FAQ - 製薬/生命科学（ライフサイエンス）における微粒子測定

質問
More and more pharmaceutical companies in France tend to sample a cubic meter per point for qualification purpose in grade A, B and sometimes C. If you have some fresh inputs from leading pharmaceutical industries in teh US or the best directly from the FDA please share them.

回答

The rationale for cubic meter certification comes from the ISO14644-1 formula for minimum sample volume required at each location:

Vs = (20 / Cnm) * 1000 (formula B.2)

If we put the value of 1 (maximum permitted number of particles at 5.0um in Class A) into the formula, we actually obtain a result of 20 m^3 to be sampled at each location. Now the EU commission realized this was la little nonsensical so changed that to require a minimum sample volume of 1 m^3 at each zone, which has since been misinterpreted to mean a fraction of an m^3 at each location, given several sites per room. However if we put the Grade B operational limit in (5.0 um = 2000) we now have 10 litres at each location, or according to ISO14644-1 1-minute minimum sample time duration.

So from here we deduce that a 1 m^3 sample is required for certification for ONLY the Grade A (At rest & operational) and Grade B (At Rest) states.

You have undoubtedly heard that there are changes afoot for the EU GMP Annex 1 limits and regulations. It is very explicit here that certification must be done in conjunction with ISO14644-1 (it is also required for the current Annex 1, but is lost in the text) and now they insist that a 1 m^3 sample is taken at each location for certification purposes as mentioned above. It is not a requirement for Grade B Operational nor is it required for Grades C and D.

That is the state of Europe right now and how it is likely to change, unfortunately there is confusion over the understanding of the requirements for particle counting and confidence limits that it imposes, a better picture is seen when one uses the old FS209E standard as a cross reference document, albeit now retired.

The USA and hence the FDA regulations are also somewhat confused. There is a requirement under the 2004 FDA Guidelines on Aseptic Manufacture that Critical areas be certified to be ISO 5 and supporting areas be certified to an ISO classification determined by the activities taking place in that room. However in a move to respond to the ICH and more specifically PIC/S they are looking at harmonizing closer to the EU GMP limits and requirements and as such do look at 5.0 um monitoring and certification, although at this time they have not imposed limits to the macro particles in an environment. In our dealings with US companies the certification has been done either historically to FS209E or currently to ISO14644-1 as described exactly in those standards, the FDA have ensured certification has met standard and that monitoring assesses the potential risks of exposure. This certification route from the EU is actually better echoing what the FDA have done, and the FDA better echo what the EU are doing for monitoring; so truly an equal harmonization process with sharing on both sides.

I hope this information helps you progress to FDA approvals.

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