Highlighted by the introduction of regulatory stipulation in August 2023, real-time monitoring for cleanrooms involves using particle counters and other devices to provide data on different parameters in a continuous manner.
In recent years, pharmaceutical cleanrooms have welcomed continuous monitoring of their commercial processes. “The main driver has been European Union (EU) Good Manufacturing Practice (GMP) Annex 1, which came into effect in August 2023,” Dr Tim Sandle, Head of Quality Assurance at GxP Compliance, Kedrion Biopharma, tells Pharmaceutical Technology.
Sandle says there has been an increase in interest as companies seek to comply with the regulation. Rising demand is especially happening with synergistic systems that control particle counts and active air samplers through a central hub, he adds.
“There is also continuing interest in rapid microbiological methods, especially with technologies that can make assessments of the air to differentiate particles and identify those considered to be microbial-carrying,” Sandle details. These types of technologies are especially suited to isolators and other barrier systems.
The Annex 1 rule
The Annex 1 rule requires aseptic operations to be monitored on a continuous basis. “The Annex has been adopted by the Pharmaceutical Inspection Co-operation Scheme (PIC/S), where the US Food and Drug Administration (FDA) is a member, so it effectively has global status,” Sandle adds.
Many in the pharmaceutical sector were already using continuous monitoring approaches, or at least some form of more expansive monitoring, following risk-based approaches, such as adopting ICH Q9R1 principles, Sandle shares. Adopted in January 2023, with the final version including stage 4, the guideline details information on quality risk management.
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In August 2023, Mark Hallworth, life sciences senior GMP scientist, at particle measuring systems, published an article in the American Pharmaceutical Review exploring how to design an environmental monitoring solution for GMP applications. In it, he states that while Annex 1 gives more emphasis “to establishing the correct sample locations and techniques based on risk and reviewing data to support product release,” it does not change many aspects of the requirements for monitoring and is “an enhancement to the documentation requirements more than the traditional expectations of a continuous system”.
However, with a spotlight on the cleanroom approach, the focus brightens on how technology can help pharmaceutical manufacturers adhere to this latest regulation. In line with that, Cherwell, a technology provider for continuous monitoring, recently launched BAMS (Bioaerosol Monitoring System), an airborne particle counter used to detect inert and microbial particles in real-time continuous monitoring.
The rise of continuous monitoring
“Continuous monitoring refers to collecting data in direct relation to a pharmaceutical process across the duration of the activity,” Sandle says. It is a requirement for aseptic processing, which is mandatory within EU GMP Grade A ISO 14644 class 5 and advisable for Grade B ISO 14644 class 7.
Continuous monitoring includes collecting data, such as conventional environmental monitoring and examining it retrospectively and assessing other environmental parameters in ‘real-time’, such as pressure differentials, airflow velocities and particle counts.
With viable monitoring, the continuous monitoring component generally involves air samples. It will consist of exposing settle plates, replacing these every four hours, and running active air samplers.
“The best active air samplers are those that can monitor continuously, taking a sample over four hours like a settling plate,” says Sandle. However, these are newer technologies. For those pharmaceutical environments using older models, a risk-based approach needs to be developed to determine the appropriate sampling intervals. “This would include at least the start, middle, and end of the aseptic processing session,” says Sandle.
“Rapid microbiological methods fit well with the continuous sampling paradigm,” Sandle details. Bioluminescent particle counters, which can detect biological metabolites, can differentiate between inert particles and those particles likely to be biological, which can pause operations to reduce the likelihood of contamination.
In August 2022, researchers published what they hailed as an “experimental study” exploring biofluorescent particle counters for real-time bioburden control in aseptic cleanroom manufacturing. It explored real-time viable particle counters in pharmaceutical cleanroom operations under ISO class 8/Annex 1 Class C ‘in operation’ conditions. The researchers found that the implementation of these can achieve a quality advantage for ISO class 8 cleanrooms for a continuous, documented control of the cleanroom status and, therefore, help to enable a reduction of air change rates (ACR) to save energy.
Progressing pharma cleanroom capabilities
There are several advantages to implementing continuous monitoring in pharmaceutical cleanroom technology. “The first is gaining a more comprehensive overview of what has happened during an aseptic processing session, including how Grades A and B interact,” says Sandle. Developing this thorough understanding increases the amount of information available for the batch record and provides a better assessment of whether a batch of medicinal products is suitable for release. It also helps to adopt a holistic approach to contamination control.
“The second is being able to pause certain aspects of the operation in ‘real-time’,” Sandle adds. Although this is not possible for all types of monitoring if there is a drop in airflow velocity, this increases the risk of turbulent air and contamination transfer or a drop in pressure between cleanrooms, which could lead to an increase in contamination transfer from a less clean area. Process personnel can pause operations and see if the data improves or take appropriate action.
Similar tracing and responding can take place with airborne particles, provided that particle counters are equipped with appropriate alarms. The tracing and responding would be a standard feature with a network of particle counters as with a facility monitoring system.
The third area is having a large set of continuous data from which trend analysis can be performed. “Most environmental monitoring makes little sense as a single reading; putting the data together enables the bigger picture to be seen, especially when the data is visually represented through charts,” Sandle continues. Time-based trends enable different events to be cross-matched against the data, which helps considerably with root cause analysis and for setting corrective and preventative actions.
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