In its first major revision since the original release in 2000, ISO 14644-2 was updated and approved as an International Standard in October 2015 and published in December 2015. This blog aims to provide a brief overview of the changes, but more importantly, how the changes affect the current PIC/S Guide to GMP for Medicinal Products – Annex 1 Manufacture of sterile medicinal products (PE009-12) and the monitoring requirements of the average pharmaceutical cleanroom including:
- The demonstration of control by monitoring, which now requires a documented monitoring plan including a risk assessment
- Clarification to in-operation monitoring requirements for processes that inherently produce particles, and
- Periodic classification or reclassification, which should now be performed annually for all classifications but can be extended.
The 2015 updates to ISO 14644-1 relating to classification, ≥5.0µm particles in Grade A and Grade B environments (ISO Class 5), and sampling changes should also be considered in conjunction with this blog.
ISO 14644-2:2015 stipulates that in order to gain assurance that a cleanroom/zone is performing, a monitoring plan shall be created, implemented and maintained. The following steps should be followed:
1. Perform a risk assessment to understand, evaluate and document the potential for adverse contamination events.
2. Develop a written monitoring plan.
3. Review and approve the plan.
4. Implement the plan by performing the monitoring.
5. Analyse, trend (where appropriate) and report performance.
6. Document and implement actions or corrective actions required.
7. Perform periodic reviews of the monitoring plan.
The schedule of testing tables, which detail reclassification frequency, contained within the 2000 edition of the standard have been removed. The updated standard states that periodic classification/reclassification should be undertaken annually, however, the frequency can be extended based on a risk assessment and the existence of consistently compliant data (as defined in the monitoring plan) from the monitoring system. Reclassification should also be performed after modification to the installation and/or operation of the system, at which point the monitoring plan should also be reviewed.
The removal of the tables of frequencies has also made the requirement for supporting tests (differential pressure, airflow velocity and volume, temperature/humidity, etc) during classification less clear. However, these supporting tests, that may influence the environment, the monitoring system or the results obtained, should be considered while defining the monitoring plan.
ISO 14644-2:2015 has recognised that in-operation monitoring may not be appropriate for processes that inherently produce particles that are of no threat to the process or product. The standard states that, in these cases, it may be appropriate to rely on periodic at-rest classification, or operational classification of simulated operations as opposed to the monitoring of airborne particles in-operation. This makes the standard more consistent with Section 9 of Annex 1 for the monitoring of Grade A zones, however Section 8 does state that “Cleanrooms and clean air devices should be routinely monitored in operation…”.
The name of ISO 14644-2:2015 has been updated to Part 2: Monitoring to provide evidence of cleanroom performance related to air cleanliness by particle concentration. The standard is now solely focused on monitoring.
The requirement for valid calibration certificates of test equipment is stated in the updated standard including a reference to ISO 21501-4 relating to the calibration of airborne particle counters.
The inclusion of two informative annexes provide guidance on:
- Developing the mandated monitoring plan including
- Risk assessment considerations,
- Pressure differential monitoring,
- Airborne particle monitoring systems,
- Airflow velocity and volume monitoring, and
- Other general considerations.
- Considerations for setting alert and action levels.
March 2015 saw a concept paper released jointly by the European Medicines Agency (EMA) and PIC/S that detailed the updating of Annex 1. While we are not certain what the update to Annex 1 might contain at this stage, we anticipate it will accommodate the 2015 revision of ISO 14644-1 and ISO 14644-2. Will we see the clarification of in-operation monitoring, reclassification frequency or the inclusion of supporting tests (differential pressure, airflow, etc.)? These issues and other hot topics will be discussed in detail at the annual GMP and Validation Forum.
You might also be interested in our blog on Microbiological Environmental Monitoring: Getting Back to Basics.