Medical and Pharmaceutical USP797 Cleanroom Guidance

All About USP797 Cleanroom

1.What’s USP797 Cleanroom
  USP General Chapter <797> of United State Pharmacopoeia (USP) provides standards for safe handling of sterile drugs at multiple stages. USP 797 cleanroom is a cleanroom that meets the requirements of the USP 797 standards. These cleanrooms are primarily used in the pharmaceutical industry, especially in manufacturing processes involving sterile compounding, to ensure product quality and safety. There are detailed provisions for cleanroom facilities, equipment, operating procedures, cleaning and maintenance in USP 797 standard, to ensure that manufacturing activities conducted in cleanrooms meet certain hygiene standards and cleanliness requirements. In addition, the level and design of the cleanroom should be determined according to the specific production requirements and product characteristics to ensure the cleanliness and safety of the production environment.

2.What are the basic compliance requirements for USP797 cleanroom?
â–ºClean Environment Standard: Dispensing must be performed in an ISO class 8 (Federal Class 209E 100,000) controlled area. This requires the clean room to be equipped with an ultra-clean laminar flow bench, biological safety cabinet, or fully sealed glove box to provide ISO class 5 (Federal 209E Class 100) air quality.

â–ºBarrier System: In order to safeguard drug sterility, patient safety, and dispenser health, USP 797 recommends the use of positive-pressure glove-boxes with a fully sealed design in cleanrooms. The glove box provides a physical barrier between the dispensing personnel and the dispensing area, helping to minimize the risk of contamination.

â–ºRisk level management: USP 797 categorizes sterile preparation mixtures into low, medium, and high risk levels and immediate use categories, specifying the conditions and management requirements for each category to ensure the safety and efficacy of the drugs.

â–ºTest methods: USP 797 also addresses test methods, including but not limited to microbiological tests, sterility tests, etc., to ensure that the drug product meets the sterility and cleanliness requirements.

â–ºInternational standards: In addition, USP 797 applies references from international standards such as EN 12469, a standard issued by the European Committee for Standardization, which covers performance requirements and test methods for biosafety benches and laminar flow hoods, particularly for application in biological laboratories.

3.What are the design parameters of USP 797 cleanroom?
â–ºClassification and testing of cleanrooms: The ISO 14644 standards specify in detail the classification of cleanrooms, testing procedures, test equipment and interpretation of results, providing uniform standards and specifications for cleanrooms worldwide. Confirmation of cleanliness levels: Cleanrooms and clean air equipment used for the production of sterile pharmaceutical products should be confirmed according to the required environmental characteristics. Cleanroom classification should be performed in both “at-rest” and “operational” conditions to ensure that manufacturing operations are conducted in an environment of the appropriate cleanliness level to minimize the risk of particulate or microbial contamination to the product or material. USP 797 cleanrooms are typically rated as ISO Class 7.

â–ºCleanroom design and layout: Cleanroom design should follow the principles of safety, functionality, economy and sustainability. The location should be far away from the source of pollution, and the layout should be reasonably arranged according to the use of functions, process flow and logistics organization and other factors.

â–ºPersonnel and material management: Experimental personnel and visitors entering the clean room need to go through the clean room training, assessment, and can enter into cleanroom only after passing the examination. Experimental personnel must maintain good personal hygiene. Before entering the workshop, they need to wear neat work clothes, work hats, work shoes, and finish hand washing and disinfection. Materials must be purified before entering the clean room, through the air shower before entry into cleanroom.

â–ºAirflow flow verification: According to ISO14644-3 and the new GMP acceptance regulation, direction of airflow in cleanroom needs to be evaluated. Air Quality and Environmental Parameters: The air quality, environmental parameters and sanitary conditions of the cleanroom have a vital impact on the quality and safety of the products. The airflow of the USP797 cleanroom is usually in the form of upward-supplying and downward-returning air pattern.

►The clean room should have unidirectional airflow device with sterilization and filtration function. In addition, indoor temperature of cleanroom should be 18-25 ℃ while relative humidity shoule be 45% -65%. Buffer room and operation room should be set up to achieve air disinfection effect by ultraviolet lamps or other suitable disinfection device.

â–ºThese basic requirements should be met to ensure the clean room environmental control, personnel and materials management, as well as the effectiveness of facilities and equipment, thus ensuring the quality of the product and guaranteeing of production efficiency
 

Typical Floor Plan of USP 797 Cleanroom
 

Typical Elevation of USP-797 Cleanroom

4.The importance of USP797 cleanroom for the pharmaceutical industry?
  The importance of USP797 cleanroom to the pharmaceutical industry is mainly reflected in the protection of product quality, regulatory compliance, improvement of production efficiency, reduction of costs and assurance of microbiological control in production environment. 

â–ºAssurance of product quality: In the pharmaceutical industry, the quality and safety of products are directly related to patient health and safety. Through cleanliness testing, contamination during the manufacturing process can be controlled to ensure the quality and safety of the products.USP797 cleanroom ensures the manufacturing quality and safety of biopharmaceutical products by strictly controlling the environmental parameters such as air quality, temperature, humidity and microbial contamination.

â–ºCompliance with regulatory requirements: all countries have strict regulatory requirements for the production environment in industries such as medical, pharmaceutical and food processing. Cleanliness testing can help companies comply with relevant regulations and avoid penalties and losses due to non-compliance. USP797 cleanroom design and operation needs to comply with strict regulations and standards, such as GMP and ISO 14644, to ensure compliance of production activities.

â–ºImprovement of production efficiency: In a clean production environment, equipment failure rates are reduced and product qualification rates are increased, thus improving production efficiency. USP797 cleanrooms strictly control air quality, temperature, humidity, and microbial contamination through the use of high-efficiency filters and air flow control technology to prevent impurities and contaminants from affecting the production process, minimizing the impact on product quality.

â–ºReduction of costs: Through cleanliness testing, companies can reduce the cost of repairing and replacing equipment, as well as reduce complaints and compensation due to product quality issues. USP797 cleanrooms provide stable environmental conditions for biopharmaceutical processes by providing precise temperature and humidity control, ensuring product consistency and stability, thereby reducing production costs.

â–ºGuarantee of microbial control: In the pharmaceutical industry, especially in the process of drug production, microbial control in the cleanroom is a key to ensure the quality and safety of drugs. The standards and requirements for microbial control in cleanrooms at home and abroad are different. USP797 cleanroom ensures the sanitary conditions of the pharmaceutical production environment by strictly controlling the air cleanliness level and the microbial control on the surface

5.What are the requirements for USP 797 clean room structure materials?
(1)Requirements for USP 797 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 797 clean room?
(1) For clothing/personal protective equipment for USP797 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.
(2）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.
(3)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.
(4) 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).
(5) All protective clothing should be rated according to the cleanest process. In the USP clean room, ISO 5 clothing is recommended.‌
(6) 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 797 clean room:
â–ºPreparation 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.
Wear clean, dust-free coveralls and underwear, avoid wearing cotton or other particle-prone clothing that may cause contamination.
(3)may produce particles.

â–º 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.

â–º 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.

â–º 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 USP797 clean room will not cause contamination to the environment.

8. How to do the cleaning, sterilization, environmental monitoring and maintenance of

USP 797 clean room?
  In order to maintain the air cleanliness class of USP797 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 USP797 clean room
â–ºHands 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.

â–ºThe 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.

â–ºWhen 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.

â–º In the clean room, wearing gloves according to the requirements and do not expose the wrist. Gloves should be replaced frequently.

â–º 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.

â–º 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.

â–º 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
(1) 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;
(2) 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.
(3) 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.
(4) 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
â–ºReplacement 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

â–ºCheck 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.

â–º 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.

â–º 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.

â–º 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