1. Definition of clean room (area)
A clean room (area) refers to a specially designed room that removes dust particles, microparticles, harmful air, bacteria, microorganisms and other pollutants in the air within a certain space, and controls the indoor temperature, cleanliness, indoor pressure, airflow speed and distribution, noise vibration, lighting, and static electricity within a certain required range. Its building structure, equipment and its functions all have the function of reducing the intervention, generation and retention of pollution sources in the room (area). Regardless of how the external air conditions change, the room can maintain the cleanliness, temperature, humidity and pressure and other properties originally set. For medical devices, clean rooms (areas) include clean production areas and clean inspection areas.
The standard "Sterile Medical Device Production Management Specification" (YY/T 0033-2000) has a clear definition of clean room (area), that is, the room (area) where the dust and microorganism content needs to be controlled, and its building structure, equipment and its function have the function of reducing the intervention, generation and retention of pollution sources in the room (area).
"Clean Room and Related Controlled Environment Part 1: Classification of Air Cleanliness Levels by Particle Concentration" (GB/T 25915.1-2021) stipulates that a clean room refers to a room where the concentration of airborne particles is controlled and graded, and its design, construction and operation all control the particles entering, generated and retained in the room. A clean area refers to a confined space where the count concentration of airborne particles is controlled and graded. Its construction and operation control the particles entering, generated and retained in the space. A clean area can be a space confined to a clean room, or it can be realized by an isolation device. The isolation device can be located either inside or outside the clean room.
2. Intended use of clean rooms (areas)
The main function of clean rooms (areas) is to control the cleanliness, temperature and humidity of the atmosphere that the product is exposed to, so that the product can be produced, manufactured and tested for microorganisms in a good environment. We call this space a clean room (area).
3. Applicable products for clean rooms (areas)
(i) Applicable to the production of medical devices and in vitro diagnostic reagents that are free of any living microorganisms through terminal sterilization methods and aseptic processing technology, such as intravascular stents, orthopedic implants, in vitro diagnostic reagents, interventional surgical instruments, etc.
(ii) Medical device varieties that need to control initial contamination bacteria, such as dialysis powder (liquid), etc.
(iii) Single packaging that is in direct contact with the product.
4. Composition of clean room (area)
Generally speaking, clean room (area) refers to the working environment required for the production and inspection of medical devices. For the production link, it should include functional rooms corresponding to the production process of the product, such as injection molding room, drying room, etc.; for the inspection link, it should include functional rooms related to inspection, such as positive control room, sterile inspection room and microbial limit room, etc.; auxiliary functional rooms serving production, such as laundry room, sanitary ware room, etc., and buffer transition channels connecting various functional rooms.
5. Cleanliness level and setting principles of clean rooms (areas)
(I) Cleanliness level
Cleanliness: The allowable statistical number of suspended particles greater than or equal to a certain particle size in a unit volume of air in a clean environment.
According to the "Management Specifications for the Production of Sterile Medical Devices" (YY/T 0033-2000), the environmental levels of clean rooms (areas) are divided into 300,000, 100,000, 10,000, 1000 and 100.
Table 1 Air cleanliness levels in the "Sterile Medical Device Production Management Specification" (YY/T 0033-2000)
|
Cleanliness level |
Maximum allowable dust（Piece/m3） |
Maximum number of microorganisms allowed |
||
|
≥0.5μm |
≥5μm |
Settling bacteria （Piece/dish） |
Planktonic bacteria （Piece/m3） |
|
|
Class100 |
3,500 |
0 |
1 |
5 |
|
Class10,000 |
350,000 |
2，000 |
3 |
100 |
|
Class100,000 |
3,500,000 |
20，000 |
10 |
500 |
|
Class300,000 |
10,500,000 |
≤60，000 |
15 |
—— |
The "Pharmaceutical Industry Cleanroom Design Standard" (GB 50457-2019) also makes relevant provisions on cleanliness levels.
II) Setting principles
In addition to the above standards, the "Appendix to the Good Manufacturing Practice for Medical Devices: Sterile Medical Devices" and "Appendix to the Good Manufacturing Practice for Medical Devices: Implantable Medical Devices" issued by the former State Food and Drug Administration in 2015 respectively stipulate the setting principles for clean rooms (areas) for sterile medical devices and clean rooms (areas) for implantable medical devices. The "Appendix to the Good Manufacturing Practice for Medical Devices: In Vitro Diagnostic Reagents" also stipulates the requirements for the production environment level of the corresponding products. Manufacturers should identify and determine the clean environment level of their own enterprises in combination with the requirements of the corresponding regulations and technical standards, and implement them after verification. If there are no provisions in the medical device regulations and standards, manufacturers can refer to the above requirements to determine the production cleanliness level of the product, or verify and determine the production cleanliness level of the product by themselves.
Principles for setting the cleanliness level of clean rooms (areas):
1. Use production technology that minimizes contamination to ensure that medical devices are not contaminated or can effectively eliminate contamination. Advocate technological progress and recommend the use of advanced production technology. Including advanced production processes, advanced equipment, tooling and facilities. Minimize human factors in the production process, minimize the exposure of products to the operating environment, and avoid direct contact between people and products as much as possible.
2. For implanted and intervening intravascular devices, the processing, final cleaning, assembly, initial packaging and sealing of uncleaned parts shall not be lower than Class 10,000. For devices implanted in human tissues, directly or indirectly in contact with blood, bone cavities or non-natural cavities, the processing, final cleaning, assembly, initial packaging and sealing of (uncleaned) parts shall not be lower than Class 100,000. For devices in contact with damaged surfaces and mucous membranes of the human body, the processing, final fine cleaning, assembly, initial packaging and sealing of (uncleaned) parts shall not be lower than Class 300,000.
The primary packaging materials that are in direct contact with the use surface of sterile medical devices and are used without cleaning should follow the same principle as the cleanliness level of the product production environment, so that the quality of the primary packaging materials meets the requirements of the sterile medical devices being packaged. If the primary packaging materials are not in direct contact with the use surface of sterile medical devices, they should not be lower than Class 300,000. For those with requirements or aseptic operation technology processing, they should be in a local Class 100 clean room (area) under Class 10,000. The air cleanliness level of the area for washing, drying and wearing clean work clothes, and the final cleaning and disinfection of special workstations and equipment can be one level lower than the production area.
Medical device regulations stipulate that the operation of high-risk biologically active materials (such as highly toxic microorganisms, spore products, hormone reagent components, and radioactive substances) should use a separate air purification system, maintain negative pressure with adjacent areas, and the exhaust air should not be recycled; the handling of negative and positive serum, plasmids or blood products should be carried out in an environment of at least Class 10,000, maintain a relative negative pressure with adjacent areas, and comply with protection regulations; the clean environment for the production of hormone reagent components should use an independent dedicated air purification system, and the purified air shall not be recycled; the highly toxic microorganism operation area and the spore product operation area shall maintain a relative negative pressure with adjacent areas, be equipped with an independent air purification system, and the exhaust air shall not be recycled. The process steps of liquid preparation, coating, packaging, film application, drying, cutting, film sticking, and inner packaging of products such as enzyme-linked immunosorbent assay reagents, immunofluorescence reagents, immunoluminescence reagents, polymerase chain reaction (PCR) reagents, gold label reagents, dry chemical reagents, cell culture media, calibrators and quality control products, enzymes, antigens, antibodies and other active components must be verified on site and must be performed in a clean environment of at least Class 100,000. The packaging of sterile materials must be carried out in a local clean environment of Class 100.
VII. Main factors affecting the cleanliness of clean rooms (areas)
(I) Characteristics of medical device products
(II) Production process of medical devices
(III) Hygiene requirements for personnel and facilities
Contamination due to bacteria carried by patients or staff themselves or due to contact with non-completely sterile utensils, equipment and people.
(IV) Atmospheric environment
Contamination due to the sedimentation, attachment or inhalation of bacteria contained in the air.
(V) Others
Contamination due to other factors such as insects may also produce toxic substances, pigments and other metabolites.
