WO1999049290A1

WO1999049290A1 - Method and apparatus for determining the integrity of packages utilizing flowing aerosols

Info

Publication number: WO1999049290A1
Application number: PCT/US1999/006687
Authority: WO
Inventors: M. Louis Arin
Original assignee: Arin M Louis
Priority date: 1998-03-27
Filing date: 1999-03-26
Publication date: 1999-09-30
Also published as: AU3366199A

Abstract

A system utilizing the combination of an aerosol and a flowing clean gas stream, to inspect sealed packages for leaks by an aerosol detector (70) and detector valve (60). In a first and second embodiment according to the invention using an aerosol generator (20), an aerosol is directed thru or applied inside package (50) via tubing (80) and two connectors (40, 41), while a substantially aerosol free gas stream, particle free, from a gas source (10) is fed thru tubing (90) to flow around the outside of package contained in a sealed test chamber (30). In the first application of the aerosol to the inside of the package, the aerosol gas stream flows through the package; in the second or static situation performed without the second connector (41), aerosol simply will fill the package. For third embodiment of the method, the aerosol flows around the outside of the package while the aerosol free gas stream flows through the inside of the package.

Description

METHOD AND APPARATUS FOR DETERMINING THE INTEGRITY OF PACKAGES UTILIZING FLOWING AEROSOLS

Field of Invention

The invention relates to systems and methods for verifying the integrity of a sealed package and more particularly to methods and apparatus for testing the integrity of sealed packages containing sterile devices.

Background of the Invention

Both physical and biological tests have been developed to measure the capability of the packaging to maintain the sterility of the enclosed medical device. However, physical tests only provide indirect indications of the capability of the package to maintain the sterility of the product. Physical tests such as package seal strength, UN light inspection, dye tests, etc., may be used to monitor the reliability of the production process but, in general, they do not correlate directly with the capability of the fabricated package to maintain sterility. For example, dye tests often provide less than conclusive results as the behavior and physical characteristics of a chemical dye are greatly different than that of a microbe or other entity that can destroy sterility within a sealed package.

Package immersion and microbial aerosol challenge tests (or whole package microbial challenge offer more direct methods for evaluating the efficacy of the package. In the immersion test, the package is submerged under a liquid and the package is examined for escaping bubbles. The package immersion test is limited to packages that can withstand liquid immersion. Moreover, the immersion test is cumbersome and labor intensive; generally considered a difficult test to perform. In the microbial aerosol challenge test, the inside of the package is examined for the presence of bacteria after being exposed to a microbial aerosol for a period of time. Numerous critical technical problems have been reported for the microbial aerosol challenge test: maintenance of a consistent microbial challenge in the chamber, efficiency of assaying the package contents after the microbial challenge, variation of test sensitivity, extended test time and the occurrence of false positive results.

Accordingly, there remains a need in the art to provide a test for sealed-package integrity that is more facile to operate and provides more conclusive data.

-1- Summary of the Invention

The methods and apparatus described herein employ an aerosol and a flowing clean gas stream, to inspect sealed packages for leaks. In a first and second embodiment of methods according to the invention, an aerosol is applied inside the package with a substantially aerosol free gas stream flowing around the outside of the package. In the first application of the aerosol to the inside of the package, the aerosol gas stream flows through the package; in the second or static situation, the aerosol fills the package. In a third embodiment of the method, the aerosol flows around the outside of the package while the aerosol free gas stream flows through the inside of the package. Other embodiments can include combinations of the methods described herein as well as variations and modifications of the steps of these methods that would be apparent to one of ordinary skill in the art.

In one embodiment of apparatus according to the invention, the package to be tested is connected to a first tube from which an aerosol (or a substantially aerosol free gas) flows. The package also connects to a second tube from which the aerosol (or substantially aerosol free gas) may exit the package. In the second or static situation, where the aerosol is allowed to fill the package, no exit tube is necessary. In all described cases, the substantially particle free gas flows into an aerosol detection system which detects any escape of the aerosol particles from or through the package and into the clean gas stream. The detection of the presence of the aerosol particles in the aerosol particle free gas stream indicates a leak or defect in the package.

The present invention reduces or eliminates the problems of whole-package microbial challenge testing by flowing an aerosol, containing either microspheres the size of bacteria or bacteria through the package. The microspheres can simulate the penetrating behavior of bacteria that may penetrate into a package through defects or leaks and lead to nonsterillity. To that end the systems of the invention can include a holding element for holding the package to be tested between an inlet and an outlet, each of which is capable of carrying an aerosol gas. The holding element and the package can be surrounded by a housing that provides a substantially aerosol free environment, or at least an environment with a known concentration of aerosol particles. An aerosol detection system can be in fluid communication with the interior of the housing for measuring and monitoring the aerosol concentration within the housing. An aerosol

-2- generator capable of generating a fluid flow of aerosol particles can be coupled to the inlet for providing a flow of aerosol particles to the package In one embodiment, the inlet can be placed in fluid communication with the interior of the package for allowing aerosol to enter the package. The gas outlet can also be placed in fluid communication with the interior of the package and can act like an exhaust for allowing aerosol to exit from the interior of the package. The aerosol detection system can be in fluid communication with the interior of the housing and will operate to detect the concentration of aerosol particles within the housing The aerosol detection system can generate a measure of the aerosol concentration and that measure can be employed for detecting a leak in the package.

The systems and methods described herein can employ any suitable aerosol material, and the selected aerosol material can be chosen according to the application of interest Moreover, it will be understood that any suitable gaseous or liquid suspension of fine particulate can be practiced with the present invention Additionally, it will be understood that any suitable microsphere material can be practiced with the present invention, and the particular microsphere material selected can be chosen according to the application of interest.

More particularly, the invention includes a system for testing the integrity of a sealed package, comprising a housing for enclosing the sealed package, a particle source for providing a flow of aerosol particles having a first concentration, a gas source for providing into the housing a flow of gas having a second concentration of aerosol particles, a fluid conduit for coupling the flow of aerosol particles to a first side of the sealed package, and a detector for monitoring the flow of gas having a second concentration of aerosol particles to determine if the sealed package has a leak. The particle source can include a source of gas and a source of microspheres. The particle source can include a plurality of sources of microspheres, to provide said aerosol with microspheres of different sizes. The particle source can include a gas supply

Optionally, the detector can comprises an aerosol particle detector, a gas detector, or any detector suitable for the aerosol being employed The system can also include a fluid conduit coupled to a second side of the sealed package, for allowing the flow of aerosol particles to leave the sealed package, as well as a source of gas coupled to the interior of the housing for purging the housing of particles

-3- The intention also provides processes for testing the integrity of a sealed package. The processes can comprise the acts of enclosing the sealed package within a housing, directing into the sealed package a flow of aerosol particles, directing over the exterior of the sealed package, a flow of gas having a known concentration of aerosol particles, and monitoring gas having been directed over the exterior of the sealed package to determine the concentration of aerosol particles therein. A processes can also include the further act of providing at a second side of the sealed package a fluid conduit, in communication with the interior of the sealed package for allowing said flow of aerosol particles to leave the interior of the sealed package, as well as directing a flow of aerosol particles into the sealed package includes the step of directing a flow of particles comprising particles of different sizes.

The present invention has many advantages including providing systems and methods that allow rapid analysis, because the microspheres or bacteria are detected immediately with a particle counter or under a microscope. Additionally, the systems and methods reduce or eliminate the time needed to culture bacteria; thereby providing tests which more quickly indicate the sterility of the package under test. Furthermore, the systems and methods described herein avoid or reduce the occurrence of false positives since the presence of microspheres or bacteria are detected directly and not indirectly through the culturing of bacteria.

-4- Brief Description Of Figures

The foregoing and other objects and advantages of the invention will be appreciated more fully from the following further description thereof, with reference to the accompanying drawings wherein; Therefore, please reference the following figures for a better understanding of the present invention:

FIG 1 is a diagrammatic view representing a first preferred embodiment of the invention;

FIG. 2 depicts an alternative embodiment of a system for verifying the integrity of sealed packages;

FIG. 3 depicts a further alternative embodiment of a system for verifying the integrity of sealed packages;

Detailed Description of the Illustrated Embodiments

To provide an overall understanding of the invention, certain illustrative embodiments will now be described, including a system for verifying the integrity of a sealed-package. However, it will be understood by one of ordinary skill in the art that the systems and methods described herein can be adapted and modified to for other suitable applications, including for determining characteristics of a sealed package, such as the size of the pores in the skin of a package, the pressure required to force an aerosol through a membrane, or any other suitable application. Other additions and modifications can be made to the invention without departing from the scope hereof.

Figure 1 depicts a first embodiment of the present invention comprising a sealed test chamber 30 into which a package undergoing testing 50 is positioned. Tubing 80 carries an aerosol from the aerosol generator 20 and the particle free or substantially particle free gas supply, e.g. air, nitrogen, etc., to the package undergoing test 50 which is conducted into the package via a connection, 40 adapted to be inserted and sealed into, or with, the package. A second tube connector, 41 adapted for insertion and for sealing with the package, is connected so that the aerosol may exit from the package into

-5- an aerosol detection system 70 The part 50, with tubing attached, is positioned in a sealed test chamber 30 containing a gas stream free of the test aerosol, which also flows into the aerosol detector system 70 The tubing 90 can carry an aerosol free gas through the chamber 30 to create a flow of aerosol free particles running past and over the package 50

The test chamber 30 can be any suitable chamber for providing a housing for the package undergoing test 50, and in one embodiment comprises a clear plastic housing that facilitates visual inspection during a test, and that is formed of a material that does not react with the materials bing flowed through the housing, is capable of sealing the package undergoing test, and the environment within the housing 30 from the exterior environment and does not give off particles that can be detected and mistaken for materials leaked from the package undergoing test 50 However, any suitable housing can be employed with the systems described herein, and the size and shape of the housing can vary according to the application at hand As such it is apparent that one of ordinary skill in the art can obtain or manufacture a housing suitable for the system

The package undergoing test 50 typically is a sealed package, optionally containing a sterilized medical instrument, and acting to protect the interior of the package, and any contents therein from being contaminated

Tubing 80 can be any suitable tubing for carrying the microspheres to the package undergoing test 50 The tubing can be flexible of rigid, and or example can comprise plastic, such as polybutylene Other materials can be employed including polyvinyl chloride, copper, stainless steel, or any other suitable material In the embodiment depicted in Fig 1, the tubing 80 ends at a connector 40, and at the other side of the package terminates at the connector 41 The tubing couples in fluid communication to these connectors 40 and 41 for delivering microsphere thereto, which can then be delivered into the package 50 Optionally, the tubing 80 can couple directly to the package 50 for delivering the microspheres directly into the package 50

The depicted connectors 40 and 41 can be any suitable device for coupling the interior of the sealed-package under test into fluid communication with the tubing 80 so that the microsphere aerosol can flow into the package For example, the connectors 40 and 41 can comprise plastic hubs that can be sealed to the package 50, such that a fluid tight seal is created between a connector and the sidewall of the package 50 Other connector elements can be employed without departing from the scope of the invention

The aerosol detector system, can be any suitable aerosol detection system such as one that comprises a particle counter One example of an aerosol detector can include electro-optical systems that include light scattering devices for detecting and measuring the concentration of air-borne particles One such technology is described in "A New Laser Aerosol Detector and Monitor for Use on High Pressure Gas Streams," W E Harrison, Jr , Frederick M Shofher, and Arther C Miller, Jr , presented at the 1977 Cryogenic Engineering Conference, Aug 2-5, 1977, Boulder, Colo Other technologies can include systems that employ detector tubes, such as the systems described in US patent 4,230,457, entitled Apparatus and method for measuring aerosols and gases with detector tubes However, other systems and technologies can be employed, including a filter located with the flow of the aerosol, which can collect particles that can later be counted with microscope to determine the quantity of particle flow

The aerosol generators employed herein can be any suitable aerosol generators, and can include reservoirs of particulate material and reservoirs of inert gases and a mixer for combining the particulate material and inert gas Systems for generating streams of aerosol particles are well known in the art and any suitable source of aerosol material can be employed with the present invention In the depicted embodiment, the aerosol generator 20 connects to a source of gas, such as nitrogen, that is used to suspend the microparticles into the aerosol flow In one embodiment, the source of gas is free of substantially free of particles, thus ensuring that the particle concentration from the aerosol generator 20 is known However, in other embodiments, any source of gas can be employed, as the particle concentration leaving the generator can be determined, such as by measuring the particle concentration in the outgoing stream or by generating a stream with a known characteristic of particle concentration It further will be understood that microparticles suitable for use with the present invention are well known in the art, and the type and size of the microparticles employed can vary depending on the application at hand Moreover, other particulate matter can be employed to substitute for the microparticles, including any suspensions, emulsions, capsules, tablets, microspheres, beads, organic material, cellular material, gas or vapor In operation, the microsphere aerosol is allowed to flow through the package 50 into the aerosol detection system 70 via detection system valve 60. Techniques for generating aerosol flow are well known in the art, and are discussed in Loo, B. W., Jaklevic, J. M., and Goulding, F. S. In "Fine Particles: Aerosol generation, measurement, sampling, and analysis." (B. Y. H Liu ed.) 1976. Thus, the concentration of the aerosol is determined. Upon completion of the aerosol concentration determination the clean gas stream, which is flowing through the test chamber 30 and on the outside of the package 50, is diverted through the detection system valve 60 into the aerosol detection system 70 while the aerosol stream is allowed to exit from the system into the surroundings through a filter. A defect or leak in the package 50 is detected when the presence of microsphere particles in the clean gas stream is detected by the aerosol detection system 70.

The concentration levels of particles to be detected by the aerosol detection system 70 can be analyzed by lab personnel to determine if the concentration levels indicate a breach in the integrity of the sealed-package. Accordingly, it is to be understood that the systems described herein are not limited to any particular levels of concentration for indicating a breach, and that the meaning of the concentration levels obtained can turn on the application. Moreover, it shall be understood that although the embodiment depicted in Fig. 1 includes an aerosol detector system, other systems such as gas detectors, or a chemical detector, can be employed with other embodiments of the invention, such as those embodiments that deliver a stream of gas having a known composition that differs from the composition of gas in the interior chamber 30, into the interior of the package 50.

A second embodiment of the invention is shown in FIG 2. The package 51 is arranged so that there is no exit connection 41 from the package and the test aerosol flowing in through tubing 80 only inflates the package undergoing test 51 , The part 51 , with tubing attached, is then positioned in a sealed test chamber 30 containing a gas stream, free of the test aerosol, which flows into the aerosol detector system 70.

The arrangement of test equipment and the package to be tested in embodiment 2 is shown in FIG. 2. After determining the microsphere aerosol concentration, it is allowed

-8- to flow into the package to inflate the package 51 While the package is inflated with the aerosol, the clean gas stream flows through the sealed test chamber 30, around the outside of the package 50, through the detector system valve 60 and into the aerosol detection system 70 A defect or leak in the package 50 is indicated when the presence of microsphere particles in the clean gas stream are detected by the aerosol detector system 60

A third embodiment of the present invention is shown in FIG 3 which comprises a sealed test chamber 30 into which a package undergoing test 50 is positioned Tubing 80 carries a microsphere aerosol into the sealed test chamber 30 containing the package 50, which flows on the outside of the package 50 A gas stream, free of the test aerosol, is conducted through the interior of the package 50 via connection 40, adapted for insertion and sealed into the package A second tube 41, adapted for insertion and sealed into the package, is connected so that the clean gas stream exits from the package into an aerosol detection system 70

The arrangement of test equipment and the package to be tested in embodiment 3 is shown in FIG 3 A clean gas stream flows through the package 50 through the detector system valve 60 into the aerosol detection system 70 while a microsphere aerosol is allowed to flow through the sealed test chamber 30 and around the outside of the package A defect or leak in the package 50 is detected when the presence of a microsphere particles in the clean gas stream are detected by the aerosol detection system 70

Aerosols may be used in numerous ways or embodiments that are appropriate to determine the integrity of all types of packages The effectiveness is independent of sizes, shapes, and packaging materials commonly used in the medical device packaging industry In the first embodiment the aerosol may be flowed through the inside of the package while a clean gas stream flows on the outside into an aerosol detector In the second embodiment, the package is inflated with the aerosol while a clean gas stream flows on the outside into an aerosol detector A third embodiment involves flowing the aerosol on the outside of the package while a clean gas stream flows through the inside into an aerosol detector

-9- The use of the present invention for the determination of the integrity of packages has the advantage over the whole package microbial challenge test, in that results can be obtained in a shorter period of time than by prior art methods, achieving savings arising from faster production and development costs Moreover, the present system allows for the use of microspheres, thus improving on prior art systems that employ a bacterial aerosol, wherein the presence of bacteria has to be determined through culturization which may take many hours Sterile laboratory conditions are not necessary with the use of microspheres, eliminating the elaborate equipment necessary to maintain sterile laboratory conditions which, in turn, leads to cost savings When microsphere or bacterial aerosols are utilized the aerosol particles are detected directly, thereby eliminating the false positives or negatives that occur when cultures are used to detect the presence of bacteria The invention may be operated near a packaging assembly line since special laboratory conditions are not necessary for its operation This will lead to a more rapid and money saving testing procedure The whole-package microbial challenge test requires the washing and collecting of any microbes that may have penetrated into the package from the outside This process may lead to false positives due to contamination In the first embodiment of the present invention, there is a dynamic flow of microsphere free gas either through, inside, or around the outside of the package The dynamic flow sweeps the unique microspheres that have penetrated through the package into the detector The use of a microsphere aerosol allows the selection of a narrow range of particle sizes, that can be detected easily and is capable of easy identification through tagging The use of a microsphere aerosol avoids or reduces the possibility of false negative results when nonviable bacteria are used A microbial aerosol may be substituted for the microsphere aerosol since both may be detected with a particle counting system

The systems described above can include computer processing system for automatically monitoring the concentrations of aerosol This allows recording of levels of aerosol as well as providing a graphical illustration of the detected levels The systems can also include computer control systems for automatically running the processes described herein Moreover, the processes described herein can be run with a plurality of aerosols, wherein the aerosols can be flowed either in parallel or in sequence In a further embodiment, the systems include a flushing system for flushing a fluid through the system for purging aerosol or bacteria from the housing and tubing An antibacterial or cleansing

-10- material can also be passed through the system for between testing decontamination of the system.

Those skilled in the art will know or be able to ascertain using no more than routine experimentation, many equivalents to the embodiments and practices described herein. Accordingly, it will be understood that the invention is not to be limited to the embodiments disclosed herein, but is to be understood from the following claims, which are to be interpreted as broadly as allowed under the law.

^■ 1 1 -

Claims

I claim:

1. A system for testing the integrity of a sealed package, comprising a housing for enclosing the sealed package, a particle source for providing a flow of aerosol particles having a first concentration, a gas source for providing into the housing a flow of gas having a second concentration of aerosol particles, a fluid conduit for coupling the flow of aerosol particles to a first side of the sealed package, and a detector for monitoring the flow of gas having a second concentration of aerosol particles to determine if the sealed package has a leak.

2. A system according to claim 1, wherein said particle source includes a source of gas and a source of microspheres.

3. A system according to claim 1 , wherein said particle source includes a plurality of sources of microspheres, to provide said aerosol with microspheres of different sizes.

4. A system according to claim 1, wherein said particle source includes a gas supply.

5. A system according to claim 1, wherein said detector comprises an aerosol particle detector.

6. A system according to claim 1, wherein said detector comprises a gas detector.

7. A system according to claim 1, further comprising a fluid conduit coupled to a second side of the sealed package, for allowing the flow of aerosol particles to leave the sealed package.

8. A system according to claim 1, further comprising a source of gas coupled to the interior of the housing for purging the housing of particles.

9. A process for testing the integrity of a sealed package, comprising the acts of

-12- enclosing the sealed package within a housing, directing into the sealed package a flow of aerosol particles, directing over the exterior of the sealed package, a flow of gas having a known concentration of aerosol particles, and monitoring gas having been directed over the exterior of the sealed package to determine the concentration of aerosol particles therein.

10. A process according to claim 9, including the further act of providing at a second side of the sealed package a fluid conduit, in communication with the interior of the sealed package for allowing said flow of aerosol particles to leave the interior of the sealed package.

11. A process according to claim 9, wherein directing a flow of aerosol particles into the sealed package includes the step of directing a flow of particles comprising particles of different sizes.

-13-