Guest Column | June 10, 2024

The Ins And Outs Of Modern Barrier Systems For Sterile Manufacturing

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Barrier systems include restricted access barrier systems (RABS) and isolators. These are technical devices where the operator does not have direct access to critical processes.

Critical processes are interventions such as correcting the filling needles if their settings have drifted over time during the filling process or if, for example, a blockage occurs during the transfer of the stoppers for stopper positioning into the open containers (vials).

To prevent direct access, barrier systems are secured with doors that have built-in gloves to intervene in the process, if necessary. In isolators, these doors are locked during the process. Due to the closed design and the integrated decontamination system, isolators can be set up in a cleanroom Grade C or D environment. Surface decon RABS are available in a variety of different designs. These differ from one another in terms of cost and risk. A passive RABS, for example, is comparatively inexpensive but carries the highest risk.

This article looks at key features of barrier systems and discusses some of their applications.

Restricted Access Barrier Systems

RABS are used in the pharmaceutical industry to ensure an aseptic environment for the manufacture of sterile drugs and biotechnological products.

RABS consist of a physical barrier separating the operator's work area from the sterile manufacturing area. This barrier can be overcome for intervention via integrated glove inserts and, in rare cases, by opening the doors. The barrier consists of a combination of tempered glass walls with integrated glove inserts and stainless steel cladding to provide an effective barrier against particles and germs.

Annex 1 defines a RABS this way:

RABS

System that provides an enclosed, but not fully sealed, environment meeting defined air quality conditions (for aseptic processing Grade A), and using a rigid-wall enclosure and integrated gloves to separate its interior from the surrounding cleanroom environment. The inner surfaces of the RABS are disinfected and decontaminated with a sporicidal agent. Operators use gloves, half suits, RTPs, and other integrated transfer ports to perform manipulations or convey materials to the interior of the RABS. Depending on the design, doors are rarely opened, and only under strictly pre-defined conditions.

 

RABS types that allow operators to intervene by opening the doors offer greater flexibility than isolators. However, this advantage is offset by the following disadvantages:

  • hightened risk to the sterile product,
  • increased product loss, since after each opening of the doors, the containers such as vials, syringes, etc., located in the manufacturing area cannot be used further, depending on the type of intervention, and
  • time-consuming and complex training of the employees who work in this area, since in addition to donning the clothing for Grade B cleanrooms, the movement sequences and movement speeds in Grade B cleanrooms must also be trained. This training is very important and time-consuming and often takes months until the employees are qualified to perform critical work processes.

A RABS is only regarded as a barrier as long as the doors are closed!

The doors should normally only be opened for setup and cleaning purposes. In rare cases, the doors can also be opened in the process, e.g., if there is no corresponding glove insert available for a required manipulation. This can be the case especially with older RABS.

Should the doors be opened regularly for interventions, it is no longer a barrier.

RABS are available in a variety of different designs. These differ from one another in terms of cost and risk. A passive RABS, for example, is comparatively inexpensive but carries the highest risk.

Passive RABS

A RABS is called a "passive RABS" if the airflow into the barrier is supplied from the HEPA filter integrated in the cleanroom ceiling. This means the passive RABS does not have its own integrated air treatment and pressure control. The overflow of air takes place in the lower area of the RABS at the air outlets back into the room.

Since there is no separate controlled air supply, undesirable pressure differences between the Grade A zone inside the passive RABS and the Grade B environment may occur. The pressure difference from the Grade A zone to the Grade B environment should be 10 Pascal as a guide value.

Ensure that there is no unwanted airflow from the Grade B area into the Grade A zone. This should be verified by smoke studies. The smoke studies should also take place during a simulated control operation to investigate possible air fluctuations caused by the employees in the Grade B area or by the process within the Grade A zone.

The doors on the passive RABS should generally be opened and closed only in exceptional cases. If doors are opened regularly, the passive RABS loses its designation as a barrier. Doors on the RABS are provided, for example, to have better access during the setup of a filling line or to be able to insert larger parts. During regular operation, the doors are kept closed.

Passive RABS are not suitable for handling highly active substances, as these can contaminate the employees as well as the environment with the medicinal substance being processed (e.g., aerosols) due to the overflow of air out into the room.

Active RABS

An active RABS differs from a passive RABS only in the integration of the air supply and pressure control into the overall system. This allows better control of the pressure from the Grade A zone to the Grade B area in the room.

Closed RABS

The difference between a closed RABS and an active or passive RABS is that the air does not escape into the room but is recirculated internally, as in an isolator. There is no overflow into the room. Another difference between an active and passive RABS is that the doors are locked when the RABS is closed and cannot be opened during regular operation.

When using special filter technologies upstream of the return air ducts and other technical safety precautions, a closed RABS can also be used for highly active substances.

Isolators

Isolators are devices used in pharmaceutical production as well as in the manufacture of biomedical substances, in the production of cell and genetically engineered medicinal substances, and in the sterile filling of, for example, vaccines.

Isolators are primarily used to protect the product from possible contamination (particles or germs) from the environment. Isolators additionally protect employees during the production of highly active substances.

What are highly active substances?

Highly active substances include, for example, conjugates of a monoclonal antibody with a highly active substance (antibody drug conjugate, ADC) or a substance with a higher biological activity, as may be the case in cell or gene production. There, viral vectors (programmed viruses) are frequently used, which may be released via aerosols when working on the open product and, if inadequately protected, can also contaminate the employee.

Aseptic working conditions inside isolators are usually ensured by cleaning and disinfection, similar to RABS, whereby all internal surfaces are freed from particles and microorganisms. Additionally, in the case of an isolator, all internal surfaces are subsequently wetted with vaporized or nebular hydrogen peroxide in an automated decontamination process in order to kill any microorganisms that may remain after cleaning.

Aseptic work inside isolators requires a high degree of care to ensure that the sterility of the pharmaceutical product is maintained throughout the manufacturing process. Specially trained personnel are necessary for this purpose.

The Annex 1 glossary defines an isolator this way.

Isolator

An isolator is an enclosure capable of being subject to reproducible interior bio-decontamination, with an internal work zone meeting Grade A conditions that provides uncompromised, continuous isolation of its interior from the external environment (e.g., surrounding cleanroom air and personnel). There are two major types of isolators:

  • Closed isolator systems exclude external contamination of the isolator's interior by accomplishing material transfer via aseptic connection to auxiliary equipment, rather than use of openings to the surrounding environment. Closed systems remain sealed throughout operations.
  • Open isolator systems are designed to allow for the continuous or semi-continuous ingress and/or egress of materials during operations through one or more openings. Openings are engineered (e.g., using continuous overpressure) to exclude the entry of external contaminant into the isolator.

 

Isolators are divided into two different system types: open and closed isolators.

Open Isolator

In an open isolator, unlike an active and passive RABS, there is no general overflow of air back into the room. Isolators are self-contained and the recirculation of air takes place via return air ducts. The doors are locked during processing of the sterile product and the necessary interventions can only take place via glove ports on the doors.

The Annex 1 glossary defines an open isolator this way.

Open isolator

Open isolator systems are designed to allow for the continuous or semi-continuous ingress and/or egress of materials during operations through one or more openings. Openings are engineered (e.g., using continuous overpressure) to exclude the entry of external contaminant into the isolator.

 

An isolator is referred to as an "open isolator" if material can be fed and/or discharged discontinuously or continuously, for example via small openings (mouse holes). This is the case, for example, in filling systems for the aseptic filling of small vials, syringes, etc. In this case, the isolator system should be installed in at least cleanroom Grade C.

Closed Isolator

Closed isolators are characterized by the fact that the material is fed in and out through validated transfer systems rather than through small openings (mouse holes).

Transfer systems are, for example, material locks that enable safe transfer from the environment (Grade C or D area) to Grade A zone by means of validated surface decontamination using vaporized or finely atomized H2O2.

The Annex 1 glossary defines a closed isolator this way:

Closed isolator

Closed isolator systems exclude external contamination of the isolator's interior by accomplishing material transfer via aseptic connection to auxiliary equipment, rather than use of openings to the surrounding environment. Closed systems remain sealed throughout operations.

 

Examples of closed isolators are sterility test isolators or process isolators for the production of cell and gene therapeutics, where the process-related apparatus such as incubator, centrifuge, or other systems are tightly integrated into the isolator system. Closed isolators should be installed in a Grade D or higher area.

Comparing The Different Barrier Systems

The overview in Figure 1 shows the most important features of the systems described.

Feature RABS Isolator
   passive active closed open closed
Cleanroom grade in the process area A
Cleanroom grade of the surrounding environment B C D
Airflow Cleanroom Grade A conditions according to Annex 1
Pressure difference 10 Pascal to the environment
Doors Not locked during
routine production
Locked during routine production
Surface disinfection/decontamination Manual disinfection with open doors Automatic decontamination with closed doors
Application example Not suitable for highly active substances Suitable for highly active substances with additional equipment

Figure 1: Comparison of RABS and isolators

 

This article is an excerpt from GMP knowledge contained in the online portal GMP Compliance Adviser, which provides in-depth information about GMP best practices and regulations with a focus on Europe, but also referring to the U.S., Japan, and many more (PIC/S, ICH, WHO, etc.).

About The Author:

Richard Denk has been working in the areas of hygienic design, containment, and the production of highly active substances for over 25 years. He developed the Containment Pyramid and founded the Containment Expert Group of the ISPE DACH in 2008. He was the initiator and responsible for the ISPE Containment Handbook published in 2015 and the second edition published in 2021. After finishing his mechanical engineering studies, he developed and headed up the containment and pharma/life science divisions in a plant engineering company from 1994 to 2007. He gives lectures on the topic of aseptic production, cell and gene therapy, containment, robotics, cleaning, and hygienic design. Reach him at denkrich@googlemail.com.