PHSS Clarity In GMP – Pharmaceutical Isolator Leak Integrity Classes and Leak Rates

PHSS Clarity in GMP Guidance: Pharmaceutical Isolator Leak Integrity Classes and Leak Rates

Background to development of PHSS Guidance on Barrier Isolator technology Leak integrity classes and leak rates/ acceptance criteria for qualification and routine monitoring.

Complex pharmaceutical isolator systems cannot comply with the requirements set out in the older generic Standard ISO 10648-2 that defines four leak integrity classes.
In the ISO standard the highest class 1 at 0.05% volume/hour leak rates typically applies to rigid nuclear glove boxes or inert atmosphere glove boxes used for oxygen and moisture sensitive material processing that can be tested at high pressures and over long test periods e.g. over 1000 pascal test pressures with up to one hour test periods (with result adjustments for variations of temperature and atmospheric pressure through the test period). Such high integrity, extended test periods and relatively high test pressures are not practical to apply to complex pharmaceutical isolators e.g. filling lines.
The ISO Class 2 leak integrity at 0.25% vol/h typically applies to small flexible film isolators and containment isolators and requires relatively high test pressures and extended test periods (in range of 30 minutes). Integrity testing at this level of integrity and extended test time is also not considered practical for production scale pharmaceutical isolators.
The ISO Class 3 leak integrity at 1% vol/h can applied to small scale pharmaceutical isolators in comparison to small laboratory/ containment Isolators the ISO10648- 2 standard was mainly drafted around.
However as a whole the ISO standard is considered impractical to apply to the full range of Pharmaceutical isolators including larger scale filling Isolator systems that include complex sealing systems with integrated process machinery. Such complex Filling isolators were not fully developed when this ISO standard was written hence not considered in drafting.
The lowest ISO class 4 leak integrity at 10% vol/h leak rate presents at leak rate that cannot be automated via a typically applied pressure decay method (instead requires a pressure hold method that is more suitable for duct work integrity testing) and would not safely contain a gaseous bio-decontamination agent e.g. VHP/VH202: vaporised hydrogen peroxide during a decontamination cycle to avoid operator exposure at the OEL. Such a high level of leakage is not considered acceptable for Pharmaceutical isolators.

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