Drug filling operations have been carefully progressing towards adopting biofluorescent particle counters (BFPCs) as a next-generation environmental monitoring (EM) method. A 2025 benchmarking report from BioPhorum Fill Finish workstream, “Alternative and Rapid Micro Methods for Biofluorescent Particle Counters (ARMM-BFPC)”, describes the progress of 11 companies towards adopting the technology, based on input from May to December, 2024. Furthermore, it cites user challenges such as interference testing and validation, and it describes trends in operational readiness and regulatory acceptance.
At Cytiva, we are excited to see this report published as it aligns with our direction, which is informed by industry trends and the needs of customers who use our robotic, gloveless isolators. According to Michael Miller, PhD, President, Microbiology Consultants, LLC, a subject matter expert (SME) who collaborated with Cytiva in the implementation of BFPCs within the SA25 aseptic filling workcell, it’s been a long haul for the industry to adopt rapid and alternative microbiological methods. He adds, “Regulators would like to see these types of technologies in place because we can react a lot faster when there is a contamination event. And of course, this is going to help us to get the drug product out to those [people] who need it the most.”
Read on to learn how working with Cytiva can help smooth your path to BFPC adoption.
Streamlining the evaluation step
The report lists the steps in evaluating BFPC technology:
- Reviewing the technology
- Selecting the vendor(s)
- Performing proof of concept/feasibility studies
- Purchasing the equipment
- Performing risk/benefit analysis
- Assessing supplier capacity
We evaluated three BFPC vendors: Plair, TSI, and Micronview, conducting a technical review of each BFPC design and a supplier attribute review of each vendor. Considerations included regulatory acceptance of the design, instrument capability to perform viable and nonviable monitoring, flow rate (1 CFM/28.3 lpm as per Annex 1), production capacity, lead time, calibration frequency and service capability, among others. Based on this process, we selected TSI as the vendor of choice with immediate compatibility with our SA25 aseptic filling workcell. We will evaluate the industry's continuous improvement of BFPCs to determine if additional vendor compatibility should be made available.
Taking the selection process a step further, we have integrated the software of the Biotrak™ Real-Time Viable Particle Counter with the software of our SA25 aseptic filling workcell, which allows alerts to appear on the human machine interface. This integration enables comprehensive batch records that show the number of components filled, if viables or nonviables were detected, and more. We completed the relevant design reviews and validation on the integrated system. Beyond that, we completed material interference studies and established baseline expectations of no viables due to machine operations – even in an uncontrolled background.
Summing up our BFPC evaluation process, Noël Long, Senior Sterility Assurance Adviser at Cytiva says, “We selected the vendor, performed proof-of-concept feasibility studies, and did interference testing. We get customers through the evaluation phase and into validation and implementation readiness when they purchase a BFPC with our machine.”
Controlling contamination
Environmental monitoring detects and quantitates particulates. But control starts with keeping out particulates and not generating them during filling. The environment matters as does the choice of aseptic filling method. The users in the BioPhorum report were split between restricted access barrier systems (RABS), isolators, and robotic isolators, with the vast majority using BFPCs in Grade A filling environments.
Robotic, gloveless isolators (RGIs) offer a high level of control. To design ours, we followed quality by design (QbD) principles to remove human interventions and indirect contact surfaces, minimize sources of particle generation, and more. This methodical approach led to a closed, standardized, gloveless workcell with horizontal, unidirectional airflow. Our system uses robotics for many operations along with presterilized and ready-to-use materials. The design allows implementation of a wide range of EM configurations, including real-time monitoring using technology such as BFPCs. Learn more about our RGIs in this infographic.
Reducing risks in implementing biofluorescent particle counters
Overall, companies in the report are at the early stages of validation, with only three having completed interference testing. Among the listed challenges was the risk of false positives, especially when interference testing isn’t complete.
According to Manny Khera, Head of Engineering – Aseptic Filling at Cytiva, RGIs like ours are well-suited for use with BFPCs, because they reduce the risks of false positives. The design makes it easy to identify the potential sources and quantities of particles, and then measure them to see if they result in any false positives. He adds, “With isolators that aren’t fully closed, you have a lot more interest points and question marks around what was the source of a viable hit – a glove or a movement here? The [ambiguity] makes it very difficult to do that analysis.”
When SA25 workcell users choose BFPCs, these systems are physically integrated. Prior to implementing BFPCs within the SA25 aseptic filling workcell, we consulted with a range of industry SMEs such as Dr. Michael Miller and engaged with key regulatory innovation forums including the European Medicine Agency’s Quality Innovation Group. The intent of these engagements was to ensure that enhancements made in our current design align with regulatory requirements, including Annex 1, and allow for appropriate positioning based on potential sources of risk and quality by design. Long summarizes, “Airflow visualization supports the computational fluid dynamics, which support the placement of where we're putting the [three BFPC probes.]”
According to the BioPhorum report, most companies are still developing their regulatory strategy with only one completing all milestones. Companies might consider that regulators are encouraging the use of modern EM methods as stated by Miller earlier in this article. Specifically, the revised Annex 1 ‘Principles’ section refers to the implementation of a Contamination Control Strategy (CCS) that supports the consideration and adoption of BPFCs in section 2.5.xiv where monitoring systems should include “an assessment of the feasibility of the introduction of scientifically sound, alternative methods that optimize the detection of environmental contamination.” Additionally in section 9.28 of Annex 1: “The adoption of suitable alternative monitoring systems such as rapid methods should be considered by manufacturers in order to expedite the detection of microbiological contamination issues and to reduce the risk to product. These rapid and automated microbial monitoring methods may be adopted after validation has demonstrated their equivalency or superiority to the established methods.”
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Progress towards implementation – Cytiva customers
The findings in the BioPhorum report align with what we have heard from members of our aseptic filling workcell user group, which includes a broad swath of biotechs, CDMOs, and large pharma companies around the globe. Environmental monitoring has been a recurring topic in this group over many years.
According to a 2024 study commissioned by Cytiva, active air sampling with settle plates is the most preferred EM method, with BFPC users showing much higher preference for BFPC than nonusers. Ten current BFPC users cite clear value propositions of BFPCs for high-value modalities compared to traditional monitoring methods – including improved sensitivity, accuracy, and specificity, as well as high return on investment and short payback period plus the ability to meet current and future regulatory standards. Three Cytiva customers are well on their way to implementing BFPCs with deliveries planned for 2025.
Moving your aseptic filling forward
If you select BFPC technology, we're here to help. It’s compatible and easily integrated with our SA25 aseptic filling workcell. That's possible because we make standardized, off-the-shelf filling machines that don't require redesign.
Working with us, you will have access to a primary validation package from the BFPC supplier. Collaborating with industry SMEs, we’ve developed a package to support qualification and implementation including a material baseline and interference study. So, all you need to do is evaluate whether the results change for your drug product and cleaning materials. This comprehensive support is designed to speed up your qualification and implementation.
Read our white paper on the evolution of environmental monitoring
Biographies
Noël Long, Senior Sterility Assurance Adviser, Cytiva
Noël Long is a contamination control and sterility assurance professional with in-depth understanding of global regulatory requirements across pharmaceutical, biopharmaceutical, medical device, and healthcare industries. Noël’s experience has focused on aseptic drug product manufacturing and contamination control and reaches across API, cell banking, cell culture, purification, formulation, filtration, aseptic filling, lyophilization, and drug product inspection activities. In her career which includes validation, manufacturing, and quality roles, Noël has held positions of increasing responsibility at Wyeth, GSK, Morphotek, Alexion Pharmaceuticals, GE Healthcare, and Cytiva. Her most recent projects include the airflow visualization studies and biofluorescent particle counter studies for Cytiva’s robotic gloveless filling isolator.
Manny Khera, Head of Engineering - Aseptic Filling, Cytiva
Manny is a dedicated Robotics and Mechatronics professional with a decade of experience in aseptic filling workcell designs. Before focusing on aseptic filling workcells, he spent several years in robotics R&D. His career began at a robotics startup, where he contributed to the development of exoskeletons for paraplegics. During this time, he designed advanced sensory systems capable of detecting and predicting spatial orientation. In addition to his work in robotics, Manny has extensive experience in industrial automation and controls, bringing a comprehensive understanding of how aseptic filling workcells integrate into larger manufacturing designs.
References
- BioPhorum. Towards the implementation of bio-fluorescent particle counting (BFPC) technology. Progress report across the pharmaceutical industry: Industry trends, status, challenges. 25 January, 2025.