Air Quality Classifications for Life Science Cleanrooms
Setting the Standard for Controlled Environments
Cleanrooms in the life sciences industry must adhere to rigorous standards to ensure product Safety, Identity Strength, Purity and Quality. Understanding these standards is essential for designing, constructing, and maintaining controlled environments that meet all regulatory and industry classification requirements.
Why are cleanroom classifications important
Air quality classifications are crucial for life sciences cleanrooms because they allow us to specify a predictable environment that ensures all aerosol contamination risks to pharmaceutical, biotechnology, and medical device manufacturing processes are mitigated. These classifications, based on global standards including ISO 14644-1, quantify the airborne particles maximums that ensure the manufactures products are safe and effective for use.
Cleanroom Classifications
Cleanroom classifications define the allowable levels of airborne particles in controlled environments, ensuring contamination control in industries like pharmaceuticals and electronics. Standards such as those described below categorize cleanrooms based on particle counts of a certain size per unit of volume. Lower classifications indicate stricter cleanliness standards required for critical manufacturing processes.
Fun Fact: Did you know that the modern cleanroom was invented in 1960 by Willis Whitfield, a physicist at Sandia National Laboratories? His design introduced HEPA filtration and laminar airflow which continuously flushed out contaminates significantly reducing particle counts. This invention, of course, has revolutionized the pharmaceutical, semiconductor and other manufacturing industries. Now you know!
ISO 14644-1: International Cleanroom Classification
First published in 1999, the ISO 14644-1 standard defines cleanroom classifications based on an allowable number of airborne particles per cubic meter of air. Common classifications include:
- ISO Class 5: “Sterile” condition required for critical operations such as aseptic filling or sterile compounding for products that cannot be terminally sterilized.
- ISO Class 7: Suitable as a background environment for Restricted Access Barrier Systems (RABS), Bio Safety Cabinets (BSCs) and Unidirectional Airflow (UAF) zones.
- ISO Class 8: Suitable as a background environment for Isolators and closed manufacturing processes utilizing pre-sterilized single use technologies.
Each classification represents an order of magnitude in the allowable concentration of aerosol particulate, emphasizing the importance of robust filtration in the HVAC system.
| CLASS | MAXIMUM PARTICLES/FT3 | ISO EQUIVALENT | ||||
|---|---|---|---|---|---|---|
| ≥0.1um | ≥0.2um | ≥0.3um | ≥0.4um | ≥0.5um | ||
| ISO 1 | 35 | 7.5 | 3 | 1 | Text | ISO 3 |
| ISO 2 | 350 | 75 | 30 | 10 | Text | ISO 4 |
| ISO 3 | 3500 | 750 | 300 | 100 | Text | ISO 5 |
| ISO 4 | 35000 | 7500 | 3000 | 1000 | Text | ISO 6 |
| ISO 5 | 350000 | 75000 | 30000 | 10000 | Text | ISO 7 |
| ISO 6 | 3.5×106 | 750000 | 300000 | 100000 | Text | ISO 8 |
US FED STD 209E
The U.S. Federal Standard 209E (FED-STD-209E), established in 1963, set cleanroom classifications standards based on the maximum number of aerosol particle counts in a cubic foot of air. It was retired in November 2001 and replaced by ISO 14644-1, which introduced an internationally standardized approach to cleanroom classification though this standard is still referenced in certain applications to this day.
| CLASS | MAXIMUM PARTICLES/FT3 | ISO EQUIVALENT | ||||
|---|---|---|---|---|---|---|
| ≥0.1um | ≥0.2um | ≥0.3um | ≥0.4um | ≥0.5um | ||
| 1 | 35 | 7.5 | 3 | 1 | Text | ISO 3 |
| 10 | 350 | 75 | 30 | 10 | Text | ISO 4 |
| 100 | 3500 | 750 | 300 | 100 | Text | ISO 5 |
| 1000 | 35000 | 7500 | 3000 | 1000 | Text | ISO 6 |
| 10000 | 350000 | 75000 | 30000 | 10000 | Text | ISO 7 |
| 100000 | 3.5×106 | 750000 | 300000 | 100000 | Text | ISO 8 |
EU GMP
EU GMP standards are considered by many, including the US FDA, as the “current state” of the art for life sciences cleanrooms. This standard sets the same limits for airborne particulate as the ISO standard but requires that cleanrooms meet particle counts in operation as well as at rest raising the bar on air quality.
| ISO Classification Number | Maximum allowable concentrations (particles/m3) for particles equal to and greater than the considered sizes, shown below |
|||||
|---|---|---|---|---|---|---|
| ≥0.1um | ≥0.2um | ≥0.3um | ≥0.4um | ≥0.5um | ||
| ISO Class 1 | 10b | d | d | d | d | e |
| ISO Class 2 | 100 | 24b | 10b | d | d | e |
| ISO Class 3 | 1,000 | 237 | 102 | 35b | d | e |
| ISO Class 4 | 10,000 | 2,370 | 1,020 | 352 | 83b | e |
| ISO Class 5 | 100,000 | 23,700 | 10,200 | 3,520 | 832 | d,e,f |
| ISO Class 6 | 1,000,000 | 237,000 | 102,000 | 35,200 | 8,320 | 293 |
| ISO Class 7 | c | c | c | 352,000 | 83,200 | 2,930 |
| ISO Class 8 | c | c | c | 3,520,000 | 832,000 | 29,300 |
| ISO Class 9g | c | c | c | 35,200,000 | 8,320,000 | 293,000 |
| a All concentrations in the table are cumulative, e.g. for ISO Class 5, the 10,200 particles shown at 0.3µm include all particles equal to and greater than this size. | ||||||
| b These concentrations will lead to air sample volumes for classification. Sequential sampling procedure may be applied. | ||||||
| c Concentration limits are not applicable in this region of the table due to very high particle concentration. | ||||||
| d Sampling and statistical limitations for particles in low concentrations make classification inappropriate. | ||||||
| e Sample collection limitations for both particles in low concentrations and sizes greater than 1µm make classification at this particle size inappropriate, due to potential losses in the sampling system. | ||||||
| g This class is only applicable for the in-operation state. | ||||||
Key Considerations for Cleanroom Standards
AIR FILTRATION AND VENTILATION
High-Efficiency Particulate Air (HEPA) filters are essential for achieving the particulate control required by cleanroom classifications. In some cases, Ultra-Low Penetration Air (ULPA) filters are utilized for even greater filtration efficiency. Proper airflow design, such as unidirectional (laminar) airflow, minimizes the risk of cross-contamination.
ENVIRONMENTAL CONTROLS
Maintaining precise temperature, humidity, and pressure differentials is critical for many life science applications. These controls ensure product stability and compliance with specific process requirements..
CONTAMINATION CONTROL
Stringent protocols for personnel gowning, equipment sterilization, and material transfer help minimize the risk of contamination. Routine decontamination of cleanroom surfaces and air ensures ongoing compliance with standards.