Barrier technology offers clean spaces for pharmaceutical
filling and packaging, as well as protection for operators
By Jack Lysfjord, Lysfjord Consulting LLC
Barrier technology is designed to replace the use of conventional ISO 5 cleanrooms in pharmaceutical filling and packaging (i.e., ampoules, vials, cartridges, and pre-filled syringes). The goal of barrier systems, isolators and restricted barrier access systems (RABS), is to segregate people from the product, ensuring that pharmaceuticals are not exposed to viable organisms or particulate contamination. When dealing with highly potent formulations, these systems can protect operators as well.
Isolators are enclosed, usually positively pressurized units with high efficiency particulate air (HEPA) filters supplying ISO 5 airflow in a unidirectional manner to the interior. Air is typically recirculated by returning it to the air handlers through sealed ductwork. Cleaning can be manual or automated (clean-in-place). Bio-decontamination occurs through an automated cycle typically using vaporized hydrogen peroxide. Access to an isolator is through glove ports and sterile transfer systems. Isolators can be located in an ISO 8 or better environment.
RABS also process in an ISO 5 environment, with varying degrees of contact with the surrounding room, which is generally classified ISO 7 or better. Bio-decontamination is performed manually in a RABS. Although doors can be opened, this is a rare occurrence, after which the system must be appropriately sanitized, a necessary line clearance performed, and the intervention documented.
Figure 1. Active RABS pressure zone. Photo courtesy of Bosch Packaging Technology, Valicare Division.
Key differences between RABS and isolators
Compared to isolators, RABS can allow for faster start-up and ease of changeover, and, accepting certain restrictions, offer increased operational flexibility and reduced validation and revalidation expenditure. Contract manufacturers tend to gravitate to RABS because of speed of changeover.
RABS air handling units operate in a fashion similar to laminar flow hoods (LFHs) in that they are fed clean air from fan units through HEPA filters and air vents from the unit into the RABS. Air exit is through openings to the room at a low level on the equipment. RABS provide separation by the barrier and by positive airflow. Isolator air handling requirements are more complicated because air is recirculated, necessitating return fans and ductwork. In order to maintain positive pressure, the air handling unit must be leak tight.
Figure 2. Aseptic powder filling in a passive RABS. Photo courtesy of Bosch Packaging Technology, Valicare Division.
There are also differences in cleaning and bio-decontamination for RABS and isolators as mentioned previously. Cleaning must occur first, removing stoppers, broken glass, and spilled product 9the dirt), and then bio-decontamination can occur. RABS are typically cleaned manually, or a CIP system can be used after manual clean-up of commodities. Isolators are bio-decontaminated through an automatic sequence by injecting vaporized hydrogen peroxide (VHP). Validation of the manual cleaning is more challenging than the automated cleaning cycle of a CIP system.
Environmental monitoring is necessary to ensure the integrity of the ISO 5 environment in both systems. Monitoring in isolator systems can only be achieved though built-in sampling ports or sterile transfer of sampling devices. The environmental monitoring requirements of an isolator system are therefore key design considerations. These same methods can be employed in RABS, but there is also the option of using portable sampling devices inserted into the floor-level air exit openings.
Responding to current trends in the pharmaceutical market
There are a number of trends within the pharmaceutical industry that will make RABS and isolators critical components of any successful packaging and processing operation.
Biotechnology is having a big impact and reshaping the processing demands on pharmaceutical firms. Live vaccines, large molecules, and protein-based drugs are increasingly the trend and require highly aseptic conditions. These products are preservative free and are usually a growth medium; therefore, they are easily contaminated.
Toxic, cytotoxic, and otherwise highly potent applications–immunosuppressive cancer drugs are a key example–also demand stringent barrier technology to protect operators.
Broadly speaking, there is a trend toward smaller volume, higher value pharmaceuticals. Manufacturing in high-throughput, mass production systems that produce millions of dosages is declining and the ultimate cost-effectiveness of constructing a large ISO 5 cleanroom facility must be addressed in the long term.
Smaller systems that meet high regulatory standards and can be customized to small product runs are an increasingly attractive option. More compact, adaptable lines allow for flexible configurations and enable manufacturers to respond rapidly to changes in market demand.
Isolators are ideal for smaller facilities that employ flexible,
reduced-footprint systems. Compared to conventional cleanroom
processing, isolators offer pharmaceutical firms significant capital
and operational cost savings. Furthermore, with a smaller isolator system there are minimized gowning costs and reduced labor and maintenance expenses.
Regulatory issues to consider
The critical regulatory concern for barrier systems is so-called “open door” interventions in a RABS. Such interventions introduce undesirable variables into the operation and potentially compromise the aseptic environment and so should be avoided or minimized.
However, when such interventions are unavoidable, appropriate measures must be taken to ensure the aseptic environment is
maintained. Open door interventions inevitably prompt heightened regulatory scrutiny, demanding particularly scrupulous observance of standard operating procedures (SOPs).
Figure 3. FLC vial filling in a passive RABS. Photo courtesy of Bosch Packaging Technology, Valicare Division.
When open door interventions are necessary, an ISO 5 vertical unidirectional airflow system outside of the RABS reduces risk of a breach in ISO 5 conditions and further safeguards the aseptic integrity of the system. Each intervention that requires opening of a door of the RABS is regarded and documented as an intervention. Interlocked RABS doors facilitate control and documentation. Following an open door intervention, appropriate line clearance and disinfection commensurate with the nature of the incident are required.
Challenges in implementing a RABS or isolator
Many companies forget the “systems” aspect of RABS and isolators. For successful implementation of these technologies, operators, maintenance personnel, and engineers must take an expansive, holistic view of their system, ensuring that it is integrated into its surrounding environment and instituting the appropriate maintenance and oversight regimes.
This includes appropriate surrounding building and room design, including HVAC and air handling systems. Proper disposal systems for bio-decontamination waste, both within the building and in relation to the exterior natural environment, are also key considerations. Drainage systems and building HVAC should also be taken into account. Building system utilities can impact isolator pressure control schemes.
Management oversight is indispensable. Proper gowning procedure, adequate training in current good manufacturing practice (cGMP), SOPs for interventions, and documentation protocols must be instituted, rigorously executed, and consistently enforced. Continuous system monitoring is also a must.
A RABS or isolator system should be understood not merely as a discrete piece of a larger manufacturing process but as deeply integrated with every other aspect of an operation. The line itself must be well integrated. Moreover, a holistic view encompassing all of these exterior concerns will ensure the successful implementation of a RABS or isolator system. Integration is easiest through the use of experienced vendors, especially those that can produce many components of the system. More vendors means more customer project management and more tasks to juggle, which can lead to potential project risk.
Jack Lysfjord is principal consultant for Lysfjord Consulting LLC. He previously served as vice president of consulting for Valicare, a division of Bosch Packaging Technology (www.boschpackaging.com).
Hello, what are the benefits of active RABS – integrated air handling system – v passive RABS using room air handling systems? Is there any regulatory preference? If possible pls rely by email. Thank you, Nancy