Notes on Annex-1 Part four

Impact of new EU-GMP Annex-1 to classification, qualification and monitoring requirements for clean rooms

Since 2021 Progress has published a series of articles on the new EU-GMP Annex-1, for which consultation started in 2020 and ended in 2021. in August 2022 the guidance document was approved and it will become effective as of August 2023. This series examines different aspects of the changes to this important GMP document. The first article focused on the concept of contamination control strategy and the selection, qualification and validation of disinfectants. The second article discussed the ins and outs of the Contamination Control Strategy in more detail, and the third article examined the potential impact of the Annex-1 to the manufacture of non-parenteral / non-sterile medicinal products. This article will discuss the changes in classification, qualification and monitoring of clean rooms.

The previous three articles on the new EU-GMP Annex-1 have all highlighted issues that may have a profound and immediate impact to established quality systems and may require updates of current procedures, or that could necessitate the definition and issuance of new strategic or procedural documents.

This article examines one more noticeable change in the content of Annex-1, but one with less impact and urgency. In the new Annex-1 the criteria for measurement of particles of 5.0μm and larger, as performed for clean room classification and qualification versus those performed for regular environmental monitoring, have changed and are now separated from each other. In previous versions there was no separation between the classification, qualification and monitoring criteria, as the same criteria were used for all purposes.

Particle measurement requirements from the new Annex-1
During its lifecycle EU-GMP Annex-1 has struggled with the requirements and acceptable limits for particles, and especially the ≥ 5.0μm particles. In the first version (1997) the limits for grade A and B areas were defined as 0 for grade A ‘at rest’ and ‘in operation’, and for grade B ‘at rest’. For grade B ‘in operation’ a limit of 2000 ≥5.0μm particles was defined; all values related to a sample of 1m3 of air. In later versions this was changed to 20 particles for grade A ‘at rest’ and ‘in operation’, 29 particles for grade B ‘at rest’ and 2900 for grade B ‘in operation’.

The new annex-1 defines the limits for ≥5.0μm particles for classification and qualification of grade A and B areas as being ‘not applicable’ for grade A ‘at rest’ and ‘in operation’ and grade B ‘at rest’. For monitoring purposes action limits have been set at 29 particles ≥5.0μm for grade A ‘at rest’ and ‘in operation’ and grade B ‘at rest’. For grade B the ‘in operation’ limit has been set at 2900 particles ≥5.0μm.

Shortly after the first publication of Annex-1 the first version of ISO-14644 was issued (1999), which was immediately recognized as the standard to follow for classifying and qualifying clean rooms. The US standard this ISO document relates to (Federal Standard 209) was declared obsolete shortly afterwards. ISO14644 does have its own classification system, in which ISO class 5 does agree with the earlier used Fed.Std. 209 classification class 100 and to the EU-GMP grade A and B ‘at rest’ conditions, while grade B in operation requirements agree with ISO class 7. ISO14644 originally defined 29 particles of 5.0μm and larger as class limit for class 5 areas, while in the version of 2015 this was changed to ‘not defined’, indicated with (-).

From its first publication the Fed.Std. 209 defined that for class 100 areas (ISO class 5) particles of 5.0μm and larger were deemed ‘not applicable’. As mentioned earlier ISO did concur with this in its 2015 version. With the current changes EU-GMP Annex-1 is at least in line again with ISO14644 for area classification and qualification, but why it is holding on to the 29 particles of 5.0μm and larger for monitoring remains unclear.

When considering that particles of 5.0μm and larger are of a size and weight that makes them less mobile than particles of 0.5μm, it can be assumed that they will not easily be airborne and float around, especially under unidirectional airflow conditions. They may be precipitated before they can be measured. In addition, most air samplers for particle measurements operate at an airflow rate of 1 ft3 (±28Ltr) per minute. To measure 1 m3 of air they will have to sample for approximately 36 minutes, a time that may fit with classification and qualification activities, but that does not work for monitoring operational activities. This also means that while monitoring operational activities, low counts of particles of 5.0μm and larger do not necessarily indicate a clean, trouble free environment. There is a serious risk that results for particles of 5.0μm and larger in grade A do not represent the actual situation. Transient spikes may go undetected.

ISO14644-3 defines that for measuring particles of 5.0μm and larger a sample volume of at least 0.28m3 is required (= 10Ft3, or 10 minute sampling).
Consider that an actual particle amount just below the class limit of 29 particles would translate to approximately 1 particle per minute on average in a system sampling at a rate of 1 Ft3/min. Therefore the counting accuracy and efficiency will be very low.

On the other hand it can be argued that 5.0μm particles are important indicators of potential system contamination or technical failures in the clean area and they could be carriers of microbial contamination. For this reason Annex-1 defines that companies should be aware of the potential shortcomings in the measurement of particles of 5.0μm and larger, but should also consider their potential role in early detection and as part of the wider contamination control strategy. Annex-1 therefore states the expectation that users will set alert levels based on historical data and that recurring results above the alert limit but below action limit are not disregarded, but are considered indicative of a problem and potential for contamination. Alert level excursions are expected to trigger an alarm, be treated as non-conformances and investigated for root cause and potential impact. Most likely the use and value of 5.0μm particles in monitoring will remain a topic for debate in the coming years.

What does this mean for quality systems?
After discussing these changes to clean room classification, qualification and monitoring in the new Annex-1 the most important question remaining will be what the practical implications for current quality systems are.

Let’s assume you are responsible for the quality system of an established, GMP-licensed company manufacturing sterile medicinal products with fully qualified clean rooms. In that case there is no urgent need to implement changes to your system once the new Annex-1 becomes effective. Your clean rooms are already qualified and their qualification status will not change. The change in monitoring requirements actually constitute a slight widening of criteria for particles of 5.0μm and larger (from 20 to 29 particles/m3).

The most important change will be the need to set alert limits, install alarms on these alert limits and start investigations and actions following any excursion of an alert limit. Such excursions should be considered important indicators for the effectiveness of the contamination control system. Furthermore you will have to evaluate the need to make changes to your clean room qualification and environmental monitoring procedures and work instructions, as well as to your review and evaluation programs. Wherever the particle limits as mentioned in Annex-1 are used: check all procedures, work instructions and other documentation and update them accordingly.

The more important change of implementing a contamination control strategy closely relates to the issue discussed in this article. Most likely you will arrive at these conclusions on qualification and monitoring of clean areas when evaluating your contamination control systems in place as part of determining the contamination control strategy.

As discussed, a new version of the EU-GMP Annex-1 has been approved and will be effectuated soon. This new version contains several important changes. One noticeable change compared to previous versions is that classification and qualification of clean rooms is now fully separate from the activity of operational environmental monitoring. At the same time changes have been made to the limits for particles of 5.0μm and larger for the grade A and B areas. For monitoring data it is expected that the users of this annex will set and actively use alert levels on the monitoring results for particles of 5.0μm and larger in grade A and B areas. As a consequence procedures and work instructions in your quality system may need updating, and technical adaptations for adjusting the alert levels may also be required.

Progress can help you in all aspects of assessing your operation, performing risk assessments and critical control point assessments, and developing and implementing the necessary changes to your quality system, including developing a suitable CCS for both Active Pharmaceutical Ingredients and Medicinal Products.