GB2223678A - Automated supply and control of sterilizing vapour - Google Patents

Abstract

When supplying a sterilizing vapour to an isolator, a variety of agents is available and most are best presented to the isolator in the gas phase with a concentration around 5 to 10 gm/kg and a Relative Humidity (RH) of 90%. Apparatus that evaporates and mixes the agent already exists, but is very slow in operation since it produces only small volumes of vapour at low concentration. A novel system of supply and control of the sterilizing vapour is disclosed which produces the desired vapour efficiently, safely and cheaply. Firstly the invention measures the temperature and relative humidity (RH) of a carrier gas (e.g. air) and then feeds sterilizing solution at an appropriate rate to an evaporation chamber (where it is evaporated into and mixed with the carrier gas to form a sterilizing vapour that is fed into the isolator) so as to achieve a high but "safe" (usually around 90%) RH in the isolator. Secondly, the invention simultaneously computes the "time to kill" required by the resulting concentration of sterilant inside the isolator. The sterilizing vapour is pumped to the isolator for the computed time after which the sterilant supply is replaced by sterile air only, thus purging the system of sterilizing vapour residues.

Description

Sterilizing Systems This invention relates to sterilizing systems, and concerns in particular the systems required to produce a sterilizer medium for use in an isolator.

In many fields of technology there is a need for work to be carried out in an environment that is safely sealed off from the rest of the world. For example, in the biological sciences it is common to work with dangerously toxic or infectious materials (such as poisons, bacteria or viruses) and it will usually be desirable to carry out this work in a fully enclosed area from which the dangerous materials cannot easily escape into, and so contaminate, the surroundings. In the pharmaceutical and electronics industries, on the other hand, it may be desirable to work on some product (such as a drug or microchip) within a scrupulously clean enclosure, so as to prevent the ambient conditions contaminating the product.

Both of these situations require a volume of space to be sealed off - isolated - from its surroundings, and to meet this need technology has produced the isolator, which comes in sizes varying from that of a large (lxlx1 m, or about 2.5x2.5x2.5 ft) box up to that of a small room).

In essence, an isolator is little more than a sealed, bubble-like envelope in the wall of which is both a hatch (though which articles can be passed in and out) as well as means whereby the bubble's contents can be manipulated. The envelope is naturally made of some (preferably transparent) material suitably resistant to whatever chemicals and other substances are likely to come into contact with it both inside and outside the isolator (typical such materials are flexible polyvinyl chloride - PVC - film or sheet, but some isolators can be made of rigid materials such as a glass or PERSPE &

One very successful form of isolator available today is a cuboidal "bubble" of flexible PVC suspehded from an external framework that both shapes and supports the bubble, and a particular example of such an isolator is the subject of our co-pending Application for Letters Patent No: 88/05,817 ("Edgeseal"). The isolator there described has a two-part structure (instead of a one piece bubble), having a canopy, or upper tent-like part, similar to the conventional bubble envelope, and a base, or lower tray-like part, similar to the conventional trays for internal use, and the two are detachably sealed to each other around their respective perimeters to procure the isolator, the seal being secured by a special long but flexible clip-like device.

On occasion, it will be necessary to supply filtered air, or a sterilizing vapour, to the isolator.

For example, isolators are frequently used in sterile applications such as the preparation of drugs for injection and parenteral nutrition, and in these cases the isolator, either empty or loaded with materials, must be rendered sterile prior to use. A variety of agents is available for this operation (common ones are 10% aqueous formaldehyde solution and 3.5% aqueous peracetic acid solution), and most are best presented to the isolator in the gas phase with a concentration around 5 to 10 gm/kg and a Relative Humidity (RH) of 90%. Apparatus that evaporates and mixes the agent already exist, but it is very slow in operation since it produces only small volumes of vapour at low concentration.And whilst attempts have been made to speed up the process by recirculating the vapour, the resulting apparatus is complex and hence large and very expensive. Moreover, previous sterilizers have also been both inconvenient and dangerous in that they have required a compressed air supply and heating of the sterilizing agent (percetic acid is explosive at concentrations above 50% and temperatures above 6OC).

The invention proposes a novel system that should produce the desired vapour efficiently, safely and cheaply, so that isolators can be used in full-scale pharmaceutical or similar production where these parameters are fundamental. More specifically, the invention suggests a novel system of supply and control of the sterilizing vapour that is to be passed through the isolator and its associated ventilation system to render them sterile. In particular, it is hoped that the new system will allow the achievement of isolator sterility in a very short time, but nevertheless witn simplicity of use, safety and low cost.

In order to appreciate the problems of minimising sterilization time, it is necessary to understand the dynamics of the sterilization process.

Microbiological studies have been undertaken to reveal the effects of differing vapour concentrations for a number of different sterilizer liquids (such as 10% aqueous formaldehyde and 3.5% aqueous peracetic acid). The time to achieve sterility - the "kill time" is commonly defined as that time needed for a "log 6 reduction" - that is, the time to reduce the viable population of spores of Bacillus Subtilis Niger on a carrier by 6 orders of magnitude Cthus, to 10---t; of its original value). This information may conveniently be presented in tne form of a graphical plot of time (to achieve a log 6 reduction) versus sterilant concentration, and such a graph is shown in the accompanying Drawings.From the results, it is clearly evident that sterilization time is related inversely to concentration, leading to the novel concept of the "integrated" sterilization dose, namely that to kill an organism requires a certain "time x concentration" dose of sterilant, which dose may, within certain practical limits, be administered either over a short or over a long period. Put very briefly, if an organism can be killed by exposure to a high concentration for a short time, then it should be possible also to kill it with a lower concentration but for a longer time. This is very much akin to the sterilizing effects of gamma radiation, and as such appears to be a new concept in microbiology.

Having established the relationship of concentration to time it is next necessary to consider ways to maximise the airborne concentration of sterilant, and hence to minimise sterilization times.

The commonly available sterilizing agents are dilute aqueous solutions of the active ingredients, and in terms of their abilities to evaporate into air may be treated as though they were pure water. Thus, the achievable airborne concentration of the agent is limited by the ability of air - the gas with which it is mixed, which is usually sterile air - to carry a water vapour load. For air this information is well-known, and available in the form of Psychrometric data. Basically, warm, dry air will accommodate relatively large quantities of water, and the warmer and drier it is to start with the more water it will hold.On the other hand, colt, humid air will accommodate relatively little water (and less the colder and moister it is). Thus, the time required to sterilize an enclosure with an air/aqueous agent is related to the temperature and humidity of the ambient air, because these factors govern how much of the agent can be taken up by the air.

The problem, then, is that if the temperature and, especially, the humidity of the air being employed are not accurately known, it is impossible to judge how much aqueous sterilizing agent has been evaporated into and mixed with the air - and thus it is not possible to determine the minimum time needed to ensure a log 6 reduction. In the past, therefore, there has been a tendency simply to assume a "worst case" situation, and to keep pumping the sterilizing vapour into the enclosure for such a long time that there is bound to have been a log 6 reduction.

This is, of course, extremely inefficient, wasting both time and materials. The invention proposes a new supply and control system that avoids such inefficiency.

Firstly, the invention samples the ambient temperature and relative humidity (RH), and then feeas sterilizing solution to an evaporation chamber (where it is evaporated into and mixed with air to form a sterilizing vapour that is fed into the isolator) at a suitable rate to achieve a high but "safe" (usually around 90%) RH in the isolator. Secondly, the invention simultaneously computes the "time to kill" required by the resulting concentration of sterilant inside the isolator, and pumps vapour to the isolator for the required time, then cutting off the sterilant supply (and blowing in sterile air only, thus purging the system of sterilizing vapour residues).

In one aspect, therefore, the invention provides a method of supplying and controlling the composition of an aqueous sterilizing medium comprising a vapourisable aqueous liquid sterilant mixed into a gas, in which met hod: the amount of vapourisable aqueous liquid sterilant mixed into the gas is controlled to a safe high value in dependence upon the ambient temperature and relative humidity of the source gas; and the time necessary to achieve an acceptable sterilizing effect using that amount at the resultant concentration is computed, the feeding and mixing of the sterilant into the gas being halted at the end thereof.

In another aspect the invention provides apparatus for carrying out the method of the invention, which apparatus comprises: mixing means, at which the sterilant is mixed into the gas; gas feed means, to feed gas supplied from a source thereof to the mixing means; sterilant feed means, to feed sterilant supplied from a source thereof to the mixing means; monitor means, to monitor the ambient temperature and relative humidity of the source gas; sterilant feed control means, to control, in dependence upon the monitor means output, the rate at which sterilant is output by its feed means such that the amount mixed with the gas has a safe high value; and time computing and sterilant supply shut-off means, to compute the time needed for an acceptable sterilization effect at the resultant concentration, and after that time to shut off the sterilant supply.

The invention provides a method for supplying and controlling a gas/sterilant mixture. The gas will normally be air, whilst the sterilant may be any of the known or proposed aqueous sterilizing solutions, such as the formaldehyde and peracetic acid solutions mentioned hereinbefore.

The method controls the amount of sterilant in the gas to a safe, high level. The prime problem to be overcome is the changeable nature of the temperature and relative humidity of the gas being used, for these parameters determine the amount of sterilant (which from this point of view is much the same as pure water) that can be vapourised into the gas; hot, dry gas will hold more sterilant than cool, moist gas. In addition to that, it is necessary to bear in mind that the sterilizing mixture produced may well be supplied to an enclosure - an isolator, say - that is either colder than the mixture or loses heat fast to its surroundings, so that the temperature of the sterilizing mixture in the encLosure cold be significantly lower than the temperature ot the mixture as it leaves the mixer and enters the enclosure.It is with reference to these points that the expressions "safe" and "high" as applied to the level of sterilant must be interpreted. "High" means that t level is near the upper physical limit (100% RH) so as to ensure the highest possible concentration of active sterilizing ingredient and the shortest possible kill time, but "safe" means that the danger of the mixture condensing out, as the temperature drops and the gas can support less and less of the sterilant, is reduced to an acceptably low level. It is difficult to provide hard and fast rules for "safe" and "high", for so much depends upon the heat-retaining properties of the enclosure to be sterilized.However, with the common isolators, made of a flexible polyvinyi chloride (PVC) tent-like canopy, the heat-retention properties are poor, the heat loss rate is high, and the temperature drop, and thus the possibility of condensation, is large - and is such that the relative humidity of the applied sterilizing mixture should very preferably be not more than 95%, and, to be on the safe side, preferably not more than 90%. Lower RHs can of course be employed, but then the concentration of active ingredient is substantially reduced, so that the kill time is substantially, and perhaps unacceptably, increased. For this reason, RHs of less than 80% are not really considered satisfactory.

Incidentally, it should be noted that the problems of the vapour condensing out to leave liquid sterilant on the various surfaces within the system are very real.

Not only are the common sterilizing active ingredients necessarily toxic to life, they are also rather corrosive to the metal contents of the system. It is therefore of paramount importance to avoid any chance of concnc,,in.

Moreover, once significant condensation has occurred it is difficult to be sure how much sterilant has been pumped through the system, and it is not easy to ensure that all the condensate is properly removed during the subsequent purging stage.

The amount of sterilant mixed with the gas is controlled in dependence upon the ambient temperature and relative humidity of the source gas. Clearly, if the amount of sterilant is to be both safe and high, and these terms are to be interpreted by reference to temperature and relative humidity, then it is necessary to ascertain the values of these parameters for the source gas in order to determine how much sterilant can be vapourised thereinto, and carried thereby.

Accordingly, the source gas is monitored as regards its temperature - the hotter it is the more sterilant it can carry, the colder the less - and as regards its relative humidity - the drier it is the more sterilant it can carry, the wetter the less - and the amount of sterilant mixed with a given amount of the gas is adjusted accordingly. Equipment for doing this is described hereinafter.

There being known the amount of sterilant mixed with (a given volume of) the gas, there is equally known the concentration of the sterilant in the resulting sterilizing medium. Accordingly, from standard, or simply predetermined, tables there may be found how long will be needed at that concentration to achieve a log 6 reduction - talus, what is the predicted kill time though it should be remembered that theoretical kill times may be significantly influenced by the efficiency with which the sterilizing medium is delivered to and swept around the "real" enclosure that has to be stex zea (a particularly effective distribution system is described and claimed in our co-pending Application for British Letters Patent No: 88/08,388.6; File P1015).

Moreover, if for any reason the sterilant concentration should change - say, the ambient conditions of temperature and/or relative humidity change - then the kill time can be re-determined taking into account the time already elapsed under the previous conditions. In other words, the area under the appropriate graph (of time-to-kill against sterilant concentration) is integrated to give a total time that will, despite the varying conditions, ensure a log 6 reduction. In a simple but nevertheless typical case, the ambient conditions will stay the same, the sterilant concentration will therefore stay the same, and computing the kill time is merely a matter of reading off the appropriate time value from a table of sterilant concentrations and times. In one preferred system this table is stored in the memory of a small computer used to control the whole operation.

Once the kill time has passed, the feeding into the gas of the sterilant may be stopped. It is then desirable to purge the entire system - the mixing parts, the pipework, and the enclosure being sterilized - of the sterilant, and this can be done simply by continuing to supply the gas thereto, but without, of course, any sterilant mixed therewith. The amount of gas supplied during this phase (or the time for which it is supplied) may be any convenient. However, to achieve a near 100% purge it will, depending upon the enclosure and the efficiency with which the gas is fed into, through and out of it (and sweeps out the whole volume, leaving no "corners" or other pockets undisturbed), be desirable to supply enough gas to change the enclosure atmosphere at least 5 times.For an isolator of 1 m-' (35 ftL-), for example, witn a flow rate of 25 m/hr (875 ft-/hr). this would mean continuing to supply gas for a further 12 minutes after stopping the sterilant feed.

The invention provides both a method for supplying and controlling a sterilizing medium and apparatus for so doing. The apparatus comprises mixing means, gas and sterilant feed means, monitor means, sterilant supply control means, and kill time computing and sterilant supply shut-off means.

The mixing means is an essence merely a mixer something that mixes, as efficiently as possible, the vapourised aqueous sterilant liquid into the gas, to form a sterilizing medium that can be supplied to the enclosure to be sterilized. The mixer can take any convenient form, but one especially convenient such form is that the subject of our co-pending Application for British Letters Patent No: 88/09, 149. 1; File P1019.This co-pending Application defines the mixer as apparatus for mixing a vapourisable liquid into a gas, which apparatus comprises: an elongate mixing chamber having at one end an entry portal via which gas may be fed into the chamber so as to swirl around and along the chamber to the other end, where there is an exit portal via which the gas can leave the chamber; and an atomiser to which can be fed the liquid to be mixed with the gas, which atomiser is so positioned in the chamber relative to the entry portal that atomised liquid produced thereby is drawn into and carried along with the swirling gas.

The sterilant feed means takes sterilant liquid from a source thereof - a container or reservoir holding the liquid - and delivers it to the mixing means, and the output of this feed means has to be controllable (by the sty. slant feed control means). Most commonly, the feed means is a pump, supplied with sterilant liquid from the source thereof, and pumping it on to the mixing means. Whilst almost any sort of pump might be useable, it has been found very beneficial to employ a peristaltic pump driven by a stepper motor to which can be fed driving pulses at a frequency appropriate to the desired output rate of the pump. Such a pump/motor combination is particularly easy to control at the very small flow rates likely to be required (from 1. 5 to 4 ml/min).

The gas feed means take gas - air, for example from a source thereof, and delivers it to the mixer at a suitable flow rate. It is the gas flow rate which defines the output flow rate of the apparatus as a whole; rates of from 10 to 30 m:'/hr (350 to 1050 ft/hr), especially 25 ma/hr (875 ft~/hr) are suitable for an enclosure of around 1 m (35 ft-). This feed means, too, is conveniently a pump of any convenient variety - a standard single- or multi-stage centifrugal fan-type pump with axial input and of an output power such that it is capable of overcoming the various flow resistances, is usually quite satisfactory.

As discussed further hereinafter the sterilant feed control means controls the sterilant feed rate in dependence upon source gas temperature and relative humidity. However, in order to do so either the feed control means needs to take into account the actual source gas flow rate, which naturally affects the concentration of the resulting sterilizing medium, or it can operate upon the basis that the flow rate is fixed at sorne pre-set value.Now, in fact gas flow can vary for a number of reasons - for example, fluctuations in the supply voltage driving the pumps, alterations in the nature . tne chamber being sterilized, changes in the efficiency of the chamber output filters, or viscosity changes as result of ambient temperatures altering. and it may be aesirable to monitor the gas flow rate and adjust the sterilant feed rate accordingly.

Alternatively - and preferably - it may be sufficient merely to adjust the drive to the gas feed means - to speed up or slow down the pump, say - so as to keep the actual flow rate at a predetermined level, "expected" by the rest of the system, regardless of whatever changes are likely to influence it. The gas flow rate may be monitored directly, using an anemometer placed just down stream of the gas feed means to provide a suitable output for the control means to sense and act upon. A typical anemometer is of the heated thermister type, the thermister being, for instance, an STC P23.

In order to decide how much sterilant liquid can safely be mixed with the gas it is necessary to know the temperature and relative humidity of the source gas.

Accordingly, there is monitoring means for each of these factors For temperature, the monitoring means is simply a thermometer, but giving an output that the control apparatus can use. For relative humidity, the monitoring means is essentially a hygrometer, again giving an output useable by the control apparatus. It is in fact preferred to use a single instrument that is a combination of the two, and a suitable device is an HMP111Y (in which the hygrometer is a "Humicap" sensor) available fron Vaisala (of Finland), giving two voltage analogue outputs related to the temperature and relative humidity.

The sterilant feed control means controls the rate at which the sterilant is fed to the mixer Cand thus it effectively controls the concentration of the sterilizing medium output by the mixer), and it does so in dependence upon the outputs of the source gas temperature ard relative humidity monitoring means.

Moreover, it also controls the sterilant feed rate in dependence upon what has previously been decided is a safe, high amount. Whilst it would be possible to provide a feedback loop from the enclosure, so that the arnount fed in is also determined by the actual conditions witnin the chamber, not only is the instrumentation likely to be damaged by exposure to the sterilant, but the chamber conditions will normally be fairly static, so once "set" the amount is unlikely to need changing. Thus, feedback is unnecessary, and indeed is best avoioec.

As explained above, the sterilant feed control means needs, one way or another, to take into account the source gas flow rate. As discussed, this is preferably effected by separately controlling the flow rate to a predetermined value regardless of whatever changes are likely to influence it.

With a particular safe, high amount in mind - for example, if it is decided that the relative humidity of the output sterilizing medium should be 90% - then, having regard to the ambient temperature and relative humidity, the control means determines (perhaps from look-up tables holding the psychrometric data) how much sterilant liquid should be fed to the gas, and adjusts accordingly both the flow rate from the sterilant feea means and the gas (air) pump flow rate. This type of determination and control operation is a job well suited to a "computer" of some variety. It could be either an analogue device or a digital one (a conventional microprocessor working under stored program control).

One such analogue system is described hereinafter with reference to the accompanying Drawings. Basically, the computer consist of a pair of operational amplifiers, and a multiplier. The former have as their inputs voltage signals indicative of the parameters being monitored (thus, ambient temperature and relative humidity), and apply a predetermined gain factor to convert the inputs into outputs indicative of the maximum amount of sterilant the ambient air can hold and of the multiplying factor converting this to the actual amount it does hold.The latter (the multiplier) multiplies the amount and its multiplying factor to give an output useable to control the sterilant feed means (in a preferred form the feed means is a peristaltic pump ariven by a stepper motor, and the multiplier's output is first fed to a voltage-to-frequency converter to put it in a form more suited to the motor's requirements). The matter is discussed in more detail hereinafter with reference to the Drawings.

As just noted, in a particularly preferred embodiment of the invention the control means' output is in the form of pulses fed to the stepper motor driving the peristaltic pump sterilant feed means, and the control exercised is the adjustment of the frequency of the pulses so as to select the appropriate output flow rate from the pump.

The final major portion of the apparatus is the time computing and sterilant shut-off means. The purpose of this part is firstly to compute the kill time required, knowing the amount of sterilant being fed in (and thus knowing the actual concentration of sterilant in the mixer output - and so in the enclosure), and secondly to note the time spent, and shut off the sterilent feed once that time becomes equal to the computed kill time.

Computing the kill time is done by making use of the integrated dose principle referred to above - the effective concentration of active ingredient (conveniently measured in terms of the concentration of the sterilant solution evaporated into the gas) multiplied by the time period for which that concentration is maintained in the volume to be sterilized equals a constant which in each case is particular, ano can be predetermined, for the specific volume concerned. Thus, knowing the actual concentration (as already calculated and delivered), and knowing tne relevant value of the volume constant, there may be computea the necessary time - the kill time - for achieving the desired log 6 reduction.For any given volume the volume constant can be one input (adJustable for different volumes) to a second multiplier (albeit one acting as an inverter), the other input being a signal indicative of the calculated concentration; from this is output a signal related to the time required.

This signal is then used to set a timer (preferably the timer is a digital one, so if the output is in analogue form it is first digitized), which then counts down and while the timer is still above zero so the sterilant/gas mixture is pumped through the system to be sterilized.

When the timer reaches zero, and the sterilant feed is switched off, it can then trigger a second timer that continues pumping source gas through the system, but without any sterilant evaporated thereinto, for a preset time (determined by the volume concerned) so as to purge the system of the sterilant, and leave it clean and sterile, ready for use.

Various embodiments of the invention are now described, though only by way of iliustration, with reference to the accompanying diagrammatic Drawings in which Figure 1 shows a perspective view from above and one end of a glove box isolator of the invention; Figure 2 represents a graph of sterilant concentration against sterilant time for a log 6 reduction; Figure 3 is a schematic diagram of a complete sterilising system according to the invent ion; Figure 4 represents a graph of actual sterilant concentration against time as an isolator is sterilized; and Figure ' is a more detailed schematic diagram of part oi Figure 3.

Tne isolator (generally 10) shown in Figure 1 has a rigid trayo e base part (11) onto which is sealingly mounted a transparent flexible tent-like canopy part (12; the canopy's supporting framework is not shown).

The isolator is a glove box, and has the usual glove pair mountings (as 19; the gloves are not shown) in the front wall (13) and hatch and hatchway (20) in the right (as viewed) end wall (14).

A flap (30) forms, with the corner surfaces of the rear wall and the ceiling, a triangular cross-section gas input manifold. The flap 30 is mounted on and stretched loosely between the rear wall and ceiling by means of press studs (as 31), and the manifold it helps form is fed with gas by a centrally-located supply pipe (32).

The isolator includes two exhaust collectors (as 33). Each is a pre-filter drum (the outer surface of which is covered with spaced apertures to enable gas access), and gas is drawn therethrough out of the isolator by the reduced pressure applied to the removal pipe (34).

This type of distributor system is the subject of our aforementioned Application No: 88/08,388.6.

The graph of Figure 2 is a plot of sterilant concentration (in gSma) within the isolator against the time needed for a log 6 reduction in Bacilius Subtilis Niger spores. It will be apparent that high concentrations need only short times while low concentrations need longer times. What may not be clear from the graph, but is nevertheless the case, is that the graph is of the form concentrat ion,terl l-nt X time,,, 6 = constant ssolwtor so that knowing the relevant constant (from previous tests on each isolator) there may be calculated the log 6 reduction time for any particular concentration.

A schematic of the isolator and its sterilizing system is snown in Figure 3. A centrifugal fan (40) supplies gas - in this case, air - at a fixed rate, irrespective of system resistance, to an evaporation chamber (41; this is part of the mixing apparatus the subject of our aforementioned Application No: 88/09, 149. 1). The air entering this fan is monitored (at 42) for temperature and relative humidity, and also for air-flow. A feed-back loop (not shown) controls the fan at a predetermined flow rate.

The evaporation chamber 41 is fed with sterilizing solution front a reservour (43) by a peristaltic pump (44) itself driven by a stepper motor (not shown separately). This motor is controlled by a computer (45) which takes data from the input air temperature and relative humidity monitor 42. The mixture of air and sterilizing vapour produced by the evaporation chamber 41 is fed via a demountable flexible hose (46) to tne isolator, and introduced between the isolator fan (47) and the isolator inlet filter (48).

The vapour passes into, through, and out of the isolator, leaving via the exhaust filter (49). It is then led to a suitable exhaust stack or furne cupboard (not shown) it a further flexible hose (50).

The operational sequence for sterilization in accordance with the invention is as follows:1. Start trl. fan 40 and the peristaltic pump 44 feeding vapour to the isolator.

2. At any time during Phase 1 the computer 45 can predict sterilization time according to the ambient conditions. After a build-up time the fan 40 and pump 44 continue to operate in the sterilization phase proper.

3. When the sterilization phase is compiete, the pump 44 is stopped, but the fan 40 continues, so that air is blown through the system to purge it of st erilant.

The actual concentration of sterilant inside the isolator as sterilization is carried out is shown by the grapn of Figure 4, which depicts the three phases involved.

In phase I there is the logarithmic build-up in gas concentration as the air originally in the isolator is replaced by the incoming sterilizing gas. The length of this period is dependent on the volume to be sterilized, but is about 10 minutes for a small 4-glove isolator (around 1 m3) and about 40 minutes for a larger single half-suit isolator (around 3 m3).

In phase II the sterilizing gas holds a steady concentration. The length of this phase is governed by the time-to-kill graph, and by the absolute concentration of gas available, given the ambient conditions of temperature and relative humidity. It is the length of this phase that is determined by the computer.

Tr third and final phase, phase III, is the logarithmic purge-out of gas as it is replaced by incoming fresh air. It is similar in length to phase I.

The sterilant solution pump is switched on during phases I and II, and off during phase III. The air fan is on during the whole cycie, and afterwards may be left on, or switched off, according to operator choice.

Though the time required for sterilization is not related to the volume of the isolator, both the time needed to build up to full concentration and the time needed to purge to an acceptable low level are - they are a function of the isolator volume and the air flow rate. They also depend on the quality of the distribution of the vapour within the isolator. These times can be considerably reduced if there is used an air aistribution system like that the subject of our aforementioned Application No: 88/08,3b & 6 - as shown in Figure 1.

Figure 5 shows more details of the "computer" 45 used in the sterilizer system of Figure 3.

The schematic circuit of this Figure comprises two operational amplifiers (51, 52) whose outputs are fed to a multiplier (53) the output of which is supplied both to a second multiplier (54) feeding a timer (and display) and to a voltage-to-frequency converter (55) driving the pump stepper motor (not shown here; see Figure 3).

Amplifier 51 has as its input a signal from the temperature monitor (42 in Figure 3) that is representative of the temperature of the ambient gas (air) being used to make, with the sterilant, the stera ng mixture. As pointed out hereinbefore, the relationship between temperature (t) and the maximum amount (per uit t volume) of water capable of being held in the air at tnat temperature (m) can, over the small temperature range involved, be approximated to a straight line definabie by an equation of the form mt = a t bt where a and o are constants. The amplifier 51 is preset with a gain factor repsenting b, so that its output represents tne quantity per unit volume of water in the air. This value is fea as one input to multiplier 53, together witn an "off set" value representing the other constant (a) in the straight line equation. In effect, therefore, the multiplier 53 is presented with a signal indicative of the maximum quantity of water the air can hold under the ambient temperature conaitions. However, the actual amount it presently holds, whicn is measurable in terms of its relative humidity, will normally be rather less, and determines how much extrs can (safely) be added to the air. This is dealt with by amplifier 52, and by a second pair of inputs to the multiplier 53.

Amplifier 52 has as its input a signal representative of the relative humidity of the ambient gas (air) being used to make, with the sterilant, the sterilizing mixture. At any given temperature (t) the relative humidity (RH) indicates the quantity of water carried by (a unit volume of) the air as a percentage of the maximum tm) which that air at that temperature is pysically capable of carrying. The actual quantity of air (per unit volume) is thus mt x RH/100 So, at an RH of 100%, the amount of air carries m , the maximum possible, whilst at an RH of 50% it carries mx50/1UO = mt/2 half the maximum amount.Operational amplifier Si has as its input tne RH output from the monitoring means, and essentially outputs a value eqivalent to RH/100, the factor by whicn the maximum amount of water has to be multiplied to give the actual amount for the ambient air.

Clearly, where the RH is less than 100% then the air can absorb more water - enough to increase its RH to 100%. So, for an RH of 40% (an amount of mt x 40/100, = 0.4 mt) the air could carry as much as 0.6mt - that is, mt - 0.4mt - more water.

As explained hereinbefore, however, it is undesirable to add so much sterilizing mixture that the RH of the air/mixture is as high as 100%, or even as high as 95%. Most preferably, indeed, the amount of sterilizing mixture added is sufficient to raise the RH to no more than 90% - so that, for an ambient input air RH of 40250 the amount of water (sterilant) that can be added and carried in safety is not mt - 0.4my = 0.6my but rather 0. 9my - 0. 4my = 0. 5my Multiplier 53 nas two pairs of inputs, and for one of these pairs one input is the RH multiplying factor from amplifier 52 whilst the other is a corresponding pre-set signal representing the relevant multiplying factor for the chosen maximum allowable relative humidity (in this case, 9 giving a factor of 90/100 = 0. 9). The two factors are subtracted (the detected from the pre-set) to give the appropriate factor in the present circumstances.

The inputs to multiplier 53 therefore define the maximum amount of water the air can hold at the ambient temperature, together with a factor by which that amount is to be multiplied to give the amount that can safely be added. This output, suitably scaled, has two uses.

First, it is converted to a frequency signal (by a voltage-to-frequency converter 55), and used to drive the peristaltic pump's stepper motor (Figure 3).

Secondly, it is supplied as an input to the second multiplier 54, here operating as an inverter, and, in accordance with the aforediscussed expression concentrationsterilant X timelog 6 = constantisolator is divided into the pre-set value "constant" (which varies from isolator to isolator, and is determined by experiment) so as to give the time required for that concentration in that isolator to achieve a log 6 reduction. This time value is then fed to a timer (possibly in the nature of a count-down device) and a display (not shown here).

Claims (21)

1. A method of supplying and controlling the composition of an aqueous sterilizing medium comprising a vaporisable aqueous liquid sterilant mixed into a gas, in which method: the amount of vaporisable aqueous liquid sterilant mixed into the gas is controlled to a safe high value in dependence upon the ambient temperature and relative humidity of the source gas; and the time necessary to achieve an acceptable sterilizing effect using that amount at the resultant concentration is computed, the feeding and mixing of the sterilant into the gas being halted at the end thereof.

2. A method as claimed in Claim 1, in which the gas is air, whilst the sterilant is a formaldehyde and peracetic acid solution.

3. A method as claimed in either of the preceding Claims, in which the safe, high level to which the amount of sterilant in the gas is controlled (the amount of sterilant being from this point of view much the same as pure water) corresponds to a Relative Humidity of not more than 90%

4. A method as claimed in any of the preceding Claims, in which computing the kill time is carried out in practice by reading off the appropriate time value from a table of sterilant concentrations and times.

5. A method as claimed in any of the preceding Claims, in which, once the kill time has passed, the feeding into the gas of the sterilant is stopped, and the system is purged of the sterilant simply by continuing to supply the gas thereto but without any sterilant mixed therewith.

6. A method as claimed in Claim 5, in which the amount of sterilant-free gas supplied is enough to change the enclosure atmosphere at least 5 times.

7. A method as claimed in any of the preceding Claims and substantially as described hereinbefore.

8. Apparatus for carrying out the method as claimed in any of the preceding Claims, which apparatus comprises: mixing means, at which the sterilant is mixed into the gas; gas feed means, to feed gas supplied from a source thereof to the mixing means; sterilant feed means, to feed sterilant supplied from a source thereof to the mixing means; monitor means, to monitor the ambient temperature and relative humidity of the source gas; sterilant feed control means, to control, in dependence upon the monitor means output, the rate at which sterilant is output by its feed means such that the amount mixed with the gas has a safe high value; and time computing and sterilant supply shut-off means, to compute the time needed for an acceptable sterilization effect at the resultant concentration, and after that time to shut off the sterilant supply.

9. Mixing apparatus as claimed in Claim 8, wherein the mixer is one as described and claimed in co-pending Application for British Letters Patent No: 88/09, 149. 1; File P1019.

10. Mixing apparatus as claimed in either of Claims 8 and 9, wherein the sterilant feed means is a peristaltic pump driven by a stepper motor to which can be fed driving pulses at a frequency appropriate to the desired output rate of the pump.

11. Mixing apparatus as claimed in Claim 10, wherein such a pump/motor combination is operated at a flow rate of from 1. 5 to 4 ml/min.

12. Mixing apparatus as claimed in any of Claims 8 to 11, wherein the gas feed means is a standard single- or multi-stage centrifugal fan-type pump with axial input and sufficient output power.

13. Mixing apparatus as claimed in Claim 12 wherein the fan-type pump provides an output flow rate of from 10 to 30 m'/hr.

14. Mixing apparatus as claimed in any of Claims 8 to 13, wherein the drive to the gas feed means is adjusted so as to keep the actual flow rate at a predetermined level.

15. Mixing apparatus as claimed in any of Claim 14, wherein to enable this the gas flow rate is monitored directly, using an anemometer placed just down stream of the gas feed means to provide a suitable output for the control means to sense and act upon.

16. Mixing apparatus as claimed in any of Claims 8 to 15, wherein the sterilant feed control means determines how much sterilant liquid should be fed to the gas, and adjusts accordingly both the flow rate from the sterilant feed means and the gas (air) pump flow rate, this determination and control operation being a Job carried out by an analogue computer system

17.Mixing apparatus as claimed in any of Claim 16, wherein the analogue computer system consists of a pair of operational amplifiers and a multiplier; the former have as their inputs voltage signals indicative of the ambient temperature and relative humidity, and apply a predetermined gain factor to convert the inputs into outputs indicative of the maximum amount of sterilant the ambient air can hold and of the multiplying factor converting this to the actual amount it does hold, while the latter (the multiplier) multiplies the amount and its multiplying factor to give an output useable to control the sterilant feed means.

18. Mixing apparatus as claimed in any of Claims 8 to 17, wherein the time computing and sterilant shut-off means makes use of the integrated dose principle - the effective concentration of active ingredient multiplied by the time period for which that concentration is maintained in the volume to be sterilized equals a constant which in each case is particular, and can be predetermined, for the specific volume concerned, so that knowing the actual concentration (as already calculated and delivered), and knowing the relevant value of the volume constant, there may be computed the necessary time.

19. Mixing apparatus as claimed in any of Claim 18, wherein, for any given volume the volume constant can be one input (adjustable for different volumes) to a second multiplier (acting as an inverter), the other input being a signal indicative of the calculated concentration; from this is output a signal related to the time required, which signal is then used to set a timer which then counts down - and while the timer is still above zero so the sterilant/gas mixture is pumped through the system to be sterilized.

20. Mixing apparatus as claimed in any of Claim 19, wherein, when the timer reaches zero, and the sterilant feed is switched off, it then triggers a second timer that continues pumping source gas through the system, but without any sterilant evaporated thereinto, for a pre-set time (determined by the volume concerned) so as to purge the system of the sterilant.

21. Mixing apparatus as claimed in any of Claims 8 to 20 and substantially as described hereinbefore.