Container integrity testing method and system

Abstract

A container integrity (CCI) test method for testing the airtightness of a stopper closure of a syringe (7), the syringe having a syringe body (71) having a longitudinal axis and a hollow interior extending between an open first axial end and a second axial end having an orifice (712), and an elastomeric stopper (73) disposed in the hollow interior through the open first axial end such that a chamber (74) is formed between the stopper (73) and the second axial end, the CCI test method including: providing the syringe (7) in a gaseous environment containing a detectable gas; moving the stopper (73) inside the hollow interior of the syringe body (71); and sensing the detectable gas exiting the chamber (74) of the syringe (7) while moving the stopper (73) inside the hollow interior of the syringe body (71).

Description

[Technical Field]

[0001] The present invention relates to a container closure integrity (CCI) testing method, a CCI testing system, a verification process, and a syringe surrogate. Such testing methods and systems can be used to test the airtightness of a stopper closure of a syringe having a syringe body with a longitudinal axis and a hollow interior extending between an open first axial end and a second axial end having an orifice, and an elastomeric stopper disposed in the hollow interior through the open first axial end such that a chamber is formed between the stopper and the second axial end. [Background technology]

[0002] In connection with the provision of pharmaceuticals and other sensitive substances, the integrity of the associated containers and packages in which the substances are placed is of great importance, whereby the integrity of a container or package generally refers to the ability to retain contents or substances inside the respective container or package and to retain harmful ambient contaminants outside the respective container or package.

[0003] For example, the integrity of a container can be affected by a leak in the container or package. A leak is typically perceived as a hole or crack of a specific diameter and length. Leakage can be a measure (mass or volume or units) of gas flow through the leak path under specific conditions. When the pressure in a 1 liter sealed container rises or falls by 1 mbar in 1 second, the leakage is 1 [mbar x 1 / s].

[0004] When containers with movable closures are involved, certain container integrity issues must be considered. In particular, syringes prefilled with pharmaceutical substances typically have a plunger rod with a stopper that must be movable during administration to expel the pharmaceutical substance through a needle or orifice. To prevent unintentional movement of the stopper, the plunger may be physically secured during shipping and other handling of the syringe.

[0005] However, during assembly and transportation of the syringe, the stopper may still undergo certain movements. For example, during assembly, particularly during assembly of the plunger rod, the stopper may undergo axial and / or rotational movements that can induce deformation of the stopper, potentially affecting the airtightness of the stopper interface. Alternatively, during transportation, the syringe may be exposed to various pressures that can induce certain linear movements of the stopper. For example, when transporting a syringe by airplane, the syringe is exposed to lower pressure during flight and higher pressure or ambient pressure before and after landing. This can create a pressure difference of approximately 500 mbar between the interior and exterior of the syringe. Because the interior of the syringe also contains gas or bubbles, such a pressure difference can induce repeated movement of the stopper, affecting the integrity of the syringe closure provided by the stopper.

[0006] To test the integrity of a syringe, an accepted procedure is to provide a culture medium within the syringe, expose the syringe to specific conditions, and demonstrate whether microbiological contaminants grow in the culture medium. However, such microbiological testing procedures are often error-prone, time-consuming, and difficult to reproduce.

[0007] Therefore, there is a need for a container integrity testing method and system that allows for testing syringes in a relatively reliable, rapid and reproducible manner. Summary of the Invention

[0008] According to the present invention, this need is solved by a container integrity (CCI) method as defined by the features of independent claim 1, a CCI system as defined by the features of independent claim 18, and a validation process for validating a CCI test method as defined by the features of independent claim 36. Preferred embodiments are the subject of the dependent claims.

[0009] In one aspect, the present invention is a CCI test method for testing the airtightness of a stopper closure of a syringe, which is advantageously an essentially fully automatic method requiring no manual interaction. The syringe has a syringe body having a longitudinal axis and a hollow interior extending between an open first axial end and a second axial end having an orifice, and an elastomeric stopper disposed in the hollow interior through the open first axial end such that a chamber is formed between the stopper and the second axial end. The CCI test method includes the following steps: (i) providing the syringe to a gas environment containing a detectable gas; (ii) moving the stopper within the hollow interior of the syringe body; and (iii) sensing the detectable gas exiting the chamber while the stopper is moving within the hollow interior of the syringe body.

[0010] Moving the stopper within the hollow interior of the syringe body involves relative movement between the stopper and the syringe body. Such relative movement can be achieved by moving the stopper and holding the syringe body. Holding the stopper and moving the syringe body is preferred because the syringe body can be more efficiently held and accurately guided in an automated process. Combinations of such relative movements are also possible.

[0011] The automatic relative movement of the stopper and syringe body allows for increased accuracy, efficiency and repeatability of the CCI test method.

[0012] Step (i) can be implemented by exposing the syringe, or at least a portion thereof, including the first and / or second axial ends of the syringe body, to a gas flow containing the detection gas or a static gas containing the detection gas at a predetermined static or variable pressure. To be exposed to the gas flow, the first and / or second axial ends can be connected to a gas source, such as a tube or pipe, that delivers the detection gas. Thus, step (i) encompasses exposing only the first axial end to the gas flow, e.g., by connecting it to the gas source; exposing only the second axial end to the gas flow, e.g., by connecting it to the gas source; or exposing both the first and second axial ends to the gas flow. In the latter case, either the first or second axial end is advantageously hermetically closed or hermetically connected to another means, such as a gas detector.

[0013] The orifice in the syringe body of the syringe may be embodied as or equipped with a connecting structure that attaches to a needle, such as a luer lock structure, or alternatively, a stake-in needle may be provided, or may be embodied as a spout.

[0014] The CCI test method according to the present invention allows for efficient testing of whether and to what extent the gas exiting the orifice contains the detectable gas present at the first axial end of the syringe body, or the gas exiting the open first axial end of the syringe body contains the detectable gas. From this, it can be concluded whether gas can pass through the stopper and enter the syringe chamber. If such gas can pass through to a predetermined extent, this can be an indication that the closure provided by the stopper is not sufficiently airtight to ensure the container integrity and sterility of the syringe contents.

[0015] Furthermore, by moving the stopper during step (iii), a dynamic testing of the container integrity can be achieved. This can be particularly important because the stopper may be sufficiently airtight before and after the movement, but not during the movement. For example, an elastomeric stopper may deform while being moved, which may temporarily affect the airtightness of the closure.

[0016] Thus, the CCI test method according to the present invention allows for testing syringes in a relatively reliable, rapid and reproducible manner.

[0017] Preferably, moving the stopper includes moving the stopper axially within the hollow interior of the syringe body.

[0018] The term "axially moving" in this context relates to movement along the longitudinal axis of the syringe body. The stopper may be moved axially within the syringe body by actively moving the stopper while holding the syringe body, by actively moving the syringe body while holding the stopper, or by a combination thereof.

[0019] This axial movement of the stopper can mimic movement induced by a pressure difference between the syringe's environment and the chamber, or by physical means, such as during plunger rod assembly. For example, some plunger rods must be mated with the stopper for assembly, which can result in the stopper moving forward and then moving back again after mating. Alternatively, other plunger rods may have threads that screw into the stopper cavity, which can result in the stopper rotating and possibly moving axially. Since axial movement is induced while a detection gas is being provided, potential leaks and their dimensions can be detected by measuring the detection gas exiting the orifice or the open first end of the syringe body. The effect of the resulting deformation of the stopper during axial movement is included.

[0020] Thus, axially moving the stopper preferably includes advancing the stopper toward the orifice and retracting the stopper toward the first axial end of the syringe body, such back and forth movement of the stopper making it possible to mimic a repeatedly changing pressure differential between the inside and outside of the syringe, such as may occur, for example, in an aircraft with repeated takeoffs and landings.

[0021] Thus, the distance between the maximum forward position of the stopper and the maximum retracted position of the stopper is preferably in the range of about 15 mm to about 25 mm, about 10 mm to about 20 mm, or about 5 mm to about 15 mm. In this way, various dimensions of syringes can be simulated.

[0022] The speed at which the stopper is moved axially inside the hollow interior is preferably in the range of about 4 mm / min to about 15 mm / min, about 9.6 mm / min, about 15 mm / min to about 25 mm / min, or about 20 mm / min.

[0023] Preferably, moving the stopper includes rotating the stopper inside the hollow interior about the longitudinal axis of the syringe body.

[0024] The stopper can be rotated within the syringe body by actively rotating the stopper while holding the syringe body, by actively rotating the syringe body while holding the stopper, or by a combination thereof.

[0025] Such rotational movement of the stopper allows for efficient simulating stopper deformation that can be induced by physical means, for example, during plunger rod assembly. For example, some plunger rods have threads that are screwed into the stopper cavity for assembly, which can result in rotation of the stopper. Thus, sealing problems during syringe assembly can be identified. The rotational movement can be the only movement of the stopper, or advantageously, a movement that is sequentially or simultaneously combined with the above-mentioned axial movement.

[0026] Thus, rotating the stopper within the hollow interior of the syringe body preferably includes rotating the stopper relative to the syringe body by about 180° or more, about 360° or more, about 720° or more, or about 900° or more. Such degrees of rotation can adequately mimic potentially occurring conditions. In this way, the airtightness of the stopper closure can be verified and approved for extreme conditions.

[0027] The speed at which the stopper is rotated within the hollow interior of the syringe body is preferably greater than about 700° / min, greater than about 5,000° / min, greater than about 20,000° / min, or greater than about 28,000° / min. Such rotation speeds also allow for relatively suitable conditions to be verified and approved.

[0028] The CCI test method may involve axial stopper movement only, rotational stopper movement only, both axial and rotational stopper movement, or a sequential combination of both. However, moving the stopper inside the hollow interior of the syringe body preferably includes at least one cycle of rotation of the stopper and multiple cycles of axial movement of the stopper. Such a multi-cycle test protocol allows for efficient and reliable certification of the tightness of the stopper closure.

[0029] Preferably, the detection gas comprises or is helium, which is a particularly suitable detection gas medium because it consists of small atoms, is relatively easy to detect, and is relatively economical.

[0030] The gaseous environment may provide the detection gas at any suitable pressure, i.e., any suitable negative or positive pressure. Preferably, however, the gaseous environment includes the detection gas at a pressure of about 1 bar. Such a pressure makes it possible to mimic ambient conditions.

[0031] The syringe may be a plastic syringe, such as a polymer syringe. Preferably, the syringe is a glass syringe with a nominal volume of 0.5 milliliters, 1 milliliter, 2.25 milliliters, 5 milliliters, or 10 milliliters. In particular, the nominal volume is advantageously between 0.5 milliliters and 10 milliliters. By incorporating the stopper movement parameters as described above, syringes of these dimensions can be efficiently verified and approved.

[0032] Preferably, providing the syringe in the gas environment includes positioning the syringe vertically with the orifice facing up or down, and the syringe is positioned in an upright position when the stopper is moved inside the hollow interior of the syringe body to sense the detection gas. Such a vertical arrangement allows for efficient handling and demonstration or testing.

[0033] The sensing of the detection may be performed at any suitable location or portion of the syringe. In one preferred embodiment, sensing the detection gas exiting the chamber comprises sensing the detection gas exiting an orifice in the syringe body while moving the stopper inside the hollow interior of the syringe body. In another preferred embodiment, sensing the detection gas exiting the chamber comprises sensing the detection gas exiting an open first axial end of the syringe body while moving the stopper inside the hollow interior of the syringe body. Such sensing allows for particularly efficient sensing.

[0034] Preferably, the CCI test method involves automatically monitoring and recording stopper movement and sensed detected gas within the hollow interior of the syringe body. Such monitoring and recording can efficiently collect information regarding stopper movement and detected gas leakage. In this manner, it is possible to evaluate at what point and / or which movement causes leakage. Such information can be useful in improving the properties of the container closure to achieve adequate hermeticity.

[0035] In the CCI test method, providing the syringe with a gas environment can involve non-hermetically connecting a gas supply, such as a specific gas chamber, to the syringe body. In particular, such a non-hermetic connection can be designed to allow leakage of the detection gas. In this way, a constant supply of detection gas to the syringe can maintain a constant detection gas concentration within the syringe during relative stopper movement, since excess detection gas can bypass and enter the environment. Therefore, the detection gas concentration and ambient pressure within the barrel can remain constant during the CCI test.

[0036] In one embodiment, the CCI test method includes preparing the syringe prior to providing the syringe to the gas environment.

[0037] Such preparation may thereby preferably include damaging the stopper of the syringe prior to providing the stopper through the open first axial end into the hollow interior of the syringe body. For example, if the stopper comprises multiple radially extending sealing lips or rings, such damage may be performed by destroying a portion of the sealing lips or rings, preferably all but one of the sealing lips or rings.

[0038] Alternatively or additionally, such preparation includes selecting a syringe body having a particular internal diameter, which may be, for example, the maximum internal diameter allowed according to any legal or practical specification, or a slightly larger internal diameter, particularly since there is typically a range of internal diameters allowed due to clearances in the manufacture of syringe bodies.

[0039] By preparing the stopper and / or syringe body as described above, efficient robustness testing can be achieved. In particular, it can be demonstrated that a detection gas, such as helium, cannot cross either the sealing lip or the ring during stopper movement. This allows one to conclude that bioburden, such as bacteria, cannot cross the sealing lip either, since bacteria are typically significantly larger than the detection gas or helium atoms.

[0040] In another aspect, the present invention provides a container integrity (CCI) testing system for testing the airtightness of a stopper closure of a syringe, the syringe having a syringe body having a longitudinal axis and a hollow interior extending between an open first axial end and a second axial end having an orifice, and an elastomeric stopper disposed in the hollow interior through the open first axial end such that a chamber is formed between the stopper and the second axial end. The CCI testing system includes a detection gas reservoir configured to contain a detection gas, a detection gas sensor, a processing unit having a gas chamber, a positioning structure, and a movement structure, and a connector device. The gas chamber of the processing unit is connected to the detection gas reservoir and configured to receive the detection gas provided by the detection gas reservoir. The positioning structure of the processing unit is configured to hold the syringe such that at least one of the open first axial end of the syringe body and the orifice at the second axial end of the syringe body is disposed within the gas chamber. The moving structure of the processing unit is configured to move the stopper within the hollow interior of the syringe body when the syringe is held by the positioning structure of the processing unit. The connector device is configured to connect the other of the open first axial end of the syringe body and the orifice in the second axial end of the syringe body to the detection gas sensor when the syringe is held by the positioning structure of the processing unit. The detection gas sensor is configured to sense detection gas exiting the chamber of the syringe while the stopper is being moved within the hollow interior of the syringe body.

[0041] If one of the orifices at the open first axial end of the syringe body and the second axial end of the syringe body is the first axial end of the syringe body, the other of the orifices at the open first axial end of the syringe body and the second axial end of the syringe body is an orifice at the second axial end of the syringe body. Conversely, if one of the orifices at the open first axial end of the syringe body and the second axial end of the syringe body is an orifice at the second axial end of the syringe body, the other of the orifices at the open first axial end of the syringe body and the second axial end of the syringe body is the first open axial end of the syringe body.

[0042] The gas chamber of the processing unit may be embodied in any manner that allows for providing the syringe with a gaseous environment containing the detection gas. For example, the gas chamber may be embodied by a rigid housing having an interior in which the detection gas is provided. Alternatively, the gas chamber may be embodied as a tube or pipe connected or attached to the syringe.

[0043] The CCI test system according to the present invention and the preferred embodiments thereof described below make it possible to automatically achieve the effects and benefits of the CCI test method according to the present invention and the preferred embodiments thereof described above. In particular, the CCI test system can be configured to implement and automatically execute the CCI test method.

[0044] Preferably, the CCI test system comprises a control unit connected to the detection gas sensor and the processing unit, which allows for advanced operation of the system and for collecting and evaluating data generated during operation of the system.

[0045] The control unit may be embodied by a computer. In this context, the term "computer" may refer to any suitable computing device, such as a laptop computer, a desktop computer, a server computer, a tablet, a smartphone, etc. The term encompasses single devices and composite devices. A computer may be a distributed system, such as a cloud solution, performing different tasks at different locations. A computer typically includes a processor or central processing unit (CPU), persistent data storage with a recording medium such as a hard disk or flash memory, random access memory (RAM), read-only memory (ROM), a communications adapter such as a universal serial bus (USB) adapter, a local area network (LAN) adapter, a wireless LAN (WLAN) adapter, a Bluetooth adapter, etc., and a user interface such as a keyboard, a mouse, a touchscreen, a display, a microphone, and speakers. A computer may be embodied with a wide variety of components, including those listed herein.

[0046] The control unit is preferably configured to evaluate the detection gas signal provided by the detection gas sensor. In this context, the term "signal" may refer to data or similar signals embodied as electromagnetic signals, such as voltage, radio waves, microwaves, or infrared signals, that can be physically transmitted over a point-to-point or point-to-multipoint communication channel. Such channels may include copper wires, optical fibers, wireless communication channels, storage media, and computer buses. The data signal may represent specific data organized according to a specific protocol, such as the protocols described above. The sensor data itself may be a digital bitstream or the like representing physical and / or logical conditions and changes, and the like. This may be in a format that is accessible and evaluable by the control unit.

[0047] Preferably, the movement structure of the processing unit is configured to axially move the stopper inside the hollow interior of the syringe body. The movement structure may be configured to actively move the stopper while the syringe body is held, to actively move the syringe body while the stopper is held, or a combination thereof.

[0048] Thereby, the control unit is preferably configured to operate the moving structure of the processing unit so that the speed at which the stopper is moved axially inside the hollow interior of the syringe body is in the range of about 5 mm / min to about 15 mm / min, about 9.6 mm / min, about 15 mm / min to about 25 mm / min, or about 20 mm / min.

[0049] The moving structure is preferably configured to move the stopper axially by advancing the stopper toward the orifice and retracting the stopper toward the first axial end of the syringe body.

[0050] The control unit is preferably configured to operate the moving structure of the processing unit so that the distance between the maximum forward position of the stopper and the maximum retracted position of the stopper is in the range of about 15 mm to about 25 mm, in the range of about 10 mm to about 20 mm, or in the range of about 5 mm to about 15 mm.

[0051] Preferably, the movement structure of the processing unit is configured to rotate the stopper inside the hollow interior about the axis of the syringe body. The movement structure may be configured to actively rotate the stopper while the syringe body is held, to actively rotate the syringe body while the stopper is held, or a combination thereof.

[0052] Thereby, the control unit is preferably configured to operate the moving structure of the processing unit such that the stopper rotates relative to the syringe body by about 360° or more, about 720° or more, or about 900° or more.

[0053] The control unit is preferably configured to operate the moving structure of the processing unit so that the speed of rotation of the stopper inside the hollow interior of the syringe body is about 700° / min or more, about 5,000° / min or more, about 20,000° / min or more, or about 28,000° / min.

[0054] The control unit is preferably configured to operate the moving structure of the processing unit such that moving the stopper includes at least one cycle of rotating the stopper and a number of cycles of axially moving the stopper.

[0055] Preferably, the detection gas comprises or is helium.

[0056] Preferably, the syringe is a glass syringe having a nominal volume of 0.5 milliliters, 1 milliliter, 2.25 milliliters, 5 milliliters, or 10 milliliters.

[0057] Preferably, the positioning structure of the processing unit is configured to position the syringe vertically with the orifice facing upwards.

[0058] Preferably, the detection gas reservoir and the gas chamber of the processing unit are configured to provide detection gas at a pressure of about 1 bar in the gas chamber of the processing unit.

[0059] Preferably, the control unit is configured to automatically monitor and record movement of the stopper inside the hollow interior of the syringe body and the detected gas sensed.

[0060] Preferably, the moving structure of the processing unit is configured to automatically move the stopper within the hollow interior of the syringe body when the syringe is held by the positioning structure of the processing unit. The automatic relative movement of the stopper and the syringe body allows for increased accuracy, efficiency, and reproducibility.

[0061] Preferably, the positioning structure of the processing unit is configured to non-airtightly connect one of the open first axial end of the syringe body and the orifice at the second axial end of the syringe body to the gas chamber. In particular, such a non-airtight connection may be designed to allow leakage of the detection gas. In this manner, a constant supply of detection gas to the syringe may allow excess detection gas to bypass and enter the environment, thereby maintaining a constant detection gas concentration in the syringe during relative stopper movement. Therefore, the detection gas concentration in the barrel and the ambient pressure may remain constant during the CCI test.

[0062] In one embodiment, the syringe stopper is damaged. If the stopper includes multiple radially extending sealing lips or rings, such damage may be accomplished by destroying a portion of the sealing lips or rings, preferably all but one of the sealing lips or rings.

[0063] Alternatively or additionally, the syringe body may be selected to have a particular internal diameter, which may be, for example, the maximum internal diameter allowed according to any legal or practical specification, or a slightly larger internal diameter, particularly since there is typically a range of internal diameters allowed due to clearances in the manufacture of syringe bodies.

[0064] In yet another aspect, the present invention is a validation process for validating the above-described CCI test method and / or the above-described CCI test system, the validation process including the steps of: (i) obtaining a syringe surrogate having a surrogate body and a micro-capillary tube, the syringe body having a longitudinal axis and a hollow interior extending between an open first axial end and a second axial end having an orifice, the micro-capillary tube being disposed in the orifice of the syringe body, (ii) providing the syringe surrogate in a gas environment containing a detectable gas, and (iii) sensing the detectable gas exiting the chamber of the syringe.

[0065] The validation process according to the present invention allows the sensitivity and therefore the appropriateness of the CCI test method and system to be demonstrated and verified. In particular, the syringe surrogate allows for the simulating of a leaking syringe, or more specifically, a syringe with a leaking stopper closure. The validation process furthermore allows for the validation to be performed in accordance with accepted standards, such as Good Manufacturing Practices (GMP), which are widely applied in the manufacture of pharmaceutical active ingredients. <1207> It allows for the verification of CCI test methods and / or CCI test systems in accordance with the chapter "Container-Closure Integrity Examination."

[0066] In another further aspect, the present invention is a syringe surrogate for use in the above-described verification process. The syringe surrogate includes a surrogate body and a microcapillary tube. The syringe body has a longitudinal axis and a hollow interior extending between an open first axial end and a second axial end having an orifice. The microcapillary tube is disposed in the orifice of the syringe body.

[0067] As used herein, the term "microcapillary" refers to a microtube, microcannula, or micropipette suitable for simulating a single orifice defect. Microcapillaries can be formed of glass or any suitable plastic or other material and can have diameters ranging from about 0.1 μm to about 500 μm, more specifically, from about 2 μm to about 9 μm. Diameters up to about 10 μm or 15 μm can be suitable for helium leak testing. Diameters up to about 30 μm can be suitable for vacuum or pressure decay testing. Microcapillaries are typically used in place of smaller diameter, shorter leak paths when performing tests that rely on gas flow measurements.

[0068] The syringe substitute according to the present invention makes it possible to carry out an accurate validation process. In particular, the micro-capillary tube can simulate a leak small enough to allow accurate validation of CCI test methods and systems.

[0069] Preferably, the surrogate is made of metal, in particular stainless steel, which allows for a robust implementation, thereby eliminating the occurrence of leaks other than the simulated leak.

[0070] Preferably, the microcapillary is made of glass, which makes it possible to provide inertness so that it can be ensured that any detection gas passing through the microcapillary is not affected.

[0071] Preferably, the microcapillary tube is fastened to the orifice of the surrogate. [Brief explanation of the drawings]

[0072] The CCI testing method according to the invention and the CCI testing system according to the invention, as well as the validation process according to the invention, are explained in more detail below by way of exemplary embodiments and with reference to the accompanying drawings, in which: [Figure 1] 1 is a schematic diagram of a CCI test system in accordance with the present invention. [Figure 2] FIG. 2 is a diagram showing details of the processing unit of the CCI test system of FIG. 1. [Figure 3] 2 is a diagram illustrating a syringe operated in a CCI testing method according to the present invention using the CCI testing system of FIG. 1; [Figure 4] 4A and 4B are diagrams illustrating the movement of the stopper of a syringe operated in the manner of FIG. 3. [Figure 5] 4A and 4B illustrate leaks from a syringe operated in the manner of FIG. 3. DETAILED DESCRIPTION OF THE INVENTION

[0073] In the following description, certain terminology is used for convenience and is not intended to limit the invention. The terms "right," "left," "up," "down," "under," and "above" refer to directions in the figures. The use of terms includes the explicitly mentioned terms as well as their derivatives and terms with similar meanings. In addition, spatially relative terms such as "beneath," "below," "lower," "above," "upper," "proximal," and "distal" may be used to describe the relationship of one element or feature shown in the figures to another element or feature. These spatially relative terms are intended to encompass various positions and orientations of the device during use or operation in addition to the positions and orientations shown in the figures. For example, if a device in the figures were inverted, elements described as "below" or "below" other elements or features would now be "above" or "above" the other elements or features. Thus, the exemplary term "downward" can encompass both upward and downward positions and orientations. The device may be otherwise oriented (rotated 90 degrees or at other orientations), and the spatially relative descriptors used herein may be interpreted accordingly. Similarly, descriptions of movement along and about various axes include various particular device positions and orientations.

[0074] To avoid repetition in the figures and descriptions of various aspects and exemplary embodiments, it should be understood that many features are common to many aspects and embodiments. If an aspect is omitted from a description or figure, this does not mean that the aspect is missing from an embodiment incorporating that aspect. Rather, the aspect may be omitted for purposes of clarity and to avoid redundant description. In this context, the following applies to the remainder of this specification: for clarity of the drawings, if a figure includes a reference sign that is not described in the directly relevant part of the specification, reference is made to the preceding or subsequent part of the specification. Furthermore, for clarity, if not all features of a part in a drawing are labeled with a reference sign, reference is made to other drawings showing the same part. Like numbers in two or more figures represent the same or similar elements.

[0075] 1 shows an embodiment of a container integrity (CCI) test system 1 according to the present invention. The CCI test system 1 includes a detector gas reservoir 2, a processing unit 3, a control unit 4, and a detector gas sensor 5. The detector gas reservoir 2 has a helium tank 21 configured to contain helium as a detector gas. The detector gas reservoir 2 includes a pressure regulator 22 that regulates the pressure of the helium supplied from the detector gas reservoir 2.

[0076] The processing unit 3 includes a gas chamber 31, a positioning structure 32, and a moving structure 33. The moving structure 33 is equipped with a rotary drive unit and a linear drive unit. The gas chamber 31 of the processing unit 3 is connected to the detection gas reservoir 2 via a gas supply pipe 23. The gas chamber 31 is further configured to contain helium as the detection gas provided by the detection gas reservoir 2 via the gas supply pipe 23.

[0077] The detection gas sensor 5 is connected to the processing unit 3 and, as will be described in more detail below, to a syringe 7 (not visible in FIG. 1 ) positioned inside the gas chamber 31 of the processing unit 3 via a leakage gas tube 51. The detection gas sensor 5 is configured to sense helium provided through the leakage gas tube 51.

[0078] FIG. 2 shows the positioning structure 32 of the processing unit 3 in more detail. As can be seen, the positioning structure 32 includes a syringe seat 321 that receives the syringe 7 in an upright or vertical position. The syringe 7 includes a glass syringe body 71 having a longitudinal axis and a hollow interior extending between an open first axial end and a second axial end having an orifice 712 (not visible in FIG. 2 ), and a plunger 72 that extends through the first axial end and into the hollow interior. The plunger 72 is equipped with an elastic stopper 73 that hermetically closes the interior of the syringe body 71 such that a dispensing chamber 74 is formed between the stopper 73 and the second axial end. The syringe 7 has a nominal capacity of 2.25 ml. The syringe seat 321 of the positioning structure 32 is a multi-part structure configured to hold the syringe 7 so that the complete syringe body 71, including its first axial end, is located within the gas chamber 31.

[0079] The CCI test system 1 further includes a connector device 6 that connects the orifice of the syringe body 31 of the syringe 7 to a leakage gas tube 51. Thus, helium exiting the syringe body 31 is provided to the detection gas sensor 5 via the leakage gas tube 51, where it is sensed and quantified.

[0080] Returning to Figure 1, the control unit 4 comprises a computer 41 running dedicated software. The computer 41 is connected to a network infrastructure 42 which is connected to a backup server 421 and a data server 422. The control unit 4 communicates with the processing unit 3 and the detection gas sensor 5. In particular, data generated by the detection gas sensor 5 is provided to the control unit 4 as a data signal via a communication channel.

[0081] The moving structure 33 of the processing unit 3 is configured to move the stopper 73 within the hollow interior of the syringe body 71 when the syringe 7 is received in the syringe seat 321 of the positioning structure 32 of the processing unit 3. More specifically, the positioning structure 32 and the moving structure 33 are designed to hold the plunger 72 together with the stopper 73 in a fixed position and move the syringe body 71 of the syringe 7 relative to the stopper 73.

[0082] The dedicated software configures the control unit 6 to apply one embodiment of a CCI test method according to the present invention. In particular, it is configured to operate the moving structure 33 so that the stopper 73 moves linearly and rotationally relative to the syringe body 71 in accordance with a particular test protocol. During the movement of the stopper 73 relative to the syringe body 71, and thus its hollow interior, the syringe 7 is exposed to helium in the gas chamber 31, and the detection gas sensor 5 senses the helium exiting the orifice of the syringe 7.

[0083] FIG. 3 shows, through a schematic diagram of the syringe 7, the movement the syringe 7 undergoes when the control unit 6 operates the moving structure 33. The leftmost diagram {0.} shows the rotational movement of the stopper 73 relative to the syringe body 71. The rotary drive of the moving structure 33 thereby rotates the syringe body 71 900° about its longitudinal axis at a speed of 1.3 revolutions per second. The other diagrams {1.}-{5.} show the axial movement of the stopper 73 relative to the syringe body 71. The linear drive of the moving structure 33 thereby moves the syringe body 71 10 millimeters forward and 10 millimeters backward along the axis relative to the stopper 73. More specifically, FIGS. {1.}-{3.} show the 10 mm backward movement of the syringe body 71 relative to the stopper 73, which induces a decrease in the volume of the dispensing chamber 74. Figures {3.} to {5.} show a 10 mm forward movement of the syringe body 71 relative to the stopper 73, which induces an increase in the volume of the dosing chamber 74. In total, the relative linear movement of the stopper 73 relative to the syringe body 71 is 20 mm per cycle.

[0084] Figure 4 shows the movement according to the test protocol applied by the control unit 6. As can be seen, the test protocol induces an equally fast first cycle of rotating the syringe body 71 relative to the stopper 73, as shown in Figure 3, diagram {0.}, followed by five cycles of linear movement of the syringe body 71 relative to the stopper 73, as shown in Figures {1.} to {5.} of Figure 3. The numbers in Figures {1.} to {5.} of Figure 3 indicate the first cycle of linear movement in Figure 4. The complete test protocol runs for approximately 650 seconds.

[0085] FIG. 5 shows the results of the detection gas sensor 5 measuring helium exiting the orifice 712 of the syringe 7 during the complete test protocol applied by the control unit 6. More specifically, the control unit 6 connected to the detection gas sensor 5 obtains the helium leak rate during the entire cycle of the test protocol. From left to right, the movements shown in diagrams {0.} to {5.} in FIG. 3 indicate where they first occurred. As can be seen, in the example on which the measurements shown in FIG. 5 are based, the leak rate is 6×10 -6 It can be seen that the Kirsch limit of mbar l / sec is exceeded.

[0086] The present specification and the accompanying drawings, which illustrate aspects and embodiments of the present invention, should not be construed as limiting the scope of the claims, which define the protected invention. In other words, while the present invention has been illustrated and described in detail in the drawings and the foregoing description, such illustration and description should be considered illustrative or exemplary, rather than limiting. Various mechanical, compositional, structural, electrical, and operational changes may be made without departing from the spirit and scope of the specification and claims. In some instances, well-known circuits, structures, and techniques have not been shown in detail so as not to obscure the invention. Accordingly, it will be understood that those skilled in the art can make changes and modifications within the scope and spirit of the following claims. In particular, the present invention encompasses further embodiments having any combination of features from the different embodiments described above and below.

[0087] In particular, in an alternative embodiment similar to that described above in connection with Figures 1 and 2, element 51 in Figure 2 is gas supply tube 23 in Figure 1, and element 6 is a gas chamber of processing unit 3 connected to detection gas reservoir 2 via gas supply tube 23. In such an embodiment, detection gas is provided into the syringe chamber through an orifice in the syringe body. The detection gas is sensed after exiting the syringe chamber through the stopper from the open first axial end of the syringe body.

[0088] Furthermore, the present disclosure encompasses all additional features that may not be described in the above or following description but are individually shown in the drawings. Also, individual alternatives to the embodiments and individual alternatives to those features described in the drawings and specification may be discarded from the subject matter of the present invention or disclosed subject matter. The present disclosure includes subject matter consisting of, and comprising, the features defined in the claims or exemplary embodiments.

[0089] Furthermore, in the claims, the word "comprising" does not exclude other elements or steps, and the indefinite articles "a" or "an" do not exclude a plurality. A single unit or step may fulfill the functions of several features recited in a claim. The fact that certain means are recited in mutually different dependent claims does not indicate that a combination of these means cannot be advantageously used. The terms "essentially," "about," "approximately," and the like, in connection with an attribute or value specifically define that very attribute or exactly that value as well. The term "about" in the context of a given numerical value or range refers, for example, to a value or range that is within 20%, within 10%, within 5%, or within 2% of the given value or range. Components described as being coupled or connected may be directly coupled electrically or mechanically or indirectly coupled via one or more intermediate components. Any reference signs in the claims should not be construed as limiting the scope.

Claims

1. 1. A container integrity (CCI) test method for testing the airtightness of a stopper closure of a syringe (7), the syringe having a syringe body (71) having a longitudinal axis and a hollow interior extending between an open first axial end and a second axial end having an orifice (712), and an elastomeric stopper (73) disposed through the open first axial end and into the hollow interior such that a chamber (74) is formed between the stopper (73) and the second axial end, the CCI test method comprising: providing the syringe (7) in a gaseous environment, the gaseous environment comprising a detection gas; moving the stopper (73) inside the hollow interior of the syringe body (71); and sensing a detected gas exiting the chamber (74) while moving the stopper (73) inside the hollow interior of the syringe body (71).

2. 2. The CCI testing method of claim 1, wherein moving the stopper (73) comprises axially moving the stopper (73) within the hollow interior of the syringe body (71).

3. 3. The CCI testing method of claim 2, wherein axially moving the stopper (73) comprises advancing the stopper (73) toward the orifice (712) and retracting the stopper (73) toward the first axial end of the syringe body (71).

4. 4. The CCI test method of claim 3, wherein the distance between the maximum advanced position of the stopper (73) and the maximum retracted position of the stopper (73) is in the range of about 15 mm to about 25 mm, in the range of about 10 mm to about 20 mm, or in the range of about 5 mm to about 15 mm.

5. 5. The CCI test method of claim 2, wherein the rate at which the stopper (73) is axially moved inside the hollow interior is in the range of about 4 mm / min to about 15 mm / min, about 9.6 mm / min, in the range of about 15 mm / min to about 25 mm / min, or about 20 mm / min.

6. 6. The CCI test method of claim 1, wherein moving the stopper (73) comprises rotating the stopper (73) inside the hollow interior about the longitudinal axis of the syringe body (71).

7. 7. The CCI test method of claim 6, wherein rotating the stopper (73) inside the hollow interior of the syringe body (71) comprises rotating the stopper (73) relative to the syringe body (71) by about 180 degrees or more, about 360 degrees or more, about 720 degrees or more, or about 900 degrees or more.

8. 8. The CCI test method of claim 6 or 7, wherein the speed at which the stopper (73) is rotated inside the hollow interior of the syringe body (71) is about 700° / min or greater, about 5,000° / min or greater, about 20,000° / min or greater, or about 28,000° / min or greater.

9. 9. The CCI test method of claim 2, wherein moving the stopper (73) inside the hollow interior of the syringe body (71) comprises at least one cycle of rotating the stopper (73) and multiple cycles of axially moving the stopper (73).

10. 10. The CCI testing method of claim 1, wherein providing the syringe (7) to the gas environment includes positioning the syringe (7) vertically so that the orifice (712) faces upward or downward, and the syringe (7) is positioned in an upright position when moving the stopper (73) inside the hollow interior of the syringe body (71) to sense the detection gas.

11. 11. The CCI testing method of claim 1, wherein sensing the detectable gas exiting the chamber (74) comprises sensing the detectable gas exiting the orifice (712) of the syringe body (71) while moving the stopper (73) inside the hollow interior of the syringe body (71).

12. 11. The CCI testing method of claim 1, wherein sensing the detectable gas exiting the chamber (74) comprises sensing the detectable gas exiting the open first axial end of the syringe body (71) while moving the stopper (73) inside the hollow interior of the syringe body (71).

13. 13. The CCI test method according to any one of claims 1 to 12, wherein the syringe (7) is a glass syringe having a nominal volume of 0.5 milliliters, 1 milliliter, 2.25 milliliters, 5 milliliters, or 10 milliliters.

14. A CCI test method according to any one of the preceding claims, wherein the syringe (7) is provided in the gas environment at a pressure of about 1 bar.

15. The CCI test method of any one of claims 1 to 14, wherein the detection gas comprises helium.

16. 16. The CCI testing method of claim 1, wherein moving the stopper (73) inside the hollow interior of the syringe body (71) comprises holding the stopper (73) and moving the syringe body (71) relative to the stopper (71).

17. 17. The CCI testing method of any one of claims 1 to 16, including automatically monitoring and recording movement of the stopper (73) inside the hollow interior of the syringe body (71) and sensed detector gas.

18. 1. A container integrity (CCI) testing system (1) for testing the airtightness of a closure of a stopper (73) of a syringe (7), comprising: The syringe (7) comprises a syringe body (71) having a longitudinal axis and a hollow interior extending between an open first axial end and a second axial end having an orifice (712), and an elastic stopper (73) disposed in the hollow interior through the open first axial end such that a chamber is formed between the stopper (73) and the second axial end; The CCI test system comprises: a detection gas reservoir (2) configured to contain a detection gas; a detection gas sensor (5); a processing unit (3) having a gas chamber (31), a positioning structure (32), and a moving structure (33); a connector device (6); the gas chamber (31) of the processing unit (3) is connected to the detection gas reservoir (2) and configured to contain the detection gas provided by the detection gas reservoir (2); the positioning structure (32) of the processing unit (3) is configured to hold the syringe (7) such that one of the open first axial end of the syringe body (71) and the orifice (712) at the second axial end of the syringe body (71) is positioned within the gas chamber (31); the moving structure (33) of the processing unit (3) is configured to move the stopper (73) within the hollow interior of the syringe body (71) when the syringe (7) is held by the positioning structure (32) of the processing unit (3); the connector device (6) is configured to connect the other of the open first axial end of the syringe body (71) and the orifice (712) at the second axial end of the syringe body (71) to the detection gas sensor (5) when the syringe (7) is held by the positioning structure (32) of the processing unit (3); and The CCI test system (1), wherein the detection gas sensor (5) is configured to sense detection gas exiting the chamber (74) of the syringe (7) while the stopper (73) is moving within the hollow interior of the syringe body (71).

19. 19. The CCI test system (1) of claim 18, comprising a control unit (4) connected to the detection gas sensor (5) and the processing unit (3).

20. 20. The CCI test system (1) of claim 19, wherein the control unit (4) is configured to evaluate a detection gas signal provided by the detection gas sensor (5).

21. A CCI test system (1) as described in any one of claims 18 to 20, wherein the moving structure (33) of the processing unit (3) is configured to move the stopper (73) axially inside the hollow interior of the syringe body (71).

22. 22. The CCI test system (1) of claim 21, wherein the control unit (4) is configured to operate the moving structure (33) of the processing unit (3) so that the speed at which the stopper (73) is axially moved inside the hollow interior of the syringe body (71) is in the range of about 5 mm / min to about 15 mm / min, about 9.6 mm / min, about 15 mm / min to about 25 mm / min, or about 20 mm / min.

23. 23. A CCI test system (1) as described in claim 21 or 22, wherein the moving structure (33) is configured to move the stopper (73) axially by advancing the stopper (73) toward the orifice (712) and retracting the stopper (73) toward the first axial end of the syringe body (71).

24. 24. The CCI test system (1) of claim 23, wherein the control unit (4) is configured to operate the moving structure (33) of the processing unit (3) so that the distance between the maximum forward position of the stopper (73) and the maximum retracted position of the stopper (73) is in the range of about 15 mm to about 25 mm, in the range of about 10 mm to about 20 mm, or in the range of about 5 mm to about 15 mm.

25. A CCI test system (1) as described in any one of claims 18 to 24, wherein the moving structure (33) of the processing unit (3) is configured to rotate the stopper (73) inside the hollow interior around the axis of the syringe body (71).

26. 26. The CCI test system (1) of claim 25, wherein the control unit (4) is configured to operate the moving structure (33) of the processing unit (3) so that the stopper (73) rotates relative to the syringe body (71) by more than about 360°, more than about 720°, or more than about 900°.

27. 27. The CCI test system (1) of claim 25 or 26, wherein the control unit (4) is configured to operate the moving structure (33) of the processing unit (3) so that the speed at which the stopper (73) is rotated inside the hollow interior of the syringe body (71) is about 700° / min or more, about 5,000° / min or more, about 20,000° / min or more, or about 28,000° / min.

28. 28. The CCI test system (1) of any one of claims 25 to 27, wherein the control unit (4) is configured to operate the moving structure (33) of the processing unit (3) so that moving the stopper (73) includes at least one cycle of rotating the stopper (73) and a plurality of cycles of axially moving the stopper (73).

29. A CCI testing system (1) as described in any one of claims 18 to 28, wherein the positioning structure (32) of the processing unit (3) is configured to vertically position the syringe (7) so that the orifice (712) is directed upward.

30. 30. The CCI test system (1) of any one of claims 18 to 29, wherein the detection gas reservoir (2) and the gas chamber (31) of the processing unit (3) are configured to provide the detection gas at a pressure of about 1 bar in the gas chamber (31) of the processing unit (3).

31. A CCI test system (1) according to any one of claims 18 to 30, wherein the syringe (7) is a glass syringe having a nominal volume of 0.5 milliliters, 1 milliliter, 2.25 milliliters, 5 milliliters or 10 milliliters.

32. A CCI test system (1) according to any one of claims 18 to 31, wherein the detection gas comprises helium.

33. 33. The CCI test system (1) of any one of claims 18 to 32, wherein the control unit (4) is configured to automatically monitor and record movement of the stopper (73) inside the hollow interior of the syringe body (71) and sensed detection gas.

34. A CCI test system (1) as described in any one of claims 18 to 33, wherein the moving structure (33) of the processing unit (3) is configured to automatically move the stopper (73) within the hollow interior of the syringe body (71) when the syringe (7) is held by the positioning structure (32) of the processing unit (3).

35. A CCI test system (1) as described in any one of claims 18 to 34, wherein the positioning structure (32) of the processing unit (3) is configured to non-airtightly connect one of the open first axial end of the syringe body (71) and the orifice (712) of the second axial end of the syringe body (71) to the gas chamber (31).

36. A validation process for validating a CCI test method according to any one of claims 1 to 17 and / or a CCI test system according to any one of claims 18 to 35, comprising: obtaining a syringe surrogate having a surrogate body and a microcapillary tube, the syringe body having a longitudinal axis and a hollow interior extending between an open first axial end and a second axial end having an orifice, the microcapillary tube being disposed within the orifice of the syringe body; providing the syringe surrogate in a gaseous environment containing a detection gas; and sensing the detection gas exiting the chamber of the syringe.

37. 37. The validation process of claim 36, wherein the surrogate body of the syringe surrogate is made of metal.

38. 38. The validation process of claim 37, wherein the metal is stainless steel.

39. 39. The validation process of claim 37 or 38, wherein the microcapillary tube of the syringe substitute is made of glass.

40. 40. The validation process of any one of claims 37 to 39, wherein the microcapillary of the syringe surrogate is clamped to the orifice of the surrogate.

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