Introduction to Clean Rooms and Controlled Environments

Clean rooms and controlled environments are specialized areas designed to maintain stringent levels of cleanliness, control various environmental parameters, and minimize contamination risks. They find applications across a wide range of industries such as pharmaceuticals, biotechnology, microelectronics, healthcare, aerospace, and more. In this guide, we will explore the key aspects, principles, and considerations associated with clean rooms and controlled environments.

Some examples of Clean Room are provided below.

Clean Room Classifications and Standards

Clean rooms are classified based on the level of cleanliness required, typically determined by the allowable concentration of airborne particles. The International Organization for Standardization (ISO) developed the ISO 14644-1 standard, which defines clean room classifications based on particle count at specified sizes. The ISO classification ranges from Class 1 (the cleanest) to Class 9 (the least clean).

The ISO standard also establishes guidelines for air sampling, particle counting methods, and statistical considerations when determining clean room cleanliness levels. Industries may have additional standards or guidelines specific to their applications, such as the Semiconductor International Standards Organization (SEMI) standards for microelectronics manufacturing.

Clean room classifications are usually expressed as “ISO Class X” (e.g., ISO Class 7), indicating the maximum allowable particle concentration for particles of a specified size.

An explanation of ISO classifications of clean rooms from Class 1 to Class 9 is as follows¹

ISO Class 1 Clean Room:

• Maximum allowable particle concentration: ≤10 particles/m³ (≥0.1 μm) which means “Maximum and no more than 10 particles, which has a molecular diameter of 0.1m or 0.1 μm, in a 1 m³ container or area“.
• Class 1 clean rooms represent the highest level of cleanliness, suitable for extremely sensitive industries like microelectronics, nanotechnology, and biotechnology.
• These clean rooms require stringent control measures, such as ultra-high-efficiency air filtration and strict gowning protocols.
• Airflow Patterns are typically laminar or unidirectional airflow, ensuring minimal particle accumulation¹.

ISO Class 2 Clean Room:

• Maximum allowable particle concentration: ≤100 particles/m³ (≥0.1 μm) Maximum and no more than 100 particles, which have a molecular diameter of 0.1m 0r 0.1 μm, in a 1 m³ container or area.
• Class 2 clean rooms are designed for industries with critical requirements, such as medical device manufacturing, pharmaceutical compounding, and semiconductor manufacturing.
• These clean rooms maintain very low particle counts to protect delicate processes or products from contamination.
• Clean room protocols, including proper gowning and surface cleaning, are strictly enforced.

ISO Class 3 Clean Room:

• Maximum allowable particle concentration: ≤1,000 particles/m³ (≥0.1 μm), which means Maximum and no more than 1,000 particles, which has a molecular diameter of 0.1m 0r 0.1 μm, in a 1 m³ container or area
• Class 3 clean rooms are commonly found in pharmaceutical manufacturing, aseptic filling, and sterile compounding environments.
• The lower particle count ensures a controlled environment to maintain product sterility and minimize the risk of particulate contamination.
• Strict protocols for gowning, cleaning, and personnel behavior must be followed.

ISO Class 4 Clean Room:

• Maximum allowable particle concentration: ≤10,000 particles/m³ (≥0.1 μm), which means Maximum and no more than 10,000 particles, which has a molecular diameter of 0.1m 0r 0.1 μm, in a 1 m³ container or area.
• Class 4 clean rooms are employed in industries such as medical device assembly, optics manufacturing, and automotive electronics.
• The controlled environment minimizes contamination risks and supports precision manufacturing processes.
• Gowning protocols, surface cleaning, and regular monitoring are implemented to maintain cleanliness standards.

ISO Class 5 Clean Room:

• Maximum allowable particle concentration: ≤100,000 particles/m³ (≥0.1 μm), which means Maximum and no more than 100,000 particles, which has a molecular diameter of 0.1m 0r 0.1 μm, in a 1 m³ container or area.
• Class 5 clean rooms are utilized in applications like pharmaceutical packaging, electronics assembly, and food processing.
• They provide a controlled environment with a low particle count to protect sensitive products or processes.
• Stringent protocols for gowning, material transfer, and cleaning procedures are followed.

ISO Class 6 Clean Room:

• Maximum allowable particle concentration: ≤1,000,000 particles/m³ (≥0.1 μm), which means Maximum and no more than 1,000,000 particles, which has a molecular diameter of 0.1m 0r 0.1 μm, in a 1 m³ container or area
• Class 6 clean rooms are used in industries such as optics inspection, biotechnology research, and some medical device manufacturing processes.
• While they have slightly higher particle counts, they still maintain a controlled environment to minimize contamination risks.
• Gowning, cleaning, and regular monitoring ensure cleanliness standards are upheld.

ISO Class 7 Clean Room:

• Maximum allowable particle concentration: ≤10,000,000 particles/m³ (≥0.1 μm), which means Maximum and no more than 10,000,000 particles, which has a molecular diameter of 0.1m 0r 0.1 μm, in a 1 m³ container or area
• Class 7 clean rooms are commonly found in applications like pharmaceutical compounding, compounding preparations, and some semiconductor manufacturing processes.
• They offer a controlled environment to minimize particle contamination and maintain product integrity.
• Gowning protocols, cleaning procedures, and regular monitoring are essential to ensure cleanliness.

ISO Class 8 Clean Room:

• Maximum allowable particle concentration: ≤100,000,000 particles/m³ (≥0.1 μm)
• Class 8 clean rooms are used in various industries, including automotive manufacturing, research laboratories, and some assembly operations.
• While the particle count is higher, these clean rooms still provide controlled environments to minimize contamination risks.
• Adherence to gowning procedures, cleaning protocols, and routine monitoring is necessary.

ISO Class 9 Clean Room:

• Maximum allowable particle concentration: >100,000,000 particles/m³ (≥0.1 μm)
• Class 9 clean rooms represent the least stringent classification within ISO standards.
• They are suitable for applications where an adjacent controlled environment is required, but the risk of particle contamination is lower or where other factors take precedence over particle cleanliness.
• Adherence to appropriate clean room protocols, including gowning, cleaning, and monitoring, is still necessary.

It’s important to note that while ISO classifications provide a general framework for clean room cleanliness, specific industries, applications, and regulations may have additional requirements beyond the ISO standard. Compliance with industry-specific guidelines and standards is crucial to meet the specific cleanliness requirements of each industry and application.

Design and Construction of Clean Rooms

Designing and constructing a clean room requires careful consideration of various factors to meet cleanliness requirements and provide a controlled environment. Key elements include:

1. Facility Layout: Clean rooms are designed as hierarchical zones, with areas of higher cleanliness located further upstream and areas of lower cleanliness located downstream.
2. Wall Systems: Clean room walls must provide an airtight seal, resist particulate shedding, and facilitate easy cleaning and maintenance.
3. Ceiling Systems: Suspended ceiling systems are common, accommodating lights, air supply diffusers, HEPA (High-Efficiency Particulate Air) filters, and other equipment.
4. Flooring: Smooth, durable, and easily cleanable flooring materials are used, often with epoxy or vinyl finishes.
5. Doors and Pass-Throughs: Doors should be properly sealed, and pass-throughs enable the transfer of materials without compromising cleanliness.

HVAC Systems and Airflow Control

Heating, ventilation, and air conditioning (HVAC) systems are critical components in clean room design and operation. They play a vital role in maintaining proper airflow, temperature, humidity, and pressure differentials. Key considerations include:

• Air Handling Units (AHUs): AHUs condition and filter the supply air before distributing it into the clean room. They incorporate filters, such as HEPA filters, to remove airborne particles.
• Airflow Patterns: Clean rooms utilize specific Airflow Patterns, such as laminar flow or turbulent flow, to control the movement of particles and ensure their removal from critical areas. For further reading on Airflow Patterns in GMP, premises Read more.
• Pressure Differentials: Differential pressure control is essential in clean rooms, where areas of higher cleanliness maintain positive pressure relative to less clean areas or surrounding environments. This prevents the ingress of contaminants. For further reading on Differential pressure in GMP premises read more.
• Filtration: HEPA filters or Ultra-Low Penetration Air (ULPA) filters remove particles of specified sizes from the air supply, ensuring high-quality, clean air.
• Temperature and Humidity Control: HVAC systems provide precise control over temperature and humidity levels within defined ranges to suit the requirements of specific processes or products. For further reading on temperature and humidity in GMP premises Read more.

Air Velocity and Air turn in ISO classes:

The specific air velocity and air turn requirements in pharma cleanrooms and controlled environments depend on several factors, including the cleanroom classification, activities performed, and regulatory guidelines. The following are general considerations, but it’s important to consult specific standards and regulations applicable to your region and industry:

Air Velocity:

• ISO 14644-1, a widely recognized standard for cleanrooms, provides recommendations for maximum allowable air velocities based on cleanroom classifications.
• For example, in ISO Class 5 cleanrooms, the recommended air velocity is typically around 0.36-0.54 meters per second (70-105 feet per minute or 1.17-1.75 feet per second.).
• Higher cleanroom classes may have lower air velocities, such as ISO Class 7 and ISO Class 8, which might range from 0.25-0.36 meters per second (50-70 feet per minute or 0.83-1.17 feet per second).
• However, it’s important to note that these are general guidelines, and specific requirements may vary depending on the activities, processes, and risk assessments conducted for a particular cleanroom.

Air Turn:

• The air turn or Airflow Patterns within a cleanroom should promote proper mixing and distribution of air, minimizing stagnant areas and ensuring uniform air quality throughout.
• Generally, the goal is to achieve a unidirectional or turbulent airflow pattern to continuously flush contaminants away from critical areas.
• Unidirectional airflow is commonly used in higher cleanliness classes, such as ISO Class 5 or Class A areas, where Airflow Patterns are directed from a clean zone (such as a ceiling-mounted filter) towards the work area and exits through low-level returns.
• In areas with lower cleanliness requirements, such as gowning areas or ante-rooms, a turbulent airflow pattern may be employed, which allows for more mixing and less strict unidirectional flow.

It’s important to note that these air velocity and air turn recommendations are general guidelines, and specific requirements may vary depending on the industry, regional regulations, and risk assessments. Cleanroom designers and validation experts should consider the specific needs and requirements of the pharmaceutical processes and products being manufactured when determining the appropriate air velocity and air turn for a particular cleanroom or controlled environment. Compliance with applicable regulations and standards is crucial to ensure proper contamination control and product safety.

Clean Room Garments, Personal Protective Equipment (PPE), and Contamination Control

To minimize contamination risks, personnel working in clean rooms must adhere to strict protocols and wear specialized garments and personal protective equipment (PPE). These measures include:

• Clean Room Garments: Clean room garments, such as coveralls, hoods, gloves, shoe covers, and face masks, are worn to prevent the shedding of particles or microbes from the body.
• Gowning Procedures: Proper gowning procedures, including thorough cleaning and donning of cleanroom garments, ensure that personnel minimizes the introduction of contaminants.
• PPE and Equipment Sterilization: PPE, tools, equipment, and materials entering the clean room are subjected to cleaning, disinfection, or sterilization procedures to maintain cleanliness.

Clean Room Monitoring and Maintenance

Regular monitoring, testing, and maintenance are essential to ensure ongoing compliance and optimal performance of clean rooms. Key aspects include:

• Environmental Monitoring: Continuous or periodic monitoring of critical parameters, such as particle counts, temperature, humidity, airflow velocity, and pressure differentials, ensures that the clean room operates within defined limits.
• Routine Testing and Calibration: Instruments and equipment used for monitoring or controlling environmental parameters must be regularly calibrated and tested for accuracy.
• Clean Room Cleaning: Regular cleaning protocols, including surface cleaning, equipment cleaning, and removal of particulate build-up, are necessary to maintain cleanliness.
• Preventive Maintenance: Scheduled maintenance activities, such as filter replacement, equipment servicing, and system checks, help identify and rectify potential issues before they impact cleanroom performance.

Clean Room Protocol and Operating Procedures

To ensure consistent adherence to clean room standards and protocols, clear operating procedures and protocols must be established. These include:

• Access Control: Strict access control measures, such as entry/exit protocols, gowning procedures, and personnel training, help maintain the integrity of the clean room environment.
• Material and Equipment Transfer: Well-defined procedures for material and equipment transfer within the clean room, including proper handling, storage, and transport methods, minimize contamination risks.
• Contamination Incident Response: Procedures for handling contamination incidents, including identification, containment, investigation, and corrective actions, are crucial to maintaining clean room integrity.
• Personnel Training: Thorough training programs for personnel working in clean rooms ensure a comprehensive understanding of protocols, gowning procedures, contamination control, and safety practices.

Importance of Clean Rooms and Controlled Environments

Clean rooms and controlled environments are essential in industries where even microscopic contaminants or deviations from desired conditions can have significant implications on product quality, safety, and performance. The main objectives of clean rooms and controlled environments are:

Importance of Clean Rooms and Controlled Environments in GMP Pharma Premises:

1. Product Quality and Safety:
   • Minimizes contamination and degradation risks.
   • Ensures consistent production of high-quality products.
   • Protects patient health.
2. Compliance with GMP Regulations:
   • Adheres to strict guidelines and standards.
   • Passes inspections and maintains compliance.
3. Contamination Control:
   • Prevents entry and spread of contaminants.
   • Reduces the risk of product contamination and recalls.
4. Process Integrity and Reproducibility:
   • Maintains consistent environmental conditions.
   • Improves batch-to-batch consistency and reliable results.
5. Worker Safety:
   • Protects workers from hazardous substances.
   • Implements strict gowning procedures and PPE usage.
6. Raw Material Protection:
   • Prevents contamination of raw materials.
   • Ensures ingredient integrity and product purity.
7. Environmental Monitoring:
   • Monitors critical parameters for cleanliness and deviations.
   • Enables proactive measures to maintain product quality.
8. Product Stability:
   • Provides controlled conditions for stability.
   • Maintains potency, efficacy, and product shelf life.

Clean rooms and controlled environments are vital in GMP pharma premises for ensuring product quality, compliance, contamination control, worker safety, process integrity, environmental monitoring, and product stability.

Regulatory Compliance and Standards

Clean rooms and controlled environments are subject to regulatory requirements and industry-specific standards. It is important to stay updated with relevant guidelines, regulations, and codes specific to your industry and geographical location. Compliance with regulatory requirements helps ensure product quality, safety, and consistency and may involve audits or inspections by regulatory bodies.

Trends and Emerging Technologies

Advancements in technology continue to impact clean room design and operation. Some emerging trends include:

• Miniaturization of Clean Rooms: The development of mini-environments or portable clean rooms for specific applications, such as medical device assembly or microelectronics manufacturing.
• Automation and Robotics: Increased utilization of automation and robotics to minimize human intervention and reduce contamination risks in clean rooms.
• Advanced Air Filtration Technologies: Research into advanced filtration technologies, such as nano-fiber filters or self-cleaning filters, to enhance cleanroom performance.
• Energy Efficiency and Sustainability: Integration of energy-efficient systems, renewable energy sources, and sustainable materials to reduce the environmental impact of clean room facilities.

Conclusion

Clean rooms and controlled environments are critical to industries where maintaining strict levels of cleanliness and environmental control is paramount. By understanding the principles, design considerations, operational protocols, and maintenance practices associated with clean rooms, organizations can ensure optimal performance, regulatory compliance, and the consistent delivery of high-quality products. As technology advances, clean room design and operation will continue to evolve, catering to emerging industry needs and challenges.

References

• https://www.iso.org/standard/53394.html
• https://thepharmalead.com/compliance-and-enforcement-in-the-context-of-good-manufacturing-practices/
• https://thepharmalead.com/premises-and-facilities-in-pharmaceutical-gmp-area/
• https://thepharmalead.com/gold-standard-deep-drive-gmp-guideline-for-temperature-humidity-air-quality/
• https://thepharmalead.com/differential-pressure-in-gmp-area/