solve the problem of not contacting the materials: one is to take a barrier to the drug, such as a mixer, a crystallizer, a powder, a liquid immersion machine, and one side of the moving shaft is in the drug. Under the working conditions, the lubrication and sealing structure is not allowed to leak to the standard of the drug. Some enterprises have many years of experimental research and results on their sealing structure (mechanical seal, packing ring, etc.); Barrier, such as the lubrication of the countertop vertical axis of the labeling machine, or the use of a wrinkle hose sleeve for the six vertical lifting rods of the rotary filling machine, has a certain effect, so as to ensure lubrication The oil and washing water in the cleaning are not in contact with the raw materials, containers, plugs, intermediates, and finished pharmaceutical products, and the contradiction of lubrication and contamination is solved from the structural design. (5) There are many different levels of dust, heat, exhaust, water, steam, etc. in the use of pharmaceutical equipment, which constitutes a threat to the production of pharmaceuticals. To eliminate it, it should be solved mainly from the device itself. Dust is more common in powder machinery, such as crushing, mixing, granulating and tableting, coating, sieving, drying, etc., and it occurs mostly in small machines and simple equipment. The manufacturer has combined the plant facilities to solve the problem, and the manufacturer has considered it less. With the implementation of GMP, the initiative of governance should be directed to the manufacture of equipment. From the current state of pharmaceutical production, small and medium-sized batches enable the equipment to be continuously turned on, and the number of units used is also uncertain. The equipment can manage itself and flexibly arrange production. It is beneficial to reduce the cost of treatment and to produce good applicability. The equipment does not pollute the environment of the room, which is an important part of the GMP inspection. In view of the different pollution caused by each type of equipment, the treatment plan and structural requirements are also different. There should be dust-collecting mechanism for dust-distributing dust; exhaust ventilation and ventilation for heat dissipation and dehumidification; When the equipment has dust, water, steam, heat, oil, noise, vibration and other mechanisms, whether it is a single operation or movement, combination, linkage, can meet the requirements of GMP regulations.

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