Classification vs monitoring: What is the difference? Part 2

Cleanroom monitoring

Non-viable airborne particle monitoring is essential. Particles are significant because they can enter a product as an extraneous contaminant and can also contaminate it biologically by acting as a vehicle for microorganisms.

There are different particle monitoring systems with remote locations such as manifold and online monitoring systems.

For manifold systems, the particle counter should be connected to a manifold unit, which changes sampling locations per defined time, such as per minute. Between each sample, there is a buffer time that allows the particle counter and manifold to clean the sampling pathway.

Understanding online monitoring

These consequential sampling manifold systems are not suitable for monitoring a sterile pharmaceutical cleanroom because monitoring should cover all durations for each sample locations without delay or interruption.

But, different than manifold systems, online particle monitoring systems have independent particle counters, with a sampling isoprobe in each critical location. Without delay and/or interventions, particle monitoring can be undertaken for the full duration of critical processing, including equipment assembly in each selected monitoring location.

When we say online monitoring, most of the people consider it to be a 7 day/24 hour approach, which is wrong. Online monitoring means before, during and after production with a reasonable time frame to cover preparation, filling/production and the cleaning cycle.

Location, location, location

For cleanroom classification, the minimum number of single sample locations are defined based on EU GMP Table A.1. The cleanroom should be divided into zones of equal size, and sampling locations should represent characteristics of each zone. For cleanroom monitoring, sample locations should be defined based on formal risk assessment.

Each representative location should be set and verified based on historical data, trend and production routines.

Normally, this representative location is not more than 30 cm away from the work site, within the airflow and during operations.

The FDA’s aseptic processing guideline recommends that measurements to confirm air cleanliness in critical areas be taken at sites where there is the most potential risk to the exposed sterilised product, containers and closures.

The particle counting probe should be placed in an orientation demonstrated to obtain a meaningful sample. Regular monitoring should be performed during each production shift.

Non-viable particle monitoring should be conducted with a remote counting system. These systems can collect more comprehensive data and are generally less invasive than portable particle counters available today.

How to select locations for monitoring

The main considerations to select locations to be sampled are:

• All locations where there is a possibility of operator intervention, for example access points to the Grade A environment
• Original room classification studies, qualification studies and the rationales for previously used sampling/monitoring arrangements
• Areas where there are normally no interventions, but sterile components/products are still potentially exposed to airborne particulate contamination due to abnormal interventions or for other reasons
• The length of time that sterile components and/or products are exposed during processing: an example might be stoppers in a feed hopper. In this instance, there is little risk of intervention. However, the stoppers may well be sitting exposed in the hopper for some time, so that there is a potential for build-up of particulate contamination over time. It would, therefore, be good practice to sample air at this location to demonstrate continued compliance with the air quality being delivered to the components over the processing time.

In this case, critical sample areas to be considered are:

• The point of fill
• Component hoppers
• Inspection hatches
• Descrambler tables
• Stopper and capping stations
• Loading of freeze driers
• Unloading of sterile components which are not protected by autoclave bags
• Interfaces between equipment and the Grade A area
• Isolator transfer devices
• Aseptic manipulations
• Operator interventions

Table 3

Table 3 highlights the main differences between classification and monitoring based on sample duration, sample volume, and the number and output of sample locations.