A guide to trending your cleanroom EM programme

Published: 13-Apr-2022

Facilities set their own rules for data trending and breaches. While there is no universally accepted method, there are a set of common factors to be considered as Microgenetics' Edward Webber explains

Environmental monitoring (EM) results should be analysed regularly to assess whether any trends can be identified in the data. Routine review of EM data provides confidence in the quality of manufacturing areas and the surrounding clean environments and ensures that any adverse trends which may be forming are detected quickly.

Detection of trends can highlight potential problems with environmental control systems. A single breach may indicate an isolated issue, however multiple breaches, or trends, may indicate a loss of control that must be addressed.

Consideration must be given to how data is grouped and analysed for trending purposes, for example, assessment of results from individual operators

Individual facilities should set rules for trending, and if these rules are breached, an out of trend investigation should be performed.

There is no universally accepted method for defining and identifying trends, but rules must achieve the goals of the EM programme and provide detail on the control of the facility. According to the 2020 draft of Annex 1: "Trends can include but are not limited to; Increasing numbers of action or alert limit breaches; Consecutive breaches of alert limits; Regular but isolated breaches of limits that may have a common cause, for example single excursions that always follow planned preventative maintenance" or "Changes in microbial flora type and numbers and predominance of specific organisms."

Some examples of trends that may be set within a facility are listed below:

  • Consecutive readings equal to or greater than the alert limits
  • Multiple recoveries of the same organism in several locations on the same day or over a course of several days
  • Three or more action level excursions for a sample type on the same day
  • Three or more excursions for a sample type in a room from four consecutive samplings
  • Increasing contamination recovery rates over a period of time
  • Unusual microorganisms detected such as gram-negative bacteria from dry areas or unusually high numbers of endospore-forming bacteria

Significant changes in microbial flora should be considered in the review of the data, and other trends should also be considered when analysing EM data, such as seasonal trends, trends for an individual person, or trends by area, lot type or shift.

Establishing trending rules

Trends are often seen as repeated breaches of alert limits, as this often indicates a lower level of contamination which may not be significant enough to breach an action limit but may still indicate a loss of control within an area or a facility.

When setting alert limits, it is important to analyse historical data to determine a normal or acceptable level of contamination for samples, and then set limits based on this. Establishing limits that reflect the normal operating conditions is important to ensure that any drift from normal operating conditions is detected.

Significant changes in microbial flora should be considered in the review of the data

Additional trend rules should be set out in the EM programme, and these should be assessed regularly to ensure that they reflect the operating status of the facility. Consideration must be given to how data is grouped and analysed for trending purposes, for example assessment of results from individual operators to demonstrate how each operator is performing.

As well as assessment of individual operators, trending across all operators may provide useful information about system-level processes such as gowning and should be assessed alongside trends of individual operators.

Consideration should also be given to graded areas, for example, a facility may only use Grade C environments for preparation of reagents to be transferred into manufacturing areas, and therefore assessment of all Grade C areas as similar units may be appropriate for trending purposes.

Alert limits should be set lower in the areas used as backgrounds for Grade A

However, some facilities may also use Grade C areas as background environment for Grade A Biological Safety Cabinets, and therefore it would not be appropriate to assess these areas in the same trending analysis as the Grade C prep areas. Alert limits should be set lower in the areas used as backgrounds for Grade A environments, as the impact of excursions in these areas is higher as there is a higher potential for contamination of the aseptic areas.

This in turn leads to the counts in these areas generally being lower because of stricter contamination controls.

Therefore, it is not appropriate to trend these different areas in the same way. These areas and locations should be defined within the EM plan and should have been identified and qualified during the validation of the EM programme.

Analysing your trends

In a busy pharmaceutical manufacturing environment, detecting and analysing trends can be challenging - there are often many samples taken each day, and there may be multiple analysts reading EM samples at the same time, or over a period of days. It can, therefore, be very difficult to pick up on an emerging trend quickly, until all of the data has been reviewed, input into a data storage system, and then analysed for trends.

For example, if a trend were triggered following two consecutive alert limit breaches, and a sample point was only monitored infrequently, it would be easy for this trend to be missed. If the analysts are reading hundreds of samples per day, or two different analysts read the samples on different days, it would be impossible for the analysts to remember the alert limit breach from a previous sample.

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Situations like this make it very difficult to act upon a trend immediately, especially if there are delays in data entry, such as awaiting identification results, or resource shortages.

This is where SmartControl can help - data is entered directly into the software and is analysed by the software immediately. Trend rules can be set by the user, and if a trend rule is breached, then the user will be notified immediately. Even if thousands of samples are entered into SmartControl, the analysis is performed automatically, and notifications can be sent to relevant managers or supervisors to trigger immediate investigation.

SmartControl even makes the investigation of these trend breaches easy - graphical analysis of personnel, locations or contamination can be instantly generated for inclusion in reports, and these can be generated on a reoccurring, consistent basis to ensure that the same information is available to everyone.

Trend analysis should be performed regularly and consistently to ensure that any changes in the facility are detected. SmartControl can help to ensure that this is done immediately and can also generate regular trending reports, making review of large volumes of data easy for facilities of any size.

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