Cleanrooms play a crucial role in the manufacturing of pharmaceutical and medical products by providing controlled environments that minimize the risk of contamination. To ensure the highest standards of cleanliness and safety, regulatory bodies around the world have established guidelines and standards for cleanroom classifications.
In this article, we will delve into the world of GMP cleanroom classifications, exploring the differences between grades, their ISO equivalents, applications, and monitoring requirements.
Introduction to GMP Cleanroom Classifications
The Good Manufacturing Practices (GMP) for cleanrooms were developed to ensure the safety, purity, and quality of pharmaceutical products. GMP standards aim to minimize the risk of contamination from particles, microorganisms, and pyrogens during the preparation and sterilization of medicines and medical devices.
These GxP standards cover various aspects of production, including quality control, packaging, personnel, and the cleanroom facility itself.
Cleanroom Grades and ISO Equivalents
According to Annex 1, GMP cleanrooms are categorized into four grades: Grade A, Grade B, Grade C, and Grade D. Each grade corresponds to specific cleanliness requirements and is associated with ISO classifications. Let’s explore the key characteristics of each grade and their ISO equivalents:
Grade A Cleanroom
Grade A cleanrooms are designated for high-risk operations that require the highest level of environmental control. They are equivalent to ISO Class 5 cleanrooms, both at rest and in operation. Grade A cleanrooms must maintain a low level of airborne particles, with a maximum permitted concentration of 3,520 particles ≥ 0.5 µm per cubic meter.
Grade B Cleanroom
Grade B cleanrooms are used for aseptic preparation, filling, and compounding processes. They are equivalent to ISO Class 5 cleanrooms at rest and ISO Class 7 cleanrooms in operation. The maximum permitted concentration of airborne particles in Grade B cleanrooms is 3,520 particles ≥ 0.5 µm per cubic meter at rest and 352,000 particles ≥ 0.5 µm per cubic meter in operation.
Grade C Cleanroom
Grade C cleanrooms are suitable for less critical stages in the manufacturing process. They are equivalent to ISO Class 7 cleanrooms at rest and ISO Class 8 cleanrooms in operation. The maximum permitted concentration of airborne particles in Grade C cleanrooms is 352,000 particles ≥ 0.5 µm per cubic meter at rest and in operation.
Grade D Cleanroom
Grade D cleanrooms are designated for less critical stages in the manufacturing process. They are equivalent to ISO Class 8 cleanrooms, both at rest and in operation. The maximum permitted concentration of airborne particles in Grade D cleanrooms is 3,520,000 particles ≥ 0.5 µm per cubic meter.
If you want to read more about Annex 1 requirements, read out article SwissMedicines Inspectorate: Interpretation of GMP Annex 1 [2022].
Cleanroom Classification States and Considerations
“At Rest” State: This is when all utilities are installed, including functioning HVAC, and equipment is installed but not operating. No personnel are present in the room.
“In Operation” State: This is when the cleanroom is fully operational, with HVAC functioning, equipment operating in the defined mode, and the maximum number of personnel present for routine work.
“At Rest” State: Establishing Baseline Cleanliness
The “At Rest” state signifies a moment of readiness without active manufacturing operations. In this phase, all utilities, including the vital Heating, Ventilation, and Air Conditioning (HVAC) system, are installed and operational.
Equipment is meticulously arranged but not yet set into motion, and notably, no personnel inhabit the room. The purpose of this state is to establish a baseline for cleanliness, offering insights into the inherent purity of the environment without the influence of human activities or equipment operation.
Total Particle Limits for “At Rest” State:
Cleanroom Class | ≥ 0.5 µm (particles/m³) | ≥ 5 µm (particles/m³) |
A | 3,520 | Not specified (a) |
B | 3,520 | Not specified (a) |
C | 352,000 | 2930 |
D | 3,520,000 | 29,300 |
(a) Classification including 5µm particles may be considered where indicated by the CCS or
historical trends.
“In Operation” State: Real-world Cleanroom Dynamics
Contrasting with the quiescence of the “At Rest” state, the “In Operation” state encapsulates the full spectrum of cleanroom functionality. HVAC is not merely operational but fully engaged, equipment hums in its defined mode, and the cleanroom is bustling with the maximum number of personnel immersed in routine work.
This state serves as a reflection of real-world manufacturing conditions, considering the dynamic factors introduced by human activities and equipment operations.
Total Particle Limits for “In Operation” State:
Cleanroom Class | ≥ 0.5 µm (particles/m³) | ≥ 5 µm (particles/m³) |
A | 3,520 | Not specified (a) |
B | 352,000 | 2,930 |
C | 3,520,000 | 29,300 |
D | Not predetermined (b) | Not predetermined (b) |
(a) Classification including 5µm particles may be considered where indicated by the CCS or historical trends.
(b) For grade D, in-operation limits are not predetermined; the manufacturer should establish in-operation limits based on a risk assessment and routine data where applicable.
Applications of GMP Cleanroom Grades
Now that we have a clear understanding of the different GMP cleanroom grades, let’s explore the specific applications for each grade:
Grade A Cleanroom Applications
Grade A cleanrooms are reserved for high-risk operations that require the utmost level of environmental control. They are commonly used for the following activities:
- Aseptic assembly of filling equipment
- Aseptic compounding and mixing
- Replenishment of sterile bulk products, containers, and closures
- Removal and cooling of unprotected items from sterilizers
- Staging and conveying of sterile primary packaging components
- Loading of a lyophilizer
Grade B Cleanroom Applications
Grade B cleanrooms are essential for aseptic preparation, filling, and compounding processes. They play a critical role in the following activities:
- Background support for the Grade A zone
- Transport of equipment, components, and ancillary items to the Grade A zone while protected from the surrounding environment
Grade C Cleanroom Applications
Grade C cleanrooms are used for less critical stages in the manufacturing process. They find applications in the following activities:
- Filling of products for terminal sterilization (at least in a Grade C environment)
- Preparation of components and most products (some products with high or unusual risks of microbial contamination may require Grade C)
- Preparation of solutions to be filtered, including weighing
Grade D Cleanroom Applications
Grade D cleanrooms are dedicated to less critical steps in the manufacturing of sterile drugs. They serve various purposes, including:
- Cleaning of equipment
- Handling of components, equipment, and accessories after washing
- Assembly of cleaned components, equipment, and accessories before sterilization
- Assembly of closed and sterilized single-use systems using intrinsic aseptic connectors
Comprehensive Assessment of Cleanrooms
Cleanroom and clean air equipment qualification encompass a holistic evaluation of compliance with their intended use. The qualification process includes:
Installed Filter System Leakage and Integrity Testing
Ensuring the integrity of the filtration system is vital to prevent contaminants from entering the cleanroom. This aspect of the qualification process is crucial for ensuring the integrity of the filtration system within the cleanroom.
The filter system is designed to remove particles and contaminants from the air supply. Integrity testing involves assessing whether the filters are properly installed, free of leaks, and capable of effectively trapping particles. This step is essential to prevent contaminants from entering the cleanroom and compromising the sterility of the manufacturing environment.
Tip: Regularly schedule and perform routine checks on filters to detect any potential leaks promptly.
Recommendation: Implement a preventive maintenance program to replace filters as needed and avoid unexpected failures during manufacturing operations.
Airflow Tests – Volume and Velocity
Airflow characteristics play a significant role in maintaining the required air quality within the cleanroom. Volume and velocity tests assess the quantity and speed of air circulation. These tests ensure that the air within the cleanroom is exchanged at the specified rate and that the airflow is uniform.
Proper airflow is crucial for carrying away particles and contaminants and maintaining a controlled environment conducive to sterile product manufacturing.
Tip: Conduct airflow tests at different locations within the cleanroom to ensure uniformity.
Recommendation: Regularly calibrate instruments used for airflow measurements to maintain accuracy and reliability.
Air Pressure Difference Test
The air pressure difference test is conducted to verify and control the direction of airflow between different areas within the cleanroom. Maintaining specific pressure differentials helps prevent the migration of contaminants from one area to another.
This is particularly important in areas with varying cleanliness requirements, such as preventing contaminants from entering critical zones where sterile products are handled.
Tip: Clearly define and document the desired air pressure differentials between different cleanroom areas.
Recommendation: Implement real-time monitoring systems to promptly detect and address any deviations in pressure differentials.
Airflow Direction Test and Visualization
This step involves confirming the intended direction of airflow within the cleanroom. Visualization techniques may be employed to observe and ensure the uniform movement of air. Proper airflow direction is critical for controlling the spread of particles and contaminants.
Visualization studies help validate the design and functionality of the cleanroom’s ventilation system, ensuring that the air moves in the intended paths to maintain cleanliness.
Tip: Use airflow visualization studies to involve personnel in understanding and confirming proper airflow patterns.
Recommendation: Conduct periodic refresher training for cleanroom personnel on the importance of maintaining correct airflow directions.
RELATED: Airflow Visualization Smoke Studies (AVS) in Cleanrooms
Microbial Airborne and Surface Contamination
Microbial contamination poses a significant risk in sterile product manufacturing. This part of the qualification process involves monitoring and limiting both airborne and surface microbial contamination.
Air and surface samples are taken and analyzed to ensure that microbial levels are within acceptable limits. This step is essential for maintaining the sterility of the environment and preventing the introduction of microorganisms that could compromise the quality of sterile products.
Tip: Establish a robust environmental monitoring program for continuous microbial surveillance.
Recommendation: Investigate any deviations from acceptable microbial limits promptly and implement corrective actions to address root causes.
Temperature and Relative Humidity Tests
Temperature and relative humidity levels are critical environmental factors in cleanrooms. These tests assess whether the cleanroom maintains the specified temperature and humidity conditions. Consistent control of these factors is essential for the stability of products and the prevention of conditions that could promote microbial growth or compromise product quality.
Tip: Place temperature and humidity sensors strategically across the cleanroom to capture variations in different areas.
Recommendation: Ensure that HVAC systems are properly calibrated and maintained to control temperature and humidity effectively.
Recovery Test
The recovery test evaluates the cleanroom’s ability to recover after disturbances or interruptions. This is particularly important in assessing how quickly the cleanroom returns to its specified conditions after events such as door openings or other disruptions. A prompt and effective recovery ensures that the cleanroom maintains its required cleanliness levels during routine operations.
Tip: Simulate potential disruptions during routine operations to assess the cleanroom’s real-world recovery capabilities.
Recommendation: Document and analyze recovery times, and use the data to optimize cleanroom protocols for minimizing downtime.
Containment Leak Test
The containment leak test evaluates the effectiveness of measures in place to contain contaminants within the cleanroom. This is especially critical in facilities where hazardous or potent materials are handled. The test assesses the integrity of barriers and containment systems to prevent the escape of contaminants, ensuring the safety of personnel and the surrounding environment.
Tip: Regularly review and update containment systems based on technological advancements and lessons learned from any past incidents.
Recommendation: Conduct thorough training for personnel on the proper use and maintenance of containment equipment to minimize the risk of leaks.
Cleanroom Classification Comparisons: Annex 1, and ISO Standard
To ensure global harmonization and consistency, cleanroom classifications in cGMP guidelines often align with international standards such as ISO Standard. Let’s compare cleanroom classifications according to Annex 1 and ISO standard:
Annex 1 Cleanroom Classifications
Annex 1 aligns with ISO 14644-1:2015 for cleanroom classifications. The grades and their associated ISO equivalents are as follows:
- Grade A: ISO Class 5 at rest and in operation
- Grade B: ISO Class 5 at rest, ISO Class 7 in operation
- Grade C: ISO Class 7 at rest, ISO Class 8 in operation
- Grade D: ISO Class 8 at rest and in operation
ISO Cleanroom Classifications
ISO 14644-1:2015 provides a comprehensive classification system for cleanrooms. The classifications are based on the maximum permitted concentration of airborne particles. The ISO classifications and their corresponding particle limits are as follows:
ISO Class | Maximum Particles/m³ |
ISO 1 | 10 |
ISO 2 | 100 |
ISO 3 | 1,000 |
ISO 4 | 10,000 |
ISO 5 | 100,000 |
ISO 6 | 1,000,000 |
ISO 7 | 10,000,000 |
ISO 8 | 100,000,000 |
Cleanroom Qualification and Validation Process
Qualification and validation are essential components of GMP cleanroom compliance. These processes provide documented evidence that the cleanroom meets the required standards and consistently produces high-quality products. The GMP guidance outlines four stages of qualification and validation:
Design Qualification (DQ)
Design qualification verifies that the cleanroom design can meet all regulatory and process requirements. It ensures that the cleanroom is designed to provide the necessary level of control and cleanliness.
If you want to learn more about Design Qualification (DQ) read our article explaining the process in detail.
Installation Qualification (IQ)
Installation qualification verifies that the cleanroom, after installation, is consistent with the specified design. It ensures that the cleanroom components and systems are correctly installed and operational.
Operational Qualification (OQ)
Operational qualification verifies that the cleanroom equipment achieves the specified operational requirements. It ensures that the cleanroom systems, such as HVAC, filtration, and monitoring, are functioning properly.
Performance/Process Qualification (PQ)
Performance qualification, also known as process qualification, verifies that the cleanroom equipment performs well together in a controlled and repeatable state. It ensures that the cleanroom processes consistently meet the required standards and produce high-quality products.
These qualification and validation stages require careful planning, execution, and documentation. It is important to work with experienced professionals to ensure the successful qualification and validation of your GMP cleanroom.
RELATED ARTICLE: Cleanroom Qualification and Validation
Sampling Methods in Cleanroom Qualification
As part of the cleanroom qualification journey, the assessment of microbial contamination employs a diverse array of sampling methods. These methods are carefully chosen to provide a comprehensive picture of the cleanliness level within the sterile manufacturing environment. The key sampling methods include:
- Air Samples: Capturing microbial content suspended in the air, air sampling is instrumental in assessing the overall cleanliness and sterility of the cleanroom atmosphere.
- Settle Plates: Positioned strategically within the cleanroom, settle plates allow for the collection of particles that naturally settle over time. This method provides insights into the cleanliness of surfaces and the effectiveness of the cleanroom environment.
- Contact Plates: By pressing contact plates against surfaces within the cleanroom, this method directly assesses the microbial contamination present on surfaces, equipment, and other critical areas.
Determining Sampling Locations:
The selection of sampling locations is a meticulous process guided by a comprehensive risk assessment. Several factors influence the determination of these locations:
- Room Classification: The designated cleanliness level of different cleanroom areas plays a pivotal role in deciding the intensity and frequency of microbial sampling.
- Air Visualization Studies: Insights gained from airflow visualization studies contribute to identifying areas where microbial contamination is more likely to occur.
- Process and Operations Knowledge: A deep understanding of the manufacturing process and associated operations aids in pinpointing critical areas prone to microbial risks.
Maximum Permitted Microbial Contamination Levels:
The success of cleanroom qualification lies in adhering to stringent limits on microbial contamination. These limits vary based on the grade of the cleanroom, with specific thresholds for air samples, settle plates, and contact plates. The limits are set to ensure that the microbial content remains within acceptable boundaries for the production of sterile products.
Maximum Permitted Microbial Contamination Levels During Qualification:
Cleanroom Class | Air Sample (CFU/m³) | Settle Plates (CFU/4 hours) | Contact Plates (CFU/plate) |
A | No growth | 10 | 5 |
B | 10 | 50 | 5 |
C | 100 | 50 | 25 |
D | 200 | 100 | 50 |
Considerations for Effective Sampling:
- Risk Assessment Integration: The sampling plan should be intricately woven into a comprehensive risk assessment, ensuring that areas with higher risks receive more thorough scrutiny.
- Real-time Monitoring: In addition to periodic sampling, implementing real-time microbial monitoring systems provides continuous insights into the cleanliness status of the cleanroom.
- Prompt Corrective Actions: Deviations from microbial contamination limits should trigger immediate corrective actions, reinforcing a proactive stance against potential risks.
Cleanroom Design Considerations for GMP Compliance
Designing a GMP-compliant cleanroom requires careful consideration of various factors. Here are some key design considerations to ensure GMP compliance:
- Airflow Control: Proper airflow control, including laminar flow and air change rates, is crucial to maintain the desired cleanliness level in each cleanroom grade.
- Filtration Systems: High-efficiency particulate air (HEPA) filters and ultralow particulate air (ULPA) filters play a vital role in removing airborne particles and maintaining cleanroom cleanliness.
- Material Selection: The selection of cleanroom materials, such as wall panels, flooring, and ceilings, should be based on their cleanability, chemical resistance, and compatibility with cleanroom processes.
- Gowning and Entry/Exit Procedures: GMP-compliant cleanrooms require well-defined gowning and entry/exit procedures to prevent contamination from personnel.
- Monitoring and Control Systems: Cleanroom monitoring systems, including particle counters and environmental control systems, should be in place to continuously monitor and control the cleanliness and environmental parameters of the cleanroom.
- Documentation and Standard Operating Procedures (SOPs): Proper documentation and SOPs should be developed and implemented to ensure consistent adherence to GMP guidelines and cleanroom protocols.
These design considerations, along with close collaboration with cleanroom design and construction experts, will help ensure a GMP-compliant cleanroom that meets your specific requirements.
FAQ
Cleanroom classification limits are generally standardized based on industry standards and regulations. However, in some cases, limits may be adjusted based on a thorough risk assessment and scientific justification, considering the specific needs of the manufacturing processes.
The frequency of requalification depends on the cleanroom grade. Grade A and B areas should be requalified every six months, while Grade C and D areas require requalification every 12 months. Requalification is also necessary after changes, remedial actions, or as determined by risk assessments.
The “clean up” period is the time taken to restore the cleanroom to its qualified state after manufacturing operations. It is crucial for maintaining consistent cleanliness levels and preventing the persistence of contaminants introduced during operations.
Conclusion
GMP cleanroom classifications are essential for ensuring the safety, purity, and quality of pharmaceutical products. Understanding the differences between grades, their ISO equivalents, applications, and monitoring requirements is crucial for compliance with GMP guidelines.
By adhering to GMP standards and implementing proper cleanroom design, qualification, monitoring, and auditing processes, pharmaceutical manufacturers can create controlled environments that minimize the risk of contamination and ensure the production of safe and effective products.
As cleanroom technology continues to evolve and global harmonization efforts progress, it is essential to stay updated on the latest standards and guidelines to maintain the highest levels of cleanliness and compliance in pharmaceutical manufacturing.
Should personnel be permitted to move back and forth between Grade C and Grade D areas with the same gowning?
Excellent question Mr. Vora.
The gowning has to be different for each grade and you have to cover that in your Gowning Procedure. Because Class C environments require a higher level of cleanliness compared to Class D, using the same gowning for both might not be adequate if you are moving from a Class D to a Class C environment. Typically, gowning requirements become more stringent as you move from a lower class (like Class D) to a higher class (like Class C). Here’s a general idea of what might be required:
Class D: Generally, gowning requirements for Class D environments might include hair covers, face masks, lab coats or frocks, and shoes for class D.
Class C: In Class C environments, gowning requirements are stricter. In addition to what is required in Class D, you might need to wear hoods, goggles, gloves, and coveralls that offer more extensive coverage and tighter particle containment.
HI ,
We would like to inquire about the low return outlets in each clean room. Could you please provide the quantities and locations for each room? should be in the opposite side ?
Dear Mr. Kachacha, thank you for your question. The number of low-return outlets required in a clean room depends on the room’s size, airflow requirements, and cleanliness classification. Typically, each clean room will have multiple return outlets to ensure proper air circulation and pressure control. Low return outlets are usually located near the floor to help remove particles and contaminants that settle downward.
They should be placed in locations that ensure a uniform air pattern and minimize turbulence.
It is common practice to place low return outlets on the opposite side of the room from high-efficiency particulate air (HEPA) filters or supply vents to promote a sweeping effect, drawing contaminants away from critical areas and ensuring a laminar airflow. If you have additional questions, feel free to contact us.