The impact of QRM on RABS
There is an additional requirement, pre GIP, to confirm that indirect product contact surfaces, such as feeder bowls, are free of cleaning residues or have no potential for trace residue release and contamination of products via mechanical transfer on stopper surfaces Picture courtesy of Steriline, Italy
Restricted Access Barrier Systems have undergone rapid development and are the topic of a new PHSS white paper. James Drinkwater, PHSS chairman and RABS Special Interest Group leader, summarises the main changes in practice covered in the paper
The Pharmaceutical and Healthcare Sciences Society (PHSS) has published a white paper1 on Restricted Access Barrier Systems (RABS), prepared by a special interest group formed of members of the pharmaceutical industry, RABS and filling machine manufacturers and related suppliers. It was reviewed by international regulators, including the UK MHRA and US FDA, prior to publication and fully supports the initiatives of Quality by Design (QbD) and Quality Risk Management (QRM).
In the past, RABS were considered as an easier step from conventional “Open” processing in cleanrooms moving towards separation of the process from the potentially most contaminating source – people – by use of physical barriers in combination with airflow protection to control against contamination ingress.
This “easier” step maintained conventional manual disinfection inside the RABS barrier for non-contact parts, with both direct and indirect product contact parts sterilised in-place or out-of-place, followed by aseptic transfer and aseptic assembly into place.
In consideration of QRM, the task of open door set-up of pre-sterilised parts or open door intervention into an aseptic process (where sterilised parts, including open product closures or partially stoppered filled containers may be exposed) has led to other RABS options. The impact of “Intervention risk” has resulted in a new generation of RABS designs and operation methodologies.
The first break from tradition is that gaseous vapour phase decontamination has become applied to RABS, using the benchmark process – hydrogen peroxide vapour – to facilitate gassing-in-place (GIP) of indirect product contact parts. Together with clean- and sterilise-in-place (CIP/SIP) or closed aseptic transfer of pre-sterilised parts, GIP provides the option for no open RABS barrier door intervention after the initial set-up, hence eliminating subsequent exposure to pre-sterilised parts.
The most recognised terms related to RABS are “Open” and “Closed” and here there has evolved a differentiation in terms when related to RABS design or aseptic process operations with respect to contamination risk related to levels of operator intervention (see table 1).
|Table 1: Adopted terms relating to RABS|
|Open Design RABS||Closed Design RABS|
|Open operation RABS||Closed Operation RABS|
At the construction stage of RABS, with interfacing to related process equipment and cleanroom, the airflow handling configuration becomes an important consideration. In addition, there is now a requirement to define whether the RABS barrier is to use a manual disinfection or automated gaseous decontamination process.
Open Design RABS define an airflow handling format that has uni-directional airflow inside the RABS EU Grade A – ISO Class 5 Process zone with air overspill around and under (lower than critical process points) the barrier separation screens to the EU Grade B (Operational) – ISO Class 7 Cleanroom surrounding environment.
Closed Design RABS define the airflow handling as down flow air inside the RABS barrier circulating inside primarily closed barrier screens where the status of RABS is maintained (and not an isolator) with the airflow protection used at transfer devices that enter directly into the critical process zone through the barrier screens.
Considering aseptic process operations the terms Open and Closed have a completely different interpretation and now apply to a statement of intended operation with different levels of intervention.
Open Operation RABS define a stage in an aseptic process where there is an intended ‘Open Door’ intervention. Closed Operation RABS provide the highest level of contamination control and assurance because the operational methodology is that there is no operator ‘Open door’ intervention after the last bio-decontamination step.
Intervention risk hierarchy
Three levels of intervention risk hierarchy apply to RABS. Type 1 and 2 interventions apply to Open Operation RABS and type 3 to both Open and Closed Operation RABS.
By defining type 1 interventions there is a clear intent provided that Open barrier door interventions will (or may) occur in aseptic processing, presenting the highest intervention risk.
By defining type 2 interventions then there is a risk reduction as Open door interventions only occur at set-up stages, including aseptic assembly of pre-sterilised parts with no further Open door intervention thereafter where open product closures are present or critical aseptic operations are in progress.
In all cases, entry through sealed glove-barrier screens for an inherent (material transfer) or corrective (correct a jam) interventions are seen as managed with such lower risk interventions not requiring line clearance or subsequent decontamination steps. The line may be held for a while to clear a jam but that should be the limit of impact.
All such deviations and interventions should be validated during the media fills and documented during production.
Related RABS types
As the application of RABS has proceeded there has been further development of RABS types, for example, with Dual Design RABS and Containment RABS.
Dual Design RABS are a simple combination of Open Design RABS and Closed Design RABS. In the Open format during production (decontaminated) stage there is down flow air overspill to the cleanroom. To decontaminate the RABS barrier, using GIP, the air supply and overspill vents are closed to facilitate standalone gaseous vapour phase decontamination.
Containment RABS are primarily applied to Closed Design RABS with additional contamination control attributes, such as the use of pressure differentials and ability
to chemically decontaminate, eliminating closed un-cleanable mechanical spaces, etc.
Transfer device types are simply categorised into three methods of transfer maintaining aseptic conditions through in-process transfers into the RABS critical zone.
Method one details transfers between remote aseptic zones, maintaining Grade A continuity, e.g. uni-directional flow transfer carts.
Method two details a transfer device using a pre-sterilised bag or transfer container holding components that include an aseptic transfer connection to maintain protection at the docking point to the barrier.
Method three details a transfer device that includes a facility to decontaminate components at the barrier immediately before entry.
Gassing-in-place (GIP) is a significant RABS development: Picture courtesy of Steriline, Italy
The process of gaseous vapour phase decontamination for GIP has to be recognised as a significant development because the process and sterility assurance requirement is that indirect product contact parts require surface sterilisation. Using the benchmark process (hydrogen peroxide vapour2,3 at invisible vapour levels) then it is possible to validate conditions of surface sterilisation, at 6 log sporicidal reduction plus and overkill factor. Under specific requirements GIP has regulatory acceptance for surface sterilisation.
To achieve such a position of regulatory acceptance means there is a recognition that the science behind the process and mode of action of the agent is understood, together with a clear differentiation between GIP as a surface treatment and classic sterilisation processes detailed in Pharmacopeias that are fully penetrative processes.
Unlike classic sterilisation with steam (moist heat), dry heat and gamma irradiation, gaseous vapour phase decontamination combines two chemical steps, cleaning and the vaporised agent. Although it is recognised that hydrogen peroxide will not exist in the presence of stainless steel (as it is a mild catalyst), it can chemically compound with residues from the cleaning step.
There is an additional requirement, pre GIP, to confirm that indirect product contact surfaces, such as feeder bowls, are free of cleaning residues or have no potential for trace residue release and contamination of products via mechanical transfer on stopper surfaces.
Bioburden reduction hierarchy
To meet the requirements of ensuring there is a differentiation between processes that are a) Sterilisation (penetrative) and b) Surface Sterilisation (gaseous vapour phase decontamination), a bioburden reduction hierarchy has been set.
To complete the hierarchy other types of general decontamination processes have been included. There is no consensus on definition for the terms Disinfection and Sanitisation, therefore to qualify the hierarchy the validation method and relative assurance of decontamination are also specified (Table 2).
|Table 2: Hierarchy of bioburden reduction processes|
|Biological Decontamination process||Comment|
|Sterilisation as defined in Pharmacopeias||6 log sporicidal reduction, plus overkill, achieving penetrative sterilisation, e.g. suitable for porous loads|
|Gaseous Vapour Phase decontamination - bench mark process hydrogen peroxide vapour||6 log sporicidal reduction, plus overkill, that can be validated to achieve conditions of surface sterilisation. Cleaning validation requires studies to ensure there are no chemical residues that may compound with hydrogen peroxide or agent used|
|Validated bio-decontamination process, 4 log to 6 log sporicidal. May be defined as Disinfection||4 log to 6 log sporicidal reduction, validated with biological challenge studies. May be a manual or automated process. Requires a pre-cleaning step but this is generally limited to being visually clean|
|Bio-decontamination procedure that may use validated agents and is monitored to confirm the impact on bio-contamination control. May be defined as Sanitisation||These decontamination procedures are typically manual or use simple agent delivery devices. There is no validated sporicidal log reduction of the process but the result would be expected to be lower than any laboratory validated agent used (typically laboratory tests are a suspension test)|
Where bio-contamination control is required, possibly together with cross-contamination control, for biological products, QRM is driving a change from conventional Open processing cleanroom operations to combined use of a cleanroom and separative devices, including RABS and isolators. The evolution of RABS bio-decontaminated with a gaseous process has impacted on cleanroom design leading to more integration and improved process and contamination control.
Through the application of a simple structured approach to RABS definitions, the provision of clear considerations for both design and operation with QRM and mitigation, and by meeting regulatory expectation, it is expected that widespread adoption and harmonisation of the PHSS RABS definitions will result.
1. Pharmaceutical & Healthcare Sciences Society – PHSS RABS White paper firstname.lastname@example.org
2. Beatriz Unger-Bimczok et al – J Pham Innov (2008) 3; 123-133
3. Watling et al PDA Journal 2002 Vol 56 No.6
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