Abstract: A GMP clean room refers to a workshop that meets the requirements of the GMP quality and safety management system. At present, most industries such as pharmaceuticals and food have mandatory requirements for the construction of GMP workshops. GMP workshops have specific requirements for room decoration requirements, temperature, humidity, electrical safety, automatic control, etc. This article focuses on introducing the construction points of a GMP clean room for pharmaceutical preparations from the perspective of engineering practice, for reference in similar engineering construction.
Keywords: GMP workshop; airtightness; differential pressure gauge; disinfection system; automatic control
1. Introduction
"GMP" is the abbreviation of "Good Manufacturing Practice", which means "good operating specifications" in Chinese, and can also be called "good manufacturing standards". This system pays special attention to the autonomous management of health safety and product quality during the production process. This system is applicable to those food or pharmaceutical industries and has mandatory standards. It requires relevant enterprises to strictly follow relevant national laws and regulations in terms of personnel, production process, raw materials, packaging and transportation, facilities and equipment, quality control, etc., so as to meet the standard sanitary quality requirements, and finally form a set of specifications that enterprises can actually operate, which will help enterprises improve their own sanitary environment and solve problems in time once they are found. Therefore, a GMP workshop refers to a workshop that meets the requirements of the GMP quality and safety management system. At present, most industries such as pharmaceuticals and food have mandatory requirements for the construction of GMP workshops. GMP workshops have specific requirements for room decoration, temperature, humidity, electrical safety, automatic control, etc. GMP workshops require that the room's partition walls, ceilings, floors and other decorative materials be environmentally friendly, washable, mildew-proof, and fireproof. The entire room system is airtight, the room air quality is excellent, the number of 0.5um particles is controlled within the specification requirements, the temperature and humidity meet the workshop's use requirements, the electrical wiring, pipeline connection, and distribution box system are required to be safe and reliable, and the automatic control requires the temperature and humidity sensors to be sensitive, accurately control the temperature and humidity, and the human-machine interface is easy to operate. This article will briefly introduce the construction points of a pharmaceutical preparation GMP workshop based on the experience of engineering practice.
2. Project Overview
A pharmaceutical preparation GMP workshop is located on the first floor with a construction area of 1155 m2. To meet the production of oral solid preparations, the functional rooms mainly include shoe changing, changing clothes, buffer, clean corridor, weighing room, grinding room, granulation room, intermediate product inspection, tableting room, mixing room, capsule filling, film coating room, inner packaging room, auxiliary room, air conditioning room, etc. Decoration requirements: The pharmaceutical preparation GMP workshop requires that the partition walls and ceilings are made of materials that are not easy to produce dust and easy to clean. The design of this project uses 50mm thick handmade glass magnesium and rock wool sandwich panel, with a fire protection grade of A and a fire resistance limit of not less than 1.5 hours. The floor uses 2mmPVC coiled floor (ground base leveling, epoxy resin self-leveling bottom layer), doors and windows use factory-customized clean and closed windows, and the connection between partition walls, ceilings and floors uses aluminum alloy professional arc aluminum profiles. Purification air conditioning requirements: The pharmaceutical preparation GMP workshop has a cleanliness level of class D, a temperature requirement of 20-24°C, and a relative humidity requirement of 45-60%. The specific design plan is that the fermentation room uses a constant temperature and humidity air handling unit JK-1, and the unit takes fresh air by itself. Other rooms in clean workshop use a combined constant temperature and humidity air handling unit JK-2, and the unit takes fresh air by itself; the combined constant temperature and humidity air handling unit adopts a plate-type primary filter G4 and bag-type medium filter F8 two-level filtration treatment method, and the air supply terminal adopts an H14 hepa filtration system. The cold source of the combined air-conditioning unit is provided by two outdoor modular air-cooled units with a cooling capacity of 260kw; one chilled water pump is used and one is reserved, with a single flow of 52m3/h and a head of 27m; the VRV system is used in ordinary areas. Electrical requirements: The workshop lighting uses LED panel lights, the ceiling wire pipes are wired through the bridge, the wire pipes from the ceiling to the sockets and switches are pre-buried inside sandwich panel partition wall, and the electrical distribution box is customized by the manufacturer. Process pipelines: The compressed air pipeline uses SUS304 stainless steel pipes. The pipelines entering the workshop need to be polished on the surface with a finish of Ra≤0.8 microns. The valves use SUS304 stainless steel ball valves. Electrical automatic control: The combined wind cabinet return air main is equipped with a temperature and humidity sensor, and the combined wind cabinet return water main is equipped with an electric proportional integral valve. The automatic control cabinet uses a PLC programming system. The proportional integral water valve, electric heating section, and humidifier will adjust the water valve, the number of heating sections, and the size of the humidifier valve according to the temperature requirements of the GMP workshop to ensure that the temperature and humidity meet the process requirements of the GMP workshop.
3. Technical exchange plan and detailed drawings for the pre-construction of GMP workshop
3.1 Drawing review
Because the requirements of GMP workshop are strict and the cleanliness, temperature and humidity of the room are high, the construction unit needs to organize a drawing review before construction. The construction unit raises questions or doubts about the drawings, and the design unit gives answers and forms a drawing review minutes.
3.2 Detailed drawings
Because there are many specialties in GMP workshops, the pipelines are basically installed on the limited mezzanine ceiling, including air conditioning ventilation ducts, smoke exhaust ducts, electrical lines, bridges, process pipelines, water supply and drainage, etc. Therefore, the construction unit should deepen the design of the entire project before entering the site, especially the secondary detailed drawings of the color steel plate partition wall and the ceiling arrangement, including the location of the air vents, the location of the lamps, the reserved switches, panels, and sockets should be reflected in the detailed drawings. Capable construction units also need to enter the BIM modeling analysis of the air conditioning room or the intersection of multiple pipelines, and deal with the intersection of pipelines as much as possible before construction.
4. Key points of GMP workshop construction
GMP regulations have been implemented for more than 20 years, and most of the key points of construction are clear to everyone. This article uses the engineering construction practice of a pharmaceutical preparation GMP workshop as a case to summarize the key points of construction that are easily overlooked.
4.1 Selection of sealant: GMP workshops have very high requirements for the airtightness of the room. If the construction unit is not careful, it will often confuse the difference between glass glue and sealant. As for sealant: it can fill the configuration gap, is an adhesive that can be sealed, can automatically deform with the shape of the sealing surface, and is not easy to flow out. The sealant has the functions of anti-leakage, waterproof, anti-vibration, sound insulation, heat insulation, etc., and has certain anti-aging properties. Glass glue: It is a commonly used adhesive in households. The main component is sodium silicate (Na2O·mSiO2), which is easily soluble in water, has viscosity, and has poor anti-aging properties. GMP workshop and clean room acceptance specifications require that for occasions with mildew prevention requirements, silicone and glass glue are not suitable for use. Neutral sealants are preferred, and appropriate amounts of antibacterial agents can also be added to them.
4.2 PVC floor construction: The pharmaceutical preparation GMP workshop is located on the first floor, so the floor of this area should be waterproofed before laying the PVC floor to prevent bubbling in the future; at the same time, before pasting the PVC roll floor, the floor should be tested on-site with a moisture content tester. The moisture content of the floor should be less than 4%. When the moisture content is between 4% and 7%, two-component glue should be used to paste the floor material. The moisture content shall not exceed 7%. If it exceeds 7%, it must be dried to ensure the pasting effect.
4.3 Insect and rodent prevention measures: The design and installation of GMP workshops and facilities should be able to effectively prevent insects or other animals from entering. Normally, protection should be provided from the following aspects:
4.3.1 The outer partition walls (including lightweight partition walls) of the GMP construction area should be partitioned to the top, and the holes of the pipes should be fireproof and sealed.
4.3.2 A 500mm high rodent-proof board should be installed at the entrance and exit of the GMP construction area.
4.3.3 The fresh air duct of the fresh air fan and constant temperature and humidity purification unit should be equipped with an electric sealing valve. The electric sealing valve and the equipment are linked. When the equipment stops running, the electric sealing valve of the fresh air duct is closed in time to prevent insects or other animals from entering the workshop through the fresh air unit and fresh air duct. This is a point that inspectors pay special attention to during the acceptance of GMP workshops.
4.3.4 A check valve is installed at the end of the exhaust fan pipe.
4.4 How to choose and install a hepa filter: It is mainly used to capture and collect dust, particles and suspended solids of 0.5um and above in size, and is generally used for filtering at the end of the filtration system. Usually, the filter material is made of ultra-fine glass fiber, the partition plate is folded with filter plate or offset paper, the seal is made of new polyurethane sealant, and the outer frame is made of stainless steel plate, galvanized plate, and aluminum alloy. The hepa filter is the core component of the GMP workshop purification system. Before installing the hepa filter, the entire air system needs to be air-blown for more than 48 hours. When installing the hepa filter, first check the integrity of the hepa filter, identify the airflow direction and front and back of the hepa filter, wear white gloves when installing, and install the air supply orifice plate in time after installing the hepa filter. In areas with higher purification requirements in GMP workshops, such as A and B levels, DOP liquid tank type hepa air filters are used, and the sealing is more reliable.
4.5 Installation of differential pressure gauge: Many people think that the more differential pressure gauges installed in GMP workshops, the better. In fact, installing too many differential pressure gauges is not very useful and wastes materials. As long as the differential pressure gauges are reasonably installed in key areas, such as between the clean area and the non-clean area; between the outdoor area and the first shift, between the dust exhaust room and the adjacent room, between different purification levels, etc. In terms of pressure difference, the pressure difference between different clean areas and between clean areas and non-clean areas should be above 10 Pascals. When purchasing a differential pressure gauge, you must buy a product from a regular manufacturer and within the effective calibration cycle. At the same time, after the installation is completed, the construction unit is required to calibrate it regularly.
4.6 Disinfection and exhaust method; cleaning and disinfection must be strictly operated in accordance with the process specifications. Usually more than one disinfectant is used for disinfection, and chemical disinfection is not replaced by ultraviolet disinfection. At present, the commonly used disinfection mode in GMP workshops is ozone disinfection, that is, adding an ozone generator disinfection section to the constant temperature and humidity purification unit. The ozone generator should be selected according to the volume of the GMP workshop and the length of the pipeline. At present, it is easy to overlook the control means of disinfection and the exhaust problem of disinfection in design and construction. If there is no normal exhaust treatment after disinfection, the ozone will slowly evaporate and dilute, which will delay a lot of time. At present, the more reasonable way is to make a bypass exhaust duct in the return air main of the air conditioning room and add an electric closed valve M1. When the room is normally supplied with air, the electric closed valve M1 is closed. In the disinfection mode, the electric closed valve M1 is opened, and the residual ozone is discharged through the exhaust duct.
4.7 Electrical installation: In terms of line aging, clean areas and non-clean areas, clean areas and contaminated areas, auxiliary work areas and main work areas, and lines with different process requirements should be laid separately. For the control cabinet, switch box and distribution cabinet of the clean room, embedded installation should be adopted, and the gap between it and the wall needs to be set with an airtight structure. As for the purification lamp, it also needs to be installed in an embedded or ceiling-mounted manner. All holes and lines that need to pass through the ceiling need to be sealed with neutral sealant. After the fire sprinkler head passes through the ceiling, a stainless steel decorative cover should be installed and sealed.
4.8 Automatic control system: For pressure transmitters, humidity transmitters, and temperature and humidity sensors, the position of the input variables needs to be truly reflected during installation, and direct airflow should be avoided at the air outlet. The bracket or sleeve should be selected according to the thickness of the insulation layer when inserting the temperature and humidity sensor into the air duct. Non-waterproof actuators installed outdoors should be protected by protective covers. When installing the electric proportional integral valve, the actuator and the valve body need to be perpendicular to the flow direction of the fluid in the pipe. At the same time, the water filter needs to be installed in the direction of the water flow, and the actuator needs to be installed above the valve body. The PLC automatic control programming system should be adjusted according to the actual needs of each GMP workshop and the teacher's functional requirements for automatic control.
4.9 Duct insulation: Condensation water is often found at the hanging holes and hanging rods of the hepa air outlet. This is caused by improper insulation treatment. In addition to doing a good job of insulation of the hepa air outlet, it is key to prevent cold bridges at the hanging holes and hanging rods of the hepa air outlet.
4.10 Comprehensive debugging: The cleanliness, pressure gradient, temperature and humidity of the GMP workshop are important indicators of the entire system. The maintenance structure, purification air conditioning system, and electrical automatic control system are independent and complementary, so when debugging, it is necessary to comprehensively consider the airtightness of the maintenance structure of the room, the airtightness of the air conditioning system, the rationality of the airflow organization, the accuracy of the automatic control components, and the logic of the PLC programming.
5. Conclusion
In summary, the key points are the key points that we have summarized based on long-term construction experience and are easily overlooked. They are also some inspection points that are often involved in the acceptance of GMP workshops. We hope these will be of some inspiration when building GMP workshops.