WO2004027383A2

WO2004027383A2 - System and method to stress test aerosol inhalation devices

Info

Publication number: WO2004027383A2
Application number: PCT/US2003/029359
Authority: WO
Inventors: Philippe Dutel
Original assignee: Glaxo Group Limited; Smithkline Beecham Corporation
Priority date: 2002-09-19
Filing date: 2003-09-17
Publication date: 2004-04-01
Also published as: AU2003272527A1; AU2003272527A8; WO2004027383A3

Abstract

A system to stress test aerosol inhalation devices comprising a waterbath and a carriage system for immersing the aerosol devices in the waterbath. In a preferred embodiment of the invention, the waterbath includes a tank portion adapted to contain a predetermined amount of water heated to a temperature in the range of approximately 40°C to 60°C and the aerosol devices are substantially continuously immersed therein for a period in the range of approximately 2.5 - 3.5 minutes.

Description

SYSTEM AND METHOD TO STRESS TEST AEROSOL INHALATION DEVICES

FIELD OF THE PRESENT INVENTION

The present invention relates generally to testing of inhalation devices. More particularly, the invention relates to a system and method to stress test aerosol inhalation devices.

BACKGROUND OF THE INVENTION

In the art of manufacturing aerosol inhalation devices, particularly, medicament inhalation devices, recent attention has been focused on detecting and rejecting nonconforming devices. Indeed, it is well known that a small percentage of aerosol inhalation devices leak or will leak due to manufacturing defects, such as improperly aligned or damaged gaskets, defective valve components, etc. Such defects can, and in most instances will, result in a loss of the aerosol propellant that can adversely affect or otherwise alter the performance of the inhalation device.

The Food and Drug Administration ("FDA") has recently become very concerned with leaking (or otherwise nonconforming or detective) aerosol inhalation devices, particularly metered dose inhalers (MDI's). The performance of an MDI can be significantly altered when the propellant leaks, particularly where the propellant leaks in significant amounts or at a significant rate. For example, a "gross leaker" may not deliver any of the prescribed medicament to a patient. MDI's that leak at more than an insignificant rate may "under deliver^" the prescribed medicament. The medicament delivery from a leaking MD! may thus not conform to the dosing regimen set forth and approved by the FDA. In many instances, f e patient may not even realize that insufficient medicament is being received (i.e., delivered to the lungs).

As a result, the FDA has mandated that manufacturers stress test aerosol inhalation devices and subsequently weigh the stressed devices to detect actual and potential nonconforming devices. The FDA has accordingly set conforming standards, including a temperature standard of 55°C ± 5C° for heat stress testing MDI's. Many methods and systems have been developed to heat stress test aerosol inhalation devices. Illustrative is the electromagnetic induction system disclosed in

Co-Pending Application S/N 60/272,970, filed March 2, 2001. The conventional systems and methods to stress test aerosol inhalation devices are, however, often complex. The systems are also relatively expensive and require extensive maintenance schedules.

It is therefore an object of the present invention to provide a system and method to stress test aerosol inhalation devices that substantially overcomes the drawbacks and disadvantages associated with prior art methods and systems.

It is another object of the invention to provide a system and method for heating and, hence, stress testing aerosol inhalation devices with minimal risk of damage to the device.

It is another object of the invention to provide a system and method for stress testing aerosol inhalation devices that includes relatively simple processing and material handling equipment.

It is yet another object of the invention to provide a highly effective and efficient system and method for stress testing aerosol inhalation devices having a high throughput.

SUMMARY OF THE INVENTION

In accordance with the above objects and those that will be mentioned and will become apparent below, the system to stress test aerosol inhalation devices in accordance with this invention includes a waterbath assembly and a carriage system for immersing the aerosol devices in the waterbath. In a preferred embodiment of the invention, the waterbath includes a tank portion adapted to contain a predetermined amount of water heated to a temperature in the range of approximately 40°C to 60°C and the aerosol devices are substantially continuously immersed therein for a period in the range of approximately 2.5 - 3.5 minutes.

The method to stress test aerosol inhalation devices in accordance with this invention comprises the steps of providing a plurality of aerosol inhalation devices and immersing the aerosol devices in heated water. Preferably, the water is similarly heated to a temperature in the range of 40°C to 60°C and the aerosol devices are substantially continuously immersed therein for a period in the range of approximately 2.5 - 3.5 minutes. In a preferred embodiment of the invention, the method includes the steps of pre-weighing each of the aerosol devices prior to the immersion step and post- weighing the aerosol devices after drying to detect non-conforming aerosol devices.

The advantages of this invention include substantially continuously heating and stressing multiple aerosol inhalation devices and, in particular, MDI's that facilitates on-line processing at high throughput. The system of the invention also advantageously employs relatively simple processing and material handling equipment that results in low investment, reduced maintenance, high efficiency and reliability.

BRIEF DESCRIPTION OF THE DRAWINGS

Further features and advantages will become apparent from the following and more particular description of the preferred embodiments of the invention, as illustrated in the accompanying drawings, and in which like referenced characters generally refer to the same parts or elements throughout the views, and in which: FIGURE 1 is perspective view of a prior art aerosol device; FIGURE 2 is a top plan view of one embodiment of the stress test system, according to the invention;

FIGURES 3 and 4 are partial side plan views of the canister feed system, according to the invention;

FIGURES 5 and 6 are partial front plan views of the waterbath and waterbath segment of the carriage system, according to the invention;

FIGURE 7 is a partial sectional front plan view of the canister disengagement system, according to the invention; FIGURE 8 is a schematic illustration of the control system, according to the invention; and FIGURE 9 is a flow chart of the stress test processing steps, according to the invention.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT The present invention substantially reduces or eliminates the disadvantages and drawbacks associated with conventional systems and methods to stress test aerosol devices. By the term "aerosol devices", as used herein, it is meant to mean and include aerosol canisters, such as the aerosol canister 12 shown in Fig. 1 , aerosol inhalation devices, and medicament inhalation devices, particularly, metered dose inhalers (MDI's).

Referring to Fig. 2, the test system 5 generally includes (i) at least one conveyor system 10 adapted to transport a plurality of aerosol devices or canisters 12, (ii) a canister feed system 21 for indexing a predetermined number of aerosol canisters 12, (iii) a carriage system 20 adapted to transport the aerosol canisters 12 to various stages of the test system 5, (iv) a waterbath 30 for heating the canisters 12, (v) a drying tunnel 40 for drying the canisters 12, (vi) a reject gate 50, (vii) an outfeed starwheel 16 and (viii) a control system 70 (see Fig. 8) for controlling the operation of test system 5.

Referring now to Figs. 3 and 4, there is shown the aerosol canister feed system 21 of the invention. As indicated, the canister feed system 21 is preferably adapted to (i) receive a plurality of aerosol canisters 12, from the conveyor system 10, (ii) index a predetermined number of the canisters 12 and (iii) transport the canisters 12 to the carriage system 20 (see Fig. 2).

As will be appreciated by one having ordinary skill in the art, various conventional means can be employed to receive and index a predetermined number of canisters 12. As illustrated in Fig. 2, in one embodiment of the invention, the canister feed system 21 includes an infeed starwheel 14 having a plurality of pockets 15; each pocket 15 preferably being adapted to receive and at least one canister 12. The infeed starwheel 14 is further adapted and positioned to transport the indexed canister 12 to the canister engagement system 22 of the invention (discussed below). In a preferred embodiment, the indexed canister 12 traverses over (i.e., slides across) the canister receiving table 11 during transport by the infeed starwheel 14. According to the invention, the canister feed system 21 also includes a canister engagement system 22 having means for transporting (i.e., raising) at least one canister 12 from the canister receiving table 11 to an engagement position within a respective one of the carriage system canister clips 24 (see Figs. 4 and 5). Various conventional means may be employed to raise the canisters 12 into the clips 24. As illustrated in Figs. 3 and 4, in one embodiment of the invention, the canisters 12 are raised to the engagement position of the canister clips 24 via a synchronized cam system 28.

Referring now to Fig. 4, the canister clips 24 of the invention preferably include two substantially spring-loaded engagement arms (designated 25a, 25b respectively). The engagement arms 25a, 25b preferably have substantially similar engagement faces 26a, 26b that are substantially correspondingly similar to at least the upper portion of a canister 12 (designated generally 13a in Fig. 1 ) to facilitate engagement thereto. As illustrated in Fig. 4, the engagement arms 25a, 25b also serve to protect the sensitive "release assembly" of the canisters 12 (e.g., valve assembly, gaskets, etc.).

As will be appreciated by one having ordinary skill in the art, various known means for spring loading (or biasing) the engagement arms 25a, 25b can be employed within the scope of the invention. Preferably, spring loading of the engagement arms 25a, 25b is achieved via a conventional spring clip 7 that is seated on the outer surfaces of each arm 25a, 25b.

In a preferred embodiment of the invention, the canister clips 24 also include a release pin 29 that is operatively connected to the engagement arms 25a, 25b. As discussed in detail below, the release pin 29 is adapted to move the engagement arms 25a, 25b to an open position, as shown in Fig. 3, when the pin 29 is moved in an inward direction denoted by arrow A and release the arms 25a, 25b, as shown in Fig. 4, when the pin 29 moves in an outward direction denoted by arrow B.

According to the invention, the canister engagement system 22 further includes a clip release wheel 27 that is also synchronized with the infeed starwheel 14, cam system 28 and carriage system 20. As illustrated in Fig. 3, the clip release wheel 27 includes a plurality of raised lobes (designated 27a-27d) that are designed to contact and move the release pin 29 of the clips 24 during rotation of the release wheel 27, whereby the engagement arms 25a, 25b are opened to receive a canister 12. After a canister 12 is raised to the engagement position in the clip 24, further rotation of the release wheel 27 allows the pin 29 to move outward, whereby the engagement arms 25a, 25b move to a closed position to engage the canister 12 (see Fig. 4).

The canister clips 24 of the invention are preferably constructed out of a material or materials suitable for pharmaceutical operations, such as high strength polymeric materials, stainless steel and combinations thereof. In a preferred embodiment, the clips 24 are primarily constructed out of a polymeric material (e.g., high density polyethylene) and clad with stainless steel.

In an additional embodiment of the invention, a turret system is employed to facilitate the indexing of the canister 12. The turret system includes a conventional turret that is preferably disposed above and is similarly synchronized with the infeed starwheel 14. The turret system also includes a synchronized clip wheel adapted to open and release the engagement arms 25a, 25b of the canister clips 24.

Referring to Fig. 2, the carriage system 20 of the invention is preferably a chain drive assembly that is driven by an inverter controlled, three-phase motor. The three-phase motor is also preferably employed to drive the canister feed system 21 and the outfeed starwheel 16.

The chain drive assembly and, hence, carriage system 20 operates at a pre-determined speed set in accordance with the programmed canister 12 immersion time (discussed in detail below) and is controlled by the control system 70 of the invention and/or directly from the operator via the operator touchscreen (or display) 72 (see Fig. 8).

Referring now to Figs. 5 and 6, the carriage system 20 of the invention further includes a waterbath segment (designated 21 ) that is preferably adapted to be lowered to a test position 23a (discussed in detail below) wherein a predetermined number of aerosol canisters 12 are immersed in the waterbath 30 and raised to a "cans clear position" (shown in phantom and designated 23b) wherein the canisters 12 are removed from the waterbath 30 upon either a signal initiated by the operator or a signal provided by the control system 70 of the invention (e.g., low water level). According to the invention, the waterbath segment 21 of the carriage system 20 is also adapted to rise to a maintenance position (not shown). Preferably, the waterbath segment 21 is raised and lowered via a three (3) phase, inverter controlled motor.

In a preferred embodiment of the invention, the waterbath segment 21 lowers the body portion (designated 13b in Fig. 1) of at least one, more preferably, at least 250 aerosol canisters 12 into the waterbath 30 when the waterbath segment 21 is lowered to the test position 23a. Even more preferably, approximately 500 canisters 12 are lowered into the waterbath 30 at the test position 23a and are substantially continuously transported therethrough when the carriage system 20 is in the run mode.

The waterbath 30 of the invention preferably includes a tank portion 32 having a water capacity in the range of 300 - 400 liters. As illustrated in Fig. 6, the waterbath 30 also includes an overflow basin 33 that is in communication with the tank portion 32 having a water capacity in the range of 50 - 80 litres. According to the invention, the tank portion 32 can comprise various shapes; provided, the tank portion 32 (i) has a water capacity in the noted preferred range, (ii) can operatively receive canisters 12 up to approximately 22 mm in diameter and up to 75 mm in height, and (iii) facilitates a canister 12 throughput (or speed) in the range of 100 - 200 canisters/min., more preferably, approximately 150 canisters/min. and a canister 12 immersion time in the tank portion 32 in the range of 2.5 - 3.5 min., more preferably, approximately 3 min. As illustrated in Fig. 2, the waterbath 30 of the invention further includes means for heating and maintaining the water (designated 31 ) contained in the tank portion 32 within a predetermined temperature range. According to the invention, various conventional means can be employed within the scope of the invention to heat and maintain the water temperature at a predetermined level. In a preferred embodiment, the waterbath 30 includes an electrical heat exchanger 34 having at least one heater associated therewith that is adapted to heat and maintain the water temperature within the range of approximately 40° C to 60° C. More preferably, the water temperature is maintained within the range of approximately 50° C to 60° C.

The waterbath 30 of the invention also preferably includes a recirculation system 36 and filtration system 38. The recirculation system 36 is preferably in communication with the heat exchanger 34 and includes a pump 37 for recirculating the water 31 in the waterbath 30. The pump 37 is preferably driven by an inverter controlled, three (3) phase motor.

The filtration system 38 includes at least one UV filter in communication with the recirculation system 36 to minimize microbial contamination. The filtration system 38 also preferably includes at least two fine filters (e.g., 2μm and 5μm filters) to provide fine filtration of the water 31 in the waterbath 30.

Preferably, the tank portion 32 and basin 33 of the waterbath 30 are constructed out of stainless steel. However, as will be appreciated by one having ordinary skill in the art, various additional conventional materials that provide excellent corrosion and chemical resistance can also be employed to construct the tank portion 32, basin 33 and other components of the waterbath 30. Referring to Fig. 6, in an additional envisioned embodiment of the invention, the waterbath 30 is disposed within an anodized aluminum enclosure (shown in phantom and designated 39). The enclosure 39 would provide two functions: (i) the enclosure 39 would serve as a safety guard (with door safety switches and door locks) to prevent personnel from inadvertently contacting moving parts; and (ii) provide a connection for a facility extraction system.

Referring back to Fig. 2, the test system 5 further includes a drying tunnel 40. According to the invention, the drying tunnel 40 includes an extraction system (not shown) and at least one blower 42 adapted to provide drying air into the drying tunnel 40. Preferably, the blower 42 is driven by an inverter controlled, three (3) phase motor. The motor and, hence, blower 42 is preferably adapted to operate (i) upon a signal received from the control system 70, or (ii) a signal initiated by the operator via the touchscreen 72.

The blower 72 is further preferably adapted to start automaticaiiy when at least one canister 12 is disposed in the "drying zone". By the term "drying zone", as used herein, it is meant to mean an area defined by approximately fifteen (15) clips 24 before the drying tunnel 40 and approximately ten (10) clips after the drying tunnel 40.

As further illustrated in Fig. 2, the test system 5 includes a reject gate 50 that is adapted to reject aerosol canisters 12 after immersion in the waterbath 30 upon either a signal initiated by the operator or a signal provided by the control system 70 (e.g., non-conforming canister, water temperature to high, etc.). A three-phase motor similarly drives the reject gate 50.

Referring now to Fig. 7, disposed proximate the end of the carriage system 20 is the canister disengagement system 60 of the invention. In the illustrated embodiment, the disengagement system 60 includes a strike plate or bar 62 having a release portion 64 disposed on the bottom portion thereof that is adapted to contact and move the release pin 29 of the clips 24 in a direction denoted by arrow A when the canisters 12 are moved via the carriage system 20 in a direction denoted by arrow C. As discussed above, when the release pin 29 is moved in the noted direction, the engagement arms 25a, 25b move to an open position to release the canister 12.

Disposed proximate the canister disengagement system 60 is the outfeed starwheel 16 of the invention (see Fig. 2). The outfeed starwheel 16 is adapted to receive the released aerosol canisters 12 from the canister disengagement system 60 and transport the canisters 12 back to the conveyor system 10. Referring now to Fig. 8, there is shown a schematic illustration of the control system 70 of the invention. As will be appreciated by one having ordinary skill in the art, various control systems and programs (e.g., microprocessor, computer module, PC, etc.) can be employed within the scope of the invention to control the test system 5. In a preferred embodiment of the invention, the control system 70 includes a DH Electrolink ™ system with a Siemens S7/300 PLC.

According to the invention, the control system 70 is in communication with and is programmed to control the (i) conveyor system 10, (ii) canister feed system 21 , (iii) carriage system 20, (iv) waterbath 30 and all components and sub- systems associated therewith, e.g., recirculation system 36, (v) drying tunnel 40, (vi) reject gate 50, and (vii) outfeed starwheel 16. The control system 70 is also in communication with the sensor system 80 of the invention (discussed below) and is adapted to receive and respond to signals provided therefrom.

As illustrated in Fig. 8, the control system 70 is also in communication with the operator touchscreen 72 and is adapted to receive commands from the touchscreen 72 and provide signals thereto. In a preferred embodiment, the touchscreen 72 comprises a Siemens Simatic™ touchscreen interface that is adapted to provide visual messages in response to signals from the control system 70. The touchscreen 72 is further preferably programmed to provide visual messages in response to operator inquiries and commands.

As indicated, the test system 5 of the invention further includes a comprehensive sensor system 80 that is in communication with the control system 70 of the invention (see Fig. 8). According to the invention, the sensor system 80 includes at least the sensors described below. Although the sensors are not illustrated, the preferred positions thereof are identified in Figs. 2, 5 and 6 by the letters (A) - (Q).

Can Infeed Queue Sensor

The can infeed sensor is preferably disposed proximate the infeed starwheel 14 (A) and is adapted to monitor the queue of canisters 12 at the infeed of the carriage system 20 (see Fig. 2). According to the invention, a queue or signal is provided to the control system 70 when the can infeed sensor is on for more than two (2) seconds.

If no queue is provided, canisters 12 will not be allowed to enter the waterbath 30. At least a first queue signal will also be provided to the control system 70 and an "infeed queue" message will preferably be displayed on the operator touchscreen 72 (see Fig. 8).

Can In Starwheel Sensor

The cans in starwheel sensor is also preferably disposed proximate the infeed starwheel 14 (B) and is adapted to detect each canister 12 as it is received by the carriage system 20 and, hence, enters the waterbath 30. The cans in starwheel sensor preferably provides at least one input signal to the control system 70 that is used to provide count data and is also entered into a shift register to enable each canister 12 to be tracked through the system 5.

Cans Out Counter Sensor The cans out sensor is preferably disposed proximate the outfeed starwheel 16 (C) and is adapted to detect each canister 12 as it leaves the system 5. The cans out sensor is preferably adapted to provide at least one output signal to the control system 70 that can be used in conjunction with the cans in sensor to calculate the number of canisters 12 in the system 5, and confirm that the canisters 12 that have entered the system 5 have also left the system 5. According to the invention, when a discrepancy is detected a further signal is provided and a "cans out" message is preferably displayed on the operator touchscreen 72.

Can Backup Sensor

The can backup sensor is preferably disposed proximate the outlet of the carriage system 20 (D) to ensure that the conveyor system 5 is clear of stationary canisters 12. According to the invention, a backup exists if the backup sensor is on for more than 0.5 seconds. If the backup sensor detects a backup, at least one backup signal is provided to the control system 70 and, in response thereto, the system 5 will be shut down. Further, all canisters 12 in the system 5 during the shutdown period will be rejected when the system 5 is restarted. Carriage System Sensor

The carriage system sensor is preferably disposed proximate the carriage system 20 (E) and is in communication therewith. According to the invention, in the event of a blockage or other obstruction to the carriage system 20, a clutch disengages the drive assembly for the carriage system 20 to prevent damage. The position of the clutch is also monitored by a proximity sensor (not shown). According to the invention, the proximity sensor provides at least a first clutch signal to the control system 70 and a "clutch" message is preferably displayed on the operator touchscreen 72 when the clutch is disengaged.

Can Clock Sensor

The can clock sensor is also preferably disposed proximate the infeed starwheel 14 (F) and is adapted to provide a clock pulse to drive a can tracking shift register that is operatively connected to the infeed starwheel 14. According to the invention, the can clock sensor is adapted to provide a clock signal to the control system 70 for each passing starwheel pocket 15.

Starwheel Clock Sensor The starwheel clock sensor is preferably disposed proximate the canister feed system 21 (G). According to the invention, the clock sensor is adapted to provide at least one synchronizing signal to the control system 70 for timing the operation of the canister feed system 21.

Carriage Raised To Maintenance Height Sensor

The carriage raised sensor is preferably disposed proximate the waterbath segment 21 of the carriage system 20 (H), as illustrated in Fig. 5. According to the invention, the carriage raised sensor is adapted to provide at least one carriage raised signal to the control system 70 indicating that the waterbath segment 21 is in the raised, maintenance position.

Cans Clear of Water Sensor

The cans clear of water sensor is also preferably disposed proximate the waterbath segment 21 of the carriage system 20 (I). According to the invention, the cans clear of water sensor 98 is adapted to provide at least one cans clear signal to the control system 70 when the waterbath segment 21 is in the raised position 23b (see Fig. 5). A "cans clear" message is also preferably displayed on the operator touchscreen 72.

Carriage Run Position Sensor

The carriage run position sensor is preferably disposed proximate the carriage system 20 (J) and is in communication therewith. According io the invention, the carriage run sensor is adapted to provide at least one carriage run position signal to the control system 70 when the carriage system 20 is in the run mode.

First Temperature Thermostat/Sensor

The first temperature thermostat (or sensor) is preferably disposed proximate the heat exchanger 34 (K). The first temperature sensor is preferably hard wired to the heater controls in a "fail-safe" configuration.

According to the invention, in the event of a high temperature condition (i.e., temperature exceeding set limit), the first temperature sensor provides at least a first temperature signal to the control system 70. In response to the first temperature signal, the heaters are turned off and the waterbath segment 21 of the carriage system 20 is raised to remove the canisters 12 from the tank portion 32. A "water temperature" message is also preferably displayed on the operator touchscreen 72.

Safety Thermostat/Sensor

The safety thermostat or sensor is preferably disposed in the tank portion 32 of the waterbath 30 (L). According to the invention, in the event of the water temperature exceeding a set value the safety sensor provides at least a second temperature signal to the control system 70. In response to the second temperature signal, the waterbath segment 21 of the carriage system 20 is similarly raised. A "water temperature" message is also displayed on the operator touchscreen 72.

First Water Level Low Sensor

The first water level sensor (i.e., level switch) is preferably disposed proximate the bottom of the water level flow switch assembly 64 (M), which is located in the overflow basin 33 of the waterbath 30 (see Fig. 6). According to the invention, if the first water level sensor detects that no water is present at the noted level, at least a first water level signal is provided to the control system 70. In response to the first water level signal, the heaters are turned off and the carriage system 20 is stopped. A "water level" message is also displayed on the operator touchscreen 72.

Second Water Level Low Sensor

The second water level sensor is preferably disposed above the first water level sensor 106 (N). According to the invention, when the water 31 in the waterbath 30 reaches the level of the second water level sensor, at least a second water level signal is communicated to the control system 70. In response to the second water level signal, a purified water valve (not shown) is opened. A "water level" message is also displayed on the operator touchscreen. This condition does not, however, affect the running of the system 5.

First Water Level High Sensor The first water level high sensor is preferably disposed above the second water level low sensor (O). According to the invention, the first water level high sensor is preferably adapted to provide at least a third water level signal to the control system 70 and close the purified water inlet valve when the water 31 has reached the level of the first water level high sensor. A "water level" message is also similarly displayed on the operator touchscreen 72.

Second Water Level High Sensor

The second water level high sensor is preferably disposed proximate the top of a float switch assembly 66 (P) and acts as a back up to the first water level high sensor. Although this condition similarly does not the affect the running of the system 5, the second water level high sensor provides at least a fourth water level signal to the control system 70 when the water level in the waterbath 30 reaches the level of the sensor 112. A "water level" message is also similarly displayed on the operator touchscreen 72.

Reject Gate Confirmation Sensor

The reject gate confirmation sensor is preferably disposed proximate the reject gate 50 of the invention (Q). According to the invention, if the reject gate sensor detects the presence of a canister 12 when the reject gate 50 should be open, at least one reject gate signal is communicated to the control system 70. In response to the reject gate signal, the carriage system 20 is stopped and an alarm sounds.

Referring now to Fig. 9, the method of the invention will be described in detail. According to the invention, the canisters 12 are initially weighed, placed on the conveyor system 5 and transported to the canister feed system 21 (designated 100).

The canister feed system 21 receives, indexes and transports the containers 12 to the carriage system 20 (102). The carriage system 20 receives the canisters 12 in the carriage system canister clips 24 and transports the canisters 12 to the various stages of the test system 5 (104). According to the invention, the first stage of the test system 5 encountered by the canisters 12 is the waterbath 30. As discussed in detail above, the canisters 12 are immersed in the waterbath 30 and substantially continuously transported therethrough via the water bath segment 21 of the carriage system 20 (106).

In a preferred embodiment of the invention, the canisters 12 are immersed in the waterbath 30 for a period in the range of approximately 2.5 - 3.5 minutes to heat said canisters 12 to a temperature in the range of approximately 50°C to 60°C. More preferably, the canisters 12 have an immersion time of approximately 3 minutes.

After the canisters 12 are immersed in the waterbath 30 for the predetermined period of time, the canisters 12 are transported via the carriage system 20 to the drying tunnel 40 (108). In the drying tunnel 40, the canisters 12 are preferably dried on all surfaces so that no water is visible to the naked eye. After leaving the drying tunnel 40, the canisters 12 are transported to the reject gate 50 (1 10). According to the invention, if a canister 12 is immersed in the waterbath 30 for a period exceeding 3 minutes, the canister 12 is deemed "non-conforming" and rejected by the reject gate 50. The non-rejected canisters (or conforming canisters) 12 are then transported to the canister disengagement system 60 of the invention (1 12). As discussed in detail above, the canister disengagement system 60 is adapted to release the canisters 12 from the carriage system clips 24 and forward the canisters 12 to the outfeed starwheel 16. The outfeed starwheel 16 then receives the released canisters 12 and transports them back to the conveyor system 10 (1 14).

After the canisters 12 are subjected to heating and, hence, stress testing via the test system 5, each canister 12 is subsequently weighed to determine if the canister 12 has lost any of the propellant contained therein (1 16). Such canisters 12 would be deemed "non-conforming" and also rejected.

According to the invention, the pre-test and post-test weighing of the canisters 12 can be conducted off-line by a conventional weighing apparatus (e.g., Tecano Europa Chekweigher). In an additional envisioned embodiment of the invention, the test system 5 includes a weighing system having at least a first weighing apparatus adapted to weigh each canister 12 prior to immersion in the waterbath 30 and after the canister 12 has been dried via the drying tunnel 40. In the noted embodiment, the weighing system is in communication with the reject gate 50 that would further be adapted to reject the "non-conforming" canisters 12. The MDI of the present invention is suitable for containing and dispensing an aerosol drug formulation. Preferably, the drug formulation comprises one or more active medicaments and a single propellant, i.e., a 2-component formulation. Preferably, the propellant is an hydrofluoroalkane ("HFA") propellant. Alternatively, the formulation may include additional HFA propellants and/or one or more excipients or adjuvants, such as surfactants, co-solvents, stabilizing agents and the like.

Medicaments which may be administered in the aerosol formulations include any drug useful in inhalation therapy. Appropriate medicaments may thus be selected from, for example, analgesics, e.g., codeine, dihydromorphine, ergotamine, fentanyl or morphine; anginal preparations, e.g., diltiazem; antiallergics, e.g., cromoglycate, ketotifen or nedocromil; antiinfectives e.g., cephalosporins, penicillins, streptomycin, sulphonamides, tetracyclines and pentamidine; antihistamines, e.g., methapyrilene; anti- inflammatories, e.g., beclomethasone dipropionate, fluticasone propionate, flunisolide, budesonide, rofleponide, mometasone furoate, ciclesonide, triamcinolone acetonide or 6α, 9α- difluoro-11 β-hydroxy-16α-methyl-3-oxo-17α-propionyloxy-androsta-1 ,4-diene-17β- carbothioic acid S-(2-oxo-tetrahydro-furan-3-yl) ester; antitussives, e.g., noscapine; bronchodilators, e.g., albuterol (e.g. as sulphate), salmeterol (e.g. as xinafoate), ephedrine, adrenaline, fenoterol (e.g as hydrobromide), formoterol (e.g., as fumarate), isoprenaline, metaproterenol, phenylephrine, phenylpropanolamine, pirbuterol (e.g., as acetate), reproterol (e.g., as hydrochloride), rimiterol, terbutaline (e.g., as sulphate), isoetharine, tulobuterol or 4-hydroxy-7-[2-[[2-[[3-(2-phenylethoxy)propyl]sulfonyl]ethyl]amino]ethyl-2(3H)- benzothiazolone; diuretics, e.g., amiloride; anticholinergics, e.g., ipratropium (e.g., as bromide), tiotropium, atropine or oxitropium; hormones, e.g., cortisone, hydrocortisone or prednisolone; xanthines, e.g., aminophylline, choline theophyllinate, lysine theophyllinate or theophylline; therapeutic proteins and peptides, e.g., insulin. It will be clear to a person skilled in the art that, where appropriate, the medicaments may be used in the form of salts, (e.g., as alkali metal or amine salts or as acid addition salts) or as esters (e.g., lower alkyl esters) or as solvates (e.g., hydrates) to optimise the activity and/or stability of the medicament. It will be further clear to a person skilled in the art that where appropriate, the medicaments may be used in the form of a pure isomer, for example, R-salbutamol or RR formoterol.

Particularly preferred medicaments for administration using aerosol formulations in accordance with the invention include anti-allergies, bronchodilators and anti-inflammatory steroids of use in the treatment of respiratory disorders such as asthma by inhalation therapy, for example cromoglycate (e.g. as the sodium salt), salbutamol (e.g. as the free base or the sulphate salt), salmeterol (e.g. as the xinafoate salt), formoterol (e.g. as the fumarate salt), terbutaline (e.g. as the sulphate salt), reproterol (e.g. as the hydrochloride salt), a beclomethasone ester (e.g. the dipropionate), a fluticasone ester (e.g. the propionate). Salmeterol, especially salmeterol xinafoate, salbutamol, fluticasone propionate, beclomethasone dipropionate and physiologically acceptable salts and solvates thereof are especially preferred.

It will be appreciated by those skilled in the art that the aerosol formulations according to the invention may, if desired, contain a combination of two or more active ingredients. Aerosol compositions containing two active ingredients are known for the treatment of respiratory disorders such as asthma, for example, formoterol (e.g. as the fumarate) and budesonide, salmeterol (e.g. as the xinafoate salt) and fluticasone (e.g. as the propionate ester), salbutamol (e.g. as free base or sulphate salt) and beclomethasone (as the dipropionate ester) are preferred.

A particularly preferred combination is a combination of fluticasone propionate and salmeterol, or a salt thereof (particularly the xinafoate salt).

Particularly preferred formulations for use in the canisters of the present invention comprise a medicament and a C<|_4 hydrofluoroalkane particularly

1 ,1 ,1 ,2-tetrafluoroethane and 1 ,1 ,1 ,2,3,3,3-n-heptafluoropropane or a mixture thereof as propellant. From the foregoing description, one of ordinary skill in the art can easily ascertain that the present invention provides a unique method and system for substantially continuously heating and stressing multiple aerosol inhalation devices and, in particular, MDI's that facilitates on-line processing at high throughput. The system of the invention also advantageously employs relatively simple processing and material handling equipment that results in low investment, reduced maintenance, high efficiency and reliability.

Without departing from the spirit and scope of this invention, one of ordinary skill can make various changes and modifications to the invention to adapt it to various usages and conditions. As such, these changes and modifications are properly, equitably, and intended to be, within the full range of equivalence of the following claims.

Claims

We Claim:

1. A test apparatus for aerosol inhalation devices, comprising: a waterbath; and a means for immersing said aerosol devices in said waterbath, wherein the aerosol inhalation device contains a drug formulation comprising one or more propellants and one or more medicaments; and wherein the medicament is a member selected from the group consisting of salmeterol, salbutamol, fluticasone, ipratropium, beclomethasone, salts, esters and solvates thereof, and combination thereof.

2. The apparatus of Claim 1 , wherein said aerosol inhalation devices are metered dose inhalers and said propellant is selected from the group consisting of 1 ,1 ,1 ,2-tetrafluoroethane and 1 ,1 ,1 ,2,3,3,3-n-heptafluoropropane and mixtures thereof.

3. The apparatus of Claim 1 , wherein said waterbath includes a tank portion having a predetermined amount of heated water.

4. The apparatus of Claim 3, wherein said water is heated to a temperature in the range of 40°C to 60°C.

5. The apparatus of Claim 1 , wherein said means for immersing said aerosol devices in said waterbath comprises a carriage system.

6. The apparatus of Claim 5, wherein said carriage system substantially continuously immerses said aerosol devices in said heated water.

7. The apparatus of Claim 6, wherein each of said aerosol devices are immersed in said heated water for a period in the range of 2.5 - 3.5 minutes.

8. The apparatus of Claim 1 , wherein said apparatus includes a drying tunnel for drying said aerosol devices after said immersion in said heated water.

9. The apparatus of Claim 5, wherein said apparatus includes a control system for regulating the speed of said carriage system and the temperature of said heated water.

10. A test apparatus for aerosol inhalation devices, comprising: a waterbath; and a system for immersing said aerosol devices in said waterbath wherein the aerosol inhalation device contains a drug formulation comprising one or more propellants and one or more medicaments; and wherein the medicament is a member selected from the group consisting of salmeterol, salbutamol, fluticasone, ipratropium, beclomethasone, salts, esters and solvates thereof, and combination thereof.

1 1. The apparatus of Claim 10, wherein said aerosol inhalation devices are metered dose inhalers and said propellant is selected from the group consisting of 1 ,1 ,1 ,2-tetrafluoroethane and 1 ,1 ,1 ,2,3,3,3-n-heptafluoropropane and mixtures thereof.

12. The apparatus of Claim 10, wherein said waterbath includes a tank portion having a predetermined amount of heated water.

13. The apparatus of Claim 12, wherein said water is heated to a temperature in the range of 40°C to 60°C.

14. The apparatus of Claim 10, wherein said system for immersing said aerosol devices in said heated water comprises a carriage system.

15. The apparatus of Claim 14, wherein said carriage system substantially continuously immerses said aerosol devices in said heated water.

16. The apparatus of Claim 15, wherein each of said aerosol devices are immersed in said heated water for a period in the range of 2.5 - 3.5 minutes.

17. The apparatus of Claim 10, wherein said apparatus includes a drying tunnel for drying said aerosol devices after said immersion in said heated water.

18. The apparatus of Claim 17, wherein said apparatus includes a control system for controlling said drying tunnel, regulating the speed of said carriage system and the temperature of said heated water.

19. A test system for aerosol inhalation devices each having a release assembly and body portion, comprising: a conveyor system for transporting a plurality of said aerosol devices; a canister feed system for receiving said aerosol devices from said conveyor system and indexing a predetermined number of said aerosol devices; a waterbath for heating said aerosol devices; a drying tunnel for drying said aerosol devices; a reject gate for rejecting non-conforming aerosol devices; a carriage system for receiving said aerosol devices from said canister feed system and transporting said aerosol devices to said waterbath, drying tunnel and reject gate; an outfeed device for receiving said aerosol devices from said carriage system and transporting said aerosol devices to said conveyor system; and a control system for controlling said conveyor system, canister feed system, carriage system, waterbath, drying tunnel, reject gate and outfeed device wherein the aerosol inhalation device contains a drug formulation comprising one or more propellants and one or more medicaments; and wherein the medicament is a member selected from the group consisting of salmeterol, salbutamol, fluticasone, ipratropium, beclomethasone, salts, esters and solvates thereof, and combination thereof.

20. The system of Claim 19, wherein said aerosol inhalation devices are metered dose inhalers and said propellant is selected from the group consisting of 1 ,1 ,1 ,2-tetrafluoroethane and 1 ,1 ,1 ,2,3,3,3-n-heptafluoropropane and mixtures thereof.

21. The system of Claim 19, wherein said system includes a weighing system having at least a first weighing apparatus for weighing each of said aerosol devices prior to said immersion in said heated water and after said aerosol devices have been dried in said drying tunnel.

22. The system of Claim 19, wherein said system has a throughput of at least 150 aerosol devices per minute.

23. A process for testing aerosol inhalation devices, comprising the steps of: providing a plurality of aerosol devices; and immersing each of said aerosol devices in heated water wherein the aerosol inhalation device contains a drug formulation comprising one or more propellants and one or more medicaments; and wherein the medicament is a member selected from the group consisting of salmeterol, salbutamol, fluticasone, ipratropium, beclomethasone, salts, esters and solvates thereof, and combination thereof.

24. The process of Claim 23, wherein said aerosol devices are metered dose inhalers and said propellant is selected from the group consisting of 1 ,1 ,1 ,2- tetrafluoroethane and 1 ,1 ,1 ,2,3,3,3-n-heptafluoropropane and mixtures thereof.

25. The process of Claim 24, wherein said heated water has a temperature in the range of approximately 40°C to 60°C.

26. The process of Claim 23, wherein said aerosol devices are immersed in said heated water for a period in the range of approximately 2.5 - 3.5 minutes.

27. The process of Claim 23, wherein said aerosol devices are substantially continuously immersed in said heated water at a rate in the range of approximately 100 - 200 aerosol devices per minute.

28. The process of Claim 23, further including the step of drying said aerosol devices after said immersion step.

29. The process of Claim 28, further including the steps of pre-weighing each of said aerosol devices prior to said immersion step and post-weighing said aerosol devices after said drying step to detect non-conforming aerosol devices.