Revised ISO Cleanroom Standards Improve Air Cleanliness Classification

The International Organization for Standardization (ISO) published the long-awaited revisions to its standards for classification and monitoring of air cleanliness in cleanrooms on Dec. 15, 2015. ISO 14644-1:2015 “Cleanrooms and associated controlled environments Part 1:Classification of air cleanliness by particle concentration” (1) replaces ISO 14644-1:1999, and ISO 14644-2:2015 “Cleanrooms and associated controlled environments Part 2: Monitoring to provide evidence of cleanroom performance related to air cleanliness by particle concentration” (2) replaces ISO 14644-2:2000.

The 2015 editions are the result of a systematic review and include changes made in response to requests by users and experts in the cleanroom community. In particular, the requests for reviewing Part 1 were related to “the basis for the number of sampling locations and, most importantly, the whole statistical basis of classification of cleanliness using the Student T-test for one to nine sampling locations,” notes Gordon Farquharson, convenor of the ISO TC209 working group 1, which performed the review and revisions. Because Part 2 is closely aligned with Part 1, the committee reviewed both parts together.

Classification by particle concentration
The addition of “by particle concentration” to the title of the standard is a long-overdue clarification, comments Karen Ginsbury, CEO at PCI Pharmaceutical Consulting. “For years, I have heard cleanroom contractors and practitioners alike wrongly describe ISO 14644-1 and 2 as cleanroom ‘validation’ or ‘qualification’ standards.” She notes that the standards only address airborne particles, not other factors crucial to cleanroom qualification, such as smoke tests to determine airflow patterns.

The introduction of Part 1 explains, “This part of ISO 14644 specifies classes of air cleanliness in terms of the number of particles expressed as a concentration in air volume. It also specifies the standard method of testing to determine cleanliness class, including selection of sampling locations” (1).

Sampling changes
The primary changes to Part 1 involve the number of samples and the selection of sampling locations. “The number of samples will increase from what was required previously,” explains Marsha Stabler Hardiman, senior consultant at ValSource. “The minimum number of samples is now determined from a lookup table (instead of an equation), and that number is set to be statistically significant.”

According to ISO, the new method for selecting the sites and number of sampling collections uses a more consistent statistical approach based “where samples are drawn randomly without replacement from a finite population. The new approach allows each location to be treated independently with at least a 95% level of confidence that at least 90% of the cleanroom or clean zone areas will comply with the maximum particle concentration limit for the target class of air cleanliness. No assumptions are made regarding the distribution of the actual particle counts over the area of the cleanroom or clean zone; while in ISO 14644-1:1999 an underlying assumption was that the particle counts follow the same normal distribution across the room” (1). The sampling locations are to be chosen representatively, meaning that “features such as cleanroom or clean zone layout, equipment disposition, and airflow systems should be considered when selecting sampling locations” (1).

This representative selection of sample locations is a big change from the previous random selection, says Hardiman. “A company now has to have a rationale and justification for sample site location to ensure that the sample locations selected are representative of the characteristics of that section.  Companies will have to look at the new number of sample locations and then determine where the representative sample locations will be collected.  If contracting out the classification activities, you should make sure that your contractor is now using your new, representative sample locations.” 

Classification of macro and nano-particles
The revision makes a change regarding large (≥ 5 µm) particles, which are required to be measured for some classifications in the EU Annex 1 GMP guidelines (3) and others. “The experts working on the revision of ISO 14644-1 were of the opinion that particles ≥ 5 µm diameter should not be used to classify ISO class 5 and cleaner environments because of the uncertainty associated with particle collection efficiency and accuracy of counting low concentrations,” says Farquharson. “In order that the European Union (EU), the Pharmaceutical Inspection Convention and Pharmaceutical Inspection Co-operation Scheme, World Health Organization, and Chinese GMPs are not left without a classification tool for their Grades A  (at rest and operational) and B (at rest), ISO 14644-1:2015 provides a mechanism of extrapolating the macro-particle descriptor for class limits of 20 and 29 particles ≥ 5 µm.”

The new document does not address nano-scale particles, which were formerly defined as ultrafine particles  in ISO 14644-1:1999, but will address these under a new Part 12, notes Farquharson, who explains, “These particles are measured using a different particle counter, and industries such as semi-conductor monitor for concentration of these very small airborne particles at critical control points. These particles are not generally of interest to the pharmaceutical and life sciences industries.”

Monitoring and testing
ISO 14644-2:2015 now requires monitoring to provide evidence of cleanroom performance, explains Farquharson. The standard addresses airborne particle concentration, airflow, and device pressure difference. New topics include monitoring of critical parameters and setting action and alert alarms.

The revised standard now allows companies to use risk management to set their periodic classification testing schedules, notes Hardiman. “In the past, the retesting was prescribed in a table and the timing was based on the ISO class of the cleanroom or clean zone. Now, companies can put more emphasis on the day-to-day data that they generate in their own facilities to help determine the appropriate testing and frequencies needed for continued cleanroom compliance. If a company is generating great data and the risk to continued cleanroom compliance is low, then they can set a longer periodic classification frequency,” explains Hardiman. She notes that risk-based sample site selection is crucial for environmental monitoring. “The key is understanding your unique products and processes and selecting sites that best address the risks that your products and processes present. It is important to be able to identify all of the potential contamination sources in each cleanroom and to select environmental monitoring sample locations in close proximity to these sources. It is also very important to understand the people, material, and waste flows,” concludes Hardiman.

Pharmaceutical cleanrooms typically already have monitoring plans, which are required by Annex 1 of the EU GMPs, says Ginsbury (3). She notes that users should, however, check with their cleanroom contractors to determine whether a contractor is qualified and familiar with the revisions, because the regulators reference the ISO standards and they must be followed, says Ginsbury. “I would recommend having the discussion now so that, by 2017, your contractors and in-house staff are fully up to speed and following the new standard,” she notes. “Even if you use contractors, the responsibility for review and approval of their results and compliance with regulatory standards lies with you. ISO may not require 5 µm particles and may let you use risk assessment to determine frequency of classification. However, EU Annex 1 still requires measuring 5 µm particles as part of classification, and current industry practice (EU [3] and FDA [4]) is to perform cleanroom classification twice a year for aseptic core. We haven’t heard the regulators on this one but I wouldn’t rush to reduce that frequency based on risk assessment,” cautions Ginsbury.

References

1. ISO, ISO 14644-1:2015, Cleanrooms and associated controlled environments – Part 1: Classification of air cleanliness by particle concentration (Geneva, 2015).
2. ISO, ISO 14644-2:2015, Cleanrooms and associated controlled environments – Part 2: Monitoring to provide evidence of cleanroom performance related to air cleanliness by particle concentration (Geneva, 2015).
3. EC, EudraLex Volume 4: Good manufacturing practice Guidelines, “Annex 1, Manufacture of Sterile Medicinal Products,” (Brussels, 2008).
4. FDA, Guidance for Industry: Sterile Drug Products Produced by Aseptic Processing-Current Good Manufacturing Practice (Rockville, MD, 2004).