Concepts in Cross contamination by WHO

Introduction

General

1.1 Where different products are manufactured at the same time, in different areas or cubicles, in a multiproduct OSD manufacturing site, measures should be taken to ensure that dust cannot move from one cubicle to another.

1.2 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 airfl ow is from the clean corridor into the cubicles, resulting in dust containment.

1.3 The corridor should be maintained at a higher pressure than the cubicles, and the cubicles at a higher pressure than atmospheric pressure.

1.4 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.

1.5 The pressure cascade regime and the direction of airflow should be appropriate to the product and processing method used.

1.6 Highly potent products should be manufactured under a pressure cascade regime that is negative relative to atmospheric pressure.

1.7 The pressure cascade for each facility should be individually assessed according to the product handled and level of protection required.

1.8 Building structure should be given special attention to accommodate the pressure cascade design.

1.9 Ceilings and walls, close fitting doors and sealed light fittings should be in place, to limit ingress or egress of air.

2.0 Displacement concept (Low pressure differential, High airflow)

2.1 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.

2.2 The velocity should be high enough to prevent turbulence within the doorway resulting in dust escaping.

2.3 This displacement airflow should be calculated as the product of the door area and the velocity, which generally results in fairly large air quantities.

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

3.1 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.

3.2 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.

3.3 In considering room pressure differentials, transient variations, such as machine extract systems, should be taken into consideration.

3.4 A pressure differential of 15 Pa is often used for achieving containment between two adjacent zones, 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 rooms being operated at the upper and lower tolerances should be evaluated. It is important to select pressures and tolerances such that a flow reversal is unlikely to occur.

3.5 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 in the acceptable operating range, e.g. 5 Pa to 15 Pa in one room and 15 Pa to 30 Pa in an adjacent room, resulting in the failure of the pressure cascade, where the first room is at the maximum pressure limit and the second room is at its minimum pressure limit.

3.6 Low pressure differentials may be acceptable when airlocks (pressure sinks or pressure bubbles) are used to segregate areas.

3.7 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.

3.8 Manual control systems, where used, should be set up during commissioning, with set point marked, and should not change unless other system conditions change.

3.9 Airlocks can be important components in setting up and maintaining pressure cascade systems and also to limit cross-contamination.

3.10 Airlocks with different pressure cascade regimes include the cascade airlock, sink airlock and bubble airlock

- Cascade airlock - Higher pressure on one side of the airlock and lower pressure on the other

- Sink airlock - Lower pressure inside the airlock and higher pressure on both outer sides

- Bubble airlock - Higher pressure inside the airlock and lower pressure on both outer sides

3.11 Doors should open to the high pressure side, so that room pressure assists in holding the door closed and in addition be provided with self closers. Should the doors open to the low pressure side, the door closer springs should be sufficient to hold the door closed and prevent the pressure differential from pushing the door open. There should be a method to indicate if both doors to airlocks are open at the same time, or alternatively these should be interlocked. The determination of which doors should be interlocked should be the subject of a risk assessment study.

3.12 Central dust extraction systems should be interlocked with the appropriate air-handling systems, to ensure that they operate simultaneously.

3.13 Room pressure differential between adjacent cubicles, which are linked by common dust extraction ducting, should be avoided.

3.14 Air should not flow through the dust extraction ducting or return air ducting from the room with the higher pressure to the room with the lower pressure (this would normally occur only if extract or return systems were inoperative). Systems should be designed to prevent dust flowing back in the opposite direction in the event of component failure or airflow failure.

3.15 Adequate room pressure differential indication should be provided so that each critical room pressure can be traced back to ambient pressure (by summation of the room pressure differentials), in order to determine the room actual absolute pressure. Room pressure indication gauges should have a range and graduation scale which enables the reading to accuracy, as appropriate; normal operating range, alert and action limits should be defined and displayed at the point of indication. A colour coding gauge may be helpful. Room pressure indication may be either analogue or digital, and may be represented as either pressure differentials or absolute pressures. Which ever system is used any out-of-specifi cation condition should be easily identifiable.

3.16 Material pass-through-hatches (PTH) or pass boxes (PB) can also be used for separating two different zones. PTHs fall into two categories, namely a dynamic PTH or a passive PTH. Dynamic PTHs have an air supply to or extraction from them, and can then be used as bubble, sink or cascade PTHs.

4.0 Physical barrier concept

4.1 Where appropriate, an impervious barrier to prevent cross contamination between two zones, such as closed systems, pumped or vacuum transfer of materials, should be used.

Displacement concept, pressure differential concept, physical barrier concept , who, cross contamination