Restricted Access Barriers - RABS definitions and performance.

Barrier technology has long been established in the pharmaceutical industry. Barriers have ranged through simple screens or demarcation, RABS (restricted access barriers) to full physical barriers in the form of isolators. The development in isolators has been significant and now they are better specified than ever. RABS however are less well defined but significant development is expected.

There are a number of reasons for the potential development, firstly in definition, followed by technical development set against clear performance requirements. The development of definition has become a clear need in the regulatory framework to provide a clarity of system claims so that they can be set against inspection requirements. Technical and design development is likely to see RABS categorized in configuration and performance requirements.

Systems may range from advanced ISO 5 zoning of a 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. This paper sets out the considerations for both definition and requirements to meet a range of performance levels.

Fundamentals of RABS

There is a fundamental issue that separates RABS from isolators. RABS provide product protection and contamination control by a combination of a ‘physical and aerodynamic barrier’ over the critical process zone. Although there are some isolator types that use this combination in the form of the isolation barrier and a ‘mouse hole’ or sterilizing tunnel the aerodynamic barrier is restricted to transfer entry or exit zones to the critical zone.

The extent of separation of the process and the surrounding environment, including the most potentially contaminating sources, people, set a scale of product protection and risk reduction of contamination during processing and in process transfers. The following diagram, a form of which has been presented at various conferences1 provides a clear picture on how process separation and product protection interact.

Aims and regulatory expectations

There is an expectation that if the system claims in performance and risk reduction contribute towards advanced aseptic processing together with being set against clear specifications and recognized guidance then there will be relief from intense inspection scrutiny. The inspection process should not be used to try and classify the RABS system in the context of aseptic processing product protection levels or level of sterility assurance by risk reduction.

For these reasons there are initiatives to better define and specify RABS. The major initiative is by ISPE2 who have a working party established in the USA, prompted by the FDA, and are in consultation internationally. A further initiative has been taken by the Parenteral Society, based in the UK, to look at setting of RABS performance levels so that groups of aseptic processing options can be established, that include RABS, isolators and traditional cleanrooms. Both initiatives have a common aim to improve definition and understanding of RABS for better application and control within the realms of advanced aseptic processing.

Traditional differences between RABS and Isolators

In advanced aseptic processing isolators have proven performance with (0-cfu) zero colony forming unit contamination expected in process operations whilst the background environment is only at ISO 8 – EC grade D level.

The balance in cost saving in the cleanroom construction and operation has been offset by the costs in complexity of isolator systems both in terms of construction and validation. The principle however of separation and high levels of sterility assurance has driven the development.

There are five critical contamination control elements that afford isolators a high level of contamination control, they are:

Isolator contamination control attributes

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 often validated to achieve 6log reduction of Geo bacillus stearothermophilus biological indicator challenges using a sporicidal gassing process e,g. hydrogen peroxide vapour.
3. There is no operator – human access to the isolator critical zone after the sporicidal bio-decontamination process and during any subsequent processing of 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 or product contact parts and prevents re-contamination of the critical process zones during all process operations and transfers.
5. The ability to environmentally monitor the critical zones to assure any deviations from performance levels of particulate and microbiological contamination are alerted and action taken.

Restricted Access Barriers – RABS Contamination control attributes

Traditionally RABS systems operate in cleanroom environments of ISO 7 – EC grade B hence are already in a good class of cleanroom. The restricted access barriers provide further zoning, by screened barriers and HEPA clean-air filtration above, such that an ISO 5 - grade A critical zone can be established.

One key consideration with RABS is that using a RABS system that provides a high level of protection against contamination from operator intervention, under validated conditions, some process operations include ‘open door’ access and manual intervention.

Traditional differences between RABS and Isolators

If you then relate the five critical elements of Isolators with that of RABS the differences are:

Restricted Access Barriers – RABS

1. RABS have a combination of a physical and aerodynamic barrier, ideally controlled at 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 system with an important interaction with the process steps of cleaning and placement of sterile product contact parts.
3. Traditionally RABS split into two types, now known as ‘active and passive RABS’. Typically there is no in-process open door access using a ‘passive RABS’ system but under certain validated system configurations and control conditions access may be included for an ‘active RABS’ system.
4. If component entry is needed after disinfection then aseptic transfer devices to prevent re-contamination of the critical process zones are used.
5. RABS, like isolators, should include the ability to environmentally monitor the critical zones to assure any deviations from performance levels of particulate and microbiological contamination are alerted and action taken.

Traditionally RABS split into two types, now known as active and passive RABS 3

The self contained, independent down-flow HEPA filtration, to the cleanroom. Typically known as ‘active RABS’.

Cleanroom integrated RABS system with drop down screens from the cleanroom HEPA ceiling, known as ‘passive RABS’. Typically no open door access is permitted during process operations due to the reduced protection.

Performance levels of RABS

There are three key factors that set the performance levels of RABS ;

• The extent of process separation from the surrounding environment and operators once the aseptic processing conditions are established and during process operations or process transfers. Typically RABS use rigid screens to form the physical barrier with vertically swinging doors to minimize the interference with cleanroom uni-directional flow conditions
• The ability to sterilize in place, or transfer aseptically, sterilized product contact parts into the critical process zone (ISO 5) that has been disinfected to a validated level. Bio-decontamination is typically validated to 6log reduction using spore form biological challenge tests.
• The extent of environmental and contamination control afforded by the design format and control of the RABS system including the classic elements of HEPA filtration, air-flow protection / particulate clean-up and pressure control.

RABS –bio-decontamination – disinfection.

The means of disinfection is a critical element for a high level of performance and sterility assurance. Isolators generally use a high level disinfection process with a sporicidal gassing agent, most commonly hydrogen peroxide vapour. Manual cleaning will always have its challenges, particularly with automated equipment with complex surfaces.

It is for these reasons considerations are given to a high level RABS system that can be sporicidally gassed to the same 6log level of bio-decontamination as an isolator. Sporicidal gassing in combination with a number of contamination control features can provide a high level of product protection and risk reduction such that it is envisaged an ISO 8 background environment can be used hence meet the performance levels of isolators in the same classification of surrounding conditions.

It may be considered there are three performance levels of RABS systems;

 User requirements ‘features and functions’

From the user requirement table it is clear by combining different features and functions the RABS product protection performance can vary. At one end of the scale, base level, RABS can be envisaged as a local improvement of cleanroom control conditions such that an ISO 5 zone can be established and the prevention of contamination from surrounding environment and people is greatly improved by barriers.

There are considerations that RABS are not closed systems and are suitable for applications where process interventions are needed. The higher class of cleanroom and sterile gowning of operators make this a different concept to isolators.

As manual interventions during processing add risk the first consideration should be to avoid such operator access but if the process demands intervention special considerations and risk reduction measures are needed to meet requirements of advanced aseptic processing.

An example of risk reduction 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 system.

At the other end of the scale leads to self contained devices, high level RABS, with capability of sporicidal gassing and many control features and functions that are comparable to isolators. E.g. pressure control at a differential higher than 15 pa, double HEPA filtration on downflow filters to reduce potential of contamination if filters are damaged between the filter integrity test durations. With such comparable performance to isolators it may be considered an ISO 8 – grade D background environment can be used.

Apart from the key issue of sporicidal gassing the one design challenge included in isolators, which is removed in RABS, is the elimination of the return air ducts. With uni-directional airflow because of the amount of air managed typically isolators re-circulate the majority of the air via return air ducts and have reduced air make up and air exhaust (typically 10%-30%).

As RABS vent to the room via controlled apertures around the critical zone then the room HVAC becomes the recirculation flow path hence no return ducts are needed. This saves in significant complexity in design and construction but most importantly removes a significant cleaning and disinfection challenge provided by return air ductwork.

There is a considerable difference between contamination control philosophies based on an advanced zoning of traditional aseptic cleanroom operations and that of a separative device that can provide a high level of separation, product protection and risk reduction in aseptic processing.

Taking a risk-based approach the selection of any systems must be based on the risk and requirement to meet operational, product sterility, quality and safety needs. In advanced aseptic processing it would be expected that the base level RABS would have very limited application and more likely the system choices would be based on standard or high level RABS.

As with any aseptic processing line media fill operations would be required to demonstrate the operators and system selected can perform under controlled conditions.

Process operation considerations

Base level RABS.

As the base level RABS critical zone, ISO 5, HEPA filtration is not independent to the cleanroom there is considerably limited potential to provide open door outward air flow and pressure control. It is considered with such an extent in reduction of product and process protection then open door manual intervention during process operations is not used.

Although it may be able to demonstrate with a high level of procedural controls, ISO 5 in operation conditions can be maintained during human intervention, risk levels in asepsis and sterility compromise are undoubtedly higher.

Standard level RABS

As standard level RABS maintain the use of manual disinfection and a Class ISO 7 background environment, with operators in sterile gowning as there is a necessary high level of procedural controls then some process operation challenges and risk 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 systems as this follows good cGMP practice for contamination control in zoned areas.

The feeder bowls e.g. for stoppers, and feeder tracks typically cannot be sterilised in place hence the timing of 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 amount 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 sterlised 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 (SIP) or aseptic transfer into position.
• Enter environmental monitoring materials to RABS via the aseptic transfer device and place in position.
• Complete production to SOP (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.

High Level RABS

The most significant difference in standard to high level RABS is the capability to use a sporicidal gassing process (as used with isolators) in the high level RABS system.

If the sporicidal gassing process is used then the complete RABS system and placed, sterile feeder bowls/tracks can be bio-decontaminated together to a high level of disinfection (6log). This takes away the issues surrounding the risk of placement of the feeder bowls/tracks and interaction with the manual disinfection process.

Although this is a significant driver to select high level RABS for advanced aseptic processing the operational and cost savings facilitated by use of an ISO 8 background environment will make a significant difference. It is this area where there is considerable potential for development in RABS.

Sporicidal gassing of RABS

There are basically two methods to sporically gas a RABS system;

1. Sealing of the RABS system with sealed Flaps that closes the aerodynamic apertures around the process critical zone.
2. Combined sporicidal gassing of the cleamroom and the RABS system.

Standalone RABS sporicidal gassing.

In this configuration the RABS system 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 injection is directly into the critical zone with high efficiency gas distribution devices used to distribute 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 system would need to meet a leak integrity level as specified for isolators.

Combined cleanroom and RABS system sporicidal gassing

The success of using hydrogen peroxide vapour for cleanroom 6log bio-decontamination has made this option viable. Room sporicidal gassing has become a routine in many biologics and biomedical facilities together with an increase in hospitals sites and some pharmaceutical plants.

Such a process is particularly useful where the facility or enclosure has complex surfaces. Risk reduction is provided in the disinfection process by automated control for process repeatability and safety together with excluding people and manual processes. The process does not replace manual cleaning but is complementary.

In this configuration the RABS HVAC remains operational through the complete room-RABS gassing process. If the room HVAC cannot be used for aeration then room aeration catalyst-HEPA devices are commonly used. Leak integrity is less critical with this type of RABS system.

Restricted Access Barrier (RABS) systems – sporicidal gassing options

Relationship with RABS and aseptic processing / sterility test isolators
A group of aseptic processing devices and facilities are now developing with options of isolators, RABS or traditional zoned cleanrooms. The selection will depend on product production and processing requirements, process quality, safety risks and cost. Generally choices for advanced aseptic processing will come from one of the following groups.

Group one. Closed isolator systems, sporicidally gassed with CIP/SIP as required and aseptic rapid transfer devices. Sited in grade D – ISO 8 cleanroom.

Group two. 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, H2 O2, UV tunnels etc and ‘mouse holes’ for controlled exit of product. Sited in grade D – ISO 8 cleanroom or better (depending on risks).

Group three. 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.

Group four. Standard level RABS, active configuration, 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.

Group five. 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.

Group six. Traditional open cleanroom, ISO 7 with ISO 5 critical zones using simple flexible barriers (curtains) and generally open for access.

Group seven. Combination solutions e.g. ‘RABS & isolator’
In some applications practical limitations lead to the need to combine RABS and isolator operational features together with integration into different zone background environments.

CONCLUSION

The consideration of combining contamination control ‘features and functions’ to set different performance levels, in terms of providing better sterility assurance and risk reduction, helps define both the groups of aseptic processing options and RABS. The defined options can then be set against individual user requirements and regulatory requirements.

The two different philosophies of either RABS as an advanced form of zoned cleanroom operations or as a separative device are key considerations. By definition separative devices have less dependence on the surrounding environment (because of a high level of separation and disinfection) hence need different strategies. RABS have the potential to cross the boundaries between enhanced cleanroom operations to separative devices so care is needed to set the strategy at the user requirement stage.

Clarity in definition will come if we keep to the fundamentals. For example fundamental to the RABS definition is providing a physical and aerodynamic barrier. This means 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. Just having simple barrier screens or flexible ‘curtains’ does not make it a RABS system.
The information provided presents new ideas and it is hoped will assist the development in both the technology and the guides and standards yet to be produced for RABS.

References

Ref 1 Separation concept presented by Gordon Farquharson, Bovis Lease Land UK, at ISPE Conferences.

Ref 1 Separation concept presented by Rick Friedman, FDA, at ISPE2 – International Society of Pharmaceutical Engineers, Washington Conference 2005.

Ref 3 Active and Passive RABS, Presented by Jack Lysfjord & Michael Porter at ISPE Washington 14th Annual Barrier Isolation Technology Forum 2005.

Author

James L Drinkwater is the Process & Validation Director of BIOQUELL UK Ltd who specialize in biological decontamination for infection / contamination control. James is a current management team member of the UK Parenteral Society and a member of ISPE.

Specialist experience is in the areas of process engineering for all aspects of contamination and infection control. Working experience comes from working ten years in the pharmaceutical industry followed by positions or Technical Director at three barrier isolator companies and the current position at BIOQUELL.