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Eight of the top 10 blockbuster products in global annual sales are therapeutic biological drugs. As the production site of biological products, the clean workshop of biological products should not only meet the special process requirements of biological products, but also consider the requirements of fire protection regulations, energy saving, personnel and environmental protection. Therefore, the preliminary design of biological products clean workshop needs to consider many factors comprehensively. With the implementation of GMP and the development of the pharmaceutical industry, many problems have been exposed in the practical application of clean workshops for biological products. Part of the problem is that the design process of the biological product clean room is not considered comprehensive. Starting from the guarantee of the quality of drugs, this paper makes statistics and analyzes on the problems existing in the preliminary design of 12 clean workshops of biological products from the perspective of the 2010 version of GMP, and puts forward suggestions. It is hoped to provide reference for the preliminary design of biological products clean workshop.
Part 1 Overview Of Frequently Asked Questions
A total of 234 problems were found in the preliminary design of 12 biological product clean room systems, which were classified according to the frequency of problems: (1) In terms of production process layout, such as poor design of people flow and logistics; (3) The overall layout of the factory area is unreasonable, mainly manifested in the site selection and layout of the factory area; (4) Other problems, such as improper water system and electrical system settings.
Part 2 Problem Analysis
1 Production Process Layout
1.1 The Flow Of People And Logistics Is Not Smooth
Article 40 of the GMP standard requires that the direction of people and logistics in the factory area and workshop should be reasonable. Part of the design of human flow and logistics is not designed smoothly, which is likely to cause confusion, mistakes and pollution. If the dirt from the filling area needs to pass through multiple operating rooms, and finally pass through the material inlet channel to the clean area, the operation is inconvenient and easy to cause pollution and cross-contamination. The dirt exit route should be redesigned. Some designs have the phenomenon that operators pass through other operation areas, such as the personnel in the fermentation centrifuge room need to pass through the fermentation room and the cell collection room, and the personnel in the freezing and thawing post need to pass through the purification centrifuge room. Such an arrangement will not only cause inconvenient operation, but also easily cause cross-posting and cross-contamination. Operators should set posts according to the actual production, so that personnel do not wear posts and avoid detours. The process layout of the biological product clean workshop should be arranged according to the production process and operating procedures, so that the flow of goods and people can be smooth, and the flow of people and goods should be reasonably separated.
1.2 Regional Planning Is Unreasonable
In some designs, key processes are placed in the center of the workshop layout, such as virus inactivation, filling and other processes. Non-production personnel (such as quality assurance personnel) need to enter the core area to conduct daily monitoring and observation, which may affect production. cause disturbance. At the same time, it is not conducive to the development of medium simulation filling, deviation investigation and other work. The ideal design of the production workshop is the design of long assembly line operation, but the production enterprises generally do not have enough space to build such workshops. Part of the design achieves the above effects through the “U-shaped” arrangement: the key processes are set on the periphery of the workshop layout, and the auxiliary workshop design is in the middle. Normal production is disrupted. At the same time, the workshops of the front and rear processes can also be connected through the “U-shaped” design, such as the raw liquid workshop and preparation workshop of vaccine products. Through this design, the flow of people and logistics routes can be optimized, and the transportation distance of materials can be minimized.
1.3 The Selection Of Production Equipment Does Not Meet The Production Demand
Article 49 of Biological Products in the Appendix of GMP Regulations requires that: when pathogens of Class II or above are used for production, the generated dirt and suspected contaminated items should be disinfected in situ, and can only be removed from the work area after being completely inactivated. Part of the design does not take into account the transfer of items in the sterile (poisonous) operation area, and lacks corresponding supporting equipment. If there is solid waste and waste liquid generated during the production process in the bacteria (poisonous) operation area, there may be uninactivated germs. Therefore, all items involved in this operation area, such as work clothes, utensils, discarded harvest liquid, waste water generated by CIP stations, etc., need to be inactivated by proven methods, and the germs used in production can be killed before leaving this area. Solid waste such as stainless steel appliances, work clothes, etc. can be sterilized by a steam pressure cooker and then passed out. Appliances that cannot withstand high temperature and high pressure, such as thermometers, pressure gauges and other precision instruments, can be sterilized by a vaporized hydrogen peroxide sterilizer (Vaporized Hydrogen Peroxide/VHP), and some designs are sterilized by ozone fumigation. bacteria, it should be evaluated whether it can achieve the expected sterilization effect.
2 Air Purification System
The main purpose of the air purification system is to ensure the ambient air quality of biological products and prevent cross-contamination. If the pharmaceutical production environment is properly designed, constructed, debugged, operated and maintained, it will help ensure product quality and improve product reliability.
2.1 Improper Differential Pressure Setting
Article 48 of the GMP standard requires that the pressure difference between clean areas and non-clean areas and between clean areas of different cleanliness levels should not be less than 10 Pascals. When necessary, an appropriate pressure gradient should also be maintained between different functional areas (operating rooms) of the same cleanliness level. Part of the design does not consider the requirements of special varieties for negative pressure gradients, and there is a problem of pressure gradient fluctuations caused by system variable air volume processes (such as starting and stopping of biological safety cabinets, switching of standby air supply/exhaust units, etc.). The above-mentioned problems can be better solved by adjusting the difference between the air supply volume and exhaust air volume in each room to ensure the pressure gradient of each room through the differential air volume control method. At the same time, the design should consider the size of negative pressure gradient and energy saving. When there is a large negative pressure, it can effectively prevent the leakage of aerosols of pathogenic biological factors, but the construction and operation costs are high; on the contrary, when the negative pressure is small, it is easy to produce aerosols of pathogenic biological factors. Leakage will cause safety problems in the production area and outside.
2.2 Unreasonable Exhaust Air Setting
GMP Specification Appendix Biological Products Article 22 requires that the sterile (poisonous) operation area should have an independent air purification system. The air from the pathogen operation area shall not be recycled; the air from the pathogen operation area with a risk level of Class II or above shall be discharged through a sterilizing filter, and the performance of the filter shall be checked regularly. Part of the air in the pathogen operation area is not treated and discharged. The air in this area is generally treated in a direct discharge method without return air, and the toxic area can be set as close to the power area as possible to achieve the purpose of energy saving.
3 The Overall Layout Of The Factory Area Is Unreasonable
It can be seen from Table 1 that the overall layout of some biological products still has unreasonable problems in the preliminary design of clean workshops. Although it only accounts for 3.9%, such problems are not easy to adjust and rectify after the project is implemented. If the site is not selected properly, the harmful gas emitted around the factory area will easily cause pollution to the pharmaceutical production. Poor layout within the plant, with living and ancillary areas obstructing production areas. It shows that there are still relatively large loopholes or defects in the overall planning.
3.1 Improper Selection Of Factory Site
Article 38 of the Good Manufacturing Practice for Drugs (revised in 2010, referred to as the GMP standard) requires that the site selection, design, layout, construction, renovation and maintenance of the plant must meet the requirements of drug production, and it should be able to avoid pollution, Cross-contamination, mix-ups and mistakes, easy to clean, operate and maintain. Some preliminary design sites are unreasonable. For example, a company is located near a petrochemical industrial zone, and the harmful gases emitted by the petrochemical industry are likely to cause pollution to pharmaceutical production. When selecting a factory site for a biological product manufacturer, it should stay away from places that emit a large amount of dust and harmful gas, so as to avoid the harmful gas emitted that may easily cause pollution to pharmaceutical production. The site selection of pharmaceutical production enterprises is the first step in pharmaceutical production planning. Enterprises should comprehensively consider factors such as their own development and regional planning direction to avoid congenital deficiencies in the preparation of factory construction.
3.2 Improper Layout In The Factory Area
Article 40 of the GMP standard requires that the overall layout of production, administration, living and auxiliary areas should be reasonable and not interfere with each other. Part of the preliminary design has comprehensive activity buildings, canteens and other supporting facilities in the production area, and appropriate separation measures should be added to separate the production area and living area in the factory area without affecting each other. In addition, some designs have only one master cell bank and do not consider alternate master cell banks. The “Preparation and Verification Procedures for Animal Cell Substrates for Production Verification of Biological Products” requires that the main cell bank and the working cell bank should be stored separately. Each pool shall be held in at least 2 different locations or areas within the manufacturing facility. As the starting material of biological products, the master cell bank is the material basis for pre-market clinical evaluation and post-market research of biological products. The research process is long and complicated. Therefore, the master cell bank is the basis for the survival and development of biological product manufacturers. Enterprises should strengthen the protection of the master cell bank to ensure that the master cell bank can take effective countermeasures in the event of emergency situations such as power outages and fires.
4 Other
There are 18 other problems, accounting for 7.7%, mainly related to drainage system problems and electrical system problems, such as poor consideration of wastewater treatment in toxic areas, unreasonable installation of power distribution cabinets, fire hydrants, etc.
4.1 Water System Aspects
Water is the carrier of many biological products. Once it is polluted, the consequences will be disastrous. Part of the design does not take into account the requirement that the preparation and storage of water for injection must prevent the growth and contamination of microorganisms. For example, water for injection can be used in a heat preservation cycle above 70 °C and used within a specified time after preparation. At the same time, in order to ensure biological safety, the waste liquid in the toxic area must be sterilized before treatment. After live treatment, it is discharged to the sewage treatment station in the factory area, and then discharged after treatment.
For the public systems of biological product manufacturers, such as water systems and gas supply systems, after the system is emptied, air passages will be formed in the pipelines. Viruses and pathogenic bacteria can contaminate other systems and the environment through the pipelines. Viruses and pathogenic bacteria should be prevented. Bacteria can contaminate other systems and environmental measures in this way. In addition, the supply pipelines of public engineering systems in toxic areas and non-toxic areas should be separated as far as possible to prevent cross-contamination.
4.2 Electrical System Aspects
Article 79 of the GMP specification requires that the maintenance and repair of equipment must not affect product quality. The daily maintenance and repair of the production equipment in the workshop is an indispensable part of ensuring the quality of drugs, but the daily maintenance and repair may have adverse effects on the environment in the workshop and even affect the product quality. In some designs, the power distribution cabinets and fire hydrants are placed in the clean area, which is not convenient for daily maintenance and repair. Under the premise of meeting fire protection and industry standards, etc., power distribution cabinets and fire hydrants should be installed in non-clean areas and non-toxic areas as much as possible.
In addition, in some designs, there is a problem that more pipeline tissues are exposed, which is not convenient for cleaning and maintenance in the clean area. The pipeline organization in the clean workshop should be planned together with the layout of various machine rooms, and different concealment measures should be taken. If the pipeline shaft is used as a vertical concentration space for various pipelines, it should be arranged adjacent to the machine room as much as possible. The technical mezzanine is used as a horizontal distribution space for pipelines, and it should provide enough space for the passage and maintenance of pipelines.
Part 4 Summary
Due to the particularity of its production varieties, the clean workshop of biological products determines the complexity of the process flow design and the special requirements of the public system. These characteristics put forward higher requirements for the preliminary design of clean workshops for biological products. In addition to meeting the requirements of the production process, factors such as biological safety, fire protection, and environmental protection regulations must also be considered. Biological product manufacturers should fully communicate with the designer, so that the designer can fully understand the production process, project positioning and special requirements of the manufacturer. In accordance with the production process and operating procedures, scientifically and rationally carry out the plane layout and equipment layout, minimize errors and cross-contamination, continuously explore, analyze and summarize during the design process, and design a more optimized plan.