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Basic requirements and relevant regulations for the six key aspects of clean rooms
2024/11/14
1. There are four levels of clean areas for the production of sterile drugs, and the specific standards for each level are specified in the GMP Sterile Drugs Appendix 9 to 11.
The following are examples of sterile drug production environments:
Class A: Critical areas for high-risk operations (e.g., aseptic production lines, filling areas, stopper trays, open inner packaging or aseptic connections under initial airflow protection). Typically, this condition is achieved by local airflow protection, such as a unidirectional flow console within a RABS or isolator. The unidirectional flow maintenance status of the entire Class A area shall be demonstrated and confirmed. Direct operator intervention in Class A areas should be minimized through plant, equipment, process and procedural design (for example, without the use of isolators and glove-box technology as protection).
Class B: For aseptic preparation and filling, this is A Class A background clean room (non-isolator). The pressure difference should be monitored continuously. Clean rooms below Class B can be considered when using isolator technology.
Class C and D: clean rooms that perform less critical steps in the production of aseptically filled sterile pharmaceutical products or serve as a background for isolators. It can also be used for the preparation/filling of terminal sterilized products. (EU GMP Appendix 1 4.4)
2. Cleanliness level confirmation
1. Clean room and clean air equipment such as unidirectional flow systems (UDAF), restricted access barrier systems (RABS) and isolators used for the production of sterile pharmaceutical products shall be identified according to the desired environmental characteristics. Production operations need to be carried out in an environment with an appropriate level of cleanliness to reduce the risk of contamination of products or materials with particles or microorganisms. Clean room validation (including grading) should be clearly distinguished from environmental monitoring. (EU GMP Appendix 1 4.23)
2. Clean room classification should be carried out in the "static" and "dynamic" states.
① "Static" means that all public facilities (including all normal operating HVAC) have been installed, the main production equipment is installed and standby as required, and no personnel are present.
"Dynamic" means a state in which the clean room is installed, the HVAC system is fully operational, the equipment is installed and operates according to the operating mode specified by the manufacturer, allowing a maximum number of people to perform or simulate daily operations on site.
③ The "self-cleaning" period should be determined during the classification period (the guidance value is less than 20 minutes). (EU GMP Appendix 1 4.29)
3. Clean rooms and clean air equipment shall be periodically reconfirmed in accordance with established procedures. The revalidation procedure shall include, at a minimum, determination of microbial and suspended particle concentrations, terminal filter integrity testing, air volume testing, and differential pressure testing. Class A zones should also be tested for air velocity. The maximum interval for reconfirmation of Class A and Class B zones is 6 months. The maximum interval for revalidation of Class C and D zones is 12 months. Revalidation should also be carried out after correction of equipment or facility deviations, or changes to equipment, facilities, or processes. (EU GMP Appendix 1 4.32)
3. people flow and logistics
1. The clean room should be reasonably designed to achieve the orderly flow and control of materials, products and personnel in the area. Plan the location of equipment scientifically to minimize the crossing of people, products and material flows. (FDA2004 Guiding Principles)
2. The movement of equipment and materials into and out of clean rooms and critical areas is one of the biggest potential sources of pollution. All activities that may affect the cleanliness of the clean room should be assessed; If the effects cannot be eliminated, appropriate control measures should be taken. (EU GMP Appendix 1 4.10)
3. Materials, equipment and components should be transferred one-way into the sterile production area, and items should be transferred as far as possible through a double-ended sterilizer embedded in the wall (for example, a double-leaf autoclave or a tunnel oven) after sterilization. If sterilization is not possible at the time of transfer, other measures to avoid introducing contamination (such as effective transfer disinfection, rapid transfer systems for isolators, gas or liquid degerming filtration) should be taken and verified. During production and after surface sterilization, material entry should be minimized. (EU GMP Appendix 1 4.11)
4.air lock design network information service
Locations where materials and people move between levels should be designed and use air locks to provide physical isolation and minimize microbial and particulate contamination in different areas. The air lock used by the flow of people and logistics should be separated as far as possible, if it cannot be achieved, it should be considered to develop procedures for wrong use. Air lock should use filtered air for effective air shower. The last section of the air lock should have the same cleanliness level as the clean room entered under "static". (EU GMP Appendix 1 4.12;)
Air lock design requirements are as follows:
Personnel air lock: An area for personnel to access higher level clean rooms. Even if the cleanliness between areas is the same, if there is a risk of cross-contamination of raw materials and medicines, additional changing rooms should be set up according to the potential risk. Adequate space should be set aside for changing clothes, storing clothes, and disposing of used clothes and other materials.
Material air lock: used for material and equipment transfer. Only materials and equipment that are included in the approved list and have been verified for transfer are allowed to be transferred to Class A or Class B by airlock transfer. Equipment and materials intended for use in Zone A are expected to be protected when moving through Zone B. Any unauthorized items that require transfer shall be subject to approval on an exceptional basis. The transfer of materials or equipment from lower or ungraded areas to higher cleanrooms should be cleaned and disinfected according to their risk. (EU GMP Appendix 1 4.12;)
Measures should be taken to prevent the simultaneous opening of both doors to access and air locks (materials and personnel), and an interlocking system should be used for air locks leading to Class A and Class B zones. At a minimum, visual and/or auditory alarm systems should be used for air locks leading to Class C and D zones. If it is necessary to maintain area isolation, the time delay between the closing and opening of the interlocking doors should be determined. (EU GMP Appendix 1 4.13;)
5. Differential pressure control network information service
1. The clean room shall be supplied with filtered air to maintain positive pressure and/or positive air flow relative to the lower level background environment under all operating conditions. Adjacent rooms of different levels shall maintain a pressure difference of at least 10Pa (guideline value). Special attention should be paid to the protection of critical areas. (EU GMP Annex 1 4.14; Japan's Guiding Principles; FDA2004 Guiding Principles)
2. In some cases, the aseptic production processing room and the adjacent clean room are the same cleanliness level, which should also maintain appropriate pressure difference to provide effective separation, there is a non-clean room adjacent to the aseptic production processing room, the aseptic production processing room should maintain at least 12.5Pa pressure difference at all times to prevent contamination. (FDA2004 Guiding Principle IV-C)
3. A differential pressure meter should be installed between the clean room and/or the isolator, and the differential pressure setting point and its critical degree should be determined. The critical pressure handicap should be continuously monitored and recorded, and the other pressure handicap should be regularly monitored and recorded. An alarm system should be set up to timely alert and warn the operator of problems such as air supply failure or pressure differential reduction. Procedures should outline the actions to be taken in the event of an alarm, and alarm signals should not be overwritten without evaluation. If an alarm delay is set, it should be evaluated and demonstrated. (EU GMP Appendix 1 4.16;)
6. Air flow organization
1. Clean room air shall be maintained at an appropriate level through the design, installation and management of suitable heating, ventilation and air conditioning systems (HVAC). (Japan Guidelines 7.2,6)
2. The airflow in the critical area (Class A zone) should be unidirectional and evenly distributed at a sufficient flow rate to quickly remove particles from the air. Adverse flow from adjacent areas into the core area should be avoided to prevent contamination. The recommended average flow rate for unidirectional systems is 0.45m/s±20%. Depending on the type or purpose of the isolator system, lower flow rates may be appropriate. Changes in flow velocity may affect airflow patterns and should be monitored regularly. (FDA2004 Guiding Principles)
3. Airflow patterns in clean rooms and cleanrooms should be visualized (e.g. smoke testing) to demonstrate that air is not entering from lower level areas to higher level area airflow. Visualization studies should be linked to air velocity measurements. Studies should be performed at both static and dynamic (e.g., simulated operator intervention), and study videos should be retained.
