What does WHO say about cross-contamination? : Pharmaguideline
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  • Apr 2, 2012

    What does WHO say about cross-contamination?

    Displacement concept (low pressure differential, high airflow), Pressure differential concept (high pressure differential, low airflow) and Physical barrier concept to minimize the cross contamination.
    1. Where different products are manufactured at the same time, in different areas or cubicles, in a multi-product OSD manufacturing site, measures should be taken to ensure that dust cannot move from one cubicle to another.
    2. Correct directional air movement and a pressure cascade system can assist in preventing cross-contamination. The pressure cascade should be such that the direction of airflow is from the clean corridor into the cubicles, resulting in dust containment.
    3. The corridor should be maintained at a higher pressure than the cubicles, and the cubicles at a higher pressure than atmospheric pressure.

    4. Containment can normally be achieved by application of the displacement concept (low-pressure differential, high airflow), or the pressure differential concept (high-pressure differential, low airflow), or the physical barrier concept.
    5. The pressure cascade regime and the direction of airflow should be appropriate to the product and processing method used.
    6. Highly potent products should be manufactured under a pressure cascade regime that is negative relative to atmospheric pressure.
    7. The pressure cascade for each facility should be individually assessed according to the product handled and level of protection required.
    8. Building structure should be given special attention to accommodate the pressure cascade design.
    9. Airtight ceilings and walls, close-fitting doors and sealed light fittings should be in place.

    Displacement concept (low-pressure differential, high airflow)

    10. Under this concept, the air should be supplied to the corridor, flow through the doorway, and be extracted from the back of the cubicle. Normally the cubicle door should be closed and the air should enter the cubicle through a door grille, although the concept can be applied to an opening without a door.
    11. The velocity should be high enough to prevent turbulence within the doorway resulting in dust escaping.
    12. This displacement airflow should be calculated as the product of the door area and the velocity, which generally results in fairly large air quantities.
    This method of containment is not the preferred method, as the measurement and monitoring of airflow velocities in doorways is difficult. This concept should ideally be applied in production processes where large amounts of dust are generated.

    Pressure differential concept (high-pressure differential, low airflow)

    13. The high-pressure differential between the clean and less clean zones should be generated by leakage through the gaps of the closed doors to the cubicle.
    14. The pressure differential should be of sufficient magnitude to ensure containment and prevention of flow reversal, but should not be so high as to create turbulence problems.
    15. In considering room pressure differentials, transient variations, such as machine extract systems, should be taken into consideration.
    The pressure differential concept may normally be used in zones where little or no dust is being generated. It may be used alone or in combination with other containment control techniques and concepts, such as a double door airlock.
    16. The pressure differential between adjacent rooms could be considered a critical parameter, depending on the outcome of risk analysis. The limits for the pressure differential between adjacent areas should be such that there is no risk of overlap, e.g. 5 Pa to 15 Pa in one room and 15 Pa to 30 Pa in an adjacent room, resulting in no pressure cascade, if the first room is at the maximum tolerance and the second room is at the minimum tolerance.
    17. Low-pressure differentials may be acceptable when airlocks (pressure sinks or pressure bubbles) are used.
    18. The pressure control and monitoring devices used should be calibrated
    and qualified. Compliance with specifications should be regularly verified and the results recorded. Pressure control devices should be linked to an alarm system set according to the levels determined by a risk analysis,
    19. Manual control systems, where used, should be set up during commissioning and should not change unless other system conditions change.
    20. Airlocks can be important components in setting up and maintaining pressure cascade systems.
    21. Airlocks with different pressure cascade regimes include the cascade airlock, sink airlock and bubble airlock.
    • Cascade airlock: high pressure on one side of the airlock and low pressure on the other.
    • Sink airlock: low pressure inside the airlock and high pressure on both outer sides.
    22. Doors should open to the high-pressure side, and be provided with self-closers. Door closer springs, if used, should be designed to hold the door closed and prevent the pressure differential from pushing the door open. Sliding doors are not recommended.
    23. Central dust extraction systems should be interlocked with the appropriate air handling systems, to ensure that they operate simultaneously.
    24. Room pressure imbalance between adjacent cubicles which are linked by common dust extraction ducting should be prevented.
    25. Air should not flow from the room with the higher pressure to the room with the lower pressure, via the dust extract ducting (this would normally occur only if the dust extraction system was inoperative).
    Bubble airlock: high pressure inside the airlock and low pressure on both outer sides.

    Physical barrier concept

    26. Where appropriate, an impervious barrier to prevent cross-contamination between two zones, such as barrier isolators or pumped transfer of materials, should be used.
    27. Spot ventilation or capture hoods may be used as appropriate. The most widely accepted pressure differential for achieving containment between two adjacent zones is 15 Pa, but pressure differentials of between 5 Pa and 20 Pa may be acceptable. Where the design pressure differential is too low and tolerances are at opposite extremities, a flow reversal can take place. For example, where a control tolerance of ±3 Pa is specified, the implications of the upper and lower tolerances on containment should be evaluated.

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