Dr David Phillips, senior global product technology specialist , clean air at Thermo Fisher Scientific looks at how the adoption of advanced Class II BSCs in cGMP environments is helping to deliver safe and effective medicines.
Cleanliness
Pharmaceutical manufacturers have a responsibility to consistently deliver safe and effective medicines, and this can be achieved by complying with the Food and Drug Administration’s (FDA) current Good Manufacturing Practice (cGMP) regulations. To meet the stringent cleanliness and containment requirements set out in the regulations, manufacturers largely rely on Class II Biological Safety Cabinets (BSCs). However, until now, regular monitoring of air cleanliness and quality within cabinets has been a key challenge. The latest advances in Class II BSCs address this issue and these systems can be easily integrated into facilities, enabling manufacturers to fully comply with cGMP standards and deliver high-quality, safe products.
A need for Good Manufacturing Practices
cGMP-regulated environments are essential for the manufacture of drugs, ensuring a clean and safe setting with no risk of contamination. Indeed, poor cGMP conditions at a manufacturing facility could ultimately pose a life-threatening health risk to a patient. As such, the manufacture of sterile products is subject to special requirements as set out in the FDA’s cGMP standards and EU Guidelines for Good Manufacturing Practice. Quality Assurance is a particularly important aspect of these regulations, and pharmaceutical manufacturers must strictly follow carefully established and validated methods of drug preparation and manufacturing procedure to comply and ensure product safety.
Where terminal sterilisation is not possible, the drug manufacturer commonly uses aseptic processing, whereby the products and containers are sterilised separately and then brought together in an extremely clean environment. Guidelines for aseptic workflows state that air cleanliness in the immediate proximity of exposed sterilised containers/closures and filling/closing operations should be ISO Class 5 (Class 100) and routine particle monitoring should be performed during each production shift.
However, this presents a challenge for traditional Class II BSCs. While they are capable of providing high-quality clean air with containment, they historically have limited monitoring capabilities.
Limitations of traditional BSCs
Class II BSCs are an essential component of pharmaceutical manufacturing workflows, providing a carefully controlled environment that safeguards therapeutic products from airborne impurities, as well as protecting operators from the materials they are working with. However, the systems were originally designed as safety devices for use in research environments where there is a low requirement for monitoring.
The ability of Class II BSCs to provide four types of protection — personnel, product/sample, environmental and protection from cross-contamination — is a major advantage compared with other types of device, such as laminar flow cabinets. Class II BSCs use controlled airflows and high-efficiency particulate air (HEPA) filters to provide protection through a precise balance of clean downflow inside the cabinet and inflow drawn from outside the cabinet. However, as the HEPA filters collect more particles, they resist the airflow and associated velocities can decline over time. This degradation in performance is an issue for pharmaceutical manufacturers needing to demonstrate that their cabinets provide the appropriate level of protection during the entire drug manufacturing process.
Advanced Class II BSCs are designed to overcome these challenges, and meet the cleanliness and containment requirements of pharmaceutical manufacturers.
Advanced Class II BSCs facilitate compliance with cleanliness and containment requirements
Pharmaceutical manufacturers need to produce evidence of a clean work area and of containment. Therefore, a Class II BSC intended for use in cGMP applications requires two capabilities at a minimum. First, a sampling capability to monitor air cleanliness in the BSC work area/sample chamber. Monitoring air cleanliness can be easily achieved with a particle counter and most Class II BSC manufacturers offer a modest customisation inserting a sampling tube or sampling probe holder to meet this need.
The second capability is to monitor containment. Using the criteria validated in accordance with the NSF International/American National Standards Institute (NSF/ANSI) 49 standard on “Biosafety Cabinetry: Design, Construction, Performance and Field Certification”, containment can be monitored by checking the inflow and downflow velocities to assure they stay within the acceptable range.
The design of Class II BSCs has advanced to provide the level of monitoring required so manufacturers can be safe in the knowledge they are complying with regulations. Many advanced Class II BSCs have been designed with innovative features, including intelligent motor/fan systems that automatically adjust to changes in resistance to maintain a constant flow. They also have an airflow monitoring/alarm system to alert the manufacturer when there have been changes in standard operating conditions and attention is needed.
Class II BSCs now incorporate separate downflow and exhaust fans to monitor and maintain inflow and downflow separately rather than as an aggregate totalled value. This has two key benefits for delivering superior containment. It maintains the balanced inflow and downflow needed for containment and does not overlook potential problems due to uneven filter loading between downflow and exhaust. Additionally, it allows for the monitoring of the pressure difference across downflow and exhaust fans separately, giving the benefit of looking at the overall flow without being as affected by differential filter loading.
The latest Class II BSCs even record an exportable log of all airflow measurements and operator activity. Many of the advanced features built into modern Class II BSCs are also designed to ensure these systems maintain certified performance for longer. As a result, if air velocity does decline over time, pharmaceutical manufacturers can quickly access detailed logs to determine when conditions deviated from specific operating parameters and by how much. If these parameters are known to have no effect on the safety or performance of therapeutic products, manufacturers are better placed to demonstrate to regulators that products are still safe to be released to the market.
Conclusion
cGMP environments require clean and safe workspaces for the manufacture of drugs. In addition, the manufacturing process needs to be carefully controlled and validated. Clean air that is contained and regularly monitored is critical for both protection of the product and personnel, and this can be achieved easily by integrating modern Class II BSCs.
The ongoing advances in the design of cabinets and inclusion of novel features, such as intelligent motor/fan systems and alarms, means the latest Class II BSCs are facilitating and simplifying compliance with FDA and EU regulations. Manufacturers using these systems can improve their workflow efficiency, and are better placed to deliver safe and effective medicines.