RABS in operation with isolators

Because restrictive access barrier systems (RABS) are not closed systems they are suitable for applications where process interventions are needed. But since manual interventions during processing add risk, the first consideration should be to avoid such operator access.

If the process demands intervention, special considerations and risk reduction measures are required. An example would be to have an open-door overhead HEPA downflow secondary barrier to improve protection against contamination from operators and protect barrier gloves and the inside door surfaces when exposed to the surrounding environment. It would also be expected that outward airflow from the RABS would be present with the door open. This would be a standard level "active" RABS. At the other end of the performance scale, self-contained devices or high level RABs with sporicidal gassing capability and other features (such as pressure control at a differential higher than 15 Pa or double HEPA filtration on downflow filters to reduce contamination if filters get damaged) provide comparable performance to isolators and may be considered an ISO 8 - grade D background environment. A design challenge with isolators not present in RABS, is the elimination of the return air ducts. With uni-directional airflow, the amount of air managed means that typical isolators must re-circulate the majority of the air via return air ducts and have reduced air make up and air exhaust (typically 10%-30%). Because RABS vent to the room via controlled apertures around the critical zone, the room heating, ventilation and air conditioning (HVAC) becomes the recirculation flow path, hence no return ducts are needed. This saves on complexity of design and construction but, most importantly, removes a significant cleaning and disinfection challenge provided by return air ductwork. There is a considerable difference between a contamination control philosophy based on an advanced zoning of traditional aseptic cleanroom operations and that of a separative device. The selection of any systems must be based on the risk and requirement to meet operational, product sterility, quality and safety needs. The base level RABS would have very limited application in advanced aseptic processing. The systems of choice would more likely be a standard or high level RABS. As with any aseptic processing line, media fill operations would be required to demonstrate that the operators and system selected can perform under controlled conditions. Because the base level RABS critical zone ISO 5 HEPA filtration is not independent of the cleanroom, there is very limited potential for open-door, outward air flow and pressure control. And because standard level RABS maintain the use of manual disinfection and a Class ISO 7 background environment, with operators in sterile gowning, a high level of procedural controls are necessary, and some operational challenges and risks are added. Although there is no requirement set out in standards for a pressure differential between the HEPA filter bank and the surrounding room, it is recommended that a positive pressure differential is maintained in the RABS, as this follows cGMP practice for contamination control in zoned areas. The feeder bowls, e.g. for stoppers, and feeder tracks typically cannot be sterilised in place, so the timing of their placement in the disinfection regime is critical. The expected process sequence would be: • clean RABS, with all doors open, HVAC operational, in preparation for set-up; • fit size/change parts that require manual disinfection in place; • disinfect RABS while HVAC operational, restricting the number of doors open at one time and locking doors when section complete; • under RABS HVAC operation and with open door downflow HEPA secondary barrier in operation, place sterilised and covered feeder bowls and tracks in RABS; • remove covers, close and lock doors; • complete final disinfection of potentially compromised surfaces during the feeder bowl/tracks placement procedure; • complete product contact parts sterilise-in-place or aseptic transfer into position; • enter environmental monitoring materials to RABS via the aseptic transfer device and place in position; • complete production to standard operating procedure with any validated manual interventions, as necessary. Interventions would be expected to be rare; • complete line clearance at end of production shift; • document production operations for necessary batch records. The most significant difference between standard and high level RABS is that the latter enables the use a sporicidal gassing process. If this process is used, the complete RABS system and placed, sterile feeder bowl or tracks can be bio-decontaminated together. This removes any issues surrounding the placement of the feeder bowls or tracks and interaction with the manual disinfection process. While this is a significant driver in selecting high level RABS, the operational and cost-savings facilitated by use of an ISO 8 background environment will make a significant difference. This is an area where there is considerable potential for development in RABS. There are two ways to sporicidally gas a RABs system: one involves sealing the RABs using flaps that close the aerodynamic apertures around the process critical zone, the other involves gassing the cleanroom and the RABS at the same time. In the first scenario, the RABS is sealed like an isolator for the duration of gassing and aeration (removal of gas residuals) only. Controlled flaps that close at the air outlet aperture around the base of the critical zone provide the sealing capability. Gas is injected directly into the critical zone, and high efficiency gas distribution devices distribute the gas in the complete RABs enclosure and through the downflow HEPA filter. To speed up the aeration process, aeration assistance catalysts can be used. Once gassed the flaps open down and outwards in conjunction with the RABS HVAC operation. The RABS would need to meet a leak integrity level as specified for isolators. The ability of the H2O2 vapour to achieve 6log bio-decontamination makes the second scenario of combined gassing of the cleanroom and RABS viable. Sporicidal gassing of rooms is routine in many biologic and pharmaceutical plants, and is particularly useful where the facility has complex surfaces. Automated control of the disinfection process provides process repeatability, added safety and, because it excludes people, reduces risk. The process does not replace manual cleaning but is complementary to it. In this configuration the RABS HVAC remains operational throughout the complete room and RABS gassing process. If the room HVAC cannot be used for aeration, room aeration catalyst-HEPA devices are commonly used. Leak integrity is less critical with this type of RAB system. Many aseptic process facilities now offer options of isolator, RABS or traditional zoned cleanroom-usage. The selection will depend on product production and processing requirements, process quality, safety risks and cost (see diagram 6). Generally, choices for advanced aseptic processing will be from the following categories: 1. Closed isolator systems: sporicidally-gassed with CIP/SIP as required and aseptic rapid transfer devices. Sited in grade D - ISO 8 cleanroom. 2. Open isolator systems: sporicidally gassed (in closed state) with CIP/SIP as required and aseptic rapid transfer devices. Controlled but open access to the critical processing zone includes sterilisation tunnels for entry of product closures, e.g. Depyro, EBeam, H2O2, UV tunnels, and "mouse holes" for controlled exit of product. Sited in grade D - ISO 8 cleanroom or better. 3. High level RABS: active configuration, sporicidally gassed with CIP/SIP as required, gloved access and aseptic rapid transfer devices sited in grade D - ISO 8 cleanroom. 4. Standard level RABS: active con-figuration, manual sporicidal disinfection, CIP/SIP as required, gloved access and aseptic rapid transfer devices sited in grade B - ISO 7 cleanroom. Possible "open door" controlled operator access in-process. 5. Base level RABS: passive configuration, manual sporicidal disinfection, CIP/SIP as required, gloved access and aseptic rapid transfer devices (as required) sited in grade B - ISO 7 cleanroom. Typically no operator open door access in-process. 6. Traditional open cleanroom: ISO 7 with ISO 5 critical zones using simple flexible barriers and generally open for access. 7. Combination solution: e.g. RABS and isolator. In some applications, RAB and isolator operational features are combined with integration into different zone background environments (see diagram 6). There are two philosophies for using RABS: as an advanced form of zoned cleanroom operation; or as a separative device. By definition, separative devices have less dependence on the surrounding environment and therefore need different strategies. RABS have the potential to cross the boundaries from enhanced cleanroom operations to separative devices, so care is needed to set out the strategy at the user requirement stage. We can achieve clear definitions if we stick to the fundamentals. For example, "providing a physical and aerodynamic barrier" is fundamental to the RABs definition. Any closed system used for more potent processing is in fact an isolator. Having open-door access to the isolator during processing does not make it a RABs system; likewise just having simple barrier screens or flexible "curtains" does not make it a RABs system. This article presents some new ideas and, it is hoped, will assist with both the technological development of RABS, and the production of guides and standards for their use.