Medical and Pharmaceutical USP800 Cleanroom Guidance

All About the USP800 Clean Room

1.What is USP 800 clean room?

USP General Chapter <800> of United State Pharmacopoeia (USP) provides standards for safe handling of hazardous drugs at multiple stages, including delivery, storage, preparation, distribution, and management. Dangerous drugs include those used in chemotherapy, immunosuppressants, bioengineered drugs, hormone therapy, etc. USP800 Clean rooms minimize the risk of exposure to healthcare personnel, patients and the environment.

2.What are the requirements of the USP800 clean rooms construction?
â–ºSafety: The clean room design and construction shall follow the principle of security to ensure structural safety, equipment operation safety and operators safety. For the possible risk factors, safety measures should be taken to protect personnel and property safety.
â–ºFunctionality: The clean room design and construction shall meet the requirements of intended usage, including process, equipment layout, logistics and personnel traffic flow, etc. At the same time, attention should be paid to the improvement of space utilization rate and operation convenience.
â–ºCost-efficiency: Under the premise of meeting the safety and functionality, the cost-efficiency should be considered in the clean room design and construction. Reasonable design can reduce the construction cost, improve the operation efficiency, and realize sustainable economic development.
â–ºSustainability: The clean room design and construction should focus on green, environmental protection and sustainability., by selection of environmentally friendly materials, energy-saving equipment, rational design of HVAC system to reduce energy consumption. At the same time, the coordination between the building and the environment should be fully considered to lay the foundation for the creation of a comfortable and healthy clean environment.
â–ºSite selection and layout: The clean room should be located with convenient transportation, away from the source of pollution. The layout should be reasonably arranged according to the intended use, process and logistics organization and other factors. The common layout is linear, surround and honeycomb type.
â–ºAir cleanliness control: The principle of separating personnel flow and logistics is adopted to reduce experimental pollution and ensure safety. The layout should be compact and reasonable, meeting the requirements of laboratory operation and air cleanliness class, and striving for scientific and economic principles.
â–ºAir filtration and purification: The clean room needs to be supplied a certain proportion of fresh air after purification and filtration, to compensate the exhaust airflow, ensuring positive pressure and personnel needs. The air volume regulating valve is used for maintaining designed clean class and adjusting the pressure gradient so so as ensure the air flows from the "clean" area to the "polluted" area.
â–ºSterilization and disinfection: The clean room is equipped with UV sterilization lamp to reduce the risk of microbial contamination.
â–ºPass through box and view window: Pass through box is made of full stainless steel, with mechanical interlock and internal sterilization device. The view windows are flush mounted with high sealing performance while the cleanroom doors are also airtight to ensure the cleanliness class of the internal environment.
â–ºNoise control: The indoor noise should be less than 60 db (A) to ensure the proper working environment.
â–ºDesign of exhaust outlet: The exhaust outlet is equipped with HEPA filter so as to make sure the exhausted air are purified before getting out.

3.How to design USP800 clean room?
â–ºClean room classification: According to the requirements of USP800, the clean room shall be divided into different areas, including high-risk operation area, general operation area, etc., in order to ensure the cleanliness and safety of the pharmaceutical production process.
â–ºAir filtration and air supply system: the air supply passes through at least three-stage filtration (primary, medium and HEPA filter), and the HEPA filter shall be set at the terminal of the system. The clean room should have sufficient air supply volume after purification and air conditioning maintaining the necessary pressure gradient (negative pressure gradient), and reasonable airflow distribution.
►Temperature and humidity control: Maintain an appropriate range of indoor temperature and humidity in accordance with the requirements of USP800. The temperature is usually at 18~25℃, and the relative humidity is usually at 40~65%;
â–ºPressure control and airflow distribution: The pressure of the USP800 clean room needs to be at least -5Pa lower than the adjacent room, (-0.5mm water column), and the airflow direction of USP800 clean room should be designed as top-supply-bottom-exhaust.
â–ºDesign of the number of air changes and cleanliness class: The clean class of the USP800 clean room should not be less than ISO 7, and the conventional air changes should not be less than 30 times / H;
â–ºBiosafety cabinet class requirements: BSC or CACI Class II 
â–ºThrough the implementation of the steps and principles above, it can be ensured that the design of USP800 clean room meets the needs of pharmaceutical production and experiments, and ensures the quality and safety of drugs.

Typical floor plan of the USP-800 clean room
 

Typical elevation of the USP-800 clean room

4.What are the design requirements of USP 800 clean room HVAC system?
The design requirements of the ‌USP800 clean room HVAC system mainly include high air exchange rate, temperature and humidity control, airflow pattern, use of high efficiency particulate filter (HEPA), room pressurization, and compliance with relevant regulations and standards.
(1) High air exchange rate: The clean room HVAC system usually have a higher air exchange rate to create a clean and safe environment. Compared to conventional systems, ‌USP800 clean room HVAC system’s air change per hour ranges from 15 to 30 or more, which helps to keep the air clean and extends the service life of the HEPA filter
Temperature and Humidity Control: The clean room HVAC system controls the temperature and humidity to different levels of accuracy to meet the comfort and process requirements. In the absence of special requirements, the temperature can be controlled at 18~25℃, and the relative humidity can be controlled at 40%~65%.
(3) Airflow pattern and room pressurization: The clean room HVAC system is distinguished from conventional systems by increasing air supply, specific airflow mode, and the use of HEPA filters, etc. In addition, the differential pressure between clean areas and non-clean areas, and between clean areas of different class shall not be less than 10 Pa(A) to prevent contamination and cross-contamination.
(4) Compliance with relevant regulations and standards: The design of clean room HVAC systems needs to follow relevant regulations and standards, such as Good Manufacturing Practice (GMP), to ensure drug quality and patient safety.
(5) In conclusion, the design of the USP800 clean room HVAC system not only needs to consider comfort and environmental control, but also needs to meet specific regulatory requirements to ensure the cleanliness class and safety of the pharmaceutical production environment.

5.What are the requirements for USP 800 clean room structure materials?
(1) Requirements for USP 800 cleanroom structural materials mainly include well-sealed walls, ceilings and floors, and high-efficiency filtration systems.‌
(2) Well-sealed walls, ceilings and floors: This is to effectively prevent the intrusion of external contaminants and ensure the purity and stability of the clean room. The well-sealed building structure provides a strong protection for the clean room, and prevents external contaminants from entering the clean area.
(3) High efficiency filtration system: Filtration system, including HEPA filters, can filter out small particles up to 0.3 microns to ensure the purity of the air inside cleanroom. High efficient filtration system is crucial to maintain the cleanliness of clean room, which can remove particles and microorganisms in the air, and ensure the quality and safety of production and experiments.
(4) In addition, the partition structure of the clean room should be considered for easy cleaning and maintenance, so as to facilitate regular cleaning and disinfection and maintain the sanitary conditions of the clean room. At the same time, the personnel and materials entering the clean room also need to go through a strict purification process, such as air shower, cloth changing and other procedures, as well as disinfection and cleaning of materials, to ensure that external contaminants are not brought into the clean area.

6.What clothing / personal protective equipment are suitable for USP 800 clean room?
â–º For clothing/personal protective equipment for USP 800 clean room, it is critical to choose the appropriate clothing and protective equipment. Here are some of the recommended clothing and protective equipment to ensure safety and hygiene in a clean room environment.
Clean room safety protective clothing: Choose breathable, one-piece hooded protective suits, such as 3M 4535 breathable one-piece hooded suits, suitable for laboratory personnel, providing dust-free protection.
â–º Chemical protective clothing: For those in the work environment that need to contact with chemical substances, choose one-piece full-body acid and alkali resistant laboratory protective clothing, to provide fully enclosed protection to prevent chemical spills and inhalation.
â–º Disposable one-piece protective clothing: For those in the working environment that require frequent change, choose disposable one-piece protective clothing, such as strip breathable membrane protective clothing, as well as the hoods, gloves, and boots (shoe covers).
â–º All protective clothing should be rated according to the cleanest process. In the USP clean room, ISO 5 clothing is recommended.‌
â–º In addition, the management of clean room coveralls should be considered, including regular cleaning and replacement, to ensure the cleanliness and protective performance of the clothing. Choosing the right clothing and protective equipment is essential to maintain the environment of the clean room and the safety of the personnel.

7.The personnel cleaning and dressing protocols for the USP 800 clean room:
1. Preparation before entering into the clean room:
(1)Before entering into the clean room, appropriate personal hygiene preparation should be made, including bathing, shampooing, nail trimming, etc., to reduce potential sources of contamination.
(2)Avoid the use of perfume, cologne and other products that may cause contamination.
(3)Wear clean, dust-free coveralls and underwear, avoid wearing cotton or other particle-prone clothing that may produce particles.

2. Dress code:
(1)Wear dust-free coveralls, including work caps, masks, and work shoes, to ensure that the body and clothing do not release particles into a clean environment.
(2)Work clothes should be made of lint-free, anti-static material to minimize static interference with the environment.
(3)The dressing order should be carried out gradually from dirty to clean to avoid cross-contamination.

3. Handling of personal belongings: 
(1)No personal items (such as watches, jewelry, etc.) are allowed to be brought into the clean room to reduce the sources of contamination.
(2)Personal protective equipment (PPE) used should be checked regularly and replaced immediately if damaged or contaminated.
 Precautions to be taken after entering the clean room:
(3)After entering the clean room, avoid running and making loud noise, in order to reduce the generation and diffusion of dust.
(4)Keep the workbench and the surrounding environment clean during operation and avoid unnecessary items placed on the workbench.
(5)After completing the operation, the workbench and tools should be arranged and sorted to maintain a good working environment.

4. Cleaning requirements:
(1)Laboratory personnel should maintain good personal hygiene habits, such as diligent bathing, changing clothes, etc.
(2)After entering the clean room, wash your hands and disinfect it.
Through the above procedures, it can be ensured that the personnel entering into the USP800 clean room will not cause contamination to the environment.

8. How to do the cleaning, sterilization, environmental monitoring and maintenance of     USP 800 clean room?
In order to maintain the air cleanliness class of USP800 clean room, relevant maintenance regulations must be strictly implemented to prevent the generation, retention and reproduction of dust particles and microorganisms in the clean room and ensure the safety of equipment and personnel.

A. Personnel management in the USP800 clean room
1. Hands are the medium of cross-contamination. Operators should wash their hands when entering the clean room, and do not touch high purified items and packaging materials with their hands. The drug production operators should also be disinfected.
2. The following personnel are not allowed to enter the clean room: patients with cold, cough, eczema and other diseases; Those who do not wash off cosmetics, nail polish and clean work clothes; Operators should wash hair, change clothes and cut nails frequently.
3. When operators work in the clean room, the action should be light, operation procedures should be strictly implemented, and big movements are not allowed that are easy to generate dust. It is not allowed to drag the feet to walk, nor make unnecessary movements; It is not allowed to wear clean work clothes to the toilet.
4. In the clean room, wearing gloves according to the requirements and do not expose the wrist. Gloves should be replaced frequently.
5. Provide related training education to the clean room personnel: Master the clean room characteristics, structure, general knowledge of cleanroom technology, personnel purification procedures and material purification route requirements, the use of clean clothes, cleaning requirements, clean room cleaning and maintenance, disinfection, clean room safety facilities and safety management regulations.
6. Clean work clothes should be dust-free and anti-static. Generally in Class 1~100,000 clean room, split-type clothes are selected; In Class 100~1,000 cleanroom, one-piece type is preferred. Clean shoe covers should be disposable and clean shoes should be washable.
7. Clean work clothes should be managed by specialized personnel, regularly checked and cleaned. General cleaning should be done once a week. After cleaning 50~100 times, it is necessary to check and determine if the clothes should be replaced.

B. Cleaning and sterilization of the clean room
(5)Cleaning of the clean room must be carried out after the completion of the production process; If it is necessary to do the cleaning before the production, the production process should be initiated after the air conditioning system runs for sufficient time to meet the cleaning requirements;
(6)In order to prevent cross-contamination, the cleaning of clean workshop facilities should be dedicated according to different product characteristics, process requirements and cleanliness class. The cleaning tools generally include fixed and mobile vacuum cleaning equipment. If it does not have the above conditions, non-fiber materials such as mercerized towels, nylon cloth can also be applied for wiping, generally 1 time a day or several times. Workbench and work equipment cleaning is generally carried out once a day. Purification of air-conditioning systems should be cleaned 1~2 times a year, and entrusted to specialized cleaning personnel.
(7)In addition, the whole clean room should be sterilized through the return air duct for 1~1.5 hours per day. It takes about 2 hours to sterilize the walls, ground and equipment.
(8)When the efficient vacuum cleaner is used in the clean workshop, the dust concentration of the vacuum cleaner must be checked regularly.

C. Main equipment maintenance
1. Replacement conditions for the HEPA filter:
1) The airflow speed drops to the minimum. Even after replacing the primary and intermediate air filters, the airflow speed still does not increase.
2) The resistance of high-efficiency filter reaches twice of the initial resistance.
3) The HEPA filter has a leakage that cannot be repaired.
4) It is recommended to replace the HEPA filters once a year

2. Check and cleaning of medium efficiency filter.
Each air conditioning unit is equipped with bag-type medium-effect filter, which is used to further filter and remove dust from the new air and return air, and it is recommended to check and replace it once every three months, or increase or decrease the frequency of checking or replacing it as the case may be. It should be taken care not to break the filter bag or deform the frame when replacing it, so as to avoid affecting the filtration effect.

3. Check and cleaning of the primary filter.
Each air conditioning unit is equipped with a primary filter near the entrance of its fresh air duct inlet, which is mainly used to prevent the dust brought by fresh air and mosquitoes from entering the air conditioning system. Therefore, it needs to be checked and replaced regularly. It is recommended to check and replace it once every 45 days, or increase or reduce the frequency of checking and replacing according to the actual situation.

4. The regulating valve is installed on the air supply duct and return duct of each air conditioning unit, in order to ensure its safety and reliability. It should be checked according to the relevant national regulations.

5. In order to ensure the accuracy of the temperature in the workshop, the operator should regularly check the purification air conditioning unit daily to determine whether the unit is running normally and whether there is abnormal sound.

9. Comparison of USP 797 and USP 800 Requirements