Barrier technologies: Isolators versus RABS
During the previous year (2022), most of different regulatory bodies published their updates for relevant guidelines of manufacturing of sterile pharmaceutical products. Current version of these GMP guidelines showed a recommendation for using and implementing new techniques for control of contamination during manufacturing; such as barrier technologies, robotic systems, rapid/alternative methods and continuous monitoring systems, Form-Fill-Seal (FFS) and Single use systems (SUS).
If we go back to the previous version of these guidelines we will find that Both of the following:
Already mentioned requirements of isolator as a barrier technology in addition to recommendation under the section “Finishing of sterile products”?of using Restricted Access Barrier Systems (RABS)?or?isolator for capping operations of vials?as they may be beneficial in assuring?the required environmental conditions and minimizing direct human interventions into the?capping operation.
The need for implementation and dependence on these new technologies arises because?human interventions considered the most difficult risk to be controlled during?aseptic processing. Reducing human interventions into the critical zones will result in obvious positive impact?on producing sterile finished product.
Stewart davenport of Upjohn (now Pfizer) in Kalamazoo, Michigan was the first one to coin RABS (Restricted Access Barrier Systems) acronym in the early 1990s. at June 2001 ISPE Barrier isolator conference; Stewart davenport presented media fill simulation data for a period of nine years of operation (about a million cumulative media fill). He gathered date from three filling lines with RABS which successfully yielded Probability of a non-sterile unit?(PNSU) data similar to the use of isolator. But here; using RABS comes with a competitive advantage over Isolators. As RABS offers:
Advanced Aseptic Processing (AAP):
AAP is a term referenced in ISPE?to cover the spectrum of Restricted Access Barrier Systems (RABS) and isolator systems.
AAP techniques simply are physical barrier methods of product protection with minimizing risks of product contamination and offers better product containment during processing.
AAP techniques are used during manufacturing operations to separate (primarily) operators from the process which will result in reduction of the associated risks of human intervention?to ensure the product is not exposed to viable organisms and particulate (non-viable) contamination.
Operations within equipment like Laminar Flow Hoods (LFHs) or Biosafety Cabinets (BSCs) do not fit within the definition of AAP. It only provides partial separation as hands and arms of the operators are not physically separated from the process. Same concept applies to curtained cleanroom areas as curtains provide little barrier. Only complete, rigid wall enclosures considered within the scope of AAP.
Isolator systems versus RABS
Isolators and RABS are considered different technologies but both, and the associated processes, should be designed to provide protection through separation of the grade A environment from the background environment.?
The hazards introduced from entry or removal of items during processing should be understood and actions should be taken to minimize?their associated risks. those actions should consider using high capability transfer technologies or validated systems that robustly prevent contamination and should consider their suitability and to be appropriate for the respective technology.?
Isolators
Basic isolator air handling requirements are more complicated than RABS. Air is re-circulated. so, return fans and ductwork is required. In order to maintain positive pressure; Leak testing of isolator systems will?require?monitoring pressure decay over time, which is required to prove the unit is sealed prior to sanitization and operation.?That requires that?the air handling unit, including the return ductwork, to be leak tight.
Ductwork is needed to be extended outside of cleanroom, and?sometimes outside of the building, to safely vent H2O2 vapour after sanitization?(when H2O2 is used).
Restricted Access Barrier Systems (RABS)
RABS operate in a same way as LFHs. They are fed with clean air from fan units through HEPA filters and the air vents from the unit into the surrounding room. The air is unidirectional via diffuser panels and multiple fan/HEPA filter locations. In RABS the air handling requirements are relatively uncomplicated. Pressure balancing involves supply and return ductwork. Return fans are not required (no circulation for air). The exception to this is closed RABS, which can have a pressure differential (typically positive pressure) to the outside background environment.
Design of Isolator systems versus RABS
Isolators:
We have two types of Isolators: open isolators and closed isolators.
Design of open isolators should ensure grade A conditions with first air protection in the critical zone and unidirectional airflow that sweeps over and away from exposed products during processing.
Design of closed isolators Where processing lines are included in closed isolators we should ensure grade A conditions with adequate protection for exposed products during processing. Airflow may not be fully unidirectional in closed isolators where simple operations are conducted. However, any turbulent airflow should not increase risk of contamination of the exposed product.
A sub-type of closed isolators is the negative pressure closed isolators (also called vacuum isolators)?which should only be used when containment of the product is considered essential (e.g. radiopharmaceutical products) and specialized risk control measures should be applied to ensure the critical zone is not compromised due to this negative pressure.
RABS:
Design of RABS should ensure grade A conditions with unidirectional airflow and first air protection in the critical zone. A positive airflow from the critical zone to the supporting background environment should be maintained.
RABS are classified into Open RABS and Closed RABS:
Open RABS:?when the air pass through the protected zone then it spills into the clean room with no further filtration.
Open RABS sub-classified into Active RABS and Passive RABS.
Active RABS: it’s equipped with and independent air ventilation system. In this case, the laminar flow required is generated by fans and filters that are parts of the RABS itself.
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Passive RABS: it’s not equipped with a dedicated air system. In this case, the air flow inside RABS should be generated externally (e.g. generated by fans and HEPA filters embedded in the false ceiling of clean room).
Closed RABS: when the air pass through the protected zone then it is re-circulated back to the supply HEPA filters or it spills into the cleanroom after being filtered.
Background environment of Isolator systems versus RABS
Background environment for either isolators or RABS should ensure the risk of transfer of contamination is minimized. The decision of the background classification should be based on risk assessment and justified in the contamination control strategy (CCS). So, higher class than what is recommended for each type should be considered in contamination control strategy (CCS) if the recommended class, mentioned below, may cause a risk of contamination or the these risks not appropriately justified.
Isolators:
Open Isolators: The background environment should generally correspond to a minimum of grade C. Airflow pattern studies should be performed at the interfaces of open isolators to demonstrate the absence of air ingress into the critical zone.
Closed Isolators: The background for closed isolators should correspond to a minimum of grade D.
RABS:
Background environment for RABS used for aseptic processing should correspond to a minimum of grade B.
Airflow pattern studies should be performed to demonstrate the absence of air ingress during interventions, including door openings if applicable.?
Glove System of Isolator systems versus RABS
Materials used for glove systems should be demonstrated to have appropriate mechanical and chemical resistance and the frequency of glove replacement should be defined. Theses aspects should be considered within the CCS.
Isolators:
Integrity / leak testing should be performed at defined intervals (generally at a minimum frequency of the beginning and end of each batch or campaign?and additional glove integrity testing may be necessary depending on the validated campaign length). Glove integrity monitoring should include a visual inspection by qualified personnel associated with each use and following any manipulation that may affect the integrity of the system.
RABS:
Gloves used in the grade A area should be sterilized before installation and sterilized or effectively bio-decontaminated by a validated method prior to each manufacturing campaign. If exposed to the background environment during operation, disinfection using an approved methodology following each exposure should be completed. Gloves should be visually examined with each use, where integrity testing should be performed at periodic intervals?which should be defined and justified within the CCS.?
Decontamination methods for Isolators and RABS:
Decontamination methods (cleaning and bio-decontamination, and where applicable inactivation for biological materials) should be appropriately defined and controlled. The cleaning process prior to the bio-decontamination step is essential as any residues that remain may inhibit the effectiveness of the decontamination process. Evidence should also be available to demonstrate that the cleaning and bio-decontamination agents used do not have adverse impact on the product produced within the RABS or isolator.
For isolators
The bio-decontamination process of the interior should be automated, validated and controlled within defined cycle parameters and should include a sporicidal agent in a suitable form (e.g. gaseous or vaporized form). Gloves should be appropriately extended with fingers separated to ensure contact with the agent. Methods used (cleaning and sporicidal bio-decontamination) should render the interior surfaces and critical zone of the isolator free from viable microorganisms.??
The bio-decontamination cycles for isolator units are mechanically complicated. For example, before injection of the H2O2 vapour (when used), the chamber and air handling ductwork must be conditioned. The purpose of the conditioning is to ensure a sufficient concentration of H2O2 vapour is injected into the system and that the H2O2 stays in vapour form during the cycle. Conditioning consists of heating the chamber and ductwork and lowering the humidity of the air in the system for low humidity bio-decontamination systems. High humidity bio-decontamination systems do not require humidity control during conditioning. After the bio-decontamination cycle is complete, out gassing of the H2O2 vapour is required to bring the concentration down to levels that are both safe for personnel, yet not high enough to affect the product being filled. Heating, Ventilation, and Air Conditioning (HVAC) systems are often required to perform these functions.
The interior of isolators are bio-decontaminated using an automatic sequence which most often includes injection of H2O2 vapour as the sanitant. These cycles are very consistent and lead to a validatable bio-decontamination method. However, manual cleaning of the interior is still required on a regular basis which should be defined and considered within the CCS. Direct contact cleaning is required to remove surface contaminants and to reduce the likelihood of biofilm formation. Also, manual cleaning is often required whenever the chamber is opened for parts changeover and other invasive events. Procedures should dictate when isolators are manually cleaned.
For RABS
The sporicidal disinfection should include the routine application of a sporicidal agent using a method that has been validated and demonstrated to robustly include all areas of the interior surfaces and ensure a suitable environment for aseptic processing.
As described in the ISPE; the bio-decontamination of RABS units is not automatic. Manual spray and wipe-down methods must be employed. The difficulty lies in performing consistent, repeatable and complete bio-decontamination using manual methods. Validation of the effectiveness of the cleaning and bio-decontamination solutions is an important step in justifying manual cleaning processes. In many cases, companies are trying to move away from manual cleaning and bio-decontamination because of consistency issues and the difficulty of validating manual methods where human error risk existing. Alternatively, some companies offer periodic cleanroom bio-decontamination services using automated equipment that can be used for RABS systems.
Conclusion:
The hereunder table summarizes the main differences between Isolators and RABS:?
Reviewed by: Ahmed SOLIMAN
References:
Program& Portfolio Manager | Change Manager
1 年Thank you for the comprehensive review, I appreciate the insight you have shared! :)
Desenvolvimento de Negócio
2 年Very useful information! Clear and comprehensive.