The pattern of the airflow through an isolator may take one of three forms: turbulent flow, unidirectional flow, or a combination of the two.
Turbulent flow is the simplest form of flow regime: air is introduced at one point and exhausted to the atmosphere (or at least to atmospheric pressure) from another. Conventionally, the flow rate through a turbulent isolator will give an air-change rate of between 10/h and 100/h, with most isolators set at around 25/h. Although this regime is simple, some thought needs to be given to the disposition and the nature of the air input and exhaust. The ideal flow pattern gives full purging of the entire volume of the isolator, with no standing vortices or dead volumes where airborne particles might accumulate and then precipitate. The input should be as far from the exhaust as practical. Ideally, the input should incorporate some form of distribution device to spread the inlet air across the isolator volume. The position of the exhaust may be dictated to some extent by the need to fit a changeable prefilter, easily accessed by the operator. It is not entirely simple to demonstrate good purging in a turbulent isolator, but introducing DOP smoke into the inlet airstream can indicate the flow pattern quite well, and the time taken to remove the smoke will indicate the degree of mixing.
Since the volume of air flowing through the isolator is quite small, perhaps 30 m3/h for a standard four-glove isolator, only small fans of about 200 W are needed to move air through the system, and the exhaust is often directly back to the isolator room. Consideration should be given, however, to the question of breach velocity, where turbulent flow is used in negative-pressure containment isolators. The breach velocity is the velocity of air passing through any inadvertent break in the isolator wall, and this is normally taken to mean the loss of a glove from its cuff ring. This velocity should be at least 0.70 m/sec to prevent the loss of airborne material to the outside. If the cuff aperture is 100 mm in diameter, this means an inflow of air at the rate of 20 m3/h. Clearly, the exhaust fan must be capable of providing this flow as a minimum. Figure 2.5 shows the ventilation system of a typical turbulent flow isolator.
Unidirectional flow The original term used here was laminar flow, but the term unidirectional flow is now more generally accepted because laminar flow may contain velocity gradients, whilst unidirectional flow is taken to have not only uniform direction but also uniform velocity. This regime was developed in various types of biological safety cabinets and in cleanrooms. The flow is usually vertically downward, although horizontal flow is used in some cases. The airflow is set to emerge from a panel HEPA filter at a velocity of around half a metre per second, the regulatory figure being given as 0.45 m/sec ± 20%. The true origins of this figure are somewhat obscure but seem to be empirical and linked to the original design of horizontal laminar flow cabinets. In practice, velocities down to 0.05 m/sec appear to give good results in isolators (see below).
Under these conditions, the airflow is unidirectional, with all the flow in one direction at one speed, which means that the flow will not entrain air from outside the flow. Thus, for instance, particles shed by an operator in a cleanroom with unidirectional downflow air will be drawn immediately to the exhaust at the floor and not allowed to rise up to the level of the work surface. If conditions were turbulent, then these particles would circulate with the air and be presented at the work surface.
The application of unidirectional flow was a major step forward in contamination control and so is now more or less obligatory in critical processes, such as the aseptic filling of pharmaceutical products. As a result, unidirectional flow is often specified in isolators, but this is not entirely logical. The concept was mainly developed to reduce the entrainment of particles shed by even fully suited operators; this problem does not arise in the isolator, where operators are, of course, physically and biologically excluded. The indicated view of the MHRA is that unidirectional flow is desirable, but not obligatory (Bill 1996).
Since isolator chambers are only about 750 mm high, the only way to approach true unidirectional downflow is to have a perforated floor. This then leads to other problems with spillages and leakages, so that the conventional way to exhaust air from a unidirectional flow isolator is via gutters along the front and back edges. In this case, laminarity can only extend perhaps halfway down the isolator before the flow breaks up to reach the exhausts, in which case the equipment near the floor of the isolator is bathed in turbulent flow. Furthermore, the sleeves or half-suits, and very often the equipment in an isolator, constitute a large fraction of the isolator volume and so readily cause turbulence.
Unidirectional flow also demands much more complex engineering in an isolator because the flow rates are much higher. For example, a four-glove isolator measuring 2000 mm long and 650 mm wide might have a flow rate of 50 m3/h in a turbulent regime. By contrast, in a unidirectional regime, it would have a flow rate of over 2000 m3/h. We then have to decide how to handle this volume of air:
• Total loss. If the application is toxic, then the flow should be exhausted to the atmosphere, in which case the isolator room heating and ventilation system must cope with this major loss.
• Return to the isolator room. The fan size needed to cope with this flow is quite appreciable and will dump several kilowatts of heat into the room. Once again, the heating, ventilation, and air conditioning (HVAC) system must be sized accordingly. The noise generated by the exhaust of this airflow may also create a problem.
• Recirculation. Most of the air leaving the isolator is returned to the top plenum chamber for recycling. A proportion, perhaps 10 percent, is exhausted and a corresponding volume of fresh air is introduced to the system — the makeup air is usually taken from the isolator room and may be exhausted to the atmosphere or returned to the room. This solves the problems of the first two options, but the engineering becomes complex: large return ducts must be provided to transfer the air from the base of the isolator to the top plenum. It is desirable to keep all air duct velocities below about 5 m/sec to keep pressure losses low (see below) and to reduce noise. Given a flow rate of 2000 m3/h, as in the standard four-glove isolator mentioned, and a duct velocity of 5 m/sec, we have to incorporate a return duct in the isolator with a diameter of almost 400 mm. As previously mentioned, the fan power needed to move this volume of air will amount to several kilowatts, which will quite quickly heat up the air in the recirculating system. Thus, air cooling will have to be incorporated to maintain the usual 20°C atmosphere inside the isolator (see below).
Having noted the disadvantages of unidirectional airflow in isolators, the significant advantage of the regime is the speed with which particles are purged from the critical working area. This is particularly useful in situations where both asepsis and containment are required, such as the processing of cytotoxic drugs. The problems associated with this type of work are discussed in more detail in Chapter 5, but briefly, negative pressure regime is often applied to cytotoxic isolators to protect the operators. Any leakage, however, may draw contamination into the isolator and put the patient at risk. If a unidirectional airflow regime is used, such particles are removed from the critical work area within seconds. Under a turbulent airflow regime, the particles may remain in circulation for minutes, thus increasing the chance of product contamination. For this reason, hospital pharmacy isolators used for cytotoxic work in the UK often use the unidirectional airflow regime. (Neiger, J.S., Negative Isolation, Cleanroom Technology, 2001; April: 24-25.)
In the final analysis, the chosen airflow regime must reflect the balance between factors such as the sensitivity of the process in the isolator, the air quality of the isolator room, and the leak-tightness ("arimosis") of the isolator.
Figure 2.6 is a schematic drawing of the airflow through a unidirectional airflow isolator.
Semiunidirectional flow Whilst this may sound like a contradiction in terms, this semiunidirectional flow has found use in some isolators, such as those used for aseptic hospital pharmacy work. In this design, just a part of the roof of the isolator is made up of a panel HEPA filter, which generates a region of unidirectional flow
within the main body of the isolator. Curtains or plates are fitted to contain the flow down to perhaps 400 mm from the isolator floor, and air then spills out to give turbulent flow in the rest of the isolator. Thus, small-scale critical operations can be carried out in the region of unidirectional flow, while less critical work goes on in the main body of the unit. All of this can be engineered without recourse to the complexities of full unidirectional downflow. Figure 2.7 shows the airflow pattern of a semiunidirectional isolator.
Although unidirectional airflow regime isolators are complex and expensive, and the benefits may be perceived rather than actual, it seems likely that they will still be used in aseptic pharmaceutical operations. Change is only likely to occur in the wake of extensive data provision, which in turn means that a fairly comprehensive research programme is required. Possibly, such a programme could be coordinated by one of the learned bodies, such as the Parenteral Society (UK) or the PDA (U.S.), and the work shared among a number of pharmaceutical companies.
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