As pharmaceutical manufacturing becomes increasingly globalized, with companies engaging both contract development and manufacturing organizations (CDMOs), as well as contract research organizations (CROs) in multiple countries, contamination precautions are increasingly important.
Biopharmaceuticals have also continued to grow in number and significance, further highlighting contamination concerns. This is especially due to the heightened need for aseptic conditions while processing these drugs. In response, the industry is looking for effective ways to decrease contamination. In fact, according to the 2016 Nice Insight Pharmaceutical Equipment Buying Trends Survey, 69% of respondents expressed interest in purchasing cleanroom equipment and systems.1 However, the sterility of processes and equipment is only part of the equation as the environment at large also contributes to contamination.
Each of the three major options for aseptic processing - human access cleanrooms, restricted-access barrier systems (RABS) and isolation technology (isolators) - are often used in combination. All rely heavily on the environment in which it exists.2 In a perfect world, these systems would offer the same aseptic conditions in every situation, but the world is far from perfect. With microbial contaminants found in the air, on surfaces, and on human operators (including gowned operators), biocontamination is a serious threat to the sterility of every process, facility and product - with the potential to present catastrophic risk to companies and patients alike. Even with the best aseptic processing facilities in place, environmental monitoring (EM) helps ensure continued performance of these systems. EM offers additional peace of mind while meeting FDA requirements for sterile process validation documentation. This is not to say, however, that EM should be the primary line of defense.
Considerations When Selecting Environmental Monitoring Systems
When in the earliest stages of selecting an EM system or related components, Tony Antrum, Associate Director, Global Product Manager Environmental Monitoring at Merck, notes that the reputation and honesty of every manufacturer/supplier should be considered from the start. In a September 2016 webinar, Environmental Monitoring in Isolators and RABS, Ancrum continues by recommending that, before anything else, all statements or claims a supplier makes about a product or service should be backed up with documentation.3 This seemingly simple notion can become important should issues or failures arise and, with this baseline established, specific performance and service requirements can be evaluated with greater confidence.
ISO 14698, “Cleanrooms and associated controlled environments, Biocontamination control,” addresses the basic principals and methodologies for monitoring cleanroom technology for biocontamination. For example, the biological and physical recovery rates in a reliable air monitoring system should be tested in accordance with Part 1 (“General Principals and Methods”), Annex B (“Guidance on Validating Air Samplers”) of this ISO standard.3 The collection of physical and biological samples should also be extremely efficient for both small and large organisms, as even one particle can contaminate a large lot.3 However, in addition to nonviable and airborne viable particulates in active and passive air, comprehensive monitoring should include airflow and pressure differentials, temperature, humidity and microbial components on surfaces, equipment and/or personnel.4 To ensure that all elements are monitored correctly over time, systems should also provide a detailed activity report.3
To achieve compliance to either the most current European Union GMPs Annex 1 (2008) or FDA GMP guidelines (2004), EM must assess all of the previously listed elements. The disinfection process must also be clearly understood and outlined.4 Though compliance requires comprehensive monitoring and effectiveness, the equipment and processes should also be evaluated to ensure a seamless transition into existing - and future - facility hardware and systems.
For example, every monitoring instrument should offer laboratory information management system (LIMS) connectivity as a quality isolator instrument (air sampler or otherwise) and should not fail, or require regular replacement, in the next two to five years. Features such as LIMS connectivity are important even if not currently in place. Future facility growth may require such a system if it is not already required.3
Finally, every automated monitoring instrument should be built into an isolator or production line and should be able to communicate directly with the entire system to minimize errors.3 When equipment has been selected, industry compliant IQ and OQ documentation - which will become part of the site’s quality system - must be finalized. Calibration should be completed concurrently with other equipment in the isolator and/or production line.3 Once in use, all service should be completed on site to decrease the risk of production downtime or contamination.3 However, it is important to note that EM is an everevolving process. As the industry’s understanding of growth cultures and biocontamination increases, along with the ability to detect microorganisms that may have been elusive in the past, monitoring systems and processes are improving.
Documenting, Controlling and Evolving Methodologies
Regulations regarding microbial testing are evolving to allow and encourage the adoption of advanced biological monitoring solutions.5 Add-ons to pharmacopeias now account for nextgeneration therapies and offer alternative options, including rapid microbiological methods (RMMs), which are often used for products with a short shelf-life or limited production size/ frequency.5 Additionally, the FDA amended its position on sterility test requirements with its final rule, effective June 2012.
According to the FDA, these changes are “intended to promote improvement and innovation in the development of sterility test methods by allowing manufacturers the flexibility needed for sterility testing of some novel products that may be introduced to the market.”6 EM is a safeguard although it remains imperfect. To illustrate, monitoring systems often do not provide quality or quantity details regarding microorganisms and are typically unable to detect those that are viable but not culturable (VBNC).4 Further, according to a 2012 report from the World Health Organization, monitoring practices may be outdated for certain drug products: “EM GMP was written in an era when bacteria and fungi were the only microorganisms that could be readily identified, and septicaemia due to intravenously administered solutions was a major problem.”7
As technology and equipment continue to improve, aseptic processing capabilities are becoming increasingly advanced at controlling the risk of contamination, rather than just monitoring its presence. With these regulatory changes continuing to evolve, one lingering question remains: Is EM as useful or effective as it was thirty years ago?
Creating the Best Environment from the Start
Simply put, eliminating the risk of contamination is better than merely monitoring it. Though it is widely understood that isolators and RABS provide more sterile environments than human-scale cleanrooms, these cleanrooms have improved drastically over the last few decades, resulting in decreased “hits” in monitoring systems.2 This is not to say that EM can or should be eliminated but, the increased introduction of automation equipment - mentioned as the single most significant factor contributing to better environments - continues to reduce the need for human contact while simultaneously decreasing the presence of biocontaminants.2 In addition, air changes per hour have drastically increased from around 100 to approximately 800; and improved growing materials are more efficient at filtering microbial elements.2 It is worth noting, however, that improvements to monitoring equipment and supplies are aiding here as well. Products such as Merck’s Isobag, for example, offer decreased human contact and easier system integration, both of which help decrease the introduction of biocontaminants, while TSI’s BioTrak Real-Time Viable Particle Counter provides instant particulate detection and identification.
These improvements have been so significant that low recovery rates in monitoring systems are leading to over-analysis of data which, in turn, has lead to additional monitoring and even unnecessary panic, stemming from a lack of understanding regarding the limits of these systems. This includes the unavoidable contamination that human interaction presents.2 Despite these improvements, EM is likely to remain important.
By controlling contamination through robust processes, evolved cGMP and the elimination of human intervention through RABS, isolators and improved cleanroom procedures, manufacturers can reduce contamination risks, but monitoring systems are critical to maintaining an acceptable Grade A, ISO 5 or other sterile environments. And, until manufacturing perfection can be reached, improved monitoring systems and methods will help to improve accuracy, offer an additional safeguard and reduce the risk of costly contamination issues.
- The 2016 Nice Insight Pharmaceutical Equipment Buying Trends Survey.
- Akers, James & Agalloco, James. “Clean Rooms, RABS and Isolators: Validation and Monitoring in the Diverse World of Aseptic Processing.” American Pharmaceutical Review. 1 May, 2011. Web.
- Klees, Anne-Grit & Ancrum, Tony. “Environmental Monitoring in Isolators and RABS US.” Webcast Presentation. Merck Webcast. 22 Sep, 2016. Web.
- Dalmaso, Gilberto & Denoya, Claudio. “Microbial Control and Monitoring in Aseptic Processing Cleanrooms.” Controlled Environments. 12 Jan, 2015. Web.
- Challener, Cynthia. “Microbiological Testing: Time is of the Essence.” BioPharm International. 29 (7) 2016. 1 Jul, 2016. Web.
- “Amendments to Sterility Test Requirements for Biological Products.” Federal Register. 3 May 2012. Web.
- “Environmental Monitoring of Clean Rooms in Vaccine Manufacturing Facilities.” World Health Organization. Nov 2012. Web.