Well protected
Barrier technology offers clean spaces for pharmaceutical operations, plus operator protection

Barrier technologies are designed to replace conventional ISO 5 cleanrooms in pharmaceutical filling and packaging (ampoules, vials, cartridges, and pre-filled syringes). The goal of barrier systems, isolators and restricted access barrier 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.
Jack Lysfjord
Isolators are enclosed units, usually under positive pressure, inside which a unidirectional flow of air at ISO 5 quality is supplied via high efficiency particulate air (HEPA) filters. Access to an isolator is through glove ports and sterile transfer systems. Isolators must be located in environments of ISO 8 standard or better. Cleaning can be manual or automated (CIP); in the case of the latter, decontamination is achieved through an automated cycle, typically using hydrogen peroxide vapor. Air handling requirements for isolators are relatively complex because the air is usually recirculated, necessitating return fans and ductwork, and in order to maintain positive pressure the air handling unit must be leak-tight.

RABS, an alternative to isolators, also create an ISO 5 environment. They have varying degrees of contact with the surrounding room, which is generally classified ISO 7 or better. RABS are typically cleaned and decontaminated manually. 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. Validation of the manual cleaning is more challenging than the automated cleaning typically used for isolators.

RABS ensure separation through the use of once-through airflow as well as the physical barrier, so their air-handling requirements are simpler than for isolators. RABS air handling units operate in a similar way to laminar flow hoods (LFHs), in that they are fed clean air from fan units, via HEPA filters, and exhaust air exits to the room through floor-level openings on the equipment.

Both isolators and RABS require environmental monitoring to ensure the integrity of the ISO 5 environment. Isolators can only be monitored though built-in sampling ports or sterile transfer of sampling devices. The environmental monitoring requirements of an isolator system are therefore key design considerations. RABS can use the same monitoring methods as isolators, but also have the option of portable sampling devices inserted into the floor-level air exit openings.

Compared to isolators, RABS allow faster start-up and ease of changeover. Accepting certain restrictions, they also offer increased operational flexibility and lower costs for validation and revalidation. Contract packagers tend to prefer RABS because of their faster changeover.

Growing popularity

A number of trends within the pharmaceutical industry will make RABS and isolators critical components of any successful packaging and processing operation.

Biotechnology is having a big impact, and is 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 usually act as growth media, so they are easily contaminated.

Smaller systems in demand

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 systems that produce millions of doses 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 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 significant capital and operational cost savings. Furthermore, smaller isolator systems reduce the costs of gowning, labor and maintenance.

The critical regulatory concern for barrier systems is the issue of so-called “open door” interventions in RABS. Such interventions introduce undesirable variables into the operation and potentially compromise the aseptic environment, so they should be avoided or minimized.

When such interventions are unavoidable, appropriate measures must be taken to ensure that the aseptic environment is maintained. Open door interventions inevitably prompt heightened regulatory scrutiny, demanding particularly scrupulous observance of SOPs (standard operating procedures).

When open door interventions are necessary, an ISO 5 vertical unidirectional airflow system outside of the RABS reduces the risk of a breach in ISO 5 conditions and further safeguards the aseptic integrity of the system.

Each intervention that requires opening a door of the RABS is 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.

Implementation challenges

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 systems, ensuring that these are 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, which can affect isolator pressure control schemes. Proper drainage systems and disposal routes for bio-decontamination waste, both within the building and in relation to the exterior natural environment, are also key. Management oversight is therefore indispensable. Proper gowning procedure, adequate training in current good manufacturing procedure (cGMP), standard operating procedures 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, and especially, vendors that can produce many components of the system. More vendors means more customer project management and more balls in the air at once, which equates to potential project risk. n