Container intergity testing method and system

Abstract

A CCI testing method to test physical container closure integrity of a container (2), comprises the steps of: (120) obtaining a container having a hollow interior, an outlet, an open end and a stopper arranged to close the hollow interior; (121) tightly connecting a first aperture being one of the outlet of the container and the open end of the container to a test gas detector; (122) connecting a second aperture being the other one of the outlet of the container and the open end of the container to a test gas supply; (123) arranging the test gas detector to apply a detector pressure at the first aperture; (124) arranging the test gas supply to provide test gas at a first test gas pressure to the second aperture; (125) measuring test gas at the first aperture by means of the test gas detector while the test gas is provided at the first test gas pressure; (126) determining a first leakage rate based on the test gas measured at the first test gas pressure; and (127, 128, 129) determining a second leakage rate at a second pressure. A first pressure difference being a difference between the first test gas pressure and the detector pressure differs from a second pressure difference being a difference between the second pressure and the detector pressure.

Description

DESC RI PTIONTitleCONTAINER INTERGITY TESTING METHOD AND SYSTEMTechnical Field

[0001] The present invention relates to a container closure integrity (CCI) testing method and a CCI testing system. 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 in the hollow interior to close the hollow interior.

[0002] The container can particularly be a primary packaging and 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 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 movable closures such as stoppers are involved. For example, syringes prefilledwith a pharmaceutical substance typically have a plunger rod provided with a stopper which has to be movable upon administration in order to expel the pharmaceutical substance through a needle, orifice or other outlet.

[0006] However, during assembly and shipping of filled syringes, stoppers may still undergo certain movements. For example, during assembly such as, particularly, assembly of a plunger rod the stopper may undergo axial and / or rotational movement which may induce deformation of the stopper potentially affecting tightness at the stopper interface. Or, during shipping the syringe can be exposed to varying pressure which may induce certain linear movement of the stopper or bubbles expend and retract.

[0007] In order to test integrity of syringe closures, an acknowledged procedure is to provide a sterile culture medium in the syringes, to expose the syringes to specific conditions and to verify if microbiological contaminants grow in the initial sterile culture medium. However, such microbiological test procedures often are comparably prone to errors, time consuming and difficult to reproduce.

[0008] 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.

[0009] 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 syringes the stoppers usually have to be movable in order to allow a user to expel a substance out of the syringe by moving the stopper. More specifically, for allowing the user to precisely dose a substance, break loose forces of stoppers in syringes are typically configured to be appropriate, i.e., not too high for a convenient application and not too low for impairing tightness. Often stoppers are provided with silicone oil in order to adapt the break loose force and / or the gliding or injection force. For CCI testing, low break loose forces may be problematic since there for testing a potential gas flow a pressure difference between the two ends of the stoppers has to be established. Such pressure difference may already inducemovement of the stoppers which can impair the testing of the static closure integrity in the assembled state.

[0010] Or, in some cases it is not sufficient to test if a gas flow occurs and to determine a dimension of such gas flow to allow an assessment of the container integrity. Rather, for giving an opinion as to potential danger of contamination, it is important to know if a size of a leak is sufficient to allow contaminants and, particularly, biological contaminates to pass the closure or leak. For example, a comparably high measured gas flow not mandatorily means that there is a sufficiently big leak since the gas flow may also be the result of a plurality of smaller leaks being identified in one integral signal or measurement.

[0011] Therefore, there is a need for a container closure integrity (CCI) testing system and method allowing testing and assessing container closures in a comparably reliable, meaningful and reproducible manner.Disclosure of the Invention

[0012] According to the invention this need is settled by a container closure integrity (CCI) testing method as it is defined by the features of independent claim 1 and by a CCI testing method as it is defined by the features of independent claim 19. Preferred embodiments are subject of the dependent claims.

[0013] In one aspect, the invention is a CCI testing method to test physical container closure integrity of a container, comprising the steps of (i) obtaining a container having a hollow interior, an outlet, an open end and a stopper arranged to close the hollow interior; (ii) tightly connecting a first aperture being one of the outlet of the container and the open end of the container to a test gas detector; (iii) connecting a second aperture being the other one of the outlet of the container and the open end of the container to a test gas supply; (iv) arranging the test gas detector to apply a detector pressure at the first aperture; (v) arranging the test gas supply to provide test gas at a first test gas pressure to the second aperture; (vi) measuring test gas at the first aperture by means of the test gas detector while the test gas is provided at the first test gas pressure; (vii) determining a first leakage rate based on the test gas measured at the first test gas pressure; and (viii) determining a second leakage rate at a second pressure. Thereby, a first pressure difference being a difference between the first test gas pressure and thedetector pressure differs from a second pressure difference being a difference between the second pressure and the detector pressure.

[0014] 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.

[0015] 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.

[0016] 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.

[0017] 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.

[0018] 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.

[0019] 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 essentiallycylindrical and made of sterilizable material such as glass or an appropriate plastic material, e.g., polypropylene.

[0020] 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.

[0021] 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.

[0022] 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). For syringes and cartridges, the CCI testing system allows to apply a non-destructive procedure.

[0023] The test gas detector advantageously is configured to detect test gas exiting the first aperture. 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.

[0024] 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.

[0025] The test gas supply typically comprises test gas. For housing the test gas, the test gas supply may be equipped with a test gas tank or a similar test gas reservoir. 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.

[0026] 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.

[0027] 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.

[0028] The term “leakage rate” as used herein relates to a measure of the amount, volume or mass passing the stopper and directly measured or indirectly determined at the first aperture. In particular, such measure can be indicative for a leakage via the stopper of the container and, thus, indicative for integrity of the container closure.

[0029] Determining the first leakage rate based on the test gas measured at the first pressure may involve a direct measurement of the first leakage rate or an evaluation of any measurement or signal to achieve the first leakage rate.

[0030] By involving two different pressure differences or, in other words, two different pressure gradients between the two sides of the container closure or stopper, additional information about the stopper or leakage behaviour can be obtained. For example, by assessing gas flow rates at least two different pressure differences it can be evaluated if the behaviour of a leak, e.g. in a stopper-barrel interface, is more of a capillary type or more of an orifice type and the associated dimensions. Like this, the involvement of multiple pressure difference measurements allows to determine a quality of the leakage or defect. Additionally, if a behaviour at two different pressure differences is similar but at ha a variable extent or dimension, it can be concluded that multiple leaks of the sametype are present. Thus, the involvement of multiple pressure difference measurements additionally allows to determine a quantity of the leak. Furthermore, it allows a CCI assessment of the static or unaltered non-moving system. For example, a dynamic behaviour of the stopper at the differing gradients can be assessed in the non-moving system which allows to identify a type of leakage. Such identification of the leakage allows to rate a potential of contamination via the stopper. Thus, a sophisticated and improved assessment of the container closure integrity is possible as well as testing and assessing container closures in a comparably reliable, meaningful and reproducible manner is achieved. Furthermore, the method allows for reusing the containers tested for further testing which may help a more detailed assessment.

[0031] In a first preferred embodiment, determining the second leakage rate in accordance with step (viii) of the method according to the invention comprises the steps of (viii.i) arranging the test gas supply to provide test gas at the second pressure to the second aperture; (viii.ii) measuring test gas at the first aperture by means of the test gas detector while test gas is provided at the second pressure; and (viii.iii) determining the second leakage rate based on the test gas measured at the second pressure.

[0032] In this first embodiment, the second gas pressure can be referred to as second test gas pressure. In order to prevent, back and forth pressure gradient application, the measuring of test gas at the smaller first test gas pressure advantageously is performed prior the measuring of test gas at the larger second pressure. Likewise, determination of the first leakage rate may be performed prior determination of the second leakage rate. Further, determining the second leakage rate based on the test gas measured at the second pressure may involve a direct measurement of the second leakage rate or an evaluation of any measurement to achieve the second leakage rate.

[0033] Thereby, the method preferably comprises a step of determining a defect by evaluating the first pressure difference, the second pressure difference, the first leakage rate and the second leakage rate.

[0034] The term “defect” can be defined or specified by a type of defect, by a dimension of leakage or defect, by a number of defects or the like, and any combination thereof. The defect can particularly be or result in a leak.

[0035] Determination of the defect allows for assessing if a leak is critical as to an intended application of the container. For example, when the container is a syringe determining the defect allows to assess is a leak is potentially prone to contamination and, more specifically, to biological contamination such as by microbes or the like.

[0036] In a second preferred embodiment, determining the second leakage rate in accordance with step (viii) of the method according to the invention comprises extrapolating the first leakage rate to the second leakage rate. Such extrapolation may achieve a faster and less laborious procedure.

[0037] Thereby, the second pressure difference preferably is about 1 bar. Such pressure difference allows for a particularly efficient and accurate extrapolation of the second leakage rate. Moreover, it can be avoided that an initial state of the components is compromised due to the force applied by the pressure. The limit at 1 bar or 1000 mbar pressure difference may be the only stated reference requirement of the regulatories such as in the USP<1207> applicable to container closure integrity testing.

[0038] Even though measuring the second leakage rate and extrapolating the second leakage rate may be alternatives to each other, the two ways of determining the second leakage rate may also be combined. Like this, a particularly accurate determination may be possible.

[0039] Determining the defect when measuring the second leakage rate or extrapolating the first leakage rate to the second leakage rate preferably comprises a step of generating reference data by processing at least two reference containers each having a known defect. The at least two reference containers may be any plurality of reference containers. In particular, such plurality of reference containers may be of the same type as the container to be tested and may have different known defects. By means of such reference data of known defects, the measured or extrapolated results of the method can be efficiently associated to a type of defect. Like this, an efficient assessment of the tested container can be achieved.

[0040] The reference data preferably is generated as a reference curve. Such reference curve allows for associating a defect to the results in a continuous range. It may be generated by a plurality of measured reference data points. The reference curvemay allow a more efficient determination than involving single reference data points or instances.

[0041] Processing the at least two reference containers preferably comprises, for each of the at least two reference containers, tightly connecting a first reference aperture being a first one of an outlet of the reference container and an open end of the reference container to the test gas detector; connecting a second reference aperture being a second one of the outlet of the reference container and the open end of the reference container to the test gas supply; arranging the test gas detector to apply the detector pressure at the first reference aperture; arranging the test gas supply to provide test gas at the first test gas pressure to the second reference aperture; measuring test gas at the first reference aperture by means of the test gas detector while test gas is provided at the first test gas pressure; determining a first reference leakage rate based on the test gas measured at the first test gas pressure; arranging the test gas supply to provide test gas at the second pressure to the second reference aperture; measuring test gas at the first reference aperture by means of the test gas detector while test gas is provided at the second pressure; and determining a second reference leakage rate based on the test gas measured at the second pressure.

[0042] In particular, advantageously, a similar test procedure at comparable conditions is applied to all reference containers having the known defects. Like this, an efficient and reliable assessment of the tested container is possible.

[0043] The first leakage rate preferably is between the first reference leakage rate of one of the at least two reference containers and the first reference leakage rate of another one of the at least two reference containers. Such relation between the first leakage rate and the fist reference leakage rates allows for an efficient assessment of the container closure integrity of the tested container.

[0044] Determining the defect or extrapolating the first leakage rate to the second leakage rate preferably comprises any of the following steps in order to achieve an efficient and accurate assessment of the container closure integrity of the tested container: Comparing the first pressure difference, the second pressure difference, the first leakage rate and / or the second leakage rate to the generated reference data; classifying leaks in the reference data; and / or obtaining a maximum allowable leakage limit. Particularly, a combination of all these three steps may allow for an efficient andaccurate assessment such as elimination of inappropriate tested containers. Obtaining the maximum allowable leakage limit may involve gathering such limit in any source or from regulatories such as in the USP<1207>, defining or setting a value, or calculating a value.

[0045] Preferably, the CCI testing method comprises a step of calculating a reference leakage ratio between the first reference leakage rate and the second reference leakage rate. The reference leakage ratio can particularly be a quotient between the first and second reference leakage rates particularly at the first and second applied pressure differences. Such reference leakage ratios allow for efficiently evaluating the reference data.

[0046] Thereby, extrapolating the first leakage rate to the second leakage rate preferably comprises multiplication of the first pressure difference by the reference leakage ratio. Such multiplication allows for accurately extrapolate the second leakage rate.

[0047] For extrapolating the first leakage rate to the second leakage rate, a defect may be assumed or predefined.

[0048] Preferably, the CCI testing method comprises a step of calculating a leakage ratio between the first leakage rate and the second leakage rate. The leakage ratio can particularly be a quotient between the first and second leakage rates. Such leakage ratio allows for efficiently evaluating the test results.

[0049] Preferably, the CCI testing method comprises a step of calculating a pressure ratio between the first pressure difference and the second pressure difference. Such pressure ratio allows for efficiently evaluating the test results.

[0050] Preferably, the detector pressure is a subatmospheric pressure. 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.

[0051] Preferably, the first pressure difference is smaller than the second pressure difference. Such relationship of the first and second pressure differences allows for reducing or preventing carryover from higher signals produced by the larger pressuredifference to the smaller pressure differenced. Like this, accuracy of the method and comparability of the results can be improved.

[0052] Preferably, the CCI testing method comprises the steps of: arranging the test gas supply to provide test gas at least one further test gas pressure to the second aperture; measuring test gas at the first aperture by means of the test gas detector while test gas is provided at each of the at least one further test gas pressure; and determining at least one further leakage rate based on the test gas measured at each of the at least one further test gas pressure. Based on additional measurements, an improved assessment of the container closure integrity may be possible.

[0053] Preferably, arranging the test gas supply to provide test gas at a first test gas pressure to the second aperture comprises regulating the test gas pressure to continuously increase from about the detection pressure to the test gas pressure.

[0054] The term “continuously increasing” in this connection relates to an increase of the test gas pressure over time. Such continuous increase may be achieved by a steadily growing increase or by a stepwise increase. In any case, the continuous increase is different from a sudden or one-step increase of the test gas pressure. The regulation of the test gas pressure can particularly be embodied by configuring a pressure regulator to increase the test gas pressure inside a chamber. By continuously increasing the test gas pressure it can be prevented that the container setup is affected resulting in less accurate test results. In particular, it allows to avoid pressure peaks exceeding a target pressure and thereby applying more force than intended or appropriate. Actual measurements may be taken at pressure plateaus in order to evaluate as well that the stable pressure leads to a stable leakage rate which may be the case for samples showing negligible permeation.

[0055] In another aspect, the invention is a CCI testing system to test physical container closure integrity of a container having a hollow interior, an outlet, an open end and a stopper provided to close the hollow interior. The system comprises a container holder, a test gas supply, a test gas detector and a chamber.

[0056] 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 thecontainer 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.

[0057] The test gas supply comprising a test gas, preferably Helium. 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 due to low background levels in atmosphere, costs, handling and availability.

[0058] 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.

[0059] The test gas detector is tightly coupled to the container holder to form a tight connection to the first aperture when the first aperture is received by the container holder. It can have any means for efficiently and accurately detecting and advantageously also quantifying the test gas. The test gas detector may include any suitable structure for measuring the test gas. For example, in headspace measurements a non-destructive tunable diode laser absorption spectroscope may be beneficial to determine the tracer gas level inside the headspace of the container. Preferably, the test gas detector comprises a mass spectrometer which allows for a comparably fast and accurate detection and quantification of the test gas.

[0060] The chamber is tightly coupled to the container holder to form an encasing of a second aperture being the outlet of the container or the open end of the container not received by the container holder when the first aperture is received by the container holder.

[0061] 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 containerholder 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.

[0062] The test gas supply is coupled to the chamber and configured to supply test gas into the chamber. It further has a pressure regulator to variably adapt a test gas pressure in the chamber in a range between a minimum pressure and a maximum pressure.

[0063] The test gas detector is configured to apply a detector pressure to the container holder and the container holder is configured to effect the detector pressure to the first aperture. The detector pressure may be effected to the first aperture by applying the pressure intrinsically induced by the test gas detector. Thereby, the detector pressure preferably is a subatmospheric pressure. 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.

[0064] The minimum pressure my particularly be a subatmospheric pressure and, more specifically, a vacuum. The maximum pressure advantageously is a pressure higher any desired test gas pressure. Preferably, the minimum pressure is about 250 mbar and the maximum pressure is about 10 bar.

[0065] The chamber is configured to expose the second aperture to the test gas pressure when the first aperture is received by the container holder and the test gas supply supplies test gas into the chamber.

[0066] By means of the pressure regulator the test gas pressure can flexibly be adjusted. In particular, it allows for efficiently provide pressure differences as desired in the method according to the invention described above. Thus, the OCI testing system according to the invention and its preferred embodiments described below may efficiently implement the effects and benefits of the CCI testing method and its preferred embodiments described above. In particular, the CCI testing system according to the invention allows for an improved container closure testing and control in a comparably reliable, quick and reproducible manner.

[0067] Preferably, the CCI testing system has a conditioning gas supply comprising conditioning gas and a valve arrangement coupled to the test gas supply and the conditioning gas supply, wherein the test gas supply is coupled to the valvearrangement, and wherein the valve arrangement is configured to selectively activate the test gas supply and / or the conditioning gas supply.

[0068] 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.

[0069] 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.

[0070] 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.

[0071] Preferably, the test gas supply houses the test gas at a pressure higher than atmospheric pressure and preferably is configured to release the conditioning gas at about 1.5 bar. Like this, an efficient and precise provision of the test gas can be achieved.

[0072] Preferably, the CCI testing system comprises a control unit coupled to the pressure regulator of the test gas supply and the test gas detector as well as 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 oneor 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.

[0073] 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.

[0074] 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.

[0075] Preferably, the control unit is configured: to arrange the test gas supply to provide test gas into the chamber at a first test gas pressure; to measure test gas at the first aperture by means of the test gas detector while the test gas supply provides test gas at the first test gas pressure; to determine a first leakage rate based on the test gas measured by the test gas detector at the first test gas pressure; and to determine a second leakage rate at a second pressure, wherein a first pressure difference being a difference between the first test gas pressure and the detector pressure differs from a second pressure difference being a difference between the second pressure and the detector pressure.

[0076] The control unit preferably is configured to arrange the test gas supply to provide test gas into the chamber at a second pressure; to measure test gas at the first aperture by means of the test gas detector while the test gas supply provides test gas atthe second pressure; and to determine the second leakage rate based on the test gas measured by the test gas detector at the second pressure.

[0077] Thereby, the control unit preferably is configured to evaluate the first pressure difference, the second pressure difference, the first leakage rate and the second leakage rate to determine a defect.

[0078] The control unit preferably is configured to determine the second leakage rate by extrapolating the first leakage rate to the second leakage rate.

[0079] Thereby, the first leakage rate preferably is between the first reference leakage rate of one of the at least two reference containers and the first leakage rate of another one of the at least two reference containers. The second pressure difference preferably is about 1 bar.

[0080] The control unit preferably is configured to determine the defect or to extrapolate the first leakage rate to the second leakage rate by processing at least two reference containers each having a known defect to generate reference data.

[0081] Thereby, the control unit preferably is configured to process each of the at least two reference containers by measuring test gas at a first reference aperture being a first one of an outlet of the reference container and an open end of the reference container by means of the test gas detector while the first reference aperture is received by the container holder, while the test gas detector applies the detector pressure to the container holder and the container holder effects the detector pressure to the first reference aperture, and while the test gas supply provides test gas at the first test gas pressure into the chamber such that a second reference aperture being a second one of the outlet of the reference container and the open end of the reference container is exposed to the first gas pressure; determining a first reference leakage rate based on the test gas measured by the test gas detector at the first test gas pressure; measuring test gas at the first reference aperture by means of the test gas detector while the first reference aperture is received by the container holder, while the test gas detector applies the detector pressure to the container holder and the container holder effects the detector pressure to the first reference aperture, and while the test gas supply provides test gas at the second pressure into the chamber such that the second reference aperture is exposed to the second gas pressure; and determining a secondreference leakage rate based on the test gas measured by the test gas detector at the second pressure.

[0082] The control unit preferably is configured to generate the reference data as a reference curve.

[0083] The control unit preferably is configured to determine the defect or to extrapolate the first leakage rate to the second leakage rate by any of the following: by comparing the first pressure difference, the second pressure difference, the first leakage rate and / or the second leakage rate to the generated reference data; by classifying leaks in the reference data; and / or by defining a maximum allowable leakage limit.

[0084] The control unit preferably is configured to calculate a reference leakage ratio between the first reference leakage rate and the second reference leakage rate.

[0085] Thereby, extrapolating the first leakage rate to the second leakage rate preferably comprises multiplication of the first pressure difference by the reference leakage ratio.

[0086] Preferably, the CCI testing system comprises a data storage, wherein the control unit is configured to associate leakage rates to pressure differences, and to store pressure differences and associated leakage rates in the data storage.

[0087] Preferably, the control unit is configured to calculate a pressure ratio between the first pressure difference and the second pressure difference.

[0088] The control unit preferably is configured to calculate a leakage ratio between the first leakage rate and the second leakage rate.

[0089] Preferably, the control unit is configured to adapt the pressure regulator to regulate the test gas pressure to continuously increase from about the detection pressure to the test gas pressure.Brief Description of the Drawings

[0090] The CCI testing Method according to the invention and the CCI testing system according to the invention are described in more detail hereinbelow by way of exemplary embodiments and with reference to the attached drawings, in which:Fig. 1 shows a schematic view of an embodiment of a CCI testing system according to the invention;Fig. 2 shows a flow scheme of an embodiment of the CCI testing method according to the invention implemented by the CCI testing system of Fig. 1 ;Fig. 3 shows a graph of test measurements of different simulated leaks at different pressure differences; andFig. 4 shows another graph of test measurements of different simulated leaks at different pressure differences.of Embodiments

[0091] 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”, “under" 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.

[0092] 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 followingdescription 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.

[0093] 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 one possible example of a 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 .

[0094] 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 pressure regulator 15, a valve arrangement 16, two gas supplies 17, a control unit 18 and a vacuum pump 19.

[0095] 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.

[0096] 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 flow or leakage rate.

[0097] The chamber 14 is coupled to the syringe holder 13 and tightly 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 inlet 142 which is connected to the pressure regulator 15 via a pipe. The pressure regulator 15 is in fluid connection with the valve arrangement 16 and the vacuum pump 19 via other pipes.

[0098] 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 Nitrogensupply 172. The gas supplies 17 are coupled to the inlet 142 of the chamber 14 via the valve arrangement 16 and the pressure regulator 15.

[0099] The control unit 18 is coupled to the pressure regulator 15, the valve arrangement 16, the gas supplies 17, the Helium detector 11 and the vacuum pump 19. In particular, the control unit 18 comprises a computer, which is in communication connection by means of wires with the Helium detector 11 , the pressure regulator 15, the valve arrangement 16 and the vacuum pump 19. Like this, data transfer between the control unit 18 and the connected Helium detector 11 , pressure regulator 15, the valve arrangement 16 as well as the vacuum pump 19 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.

[0100] The computer of the control unit 18 runs a dedicated software to implement an embodiment of a CCI testing method according to the invention as shown in Fig. 2. In particular, the method includes a sequence of steps including the following, wherein particularly the automated steps thereof are implemented by the software:

[0101] In preparation of the CCI testing method, a sequence of preparation is repeated for each of a number n of reference syringes, each having a known defect. In particular, for each of the n reference syringes, in a step 100 the respective reference syringe is obtained. In a step 101 , the outlet of the reference syringe as first reference aperture is tightly connected to the Helium detector 11 . Thereby, the open end of the reference syringe is positioned in the chamber 14 such that it is connected to the Helium supply 171 via the valve arrangement 16 and the pressure regulator 15 via respective pipes.

[0102] In a step 102, the control unit 18 adapts the Helium detector 11 to apply a vacuum as detector pressure at the first reference aperture. Further, in a step 103, the control unit 18 opens the first valve 161 to arrange the Helium supply 171 to provide Helium to the pressure regulator 15. In a step 104, the pressure regulator 15 continuously increases the Helium pressure inside the chamber 14 over a predefined time interval up to a first Helium pressure. The Helium is then provided to the second aperture of the reference syringe at the first Helium pressure.

[0103] In a step 105, the control unit 18 arranges the Helium detector 11 to measure Helium at the first reference aperture while the Helium is provided at the first Heliumpressure. The control unit 18 then determines a first reference leakage rate based on the Helium measured at the first Helium pressure in a step 106 and stores data related to the first reference leakage rate in a database as reference data.

[0104] In a step 107, the control unit 18 arranges the pressure regulator 15 to increase the Helium pressure inside the chamber 14 to a second Helium pressure. Like this, Helium is provided to the second reference aperture of the reference syringe at the second Helium pressure, which is higher than the first Helium pressure. In other words, a first pressure difference being a difference between the first Helium pressure and vacuum is smaller than a second pressure difference being a difference between the second Helium pressure and vacuum.

[0105] In a step 108, the control unit 18 arranges the Helium detector 11 to measure Helium at the first reference aperture of the reference syringe while Helium is provided at the second Helium pressure. The control unit 18 then determines a second reference leakage rate based on the Helium measured at the second Helium pressure in a step 109 and continuously stores data related to the second reference leakage rate in the database as the reference data.

[0106] Before any further steps, the control unit 18 induces a clearing of the system by closing the first valve 161 and activating the vacuum pump 19 to remove Helium from the chamber 14. Then the control unit 18 opens the second valve 162 and adapts the pressure regulator 15 to provide Nitrogen from the Nitrogen supply 172 into the chamber 14. The vacuum pump 19 can be reactivated to remove Nitrogen from the chamber 14 and to provide vacuum inside the chamber 14 after removing the first reference syringe and positioning the second reference syringe. In particular, the steps 100 to 109 are then repeated for each of the n reference syringes. Thereby, the reference data is created as a sufficient set of data relating to the known defect in the reference syringes.

[0107] After gathering data from all n reference syringes, the reference data is pre-processed by the control unit 18. In a step 110, the control unit 18 classifies the known defects in the reference data into specific leaks. Then, in a step 11 1 , the control unit defines or obtains a maximum allowable leakage limit. Further, in a step 112, the control unit calculates a reference leakage ratio between the first reference leakage rate and the second reference leakage rate for each of the n reference syringes.

[0108] When the reference data is pre-processed, testing of the syringe 2 is performed in the CCI testing system 1. In particular, in a step 120 the syringe is obtained and, in a step 121 , its first aperture is tightly received in the syringe seat 131 of the syringe holder and thereby tightly connected to the Helium detector 11 via the channel 132 as shown in Fig. 1 . Thereby, rest of the syringe 2 including the second aperture is enclosed by the chamber 14 such that, in step 122, the second aperture is connected to the Helium supply 171 and Nitrogen supply 172 via the valve arrangement 16 and the pressure regulator 15.

[0109] In a step 123, the control unit 18 arranges the Helium detector 11 to apply the vacuum at the first aperture of the syringe 2. Further, in a step 124, the control unit 18 continuously increases the Helium pressure inside the chamber 14 by adapting the pressure generator 15 until the first Helium pressure is provided to the second aperture of the syringe 2. In a step 125, the control unit 18 adapts the Helium detector 11 to measure Helium at the first aperture of the syringe 2 while the Helium is provided at the first Helium pressure. The control unit 18 determines in a step 126 a first leakage rate based on the Helium measured at the first Helium pressure.[001 10] In a step 127, the control unit 18 adapts the pressure generator 15 to raise the Helium pressure until the second Helium pressure is provided to the second aperture of the syringe 2. The Helium detector 11 measures Helium at the first aperture of the syringe in a step 128. Then, in a step 129, the control unit 18 determines a second leakage rate based on the Helium measured at the second Helium pressure.[001 11] After all relevant data about the tested syringe 2 is gathered, in a step 130, the control unit 18 calculates a leakage ratio between the first leakage rate and the second leakage rate. In a step 131 , the control unit calculates a pressure ratio between the first pressure difference and the second pressure difference.[001 12] Then, as a last step 132 of evaluation, the control unit compares the leakage ratio to the classified reference leakage ratios. If the evaluated leak is classified to be above the maximum allowable leakage limit, the syringe 2 is rated as non-compliant or as not having sufficient closure integrity.[001 13] Fig. 3 shows graphs of test measurements of different simulated leak types or defects at different pressure differences. In Figure 3, the dotted line represents thevarying pressure differences, wherein its absolute measure is depicted on the left side axis of ordinates. The full line and the chain dotted line represent gas flow rates of two simulated types of leaks or defects, e.g., in a stopper of a syringe. Thereby, the respective gas flow rates are depicted on the right side axis of ordinates. The axis of abscissae depicts time.[001 14] More specifically, a capillary like defect is simulated by a capillary being six hundred times longer and seven times wider than the orifice, e.g. the capillary being of 30 mm length having an inner diameter of 15 pm. The capillary like defect is represented by the full line. Further, an orifice like defect is simulated by a blind having a bore, wherein a thickness of the blind is about twenty-five times a diameter of the bore, e.g., the blind having a 50 pm thickness and the bore a 2 pm diameter. The orifice like defect is represented by the chain dotted line.[001 15] As can be seen in Fig. 3, whereas the flow rate of the orifice like defect more or less linearly increases with respect to an increasing pressure difference, the flow rate of the capillary like defect disproportionately or exponentially increases with increasing pressure difference.[001 16] Further, in Fig. 3 it is shown that flow rates are about the same at a usually applied pressure difference of 1 bar (see about half way of the time depicted on the axis of abscissae). Thus, by considering one single pressure difference when evaluating the flow rates of a leak or defect, it may be concluded that the leaks or defects are about the same or have about the same behaviour. As derivable from the other flow rate measurements, it can be proven that such conclusion is wrong and that the two defects or leaks have an essentially differing structure (defect geometry) and, thus, behaviour.[001 17] Thus, when measuring flow rates of a real defect at a plurality of increasing pressure differences it can be assessed if the defect is more of an elongated geometry (capillary type) or of a short geometry (orifice type). Compared to measuring flow rates at one single pressure difference, the multiple pressure difference measuring of flow rates allows an improved evaluation or determination of a quality of a defect or leak.[001 18] Fig. 4 also shows graphs of test measurements of different simulated leaks at different pressure differences. In Figure 4, the dotted line represents the varying pressure differences, wherein its absolute measure is depicted in the left side axis ofordinates. The full line and the chain dotted line represent gas flow rates of two simulated types of leaks, e.g., in a stopper of a syringe. Thereby, the respective normalized gas flow rates are depicted on the right side axis of ordinates. The axis of abscissae depicts time.[001 19] More specifically, a single capillary like defect is simulated by a capillary of 30 mm lengths having an inner diameter of 15 pm. The single capillary like defect is represented by the full line. Further, a multiple capillaries like defect is simulated by ten capillaries each having a length of 25 mm and an inner diameter of 15 pm. The multiple capillaries like defect is represented by the chain dotted line. It is to note that the flow rate measurements of the two defects are normalized by dividing the multiple capillaries like defect flow rates by ten.

[0120] As can be seen in Fig. 4, even though being a little different in dimension due to the differing capillary lengths, the flow rates more or less have the same behaviour at different pressure differences. Thus, when measuring flow rates of a real defect it can be concluded that there is a plurality of (here capillary like) defects present. Compared to measuring flow rates at one single pressure difference, the multiple pressure difference measuring of flow rates allows for an improved evaluation or determination of a quantity of a defect or leak.

[0121] 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. For example, instead of determining the second leakage rate by means of steps 107 to 109 describe above, the second leakage rate may also be extrapolated as specified in the description of the invention.

[0122] The disclosure also covers all further features shown in the Figs, 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. Le., 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.

[0123] 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

CLAIMS1 . A CCI testing method to test physical container closure integrity of a container (2), comprising obtaining a container (2) having a hollow interior (223), an outlet (221 ), an open end (222) and a stopper (21 ) arranged to close the hollow interior (223); tightly connecting a first aperture being one of the outlet (221 ) of the container (2) and the open end (222) of the container (2) to a test gas detector (11 ); connecting a second aperture being the other one of the outlet (221 ) of the container (2) and the open end (222) of the container (2) to a test gas supply (171 ); arranging the test gas detector (11 ) to apply a detector pressure at the first aperture; arranging the test gas supply (171 ) to provide test gas at a first test gas pressure to the second aperture; measuring test gas at the first aperture by means of the test gas detector (1 1 ) while the test gas is provided at the first test gas pressure; determining a first leakage rate based on the test gas measured at the first test gas pressure; and determining a second leakage rate at a second pressure, wherein a first pressure difference being a difference between the first test gas pressure and the detector pressure differs from a second pressure difference being a difference between the second pressure and the detector pressure.

2. The CCI testing method of claim 1 , wherein the detector pressure is a subatmospheric pressure.

3. The CCI testing method of claim 1 , wherein the test gas is Helium.

4. The CCI testing method of claim any one of the preceding claims, wherein determining the second leakage rate comprises arranging the test gas supply (171 ) to provide test gas at the second pressure to the second aperture; measuring test gas at the first aperture by means of the test gas detector (1 1 ) while test gas is provided at the second pressure; and determining the second leakage rate based on the test gas measured at the second pressure.

5. The CCI testing method of any one of the preceding claims, comprising a step of determining a defect by evaluating the first pressure difference, the second pressure difference, the first leakage rate and the second leakage rate.

6. The CCI testing method of any one of claims 1 to 3, wherein determining the second leakage rate comprises extrapolating the first leakage rate to the second leakage rate.

7. The CCI testing method of claim 6, wherein the second pressure difference is about 1 bar.

8. The CCI testing method of any one of claims 5 to 7, wherein determining the defect or extrapolating the first leakage rate to the second leakage rate comprises a step of generating reference data by processing at least two reference containers (2) each having a known defect.

9. The CCI testing method of claim 8, wherein the reference data is generated as a reference curve.

10. The CCI testing method of claim 8 or 9, wherein processing the at least two reference containers (2) comprises, for each of the at least two reference containers (2), tightly connecting a first reference aperture being a first one of an outlet (221 ) of the reference container (2) and an open end (222) of the reference container (2) to the test gas detector (11 );connecting a second reference aperture being a second one of the outlet (221 ) of the reference container (2) and the open end (222) of the reference container (2) to the test gas supply (171 ); arranging the test gas detector (11 ) to apply the detector pressure at the first reference aperture; arranging the test gas supply (171 ) to provide test gas at the first test gas pressure to the second reference aperture; measuring test gas at the first reference aperture by means of the test gas detector (11 ) while test gas is provided at the first test gas pressure; determining a first reference leakage rate based on the test gas measured at the first test gas pressure; arranging the test gas supply (171 ) to provide test gas at the second pressure to the second reference aperture; measuring test gas at the first reference aperture by means of the test gas detector (11 ) while test gas is provided at the second pressure; and determining a second reference leakage rate based on the test gas measured at the second pressure.1 1 . The CCI testing method of claim 3 or 4 and claim 6, wherein the first leakage rate is between the first reference leakage rate of one of the at least two reference containers and the first reference leakage rate of another one of the at least two reference containers.

12. The CCI testing method of any one of claims 6 to 9, wherein determining the defect or extrapolating the first leakage rate to the second leakage rate comprises a step of comparing the first pressure difference, the second pressure difference, the first leakage rate and / or the second leakage rate to the generated reference data; and / or a step of classifying leaks in the reference data; and / or a step of obtaining a maximum allowable leakage limit.

13. The CCI testing method of any one of claims 6 to 8, comprising a step of calculating a reference leakage ratio between the first reference leakage rate and the second reference leakage rate.

14. The CCI testing method of claim 4 and of claim 9, wherein extrapolating the first leakage rate to the second leakage rate comprises multiplication of the first pressure difference by the reference leakage ratio.

15. The CCI testing method of any one of the preceding claims, comprising a step of calculating a leakage ratio between the first leakage rate and the second leakage rate; and / or a step of calculating a pressure ratio between the first pressure difference and the second pressure difference.

16. The CCI testing method of any one of the preceding claims, wherein the first pressure difference is smaller than the second pressure difference.

17. The CCI testing method of any one of the preceding claims, comprising arranging the test gas supply (171 ) to provide test gas at least one further test gas pressure to the second aperture; measuring test gas at the first aperture by means of the test gas detector (11 ) while test gas is provided at each of the at least one further test gas pressure; and determining at least one further leakage rate based on the test gas measured at each of the at least one further test gas pressure.

18. The CCI testing method of any one of the preceding claims, wherein arranging the test gas supply (171 ) to provide test gas at a first test gas pressure to the second aperture comprises regulating the test gas pressure to continuously increase from about the detection pressure to the test gas pressure.

19. A CCI testing system to control physical container closure integrity of 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), comprising a container holder (13) configured to tightly receive a first aperture being one of the outlet (221 ) of the container (2) or the open end (222) 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) to form a tight connection to the first aperture when the first aperture is received by the container holder (13); and a chamber (14) tightly coupled to the container holder (13) to form an encasing of a second aperture being the outlet (221 ) of the container (2) or the open end (222) of the container (2) not received by the container holder (13) when the first aperture is received by the container holder (13), wherein the test gas supply (171 ) is coupled to the chamber (14) and configured to supply test gas into the chamber (14), wherein the test gas supply (171 ) has a pressure regulator (15) to variably adapt a test gas pressure in the chamber (14) in a range between a minimum pressure and a maximum pressure, wherein the test gas detector (11 ) is configured to apply a detector pressure to the container holder (13) and the container holder (13) is configured to effect the detector pressure to the first aperture, and wherein the chamber (14) is configured to expose the second aperture to the test gas pressure when the first aperture is received by the container holder (13) and the test gas supply (171 ) supplies test gas into the chamber (14).

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