WO2025045990A1

WO2025045990A1 - Container integrity testing system and method

Info

Publication number: WO2025045990A1
Application number: PCT/EP2024/074154
Authority: WO
Inventors: Lars ABEL; Christian PROFF
Original assignee: F Hoffmann La Roche AG; Hoffmann La Roche Inc
Current assignee: F Hoffmann La Roche AG; Hoffmann La Roche Inc
Priority date: 2023-08-31
Filing date: 2024-08-29
Publication date: 2025-03-06
Anticipated expiration: 2026-02-28

Abstract

A CCI testing system (1) to test closure integrity of a container (2) with a hollow interior (223), an outlet (221), an open end (222) and a stopper (21) arranged to close the hollow interior (223), comprises a container holder (13), a test gas supply (171), a test gas detector (11) and a chamber (14). The container holder (13) is configured to tightly receive a first aperture being one of the open end (222) of the container (2) or the outlet (221) of the container (2). The test gas supply (171) comprises a test gas. The test gas detector (11) is tightly coupled to the container holder (13) and configured to detect test gas exiting the first aperture when being received by the container holder (13). The chamber (14) is coupled to the container holder (13) to form an encasing of a second aperture being the other one of the open end (222) of the container (2) or the outlet (221) of the container (2) when the first aperture is received by the container holder (13). The test gas supply (171) is coupled to the chamber (14). The test gas detector (11) is configured to apply a subatmospheric pressure to the container holder (13) and the container holder (13) is configured to effect the subatmospheric pressure to the first aperture. The test gas supply (171) is configured to supply test gas into the chamber (14). The chamber (14) has an exhaust outlet (141). The chamber (14) is configured to expose the second aperture to a gas flow generated by the test gas supply (171) supplying test gas into the chamber (14) and out of the chamber (14) via the exhaust outlet (141), when the first aperture is received by the container holder (13).

Description

DESCRI PTION

Title

CONTAINER INTEGRITY TESTING SYSTEM AND METHOD

Technical Field

[0001] The present invention relates to a container closure integrity (CCI) testing system and a method of CCI testing a container. Such CCI testing method and system can be used for testing tightness of a stopper closure of a container, wherein the container has a hollow interior, an outlet, an open end and a stopper arranged to close the hollow interior.

[0002] The container can particularly be a primary packaging and be filled or intended to be filled with a pharmaceutical, chemical or drug substance.

Background Art

[0003] In connection with provision of pharmaceutical and other sensitive substances, integrity of involved container and primary packagings, in which the substances are filled, is of high importance. Thereby, integrity of a container or primary packaging generally indicates the ability of keeping a content or substance inside the respective container or packaging and of keeping detrimental environmental contaminants outside the respective container or packaging.

[0004] For example, integrity of containers can be affected by a leak in the container or packaging. Leaks are typically perceived as holes or cracks of a certain diameter and length. Leakage may be a measure of gas flow (in mass or volume or units) that passes through a leak path under specific conditions. Leakage of 1 [mbar x I I sec] is given when the pressure in a closed container of 1 liter rises or falls within 1 sec by 1 mbar.

[0005] Specific container integrity issues have to be considered when containers having stoppers as closures are involved. For example, during assembly and shipping

SUBSTITUTE SHEET (RULE 26) of syringes, cartridges and vials, stoppers may undergo certain movements or deformations, or the stoppers may be or get impaired such that tightness may be affected.

[0006] In order to test integrity of container closures, an acknowledged procedure is to provide a culture medium in the container, to expose the containers to specific conditions and to verify if microbiological contaminants grow in the culture medium. However, such microbiological test procedures often are comparably prone to errors, time consuming and difficult to reproduce.

[0007] Another approach to test container closure integrity (CCI) is to provide a test gas into the interior of the container and to measure the test gas outside the container or vice versa. For example, an open end or back side of a syringe may be exposed to a test gas at a specific pressure and concentration. For verifying if a leakage via a stopper into the interior of the syringe is possible, test gas concentration is measured at an outlet of the syringe.

[0008] Even though such test gas involving CCI testing methods may be comparably quick and useful, they still have some downsides which decrease accuracy, reliability and reproducibility. For example, in case there is leakage, the pressure of the test gas decreases when test gas passes the stopper and exits the outlet. Thus, the pressure difference between test gas side and the outlet side varies and the test gas signal varies accordingly. Such varying pressure difference may affect accuracy of the measurements.

[0009] Therefore, there is a need for a container closure integrity (CCI) testing system and method allowing testing containers in a comparably reliable, quick and reproducible manner.

Disclosure of the Invention

[0010] According to the invention this need is settled by a CCI testing system as it is defined by the features of independent claim 1 , and by a method of CCI testing a container as it is defined by the features of independent claim 23. Preferred embodiments are subject of the dependent claims. [0011] In particular, in one aspect the invention is a container closure integrity (CCI) testing system to test or control physical container closure integrity of a container. The container has a hollow interior, an outlet, an open end and a stopper arranged to close the hollow interior.

[0012] The container can be any suitable receptacle for receiving a chemical or pharmaceutical substance such as a drug substance. In the pharmaceutical field, such containers often are used as primary packaging.

[0013] The term “drug” as used herein relates to a therapeutically active agent, also commonly called active pharmaceutical ingredient (API), as well as to a combination of plural such therapeutically active substances. The term also encompasses diagnostic or imaging agents, like for example contrast agents (e.g. MRI contrast agents), tracers (e.g. PET tracers) and hormones, that need to be administered in liquid form to the patient.

[0014] The term “drug substance” as used herein relates to a drug as defined above formulated or reconstituted in a form that is suitable for administration to the patient. For example, besides the drug, a drug substance may additionally comprise an excipient and/or other auxiliary ingredients. A particularly preferred drug substance in the context of the invention is a drug solution, in particular a solution for oral administration, injection or infusion.

[0015] The term “drug product” as used herein relates to a finished end product comprising a drug substance or a plurality of drug substances. In particular, a drug product may be a ready to use product having the drug substance in an appropriate dosage and/or in an appropriate form for administration. For example, a drug product may include an administration device such as a prefilled container or the like.

[0016] Typically, containers of the kind have a body such as a barrel which forms the hollow interior. The term “barrel” in connection with the container can relate to a hollow body designed to receive a chemical, pharmaceutical or drug substance. In many containers such as syringes, cartridges and vials, the barrel or body is essentially cylindrical and made of sterilizable material such as glass or an appropriate plastic material, e.g., polypropylene. [0017] Specifically, the container can be a prepared vial or cartridge. The term “vial” as used herein can relate to vials in the literal sense, i.e. a comparably small vessel or bottle, often used to store pharmaceutical products or pharmaceuticals or medications in liquid, powdered or capsuled form. The vial typically comprises a cover or cap including a sealing such as a rubber stopper or a septum which for some applications may be designed to be pierced.

[0018] The genuine or original opening of the cartridge or vial can be the outlet of the container. Particularly when the container is a vial, the open end can be generated in a preparation step by cutting-off or otherwise removing a bottom of the vial or by otherwise providing a hole in the bottom or any other suitable location. Instead of a stopper in the literal sense, for closing, the genuine opening of the vial, it can be provided with a stopper or a septum which is likewise covered by the term “stopper” in such case. In other configurations the stopper may be any closure closing the hollow interior. For example, in syringes such stoppers may also be tip caps or the like. Even though also suitable for other types of containers, the CCI testing system may be particularly advantageous for containers being syringes and, more specifically, pre-filled syringes (PFS).

[0019] The CCI testing system according to the invention comprises a container holder, a test gas supply, a test gas detector and a chamber. The container holder is configured to tightly receive a first aperture being one of the outlet of the container or the open end of the container. For receiving the first aperture, the container holder can be equipped with a seat in which a portion of the container comprising the second aperture can be arranged. The container holder can also comprise an adapter to mount the container. Such adapter may be particularly useful for achieving tightness. In particular, the adapter my include an O-ring or a similar gasket to be tightened towards the container.

[0020] The test gas supply comprises a test gas. For housing the test gas, the test gas supply may be equipped with a test gas tank or the like. Even though a variety of test gases may be used, preferably the test gas is Helium. It may have advantageous properties as to detectability, sterility, costs, handling and availability.

[0021] For housing the test gas, the test gas supply can comprise a test gas reservoir or tank and a structure to forward the test gas from the test gas reservoir into the chamber. Such structure may include a pressure member to pressurize the test gas inside the test gas reservoir relative to other portions of the system. It can additionally or alternatively have a pump or other gas forwarding member. By all such structure a pressure gradient from the gas reservoir to the chamber can be generated which may induce the gas flow.

[0022] The test gas detector is tightly coupled to the container holder and configured to detect test gas exiting the first aperture when being received by the container holder. It can have any means for efficiently and accurately detecting and advantageously also quantifying the test gas. Preferably, the test gas detector comprises a mass spectrometer which allows for a comparably fast and accurate detection and quantification of the test gas.

[0023] The chamber is coupled to the container holder to form an encasing of a second aperture being the other one of the open end of the container or the outlet of the container when the first aperture is received by the container holder. It has an exhaust outlet. The test gas supply is coupled to the chamber.

[0024] The term “couple” as used herein relates to a direct or indirect connection between two or more units. For example, the chamber can be coupled to the container holder by being directly mounted to the container holder or by indirectly being connected, e.g., via another element of the system such as the test gas detector.

[0025] In connection with the invention, the first aperture either is the open end or the outlet of the container and the second aperture is the other one of the open end and outlet of the container which is not the first aperture. For example, when the container is a syringe, the first aperture may be the outlet which is the end of the barrel of the syringe where a needle is mounted or where a needle is to be mounted. In this example, the second aperture is the open end of the barrel where the stopper is provided through for forming a dosage chamber inside the barrel.

[0026] The exhaust outlet can be embodied in any suitable manner. For example, a separate opening can be provided in the chamber through which the test gas exits the chamber in operation. Or, the exhaust outlet can be embodied by coupling the chamber to the container holder in a non-tight fashion such that test gas may exit. [0027] The test gas detector is configured to apply a subatmospheric pressure to the container holder and the container holder is configured to effect the subatmospheric pressure to the first aperture. The term “subatmospheric pressure” as used herein, which may also be referred to as negative pressure, can relate to any pressure below ambient or atmospheric pressure including vacuum or near vacuum.

[0028] The test gas supply is configured to supply test gas into the chamber, the chamber is configured to expose the container holder to a gas flow generated by the test gas supply supplying test gas into the chamber and out of the chamber via the exhaust outlet. More specifically, in order to provide test gas of the gas flow generated by the test gas supply into the hollow interior, the container holder may expose the second aperture to the gas flow in the chamber.

[0029] The invention allows to provide a robust testing and control of container closure integrity. In particular, the setup according to the invention achieves an accurate and reproducible detection and measurement of the test gas, thereby allowing to detect and evaluate leakage in primary packaging. For example, leakage occurring due to not properly seal or moving stoppers may efficiently be detected.

[0030] In particular, by providing the flow of test gas a pressure difference between the first and second apertures can be held at a more or less constant level. Such pressure difference may be calculated by deducting subatmospheric pressure at the first aperture from pressure at which the test gas is provided by the test gas supply. In case the subatmospheric pressure is a vacuum or a near vacuum, at least approximately, the pressure difference may equal the test gas pressure at the second aperture. In particular, the pressure in the chamber can be held at about atmospheric pressure such that the pressure difference constantly is about 1 bar.

[0031] By holding the pressure difference at the constant level it can be prevented that a leakage signal, which depends on the detected test gas, decreases or increase over time. Such leakage signal may be a partial pressure of the test gas at the first aperture. Thus, the effect of detection errors may be minimized as well as leakage behavior over time can be properly monitored.

[0032] Thus, the CCI testing system allows container closure integrity testing and control in a comparably reliable, quick and reproducible manner. Like this, quality of CCI testing can be improved. For example, additional information about potential leakage in containers can be gathered which may increase safety or accuracy in evaluating container leakage.

[0033] Preferably, the CCI testing system comprises a conditioning gas supply and a valve arrangement, wherein the conditioning gas supply comprises a conditioning gas, wherein the valve arrangement is coupled to the test gas supply and the conditioning gas supply, and wherein the valve arrangement is configured to selectively activate the test gas supply and/or the conditioning gas supply.

[0034] The term “conditioning gas” in this connection relates to any suitable gas different from or not comprising test gas. It can be ambient air, an air-like gas, Nitrogen or a similar pure and particularly inert gas appropriate for the specific application of the CCI testing system.

[0035] The term “activate” in connection with the gas supplies can relate to configuring the respective gas supply to provide gas. In particular, in connection with the valve arrangement activation of the gas supplies can relate to opening a pressurized gas reservoir. More specifically, the valve arrangement can be embodied to activate the test gas supply and/or the conditioning gas supply by opening or closing respective test gas or conditioning gas reservoirs and/or a supply pipe. For example, the gas supplies can have pressurized reservoirs containing the respective gases and the valve arrangement opens and closes the reservoirs to allow efficient provision of the gases as the need may be.

[0036] Thereby, the conditioning gas supply preferably houses the conditioning gas at a pressure higher than atmospheric pressure and preferably is configured to release the conditioning gas at about 6 bar. For this purpose, the conditioning gas supply advantageously comprises a conditioning gas reservoir such as a pressurized tank or containment. By having the conditioning gas at elevated pressure, an efficient flushing of the chamber and other components can be achieved.

[0037] Preferably, the test gas supply houses the test gas at a pressure higher than atmospheric pressure and is configured to release the test gas at about 1 .5 bar. Like this, an efficient and precise provision of the test gas can be achieved. [0038] Preferably, the CCI testing system comprises a flow regulation unit configured to determine an extent of flow into the chamber. By such unit, the gas flow into the chamber can be efficiently adjusted and, eventually, monitored. This may apply to the flow of test gas as well as to the flow of conditioning gas, if any. Advantageously, the flow regulation unit includes a flow meter or flow sensor to determine a dimension of the regulated flow. Like this, the flow can be verified and accurately adjusted, if required.

[0039] Preferably, the CCI testing system comprises a control unit coupled to the test gas supply and the test gas detector. In embodiments having a flow regulation unit, the control unit can be coupled to the flow regulation unit to achieve an indirect coupling to the test gas supply and/or the conditioning gas supply, if any. The control unit can be coupled to the test gas supply and the test gas detector as well as to other components by being in communication with these components. In particular, coupling of the control unit can be embodied by a data transmission connection, wherein the data transmission can be established in one or both ways. Thereby, the data transmission connection can be a wired or a wireless connection. The control unit allows to efficiently control and operate the CCI testing system or specific components thereof.

[0040] The control unit can be or comprise a computer. Thereby, as used herein, the term "computer" relates to any electronic data processing device. It includes individual devices such as laptop computers, desktop computers, server computers, tablets, smartphones, systems embedded in other devices (embedded systems), or the like. It also covers combined devices or computer networks such as distributed system emit components in different locations.

[0041] Typically, computers are composed of various building blocks or components such as processors (CPU), permanent data storage devices with a recording medium such as a hard disk, flash memory or something similar, random access memories (RAM), read-only memory (ROM), communication adapters such as USB adapters, LAN adapters, WLAN adapters, Bluetooth adapters or the like, user interfaces such as keyboards, mice, touch screens, monitors, microphones, speakers, and other components. Computers can be composed of the above components and/or other components in a broad variety of embodiments. The computer can be configured in accordance with embodiments of the invention by comprising and running a specific software. Such software may comprise a set of commands affecting the computer to perform certain actions when being executed. [0042] The control unit preferably is configured to apply a test cycle according to a test protocol. By implementing the test protocol in the control unit, an accurate and efficient test cycle can be achieved.

[0043] Thereby, the test protocol preferably comprises a step of flushing the test gas through the chamber for a gassing duration. The flushing of the test gas can be achieved by the control unit providing instructions or commands to the test gas supply and/or the valve arrangement and/or the flow regulation unit. Further, the control unit can receive information or data from the flow regulation unit in order to accurately control the flushing of the chamber with test gas. By flushing the test gas through the chamber, the flow of test gas inside the chamber can efficiently be achieved. Like this, the test gas can be provided at a constant pressure to the second aperture of the container.

[0044] Thereby, the gassing duration preferably is in a range of about 5 seconds to about 10 minutes and, advantageously, in a range of about 20 seconds to about 120 seconds. Such flushing durations allow the test gas detector to generate a reliable and robust signal. Like, this accuracy of test gas detection can be comparably high and, still, the testing duration can be suitably or appropriately short or fast.

[0045] The control unit preferably is coupled to the valve arrangement, wherein the control unit is configured to adapt the valve arrangement to activate the test gas supply for the gassing duration to flush the test gas through the chamber. Such adaptation of the valve arrangement by the control unit allows for an accurate test gas flushing by comparably simple means.

[0046] The control unit preferably is configured to evaluate test gas measurements of the test gas detector collected during flushing the test gas through the chamber. Such evaluation may result in an assessment of the leakage situation of the container. In particular, a dimension of leakage can be determined and the container can be rated as to its conformity with certain standards.

[0047] Preferably, the test protocol comprises a step of flushing conditioning gas through the chamber for a conditioning duration. Such conditioning gas flushing allows for removing other gas such as test gas from the chamber. Like this, disturbance of measurements or detection can be prevented or at least essentially lowered such that accurate operation and assessment can be achieved.

[0048] Thereby, the conditioning duration preferably is in a range of about 5 seconds to about 20 seconds and advantageously is about 10 seconds. Such conditioning durations allow for a sufficient and efficient conditioning of the system.

[0049] The control unit preferably is coupled to the valve arrangement, wherein the control unit is configured adapt the valve arrangement to activate the conditioning gas supply for the conditioning duration to flush the conditioning gas through the chamber. Such adaptation of the valve arrangement by the control unit allows for an accurate conditioning gas flushing by comparably simple means.

[0050] The control unit preferably is configured to adapt the valve arrangement to deactivate the conditioning gas supply when the test gas supply is activated and to adapt the valve arrangement to deactivate the test gas supply when the conditioning gas supply is activated. Like this, a proper sequence of flushing can be achieved and the conditioning gas flushing can be separated from the test gas flushing.

[0051] Preferably, the test protocol comprises a step of clearing a tight connection between the container holder and the test gas detector for a clearing duration. The tight connection can be embodied by a channel, tube, pipe, hose and/or similar structure. Like this, disturbance of detection or measurement by residuals in the tight connection, e.g., stemming from earlier test cycles, can be prevented or essentially lowered.

[0052] Thereby, the clearing duration preferably is in a range of about 10 seconds to about 30 seconds and particularly is about 20 seconds. Such clearing durations allow for a sufficient and efficient clearing of the system.

[0053] The clearing step comprises applying a subatmospheric pressure such as a vacuum to the tight connection. Such vacuum application allows for efficiently clearing or preparing the system.

[0054] Preferably, the container holder is configured to horizontally hold the container when receiving the first aperture. Such horizontal arrangement can be particularly useful when flushing the test gas. [0055] Advantageously, the control unit is coupled to the exhaust outlet and configured to selectively open and close the exhaust outlet.

[0056] In another aspect, the invention is a method of CCI testing a container to control physical container closure integrity of the container. The method comprises the steps of: (i) obtaining a container having a hollow interior, an outlet, an open end and a stopper provided to close the hollow interior; (ii) mounting the container to a container holder by tightly receiving a first aperture being one of the outlet of the container or the open end of the container, wherein the container holder is tightly coupled to a test gas detector which is configured to detect test gas, such as Helium, exiting the first aperture when being received by the container holder; (iii) arranging a chamber such that it tightly couples to the container holder to form an encasing of a second aperture being the other one of the open end of the container or the outlet of the container when the first aperture is received by the container holder; and (iv) applying a test cycle according to a test protocol.

[0057] Even though the method according to the invention is listed in a sequence of numbered steps, this sequence is not limiting the method to a specific order unless being explicitly specified or not feasible otherwise. In particular, a step assigned with a higher number may be performed earlier than other steps assigned with lower numbers.

[0058] The method according to the invention and its preferred embodiments described below may efficiently implement the effects and benefits of the CCI testing system and its preferred embodiments described above. In particular, the method according to the invention allows for an improved container closure testing and control in a comparably reliable, quick and reproducible manner.

[0059] Preferably, the test protocol comprises a step of flushing the test gas through the chamber for a gassing duration. Thereby, the gassing duration preferably is in a range of about 5 seconds to about 10 minutes and, preferably, in a range of about 20 seconds to about 120 seconds.

[0060] The method preferably comprises a step of evaluating at least one test gas measurement of the test gas detector collected during flushing the test gas through the chamber. [0061] Preferably, the test protocol comprises a step of flushing a conditioning gas through the chamber for a conditioning duration. Thereby, the conditioning duration preferably is in a range of about 5 seconds to about 20 seconds and particularly is about 10 seconds. The step of flushing the test gas through the chamber preferably is applied before the step of flushing the conditioning gas through the chamber.

[0062] Preferably, the test protocol comprises a step of clearing a tight connection between the test gas detector and the first aperture for a clearing duration. Thereby, the clearing duration preferably is in a range of about 10 seconds to about 30 seconds and particularly is about 20 seconds. The clearing step preferably comprises applying a subatmospheric pressure to the tight connection. The step of flushing the test gas through the chamber preferably is applied after the step of clearing the chamber.

[0063] Preferably, the method involves a CCI testing system as described above. Such system allows for a particularly efficient implementation of the method. Thereby, the control unit of the CCI testing system can be configured to apply the test cycle according to the test protocol.

Brief Description of the Drawings

[0064] The CCI testing system according to the invention and the method according to the invention are described in more detail hereinbelow by way of an exemplary embodiment and with reference to the attached Fig. 1 showing a schematic view of an embodiment of a CCI testing system according to the invention.

Description of Embodiments

[0065] In the following description certain terms are used for reasons of convenience and are not intended to limit the invention. The terms “right”, “left”, “up”, “down”, “under¹' and “above" refer to directions in the figures. The terminology comprises the explicitly mentioned terms as well as their derivations and terms with a similar meaning. Also, spatially relative terms, such as "beneath", "below", "lower", "above", "upper", "proximal", "distal", and the like, may be used to describe one element's or feature's relationship to another element or feature as illustrated in the figures. These spatially relative terms are intended to encompass different positions and orientations of the devices in use or operation in addition to the position and orientation shown in the figures. For example, if a device in the figures is turned over, elements described as "below" or "beneath" other elements or features would then be "above" or "over" the other elements or features. Thus, the exemplary term "below" can encompass both positions and orientations of above and below. The devices may be otherwise oriented (rotated 90 degrees or at other orientations), and the spatially relative descriptors used herein interpreted accordingly. Likewise, descriptions of movement along and around various axes include various special device positions and orientations.

[0066] To avoid repetition in the figures and the descriptions of the various aspects and illustrative embodiments, it should be understood that many features are common to many aspects and embodiments. Omission of an aspect from a description or figure does not imply that the aspect is missing from embodiments that incorporate that aspect. Instead, the aspect may have been omitted for clarity and to avoid prolix description. In this context, the following applies to the rest of this description: If, in order to clarify the drawings, a figure contains reference signs which are not explained in the directly associated part of the description, then it is referred to previous or following description sections. Further, for reason of lucidity, if in a drawing not all features of a part are provided with reference signs it is referred to other drawings showing the same part. Like numbers in two or more figures represent the same or similar elements.

[0067] Fig. 1 shows an embodiment of CCI testing system 1 according to the invention. The CCI testing system 1 is designed to test closure integrity of a syringe 2 as container. The syringe 2 has a barrel 22 with a hollow interior 223 an outlet 221 forming a first aperture of the syringe 2 and an open end 222 forming a second aperture of the syringe 2. Through the open end 222 a stopper 21 is provided into the hollow interior 223 closing the hollow interior 223 and forming a dosage chamber between the stopper 21 and the outlet 221 .

[0068] The CCI testing system 1 comprises a Helium detector 11 as test gas detector, a syringe holder 13 as container holder, a chamber 14, a flow regulator 15 equipped with a flow meter as flow regulation unit, a valve arrangement 16, two gas supplies 17 and a control unit 18.

[0069] The syringe holder 13 has a body with a seat 131 to tightly receive a front portion of the syringe 2 including the outlet 221 . By means of the seat 131 , the syringe 2 is safely held in a horizontal position. [0070] The body of the syringe holder 13 is equipped with a channel 132. The channel 132 connects the seat 131 and, more specifically, the outlet 221 of the syringe 2 when being received in the seat 131 to the Helium detector 11 . The Helium detector 11 has a spectrometer for detecting and quantifying Helium.

[0071] The chamber 14 is coupled to the syringe holder 13 and encases the complete syringe 2 extending out of the seat 131 of the syringe holder 13, when the outlet 221 is received by seat 131. It has an exhaust outlet 141 at a bottom to allow gas to exit the chamber 14. Further, it has an inlet 142 which is connected to the flow regulator 15 via a pipe. The flow regulator 15 is in fluid connection with the valve arrangement 16 via another pipe.

[0072] The gas supplies 17 comprise a Helium supply 171 having a pressure tank filled with Helium as test gas and a Nitrogen supply 172 having a pressure tank filled with Nitrogen as conditioning gas. The valve arrangement 16 has a first valve 161 associated to the Helium supply 171 and a second valve 162 associated to the Nitrogen supply 172. By means of the first and second valves 161 , 162 the valve arrangement 16 is configured to selectively open and close the Helium supply 171 and the Nitrogen supply 172. The gas supplies 17 are coupled to the inlet 142 of the chamber 14 via the valve arrangement 16 and the flow regulator 15.

[0073] The control unit 18 is coupled to the flow regulator 15, the valve arrangement 16, the gas supplies 17 and the Helium detector 11. In particular, the control unit 18 comprises a computer, which is in communication connection by means of wires with the Helium detector 11 , the flow regulator 15 and the valve arrangement 16. Like this, data transfer between the control unit 18 and the connected Helium detector 11 , flow regulator 15 and valve arrangement 16 is possible. For example, the Helium detector 11 can be controlled by the control unit 18 and data gathered by the Helium detector 11 can be transferred to and evaluated by the control unit 18.

[0074] The computer of the control unit 18 runs a dedicated software to implement a test protocol for applying a test cycle. More specifically, the test protocol includes a sequence of steps to be performed in the test cycle including the following.

[0075] In a clearing step the control unit 18 activates the Helium detector 11 to apply a vacuum to the container holder 13 for 20 seconds. The connection pipe between the Helium detector 11 and the container holder 13 as well as the channel 132 of the container holder 13 form a tight connection between the Helium detector 11 and the syringe seat 131 and, thus, the outlet 221 of the syringe 2. The container holder 13 is configured to effect the vacuum of the Helium detector 11 to the outlet 221 of the syringe 2.

[0076] After the clearing step, the control unit 18 applies a gassing step for a gassing duration of 30 seconds. Therefore, the control unit 18 adapts the valve arrangement 16 to open the first valve 161 , thereby activating the Helium supply 171 , and to close the second valve 162, thereby deactivating the Nitrogen supply 172. Since the Helium is held at an overpressure in the pressure tank of the Helium supply 171 , which is configured to release the Helium at about 1.5 bar, the control unit 18 can adjust a flow rate and pressure provided by adjusting the flow regulator 15. The flow rate further is monitored by the flow meter of the flow regulator 15 such that the control unit 18 accurately sets a predefined flow rate by opening the first valve 161 and controlling the flow regulator 15. The Helium passing the first valve 161 flows into the chamber 14 via the inlet 142 and exits the chamber 14 vis the exhaust outlet 141. Like this, the chamber 14 is flushed by Helium.

[0077] By flushing the chamber 14 with Helium, the open end 222 of the syringe 2 is exposed to a Helium flow. By adjusting the Helium flow rate inside the chamber 14, a pressure difference between the interior 223 of the syringe and the inside of the chamber 14 can precisely and constantly be set. During the gassing duration, the Helium detector 11 measures for Helium exiting the outlet 221 of the syringe 2. The Helium measurements collected by the Helium detector 11 are transferred to the control unit 18 which evaluates the Helium measurements to establish an assessment of the closure integrity of the syringe 2 being closed by the stopper 21 .

[0078] After the gassing step, the control unit 18 applies a conditioning step for a conditioning duration of 10 seconds. For this purpose, the control unit 18 adapts the valve arrangement 16 to close the first valve 161 , thereby deactivating the Helium supply 171 , and to open the second valve 162, thereby activating the Nitrogen supply 172. Since the Nitrogen is held at an overpressure in the pressure tank of the Nitrogen supply 172 which is configured to release the Nitrogen at about 6 bar, the Nitrogen supply 172 provides Nitrogen, wherein a flow of Nitrogen is adjusted by the control unit 18 based on data obtained from the flow regulator 15. The Nitrogen flushes the chamber 14 by entering its inlet 142 and exiting its exhaust outlet 141 .

[0079] This description and the accompanying drawings that illustrate aspects and embodiments of the present invention should not be taken as limiting the claims defining the protected invention. In other words, while the invention has been illustrated and described in detail in the drawings and foregoing description, such illustration and description are to be considered illustrative or exemplary and not restrictive. Various mechanical, compositional, structural, electrical, and operational changes may be made without departing from the spirit and scope of this description and the claims. In some instances, well-known circuits, structures and techniques have not been shown in detail in order not to obscure the invention. Thus, it will be understood that changes and modifications may be made by those of ordinary skill within the scope and spirit of the following claims. In particular, the present invention covers further embodiments with any combination of features from different embodiments described above and below.

[0080] The disclosure also covers all further features shown in the Fig. individually although they may not have been described in the afore or following description. Also, single alternatives of the embodiments described in the figures and the description and single alternatives of features thereof can be disclaimed from the subject matter of the invention or from disclosed subject matter. The disclosure comprises subject matter consisting of the features defined in the claims or the exemplary embodiments as well as subject matter comprising said features. Also, the present disclosure covers intermediate generalisations of features or groups of features of the embodiments described and shown in the figures. I.e., specific features or groups of features as disclosed in the figures and the associated sections of the description may be combined with the more general embodiments of the invention as disclosed in connection with the description of the invention. In particular, such specific features or groups of features may be provided in the more general embodiments of the invention in isolation from further specific features shown in the figures. For example, the pipes shown in the Fig. and described in the associated sections may be implemented in the more generic CCI testing system of the invention or its preferred embodiments without requiring other features to be implemented as well. It is understood that those skilled in the art are able to incorporate specific features from the description of the figures into the embodiments of the description of the invention. [0081] Furthermore, in the claims the word "comprising" does not exclude other elements or steps, and the indefinite article "a" or "an" does not exclude a plurality. A single unit or step may fulfil the functions of several features recited in the claims. The mere fact that certain measures are recited in mutually different dependent claims does not indicate that a combination of these measures cannot be used to advantage. The terms “essentially”, “about”, “approximately” and the like in connection with an attribute or a value particularly also define exactly the attribute or exactly the value, respectively. The term “about” in the context of a given numerate value or range refers to a value or range that is, e.g., within 20%, within 10%, within 5%, or within 2% of the given value or range. Components described as coupled or connected may be electrically or mechanically directly coupled, or they may be indirectly coupled via one or more intermediate components. Any reference signs in the claims should not be construed as limiting the scope.

Claims

1 . A CCI testing system (1 ) to test closure integrity of a container (2) with a hollow interior (223), an outlet (221 ), an open end (222) and a stopper (21 ) arranged to close the hollow interior (223), comprising a container holder (13) configured to tightly receive a first aperture being one of the open end (222) of the container (2) or the outlet (221 ) of the container (2); a test gas supply (171 ) comprising a test gas; a test gas detector (11 ) tightly coupled to the container holder (13) and configured to detect test gas exiting the first aperture when being received by the container holder (13); and a chamber (14) coupled to the container holder (13) to form an encasing of a second aperture being the other one of the outlet (221 ) of the container (2) or the open end (222) of the container (2) when the first aperture is received by the container holder (13), wherein the test gas supply (171 ) is coupled to the chamber (14), wherein the test gas detector (11 ) is configured to apply a subatmospheric pressure to the container holder (13) and the container holder (13) is configured to effect the subatmospheric pressure to the first aperture, wherein the test gas supply (171 ) is configured to supply test gas into the chamber (14), wherein the chamber (14) has an exhaust outlet (141 ), and wherein the chamber (14) is configured to expose the second aperture to a gas flow generated by the test gas supply (171 ) supplying test gas into the chamber (14) and out of the chamber (14) via the exhaust outlet (141 ), when the first aperture is received by the container holder (13).

2. The CCI testing system (1 ) of claim 1 , comprising a conditioning gas supply (172) and a valve arrangement (16), wherein the conditioning gas supply (172) comprises a conditioning gas, wherein the valve arrangement (16) is coupled to the test gas supply (171 ) and the conditioning gas supply (172), and wherein the valve arrangement (16) is configured to selectively activate the test gas supply (171 ) and/or the conditioning gas supply (172).

3. The CCI testing system (1 ) of any one of the preceding claims, wherein the test gas supply (171 ) houses the test gas at a pressure higher than atmospheric pressure.

4. The CCI testing system (1 ) of claim 3, wherein the test gas supply (171 ) is configured to release the test gas at about 1 .5 bar.

5. The CCI testing system (1 ) of any one of the preceding claims, comprising a flow regulation unit (15) configured to determine an extent of flow into the chamber (14).

6. The CCI testing system (1 ) of any one of the preceding claims, wherein the test gas is Helium and/or the test gas detector (11 ) comprises a mass spectrometer.

7. The CCI testing system (1 ) of any one of the preceding claims, comprising a control unit (18) coupled to the test gas supply (171 ) and the test gas detector (11 ),

8. The CCI testing system (1 ) of claim 7, wherein the control unit (18) is configured to apply a test cycle according to a test protocol.

9. The CCI testing system (1 ) of claim 8, wherein the test protocol comprises a step of flushing the test gas through the chamber (14) for a gassing duration.

10. The CCI testing system (1 ) of claim 9, wherein the gassing duration is in a range of about 5 seconds to about 10 minutes or in a range of about 20 seconds to about 120 seconds.

11. The CCI testing system (1 ) of claim 2 and claim 9 or 10, wherein the control unit (18) is coupled to the valve arrangement and wherein the control unit (18) is configured to adapt the valve arrangement (16) to activate the test gas supply (171 ) for the gassing duration to flush the test gas through the chamber (14).

12. The CCI testing system (1 ) of claim 10 or 11 , wherein the control unit (18) is configured to evaluate test gas measurements of the test gas detector (11 ) collected during flushing the test gas through the chamber (1 ).

13. The CCI testing system (1 ) of any one of claims 8 to 12, wherein the test protocol comprises a step of flushing conditioning gas through the chamber (14) for a conditioning duration.

14. The CCI testing system (1 ) of claim 13, wherein the conditioning duration is in a range of about 5 seconds to about 20 seconds and particularly is about 10 seconds.

15. The CCI testing system (1 ) of claim 2 and claim 13 or 14, wherein the control unit (18) is coupled to the valve arrangement (16) and wherein the control unit (18) is configured adapt the valve arrangement (16) to activate the conditioning gas supply (172) for the conditioning duration to flush the conditioning gas through the chamber (14).

16. The CCI testing system (1 ) of claim 11 and 15, wherein the control unit (18) is configured to adapt the valve arrangement (16) to deactivate the conditioning gas supply (172) when the test gas supply (171 ) is activated and to adapt the valve arrangement (16) to deactivate the test gas supply (171 ) when the conditioning gas supply (172) is activated.

17. The CCI testing system (1 ) of any one of claims 9 to 16, wherein the test protocol comprises a step of clearing a tight connection (132) between the container holder (13) and the test gas detector (11 ) for a clearing duration.

18. The CCI testing system (1 ) of claim 17, wherein the clearing duration is in a range of about 10 seconds to about 30 seconds and particularly is about 20 seconds.

19. The CCI testing system (1 ) of claim 17 or 18, wherein the clearing step comprises applying a subatmospheric pressure to the tight connection.

20. The CCI testing system (1 ) of any one of the preceding claims, wherein the container holder (13) is configured to horizontally hold the container (2) when receiving the first aperture.

21. The CCI testing system (1 ) of any one of claims 2 to 20, wherein the conditioning gas supply (172) houses the conditioning gas at a pressure higher than atmospheric pressure.

22. The CCI testing system (1 ) of any one of claims 2 to 21 , wherein the conditioning gas supply (172) is configured to release the conditioning gas at about 6 bar.

23. A method of CCI testing a container (2) to control physical container closure integrity of the container (2), comprising obtaining a container (2) having a hollow interior (223), an outlet (221 ), an open end (222) and a stopper (21 ) provided to close the hollow interior (223); mounting the container (2) to a container holder (13) by tightly receiving a first aperture being one of the outlet (221 ) of the container (2) or the open end (222) of the container (2), wherein the container holder (13) is tightly coupled to a test gas detector (11 ) which is configured to detect test gas exiting the first aperture when being received by the container holder (13); arranging a chamber (14) such that it tightly couples to the container holder (13) to form an encasing of a second aperture being the other one of the open end (222) of the container (2) or the outlet (221 ) of the container (2) when the first aperture is received by the container holder (13); and applying a test cycle according to a test protocol.

24. The method of claim 23, wherein the test protocol comprises a step of flushing the test gas through the chamber (14) for a gassing duration.

25. The method of claim 24, wherein the gassing duration is in a range of about 5 seconds to about 10 minutes and, preferably, in a range of about 20 seconds to about 120 seconds.

26. The method of claim 24 or 25, comprising a step of evaluating at least one test gas measurement of the test gas detector (11 ) collected during flushing the test gas through the chamber (14).

27. The method of any one of claims 23 to 26, wherein the test protocol comprises a step of flushing a conditioning gas through the chamber (14) for a conditioning duration.

28. The method of claim 27, wherein the conditioning duration is in a range of about 5 seconds to about 20 seconds and particularly is about 10 seconds.

29. The method of any one of claims 23 to 26 and claim 27 or 28, wherein the step of flushing the test gas through the chamber (14) is applied before the step of flushing the conditioning gas through the chamber (14).

30. The method of any one of claims 23 to 29, wherein the test protocol comprises a step of clearing a tight connection between the test gas detector (11 ) and the first aperture for a clearing duration.

31. The method of claim 30, wherein the clearing duration is in a range of about 10 seconds to about 30 seconds and particularly is about 20 seconds.

32. The method of claim 30 or 31 , wherein the clearing step comprises applying a subatmospheric pressure to the tight connection.

33. The method of any one of claims 30 to 32, wherein the step of flushing the test gas through the chamber (14) is applied after the step of clearing the chamber (14).

34. The method of any one of claims 23 to 33, wherein the test gas is Helium.