Cleanroom technology for GMP production rooms: Changes in ISO 14644-1, -2 & -3

Norbert Otto

Table 1: Excerpt from the current DIN EN ISO 14644-1:2016 (German version) for the classification of air cleanliness based on particle concentration. (Source: DIN EN ISO 14644-1)

Table 1 (Increase in measurement points <2015 / >2016) (Source: c-tec GmbH)

Table 2 (Growth rate of the most common cleanroom areas) (Source: c-tec GmbH)

The DIN EN ISO standards 14644-1 and 14644-2 for classifying air cleanliness based on particle concentration (-1) and for monitoring the performance of cleanrooms and particle measurement (-2) are now also available in the German version (available through Beuth Verlag).

What’s new? How should the 5 µm particles be handled? How many sampling locations are added?

Norbert Otto, who contributed to the revision as a member of the Technical Committee ISO/TC 209 "Cleanrooms and associated controlled environments" for ISO 14644-3, addresses these questions. His concise answers can be read in today's overview.

ISO 14644-1:2015 (Classification of air cleanliness)

ISO 14644-1:2015 was developed by the Technical Committee ISO/TC 209 "Cleanrooms and associated controlled environments" in collaboration with the Technical Committee CEN/TC 243 "Cleanroom technology," whose secretariat (Convenor) is held by BSI (British Standards Institution). This part of ISO 14644 specifies classes of air cleanliness based on the number of particles, expressed as a concentration per volume of air, and the selection of sampling locations.

The appendices have been reorganized to improve the logical structure of ISO 14644, and parts of the content from ISO 14644-3:2005 regarding testing and test equipment have been incorporated into certain appendices.

The rolling of sampling locations required in draft ISO/DIN 14644-1:2013 was not included in the final version.

ISO/DIN 14644-1:2015 addresses issues concerning particles ≥ 5 µm for ISO Class 5 in relation to sterile products in the EU, PIC/S (Pharmaceutical Inspection Convention and Pharmaceutical Inspection Co-operation Scheme), and WHO GMP guidelines by adopting the macro-particle concept. The classification table no longer provides a count value for particles ≥ 5 µm in ISO Class 5. However, an M-descriptor (see Appendix C) can be used to quantify macro-particle groups (particles ≥ 5 µm).

This also means that 5.0 µm particles are not eliminated. They should still be recorded for GMP cleanrooms (in accordance with Annex 1 of the EU GMP Guide). Furthermore, the new ISO 14644-1 requires measuring with a second channel, which, in GMP terms, would be the measurement channel with particles of 0.5 µm size.

§ C.4.1 Measurement of macro-particles

When sampling particles ≥ 1 µm, the length of the transfer section should not exceed the length and diameter recommended by the manufacturer, which is "usually" not longer than 1 meter.

Due to equipment constraints, this is rarely feasible. This requirement is entirely impractical and has rendered measurements since 1969 (US Fed Std 209) and 1999 (ISO 14644-1) absurd. The velocities in the sampling hoses are still sufficient to prevent particle loss. It should also be noted in the new Annex 1 that this is a "recommendation."

ISO/DIN 14644-2:2015 (Specifications for monitoring and periodic testing to demonstrate continued compliance)

§ 5 Regular classification of air cleanliness based on particle concentration

The regular classification testing must now be performed annually according to ISO 14644-1 and -3. This frequency can be increased based on risk assessment, the scope of the monitoring system, and data that consistently stay within acceptance limits or the levels defined in the monitoring plan.

ISO/DIN 14644-3 / F-DIS:2016 (Test methods)

ISO 14644-3 specifies additional tests related to other aspects of cleanroom performance, such as leak testing, pressure differentials, airflow, etc.
The draft (final draft) is currently circulating and is expected to be approved later this year. Changes regarding the calculation of the test aerosol amount (raw air concentration) and the performance criteria of particle counters (corresponding to ISO 21501-4), among others, have been incorporated, as well as a segregation test.

Among others, the following have been outsourced to ISO 14644-1:

• Measurement of airborne particle concentration
• Classification tests
• Measurement of ultrafine particle concentration
• Macro-particle testing

Classification of air cleanliness based on particle concentration

See Table 1: Excerpt from the current DIN EN ISO 14644-1:2016 (German version) for classifying air cleanliness based on particle concentration. (Source: DIN EN ISO 14644-1)

Number of sampling locations

Regarding the new determination of the number of sampling locations, the number has increased significantly compared to the previous version. The table below lists rooms with typical areas (see Table 2), as is common in GMP environments, as examples of increased sampling points.

See Table 2: Number of sampling locations according to ISO 14644-1,

Pre-2015 (old) vs. since 2015 (new) (see Table 1: (Increase in measurement points 2016, source: C-tec GmbH))

Increase in the number of sampling locations in the most common production areas

See Table 2 (growth rate of the most common cleanroom areas) (source: C-tec GmbH)

Summary

For GMP cleanrooms, particles ≥ 5 µm can still be measured according to ISO 14644-1:2015 using the M-descriptor. There have been some misunderstandings here.

The number of sampling locations has increased significantly depending on the size of the cleanroom (up to 1.7 times).

It remains to be seen how the ISO standards will be implemented in GMP regulations—particularly in Annex 1 of the EU GMP Guide.