Risk-based approach in cleanroom validation: beyond the simple monitoring of particle concentration.

According to the standard for cleanroom testing [1] "ISO 14644-1 shall be carried out in order to classify a cleanroom or clean zone by airborne particle concentration. Additional cleanliness attributes should be chosen if required". As a matter of fact, however, cleanroom validation is more than simply counting particles: it includes numerous supporting tests that should be performed to verify that the cleanroom is fit for its intended use and meets the requirements set forth for the classification.

The risk-based approach

Risk based thinking is at the forefront of the new ISO 9001:2015, ISO 17025:2017, ISO 14001:2015 and regulatory authorities are increasingly asking manufacturers about this subject. Also the new cleanroom testing standard [1] makes reference to risk assessment to be performed to establish the appropriate intervals for periodic testing. We believe that also the selection of the supporting tests should be included in such risk assessment.

So how does one determine which tests need to be performed during a Cleanroom Validation?

At present, no definitive method exists, and the various approaches differ in the degree of complexity involved: some companies just choose the most common tests (air velocity and differential pressure test), others select the number of tests according to their budget, others decide to carry out internally all the supporting tests.

The example of the airflow visualization test

An example of the risk thinking application is described by Sandle et al. [2] and Whyte et al. [3]. They observed that the airflow visualization test can be useful to choose the location of the sampling points for particle count. In turbulent flow clean rooms, air currents do not follow a predictable path and therefore the particles can move in any direction and be lifted from a surface or from the floor. The deposition will be more likely when the air revolves around the objects, the shape of which can give rise to vortices or "areas of stagnation of the particles" (for example under the workstations). Therefore, users of clean rooms should go beyond simply monitoring the concentration of particles in the air and should consider the probability that these particles can deposit on surfaces. The verification of the air flow can be carried out by displaying air movement patterns. The test is useful to detect the turbulence or eddy currents that can act as a channel or reservoir for air contaminants: understanding the movement of air can help understand the path of the flow of particles and identify areas at risk.

When writing a validation protocol, the sampling points for particle count are usually randomly allocated. However, in case of new installations or equipment relocation, it can be helpful to include the airflow visualization test in the validation plan, in order to choose the location of points for particle count based on the risk of particles stagnation.

The HEPA Filters Leak Test

To overcome the need to test the HEPA filters individually, particle counting is often used to prove that the facility is free of particulate and meets the standard. The common mistake is to assume that newly installed HEPA filters pass the leak test by default. However, it is important to also verify that the installation of new filters was done properly. It is worth remembering that a cleanroom whose HEPA filters have been tested and passed will not fail a particle count unless the particles are generated within the facility being tested. Long term, correct application to the HEPA filter test should reduce costs – particularly the costs not always counted and seen – and down time caused by having to repeatedly remove and re-insert HEPA filters which are apparently leaking.

Recovery studies

A key characteristic of cleanroom performance is the ability of the installation to dynamically remove particles from the air. The purpose of the recovery test is to establish how long it takes for the cleanroom to recover from a challenge concentration to the target cleanliness level. This test might be useful when there is a probability of chemical or aerosol spillage.
Manufacturing procedures such as mixing, concentration, centrifugation, or transfer may also generate spills or aerosols that spread widely through production areas.

The containment test

If you suspect that there is dirty air intrusion in your cleanroom, if there are significant containment requirements or if there is a need for biological containment, it is important to carry out this test. Also, if you process potent/toxic materials in an isolator, the room should provide Secondary Containment by having a lower pressure relative to adjoining areas. In these cases you can check the construction of your cleanroom to ensure that no airborne contamination can occur via leaks from higher pressure work areas adjacent to it.

All these aspects might be gathered in a FMEA model, that can be yearly updated to determine which test should be included, along with the particle count test, in the validation protocol.

The use of risk assessment approaches is an important current tool in cleanroom environmental monitoring. It helps to better address the specific problems inherent to different uses of the cleanrooms and to product-specific manufacturing steps.

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References

[1] ISO 14644:3 (2019). Cleanrooms and associated controlled environments — Part 3: Test methods. [2] 1. Sandle, T., Budini, M. and Rajesh, T. (2017). Airflow studies and airflow mapping. In: Sandle, T. and Saghee, M.R. Cleanroom Management in Pharmaceuticals and Healthcare, Euromed Communications: Passfield, UK, pp361-376 [3] Whyte W, Agricola K and Derks M (2015). Airborne particle deposition in cleanrooms: Deposition mechanisms. Clean Air and Containment Review, Issue 24, pp4-9