Clean Room Design of Pharmaceutical Plant under GMP Standard

Clean room is the product of the development of modern science and technology, it will be a specific space in the air of dust, particles, harmful air, bacteria and other pollutants out, and the indoor temperature, humidity, cleanliness control within a certain range of special environment. Since the development of the 1960s, clean rooms have been widely used in pharmaceutical biology, electronic information, aerospace, precision instruments and other industries. These industries rely on clean rooms to ensure product quality and safety by minimizing environmental contaminants and maintaining precise cleaning standards. According to the main control objects of the clean room, the clean room can be divided into: biological clean room and industrial clean room. The industrial clean room is to control the pollution of non-biological particles as the main task, while the biological clean room is to control the pollution of biological particles.

Biopharmaceutical clean room is a key link in the biopharmaceutical industry and plays an important role in biopharmaceutical, and the strict control of its environment is directly related to drug quality and production efficiency. Strict regulations drive clean room technology and ensure a sterile environment for the safe production of drugs. When we are engaged in the biopharmaceutical industry, the whole process of production usually must meet the Good Manufacturing Practice (GMP) to ensure the quality of the product. GMP standards are designed to minimize the risk of contamination, cross-contamination, confusion, and errors during the manufacturing of pharmaceutical products. GMP standards cover the selection of raw materials, production processes, equipment and facilities, product quality control and other production links.

In general, biopharmaceutical workshop clean areas will be divided into different levels according to GMP standards, for different levels of clean areas, there are specific and strict requirements, these requirements cover a number of aspects, including suspended particles, fallout bacteria, floating bacteria and surface microorganisms limit standards. These standards are not only the basis for the development of cleaning and disinfection procedures, but also an important reference for evaluating the effectiveness of cleaning and disinfection, ensuring that the drug production environment continues to meet the cleanliness standards, and ensuring product quality and safety.

(1) Classification and standards of clean areas

The classification of cleanliness level is mainly based on the number of particles in the air and the cleanliness of the air. Particulate matter: GMP provides for strict control of airborne particulate matter in clean areas. According to the production process and quality requirements of drugs, clean areas are usually divided into four levels: A, B, C, and D. Different levels of clean zones have strict regulations on the number of particles in the air, microbial limits, temperature, humidity and pressure differences. Class A clean area: for high-risk operation areas, such as filling areas, areas where plastic plug buckets are placed and open packaging containers in direct contact with sterile preparations, and areas where sterile assembly or connection operations are performed, unidirectional flow operating stations (covers) are usually used to maintain the environmental status of the area.

Class B clean area: refers to the background area of Class A clean area for high-risk operations such as aseptic preparation and filling. Class C clean area and Class D clean area: They are clean operating areas of low importance in the production process of sterile drugs. In terms of specific values, Class A zones may require the concentration of suspended particles to reach the level of "class 100" (that is, the number of suspended particles per cubic meter of air does not exceed a certain number, such as the number of particles of certain sizes under the ISO 4.8 standard), while Class B, C, and D zones will be relaxed in turn.

Sedimentation bacteria: Sedimentation bacteria are microorganisms that can settle on the ground or surface of objects. GMP also has a clear limit on the number of settling bacteria in the clean area. The tolerance of sedimentation bacteria is different in areas of different clean levels, and the requirements of high-level areas are more stringent. For example, under some GMP standards, the number of settling-bacteria in A Class A area may be required to be extremely low or even close to sterile; Although the requirements of the D-level area are relatively low, they still need to be controlled within a certain range.

Planktonic bacteria: Planktonic bacteria are microorganisms suspended in the air. GMP also regulates the amount of bacteria floating in clean areas. Similar to settling bacteria, the tolerance of floating bacteria varies in areas with different cleanliness levels. The monitoring and control of phytoplankton is important for assessing the sterility of clean zones because the presence of phytoplankton may directly threaten the sterility of products.

Surface microorganisms: GMP also specifies microbial limits for surfaces (such as equipment, walls, floors, etc.) in clean areas. These surfaces are important places where microbes can breed and spread, so they must be cleaned and disinfected regularly. Microbiological monitoring of surfaces in clean areas usually includes sampling and culture using contact dish method, cotton swab wiping method and other methods to assess the microbial contamination status of the surface.

Biosafety laboratories

Biosafety laboratories are biological laboratories and animal laboratories that achieve biosafety requirements through protective barriers and management measures to avoid or control the harm of harmful biological factors that are operated. As an important application field of biological clean room, biosafety laboratory has more stringent requirements for the control of particles and microorganisms in clean space. Compared with ordinary biological clean room, biosafety laboratory adopts negative pressure structure, and has more stringent requirements for cleanliness, minimum air changes, temperature, humidity and other indicators.

we can choose different levels of biopharmaceutical clean workshops according to different production needs. The following is the requirement of GMP cleanliness level for clean areas of various common biopharmaceutical workshops:

• Aseptic production workshop: aseptic production workshop is used to produce sterile drugs, such as injections, eye drops, etc. Under GMP regulations, clean areas in such workshops need to meet the highest level of cleanliness, usually GMP Class A.

• Biologics workshop: Biologics workshop is used to produce biological drugs, such as antibody drugs, vaccines, etc. The cleanliness level requirements for clean areas in such workshops may vary depending on the production process, but are usually required to achieve at least GMP Class B.

• Cell culture workshops: Cell culture workshops are used for cell culture-related operations such as cell isolation, cell culture, cell freezing, etc. The cleanliness level requirements for clean areas in such workshops may vary depending on the operation, but are usually required to achieve at least GMP Class C.

 

• Hazardous substance treatment workshop: hazardous substance treatment workshop is used to deal with hazardous substances, such as radioactive substances, toxic drugs, etc. The requirements for the cleanliness level of the clean area in such workshops may vary depending on the hazard of the substance and the handling process, but usually at least GMP level D is required.

(2) Environmental requirements for clean areas

Environmental control is the first line of defense for microbial prevention and control. Precise temperature and humidity control, efficient ventilation systems and advanced air purification equipment can significantly reduce the number of microorganisms in GMP workshops. In addition, regular cleaning and deep cleaning of the workshop is also an essential link. For example, microorganisms in the air can enter the workshop through the ventilation system and attach to the surface of the equipment and products. Strict control of temperature, humidity and differential pressure.

• Temperature: The appropriate temperature range can ensure the stability of the material and the comfort of the operator during the production process, generally controlled at 18-26 ℃.

• Humidity: Relative humidity is usually controlled at 45%-65% to prevent microbial growth and material moisture absorption.

• Pressure difference: An appropriate pressure difference should be maintained between areas of different cleanliness levels to prevent contamination and cross-contamination. In general, the pressure difference between the clean area and the unclean area should be no less than 10 pascals, and the pressure difference between adjacent clean areas of different levels should be no less than 5 pascals.

• Air quality and particulate monitoring

• Air quality: The number of microorganisms and dust particles in the air should be regularly tested to ensure that they meet the requirements of the corresponding cleanliness level.

• Particulate monitoring: Using appropriate monitoring equipment and methods, real-time monitoring of the size and number of particles in the air, and analysis and evaluation of monitoring data.

The inner surface of the clean room (area) shall meet the following standards:

• Flat and smooth: the inner surface must be flat and smooth, without cracks and particles falling off.

• Tight interface: The interface should be tight to prevent the entry of pollutants.

• Resistant to cleaning and disinfection: The material must be able to withstand frequent cleaning and disinfection.

• Curved design: the boundary between the wall and the floor should be curved, or other measures should be taken to reduce accumulation and facilitate cleaning.

• Lighting: the illuminance of the clean area should not be less than 300 lux, and local lighting can be set up in the production parts with special requirements

As an internationally accepted quality management standard for drug production, GMP puts forward clear requirements for the environmental management of clean areas in pharmaceutical factories. For pharmaceutical enterprises, meeting the requirements of GMP is an inevitable choice to ensure the quality of drugs. With the continuous progress of technology and the continuous demand of the market, GMP purification project will certainly show a series of new development trends.

In the future, GMP purification project will pay more attention to intelligent, green environmental protection and global cooperation, and the market scale will be further expanded to provide a more efficient, safe and environmentally friendly production environment for pharmaceutical, food and other industries. First, technology integration and intelligence, clean workshop will be deeply integrated with the Internet of Things, big data, artificial intelligence and other technologies, to achieve real-time monitoring of environmental parameters, automatic control, fault warning and other functions, improve production efficiency and quality control level. With the opening of the global pharmaceutical and medical device markets, the design, construction and operation of GMP clean workshops will be more compliant with international standards, such as ISO, FDA, etc., to meet the needs of transnational production and export certification. Third, green building and sustainable development, clean workshops will use energy saving, water saving, emission reduction, renewable materials and other green building technologies to reduce energy consumption, reduce environmental pollution, and achieve sustainable development. Fourth, service model innovation and industry chain integration, clean workshop providers will provide one-stop services from design, construction, verification, operation and maintenance to training, consulting, at the same time, with upstream equipment suppliers, downstream production enterprises to establish close cooperation, the formation of industrial chain synergies, enhance the overall competitiveness of the industry.