Companies producing medicines and biotech products are concerned with airborne microbial contamination. They need to ensure that products and people are kept safe. The traditional, accepted method to test for microorganisms at critical locations in a process is the use of active air samplers or settling plates. Typically, 1-meter-cubed samples are taken onto agar plates and sent to a lab for culturing. The colony forming units (CFUs) results come back from the lab after four to ten days. Only after this waiting period will end users know whether the manufacturing environment was in control. Recently, the commercialization of a technology based on laser induced fluorescence (LIF) has made it possible to look at airborne viable microbial counts in real time. The potential to instantly respond to an airborne microbiological event when it happens is exciting—and beneficial.
Root cause analysis
Results from active air samplers are important—they can inform us that there has been a problem, possibly an excursion of some kind, and also enable identification of the microorganism to support a root cause investigation. However, they do not tell us when the contamination happened, or the source of the contamination. New LIF-based bio-detection products can provide better insight into these unknowns by measuring airborne viable particle counts and displaying this data in real-time. The data can be viewed via a local display or integrated directly into a facility monitoring system (FMS).
One quality assurance professional recently stated that their company spends thousands of dollars each year looking for root cause of microbial contaminations, with limited success. Positioning air samplers or settle plates to narrow down the source of airborne microbiological contamination is difficult and time consuming. Even when using good scientific and risk-based approaches, there is at least a four-day wait to know the result. And, taking periodic samples simply does not provide enough information to find root cause. But, with real-time viable particle counters, time-resolved data can provide valuable insights into root cause. An immediate notification to presence of airborne viable particles means finding the source could potentially take minutes instead of days or weeks. Furthermore, the instrument sample probe can be attached to sample tubing and is identical to ones used by standard optical particle counters. The probe can be configured to beep every time an airborne viable particle is detected, just like a Geiger counter, enabling end users to sniff out the exact location of the contamination source.
Another example is contamination that comes from workers, particularly when they start a shift in a cleanroom. By having data to support the impact of gowning practices on cleanliness, companies can provide enhanced training programs. Once root causes are identified, actions can be taken to rectify the issue, be it training, ventilation, filtration, machine maintenance, or facility adjustments.
Regulatory authorities are very interested in root cause investigations, and what preventative and corrective actions were taken to ensure the problem will not occur again. When real-time viable particle counters are integrated into a FMS software package, the data can become the basis of informational reports that offer insight into processes, providing alarms, warnings, and trending. Quality control is typically concerned with product, alarms, excursions, and corrective actions. Quality assurance is more concerned with process, trending, and preventative actions. With real-time airborne microbial data, reports can be viewed with an eye toward preventative maintenance and identifying adverse trends before a microbial excursion occurs. (Figure 1)
One challenge in critical ISO 5 or Grade A pharmaceutical processing environments is that they are very clean. Much cleaner than when the cleanliness limits detailed in the cGMP Aseptic Processing guidance was conceived. Today, Grade A isolators are continuously monitored for airborne contamination using active air samplers, settle plates, and traditional optical particle counting technology. When correctly designed, these environments easily meet and exceed the airborne cleanliness requirements as defined in the GMPs. In some cases, many weeks, months, and even years will pass without any airborne microbial contamination being detected using current methods. Similarly, low numbers are seen in surrounding Grade B environments.
It is surprising, then, that these very clean critical processes have to be interrupted, growth media introduced or manipulated, in order to meet the regulatory requirement for AAS environmental monitoring. The good news is these potentially hazardous and disruptive process steps are unnecessary with real-time airborne viable particle counting technology. Real-time viable particle counters not only offer the potential to monitor these very clean and well-controlled environments, but can also provide continuous data when integrated into an FMS system.
Saving time and money
In today’s competitive environments, facilities are always looking for ways to save time and money. Real-time viable particle counters provide opportunities for real savings. Similar to the example above, let’s look at an isolator. One pharmaceutical company has calculated that they could increase line capacity of an isolator by over 20% by reducing the downtime required to change agar plates with active air samplers. Agar plates have to be changed every three to four hours as they will dry out and not support growth. By using a real-time viable particle counter, the need for changing agar plates could potentially be eliminated, or at least minimized, saving valuable equipment downtime and optimizing labor. This also saves on the production time required to re-establish a clean environment in the isolator before production can begin again. This approach could potentially save thousands of dollars per year for each isolator.
Room certification after construction, renovation, and room changeover can be a lengthy and expensive process for facilities, taking upwards of three to seven days while waiting for incubation results to release a zone. However, with real-time viable data in an FMS system, rooms could be released in an hour or less, providing facilities with the opportunity to increase utilization rates of expensive rooms and equipment.
Another operational concern is energy. Energy is expensive. And cleanrooms, with a high number of air changes and HEPA filtration, generally use a lot of energy. If the air change rate could be reduced, while maintaining cleanliness levels, facilities could potentially see significant savings. Cleanroom studies can be performed with a real-time viable particle counter to see if air change rates can be reduced. Of course, at no time should any energy-saving measures take precedence over product safety.
Modern technology continues to move forward, providing better measurements and data. In the case of microbial detection, new LIF-based products provide real-time viable particle counts. This data, when integrated into a facility monitoring system, allows users to see information in the form of reports and test results. Then, the information can be used to develop knowledge of facilities and systems. Knowledge is a powerful tool when looking for root causes of excursions, for process improvements, and for opportunities to save time and money.
But do regulators embrace this new technology and information? The answer appears to be yes. Regulatory bodies certainly want to ensure that medicines and biotech products are safe for consumers. To that end, they want to be sure that root causes are identified, with corrective and preventative actions put in place. And they want process improvements to provide an even higher level of safety in the future. Vendors of real-time viable particle counters have submitted a Type V Drug Master File (DMF) with the U.S. FDA. This provides the FDA and customers with a file that demonstrates the science behind the technology, as well as the test results to support the measurements.
Troy Tillman is a Senior Global Marketing Manager for Contamination Control at TSI Inc. He has spent over 20 years defining and developing products for markets such as pharmaceutical cleanrooms, laboratories, hospitals, and vivariums. He has been an active member in IEST, ASHRAE, and CETA, speaking at numerous conferences. www.tsi.com; firstname.lastname@example.org.
This article appeared in the September 2014 issue of Controlled Environments.