Issue



RABS find an expanded role in aseptic processing


08/01/2008







The development of a comprehensive PHSS monograph will enhance the recognition of RABS as an alternative to isolators and provide a framework for regulatory compliance

By James Drinkwater, Bioquell UK

As aseptic processing and related activities follow risk-based approach initiatives, separation of the process from the most potentially contaminating source–operators and associated process personnel–becomes a key consideration. Conventional cleanroom “open” aseptic processing, including filling and related processes where “operator-to-process” separation relies on gowning and simple barriers, is starting to be challenged as current Good Manufacturing Practice (cGMP).1

The basis of cGMPs requires that pharmaceutical facilities take reasonable advantage of available technology to improve quality assurance. With a clear need for separative barrier systems, the development of restricted access barrier systems (RABS) has provided an alternative to traditional isolators. Not every process is suited to isolation barrier technology; this is a step change from conventional cleanroom operations and can impose design challenges that restrict production operations.

The contamination control performance of isolators in meeting regulatory requirements is well established. To be a viable alternative, RABS must combine a number of contamination control measures using a system approach to achieve quality by design for risk-assessed operations.

Separation between operators and an aseptic process or related procedure is considered essential for reducing the risk of potential biocontamination. With a system approach this must be complemented by controls for the environment, operator access, and all aseptic and sterile process transfers.

RABS have been available for some time, but a clear definition, a framework of RABS types, and RABS operating methods have not been the subject of an international monograph or standard.

RABS definition and monograph development

The U.S. Food and Drug Administration (FDA) prompted initiatives for clearer definitions of RABS. The International Society of Pharmaceutical Engineers’ (ISPE) Joint USA and European working group formed to provide a definition document.2 This was recognized as a key step toward establishing RABS technology as a significant contamination control measure for aseptic manufacturing.

Since publication of the ISPE definition, RABS development has continued in the areas of specification, application, and operating principles. The ISPE baseline definition includes key requirements of RABS situated in a minimum ISO Class 7 background environment and RABS barrier manual disinfection in association with sterilization of direct and indirect product-contacting parts. For example, direct product-contacting parts are the product delivery system and product closures/containers. Indirect product-contacting parts would be feeder bowls, trackways, stopper delivery chutes, and any gloves likely to make contact with contacting parts during processing or related activities.

Since the ISPE initiative, the European-based Pharmaceutical and Healthcare Sciences Society (PHSS) formed a RABS special interest group to develop a technical monograph3 that provides information regarding RABS developments and advances.

PHSS completed a comprehensive review of current industrial RABS that meet international regulatory authority requirements. During the review process it also became clear that there were some simple restrictive screen barriers that could not be considered RABS and did not offer adequate contamination control for more challenging aseptic processes. By more clearly specifying RABS, such inadequate contamination control measures would be unable to claim the control attributes and risk reduction provided by RABS.

The RABS concept

The RABS barrier concept differs from an isolator in that the contamination control attributes of RABS include a combination of a physical personnel access barrier (rigid screens) and aerodynamic barrier (HEPA-filtered) downflow air, typically with overspill air to the surrounding environment. This combination of physical and airflow barrier surrounding the ISO Class 5 critical process zone is one of the key specifications that differentiates RABS from isolators. Another discerning factor is that the minimum background environment for RABS is ISO Class 7 in variance to isolators that can be installed in a minimum ISO Class 8 environment.

ISPE set out the principle of “active” and “passive” RABS relating to associated air handling (HVAC) systems. Active RABS have dedicated, onboard, downflow air handling systems. Passive RABS share the downflow air handling system with the cleanroom. PHSS has continued to use this classification within the new technical monograph.

Considerations for RABS selection

Operational principles of barrier function, sterilization processes, barrier/equipment disinfection, and process operations/procedures all have to be integrated for RABS to be an effective contamination control measure. With the separation concept established4–operator-to-process separation–operator intervention under barrier-aseptic conditions becomes a significant event. Avoidance of such interventions should be the starting point for any defined aseptic process. Unavoidable interventions (open-door operator access to the ISO Class 5 process zone during aseptic operations) would need justification supported by risk assessments and adequate risk reduction measures. Such deviations are likely to be subject to more intense scrutiny.

The combination of contamination control methods becomes a key consideration in RABS selection. There are different processes, different levels of biocontamination risk, and varying operational requirements. The PHSS RABS monograph considers the operational challenges and variance in user requirements, together with providing a framework for RABS types and practices to meet current and future challenges.

How sterilization and disinfection technologies interact in the aseptic process are critical components in the RABS selection process.

There is a key separation in RABS operating principles based on the type of disinfection process (manual disinfection or automatic sporicidal gassing) and how the necessary sterilization processes are applied to product-contact parts.

With isolators, it has become an accepted practice that indirect product-contacting parts can be disinfected in place (without need for pre-sterilization), provided the high-level disinfection process can be validated with sporicidal challenge biological indicators and achieves robust and repeatable 6-log reduction. Such disinfection performance is typically only achieved by automated sporicidal gassing processes.

RABS may also be specified with sporicidal gassing, thus adopting the same technique used for disinfecting isolators.

Alternatively, with manual disinfection of the RABS, indirect product-contacting parts would be subject to a sterilization process.


Figure 1. Left: An “active” RABs has a dedicated, onboard downflow air handling system. Right: A “passive” RABS shares the downflow air handling system with the clean environment. Photos courtesy of Franz Ziel Germany and Boehringer Ingelheim Pharma, respectively.
Click here to enlarge image

In all cases, sterilization is required for all direct product-contact parts (e.g., product delivery path, delivery pumps, associated filling needles, and product closures). This process can be completed via a validated clean-in-place and sterilize-in-place (CIP/SIP) process or sterilization out-of-place with subsequent aseptic transfer and assembly into place.

Manual vs. automated disinfection

It is recommended to base RABS disinfection validation on disinfectant standards published by the European Committee for Standardization (CEN).5

A manual “wet and wipe” disinfection process may be used for the RABS barrier and enclosed process equipment (non-critical surfaces) if the disinfection process is capable of validation with repeatable efficacy. There is an important distinction between validation of a disinfectant (under standard conditions) and a disinfection process (under operational conditions). The process of disinfection is completed with the RABS airflow systems fully operational, so it is subject to process variables including drying effects that reduce contact time.

If a manual disinfection process is used for the RABS barrier and non-critical surfaces of the enclosed process equipment, then it will be necessary to use sterilization processes for all indirect product-contact parts. Sterilization would normally be out-of-place–with aseptic transfer and assembly of all indirect product-contacting parts, including feeder bowls, trackways, chutes, and glovesleeves that are specified as potentially making contact with sterilized surfaces during aseptic processing or related procedures.

RABS may also be integrated with an automated sporicidal vapor disinfection system for high-level disinfection achieving 6-log sporicidal reduction on specified RABS barrier and associated process equipment surfaces.

The most widely used sporicidal vapor gassing process for isolators–which may also be applied to RABS–is hydrogen peroxide vapor.6

The sporicidal gassing process for RABS should be low temperature (guidance figure: within ~10??C of ambient conditions) and residue free, therefore requiring no post-gassing cleaning as part of the process.

Indirect product-contact parts (e.g., feeder bowls, feeder trackways, chutes, and specified gloves/sleeves) can be disinfected in place using the automated gassing-in-place (GIP) high-level sporicidal disinfection process. Typically Geo bacillus stearothermophilus biological indicators (being much more resistant than commonly found flora) are used to validate for 6-log sporicidal reduction.

For vaporized sporicidal gassing, RABS are either closed for gas containment or the complete RABS line is gassed simultaneously with the surrounding cleanroom.

Together with a GIP process, sterilization is required for all direct product-contact parts (e.g., product delivery path, any delivery pumps, associated filling needles, and product closure parts).

Operating principles

There are three principal operating methods for RABS based on barrier configurations and environmental controls:

  1. RABS barrier with airflow overspill to an ISO Class 7 surrounding environment, comprising an airflow barrier (separating operators from the aseptic process) over the complete critical process zone. Essentially the RABS’ unidirectional, HEPA-filtered airflow inside the barrier screens flows over the critical zone then overspills to the surrounding ISO Class 7 (minimum) area. For process transfers across the RABS barrier, auxiliary HEPA downflow ISO Class 5 airflow protection may be utilized.
  2. RABS barrier with airflow overspill to an ISO Class 5 surrounding environment, comprising an airflow barrier (separating operators from the aseptic process) over the complete critical process zone. The RABS’ unidirectional, HEPA-filtered airflow inside the barrier screens flows over the critical zone then overspills to the surrounding ISO Class 5 area. With a surrounding environment of ISO Class 5, there is inherent risk reduction against contamination at process transfers.
  3. Closed RABS barrier with airflow protection at barrier transfers, comprising a closed physical barrier over the critical process zone and open airflow barriers over the component transfer paths into the RABS system. Airflow protection at transfers with ISO Class 5 airflow may be via local auxiliary downflow units in a minimum background environment of ISO Class 7 or the complete RABS surrounding environment may be ISO Class 5.

Considering the two principal methods of RABS barrier disinfection, process flow diagrams can be formulated.

  1. Manual RABS barrier disinfection together with direct and indirect product-contact parts sterilization out-of-place and aseptic transfer and assembly into place.

    1. Automated vaporized sporicidal (6-log) gassing for RABS barrier and indirect product-contact parts together with either CIP/SIP of product contact parts or sterilization out-of-place and aseptic transfer and assembly into place.

    Any of the three environmental control methods can be combined with either manual disinfection or automated vaporized sporicidal gassing. RABS may be specifically designed for closed vaporized sporicidal gassing or any RABS type may be gassed together with the cleanroom. In the combined cleanroom/RABS gassing application the barrier screens would normally be closed or have automated closure devices actuated before personnel re-enter.

    PHSS RABS types

    PHSS RABS types have been designated that combine different environmental control and disinfection technologies to provide options that meet desired operating methods and, where required by risk assessment, increased levels of biocontamination control assurance.

    • Active type 1. Onboard downflow air handling system with air overspill to the surrounding environment.
    • Active type 2. Onboard downflow air handling system with two modes of operation: 1) production mode, downflow air with overspill to surrounding environment; 2) air vents closed to RABS sporicidal gassing.
    • Active type C. Closed RABS with closed physical barrier together with air return paths for recirculation of downflow air. In addition, the transfer devices into the ISO zone utilize an aerodynamic barrier during connection or transfer from an aseptic or sterile transfer device.
    • Passive type 1. RABS ISO Class 5 downflow is via the cleanroom HVAC ceiling system with no physical connection to the ceiling grid (gap between RABS barrier screens and the cleanroom ceiling).Passive type 2. RABS ISO Class 5 downflow is via the cleanroom HVAC ceiling system with a physical connection to the ceiling grid (no gap between RABS barrier screens and the cleanroom ceiling).Type I (integrated) RABS. Any of the RABS types integrated together or a RABS and isolator system integrated to form a barrier system.

    Development of closed RABS concept

    Taking the concept of RABS as a combination between physical and aerodynamic barriers then “closing” the physical barrier so there is no overspill to the surrounding environment means surely this is an isolator. If the transfer device also used a closed transfer principle, as with rapid transfer ports (RTPs)–alpha-beta ports–then this indeed would be an isolator. The development of closed RABS has opened the path to using simpler transfer devices that have aerodynamic, ISO Class 5 grade air protection (with the ISO Class 7 background) at either open connections or non-sealed interfaces from an aseptic or sterile transfer device. RTP-type canister/bag connector transfer devices can be used for other types of RABS but this adds another level of complexity. Closed RABS offer the capability of high-level disinfection by sporicidal gassing where leak tightness of the RABS relates specifically to safety in gas containment.

    Three areas of development are currently of interest in supporting RABS technology.

    • ISO Class 5 continuity in process transfers. With the minimum background environment of ISO Class 7, it is possible to maintain ISO Class 5 continuity from zone to zone without having integrated connection notably found in isolator filling lines. The use of mobile ISO Class 5 carts and offload ISO Class 5 downflow hoods at sterilizers, lyophilizers, etc., facilitates transfer of aseptic or sterile components between satellite process zones without the need for direct connection. Such design flexibility can open up advantages for RABS installations.

    • RABS glovesleeve testing via wireless LAN. Glovesleeve devices used as part of the RABS physical barrier require integrity testing; a new development in glove test methods has reduced the time and impact on process operations when in situ testing is required. The new system uses a pressure decay method, but control is provided via a computer using wireless LAN. All selected gloves can be tested simultaneously, significantly reducing test time. A full integrity test report is generated in a secure file, making this a significant step forward in combined glovesleeve and gloveport connection testing technology.

    • RABS and room sporicidal gassing. There are significant advantages to using an automated, high-level disinfection system (typically vaporized hydrogen peroxide), both to reduce the challenges and risks of manual disinfection qualification, with spore form biological indicator challenges, and facilitate in-place, 6-log sporicidal reduction of indirect product-contact parts. Some RABS types can be closed for gassing, but with the development of cleanroom sporicidal gassing systems the combined RABS and room gassing approach is a viable option. Cleanroom volumes up to 400 m3 are routinely gassed with hydrogen peroxide vapor, achieving 6-log sporicidal reduction and validated with biological indicators.


    Figure 2. The hydrogen peroxide Z Generator for zone biodecontamination offers a low-temperature, residue-free process for combined room and RABS equipment disinfection. Photo courtesy of Bioquell UK Inc.
    Click here to enlarge image

    The latest technology includes parametric control, taking real-time measurements of starting temperature and relative humidity in the environment, and running control algorithms to set control limits. Real-time measurement of the hydrogen peroxide vapor profile is then monitored to known process lethal conditions inside the control limits. Such technology has revolutionized high-level room disinfection in hospitals and biomedical, biologics, and, increasingly, pharmaceutical sectors that have requirements for combined rooms and process equipment, including sensitive and complex surfaces that make it difficult to achieve high-level disinfection in any other way.

    Summary

    RABS are evolving at a significant rate and taking advantage of the latest technology. These developments are enabling RABS to be considered a viable alternative to the accepted isolator barrier technology, using a system approach to design and risked-based approach in selecting contamination control attributes and operating methods. The development of the comprehensive PHSS monograph will further promote recognition, assist the selection process, and provide a framework for regulatory compliance.

    James Drinkwater is process director of Bioquell UK (www.bioquell.com) and vice chairman of the Pharmaceutical and Healthcare Sciences Society ??? PHSS (formerly the Parenteral Society; www.phss.co.uk).

    References

    1. G. Farquharson, “Conventional ‘Open’ Cleanroom Processing Challenged as cGMP,” pres. at Informa Aseptic Processing Conference, London, 2008.
    2. ISPE RABS Definition Document, published Aug. 16, 2005.
    3. PHSS RABS Technical Monograph 15, in final stages of review, to be published September 2008.
    4. R. Friedman, Separation Concept, pres. at ISPE Washington Barrier Conference, June 2005.
    5. CEN Disinfectant Standards, published by the European Committee for Standardization (CEN): “EN 1276 Chemical disinfectants and antiseptics ??? Quantitive suspension tests, Bactericidal activity,” “EN 1650 Chemical disinfectants and antiseptics ??? Quantitive suspension tests, Fungicidal activity,” “EN 13704 Chemical disinfectants and antiseptics ??? Quantitive suspension tests, Sporicidal activity,” “EN 13697 ??? Non porous surface test for evaluation of bactericidal and/or fungicidal/sporicidal activity.”
    6. M. Porter, J. Lysfjord, ISPE Isolator Survey, pres. at the Washington Barrier Conference, 2005.