Another important aspect of isolator technology is that it requires the biodecontamination of all machinery and isolator surfaces
in the aseptic-process area before each production run. Biodecontamination is necessary because the isolator typically is
opened for maintenance, format changes, cleaning, and product changeover. Opening the isolator removes the physical separation
of the cleanroom and the potentially contaminated surrounding area. The most common biodecontamination systems for isolators
use H2O2 vapor. In the conditioning phase, H2O2 vapor is introduced into the sealed isolator until it reaches a specified concentration. Next, H2O2 is held at this concentration for a specific duration. Finally, during the aeration phase, the H2O2 vapor is removed by purging the isolator with fresh, filtered air. This process can take 3–10 h, depending on the biodecontamination
system, isolator size, surface areas, and air-filter size. During this period, the process line cannot be used, although other
procedures such as cleaning and steaming in place of the filling system can be performed during aeration.
Table I: A comparison of cleanrooms, restricted-access barrier systems (RABS), and isolators.
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The long duration of a biodecontamination cycle reduces operational flexibility when working with an isolator. This procedure,
however, does guarantee that each production run begins with a biodecontaminated system, which is nearly sterile (demonstrating
a 6-log inactivation of biodecontaminants).
Manual operations within the aseptic area are more difficult with isolators. Gloveports must be used in place of direct operator
access. This technique requires greater reliability and automation for process machinery inside an isolator than is required
in a traditional cleanroom. All interfaces, gloveports, mouseholes, and transfer ports must be integrated into the physical
barrier because they separate the clean process area from the potentially contaminated exterior areas.
Isolators always have their own air-handling system to maintain production conditions and achieve the optimal conditions for
the biodecontamination cycle.
RABS: an alternative.
The restricted-access barrier system (RABS) can be an alternative to isolators and cleanrooms. The RABS concept entails a
physical barrier between operators and production areas, but the barrier is limited. A limited barrier is acceptable because
RABS always must be set up in high-class cleanrooms (at least ISO 7). Thus, RABS do not require their own biodecontamination
system (6).
Guidelines and standards for RABS
Figure 3: Vial-filling line with a passive RABS.
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To date, no specific standards or regulations for RABS have been developed. Manufacturers should follow existing norms and
regulations for the basic processing of sterile pharmaceutical products. Operators can consult ISO Standard 14644, Part 7
for guidance when using RABS as a protective solution (5). Appendix A of Part 7 features a diagram that shows the reliability
of a separation versus the separation method. It demonstrates that RABS can be considered an aerodynamic measure that has a high physical separation.
The system's interior atmosphere can be controlled, but pressure control is limited. In contrast, the diagram shows that isolator
solutions have a small leak rate and appropriate positive or negative pressure control.
The US Food and Drug Administration is the first authority to offer preliminary definitions of the approximately 75 existing
RABS installations worldwide (6). A working group of industrial experts drafted a definition of RABS and guidelines for RABS
operation for FDA. This draft emphasizes that:
"RABS can operate as 'doors closed' for processing with very low risk of contamination similar to isolators, or permit
rare 'open door interventions' provided appropriate measures are taken (7)."
Opening the main doors during production is permissible and only requires in-depth documentation in exceptional cases. The
same is not true for the transfer doors because the physical and aerodynamic barrier to the external area is only guaranteed
when the doors are closed. Sometimes, industrial safety concerns prohibit the opening of RABS doors during production, regardless
of aseptic considerations.
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