RABS: performance levels defined

Barrier technology has long been used in the pharmaceutical industry and ranges from simple screens or restricted access barriers (RABs) to full physical barriers in the form of isolators.

Recent isolator development has been significant and such systems are now better specified than ever. RAB systems (RABS), however, are less well developed or defined. But significant development is expected, and there is a clear need for better definition of the different systems so that they can be measured against inspection requirements within the regulatory framework. In the future, RABS are likely to be categorised in terms of configuration and performance requirements. Systems may range from advanced ISO 5 zoning of an ISO 7 aseptic processing cleanroom to separative devices that may meet the contamination control performance of isolators with ISO 5 critical zone and ISO 8 surrounding environment levels. There is a fundamental difference between RABS and isolators. RABS offer product protection and contamination control by providing a "physical and aerodynamic barrier" over the critical process zone. While there are some isolators that use this combination in the form of the isolation barrier and a "mouse hole" or sterilising tunnel, the aerodynamic barrier is restricted to transfer entry or exit zones into and from the critical zone. The extent of separation of process, people and environment provides a sliding scale of product protection (see diagram 1).¹ Some people think that claims made about a RAB system's performance in aseptic processing may reduce inspection scrutiny. However, one should not try to classify a RABS in terms of aseptic processing product protection levels or sterility assurance. There are better methods to define and specify RABS. The main one is provided by the ISPE,² which set up a working party in the US and which consults internationally; another is provided by the Parenteral Society, in the UK, which is looking at RABS performance levels. Both initiatives have a common aim to improve the definition and understanding of RABS and to improve their application in advanced aseptic processing. In advanced aseptic processing facilities, it has been proven that isolators can provide zero colony forming unit (0cfu) contamination in process operations, while the background environment is only at ISO 8 - EC grade D level. But cost-savings in cleanroom construction and operation are offset by the construction and validation costs of the isolator system. Five critical elements give isolators a high level of contamination control: 1. The physical barrier, typically controlled at positive pressure with clean-air filtration providing air exchanges and particulate clean up for an ISO 5 critical process zone. 2. The ability to bio-decontaminate to a high level with a combined cleaning and sporicidal process using, for example, hydrogen peroxide (H₂O₂) vapour, and validated to a 6log reduction of biological indicator (BI) Geo bacillus stearothermophilus. 3. There is no operator access to the isolator critical zone after the sporicidal decontamination process and during any subsequent process transfer steps. 4. All product contact parts are cleaned and sterilised in place (CIP/SIP) or enter the sporicidally disinfected isolator system using aseptic transfer devices. Closed processing post-gassing maintains sterility of product contact parts and prevents re-contamination of the critical process zones during all processing and transfers. 5. The ability to environmentally monitor the critical zones to ensure any deviations from performance levels of particulate and microbiological contamination are alerted, so that action can be taken. Traditionally RABs operate in cleanroom environments of ISO 7 - EC grade B. They can provide further zoning via screened barriers and HEPA clean-air filtration, such that an ISO 5 - grade A critical zone can be established. One key consideration, particularly where process operations require "open door" access and manual intervention, is that RABS provide a high level of protection against contamination from operator intervention. Some of the key differences between RABS and isolators are: 1. RABS offer a combined physical and aerodynamic barrier, ideally controlled by positive pressure with clean-air filtration providing air exchanges and particulate clean up for an ISO 5 critical process zone. 2. Disinfection is typically manual in a standard RABS involving interaction with the process for cleaning. 3. Traditionally, RABS come in two types: "passive", where there is no in-process open door access; and "active" where, under certain validated system configurations and control conditions, access may be included.³ 4. With RABS, if component entry is needed after disinfection, then aseptic transfer devices are used to prevent re-contamination of the critical process zones. 5. RABS should include environmental monitoring of critical zones to ensure operators are alerted to deviations from performance levels of particulate and microbiological contamination, so that action can be taken. Diagram 2 shows self-contained, independent downflow HEPA filtration of a cleanroom, typically known as "active RABS", whereas the cleanroom-integrated RABs system with drop-down screens from the cleanroom HEPA ceiling, shown in diagram 3, is known as "passive RABS" and typically does not permit open door access during process operations. There are three key factors that define the performance levels of RABS: • The extent of process separation from the surrounding environment and operators once the aseptic processing conditions are established. Typically RABs use rigid screens to form the physical barrier with vertically swinging doors to minimise the interference with cleanroom uni-directional flow conditions. • The ability to sterilise in place, or transfer aseptically sterilised product contact parts (ISO 5) that have been disinfected to a validated level (6log reduction using spore form BI challenge tests) into the critical process zone. • The extent of environmental and contamination control provided by the RABS, including elements such as HEPA filtration, air-flow protection, particulate clean-up and pressure control. Disinfection is critical for high level sterility assurance. Isolators generally use a high level disinfection process with a sporicidal gassing agent, commonly H2O2 vapour. Manual cleaning will always provide challenges, particularly where there is automated equipment with complex surfaces, which is why high level RABS that can be sporicidally gassed to the same 6log level of bio-decontamination as an isolator are often considered. Sporicidal gassing in combination with other contamination control features can provide such a high level of protection that an ISO 8 background environment can be used and yet meet the performance levels of isolators in the same classification for surrounding conditions. Table 1 shows that by combining different features and functions, the RABS product protection performance can vary. At one end of the scale – base level – RABS can provide improved local cleanroom control such that an ISO 5 zone can be established and contamination control from the surrounding environment and people is greatly improved. At the other end of the scale, self-contained devices or high level RABS with sporicidal gassing capability and other features of isolators provide comparable performance to isolators and may be considered an ISO 8 - grade D background environment.