Medical Device Clean Room (Area) Inspection Guide

Cleanrooms are vital for producing sterile medical devices, impacting product quality. This guide assists regulators in understanding and inspecting cleanroom processes, based on current regulations, and provides management references for manufacturers. It emphasizes compliance during inspections.

Inspection points and procedures

1. On-site observation of the company's production and inspection of the clean room (area) environment

(1) Whether the flow of people and logistics in the clean room (area) intersects

(2) Whether shoes are changed, outer clothes are taken off, and hands are washed when entering the first shift, whether induction faucets, long-handled faucets, or foot-operated faucets are installed, whether dryers are installed, whether door stops and anti-insect facilities are installed, and whether hand washing procedures are posted.

(3) Whether clean work clothes (shoes) or sterile work clothes (shoes), masks, hats, and hand disinfection are worn when entering the second shift. Whether hand disinfectants are replaced regularly to prevent the generation of drug-resistant bacteria.

(4) Whether the second shift is equipped with a dressing mirror and facilities for wearing clean work clothes or sterile work clothes, and whether the changing process is posted. Whether storage and hanging facilities are set up. Are there any anti-pollution measures for the clean work clothes and work hats temporarily stored in the second shift? Do the clean work clothes and work hats effectively cover underwear and hair? For sterile work clothes, can they also cover the feet and block human body debris? Are the shoes used in the first shift effectively separated from the shoes used in the clean room (area)? 

(5) Is there a buffer room or air shower? If there are more than 5 staff in the clean room (area), is there a bypass door next to the air shower? Are there any measures to prevent the doors of the air shower from being opened at the same time?

(6) Do the staff in the clean room (area) wear slippers, put on makeup, wear accessories, etc., and do they bring personal items into the clean room (area)?

(7) Are there any auxiliary function rooms such as sanitary ware rooms, laundry rooms, workstation equipment rooms, and intermediate warehouses in the clean room (area)? Is there a clothes drying area in the laundry room? 

(8) Whether the necessary water pipes and pools are set up in the sanitary ware room, laundry room, workstation tool room and functional room that needs to use process water, and whether the type and flow direction of process water are marked. Whether floor drains are set up (floor drains should not be set up in clean rooms (areas) of Class 10,000 and above), and whether the floor drains have anti-backflow measures. Whether the floor drains are cleaned and disinfected in time.

(9) Whether special functional rooms or areas corresponding to the product production process are set up, such as injection molding room, drying room, etc., whether the supply and return air management and configuration equipment meet the requirements of regulations and standards and process requirements, and whether a buffer or airlock room is set up when necessary. Whether a mold storage area is set up in the injection molding room, and effective protective measures are taken.

(10) Whether a material entrance is set up, whether an air shower or transfer window is used at the entrance, whether purification treatment is carried out, whether there are measures to prevent windows from being opened at the same time, and whether the doors and windows are well sealed.

(11) Whether an independent finished product exit is set up in the clean room (area).

(12) For manufacturers of sterile and implantable medical devices, for newly built laboratories, whether the manufacturer has established a sterile test room, a microbial limit room and a positive control room with a local level of 100 under 10,000 (including relatively independent flow of people and logistics). 

(13) Whether the walls, floors and ceilings of the clean room (area) are flat, smooth, and free of cracks and marks; whether the interfaces are tight, free of particles from falling off, not prone to dust accumulation, easy to clean, and resistant to cleaning and disinfection. Whether the pipes and wall facilities in the clean room (area) are sealed at the contact points with the walls or ceilings.

(14) Whether cleaning and sanitation tools that do not fall off, are easy to clean and disinfect are used in the clean room (area).

(15) Whether the doors between functional rooms of different cleanliness levels in the clean room (area) are opened in the direction of the higher cleanliness level, and whether the doors are well sealed. Whether the return air outlet in the clean room (area) is blocked:

(16) Whether a safety door is installed in the clean room (area) and whether there are knocking tools.

(17) Whether painted or wooden items are used in the clean room (area). Whether the operating table is smooth, flat, free of gaps, free of dust particles and fibers, not prone to dust accumulation, and easy to clean and disinfect. 

(18) Whether a differential pressure gauge is installed between adjacent functional rooms of different clean levels, and whether the differential pressure gauge is affixed with a calibration mark. Whether the accuracy of the differential pressure gauge meets the requirements. Whether the differential pressure gradient between clean rooms (areas) of the same cleanliness level is reasonable.

(19) Whether the thermometer and hygrometer are reasonably installed in the clean room (area), and whether the calibration mark is affixed. 

(20) Whether an air disinfection device is installed in the clean room (area), such as an ultraviolet lamp, and whether a main switch is installed. Whether the ultraviolet lamp tube is replaced regularly.

(21) If the product production process requires the use of process gas, whether a process gas channel is installed, whether the process gas channel is equipped with a purification treatment device, and whether the air compressor can be effectively protected.

(22) If a special production process in the clean room (area) requires a Class 100 clean environment, whether it is equipped with laminar flow hoods, clean workbenches and other equipment. Whether the treatment of in vitro diagnostic reagent positive substances is carried out in a positive room under a Class 10,000 environment and equipped with a biosafety cabinet. Whether the positive room is equipped with inactivation facilities and in-situ disinfection facilities. 

(23) Whether the clean room (area) environmental monitoring equipment and supporting experimental equipment are configured, such as dust particle counters, air volume hoods or anemometers, and incubators (culturing bacteria or fungi, toxins) and culture dishes for sedimentation bacteria or floating bacteria detection, and reagents used for preparation, etc.

(24) Whether the air conditioning unit is set up reasonably, whether the differential pressure gauge is calibrated, and whether the initial and intermediate positions and airflow direction are marked. Whether an ozone generator is configured for environmental disinfection using ozone. For drying requirements, whether dehumidification equipment is configured.

(25) Whether the material transfer between areas with different air cleanliness levels is carried out in sections when a conveyor belt is used.

2. Review the relevant management documents and records of the company's clean room (area)

(1) Whether the floor plan of the clean room (area) is provided, whether it is consistent with the actual situation, whether the clean environment corresponding to different products and different processes is marked, and whether the intersection of human and material flows is avoided.

(2) Whether personnel hygiene management regulations have been formulated.

(3) Whether the records of staff entering and leaving the clean room (area) are provided, and whether personnel registration records are provided when outsiders inspect or visit.

(4) Whether the regular physical examination certificate of clean room (area) staff issued by a third-party physical examination agency is provided to control the entry of special disease personnel into the clean room (area) and direct contact with product elements

(5) Whether the hand disinfection record of clean room (area) staff is provided.

(6) Whether the detection record of the total number of bacteria on the hands of clean room (area) staff is provided.

(7) Whether the staff in the clean room (area) have been trained in microbiological knowledge and other aspects, and whether the training records are kept.

(8) Whether material purification management regulations have been formulated.

(9) Have clean (sterile) work clothes management regulations been formulated?

(10) Have records of cleaning, disinfection and sterilization of clean (sterile) work clothes been provided?

(11) Have clean room (area) hygiene management regulations been formulated, including equipment, tooling and molds, and workstation equipment cleaning and storage regulations; operating table, site, wall, ceiling cleaning regulations and cleaning and storage regulations for cleaning tools; management regulations for the selection and use of disinfectants; air disinfection regulations; site clearance management regulations and daily monitoring management regulations for clean environments, etc.

(12) Have records of cleaning, disinfection and sterilization of workstation equipment been provided?

(13) Have clean room (area) hygiene cleaning records been provided？

(14) Whether the clean room (area) air disinfection record is provided？

(15) If ultraviolet lamps are used for clean environment disinfection, whether the use record of the case line lamp is provided？

(16) Whether the clean environment clearing record is provided？

(17) Whether the clean room (area) sedimentation bacteria (or floating bacteria) monitoring point map is provided？

(18) Whether the daily monitoring record of the clean environment is provided？

(19) If the air conditioning system is not turned on continuously, whether the air conditioning system switching time and the clean room (area) use time are recorded.

(20) Whether the process gas detection record is provided？

(21) Whether the monitoring record of the third-party inspection agency of the clean environment and the measurement certificate of the testing equipment are provided.

(22) Whether the maintenance records such as the mid-efficiency cleaning, high-efficiency replacement, and pressure difference monitoring of the air conditioning unit are provided.

References

1. Definition of clean room (area)

A CleanRoom is a specially designed space that controls dust, microbes, temperature, and pressure to minimize pollutants. Defined in regulations, it ensures a controlled environment for producing and inspecting medical devices, maintaining cleanliness regardless of external conditions.

2. Intended use of clean rooms (areas)

The main function of A Clean Room (area) is to control the cleanliness, temperature and humidity of the atmosphere to which the product is exposed, 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. Products applicable to clean rooms (areas)

• Applicable to the production of medical devices and in vitro diagnostic reagents that are free of any viable microorganisms through terminal sterilization methods and aseptic processing technology. Such as intravascular stents, orthopedic implants, in vitro diagnostic reagents, etc.

• Medical device varieties that need to control initial contamination bacteria, such as dialysis powder (liquid), etc.

• Single packaging 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 transition passages connecting various functional rooms.

5. Cleanliness level and setting principles of clean room (area)

a. Cleanliness level

Cleanliness: the allowable statistical number of suspended particles greater than or equal to a certain particle size per unit volume of air in a clean environment.

According to the "Sterile Medical Device Production Management Specification" (YY0033-2000) standard, the environmental levels of clean rooms (areas) are divided into Class 300,000, Class 100,000, Class 10,000 and Class 100.

b. Setting principles

The "Medical Device Production Quality Management Standards" (Trial) from 2009 outlines clean room requirements for implantable and sterile medical devices. Manufacturers must determine and verify their clean environment levels based on these standards and regulatory guidelines.

To minimize contamination, manufacturers should employ advanced production technologies and processes. Reducing human interaction with products is essential, aiming to limit exposure to the operating environment and avoid direct contact whenever possible.

Implantable devices require processing in Class 10,000 environments, while those in contact with tissues need Class 100,000. Packaging materials must match the cleanliness of the production environment or meet at least Class 300,000 standards if not directly contacting sterile devices.

Sterile laboratories should consist of three Class 100 Clean rooms under a Class 10,000 standard. These labs need independent air systems and logistics. Signage at clean room entrances should detail the layout, environmental control levels, and personnel pathways.

Clean room (area) management requirements

1. General requirements for clean rooms (areas)

Sterile medical devices and diagnostic reagents should be produced in environments with fresh air, low dust, and minimal bacteria. Avoid locations with wind, sand, or industrial pollution, and select sites upwind from pollution sources. Clean rooms need to be distanced from railways and highways.

Clean room layouts should minimize human and material movement, with higher cleanliness areas receiving clean air first. Pollution-prone processes should be near exhaust vents, and only essential, non-dust-generating equipment should remain inside the clean rooms.

Manufacturers must ensure a clean production environment with suitable facilities and smooth, easy-to-clean equipment surfaces. Disinfectants should be rotated to prevent resistance, aligning with the "Sterile Medical Device Production Management Specification" (YY0033-2000) for effective pollution control.

2. Design and decoration requirements for clean rooms (areas) This part is not the focus of this guide. Manufacturers should choose units with clean room (area) design qualifications and legal construction units to build Clean Rooms (areas). For details, please refer to the "Cleanroom design Specification" (GB50073-2001), "Cleanroom Construction and Acceptance Specification" (GB50591-2010), "Pharmaceutical Process Cleanroom Design Specification" (GB 50457-2008) and "Sterile Medical Device County Production Management Specification" (Y0033-2000). Pay attention to identifying the requirements of regulations for clean room (area) design and decoration.

3. Clean room (area) environmental control requirements

The air purification process involves several key aspects:

①Filtration

Filters control the cleanliness of air entering the room, effectively removing bacteria that attach to particles.

②Airflow Management

Proper airflow helps eliminate existing pollutants, diluting particles and bacteria with clean air, which then enters the return air duct and is mixed with filtered outdoor air before re-entering the room. This cycle maintains pollution at stable levels below the cleanliness standard.

③Air Pressure Control

Maintaining a static air pressure greater than 5 Pa (and over 10 Pa compared to the outdoor atmosphere) in clean rooms prevents external pollution and cross-contamination.

Control Requirements for Clean Room Environments：

According to the "Sterile Medical Device Production Management Specification" (YY0033-2000), sterile devices and packaging must be produced in designated clean areas. The clean room's design should minimize sources of pollution and control dust, as even small amounts can lead to serious health issues.

When designing clean rooms, it’s vital to regulate particle-generating elements, manage air quality, and establish separate pathways for personnel and materials to limit contamination.

In addition to dust control, there must be strict regulations regarding active microorganisms, as they pose a greater risk to human health. These microorganisms can proliferate under suitable conditions, making their management especially challenging.

To effectively control dust and microbial contamination, four principles should be followed:

• Ensure air entering the clean room is fully sterilized.

• Rapidly absorb and expel indoor microbial particles.

• Prevent the accumulation and reproduction of these particles.

• Limit the spread of bacteria from people or objects entering the room.

For example, human activities can generate millions of particles, highlighting the need for strict management and effective dust removal and sterilization technologies. Controlling cross-contamination from human movement and production processes is essential for maintaining clean room standards.

Pressure difference control of clean room (area)

In order to prevent external pollutants from entering the clean room (area) with air from the doors and windows of the enclosure structure or other gaps, and to prevent air from flowing back from the low clean room (area) to the high clean room (area) when the door is opened, the air in the clean room (area) must be kept higher than the static pressure value of the adjacent area. This is another important measure in air purification. The positive pressure of the clean room (area) is achieved by making the air supply volume of the purification system greater than the return air volume and exhaust air volume. The air volume required to maintain the positive pressure of the clean room (area) should be determined according to the sealing performance of the clean room (area). 

Airflow organization form and ventilation requirements of clean room (area)

Airflow organization refers to creating specific airflow patterns indoors. It minimizes vortices and aims for uniform dust distribution by efficiently directing clean air to working areas and removing contaminants. Clean rooms use either non-laminar (turbulent) or laminar flow methods for effective purification.

Air purification in clean rooms (areas)

Air Purification Measures

Cleanrooms control air pollution through three main methods: air filtration, airflow organization, and indoor air pressure management to ensure air cleanliness meets production requirements.

Environmental Control

cleanroom air must meet cleanliness, temperature (18-28°C), and humidity (45-65%) requirements. The fresh air ratio should be at least 15%, adjustable based on regional needs.

Filtration System Design

Air purification systems use a three-level filtration process (primary, medium, high-efficiency filters), with additional filters for higher cleanliness levels, ensuring optimal air quality in cleanrooms.

Disinfection control requirements for clean rooms (areas)

The clean rooms (areas) used for medical device production are different from other industrial clean rooms (areas). The disinfection methods for clean rooms (areas) should be determined according to the process flow of different products and the risk control requirements for the products. Especially in the aseptic operation production process, it is necessary not only to control the floating particles in the air, but also to control the number of active microorganisms, that is, to provide the so-called "aseptic operation" environment. 

"Aseptic" is relative, indicated by aseptic assurance levels. Microbial particles can exist in clean rooms, necessitating regular disinfection and sterilization of surfaces, personnel, and materials using methods like UV light, ozone, and peroxyacetic acid to eliminate contamination effectively.

1. Ultraviolet light sterilization

Ultraviolet sterilization lamps are widely used by manufacturers. They are mainly used for disinfection of clean workbenches, laminar flow hoods, material transfer windows, air showers and even the entire clean room. When the ultraviolet wavelength is 136~390nm, the bactericidal power of 253nm is the strongest, but the ultraviolet penetration is extremely weak and there is a dead angle for irradiation, which is only suitable for surface sterilization. Generally speaking, the life of domestic ultraviolet lamps is 2000 hours.

2. Ozone disinfection

Ozone, found in nature, disinfects by decomposing into oxygen and reactive oxygen atoms, which effectively kill bacteria by damaging their cell membranes. Ozone generators must be calibrated for output, concentration, and timing to verify disinfection effectiveness.

3. Gas sterilization

Traditional air sterilization involves using disinfectants like formaldehyde to produce gas fumigation. Formaldehyde is most effective at 65% humidity and 24-40°C. However, it can precipitate white powder and is harmful, requiring careful ventilation and monitoring post-disinfection.

4. Disinfectant fire bacteria

The walls, ceilings, doors, windows, machinery and equipment, instruments, operating tables, carts, tables, chairs and other surfaces of clean rooms (areas) and human hands should be cleaned regularly and sprayed with disinfectants during daily production. Common disinfectants include propanol (75%), hexanol (75%), glutaraldehyde, and chlorhexidine. The spraying method is to put the disinfectant in an automatic sprayer with time control, and spray it after get off work or on weekends when no one is in the room. The spraying amount and spraying time can be set, and the air conditioning system should stop working during the spraying period. 

Drainage control requirements for clean rooms (areas)

1. The clean room drainage system quickly discharges sewage while preventing harmful gases and pests from entering. It manages domestic sewage and production wastewater, adhering to regulations by minimizing water buckets and floor drains.

2. The parts below the discharge outlet of equipment, cleaning utensils and drainage equipment connected to the sewer pipe in the clean room (area) must be designed as water bends or water seal devices.

3. The floor drain in the clean room (area) requires the inner surface of the material to be smooth, not easy to corrode, not easy to scale, with a sealing cover, easy to open, and can prevent the backflow of wastewater and waste gas. If necessary, it should be disinfected and sterilized with disinfectants according to the product process requirements, so as to better prevent pollution.

4. Acid and alkali cleaning wastewater generated in production should also be equipped with special pipelines, and should be led to the acid treatment device through corrosion-resistant stainless steel pipes, PVC plastic pipes or ABS engineering plastic pipes.