Particle count in each class is measured based on particles of a certain size per cubic meter. As the class number decreases and requirements become more strict, the allowed number particles is reduced, as well as the size of those particles. You can see, for example, the difference between particle count and size allowed in Class 7 cleanrooms (352,000 at 0.5 per cubic meter) versus a Class 5 cleanroom (only 3,520 at 0.5 per cubic meter). 

Particle size is measured in microns (µm) per cubic meter. In stricter classes, even the tiniest particles can interfere with and contaminate products and operations within a controlled cleanroom environment. As the classification becomes more stringent, smaller particles must be filtered out using specialized filters. Cleanrooms use a specially designed airflow pattern that makes use of filters in the most efficient and effective way possible to trap and remove particles, and replace the air in the room with air that is fresh and contaminant-free. The rate at which this process completely changes and replaces the room’s air is called the air change rate.

In ISO Classes 4-9, air change rates are expressed as the rate per hour the air in the cleanroom is completely refreshed (ACH = air changes per hour). As cleanroom classifications become more stringent, the air change rate must increase to remove particles and keep the air cleaner. In Class 5 and below, the strictest cleanroom classifications, the air change rate is so rapid it is expressed instead as airflow velocity, either in meters per second or feet per minute. These cleanroom environments require air that is extremely clean, so the constant changing of contaminant-free air is vital to maintain classification standards.

When upgrading to a stricter cleanroom classification, an important step is to increase the filtration and air change rate to remove more particles of a smaller size from the air. For example, ISO Class 7 requires between 60-90 ACH and allows for 352,000 particles at 0.5 microns per cubic meter. To move to an ISO Class 6, the facility would need to increase to 150-240 ACH to filter all but 35,200 particles at 0.5 microns per cubic meter. The more stringent the classification, the more extreme the standards of cleanliness. Extremely clean cleanrooms require extensive filtration and powerful HVAC systems to maintain classification standards.

US Pharmacopeia (USP) has a set of standards used to regulate cleanrooms developing, manufacturing, and packaging pharmaceutical products either for use in human or animal treatments. Most pharmaceutical cleanrooms must abide by USP 795, 797, or 800 standards.

• USP 795: non-sterile pharmaceutical compounds
• USP 797: sterile non-hazardous compounds
• USP 800: sterile hazardous compounds

USP Standards exist to ensure product strength, quality, and purity so that all compounds are certified to be high quality, safe to use, and effective as a treatment or therapy.

Depending on your cleanroom classification, you are required to filter out a certain number of particles of a specific size. To provide consistent and contaminant-free air, particles are removed using HEPA or ULPA filters, depending on target particle size:

• HEPA filters, or High-Efficiency Particulate Air filters, are used to remove 99.99% of particles 0.3µm or larger in diameter. 
• ULPA filters, or Ultra Low Particulate Air filters, function similarly to HEPA filters, but are rated to remove 99.999% of all contaminants larger than 0.12µm.

Most cleanrooms utilize multi-stage filtration to extend the life of expensive HEPA filters and trap contaminants more effectively and efficiently. To do this, pre-filters are placed before  HEPA or ULPA filters to draw out larger particles. Prefilters are generally replaced every other month, while HEPA and ULPA filters can last up to 7 years.

Fan filter units (FFUs) push out clean, filtered air into the cleanroom space. The frequency of these units makes up the cleanroom’s ceiling coverage. Optimal ceiling coverage depends on the size of the cleanroom and the desired level of filtration or cleanliness. A good equation for calculating ceiling coverage, or necessary number of FFUs, is to take your cleanroom’s ACH divided by 60, and multiply it by the cubic footage of the room, divided by 650 (the CFM output of a FFU). In mathematical form, this looks like: FFUs = (ACH / 60) x (ft3 / 650).

Airflow patterns are critical to ensure and consistent flow of clean air and assist filters in doing their job effectively. Most cleanrooms use laminar airflow. This pattern pushes clean air in one direction through the space to limit particles and contaminants from settling or accumulating in one spot.

Your cleanroom layout should allow the air to flow according to its pattern without creating any spaces where contaminants could build up or block filters. During cleanroom design, computational fluid dynamics software can be used to model airflow patterns to determine the optimal placement of FFUs, cleanroom walls, and even equipment and cleanroom furniture.

Another important cleanroom design feature is cleanroom pressurization. Pressure within the cleanroom is determined by the amount and direction of air flowing in and out of the cleanroom environment. Most cleanrooms use positive pressure, which means more air is filtered into the space than removed. Positive pressure prevents air from leaking around doors, seams, or any crevices and into the cleanroom environment where it could cause contamination. 

Some cleanrooms, particularly those working with hazardous or infectious substances, use negative pressure. In negative pressure cleanrooms, more air is filtered out than is brought into the cleanroom in order to prevent contaminants inside the cleanroom from escaping.

Per ASTM E2352, aerospace cleanrooms must meet International Organization of Standards (ISO) 14644-1, starting from a minimum ISO Class 7/Federal Standard 209 Class 10,000 requirement. More extreme standards apply for highly sensitive applications, where airborne particle concentrations must be strictly controlled such as in the development of spacecraft hardware, fine electronics, or optical devices.

Medical research laboratories require strict cleanroom conditions, and usually fall within ISO Class 5-7. The rigorousness of the standard is dictated by the risk level of contaminants to cleanroom operations and safety. 

The minimum standard for pharmaceutical cleanrooms is generally ISO 5 (Federal Standard 209 Class 100), which requires 240-600 air changes per hour and 35-70 percent ceiling coverage to maintain an environment of 100,000 0.1μm particles per cubic meter. Pharmaceutical cleanrooms are also governed by additional regulations by US Pharmacopeia, or USP Standards. 

Medical device production, assembly, and packaging have different cleanliness requirements, and often fall under separate classifications. Most medical device manufacturing cleanrooms must comply with ISO 5-8 standards, per ISO 14644-1, while medical device packaging requires ISO 7-8. All medical device cleanrooms must also comply with ISO 13485:2016 which designates a quality management system to ensure product quality and assess risk throughout the device’s lifetime.