In May 2003, the European Medicines Agency (EMEA) published a revision to Annex 1 of the EU GMPs that was implemented in September 2003 (5). The 2003 version of the sterile products requirements was created in response to the publication of ISO 14644-1:1999, the internationally accepted standard for airborne-contamination control. In particular, this version of the EU guidance tried to clarify a perceived requirement to control ≥5.0-μm airborne particles at very low levels with the ability to measure such low concentrations reliably. The net effect of the September 2003 changes was to frustrate and confuse industry with requirements that were written poorly in some areas or were plain bad science in others. In response to industry's negative reaction, the EMEA initiated another revision to the Annex 1 document. Proposals for the further changes were published on the Eudralex Web site in November 2004, with a closing date of April 30, 2006 for public comments (6).

The EU GMPs have a much greater impact than on just EU nations and those supplying them with medicines. The complete EU GMPs are adopted by the Pharmaceutical Inspection Convention and the Pharmaceutical Inspection Co-operation Scheme and are referred to as the PIC/S GMPs (7). In turn, many nations adopt this document as their GMPs. Thus, the effect of poorly written documents with elements of poor science could reverberate around the world and lead to confusion and unnecessary environmental control, monitoring, and deviation investigation work.

Table I: Proposed number of airborne particles in environmental grades A–D (per the November 2005 draft proposals).

Grade limits for airborne particles: classification

The following list includes the effects of the November 2005 draft proposals for airborne particles (see Table I) and associated requirements for classification and monitoring:

• Industry wants and expects to have excellent control of ≥0.5-μm particles and expects negligible concentrations of ≥5.0-μm particles in Grades A (at rest and operational) and B (at rest).
• Industry wants to avoid extremely large sample sizes for formal classification that would be required by specifying a very low limit.
• 1-m³ samples must be taken at each location for a formal classification of Grade A zones at rest and in operation, which is much more demanding than the current requirement to collect a total of 1 m³ for the zone under consideration.
• The sample size for Grade B at rest is not provided in the guidance. It might be thought that the 1-m³ sample size applies, however. If this is the case, then industry will bear a huge burden of airborne particle counting with limited value. It is for this reason that a formal classification of ≥5.0-μm particles in Grade B at rest should be avoided.
• Industry must avoid triggering classification or monitoring failures because airborne particles measurements could be in a range for which real and false counts might be confused. In formal classification, the proposed acceptance of a limit of 20 particles/m³ will be very helpful.
• A full classification of "in operation" conditions is required. This process would require an invasive testing regime not demanded previously. It always has been accepted that adequate confidence can be obtained from the "at rest" classification combined with operational monitoring. The guidance proposals suggest this "operational" classification could be carried out during media fills. Many parties will find it is an inappropriate time to add challenge to the process environment.