Automated environmental monitoring in sterile pharmaceutical production

In the context of EU GMP Annex 1, cleanroom monitoring has gained further importance. © Syntegon / In the context of EU GMP Annex 1, environmental monitoring has become increasingly important. © Syntegon

The new Settle Plate Changer (SPC) 2000 from Syntegon automates passive microbial monitoring. © Syntegon

The compact SPC can be seamlessly integrated into machines from Syntegon and third-party suppliers. © Syntegon

Muhammed Ali Turac, Project Manager Automation, Syntegon Technology © Syntegon / Muhammed Ali Turac, Project Manager Automation, Syntegon Technology © Syntegon

Steffen Gröber, Global Product Manager, Syntegon Service © Syntegon / Steffen Gröber, Global Product Manager, Syntegon Service © Syntegon

In sterile pharmaceutical production, cleanroom quality plays a crucial role and must be monitored continuously. Alongside particle measurement, viable monitoring is a key priority. New, automated systems help minimize the risk of contamination while simultaneously increasing productivity by reducing the need for manual intervention.

Robust sterile processes are essential to maintaining the quality of parenteral pharmaceuticals. A key factor influencing these processes is the condition of the production environment. Any step involving the aseptic processing of sterile products, ingredients, containers, carriers, or components must take place in a cleanroom environment, as defined in detail by relevant ISO standards and regulations such as EU GMP Annex 1 or FDA GMP Guidance. Criteria for particle concentration and size are specified to achieve a certain cleanroom class.

Particle measurement and viable monitoring

Stable quality in the production environment requires controlled temperature and humidity, continuous air exchange, a defined air flow, and regulated positive pressure relative to the environment of lower cleanroom classes. However, even when all these requirements are met, continuous monitoring remains essential to detect deviations at an early stage and ensure consistent cleanroom quality. Particle measurements can be carried out using physical measurement technology, which reliably indicates the size and number per volume element and can warn when defined limit values are exceeded or shut down production.

With microorganisms, the situation is more complex: individual microorganisms are too small to be detected in real time using microscopic methods or to be reliably distinguished from non-viable particles. However, microbial colonies can be counted and identified when grown on a suitable culture medium. The microbial count can be determined using both active and passive methods. In active sampling, a defined volume of cleanroom air is continuously or intermittently drawn through a culture medium. In passive sampling, culture media are exposed to the cleanroom environment at critical points in the production process. The sedimentation rate of viable microorganisms per unit of time is then measured using culture medium plates.

The challenge of settle plates

The placement of culture medium plates required for passive viable monitoring – commonly referred to as settle plates in the pharmaceutical industry – presents several challenges. These plates should be positioned close to critical process steps, such as filling. At the same time, they must not obstruct access to technical equipment that requires manual setup, changeovers, or adjustment. Ideally, the settle plates are placed at product level, allowing airborne microorganisms to come into contact with the culture medium through the surrounding airflow.

Adding to the complexity, Annex 1 requires these settle plates to be replaced after no more than four hours – a process that previously involved manual intervention by operating personnel within the pharmaceutical process zone. In the filling and sealing of injectable solutions, Restricted Access Barrier Systems (RABS) and isolators are commonly used, with glove ports enabling the replacement of culture media. However, the gloves must be checked for integrity before and after each intervention. This entire process can take up to an hour and, particularly during extended production campaigns or with high-value pharmaceuticals, can lead to economically significant losses.

Higher efficiency in production

Automated settle plate changers offer an effective solution: the settle plates are automatically replaced after the prescribed four-hour interval without human intervention. This represents a significant productivity gain, particularly for filling lines with longer batch times, such as in the production of insulin, vaccines, or heparins, which are typically processed over several days. However, the use of these settle plate changers is also beneficial for shorter batches, as they reduce the number of glove interventions required for routine tasks.

To enable retrofitting on existing lines, these systems are compact in design and require no major modifications to the machine base plate. Only a power supply and a data connection are needed. Particularly in existing lines, it is essential that the changer systems can accommodate settle plates already in use at the defined sampling positions. In some cases, this also requires compatibility with settle plates featuring lockable lids. Integrating a data matrix code reader that links each plate’s unique serial number with its exposure time is a useful addition for automated workflows, traceability, complete documentation, and error-free evaluation of culture media.

Use case: SPC from Syntegon

The systems available on the market can hold up to six or twelve Petri dishes per magazine, enabling a maximum of 24 or 48 hours of uninterrupted production before a magazine change is required. This also applies to the new Settle Plate Changer (SPC) from Syntegon. First presented at Achema in June 2024 and winner of the German Packaging Award, this solution automates the replacement of settle plates. Calculations have shown that machine availability can be increased by up to 300 hours per year. In addition, optional data matrix code scanning ensures greater process reliability and traceability.

In addition to significant productivity benefits, the SPC fulfills an important requirement of Annex 1: in the second chapter, the document specifically highlights automation and robot systems for maintaining sterility under the heading “appropriate technologies.” Manual intervention in the process zone for cleanroom monitoring can be reduced by up to 80 percent with the SPC, thereby minimizing the risk of contamination. The new system from Syntegon is available both with the purchase of a new machine and as a retrofit for existing systems. It can also be easily integrated into third-party machines.

Heading into an automated future

Regulatory requirements make it clear: the pharmaceutical industry must – and will – increasingly shift toward automated processes. This applies not only to the production steps themselves but also to passive viable monitoring in cleanrooms. Fewer manual (glove) interventions reduce the risk of contamination. Combined with improved traceability and data consistency during sampling, this leads to significantly higher cleanroom monitoring quality. For pharmaceutical manufacturers operating in a cost-sensitive market, increased productivity is another important factor – and will gradually pave the way from conventional to fully automated systems.