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In the pharmaceutical industry, a dust-free and clean environment is of vital importance for the production of pharmaceutical enterprises. Especially for products that require aseptic production, any contamination during the production process would be more harmful. Therefore, establishing a clean room (cleaning workshop) that complies with GMP standards is particularly important. Due to the differences in product characteristics and requirements, the level and standards of the clean room also vary.
01 Definition of Cleanroom
A cleanroom, also known as a dust-free room or a sterile room, refers to a specially designed room where the micro-particles, harmful air, bacteria and other pollutants within a certain space are removed, and the temperature, cleanliness, indoor pressure/differential pressure, air flow speed and distribution, noise vibration, lighting, and static electricity are controlled within a certain required range. GMP cleanroom is a cleanroom that meets GMP standards and is used for pharmaceutical production.
02 Origin and Classification of Cleanroom Levels
The cleanliness levels of cleanrooms (zones) were initially classified according to the US Federal Standard FED-STD-209E: Class 1, Class 10, Class 100 (100th level), Class 1,000, Class 10,000, and Class 100,000. This standard first proposed the concept of cleanroom classification and used classification standards such as hundred-level, ten-thousand-level, and one-hundred-thousand-level. However, this standard was officially abolished on November 29, 2001, and was replaced by the ISO 14644 standard.
Currently, ISO14644-1 is the main reference for classifying the cleanliness level of cleanrooms. It divides cleanrooms into 1 to 9 levels based on the different concentrations of particulate matter in the air. In the GMP environment, cleanrooms of different levels are suitable for different types of production and operation processes. For example, levels 5 to 8 are suitable for sterile products and other pharmaceutical production processes that require control of suspended particles.
The standards for cleanrooms in China have gone through a process from imitation to independent innovation. Initially, they adopted standards similar to the US FS 209E. Later, they gradually transitioned to being based on ISO 14644 and made appropriate adjustments according to the actual situation of the country. The new version of GMP in China divides cleanrooms into four grades: A, B, C, and D. Each grade defines the limits for the number of particles of ≥0.5μm and ≥5.0μm. The first three grades set "static" and "dynamic" limits respectively, and the D grade currently sets the "static" limit.
Class A: High-risk operation areas, such as filling areas, areas where rubber stoppers are placed, areas with open packaging containers in direct contact with sterile preparations, and areas for sterile assembly or connection operations.
Class B: Background areas of Class A, that is, the surrounding environment where high-risk operations such as sterile preparation and filling occur.
Classes C and D: Clean areas for less critical operation steps in the production of sterile drugs, or environments for non-sterile drug production.
The European Union and other developed countries have also, based on their own national conditions and development needs, referred to ISO 14644-1 and formulated or updated their own cleanroom standards.
03 Key Supervisory Points for GMP Cleanrooms
GMP cleanrooms, as the core area of pharmaceutical production, play a crucial role. They not only bear the responsibility of maintaining extremely low levels of particulate and microbial contamination, but also need to precisely control multiple environmental parameters such as temperature, humidity, pressure difference, illumination, and noise to prevent contamination of the pharmaceutical production process. Based on in-depth research of GMP regulations both domestically and internationally, we have summarized 7 major key supervisory points, aiming to help pharmaceutical enterprises deeply understand and implement these key requirements, in order to establish a clean environment that not only complies with GMP standards but also meets production needs.
1. Suspension particles
The design of the clean area must comply with the requirements of the corresponding cleanliness level. The standards for suspended particles in clean areas at different levels vary among China, the United States and Europe. However, all of them have detailed regulations on the number of particles under both "static" and "dynamic" conditions.
2. Microorganisms
In terms of microbial limits, the Chinese GMP and the US FDA's aseptic process guidelines mainly stipulate that microbial monitoring should be conducted during dynamic environmental monitoring. However, the EU GMP Appendix 1 requires that microbial monitoring should be carried out both in the validation of clean rooms (static) and in environmental monitoring (dynamic).
3. Temperature and Humidity
Currently, GMP does not have specific mandatory values for temperature and humidity. Enterprises should, based on the product's process risks, consider the corresponding national standards/industry standards and technical guidelines to formulate corresponding temperature and humidity standards. For example, in the Design Standard for Cleanrooms in Pharmaceutical Industry GB 50457-2019, it is written as follows:
When the pharmaceutical production process and the product have no special requirements for temperature and humidity, the temperature of pharmaceutical cleanrooms with air cleanliness levels A, B, and C should be 20℃ to 24℃, and the relative humidity should be 45%-60%;
The temperature of pharmaceutical cleanrooms with air cleanliness level D should be 18℃ to 26℃, and the relative humidity should be 45%-65%.
4. Pressure Difference
To ensure that the air cleanliness of the clean area is not disturbed by the polluted air, a certain pressure difference needs to be maintained between different levels of clean areas and between the clean area and non-clean areas. The requirements for pressure difference in clean areas in China, the United States and Europe are basically the same.
5. Illumination and Noise
Currently, GMP does not set specific mandatory standards for illumination and noise.
Enterprises should start from aspects such as product process risks and personnel comfort/occupational protection, and consider corresponding national standards/industry standards and technical guidelines to formulate corresponding standards. For example, in the Design Standard for Cleanrooms in Pharmaceutical Industry GB 50457-2019, it is stated that the illuminance value of general lighting in the main working area should be 300 lx; the illuminance values for auxiliary working areas, corridors, airlocks, personnel purification and material purification rooms should be 200 lx. The noise level (in the idle state) of non-unidirectional flow pharmaceutical cleanrooms should not exceed 60 dB(A), while that of unidirectional flow and mixed flow pharmaceutical cleanrooms should not exceed 65 dB(A).
6. Ventilation
Many GMP regulations and guidelines do not explicitly specify the ventilation volume. Instead, it is left to the project designers to analyze and define it. However, through the study of GMP regulations and guidelines from various countries, it was found that GMP stipulates that the guidance value for the ventilation frequency of a cleanroom is 20 times per hour (ACH), and the guidance value for the self-purification (also known as recovery) time is 15 to 20 minutes. The recovery process of a cleanroom from the usage state to the stationary state is directly related to the ventilation frequency. The higher the ventilation frequency, the faster the recovery process.
7. Personnel Control
The requirements for personnel control in cleanroom settings as stipulated by GMP regulations in China, the United States, and the European Union are fundamentally consistent in their core principles. They all emphasize aspects such as personnel quantity control, personnel training, personal hygiene, protective clothing and equipment, and behavioral constraints. However, there may be certain differences in specific training contents, health check requirements, details of clothing and protection, and behavioral restraint measures among the GMP regulations of these countries.
In terms of personnel control, GMPs in China, the United States and Europe all emphasize the need to strictly control the number of people entering the clean area to reduce the pollution risk caused by human activities. Relevant clean areas can consider designing access control systems to restrict unauthorized personnel from entering and controlling the number of people entering and exiting. The maximum allowable number of people entering different rooms in the clean area can be calculated in the following way, and the minimum value of the calculated result is taken to determine the maximum allowable number of people entering each clean area room:
Calculate based on the fresh air volume in the clean area;
Calculate according to different air cleanliness grades and the number of staff.
In conclusion, the standards and establishment of GMP cleanrooms involve multiple aspects and require comprehensive consideration of product characteristics, production processes, and the requirements of GMP regulations in various countries. By deeply analyzing the GMP regulations of China, the United States, and Europe, we can more comprehensively understand the specific requirements for suspended particles, microorganisms, temperature and humidity, pressure difference, illumination, noise, ventilation, and personnel control in cleanrooms, thereby ensuring that the production environment of pharmaceutical products meets GMP standards.
