RABS find an expanded role in aseptic processing

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


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