EU GMP Annex 1 is a guideline that outlines the specific requirements for the manufacture of sterile medicinal products in the European Union. It was revised to cover the current regulatory and technological developments in sterile product manufacturing, and the final version was published on August 25, 2022 and began enforcement on August, 25 2023. This complete rewrite of the Annex raises interest in understanding the nuances of cleanroom operations, particularly in terms of occupancy states, classification, and monitoring. Let’s discuss these intricacies.

1. Annex 1: A Brief Overview

Annex 1 Environmental Monitoring has been a topic of discussion for professionals in the field. This document, which has been in development with contributions from the PDA and ISO, emphasizes the importance of a holistic contamination control strategy (CCS). The CCS provides a comprehensive approach to understanding how different contamination aspects interact within a facility. Monitoring, in this context, is not just a routine task, but a critical tool that demonstrates the effectiveness of the contamination strategy.

2. Occupancy States: In-Operation vs. At-Rest

One of the primary areas of focus in Annex 1 is the differentiation between “in-operation” and “at-rest” states. But what do these terms mean?

• At-Rest: This state refers to a cleanroom where all equipment is installed and operational, but no personnel are present. It’s essentially the room’s baseline condition, where everything is switched on, and airflow patterns are established as per the design criteria.
• In-Operation: This is the state where all equipment is functioning, and the specified number of personnel are present, performing their regular tasks.

ISO14644-1:2015 and EU GMP Annex 1 provide clear guidelines on these states. The distinction is crucial for both classification and monitoring purposes. For instance, the “at-rest” state is essential for the classification certification process, reflecting the room’s two extremes of functionality. On the other hand, the “in-operation” state is more about the room’s real-world operation, with personnel present and equipment in use.

3. Classification vs. Monitoring

A common misconception is that classification and monitoring are interchangeable. However, they serve distinct purposes:

• Classification: This is about certifying the cleanroom’s state. For instance, when certifying the “at-rest” state, the particle counter is activated, and after a delay, the operator leaves the room, allowing the counter to run without any personnel interference.
• Monitoring: This is a continuous process that ensures the cleanroom maintains its specified conditions. The room should achieve the “at-rest” state within fifteen minutes of personnel leaving. Monitoring helps demonstrate this capability.

4. Key Questions Addressed

With the introduction of Annex 1, several pertinent questions have emerged:

• Tubing Lengths: Earlier versions of the document mentioned a “short length” for tubing without specifying. The new revision clarifies that “short” should be about a meter.
• Occupancy State for Different Activities: Whether it’s inventory of raw materials or other non-manufacturing activities, the operational state should be defined based on the required number of personnel, which may not always be the maximum occupancy state.
• EM Sampling Personnel: For tasks like surface monitoring, it’s challenging to maintain the “at-rest” state since an operator needs to be present. Such nuances should be documented and noted in the record.

Understanding the intricacies of Annex 1 is not just about compliance but ensuring that cleanrooms maintain their integrity. Differentiating between occupancy states, classification, and monitoring is crucial for this. Now that Annex 1:2023 has been implemented, it is essential for professionals in the field to equip themselves with this knowledge to ensure that their cleanrooms operate at the highest standards.

In the ever-evolving landscape of cleanroom operations, staying updated with guidelines like Annex 1 is not just a regulatory requirement but a testament to an organization’s commitment to quality and excellence.

 

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Annex 1 Insights & Updates

The European Commission released its long-awaited Annex 1 regulation in August 2022. Our experts have reviewed this document carefully and have shared their insights with you. Read our latest Annex 1 Application Notes by clicking the titles below:

Review of Annex 1: 2022

Annex 1 2022 vs. Annex 1 2008: A side-by-side comparison

Validation and Qualification Approach Outlined in New Annex 1 Revision