Selecting particle count points for a continuous FMS system

Here, based on practical experience and regulatory commentary, Joe Gecsey of Hach Ultra offers his view of “best practices” to provide a basis for sample point selection in both aseptic and general cleanroom areas.

The most frequent questions from users designing a continuous or nearly-continuous monitoring system for airborne non-viable particle counts are: “How do I select the best sampling positions?” And: “How many sample positions are needed?” Well-chosen positions and sampling strategies can offer a solid profile of the process occurring in the clean zone and provide good data to satisfy regulatory scrutiny as well as the internal quality need for sufficient information for root cause analysis. Poor or insufficient sample positions will leave the quality group without good knowledge of the quality of the air envelope surrounding the process if the results of a process are less than adequate and perhaps lead to challenges by regulatory authorities of the data obtained.

Both the European and American authorities are encouraging the shift to more detailed and automated systems, especially for aseptic processes, for which the effects of contamination is of greater concern because there is no terminal sterilisation of the final product. These areas, known as “critical” zones or “grade A” receive specific attention in the guidances regarding monitoring non-viable airborne particles. But these documents are mute regarding the number and placement of sample points. The most direct guidance is from the American document, suggesting that the sample positions for the “critical” area be set within 1 foot (30 cm) of the exposed components or product and within the airflow and that sampling be done during the filling/closing operations. But no mention is made about the number of positions. The EU GMP Annex I provides no assistance in these decisions.

For a process area already in use, it is common for the end-user to start with the number and position of points selected by the quality group for their daily, weekly and monthly sampling. Invariably, this number of points is too large – often by a factor of 10 – for an affordable continuous monitoring system. Also the system designer must consider the amount of data that the system and its users will need to assimilate. If sampling occurs at one-minute intervals, each point would produce almost 500 data points for each monitored size during an eight-hour production period. Often there are two sizes monitored – 0.5 microns and 5 microns – so the number of data points doubles to 1000 per shift per sample point.

Another standard that users often turn to is ISO 14644-1, which helps classify cleanrooms and zones according to the airborne non-viable count. However, these standards are intended for formal testing at intervals of every six or twelve months not for daily monitoring. ISO 14644-2 does briefly discuss daily monitoring but offers no specific guidelines. In a forthcoming update to 14644-1 and 14644-2, there may be some expansion of this discussion but these documents offer little help today in setting up a sampling strategy.

If we consider this example of an aseptic filling room with a vial washing system on the left and freeze dryers in Figure 1, ISO 14644-1 would suggest monitoring at nine or more positions to conduct a certification of the room.

But considering the actual filling equipment being used, the presence of an entryway and the need for maintaining the air quality in the loading area of the freeze dryers (Figure 2), the suggestion would be to sample 14 positions to characterise this area on a six-month basis. But this still will be more points than are needed for a general continuous monitoring system where the focus is on having sufficient information to assure everyone – including the regulators – that the area is under control.

In Figure 3, we decide to use only the key positions that will give us the most help in root cause analyses. These points are determined by the places where the operators are most likely to make an intervention during the process. Because operators, and the interference with the airflow caused by their movements, represent the greatest opportunity for the occurrence of a contamination event, the points of intervention should be monitored. Additionally, a general room sample point located near the doors will provide a view of the grade B or surrounding area as well as offer the possibility of an alarm if contamination were to enter the room through the doorways. If the area were strictly a liquid filling process, and the freeze dryers were not used, then the points at the far right of the diagram (numbers 7 and 8) would not be needed. All of the sample points would be mounted near the working height in order to effectively show the particulate air quality that the exposed sterile materials are moving through.

So, the key issues in setting up monitoring points are a) where the work is being done, b) the potential exposure of the product or components at that point, and c) the possibility of operator intervention in the process. The sample points should reflect an assessment that the risk to the product at that point is high enough to justify the expense of monitoring it continuously.

The following example is for a non-sterile process being conducted in a larger room, rated as ISO Class 7 (grade C or “Class 10,000”). Setting up sample points following ISO 14644-1 would dictate that a minimum of 40 positions should be sampled using a grid pattern. This would provide the certification of this area on an annual basis. But this method does not reflect the nature of the installed equipment, the operators’ activities and the flow of the product. Again, thinking about the activities and risk of contamination of the product at the various positions can help to determine the most valuable points for a continuous system. The end result is the selection of 17 sampling positions in this large area as being the most crucial for understanding and (if necessary) defending the air quality during a process. This number of positions is far fewer than the number dictated by ISO 14644-1, and, more importantly, are selected to help understand that potential contamination to the product by operators and by process equipment at the positions where the product is most vulnerable.

There are 3 general styles of monitoring for airborne counting: manual, sequential and continuous. Different types of instrumentation are used in each style. It is interested to note that although the EU GMP Annex I uses the term “continuous” for the sampling of grade A, sequential systems based on manifolds have been deemed acceptable in many critical areas. This style of monitoring, using one counter that is sequenced through the sampling points with the aid of a manifold, would be considered “nearly continuous” by most in the industry, whereas the remote style of counter – where a dedicated sensor is placed at each sample point – is a true continuous sampling style.

Joe Gecsey is the Life Sciences Application Manager at Hach Ultra in Grants Pass, Oregon, USA. He is responsible for tracking regulatory changes regarding particulate counting in the life science industry. He has conducted seminars throughout the world on particle counter design and applications. He received a Bachelor of Science degree from the University of California in 1974 and has been employed as an engineer and technical advisor by Hach Ultra (previously Met One) since 1984. He can be reached by telephone at: +1 541 4726526 or by email: jgecsey@hachultra.com.

“A continuous measurement system should be used for monitoring the concentration of particles in the grade A zone, and is recommended for the surrounding grade B areas” – from the EU GMP Annex I

“Nonviable particle monitoring with a remote counting system is generally less invasive than the use of portable counting units and provides the most comprehensive data” – from the FDA Guidance for Industry: Sterile Drug Products Produced by Aseptic Processing