The EU GMP Annex 1 (2022) and the 5 µm Particles in Grade A & B

The 2022 EU GMP Annex 1 guideline is bringing some changes to cleanroom classification and monitoring, particularly about the 5 µm particles in cleanroom grade A and B. This has led to a discussion within the industry regarding the interpretation and practical application of these requirements.

Classification vs. Monitoring

Annex 1 differentiates between classification and monitoring for the 5 µm particles in grade A and B. For cleanroom grades A, B, C, and D, the number of permissible particles correlates with room size, equipment, and personnel. These limits, derived from historical standards and current guidelines, are as follows:

ISO 14644 states: Low 5 µm-values (> 5 µm are "macroparticles") - as 29 pcs - are for technical measurement reasons and statistically irrelevant and therefore - science and risk-based - cannot be the basis for a cleanroom classification.
Annex 1 is accepting this - but keeps the 5 µm requirement for monitoring. This is explained as follows:
"The occasional indication of macro particle counts, especially >= 5 µm, within grade A may be considered to be false counts due to electronic noise, stray light, coincidence loss etc. However, consecutive or regular counting of low levels may be indicative of a possible contamination event and should be investigated. Such events may indicate early failure of the room air supply filtration system, equipment failure, or may also be diagnostic of poor practices during machine set-up and routine operation."

Monitoring, however, demands continuous assessment to capture all interventions, transient events, and any system deterioration. The challenge lies in the volume of air to be monitored: While a cubic meter is the standard for classification, a cubic foot is often suggested for monitoring due to the practicality of existing equipment and the shorter measuring time.

The 1 (one) Particle Alarm Dilemma

When shifting the limit from cubic meter to cubic foot for 5 µm particles, a single particle detection triggers an alarm. This essentially suggests a requirement for the absence of any >= 5 µm particles. One approach to this stringent requirement is to study historical trends and adjust the limits: Increasing the 5 µm particle limit above one and decreasing the 0.5 µm particle limit below 100.

Historical Context and the FED 209D Specification

Historical cleanroom standards, such as FED 209D, offer valuable insights.
FED 209D was based on different particle sizes per cubic foot, a unit still used by many particle counters. When ISO 14644 replaced FED 209D, particle counts were adjusted for cubic meters, resulting in the odd numbers seen today (e.g., 35,200 or 352,000 particles for 0.5µm). Annex 1's limits, when correlated to these historical standards, can be rationalized and adapted.
To set practical limits for 5 µm particles, considering a rolling time window can be effective. For example, a 5-minute sampling period can allow for adjustments based on real-time data, where 29 particles per cubic meter translate to approximately four particles per 141.5 liters. However, the potential for false alarms due to short sampling times necessitates careful consideration.

Continuous Monitoring Strategies

Continuous monitoring does not imply continuous data but rather consistent sampling. Strategies to address the 1 particle/ft³ alarm include:
1. Extended Sampling Periods: Taking samples longer than one minute to reduce the multiplication factor.
2. Rolling Averages: Responding based on a rolling average of several minutes' data.
3. Frequent Short Samples: Taking shorter samples but averaging over time to mitigate false alarms.
4. Rate of Occurrence: Focusing on the frequency of particle counts rather than single instances, akin to viable particle monitoring in USP 1116.

Conclusion

The revised Annex 1 guideline emphasizes the monitoring of >= 5µm particles, necessitating practical and scientifically sound approaches to compliance.

By understanding historical standards, leveraging continuous monitoring strategies, and adjusting particle limits based on data trends, pharmaceutical manufacturers can maintain rigorous cleanroom standards while minimizing unnecessary alarms.
Each facility may need to tailor its approach based on specific operational requirements and historical performance data, ensuring both compliance and operational efficiency.