The presence of clean rooms in various sectors of the pharmaceutical manufacturing industry is mandatory to ensure high product quality. Compliance with Good Manufacturing Practice (GMP) requirements is essential in the design of clean rooms and pharmaceutical company facilities. Below is a list of considerations that should be addressed prior to design:
• Edge-free design for doors, windows, walls, and ceilings
• Monitoring of environmental and microbial conditions
• Airlocks (PAL/MAL)
• Interlock system
• At rest vs. in operation states
• HVAC system
• Sinks and drainage
2-1 Edge-Free Design for Doors, Windows, Walls, and Ceilings
When designing GMP-compliant facilities, an edge-free design for windows, walls, ceilings, and doors takes priority. This is because such designs are easier to clean and reduce the accumulation of contaminants. GMP-compliant doors must be seamless to prevent the buildup of bacteria and contaminants (which is why sliding doors are not recommended). Entrances should also be easy to clean and resistant to cleaning agents. When selecting a door type, the sealing performance of the doors is also critical.
محلهای نمونه 2-2- Monitoring of Environmental and Microbial Conditions GMP guidelines for monitoring and sampling particles are stricter than those of ISO 14644. This is why, for the production of sterile pharmaceuticals, sampling frequency for each clean room grade is conducted in accordance with GMP guidelines. In a clean room, in addition to environmental monitoring (temperature, pressure, humidity, and airborne particles), microbiological monitoring is also required. In Grade A and Grade B clean rooms, particle monitoring must be conducted online with an alarm system in place, which triggers an alert if the particle count exceeds standard limits. In the classification of clean rooms based on the ISO standard, specific numbers and locations for air particle sampling are defined. For example, in an ISO 5 clean room, sampling is performed as shown in the example to ensure that the entire clean room consistently maintains ISO 5 standards (see figure below).
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In GMP, due to the unique nature of each manufacturing process, determining the number and locations of sampling points can be more complex (see figure below). In such cases, sampling should be conducted in areas where there is a higher risk of product exposure to contamination. In other words, a risk assessment must be utilized to determine the number and locations of sampling points.
On the other hand, microbial monitoring involves assessing the microbial load in the clean room air and on internal surfaces of the clean room. The purpose is to analyze and control the microbial load within the clean room.
Current Good Manufacturing Practice (cGMP) regulations establish recommended limits for microbial contamination for each clean room grade. The Colony Forming Unit (CFU) is the unit of measurement for the concentration of microorganisms, bacterial colonies, and fungal colonies found in various test samples. Below is a GMP chart illustrating the maximum CFU values that may be detected inside a clean room:
For the results of particle and microbial monitoring, appropriate alert and action thresholds must be defined. If these limits are exceeded, corrective actions should be implemented. 2-3- Airlocks (PAL/MAL)In clean rooms, special attention must be paid to personnel airlocks (PAL) and material airlocks (MAL) for entry and exit, as contamination can enter the clean room through these access points. Airlocks are enclosed chambers with two or more doors that connect two spaces with different cleanliness standards, such as Class B and Class C, or two rooms with the same cleanliness level. These airlocks restrict direct airflow between these spaces during the entry of materials (MAL) or personnel (PAL). A pass box, on the other hand, is a compartment installed in a wall between two or more adjacent spaces to facilitate the transfer of materials from one side of the clean room to the other. In other words, it is a smaller airlock embedded in the wall, designed solely for material transfer.
2-4- Interlock SystemPersonnel and material airlocks must be equipped with a GMP-compliant interlock system that prevents more than one door from being opened at a time. In a controlled environment, such as a clean room, interlock systems are designed to provide a safe, efficient, and straightforward method for opening and closing doors. Without this system, when both doors are open simultaneously, an air corridor is created, pushing microorganisms and airborne particles toward the clean room. The interlocked door system minimizes the pressure drop that occurs when two doors are opened at once, preserving the clean room’s air quality and preventing airborne contaminants from entering the production clean room. 2-5- At Rest vs. In OperationAccording to GMP guidelines, there are two cleanliness levels within a clean room: “at rest” and “in operation,” distinguished by the presence or absence of personnel in the clean room. For example, if you have a Grade B clean room, it must comply with ISO 5 standards in the “at rest” state, but in the “in operation” state, it must meet ISO 7 standards (as per ISO 14644-1)..
2-6- HVAC SystemThe European Union GMP guidelines do not specify the number of air changes per hour for a clean room. However, the table below presents the FS209E classification for air change rates. In practice, a risk assessment is used to determine the appropriate number of air changes for each room.
2-7 Sinks and Drains
Sinks and drains are prohibited in Grade A and B areas according to GMP. However, they can be located in spaces where aseptic work is not performed. In this case, there must be a seal in the sink or drain path to prevent backflow into the cleanroom.
