Discussion On Several Problems In Layout Design Of Pharmaceutical Workshop

Part 1 Question Formulation

At present, China’s pharmaceutical factories are developing vigorously. However, with the construction of a large number of pharmaceutical factories, some problems have been exposed in the preliminary design of pharmaceutical workshops, most of which are due to the lack of consideration in the specific layout design process. week, improper design, underdesign, or overdesign. As we all know, to engage in drug production activities, you should abide by the drug production quality management standards and related laws and regulations. Production quality, while improving production efficiency, other conventional design considerations such as fire protection, safety, environmental protection, and energy saving have not been discussed emphatically.

The layout design of pharmaceutical workshops should first pay attention to the quality of drug production, and minimize the risks of drug contamination, cross-contamination, confusion and errors. In the field of pharmaceutical production, the concept of QbD (Quality by Design) points out that the quality of pharmaceuticals is firstly designed and then produced, not by final inspection. QbD shifts the focus of quality control forward, strengthens the overall design of the system in the early stage, estimates the quality of the product to be produced, and strictly implements the production process to achieve the expected drug quality.

Whether the design of the factory buildings, facilities, equipment, processes, etc. of the pharmaceutical factory is scientific, reasonable, and meticulous will have a fundamental, supportive, and lasting impact on the quality of pharmaceutical production in a subtle way. Good process layout design of pharmaceutical factory buildings can improve the quality of pharmaceutical production, improve the production efficiency of pharmaceutical factories, increase the level of safety and environmental protection, and reduce unnecessary costs of factory building construction and operation. The quality of pharmaceutical engineering design work, from a large perspective, can directly affect the production quality of medicines, and is also related to the life and health of patients taking medication; from a small perspective, it can affect the utilization efficiency of pharmaceutical production plants. The design plan is not strictly controlled. When the project is implemented, it will lead to minor changes and minor repairs, and it will cause a lot of rework and waste, which affects the initial construction investment and daily operating costs of the pharmaceutical factory, which is related to the market competitiveness of the pharmaceutical factory.

Part 2 Analysis Of The Problem

GMP was born as early as 1963, and it was born out of a real major pharmaceutical production quality accident disaster. Today, GMP has been recognized by the pharmaceutical industry in China and abroad. It conforms to the basic laws of drug production quality management and represents the direction of modern drug production quality management. It focuses on the organic combination of management concepts and science and technology, and attaches great importance to the production quality and safety of drugs. And controlled, comprehensively regulate every factor affecting the quality of drug production, such as hardware, software, personnel, materials, etc., but it is strict but not mechanically dogmatic, and pursues continuous improvement based on scientific knowledge, experimental data, and risk assessment (Continual Improvement) spirit. Of course, the connotation based on risk assessment cannot be misunderstood. It is a risk analysis based on scientific knowledge, experimental data and rich experience, and it is not a random decision.

With the development of the Internet, the exchange of information, and the digestion and absorption of Chinese pharmaceutical people, many advanced pharmaceutical production concepts have appeared in the design plans of Chinese pharmaceutical factories. For example: prefabricated modular operation room (plant) design; three-dimensional gravity flow solid preparation workshop layout; dust-free closed production and material transfer to prevent dust cross-contamination concept; through the isolator technology (Isolator Technology) in the core operation area Reduce the environmental conditions in the background area of sterile drug production; reduce the environmental conditions in the background area of sterile drug production through the blow-fill-seal technology (Blow/Fill/Seal Technology) in the core operation area; pay attention to the maintenance operation of the interlayer and/or technical layer, The wall-through and floor-through design is adopted to minimize adverse interference to the clean area; attention is paid to the design of the inspection surface for the main operating procedures of the workshop, so that people can intuitively understand the on-site operation of key processes without cumbersome changing clothes; for high-efficiency, Sealed and green production of highly active HPAPIs (Highly Potent) drugs, one-way flow concept, integrated quality protection, personnel protection and environmental protection; a super body integrating production, storage, quality inspection, public works and auxiliary facilities Quantity-integrated plant ideas; air-conditioning zoning and layout zoning concepts; refined production ideas such as precise feeding and use of materials; air break (Air Break) for clean room drainage, etc. Pharmaceutical engineering design requires advancement and practicability. Pharmaceutical engineering designers should continue to learn, keep pace with the times, and try to make the design concept leading in China and advanced in the world.

However, in the specific field of Chinese pharmaceutical plant design, there are many cases of failure or lack of design. Common design deficiencies or defects include:

(1) The flow of people and logistics routes are not smooth, loose and not compact, and the route design is bloated, and there are often “wrong roads”. Especially for the logistics route of manual transfer of bulk materials, it is very important for the material transportation route to be simple. If the unnecessary route is too long, it will not only increase the labor burden of the operator, prolong the working time, reduce the work efficiency, but also increase the material Risk of confusion and errors due to contamination along the way. For example, in the design of specific pharmaceutical workshop logistics routes, U-shaped arrangement of long assembly line operations can be adopted to optimize the flow of people and logistics routes, and minimize the transfer distance of materials, especially bulk logistics. In the design of the flow of people and logistics routes, “the direction of people and logistics in the factory area and the plant should be reasonable”, and it cannot be mechanically understood that the flow of people does not cross. Usually, in the layout design, the “total flow of people” and the “total logistics of the factory Keep a certain distance from each other to prevent adverse interference, but you can’t dogmatically think that all logistics and logistics are separated, otherwise it will not be possible to explain the problem of the transfer of people and goods. GMP focuses on the route design of human logistics, which should first ensure that raw and auxiliary materials, packaging materials, intermediate products, and finished products are prevented from being polluted when they pass through buildings and between buildings. The design of human logistics routes in pharmaceutical workshops should grasp this. The key point, otherwise it will get twice the result with half the effort.

(2) The area of the clean area is bloated, or the B-level area is bloated, and the clean area (room) is “puffy”, resulting in unnecessary waste of air conditioning, equipment, and energy consumption. Multiple sets of process equipment with the same function are installed in the same clean operation room. Considering the production operation of a specific process, if it cannot be proved that it is completely airtight, two different product varieties cannot be produced in the same clean room at the same time. If a single The area of the process operation room is too large. Although the area can meet the simultaneous production of multiple products, it can only produce the same product at the same time, which will inevitably lead to idle waste of resources such as the operation room, area, and equipment. In addition, for areas where HPAPIs-containing materials are exposed, if it cannot be proved that there is no cross-contamination of personnel and materials flowing in the same clean area, two different drug varieties containing HPAPIs-containing materials cannot be produced in the same clean area at the same time. If the area of the same clean area is too large, when a certain HPAPIs product is produced, other varieties cannot be produced in this clean area at the same time, which also causes unnecessary clean area (room), equipment and other resources to be idle and waste, reducing the use efficiency . When designing the layout of the clean area of a pharmaceutical factory, it is necessary not only to avoid too large a single clean room, but also to avoid too many clean rooms. As we all know, the clean room of a pharmaceutical factory must be regularly confirmed and verified for cleanliness and daily environmental monitoring. One more clean room means one more cost for QC cleanliness testing. This is also the same for purified water, water for injection and other point-of-use settings. One more water point means one more cost for QC water quality testing. Therefore, reducing unnecessary clean rooms, reducing unnecessary pure water points and injection water points, and “slimming” can improve vitality and competitiveness.

(3) The air-conditioning room, water treatment and other public engineering rooms, warehouses, etc. in the same factory building are interspersed with the production workshop during design, which must be considered comprehensively. If no attention is paid to the scheme design, it is easy to happen cross-posts during production operations. The normal operation and maintenance of public works such as air-conditioning and water production, and the entry and exit passages of the maintenance work, and the entry and exit of the normal process production operations of the workshop are hindered and interfered. “Appropriate measures should be taken to prevent the entry of unauthorized personnel. The production, storage and quality control areas should not be used as direct passages for non-local staff.” If each area is properly designed independently, it will bring problems for daily operation and maintenance. Many conveniences, more importantly, minimize the negative impact on the normal production operation of the workshop.

(4) In the production process, the operation rooms in adjacent processes could have been arranged adjacent to each other, but they were dismantled and separated when designing the internal process layout of the workshop. “The process flow line is loose, not compact, and not compacted.” As a result, the transportation and transfer of materials in the upstream and downstream processes are far apart and the distance is too large, which greatly sacrifices production efficiency, brings unnecessary negative effects on the quality of pharmaceutical production, and increases additional quality risks.

(5) The OSD (Oral Solid Dosage) clean area of the oral solid preparation workshop is “unclean in the clean corridor”. In the design of conventional OSD workshops, clean corridors are widely used. Through clean corridors, multiple process operation rooms can be opened, which greatly facilitates production operations. In order to effectively reduce dust cross-contamination, especially in single-corridor OSD workshops, the clean corridor usually has the largest positive pressure difference. In theory, the clean corridor with the largest positive pressure can effectively separate the air cross-contamination between the clean operations on both sides. The air in the dust-prone operation room cannot be diffused and flowed out to other rooms. But such a clean corridor is also the “vital gate” of dust pollution in the OSD workshop. Just imagine, if the clean corridor is polluted, it will inevitably pollute all solid workshop clean rooms. In this way, it is understood why it is not appropriate to open the door directly between the clean operation room and the clean corridor that are prone to dust exposure. Adding the necessary buffer front room to the dust-prone and pollution-prone operation room connected to the clean corridor is not an “excessive move”, but a “wise move” to effectively reduce dust cross-contamination.

(6)”Abuse of clean corridors”. It may be that the designers have established a common practice in the design of the clean area of the solid preparation workshop. No matter what clean area they encounter, they first think of setting up a clean corridor. So the pharmaceutical factory has not only D-level corridors, but also many C-level corridors and B-level corridors. First of all, to get rid of the stereotyped thinking, the clean corridor is not necessary in the layout design of the pharmaceutical factory workshop. Multiple different product operations for a process. If in the design of a specific clean area, it is only aimed at a specific process and only produces a certain product at the same time, for example, when designing a freeze-dried powder injection workshop, the C-level liquid dispensing process is independently designed and integrated, and its personnel The purification room and material purification room are set separately, and other auxiliary rooms such as cleaning room, storage room, weighing room, etc. can open directly to the liquid distribution room. For the compact and centralized layout of the liquid distribution clean area, if a C The first-level corridor is “additional to the superfluous”. Similarly, in the B+A level filling machine room of the freeze-drying workshop, there is no need to design the outlet of the rubber stopper sterilization cabinet and tool sterilization cabinet as a rear room for sterilization, and then pass through the B-level corridor and the filling machine room. are connected. Considering that the current sterilizer equipment manufacturing technology is mature, all of which have the functions of sterilization, drying, and cooling, the double-door sterilizer will no longer have the phenomenon of steam evaporation when the exit door is opened, and will not affect the clean environment of the filling room. Therefore, it is completely possible to install the outlet of the sterilizer directly in the filling room, canceling the post-sterilization room and B-level corridor, which not only saves the area of the B-level clean area, but also effectively shortens the transfer of items after sterilization The length of the route to the filling machine reduces the risk of contamination such as re-contamination of sterilized sterile items due to transfer.

(7) Understand the mechanization and dogma of “cross-level” connected rooms with doors or transfer holes (Transfer Hole or Mousehole) between them. When designing the layout of clean rooms in pharmaceutical factories, it is mechanically considered that only Class C clean rooms can be connected to Class B clean rooms, and only Class D clean rooms can be connected to Class C clean rooms; when people (or things) enter the clean area, the mechanical It is believed that only after entering the Class D clean room from the unclean area can the Class C clean room be entered, and only after entering the Class C clean room can the Class B clean room be entered; similarly, when a person (or object) exits the clean area At that time, it is mechanically considered that only after exiting from the B-class clean room to the C-class clean room, can the C-class clean room be exited to the D-class clean room, and then from the D-class clean room to the non-purified area. This is a typical rigid and dogmatic understanding of the GMP clean room shell-like contamination control concept. In the layout design of the actual clean room, it should be considered comprehensively according to the variety attributes, production capacity, process characteristics, equipment form and other factors of the products produced by the pharmaceutical factory, and specific problems should be analyzed in detail. For example, a person may enter a Class B clean area directly from a non-decontaminated area through a suitably designed changing room. This design takes care that the final stage of the changing room should be statically as clean as the clean room it leads to. It does not have to be It is designed as a changing mode of “putting on Class C clean clothes to enter Class C clean area first, then changing them, and wearing Class B clean clothes to enter Class B clean area”.

In addition, the filled and sealed terminally sterilized aseptic products can be directly transferred from the C-level filling room to the non-clean production operation area by using the transfer hole method, and the filled non-terminal sterilized products can also be transferred by using the transfer hole method. Aseptic products are directly passed from the B-level filling room to the non-clean production operation area. Some enterprises or designers of clean workshops worry that if the product is transferred from the high-level clean area to the low-level area through the transfer hole through the conveyor belt, due to the large pressure difference between the two sides of the transfer hole, whether air vortex will be generated in the low-level area and affect the high-level area. Contamination in the clean area? The actual test shows that the vortex flows with the airflow to the low-level area, and it is impossible to pour back into the high-level clean area. For terminally sterilized products, there is a positive pressure difference of more than 20 Pa from the C-level area to the non-clean production operation area, and the capped products are sent to the sterilization area located in the non-clean production operation area through the transfer hole through the conveyor belt. The above pressure difference is enough to prevent pollution from the non-clean production operation area, and there is no need to set up a separate air supply channel between the C-level area and the non-clean production operation area to form a “D-level buffer zone” that is actually unmanned. For non-terminal sterilized products, if the ampoule product that needs to be heat-treated by circulating steam is transferred from the transfer hole to the unclean production operation area, since the product has been melted and sealed in the A-level area, it can be directly filled from the B-level area. Enclosure came out. If the aseptic process is used to produce vial filling products, the capping is completed in the A-level area or the A-level air supply environment, and the capped vials can be transferred from the B-level area to the C-level area through the transfer hole through the conveyor belt, or The outsourcing area transferred from the C-level area to the non-clean production operation area can also be directly transferred from the B-level capping room or the C-level capping room.

With regard to cross-level transfer, the second edition of the European Union’s sterile drug consultation draft deleted the clause “generally speaking, only Class C clean rooms can be connected to Class B sterile process areas” and added a clause for cross-level transfer holes, which is consistent with The relevant FDA regulations remain consistent. Both believe that it is possible to “use the transfer hole to transfer the potting and sealing product from the sterile room to the adjacent unclassified room”, emphasizing that the airflow pattern test here should prove that the air will not flow back, and the two sides of the transfer hole need to Continuously maintaining a sufficient positive pressure difference requires continuous monitoring to ensure that when the pressure difference is too low, it can be detected in time and corrective measures can be taken to restore the clean environment of the sterile process room.

(8) The understanding of the passage of waste from the clean area is mechanically dogmatic. In the layout design of the clean room of a pharmaceutical factory, it is mechanically considered that each clean area must have an independent waste delivery channel. Article 5.3.5 of GB 50457-2019 “Design Standards for Clean Workshops in the Pharmaceutical Industry” on waste channels: “Wastes generated in pharmaceutical clean rooms should have outgoing channels. Wastes that are prone to pollution should be provided with separate outlets. Active or Toxic biological waste should be passed out after inactivation.” The text of this article is interpreted as: the production process of pharmaceutical clean rooms will produce various wastes, such as waste glass slag, waste inner packaging materials, waste from intermediate quality inspection, waste liquid produced by biological fermentation or animal cell culture, waste tissue cells wait. Whether to set up a separate outlet should be determined according to the production process and production scale, as well as the nature and quantity of waste. Some wastes must be passed out of the production area in time to avoid polluting the production environment, such as waste glass slag after ampoule drawing and sealing in water needle production, discarded animal cells (such as chicken embryos), etc., which are large in number, pollute, and are not easy to seal , Staying in the clean area will cause environmental pollution, so a dedicated waste channel should be set up to disseminate it in time. Some toxic and active wastes produced in the production process of biological products must be inactivated before they are released to avoid biosafety accidents, and corresponding inactivation facilities (such as steam sterilizers, etc.) must be configured for this. For small-scale production, simple process, and a small amount of waste, the layout of the layout and the entrance of raw and auxiliary materials can be combined to comprehensively consider the outgoing channels of waste. For example, a small amount of waste generated during the production process can be properly stored and sealed in packaging, and passed out through the raw material inlet air lock or transfer cabinet after production is completed. For the aseptic clean room, if there is not much waste, the packaging is good, and there will be no pollution, the waste can also be passed out through the adjacent low-level area, without directly setting up a dedicated waste transfer channel from the sterile clean room .

(9) In a specific clean room, the factor of indoor wind direction is usually ignored when the return (exhaust) air outlet and ventilation equipment are arranged. When selecting the site of a pharmaceutical factory and planning the layout of the factory area, the requirements of the wind direction are usually considered, and the source of air pollution should be kept away. If it cannot be far away, the source of air pollution should be located on the downwind side of the maximum frequency wind direction of the factory area throughout the year, so as to minimize the impact of the pollution source on the clean workshop of the pharmaceutical industry. Impact. In a specific clean room, attention should also be paid to the wind direction requirements in the room. If there is an air pollution source in the clean room, the air pollution of the clean room by the air pollution source in the room should be reduced as much as possible. The air flows from a relatively clean area to a relatively polluted area, and the dirty air in the room cannot be allowed to diffuse freely; if there is a sterile Class A area in the clean room, the sterile air should flow to the non-sterile area, and the non-sterile air should not be allowed to flow. Sterile air flows into the sterile area. For example, when setting the return and exhaust outlets of the “clean clothes room” entering the clean area, the return and exhaust outlets should be located on the side where the clean clothes have not been worn, and should not be set on the side where the clean clothes have been put on. In the “Class B clean clothes room” entering the Class B area, considering that sterile clothes are worn, the outlet of the double-door clothing sterilizer is usually set in the “Class B clean clothes room” in the layout design of the workshop, but It should be noted that the outlet of the clothes sterilizer should also be set on the side where the sterile clothes have been put on, not on the side where the sterile clothes have not been put on. Studies have shown that a large number of particles are produced on the surface of the human body all the time, and the breathing, speaking and communication of personnel will also spread microorganisms into the air. Therefore, operators are the largest source of pollution in aseptic production clean rooms and the largest source of contamination risk for aseptic products. In the design, the wind direction and human flow route in the aseptic production clean room should be reasonably designed to avoid passing through the core operating area protected by one-way flow. At the same time, the personnel’s station must be reasonably designed and should be in the downwind direction of the indoor airflow to prevent product contamination. Also for the sake of reducing pollution in the clean room of aseptic production, unnecessary personnel, unnecessary activities (such as routine intermediate testing), unnecessary rooms (such as storage of sanitary ware), etc. should be avoided as much as possible.

(10) When designing the layout of pharmaceutical plants, underestimate the attributes and characteristics of products such as allergenicity, pathogenicity, toxicity, and activity. Chinese pharmaceutical companies usually have a large number of products, and due to the awareness of the importance of R&D and innovation, new products emerge in an endless stream. In order to save investment, pharmaceutical factory workshops and testing rooms usually encounter products with different attributes. Especially in the layout design of the production workshop, in order to facilitate the overall changing management of personnel, some companies often adopt a centralized overall changing layout for the production areas of ordinary products and toxic active products. Enter the respective production clean area and packaging room respectively. Ideally, the drug exposure is in the clean area, and the clean area has been separated, so that the pollution of toxic and active products to ordinary products can be avoided. However, in detail, in the actual plant layout and production operation of a pharmaceutical factory, the clean area of the workshop is usually designed with a transfer hole on the color board wall to connect the clean area with the packaging line in the ordinary area, and the substances containing active products may pass through the transfer hole. When it flows out to the packaging room, if active substances adhere to the outer surface of the product when it comes out of the clean area, the active substances will also be taken out of the clean area. In addition, if the toxic active product is damaged when it is packaged in the ordinary area, it will also pollute the packaging workers. When the active substance is adsorbed on the work clothes of the packing workers, the packing workers may spread the active substance to other places when walking in the workshop; the maintenance personnel of the active product workshop may come into contact with the active substance due to maintenance of process equipment or replacement of active substance filters, etc. If you go to the clean area of the ordinary product workshop to perform maintenance work, it may also cause the active substance to diffuse into the ordinary product workshop. Therefore, it is not superfluous but wise to carry out appropriate sub-factory layout (and/or) zoning layout according to product attributes.

(11) In addition, in the design of the factory area and workshop buildings, whether to adopt the shape first and then the internal layout, or the form of the inside and then the outside; The layout, or the process layout should determine the shape. Designers should make overall plans and take all considerations into account. They can’t simply decide who to identify. Instead, they should analyze specific issues in combination with the actual situation of the plant construction project and planning requirements.

The depth of the design of the pharmaceutical workshop is very important. The big precautions are easy to grasp and easy to attract people’s attention. It is like observing with a “telescope”. However, the value of pharmaceutical workshop design is ultimately reflected in production and use, which requires long-term, immersive, and day-to-day operation and use by specific operators. Easy to use, just like observing with a “microscope”.

In the engineering construction of Chinese pharmaceutical factories, there is a mantra “good engineering comes from good secondary design”. “Secondary deepening design” is often required in engineering construction. Many pharmaceutical factory workshop construction projects have insufficient design depth, or because the design requirements are not clear enough, design requirements have changed, etc., resulting in rooms (areas) that are either too small or too large, and the floor height is either too low or too high. The equipment is not highly integrated, the same major and different majors fight, but what should be reserved is not reserved, the reservation is inaccurate, and it is not easy to expand flexibly. Although it is quite satisfactory, it is not easy to use. In addition, the factory building is for human use, which involves human factors engineering HFE (Human Factors Engineering). , color matching and other design aspects need to consider the user’s physical and mental feelings more. The layout design of specific pharmaceutical workshops cannot be copied. It should be targeted according to the actual situation of each pharmaceutical factory, the specific variety, attributes and production capacity requirements of the product, the specific process of the production process, and the selection of process equipment. Carry out the design work in a timely manner, and strive to make the design plan scientific and reasonable and match the objective conditions (Scientific & Commensurate).

Part 3 Example Explanation

At present, macromolecular drugs have accounted for more than half of the world’s best-selling drugs list. Most macromolecular drugs are often sterile because they cannot be taken orally, and cannot be sterilized by high temperature. Sterile aseptic workshop. In the layout design of the workshop, the production process must first be sorted out and targeted. According to the relevant specification requirements of non-terminal sterilized sterile products, the workshop is roughly divided into 3 purification areas according to the cleanliness from high to low: “B+A grade” “filling area” for aseptic filling of products , Class C “preparation area” for drug preparation, and Class D “bottle washing area” for washing out bottles, rubber stoppers, aluminum caps, utensils, and clean clothes.

About the layout design idea of “filling area”: In order to facilitate the transfer of post-sterilized tools, rubber plugs, aluminum caps, etc., and reduce unnecessary door opening and closing operations, the post-sterilization room or Class B clean corridor is not designed separately, but the Product filling, aseptic tools, and the transfer of aluminum caps and rubber stoppers after sterilization are set up as a large filling room, and the purification requirements of this room are partly A-level with a B-level background. In order to make it easier for employees to check the actual situation in the filling room without going through tedious aseptic changing, the filling room adopts a design layout that can be visited, and double-layer air return glass is set near the peripheral corridor, which not only meets the convenience requirements for visiting and checking, but also Consider the requirements of the return air clamping wall with a large air volume. The operator enters the filling room by directly changing clothes from the outer ordinary corridor, and wears sterile outerwear in the third shift room. The third shift room is designed for one-way flow of personnel, and the exit of the double-door sterilization cabinet for sterile clothes is set in the third shift room. , Try to shorten the transfer route of sterile clothing. In consideration of minimizing the contamination of sterile clothing when wearing sterile clothing, the third shift room is managed by drawing lines on the ground, and the front and rear of dressing are strictly separated. The return air outlet of the third shift room is located on the side before dressing, and the sterile clothing is sterilized The exit of the cabinet is located on the side after dressing, and the sterilized clean clothes are taken out by the personnel who have put on the sterile coat, so as to minimize the risk of contamination of the sterilized sterile clothes. The door of the third shift room is set to be interlocked and cannot be opened at the same time, and the delay time for the door to enter the filling room after the entrance door of the third shift room is closed is determined by the verification data. The cleanliness requirement of the third shift room is to meet the requirements of Class B under static conditions. In order to ensure the aseptic level of changing clothes in the third shift room, the third shift room is designed as a one-way flow that can only enter and exit. The personnel in the filling room exit through a separate return channel for taking off clean clothes. The return channel is adjacent to the filling The room in the room is designed as an air lock room. The door of the air lock room cannot be opened at the same time, and a delay function is also provided to prevent it from adversely affecting the cleanliness of the filling room. The cleanliness of this room is set to be under static conditions. It is sufficient to meet the requirements of Class B. The used tools and utensils in the filling room are sent out through the transfer window with an air shower device, cleaned and sterilized in the adjacent utensil cleaning room next door, and then returned to the filling room for use. After the non-terminal sterilized cartridge injection products are crimped and sealed, they come out of the capping station in the A-level area of the filling machine and then enter the B-level filling room. In order to facilitate the automatic transportation of the conveyor line, the B-level filling room passes The small hole directly leaves the filling room and enters the “product outlet buffer room”. Note that the conveyor belt should be disconnected in areas with different cleanliness requirements. The product exits the buffer room, which is not strictly a clean room. The packaging and light inspection personnel can directly enter this room wearing the work clothes of the ordinary area. The cleanliness is set to meet the requirements of Class C under static conditions. The air is supplied by the purification air-conditioning box in the filling room together, but it is not suitable to return the air from the buffer room to the purification air-conditioning box in the filling room. The buffer room can only send air but not return it, and fully exhaust the air. A real-time differential pressure monitoring device should be installed between the filling room and the product outlet buffer room, and it is required to maintain sufficient positive pressure continuously. The pressure limit is set to 15 ~ 20 Pa. When it is lower than the warning limit, the pressure difference monitoring system will sound and light alarm and prompt relevant personnel to find out the cause in time and increase the pressure difference to return to the acceptable range; here, the pressure difference value action limit is set It is set at 10 ~ 15 Pa. When it is lower than the action limit, not only the alarm and recovery are required, but also the cleanliness of the filling room should be confirmed in time.

About the layout design idea of “preparation area”: In order to shorten the distance from the preparation system to the filling machine as much as possible, the preparation tank is positioned on the side adjacent to the filling room. Considering that the function of this preparation area is relatively simple, it usually does not appear In the case of preparing different products at the same time, the layout of the clean area of this workshop does not design a C-level clean corridor, but uses a large main operation room – preparation room, and some small functional suites are opened in the preparation room, such as cleaning room and storage room , weighing room. The preparation room and its connected functional rooms are strictly Class C clean areas. The passenger flow airlock and logistics airlock in the preparation area are designed as static C-level. The people flow air lock room also has the function of wearing clean clothes, and the floor of the people flow air lock room is managed by marking lines to strictly distinguish the “rear area” that has worn clean clothes and the “front area” that has not worn clean clothes to avoid the gap between the two areas. Randomly cross between. In the same way, the logistics air lock room also has the function of disinfecting items, and also adopts line management to strictly distinguish the “rear area” where items have been disinfected and the “front area” that has not been disinfected, and pay attention to avoid random crossing. The return air outlets of the air locks are all set on the side close to the lower cleanliness requirements to ensure that the indoor air flow in the air locks flows from the clean area to the relatively dirty area. In addition, in order to protect the cleanliness of the air lock room, the peripheral “one shift room” and “outside cleaning room” usually use high-efficiency air filters to supply air, but they only send air and do not return it. The form of full exhaust air is adopted, and its cleanliness It is required that the internal control of the enterprise can only reach D level when it is static.

About the layout design idea of “bottle washing area”: the bottle washing machine, tunnel oven, rubber stopper cleaning and sterilizing machine, and aluminum cap sterilizing machine are arranged in a large bottle washing room, and the bottles, rubber stoppers and aluminum caps are set separately The larger material air lock room directly enters the bottle washing room, shortening the transfer distance of bulk logistics, improving production efficiency and reducing labor intensity. In addition, the transfer window for tools and utensils coming out of the filling room, the tool and utensil sterilizing cabinet, and the preparation of disinfectant solution are all designed and arranged in the utensil cleaning room, so as to shorten the passing, cleaning, sterilization and reintroduction of tools and utensils as much as possible Length of transfer path between fills. Considering the compact layout of the workshop design and reducing unnecessary area waste, the clean clothes in the filling area, preparation area and bottle washing area are all set up in one laundry room for centralized laundry. Considering that the clean clothes used in different clean areas, it is advisable to use Three washing machines, namely the washing machine for Class B clean clothes, the washing machine for Class C clean clothes, and the washing machine for Class D clean clothes, respectively wash their respective clean clothes to reduce the workload of cleaning verification of clean clothes.

Part 4 Conclusion

At present, the development of the global pharmaceutical industry is quite rapid, and the concepts, ideas, rules, and precautions for the design of pharmaceutical workshops are becoming more and more mature and perfect. Many problems and doubts encountered in the layout design of pharmaceutical workshops are usually not It was the first time for the designer to encounter some problems in the layout design of pharmaceutical workshops. In fact, they have been carefully considered and analyzed by Chinese and foreign pharmaceutical seniors, experts and scholars, and proposed solutions, improvements or optimization solutions. Therefore, when designing the layout plan of a pharmaceutical workshop, it is necessary to search, study, and think about Chinese and foreign pharmaceutical production norms, related design standards, clause descriptions, expert answers, and pharmaceutical factory cases in large quantities, extensively, and comprehensively. For example, EU GMP usually covers a lot, including Basic Requirements for Medicinal Products, Basic Requirements for Active Substances used as Starting Materials, GMP Related Documents; ATMPs Drug GMP Requirements (GMP Requirements for Advanced Therapy Medicinal Products), and about 20 appendices (Annexes), another glossary (Glossary) and other GMP-related documents (Other Documents Related to GMP). China’s GMP also has general rules and numerous appendices, drug GMP guidelines, etc. In addition, Chinese experienced scholars and experts have given a lot of specific answers to GMP implementation.

In order to ensure the quality of pharmaceutical production, it is necessary to systematically, extensively, and in-depth study the relevant GMP regulations and guidelines when designing the layout of pharmaceutical workshops, so as to achieve “knowledge, interrogation, prudence, discernment, and earnest practice”. GMP is an imported product, and there are many advanced ideas, concepts, methods, cases, etc., which are worth learning by designers. The design of the pharmaceutical workshop should have the spirit of Tang Monk learning from the scriptures, learn from foreigners to improve themselves, not only to learn the Chinese version of GMP, but also to learn the original international version of GMP. In pharmaceutical engineering design, it is first necessary to study and thoroughly understand GMP knowledge, norms, guidelines, pharmaceutical regulations and related policies, design standards, clauses, etc., in order to achieve the compliance of pharmaceutical engineering design. In addition, it is far from enough to memorize the normative clauses by rote. What is more important is to personally participate in the practice of the technical transformation project of the pharmaceutical factory, and gain insights and experience in the specific practice. At the same time, it is necessary to extensively study the design cases of pharmaceutical factories to achieve the advanced nature and practicality of pharmaceutical engineering design.

At present, the new crown epidemic is still raging around the world. Some developed countries have increased trade and technology frictions, and China’s pharmaceutical industry has also been adversely affected. However, risks and opportunities coexist. It will promote the self-improvement of China’s pharmaceutical industry and build a pharmaceutical powerhouse as soon as possible. details make a difference. Only when pharmaceutical engineering design is based on the very familiarity with scientific knowledge such as normative clauses, technological processes, equipment, and regulations and policies, as well as rich experience and experience, can a good design be produced, which can not only meet the legality, compliance, and It is advanced and practical, and realizes the quality control of pharmaceutical production plants (reducing pollution, cross-contamination and confusion errors in pharmaceutical production), easy-to-use production (easy operation, high efficiency, scalable flexibility), safety, environmental protection and energy saving, etc. Organic unity. You must first be familiar with the production process, then the equipment, and then talk about the design. In the design of pharmaceutical workshops, we must also vigorously promote the spirit of craftsmanship, be in awe of the profession, be persistent in work, be brave in taking responsibility for the design plan, pay great attention to details, carefully design, and never stop on the road of continuous improvement.