The new Annex 1 and 5 µm Particles

Recommendation

17-19 September 2024

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In the current EU GMP Annex 1, the monitoring of 0.5 and 5 µm particles in clean rooms is a requirement. It refers to technical document ISO 14644, Part 1 for measurement. However, the limit for 5 µm for class ISO 5 (ISO 4.8) has been removed from this document. That is why there had been great expectations for the revised Annex 1 draft. The main question was whether the new Annex 1 would require the measurement of 5 µm particles or not. An EMA statement about the transition period in which Annex 1 will be revised can be found on the EMA's Q&A website:

"Annex 1 of the EU GMP guide is currently under revision and will take account of the updated ISO standard. In the meantime, for qualification or re-qualification of clean room facilities, medicinal product manufacturers may apply the updated ISO standard with reference to Annex C (counting of macroparticles), or may continue to follow the previous ISO standard. Routine monitoring, however, should continue to be carried out in accordance with the existing Annex 1."

Opinions varied within the pharmaceutical industry. For one thing, the trends for 0.5 and 5 µm particles are usually concurrent. On the other hand, 5 µm particles show issues in the clean room or in the room air more clearly. The new Annex 1 draft approaches the issue proficiently. It clearly differentiates between classification (in the course of qualification) and clean room monitoring.

The new chapter 5.25 includes a table with clean room zones and particle limits for the classification of a clean room. It does not contain specifications for 5 µm particles for the zones A, B, C and D. The limits for 5 µm particles for the "at rest" and "in operation" status equal the ones from the currently applicable document (chapter 4). However, the descriptive text of the new chapter names 0,5 µm or bigger particles for the classification of a clean room. For the initial classification, the document once more refers to ISO 14644-1, and states that a larger number of sampling points will be necessary especially for zones A and B in order to cover all critical locations. During the initial classification, sampling points should be spread evenly around the room. In later stages, e.g. during performance qualification (PQ), sampling points should be spread throughout the room based on a risk analysis. Here, the new document further differs from the old one; the chapter "Non-viable Monitoring" (9.13) once again lists the already mentioned table, this time including requirements for 5 µm particles for the zones A, B, C, and D (in zone D only for "at rest" status). The values equal the provisions from the table of the currently applicable Annex 1. The limit for 5 µm particles in zone A is further described with 20 per m3. This was supposedly chosen because of measurement limitations. In practice, alert limits are to be based on historical data or the qualification.

Back to the main question: what does the new Annex 1 draft say about the issue of 5 µm particles? - In reality, these particles must still be tested for, because who would classify a clean room and disregard a particle size which they will have to monitor later?

The original Annex 1 draft can be found on the EU Commission's website. Comments may be submitted until 20 March, 2018.