Automated system for impactor testing

One aspect of the invention provides an automated system for performing repeated testing using an impactor which comprises a cup manifold defining multiple impaction cups, an impactor head defining transfer passages, and a nozzle manifold which defines multiple nozzles and is disposable between the cup manifold and the impactor head, so that in the assembled impactor a route is defined for through-flow via the impaction cups, the nozzles and the transfer passages. The system comprises an impaction station for performing impaction testing using the assembled impactor; a cup manifold recovery station for recovering sample material from the impactor cups in a solvent; an impactor head cleaning station; and at least one handling system for assembling the impactor for impaction, and for subsequently disassembling the impactor and delivering the cup manifold and the impactor head to their respective stations.

BACKGROUND TO THE INVENTION

The present invention is concerned with a system for automatically carrying out testing using a cascade impactor.

Cascade impactors are in themselves well known. They are used for analysis of aerosols, and more specifically for obtaining information about the size distribution of particles in an aerosol. Particulate material can be entrained in a gas flow to form an aerosol for analysis. The aerosol is passed through a sequence of impaction stages, larger particles tending to collect in the earlier stages and smaller particles in the later ones. In this context, the term “aerosol” is to be understood to refer to particles suspended in a fluid. The fluid in question is typically a gas although in principle it could be a liquid. The particles may be solid, liquid, or a mixture of the two.

Cascade impactors can be used for a range of purposes including for example analysis of air pollution. However, an application of particular importance in the present context involves testing of drug delivery devices such as inhalers. These are used to deliver a controlled dose of a drug to the respiratory tract of a patient. Typically the target area is the lungs, or particular areas thereof. A proportion of the dose will inevitably be retained in the mouth and throat. Inhalers are very commonly used in the treatment of asthma, but can also be used for delivery of drugs to treat other diseases, respiratory or otherwise. To demonstrate that the correct dose is being dispensed, analysis is required of particle size in the inhaler output. In a dry powder inhaler the pharmaceutical material is stored in powder form, but air drawn through the inhaler in use causes the powder to be entrained in an aerosol. There are other forms of inhaler which are relevant for present purposes including the pressurised metered dose inhaler (pMDI) in which the drug formulation comprises drug which is suspended or dissolved in a propellant (e.g. HFA 134a or HFA 227), the formulation optionally including one or more excipients, such as a surfactant. The propellant is used to create an aerosol which is then entrained in the inspiratory airflow of the patient. Nebulizer devices may also be tested using impactors of the type referred to herein. Pharmaceutical companies have a requirement to carry out batch testing on large numbers of inhalers. It is known to carry out such testing by firing the inhaler into an impactor. The powdered pharmaceutical material collects upon component parts of the impactor, from which it is then recovered for analysis. This recovery has traditionally been done by solvent rinsing in a manual process, but the labour involved is considerable and the process is slow. Hence it is highly desirable to automate impactor testing.

A form of impactor sometimes referred to as the “next generation impactor” has been developed by MSP Corporation of Minneapolis and is described for example in UK Patent 2351155. It has a tray defining multiple side-by-side impaction cups, with an impactor head to be placed upon the tray defining transfer passages from one cup to another. A nozzle plate positioned between the cup tray and the impactor head forms nozzles at the outlet of each transfer passage, the nozzles having successively smaller openings for through-passage of the aerosol, and particles with diminishing sizes are trapped in the successive impaction cups. The next generation impactor needs, after it has been dosed with one or more samples from an inhaler, to be disassembled to permit recovery of sample material from its component parts, by immersing the relevant surfaces in solvent to obtain solutions containing the sample material. This form of sample recovery is carried out on the individual cups, and also on an induction port through which the impactor interfaces with the inhaler, and in some cases on an optional preseparator used to remove the largest particles from the aerosol before it enters the impactor itself. After the recovery of the sample material, components of the impactor need to be washed and re-assembled ready for re-use.

Some details of an automation system for an impactor of this type are to be found in published United States Patent Application 2004/0250634, assignee MSP Corporation, and also in published International Patent Application WO 02/063277, applicant MSP Corporation. Both documents describe, in somewhat schematic terms, a system for carrying out repeated impaction testing automatically. However, significant technical challenges remain in practically implementing such a system.

SUMMARY OF THE INVENTION

In a first aspect, the present invention relates to an automated system for performing repeated testing using an impactor which comprises a cup manifold defining multiple impaction cups, an impactor head defining transfer passages, and a nozzle manifold which defines multiple nozzles and is disposable between the cup manifold and the impactor head, so that in the assembled impactor a route is defined for through-flow via the impaction cups, the nozzles and the transfer passages, the system comprising

An impaction station for performing impaction testing using the assembled impactor;

a cup manifold recovery station for recovering sample material from the impactor cups in a solvent;

an impactor head cleaning station; and

at least one handling system for assembling the impactor for impaction, and for subsequently disassembling the impactor and delivering the cup manifold and the impactor head to their respective stations.

The requirement for on-line cleaning of the impactor head is not recognised in the known prior art.

In a particularly preferred embodiment, the system further comprises an impactor head handling device having a movable support for carrying the impactor head between stations and an engagement device for releasably coupling the nozzle manifold to the impactor head.

Where necessary, the handling device can move the nozzle manifold and impactor head as a unit, but the releasable coupling permits the handling device to manipulate the impactor head on its own when necessary.

According to a further aspect of the present invention, there is an impaction testing arrangement comprising an impactor which has a cup manifold defining multiple impaction cups and an impactor head defining transfer passages each communicating with a respective nozzle, so that in the assembled impactor a route is defined for through-flow via the impaction cups, the nozzles and the transfer passages, the arrangement further comprising an impactor head clean up device having an exposed contact plate provided with multiple fluid outlet apertures connected to a fluid source, the fluid outlet apertures being positioned to correspond to openings of the transfer passages in the impactor head, so that when the impactor head is presented to the seal plate, fluid is able to be output into the transfer passages to clean them.

According to still a further aspect of the present invention, there is an impaction testing arrangement comprising an impactor which comprises a cup manifold defining multiple impaction cups, an impactor head defining transfer passages, and a nozzle manifold which defines multiple nozzles and is disposable between the cup manifold and the impactor head, so that in the assembled impactor a route is defined for through-flow via the impaction cups, the nozzles and the transfer passages, the arrangement further comprising a nozzle manifold wash module comprising upper and lower wash manifolds shaped to receive the nozzle manifold between themselves, an opening mechanism for moving at least one of the upper and lower wash manifolds with respect to the other between (a) an open configuration which permits the nozzle manifold to be introduced between them and (b) a closed configuration in which each nozzle is contained in a sealed enclosure defined between the upper and lower wash manifolds, and ports communicating with the said sealed enclosure and connectable to a fluid source for passing fluid through the sealed enclosure to carry out washing of the nozzle manifold.

In some applications, a preseparator is fitted to the impactor to remove the largest particles in the aerosol. The preseparator typically has an internal impaction cup, part-filled with liquid, to collect these large particles. After each use and clean up, the impaction cup needs to be replenished with fluid, and it is desirable to achieve this in a straightforward manner and without disassembly of the preseparator.

In accordance with still a further aspect of the present invention, there is a method of cleaning a cascade impactor which comprises a cup manifold defining multiple impaction cups, an impactor head defining transfer passages, and a nozzle manifold which defines multiple nozzles and is disposable between the cup manifold and the impactor head, so that in the assembled impactor a route is defined for through-flow via the impaction cups, the nozzles and the transfer passages, the method comprising separating the impactor head from the nozzle manifold and washing these components separately.

In accordance with yet another aspect of the present invention, there is an automated system for washing components of a cascade impactor which comprises a cup manifold defining multiple impaction cups, an impactor head defining transfer passages, and a nozzle manifold which defines multiple nozzles and is disposable between the cup manifold and the impactor head, so that in the assembled impactor a route is defined for through-flow via the impaction cups, the nozzles and the transfer passages, the system comprising an impactor head wash station, a nozzle manifold wash station, and at least one manipulation arrangement for separating the impactor head from the nozzle manifold and delivering them to their respective wash stations.

In accordance with yet a further aspect of the present invention, there is a wash station for use in an automated system for performing repeated testing using an impactor which comprises a cup manifold defining multiple impaction cups, an impactor head defining transfer passages, and a nozzle manifold which defines multiple nozzles and is disposable between the cup manifold and the impactor head, so that in the assembled impactor a route is defined for through-flow via the impaction cups, the nozzles and the transfer passages, the wash station being adapted to receive and clean the impactor head. Preferably, the wash station comprises a contact surface which is exposed enabling the impactor head to be placed against it, a plurality of wash fluid outlets being arranged on the contact surface to dispense wash fluid into the transfer passages. In principle, the wash station may be adapted to wash an assembly comprising both the impactor head and the nozzle manifold. Preferably however it is adapted to wash the impactor head alone.

It will be appreciated from the following detailed description that further aspects and features are comprised in the present invention.

DETAILED DESCRIPTION OF THE EMBODIMENT

The cascade impactor10illustrated inFIGS. 12aandbis a known device which is commercially available from MSP Corporation of Minneapolis. For detail about its construction, the reader is directed to UK patent 2372719 and to U.S. Pat. No. 6,453,758, the content of which is incorporated herein by reference. It is used for analysis of solid particles in aerosols, and particularly for analysis of particle size distribution. This particular impactor is intended for use in the testing of inhalers of the type used to deliver metered doses of a drug to the lungs of a patient, e.g. for the treatment of asthma. Typically, the inhaler is a dry powder inhaler (DPI) or a metered dose inhaler (pMDI), as known in the art. A vacuum applied to the impactor's exhaust12causes the aerosol from the inhaler to be drawn into the impactor through an induction port14(sometimes referred to as the “throat”), then through a preseparator16and through a series of impaction stages defined between an impactor head18and a base plate20carrying a cup tray22.

The induction port14is an elbowed tubular component which releasably connects to the preseparator16through a tapered fitting, which forms the lower end of the induction port and is not seen inFIG. 1. The preseparator serves to collect the largest particles in the aerosol and is releasably mounted to the impactor head, projecting upwardly from it. The cup tray22is a sheet metal component defining a series of shallow, ovoid cups24. A corresponding set of nozzles26is formed in a nozzle tray28mounted at the underside of the impactor head18, each nozzle being arranged so that when the impactor is closed it lies over a respective cup, to direct the aerosol toward the cup. Each nozzle has numerous individual apertures, the size of the nozzle apertures becoming progressively finer in successive nozzles26. Each nozzle communicates, through a respective transfer passage formed in the impactor head and not seen in the drawings, with a respective outlet aperture30, each of which is arranged to lie over, and so receive the flow of aerosol from, a respective cup24. Each transfer passage, except for the last, leads to the next nozzle26, forming a route for passage of the aerosol through the successive impaction stages, formed by the cups24and nozzles26, to the impactor exhaust12.

Particles from the aerosol collect in the various components of the impactor, based on their particle size, whence they need to be recovered and collected for analysis in a solvent. To facilitate this, the impactor is able to be disassembled by removing the induction port14and preseparator16, lifting the impactor head18away from the base plate20, and removing the cup tray22, and when necessary the nozzle tray28. The base plate20and the impactor head18are in these drawings connected in the manner of a clam shell through hinges32, but these—and a handle on the impactor head18—are dispensed with in accordance with the present invention.

The testing of devices such as inhalers typically involves a large number of individual trials with the impactor. In principle the process can be carried out manually, and this has been a common practice, but the system to be described below serves to automate all of the major steps involved in use of the impactor, enabling a batch of trials to be conducted without intervention by an operator. The steps involved are:dosing of the impactor—i.e. firing the inhaler into the impactor, causing the pharmaceutical dose to be collected in it;dose recovery and collection from each of the relevant components of the impactor, which is done by solvent immersion of the impactor components (or at least of the relevant surfaces of the components) following its disassembly, yielding a set of solvent/pharmaceutical mixture samples (typically solutions, although in principle they could be suspensions);clean up of the equipment. This is necessary to prevent contamination of one trial by material collected in a previous trial;storage of the samples; andpreparation of the impactor components for re-use, which includes in some procedures coating of the cups24and addition of a dose of solvent to an internal collection cup of the preseparator16, after re-assembly of the impactor.

The system100(FIG. 1a-d) used to carry out these functions is complex. It comprises (a) modules dedicated to specific functions and (b) shared automation systems, serving demands from multiple dedicated modules. The dedicated modules comprise:an impactor assembly, dosing and disassembly (IADDM) module200;a cup coating module300;a cup tray recovery and collection module400;an induction port recovery and collection module500;a preseparator recovery and collection module600;a component drying module700; anda nozzle tray wash unit800.

The shared automation systems comprise:a fluid handling robot900;a tray handling system1000; andan induction port and preseparator handling system1100.

The system utilises a slightly modified version of the impactor shown inFIGS. 12a-bfor effectuation of the automated processing.

The functions of the IADDM module200are represented schematically inFIG. 2a. It serves to assemble the impactor10after preparation of its component parts, to carry out the actual dosing of the impactor10from the inhaler device (a process also referred to herein as “impaction”), and to disassemble the component parts of the impactor10ready for recovery of pharmaceutical material from them.

The base plate20of the impactor10is fixedly mounted upon a stand202(seeFIG. 2b) and its exhaust is connected via an optional protective filter204to a vacuum flow channel206(seeFIG. 2e) leading to a vacuum pump208, to draw the aerosol through the impactor10.

The impactor head18is mounted on an IADDM transfer mechanism210(seeFIG. 2din particular) comprising a traveler212mounted upon guide rails214extending in the X direction of the system (the X, Y and Z directions, or equivalently the side-to-side, fore-and-aft and up-and-down directions, are marked onFIG. 1a). Means are provided for moving the traveler212along the guide rails. Numerous suitable devices are known to those skilled in the art, but in the present embodiment the rails214form the cylinders of linear pneumatic actuators. The actuators move the traveler212between two end stops, defining its two operative positions. The details of the pneumatic actuators is not illustrated, since such devices are well known to those skilled in the art. The traveler212carries an impactor head actuator216(FIG. 2c) which carries the impactor head18and acts along the Z direction to advance/withdraw the impactor head for assembly/disassembly of the impactor. The impactor head actuator216also serves, when the impactor10is assembled, to urge the impactor head18into sealing engagement with the base plate20with a controlled clamping force.

The clamping force has a potential bearing upon the performance of the impactor because the head18and base plate20are separated by shallow resilient sealing rings surrounding each of the cups24, to provide each impaction stage with the necessary air tight seal. An inadequate clamping force might not create the necessary seal. An excessive clamping force would, by excessive deformation of the seals, change the relative positions of the impactor components, and so could change impactor performance. To control the clamping force, the impactor head actuator216is supplied with air at controlled pressure by an electro pneumatic regulator (which is not depicted, but is of a type known to those skilled in the art). Note also that the impactor head18has a resilient mounting, to equalise the clamping pressure across its length and width despite any minor misalignment. Specifically, the clamping force is transmitted to the impactor head18through compression springs218. A transducer (which is not clearly seen in the drawings, although its movable tip is just visible at219) is a low voltage (“LVDT”—low voltage displacement transducer) device. Its sensor tip219is depressed by a bracket221(FIG. 2g) carried upon the impactor head18, in order to measure the position of the impactor head18when it is clamped in place, so that mis-positioning of the head, due to wear of its seals, for example, or to misalignment of the head18and base plate20, triggers an error handling procedure.

For recovery and clean up, the nozzle tray28is to be separated from the impactor head18. To this end, it is releasably retainable beneath the impactor head18by means of an opposed pair of pneumatic nozzle tray attachment clamps220(see e.g.FIG. 2g) disposed at either end of the impactor head18.FIG. 2hshows a nozzle tray28which has been modified (as compared with the known version seen inFIG. 12) in accordance with the present invention. It has a pair of upstanding carrying brackets233,235at its opposite extremities, and these are arranged on the line about which the nozzle tray28balances, so that when suspended through openings237,238the nozzle tray28is approximately horizontal—i.e. lying approximately in the X-Y plane of the system. As shown inFIG. 2g, the attachment clamps220each have a respective movable bolt240insertable through a respective opening236,238to engage the nozzle tray28, and raising the head18causes the nozzle tray28to be suspended from the bolts. Note that the openings236,238are oversize so that when the impactor is assembled they do not carry any of the clamping force.

The amount of pharmaceutical material collected on and in the impactor head18is small, and this need not be collected for analysis. Clean up of this component is not required after every use. However experience has shown that periodic clean up is needed, and to this end the IADDM module includes an impactor head clean up unit222(FIGS. 2cand2f). When necessary the impactor head18is placed on this unit by means of the IADDM transfer mechanism210, the nozzle tray28being released from it and left on the base plate20. The impactor head clean up unit222has a contact plate224provided with recesses226arranged to align with the nozzle and outlet openings26,30of the impactor head18. Through spray nozzles228formed in the recesses, cleaning fluid can be jetted onto the interior surfaces of the impactor head. Drainage openings229are used to exhaust the liquid after use.

Prior to dosing, to test the seal integrity between the impactor components, a leak test may be carried out by the IADDM module. In this process a bung is presented to the impactor inlet formed by the induction port14. Vacuum pump208(FIG. 2e) is run to create low pressure in the impactor10. Proportional solenoid valve232is opened slightly to admit air, until a chosen (sub-atmospheric) pressure is detected by an absolute pressure transducer234, at which point the valve232is closed. Pressure rise at transducer234is then monitored over a chosen period, excessive pressure rise indicative of poor seal integrity triggering an error handling routine.

Also prior to dosing a flow adjustment sequence may be carried out, to determine what valve aperture is required to achieve the specified flow rate through the inhalation device. This is done using a dummy device having the same flow resistance characteristics as the real device (without releasing pharmaceutical). While a partial vacuum is applied to the impactor10by the vacuum pump208, the opening of the proportional solenoid valve232is adjusted based upon flow rate measured by flow meter236, in a closed loop, until the desired flow rate is achieved.

Dosing involves introduction of an inhaler device to the induction port14(the means used for this, which must be specific to the device, are not shown herein and do not themselves form part of the present invention, but suitable robotic devices are known to those skilled in this art) and application of a partial vacuum for a chosen period. A single dose, or multiple doses, may be fired in to the impactor10in this way in each cycle.

The impactor is then disassembled for recovery and clean up.

Cup Coating Module (CCM)300

The cups24of the impactor10may in some applications require pre-coating with a substance which promotes adhesion of the particles in the aerosol to the cups24. The substance may be silicone. This may be applied by applying a liquid comprising silicone oil and hexane to the cups24. Being volatile, the hexane evaporates away quickly after application to leave behind an acceptably uniform silicone coating. After clean up the cup tray22is delivered to the cup coating module300(FIG. 3b) by means of the tray handling system (THS)1000, being positioned on the cup coating module3000on ledges302of a support structure304beneath a carrier plate306. There are three of sets of ledges, to allow three cup trays22to be stored, and when necessary the trays are re-arranged using the CTHS1000to place the tray to be coated on the top set of ledges302. Upon the carrier plate306are multiple peristaltic pumps308to supply respective, controlled quantities of coating fluid through respective outlets310onto the cups beneath. The first and last impactor cups are larger than the others and their associated pumps308acorrespondingly have a larger working volume than the remaining pumps, to deliver a larger quantity of fluid.

Cup Tray Recovery and Collection Module (CTRCM)400

After dosing, the cup tray22, carrying pharmaceutical material to be recovered, is transferred by the CTHS1000from the IADDM module200(FIGS. 2a-h) to the cup tray recovery and collection module400(FIGS. 4a-d), which serves to deliver a controlled quantity of solvent to each cup24, then to agitate the cup tray22to promote dissolution of the collected pharmaceutical in the solvent, then to facilitate collection of a sample of the resulting solution from the cups by the fluid handling robot (FHR)900, and finally to carry out clean up and first stage drying of the cup tray22.

A bottom plate402of the CTRCM module400is recessed to receive the cup tray22and is disposed beneath a top plate404, so that the cup tray22can be sandwiched between the two. The bottom plate402is mounted for movement along the Z direction upon a pneumatic actuator406. The actuator406is in turn mounted to the top plate404through brackets408, and the resulting assembly is suspended from pivot bars410projecting from opposite ends of the top plate404. Note that on its underside the top plate404has resilient seals412whose shapes and positions correspond to those of the cups24. In use, the bottom plate402is first moved away from the top plate using actuator406, to allow the cup tray22to be inserted by the CTHS1000. The bottom plate402is then urged against the cup tray and urges the cup tray22against the top plate404, so that each cup24forms a separate, sealed recovery chamber along with the adjacent top plate404.

A support framework414carries bearings416which receive the pivot bars410and so mount the assembly, allowing it to rotate about an axis which is generally horizontal (i.e. generally in the X-Y plane). Within a guard418is a drive mechanism coupled to a servo motor420for applying a rocking motion to the assembly. That is, the assembly is swung back and forth to either side of its upright position, in the manner of a baby's cradle. This provides the agitation necessary to promote dissolution of the pharmaceutical in the solvent.

Each cup24has an associated fluid delivery and exhaust system, one of which is schematically represented inFIG. 4d. Solvent dispense pump422is a displacement type pump arranged and calibrated to draw a controlled quantity of solvent via a solvent selection valve424from any of a set of holding tanks426. In the illustrated embodiment there are five of these, and any combination of the solvents can be used, under software control. Other modules which carry out solvent delivery are likewise able to draw any of the five available solvents, but to avoid repetition the fluid connections will not be illustrated and described for each. The solvent is delivered through a port405in the top plate404to the cup24. At the end of each solvent dispense step, solvent remaining in the pipe425is ejected into the cup24by compressed air from means of an air valve427. This ensures that the correct volume is dispensed and that no droplet forms on the nozzles. Agitation then takes place, as just described, to dissolve the pharmaceutical in the solvent.

The resulting solution in the cup will form one of the assays for analysis, and a quantity of it must be withdrawn and stored for this purpose. This is done using the fluid handling robot900(seeFIG. 9), whose collection needle is inserted through a self sealing resilient septum in the top plate404, this component being schematically represented at428inFIG. 4d. Note that the cup24is shallow and flat bottomed, so that withdrawal of fluid could in principle be problematic due to small fluid depth in it. Such problems are avoided by inclining the cup tray22, using the drive mechanism, causing fluid to flow toward the low end of the cup to locally increase its depth. Note that each cup24has a narrow end and a wider end. To maximise fluid depth, the cups are to be inclined downwardly toward their narrow ends. Note also that the narrow cup ends alternate, with one cup having its narrow end toward the left or the impactor and its neighbours having their narrow ends toward the right. Hence the process involves inclining the impactor10first one way, to collect from cups1,3,5and7, and then the other, to collect from cups2,4,6and8. Although the septum428is schematically shown in the middle of the cup24inFIG. 4d, it is in fact positioned toward the cup's narrow end. The fluid handling robot's needle is inserted though each septum,428while the assembly is inclined, into the region where fluid depth is greatest.

After collection of all the required samples the cup tray22is to be emptied and cleaned. Emptying of each cup24is carried out through an exhaust430, again arranged at the narrow end of the cup so that to minimise the liquid quantity left in the cup24, the cup tray22is suitably inclined. Cleaning involves dispensing a quantity of cleaning solution to each cup via the solvent dispense pump422and solvent selection valve424, then agitating as previously described, then once more emptying the cups. The clean cup tray22is then transferred to the cup coating module300, for coating and storage, by the tray handling system1000.

Induction Port Recovery and Collection Module (IPRCM)500

After dosing, the induction port14, carrying pharmaceutical material to be recovered, is transferred from the IADDM module200to the induction port recovery and collection module (IPRCM)500(FIGS. 5a-d) by means of the induction port and preseparator handling system1100(FIGS. 11a-c). This serves to dispense a known quantity of solvent into the induction port14, then to agitate it to promote dissolution of the collected pharmaceutical in the solvent, then to facilitate collection of samples of the resulting solution for analysis, and then to clean up the induction port ready for re-use.

FIG. 5ais a schematic representation of some parts of the IPRCM module500. As mentioned above, the induction port14terminates, at its outlet end, in a tapered fitting. This is seen at502. At its other end it has a mouthpiece504, which may for example be formed of an elastomer, for seating against and sealing to the mouthpiece of the inhaler device. Both ends are to be closed, to form a sealed chamber within the induction port14for receiving solvent. This is done by means of an induction port clamping mechanism506which urges the tapered fitting502against a complementarily formed seat508, having a tapered bore510to receive the tapered fitting502, and a mouthpiece sealing mechanism512. The induction module is then tumbled to agitate the mixture within. The word “tumble” is used herein to refer to rotational motion about a non-vertical axis. In the illustrated embodiment this axis is horizontal, and perpendicular to the plane of the paper inFIG. 5a. The tumbling motion could be about more than one axis. Note also that to increase the volume of solvent an extension chamber516communicates with the interior of the induction port14through the bore510.

FIGS. 5b-dshow the physical construction of the IPRCM500. The mouthpiece sealing mechanism512and the induction port clamping mechanism506are carried upon an approximately “U” shaped rotor frame518, forming an assembly which is rotatable about an axis defined by bearings520,522. The bearings are mounted upon fixed uprights524,526. A drive mechanism528, including a servo motor and gearbox, is used to rotate the assembly about the said axis.

The elbow of the induction port14seats upon a shaped cradle530which is movable by means of a pneumatic induction port clamping actuator523, to bring the cradle and the tapered fitting of the induction port14into engagement with the seat508, seen inFIG. 5cto have a seal piece534shaped to receive and seal against the said fitting. The seat508communicates with an optional extension chamber516, which is mounted upon the seat534.

The mouthpiece sealing mechanism512comprises an arm536pivotally mounted between a pair of brackets538projecting from the rotor frame518. On one side of its pivotal axis, the arm536has a pivotal coupling540to the piston rod542of an induction port sealing actuator544. On the other side of its pivotal axis, the arm536carries a seal514. The actuator544is thus able to move the seal514between a raised position (shown in the drawings) in which it is disengaged from the induction port mouthpiece504, and a sealing position in which it closes the mouthpiece.

Delivery of solvent to the interior of the induction port14is made through a dispense arm548(FIG. 5d) mounted upon a rotary actuator550. The rotary actuator550is mounted upon upright526and so does not rotate along with the induction port14during agitation, thus avoiding the need to form a fluid link to a rotating part. Instead, the dispense arm548is movable by means of the rotary actuator550between an operative position (seen inFIG. 5) in which it is positioned to dispense solvent via a conduit552into the open mouthpiece of the induction port14, and a safe position in which it is withdrawn from the vicinity of the induction port and so does not foul the assembly carrying the induction port14during its rotation. Exhaustion of liquid is achieved by rotating the induction port14to pour its contents into a waste chute554.

In operation, the induction port14is released from the impactor10by means of the induction port and preseparator handling system1100(FIGS. 11a-c), using a twist and pull action to release the tapered fitting502, and is transferred by the same system to the IPRCM500where it is seated upon the cradle530and retained in position by the induction port clamping mechanism506. Note that during its transfer, the induction port14is held with its elbow lowermost—i.e. it is arranged in a “V”, with its open ends uppermost, to avoid spillage of collected pharmaceutical material. A controlled dose of solvent is introduced to the induction port, which is then rotated to agitate. A sample is collected using the fluid handling robot900(FIG. 9) through the mouthpiece504, and the remaining solution is then poured into a waste chute554(FIG. 5b). Clean up is carried out by solvent addition and agitation.

Preseparator Recovery and Collection Module (PRCM)600

After dosing, the preseparator16, carrying pharmaceutical material to be recovered, is transferred from the IADDM200to the preseparator recovery and collection module (PRCM)600(FIGS. 6a-d) by the IPPHS1100(FIGS. 11a-c). The PRCM600serves to deliver a controlled quantity of solvent to the interior of the preseparator16, then to agitate it to promote dissolution of the collected pharmaceutical in the solvent, then to facilitate collection of samples of the resulting solution for analysis, and to clean up the preseparator ready for re-use.

The preseparator16seats in a mounting cup602. A generally “U” shaped support frame604carries the mounting cup602and is itself mounted for rotation about a generally horizontal axis between a pair of uprights606. A single electric servo motor608provides two-axis motion of the mounting cup602and the preseparator16, for agitation. Drive from the motor608is applied directly to the support frame604to turn it about its horizontal axis. Drive from the motor608is also transmitted, through a gear train, to the mounting cup602, to spin the mounting cup about its own axis. The gear train comprises a first gear612which is fixed and lies upon the axis of rotation of the support frame604to engage with a second gear614mounted upon the support frame itself. Rotation of the second gear614is transmitted through further gearing carried on the support frame604, comprising a third gear616meshing with the second gear614and coupled through a shaft to a bevel cog618which meshes at right angles with a bevel gear620coupled to the base of the mounting cup602.

A spring loaded clamping yolk621is used to keep the preseparator16in position. It is pivotally mounted upon a clamp shaft624, running between a pair of mounting stubs626, and is urged toward its closed position (shown) by a torsion spring628. The yolk621has a pair of fingers630carrying a clamp insert632which, in the closed configuration, abuts the upper periphery of the preseparator16to locate it. Release of the clamp is only possible while the support frame604is upright, as shown, and is achieved by means of a catch634having an undercut recess shaped to receive and engage an opening bar636at the rear of the clamping yolk622. By pulling downwardly on this bar, the catch raises the yolk's fingers630and its insert632, against the spring biasing, to release the preseparator16. The force required for this is provided by an upright pneumatic release actuator638upon which the catch634is mounted. During agitation, the catch634is disengaged and both the catch634and the release actuator638are moved to a safe position, away from the path of the rotating assembly, using a pneumatic withdrawal actuator640which is mounted in a base plate642of the module600.

InFIG. 6bthe top part of the preseparator16can be seen at644. It receives, as a sealing fit and through a bayonet fitting (not shown), a stopper assembly646having an internal reservoir648(FIG. 6d). To appreciate the function of the reservoir648, refer toFIG. 6c, which is a highly schematic representation of a preseparator16and shows a collection cup17within it. The sample solution is collected from the cup17using the FHR900(FIG. 9), and for this purpose, at the end of the recovery process, it is necessary to ensure that this collection cup17contains sample solution. The reservoir648serves to supply this. Referring toFIG. 6d, the reservoir is defined by a tubular body645of the stopper assembly646to be inserted into the preseparator16, and is closed but for a small dispense opening650at its closed lower end and small vent openings652at its upper end. During the recovery process, after agitation has taken place to dissolve the sample material, the preseparator16is inverted to submerge the reservoir648. After a sufficient period for the reservoir to fill with liquid, the preseparator is restored to an upright position, causing the liquid in the reservoir to escape through the dispense opening650into the collection cup17.

Referring once more toFIGS. 6aandb, during recovery and clean up dispensing of solvent to the interior of the preseparator16is carried out using a preseparator dispense arm654which is mounted upon a rotary actuator656and so movable between a dispense position, in which a delivery nozzle658lies above the open mouth of the preseparator16, and a safe position (shown) in which the dispense arm654will not foul the rotating parts during agitation.

In use, a controlled dose of solvent is introduced to the preseparator16, which is then closed and rotated to agitate. A sample is collected using the fluid handling robot900(FIGS. 8a-b), and the solution is then poured into a waste chute. Clean up is carried out by solvent addition and agitation.

Component Drying Module (CDM)700

Some impactor components need to be dried and stored after the recovery and clean up processes, and this is done in the component drying module (CDM)700(FIGS. 7aand7b). Note that to ensure that the system is not held up waiting for dry components to become available, the relevant impactor components are provided in triplicate. The CDM700carries out forced air drying of the induction ports14, preseparators16and stopper assemblies646by drawing air through them.

A CDM base plate702supports the components while they are being dried. It carries a set of sealing fittings each adapted to receive one of the components14,16,646to be dried. The sealing fittings are hidden from view in the drawings by the components themselves, but each comprise a boss upon which the component seats, the boss having a through-passage for drying air. To avoid the need for a vacuum pump (as opposed to a compressor) air lines704leading from each sealing fitting each have a venturi device706, of well known type, which receives compressed air through a line708from a valve710and in response creates the partial vacuum required, to draw air through the component14,16,646. The valves710are independently controllable, and the vacuum to any given sealing fitting is switched off after the drying operation.

Nozzle Tray Wash Module (NTWM)800

While washing of the nozzle tray28is not needed after every impactor dosing, it has been found that periodic washing is needed and this is carried out by the NTWM800shown inFIGS. 8aand8b. The nozzle tray28is placed by means of the CTHS1000(FIG. 10) upon a lower manifold802of the NTWM800having respective depressions804to receive each of the nozzles26of the nozzle tray28, and an upper manifold806is lowered into position over the nozzle tray by means of a pneumatic overhead actuator808on which it is mounted, so that each nozzle26of the nozzle tray28is contained in a sealed chamber formed between the upper and lower manifolds806,802. Solvent is then jetted through each nozzle26in turn by means of pumps810and fluid lines812to carry out washing. The fluid passes through the nozzles into the said sealed chambers, from which it is exhausted via outlets (not shown, but formed in the lower manifold802). This is done for each nozzle26in turn, since the resistance to flow of different nozzles26is dramatically different.

Fluid Handling Robot (FHR)900

The FHR900(FIG. 9) serves in particular to collects assay solutions for analysis from the induction port14, the preseparator16, and each of the cups24. However it also performs, where necessary, subsequent dilution of the assays in preparation for their analysis, injection of the assay solutions into analysis ports, transportation of well plates used for storage of the assays, and transfer of standard solutions to the well plates.

Fluid handling robots as such are well known and the FHR900is constructed from “off the shelf” components.FIG. 9shows a cantilevered fluid handling arm901mounted for travel along the X axis upon a beam902. Its probes904, through which fluids are collected and exhausted, are movable along the Z axis to enable them to be inserted in the various receptacles, and are movable along the Y direction upon the arm901. Also shown in the drawing are well plates906to receive the assays themselves. Assays drawn from the induction port etc are ejected into the well plates906, and the result of a protracted run of the system will be a set of well plates906filled with assays for analysis. The well plates906are mounted on a temperature regulating device916, which in the present embodiment is of a known type using Peltier solid state heat pumps. The well plates906are releasably clamped in place so that they are not moved when accessed by the FHR900(FIG. 9).

The FHR900has, in this embodiment, four probe needles904. Thus for example during collection of samples from the cup tray22, assays are collected from four of the cups serially using respective needles, but the discharge of these four assays to respective locations on the well plate906is concurrent. Filled well plates906are placed on any of five plate racks908by means of a plate handling arm910, which again is mounted upon the beam902and has a gripper912movable along three axes, and is also able to rotate.

Washing of each probe needles904, and its associated conduits, is achieved by inserting the probe needle in a wash pot and discharging a quantity of system fluid through it. The discharge washes internal surfaces. Fluid in the wash pot serves to wash the probe needle's external surfaces.

If a user requires access to a well plate906, this can be achieved through an access station comprising a drawer918. In response to a user request, the plate handling arm910places the chosen well plate906in the drawer918, which is then released so that the user can open it and remove the well plate906.

The analysis itself, typically by chromatographic techniques, may be carried out by a separate system to which the well plates906are delivered. HoweverFIG. 9shows an injection module to which the assays are delivered, using the FHR900, for transfer to an “on-line” analytical instrument.

The FHR900can also be used to collect and discharge solvent for dilution of the assays.

It can be seen inFIG. 1bthat the FHR900, CTRCM400, PRCM500and PRCM600are all positioned to the same side in the system100to enable the FHR900to perform the above-described collection functions on the CTRCM400, IPRCM500and PRCM600.

Tray Handling System (THS)1000

This shared system, shown inFIG. 10, is mounted at low level in the system100and carries out pick and place operations on the cup trays22and the nozzle trays28:from one ledge to another within the CCM300(for cup coating);from the CDM700to the IADDM200(when cup coating is not required);from the IADDM200to the CDM700(when a leak test is failed, and re-assembly of the impactor10is to be carried out);from the IADDM200to the CTRCM400, for recovery and clean up; andfrom the CTRCM400to the CDM700, when secondary drying is required.From the IADDM200to the NTWM800for nozzle tray wash.

The THS1000provides for motion along all three axes. It comprises a parallel pair of bed bars1002extending along the X axis direction and a traveler bar1004which is movable along the bed bars under software control. For this purpose the bed bars1002are formed as servo driven linear actuators, incorporating a belt drive for the traveler bar1004. These are well known and proprietary units, and other forms of actuator could be used. Likewise the traveler bar1004forms a servo driven linear actuator for moving carriage1006along its length in the Y direction. The traveler bar1004supports a servo driven linear actuator1008which carries a top frame assembly1010whose upwardly projecting “C” shaped arms1012are adapted to receive, support and locate the cup tray22through projections1014which engage with complementary features of the cup tray22. Lifting the cup tray22involves positioning the arms1012beneath it and raising them to engage the tray. Putting the tray down is simply the reverse process. The upstanding arms1012enable the cup trays to be placed within both the cup coating module300and the cup tray recovery and collection module400and the IADDM200.

The location of the THS1000is difficult to appreciate fromFIG. 1as it is largely obscured, butFIG. 11bshows its position with respect to the framework of the system100as a whole, and to the IPPHS1100. Also the top frame assembly1010of the THS1000is seen inFIG. 1b.

Induction Port and Preseparator Handling System (IPPHS)1100

The IPPHS1100shown inFIGS. 11ato11c, is mounted overhead in the system100and serves to move the induction ports14:from the CDM700to the IADDM200, for assembly;from the IADDM200to the CDM700(when a leak test is failed, and re-assembly of the impactor10is to be carried out);from the IADDM200to the IPRCM500, for recovery and clean up; andfrom the IPRCM500to the CDM700, when drying is required.

It also serves to move the preseparators16:from the CDM700to the IADDM200, for assembly;from the IADDM200to the CDM700(when a leak test is failed, and re-assembly of the impactor10is to be carried out);from the IADDM200to the PRCM600, for recovery and clean up; andfrom the PRCM600to the CDM700, when drying is required.

Finally it serves to move the stopper assemblies646from the CDM700to the PRCM600.

The IPPHS1100engages the induction ports14and the preseparators16through a pair of shaped jaws1102which have three axes of translational motion—X, Y, Z—and also two axes of rotational motion—wrist (rotation of the jaws about their axis) and pitch. It comprises a parallel pair of overhead bed bars1104extending along the X axis direction and an overhead traveler bar1106movable along the overhead bed bars1104. Again the bars1104form servo driven linear actuators. An overhead carriage1108is movable along the overhead traveler bar1106in the Y direction and supports an upright guide bar1110supporting a Z axis carriage1112which in its turn carries an integrated manipulation unit1114(FIG. 11c) providing for rotational (wrist and pitch) motion of the jaws1102. The actual release/grip motion of the jaws is provided by a pneumatic actuator1116. The jaws1102have opposed lower part cylindrical recesses1118(FIG. 11a) for holding the throat and preseparator, and upper part cylindrical recesses1120(FIG. 11c), whose axis is at right angles to that of the lower recesses1118, used for gripping the stopper assembly646. For this purpose the jaws102are turned through 90 degrees using the wrist articulation in order to grip the assembly646, and rotated through 90 degrees to release the bayonet fitting.

The specific embodiments of the invention described above with reference to the accompanying Figures are by way of example only, and the scope of the present invention extends to other embodiments and variations within the scope of the appended claims.