Container integrity testing method and system

Abstract

A CCI test method for testing physical container closure integrity of a container (2), the CCI test method comprising 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; tightly connecting (121) a first orifice, which is one of the outlet of the container and the open end of the container, to a test gas detector; connecting (122) a second orifice, which is the other of the outlet of the container and the open end of the container, to a test gas supply; arranging (123) the test gas detector to apply a detector pressure at the first orifice; arranging (124) the test gas supply to provide a test gas to the second orifice at a first test gas pressure; measuring (125) a test gas at the first orifice by means of the test gas detector while providing the test gas at the first test gas pressure; determining (126) a first leak rate based on the test gas measured at the first test gas pressure; and determining (127, 128, 129) a second leakage rate at a second pressure. A first pressure difference, which is a difference between the first test gas pressure and the detector pressure, is different from a second pressure difference, which is a difference between the second pressure and the detector pressure.

Description

TECHNICAL FIELD

[0001] The present invention relates to a container closure integrity (CCI) test method and a CCI test system. Such CCI test method and system can be used to test the 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 in particular be a primary package and is intended to be filled with a pharmaceutical substance, a chemical substance, or a drug substance. BACKGROUND

[0003] With respect to the provision of pharmaceuticals and other sensitive substances, the integrity of the containers and primary packages in which the substances are filled is of great importance. Thus, the integrity of a container or primary package generally indicates the ability to keep the content or substance inside the respective container or package and to keep harmful environmental contaminants outside the respective container or package.

[0004] For example, the integrity of a container can be affected by a breach in the container or package. A leak point is generally considered to be a hole or a crack having a certain diameter and length. Leakage can be a measure of the gas flow (expressed in mass or volume or units) through the breach path under certain conditions. There is a leak of 1 if the pressure in a 1 liter closed container rises or falls by 1 mbar within 1 sec.

[0005] When dealing with containers having a movable closure, such as a stopper, certain container integrity issues have to be considered. For example, a syringe pre-filled with a pharmaceutical substance typically has a plunger rod provided with a stopper which has to be movable in order to expel the pharmaceutical substance through a needle, orifice or other outlet upon administration.

[0006] However, during assembly and shipping of the filled syringe, some movement of the stopper can still occur. For example, during assembly, such as in particular assembly of the plunger rod, axial and / or rotational movement of the stopper can occur which can induce deformation of the stopper which can affect the tightness at the stopper interface. Or, during shipping, the syringe can be exposed to varying pressure which can induce some linear movement of the stopper or bubble expansion and contraction.

[0007] In order to test the integrity of the syringe closure, a recognized procedure is to provide a sterile medium in the syringe, to expose the syringe to certain conditions and to verify whether a microbial contaminant grows in the initial sterile medium. However, such microbial test procedure is typically error prone, time consuming and difficult to reproduce.

[0008] Another method to test the 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, the open end or the back of a syringe can be exposed to a test gas at a certain pressure and concentration. In order to verify whether it is possible to leak into the interior of the syringe via the stopper, the test gas concentration is measured at the outlet of the syringe.

[0009] Although such test gases involving CCI test methods can be relatively fast and useful, they still have some drawbacks that can reduce accuracy, reliability and reproducibility. For example, in a syringe, the stopper usually has to be movable in order to allow a user to expel a substance out of the syringe by moving the stopper. More specifically, in order to allow a user to dose a substance precisely, the loosening force of the stopper in a syringe is usually configured to be appropriate, i.e. not too high for a convenient application and not too low for compromising tightness. Usually, the stopper is provided with silicone oil in order to accommodate the loosening force and / or the sliding or ramming force. For CCI testing, a low loosening force can be problematic because, in order to test for a potential gas flow, a pressure difference between both ends of the stopper has to be established. Such a pressure difference can already induce a movement of the stopper, which can compromise the test of the static closure integrity in the assembled state.

[0010] Alternatively, in some cases, it is not sufficient to test whether a gas flow occurs and to determine the size of such a gas flow to allow an evaluation of the container integrity. Rather, in order to give an opinion about the potential danger of contamination, it is important to know whether the size of the leak is sufficient to allow a contaminant and in particular a biological contaminant to pass the closure or the leak. For example, a relatively high measured gas flow does not necessarily mean that there is a sufficiently large leak because the gas flow can also be the result of a plurality of smaller leaks identified in one integral signal or measurement.

[0011] Therefore, there is a need for a container closure integrity (CCI) test system and method that allows to test and evaluate the container closure of a container closure in a relatively reliable, meaningful and reproducible way. SUMMARY

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

[0013] In one aspect, the present invention is a CCI testing method to test the physical container closure integrity of a container, the method 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 orifice being one of the outlet of the container and the open end of the container to a test gas detector; (iii) connecting a second orifice being the other 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 exert a detector pressure at the first orifice; (v) arranging the test gas supply to provide a test gas to the second orifice at a first test gas pressure; (vi) while providing the test gas at the first test gas pressure, measuring the test gas at the first orifice by means of the test gas detector; (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. Thus, a first pressure difference being the difference between the first test gas pressure and the detector pressure is different from a second pressure difference being the difference between the second pressure and the detector pressure.

[0014] Even if the method according to the present invention is listed in a sequence of numbered steps, this sequence does not limit the method to a particular order, unless explicitly specified or not feasible. In particular, a step assigned with a higher number can be performed earlier than another step assigned with a lower number.

[0015] The container can be any suitable container for receiving a chemical or pharmaceutical substance, such as a drug substance. In the pharmaceutical field, such containers are commonly used as primary packaging.

[0016] As used herein, the term "drug" relates to a therapeutically active agent, also commonly referred to as active pharmaceutical ingredient (API), and to combinations of a plurality of such therapeutically active substances. The term also encompasses diagnostic or imaging agents, like e.g. contrast agents (e.g. MRI contrast agents), tracers (e.g. PET tracers) and hormones, which need to be administered to a patient in liquid form.

[0017] As used herein, the term "drug substance" relates to a drug as defined above, formulated or reconstituted in a form suitable for administration to a patient. For example, in addition to the drug, a drug substance can additionally comprise excipients and / or other auxiliary ingredients. Particularly preferred drug substances in the context of the present invention are solutions, in particular solutions for oral administration, injection or infusion.

[0018] As used herein, the term "drug product" relates to a final product comprising one drug substance or a plurality of drug substances. In particular, the drug product can be a ready-to-use product having a drug substance in an appropriate dose and / or in an appropriate form for administration. For example, the drug product can comprise an administration device, such as a pre-filled container or the like.

[0019] Generally, this type of container has a body, such as a barrel forming a hollow interior. The term "barrel" in connection with a container can relate to a hollow body designed to receive a chemical substance, a pharmaceutical substance or a drug substance. In many containers, such as syringes, cartridges and vials, the barrel or body is essentially cylindrical and made of a sterilizable material, such as glass or an appropriate plastic material, e.g. polypropylene.

[0020] In particular, the container can be a prepared vial or a cartridge. The term "vial" as used herein can refer to a vial in the literal sense, i.e. a relatively small vessel or bottle, typically used for storing a pharmaceutical product or drug or a medicament in liquid, powder or capsule form. The vial typically comprises a cap or a lid including a seal, such as a rubber stopper or a septum, which for some applications can be designed to be pierceable.

[0021] The real or original opening of the cartridge or vial can be an outlet of the container. In particular when the container is a vial, the opening end can be generated in a preparation step by cutting off or otherwise removing the bottom of the vial or by otherwise providing an aperture at the bottom or any other suitable location. Instead of a stopper in the literal sense, in order to close the real opening of the vial it can be provided with a stopper or a septum, which in such cases is likewise encompassed by the term "stopper".

[0022] While also applicable to other types of containers, the CCI test system can be particularly advantageous for containers being syringes, and more specifically pre-filled syringes (PFS). For syringes and cartridges, the CCI test system allows for the application of a non-destructive procedure.

[0023] The test gas detector is advantageously configured to detect the test gas leaving the first orifice. It can have any way for efficiently and accurately detecting and also advantageously quantifying the test gas. Preferably, the test gas detector comprises a mass spectrometer, which allows for a relatively fast and accurate detection and quantification of the test gas.

[0024] With respect to the present invention, the first orifice is either of the open end or the outlet of the container, and the second orifice is the other of the open end and the outlet of the container, other than the first orifice. For example, when the container is a syringe, the first orifice can be the outlet, which is the end of the barrel of the syringe at which a needle is mounted or is to be mounted. In this example, the second orifice is the open end of the barrel, at which a stopper is provided through which to form a dosage chamber within the barrel.

[0025] The test gas supply typically comprises the test gas. To accommodate the test gas, the test gas supply can be equipped with a test gas tank or similar test gas reservoir. Although various test gases can be used, preferably the test gas is helium. It can have advantageous properties in terms of detectability, sterility, cost, handling and availability.

[0026] Although various test gases can be used, preferably the test gas is helium. It can have advantageous properties in terms of detectability, sterility, cost, handling and availability.

[0027] To accommodate the test gas, the test gas supply can comprise a test gas reservoir or tank, and structure to forward the test gas from the test gas reservoir to the chamber. Such structure can comprise a pressure member to pressurize the test gas within the test gas reservoir relative to other parts 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 can induce a gas flow.

[0028] The term“leak rate” as used herein relates to a measure of an amount, volume or mass that passes through the stopper and is measured directly at the first orifice or determined indirectly. In particular, such measure can be indicative of a leak occurring via the stopper of the container and thus of the integrity of the container closure.

[0029] Determining the first leak rate based on the test gas measured at the first pressure can involve a direct measurement of the first leak rate or an evaluation of any measurement or signal to achieve the first leak 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 plug, additional information about the plug or leak behavior can be obtained. For example, by evaluating the gas flow at at least two different pressure differences, it can be evaluated whether the behavior of the leak (e.g. in the plug-cartridge interface) is more like a capillary type or an orifice type and the related dimensions. In this way, the involvement of the multi-pressure difference measurement allows to determine the quality of the leak or defect. Furthermore, if the behavior at two different pressure differences is similar but at different degrees or dimensions, it can be concluded that there are multiple leaks of the same type. Thus, the involvement of the multi-pressure difference measurement additionally allows to determine the quantity of the leak. Furthermore, it allows to make a CCI evaluation of a static or unaltered non-moving system. For example, the dynamic behavior of the plug at different gradients can be evaluated in a non-moving system which allows to identify the type of leak. Such identification of the leak allows to rate the potential of contamination occurring via the plug. Thus, a fine and improved evaluation of the container closure integrity is possible, the testing and evaluation of the container closure is realized in a relatively reliable, meaningful and reproducible way. Furthermore, the method allows to reuse the tested container for further testing which can contribute to a more detailed evaluation.

[0031] In a first preferred embodiment, the step (viii) of determining a second leak rate of the method according to the present application comprises the steps of: (viii.i) arranging the test gas supply to provide the test gas to the second orifice at a second pressure; (viii.ii) measuring the test gas at the first orifice by means of the test gas detector while the test gas is provided at the second pressure; and (viii.iii) determining the second leak 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 the second test gas pressure. To prevent going back and forth with the pressure gradient application, the measurement of the test gas at the second, larger pressure is advantageously preceded by a measurement of the test gas at the first, smaller test gas pressure. Likewise, the determination of the first leak rate can be performed prior to the determination of the second leak rate. Furthermore, determining the second leak rate based on the test gas measured at the second pressure can involve a direct measurement of the second leak rate or an evaluation of any measurement to achieve the second leak rate.

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

[0034] The term "defect" can be defined or specified by the type of defect, by the size of the leak or defect, by the number of defects, etc. and any combination thereof. The defect can in particular be or result in a leak.

[0035] Identifying defects allows for the assessment of whether a leak is critical to the intended application of the container. For example, when the container is a syringe, identifying defects allows for the assessment of whether the leak is potentially susceptible to contamination, and more specifically, to biological contamination such as microorganisms.

[0036] In a second preferred embodiment, step (viii) of the method according to the invention, determining the second leakage rate, includes extrapolating the first leakage rate to the second leakage rate. Such extrapolation allows for a faster and less laborious procedure.

[0037] Therefore, the second pressure differential is preferably about 1 bar. This type of pressure differential allows for particularly efficient and accurate extrapolation of the second leakage rate. Furthermore, damage to the initial state of the component due to the force applied by the pressure can be avoided. Limits at a pressure differential of 1 bar or 1000 mbar can be based on regulations applicable to the integrity testing of container closures (such as those in the USP). <1207> The only reference requirement stipulated in China.

[0038] Even if measuring the second leakage rate and extrapolating the second leakage rate can be interchangeable, the two methods for determining the second leakage rate can be combined. In this way, a particularly accurate determination may be possible.

[0039] Determining defects or extrapolating the first leakage rate to the second leakage rate when measuring the second leakage rate preferably includes the step of generating reference data by processing at least two reference containers, each having known defects. These at least two reference containers can be any plurality of reference containers. In particular, such plurality of reference containers can belong to the same type as the container under test and can have different known defects. With the aid of such reference data with known defects, the measured or extrapolated results of the method can be efficiently correlated with the type of defect. This allows for efficient evaluation of the tested container.

[0040] The reference data is preferably generated as a reference curve. Such a reference curve allows for the correlation of defects with results over a continuous range. It can be generated from multiple measured reference data points. Reference curves allow for more efficient determination than those involving a single reference data point or instance.

[0041] Processing the at least two reference containers preferably includes: for each of the at least two reference containers, tightly connecting a first reference orifice, which serves as the outlet and open end of the reference container, to a test gas detector; connecting a second reference orifice, which serves as the outlet and open end of the reference container, to a test gas supply; arranging the test gas detector to apply detector pressure at the first reference orifice; arranging the test gas supply to supply test gas to the second reference orifice at the first test gas pressure; simultaneously supplying test gas at the first test gas pressure and measuring the test gas at the first reference orifice using the test gas detector; determining a first reference leakage rate based on the test gas measured at the first test gas pressure; arranging the test gas supply to supply test gas to the second reference orifice at a second pressure; simultaneously supplying test gas at the second pressure and measuring the test gas at the first reference orifice using the test gas detector; and determining a second reference leakage rate based on the test gas measured at the second pressure.

[0042] In particular, and advantageously, similar test procedures under comparable conditions are applied to all reference containers with known defects. This makes efficient and reliable evaluation of the tested containers possible.

[0043] The first leakage rate is preferably between the first reference leakage rate of one of the at least two reference containers and the first reference leakage rate of the other of the at least two reference containers. This relationship between the first leakage rate and the first reference leakage rate allows for efficient assessment of the container closure integrity of the tested container.

[0044] Identifying defects or extrapolating a first leakage rate to a second leakage rate preferably includes any of the following steps to achieve an efficient and accurate assessment of the container closure integrity of the tested container: comparing a first pressure differential, a second pressure differential, a first leakage rate, and / or a second leakage rate with generated reference data; classifying leaks in the reference data; and / or obtaining a maximum permissible leakage limit. In particular, a combination of all three steps can allow for efficient and accurate assessments, such as eliminating inappropriately tested containers. Obtaining the maximum permissible leakage limit may involve any source or regulation (such as in the USP) that is in place or from regulations. <1207> (In China) collect such limits, restrictions, or set values, or calculate values.

[0045] Preferably, the CCI testing method includes the step of calculating a reference leakage ratio between a first reference leakage rate and a second reference leakage rate. The reference leakage ratio can be, in particular, the quotient between the first and second reference leakage rates, especially under a first applied pressure difference and a second applied pressure difference. Such a reference leakage ratio allows for efficient evaluation of reference data.

[0046] Therefore, extrapolating the first leakage rate to the second leakage rate preferably involves multiplying the first pressure difference by a reference leakage ratio. Such multiplication allows for accurate extrapolation of the second leakage rate.

[0047] To extrapolate the first leakage rate to the second leakage rate, defects can be assumed or predefined.

[0048] Preferably, the CCI testing method includes the step of calculating a leakage ratio between a first leakage rate and a second leakage rate. The leakage ratio can be, in particular, the quotient between the first leakage rate and the second leakage rate. Such a leakage ratio allows for efficient evaluation of test results.

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

[0050] Preferably, the detector pressure is below atmospheric pressure. As used herein, the term "below atmospheric pressure" (which may also be referred to as negative pressure) can refer 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. This relationship between the first and second pressure differences allows for the reduction or prevention of higher signals resulting from a larger pressure difference being carried over to a smaller pressure difference. This improves the accuracy of the method and the comparability of the results.

[0052] Preferably, the CCI testing method includes the following steps: arranging a test gas supply to provide test gas to a second orifice at at least one additional test gas pressure; simultaneously providing test gas at each of the at least one additional test gas pressure, measuring the test gas at a first orifice using a test gas detector; and determining at least one additional leakage rate based on the test gas measured at each of the at least one additional test gas pressure. Based on these additional measurements, an improved assessment of the container closure integrity may be possible.

[0053] Preferably, arranging the test gas supply to provide test gas to the second orifice at a first test gas pressure includes: adjusting the test gas pressure to continuously increase from approximately the detection pressure to the test gas pressure.

[0054] The term "continuous increase" in this respect refers to an increase in test gas pressure over time. Such a continuous increase can be achieved through steady increases or gradual increases. In any case, a continuous increase is different from a sudden or one-step increase in test gas pressure. The regulation of test gas pressure can be specifically embodied by configuring a pressure regulator to increase the test gas pressure within the chamber. By continuously increasing the test gas pressure, it is possible to prevent the container setup from being affected, which would lead to less accurate test results. In particular, it allows for the avoidance of pressure peaks exceeding the target pressure and thus applying a force greater than expected or appropriate. Actual measurements can be taken at the pressure plateau to also assess whether a stable pressure produces a stable leakage rate, which may be the case for samples showing negligible permeation.

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

[0056] The container retainer is configured to tightly receive a first orifice, which is either the outlet of the container or the open end of the container. For receiving the first orifice, the container retainer may be equipped with a base in which a portion of the container, including a second orifice, can be arranged. The container retainer may also include an adapter for mounting the container. Such an adapter may be particularly useful for achieving a tight seal. In particular, the adapter includes an O-ring or similar washer to be screwed toward the container.

[0057] The test gas supply unit includes a test gas, preferably helium. To contain the test gas, the test gas supply unit may be equipped with a test gas canister, etc. Although various test gases can be used, helium is preferred. It may have advantageous characteristics in terms of detectability due to its lower background levels in the atmosphere, lower cost, lower handling requirements, and lower availability.

[0058] To contain the test gas, the test gas supply unit may include a test gas storage tank or canister, and structures for transferring the test gas from the test gas storage tank to the chamber. Such structures may include pressure members to pressurize the test gas within the test gas storage tank relative to other parts of the system. It may additionally or alternatively have pumps or other gas transfer members. Through all such structures, a pressure gradient can be generated from the gas storage tank to the chamber, which can induce airflow.

[0059] The test gas detector is tightly coupled to the container holder to form a tight connection with the first orifice when it is received by the container holder. It can have any manner for efficient and accurate detection and also advantageous quantification of the test gas. The test gas detector can include any suitable structure for measuring the test gas. For example, in headspace measurements, non-destructive tunable diode laser absorption spectroscopy may be beneficial for determining the tracer gas level within the headspace of the container. Preferably, the test gas detector includes a mass spectrometer, which allows for relatively rapid and accurate detection and quantification of the test gas.

[0060] The chamber is tightly connected to the container holder to form a enclosure around a second opening when the first opening is received by the container holder. The second opening is the outlet of the container or the open end of the container that is not received by the container holder.

[0061] As used herein, the term "coupling" refers to a direct or indirect connection between two or more units. For example, a chamber can be coupled to a container holder by direct mounting or by indirect connection, for example, via another element of the system, such as a test gas detector.

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

[0063] The test gas detector is configured to apply detector pressure to a container holder, and the container holder is configured to cause the detector pressure to act on a first orifice. The detector pressure acting on the first orifice can be achieved by applying a pressure inherently induced by the test gas detector. Therefore, the detector pressure is preferably below atmospheric pressure. The term "below atmospheric pressure" as used herein (which may also be referred to as negative pressure) can refer to any pressure below ambient or atmospheric pressure, including vacuum or near-vacuum.

[0064] The minimum pressure can be, in particular, below atmospheric pressure, and more specifically, a vacuum. The maximum pressure is advantageously above 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 such that when the first orifice is received by the container holder and the test gas supply is supplied to the chamber, the second orifice is exposed to the test gas pressure.

[0066] The pressure regulator allows for flexible adjustment of the test gas pressure. In particular, it enables the efficient provision of the desired pressure differential in the method described above according to the invention. Therefore, the CCI testing system according to the invention and its preferred embodiments described below can effectively implement the effects and benefits of the CCI testing method and its preferred embodiments described above. Specifically, the CCI testing system according to the invention allows for improved testing and control of container closures in a relatively reliable, rapid, and reproducible manner.

[0067] Preferably, the CCI testing system has a regulating gas supply including a regulating gas and a valve arrangement connected to the test gas supply and the regulating gas supply, wherein the test gas supply is connected to the valve arrangement, and wherein the valve arrangement is configured to selectively activate the test gas supply and / or the regulating gas supply.

[0068] The term "conditioning gas" in this respect refers to any suitable gas that differs from or does not include the test gas. It can be ambient air, an air-like gas, nitrogen, or a similar pure and particularly inert gas suitable for the specific application of the CCI testing system.

[0069] The term "activation" in relation to gas supply components can refer to configuring the corresponding gas supply component to provide gas. Specifically, regarding valve arrangements, activation of a gas supply component can involve opening a pressurized gas storage tank. More specifically, valve arrangements can be specified to activate test gas and / or regulating gas supplies by opening or closing the corresponding test gas or regulating gas storage tank and / or supply line. For example, a gas supply component may have a pressurized storage tank containing the corresponding gas, and the valve arrangement may open and close the tank to allow for efficient gas supply as needed.

[0070] The regulating gas supply unit preferably contains regulating gas at a pressure higher than atmospheric pressure, and is preferably configured to release the regulating gas at about 6 bar. For this purpose, the regulating gas supply unit advantageously includes a regulating gas reservoir, such as a pressurized tank or a sealed container. Efficient flushing of chambers and other components can be achieved by having regulating gas at elevated pressure.

[0071] Preferably, the test gas supply unit contains the test gas at a pressure higher than atmospheric pressure, and is preferably configured to release conditioning gas at approximately 1.5 bar. This allows for efficient and accurate supply of the test gas.

[0072] Preferably, the CCI testing system includes a pressure regulator and a test gas detector coupled to a test gas supply, as well as a control unit for regulating the gas supply (if any). The control unit can be coupled to the test gas supply, the test gas detector, and other components through communication. Specifically, the coupling of the control unit can be embodied through a data transmission connection, wherein data transmission can be established in one or both ways. Therefore, the data transmission connection can be wired or wireless. The control unit allows for efficient control and operation of the CCI testing system or specific components thereof.

[0073] The control unit may be or includes a computer. Therefore, as used herein, the term "computer" refers to any electronic data processing device. It includes individual devices such as laptops, desktop computers, server computers, tablets, smartphones, systems embedded in other devices (embedded systems), etc. It also encompasses combined devices or computer networks, such as distributed system transmitters in different locations.

[0074] Typically, a computer consists of various building blocks or components, such as a processor (CPU), a permanent data storage device with a recording medium (such as a hard disk, flash memory, or the like), random access memory (RAM), read-only memory (ROM), communication adapters (such as USB adapters, LAN adapters, WLAN adapters, Bluetooth adapters, etc.), a user interface (such as a keyboard, mouse, touchscreen, monitor, microphone, speaker, and other components). In a variety of embodiments, a computer may consist of the aforementioned components and / or other components. A computer can be configured by including and running specific software according to embodiments of the invention. Such software may include a set of commands that influence certain actions performed by the computer when executed.

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

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

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

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

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

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

[0081] Therefore, the control unit is preferably configured to process each of the at least two reference containers in such a way that, while the first reference orifice of the first of the reference containers (serving as the outlet and the open end) is received by the container holder, the test gas detector applies detector pressure to the container holder and the container holder applies detector pressure to the first reference orifice, and the test gas supply provides test gas to the chamber at the first test gas pressure, exposing the second reference orifice of the second of the reference containers (serving as the outlet and the open end) to the first gas pressure, the control unit, by means of the test gas detector, in the first reference... The test gas is measured at the orifice; a first reference leakage rate is determined based on the test gas measured by the test gas detector at a first test gas pressure; while the first reference orifice is received by the container holder, the test gas detector applies detector pressure to the container holder and the container holder causes the detector pressure to act on the first reference orifice, and the test gas supply provides test gas to the chamber at a second pressure, exposing the second reference orifice to a second gas pressure, the test gas is measured at the first reference orifice by means of the test gas detector; and a second reference leakage rate is determined based on the test gas measured by the test gas detector at the second pressure.

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

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

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

[0085] Therefore, extrapolating the first leakage rate to the second leakage rate preferably includes multiplying the first pressure difference by a reference leakage ratio.

[0086] Preferably, the CCI testing system includes a data storage device, wherein the control unit is configured to correlate the leakage rate with the pressure difference, and to store the pressure difference and the associated leakage rate in the data storage device.

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

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

[0089] Preferably, the control unit is configured to adjust the pressure regulator to regulate the test gas pressure, continuously increasing it from approximately the detection pressure to the test gas pressure. Attached Figure Description

[0090] CCI test method according to the present invention and CCI according to the present invention The testing system is described in more detail below with reference to exemplary embodiments and the accompanying drawings, wherein: Figure 1 shows a schematic diagram of an embodiment of the CCI testing system according to the present invention; Figure 2 shows a flowchart of an embodiment of the CCI testing method according to the present invention implemented by the CCI testing system of Figure 1; Figure 3 shows the test measurement diagrams for different simulated leaks under different pressure differentials; and Figure 4 shows another test measurement diagram of different simulated leaks under different pressure differences. Detailed Implementation

[0091] In the following description, certain terms are used for convenience and are not intended to limit the invention. The terms “right,” “left,” “up,” “down,” “below,” and “above” refer to directions in the figures. Terms include explicitly mentioned terms and their derivatives, as well as terms with similar meanings. Additionally, spatial relative terms such as “below,” “below,” “below,” “above,” “on top,” “near,” “far,” etc., may be used to describe the relationship between one element or feature and another element or feature as shown in the figures. These spatial relative terms are intended to cover different positions and orientations of the device in use or operation, in addition to those shown in the figures. For example, if the device in the figures is flipped, an element described as “below” or “below” other elements or features will be “above” or “above” other elements or features. Thus, the exemplary term “below” can cover both above and below positions and orientations. The device may be oriented in other ways (rotated 90 degrees or otherwise oriented), and the spatial relative descriptive terms used herein will be interpreted accordingly. Similarly, descriptions of movement along and around various axes include various specific device positions and orientations.

[0092] To avoid repetition in the description of the accompanying drawings and various aspects, as well as the illustrative embodiments, it should be understood that many features are common to many aspects and embodiments. The omission of an aspect in the description or drawings does not imply that that aspect is missing in the embodiment that includes it. Rather, the aspect may be omitted for clarity and to avoid lengthy descriptions. In this context, the following description applies to the remainder of this specification: if reference numerals in the drawings are not explained in the directly relevant parts of the specification for the purpose of clarifying the drawings, reference may be made to preceding or following sections of the specification. Furthermore, for clarity, if reference numerals in the drawings do not provide all features of a component, reference may be made to other drawings showing the same component. Similar reference numerals in two or more drawings denote the same or similar elements.

[0093] Figure 1 illustrates an embodiment of the CCI testing system 1 according to the present invention. The CCI testing system 1 is designed to test the closure integrity of a syringe 2, which is a possible example of a container. The syringe 2 has a barrel 22 with a hollow interior 223, an outlet 221 forming a first orifice of the syringe 2, and an open end 222 forming a second orifice of the syringe 2. A stopper 21 is disposed in the hollow interior 223 through the open end 222, thereby sealing the hollow interior 223 and forming a dosing chamber between the stopper 21 and the outlet 221.

[0094] The CCI test system 1 includes a helium detector 11 as a test gas detector, a syringe holder 13 as a container holder, a chamber 14, a pressure regulator 15, a valve arrangement structure 16, two gas supply units 17, a control unit 18, and a vacuum pump 19.

[0095] The syringe holder 13 has a body with a base 131 to tightly receive the front portion of the syringe 2, including the outlet 221. The syringe 2 is securely held in a horizontal position by means of the base 131.

[0096] The body of the syringe holder 13 is equipped with a channel 132. The channel 132 connects the base 131, and more specifically the outlet 221 of the syringe 2 (when received in the base 131), to the helium detector 11. The helium detector 11 has a spectrometer for detecting and quantifying the helium flow rate or leakage rate.

[0097] When outlet 221 is received by base 131, chamber 14 is coupled to syringe holder 13 and tightly surrounds the complete syringe 2 extending from base 131 of syringe holder 13. It has inlet 142 connected via conduit to pressure regulator 15. Pressure regulator 15 is fluidly connected via other conduit to valve arrangement 16 and vacuum pump 19.

[0098] Gas supply unit 17 includes a helium supply unit 171 and a nitrogen supply unit 172. The helium supply unit has a pressure vessel filled with helium as a test gas, and the nitrogen supply unit has a pressure vessel filled with nitrogen as a regulating gas. Valve arrangement 16 has a first valve 161 associated with the helium supply unit 171 and a second valve 162 associated with the nitrogen supply unit 172. By means of the first valve 161 and the second valve 162, valve arrangement 16 is configured to selectively open and close the helium supply unit 171 and the nitrogen supply unit 172. Gas supply unit 17 is connected to inlet 142 of chamber 14 via valve arrangement 16 and pressure regulator 15.

[0099] The control unit 18 is connected to the pressure regulator 15, the valve arrangement 16, the gas supply unit 17, the helium detector 11, and the vacuum pump 19. Specifically, the control unit 18 includes a computer that is communicatively connected to the helium detector 11, the pressure regulator 15, the valve arrangement 16, and the vacuum pump 19 via wires. This enables data transmission between the control unit 18 and the connected helium detector 11, pressure regulator 15, valve arrangement 16, and vacuum pump 19. For example, the helium detector 11 can be controlled by the control unit 18, and the data collected by the helium detector 11 can be transmitted to and evaluated by the control unit.

[0100] The computer of control unit 18 runs dedicated software to implement an embodiment of the CCI testing method according to the present invention, as shown in FIG2. Specifically, the method includes a series of steps, wherein, in particular, its automated steps are implemented by software: In the preparation of the CCI test method, a series of preparations are repeated for each of a number of n reference syringes, each with known defects. Specifically, for each of the n reference syringes, a corresponding reference syringe is obtained in step 100. In step 101, the outlet of the reference syringe, serving as the first reference orifice, is tightly connected to the helium detector 11. Therefore, the open end of the reference syringe is positioned in the chamber 14 such that this open end is connected to the helium supply unit 171 via a valve arrangement structure 16 and a pressure regulator 15 through a corresponding conduit.

[0101] In step 102, the control unit 18 adjusts the helium detector 11 to apply a vacuum as detector pressure at the first reference orifice. Furthermore, in step 103, the control unit 18 opens the first valve 161 to arrange the helium supply element 171 to supply helium to the pressure regulator 15. In step 104, the pressure regulator 15 continuously increases the helium pressure in the chamber 14 at predetermined time intervals, up to a first helium pressure. Helium is then supplied to the second orifice of the reference syringe at the first helium pressure.

[0102] In step 105, while supplying helium at the first helium pressure, the control unit 18 deploys the helium detector 11 to measure the helium at the first reference orifice. Then, in step 106, the control unit 18 determines a first reference leakage rate based on the helium measured at the first helium pressure and stores the data related to the first reference leakage rate in a database as reference data.

[0103] In step 107, the control unit 18 arranges a pressure regulator 15 to increase the helium pressure within the chamber 14 to a second helium pressure. This allows helium to be supplied to the second reference orifice of the reference injector at a second helium pressure higher than the first helium pressure. In other words, the first pressure difference, which is the difference between the first helium pressure and vacuum, is less than the second pressure difference, which is the difference between the second helium pressure and vacuum.

[0104] In step 108, while supplying helium at the second helium pressure, the control unit 18 deploys the helium detector 11 to measure the helium at the first reference orifice of the reference injector. Then, in step 109, the control unit 18 determines a second reference leakage rate based on the helium measured at the second helium pressure, and continuously stores data related to the second reference leakage rate in a database as reference data.

[0105] Before any other steps, control unit 18 induces system purging by closing first valve 161 and activating vacuum pump 19 to remove helium from chamber 14. Control unit 18 then opens second valve 162 and adjusts pressure regulator 15 to supply nitrogen from nitrogen supply unit 172 into chamber 14. After removing the first reference syringe and positioning the second reference syringe, vacuum pump 19 can be reactivated to remove nitrogen from chamber 14 and provide a vacuum within chamber 14. Specifically, steps 100 to 109 are then repeated for each of the n reference syringes. Thus, reference data is created as a sufficient dataset relating to known defects in the reference syringes.

[0106] After collecting data from all n reference syringes, the reference data is preprocessed by control unit 18. In step 110, control unit 18 classifies known defects in the reference data into specific leaks. Then, in step 111, control unit limits or obtains the maximum permissible leak limit. Furthermore, in step 112, control unit calculates the reference leak ratio between a first reference leak rate and a second reference leak rate for each of the n reference syringes.

[0107] While the reference data is preprocessed, the testing of syringe 2 is performed in CCI test system 1. Specifically, in step 120, the syringe is obtained, and in step 121, the first orifice of the syringe is tightly received in the syringe base 131 of the syringe holder, and thus tightly connected to the helium detector 11 via channel 132, as shown in FIG1. ​​Therefore, the remainder of syringe 2, including the second orifice, is closed by chamber 14, such that in step 122, the second orifice is connected to the helium supply 171 and nitrogen supply 172 via valve arrangement structure 16 and pressure regulator 15.

[0108] In step 123, the control unit 18 positions the helium detector 11 to apply a vacuum at the first orifice of the syringe 2. Furthermore, in step 124, the control unit 18 continuously increases the helium pressure within the chamber 14 by adjusting the pressure generator 15 until a first helium pressure is supplied to the second orifice of the syringe 2. In step 125, while supplying helium at the first helium pressure, the control unit 18 adjusts the helium detector 11 to measure the helium level at the first orifice of the syringe 2. In step 126, the control unit 18 determines a first leakage rate based on the helium level measured at the first helium pressure.

[0109] In step 127, the control unit 18 adjusts the pressure generator 15 to increase the helium pressure until a second helium pressure is provided to the second orifice of the syringe 2. In step 128, the helium detector 11 measures the helium at the first orifice of the syringe. Then, in step 129, the control unit 18 determines a second leakage rate based on the helium measured at the second helium pressure.

[0110] After collecting all relevant data about the tested syringe 2, in step 130, the control unit 18 calculates the leakage ratio between the first leakage rate and the second leakage rate. In step 131, the control unit calculates the pressure ratio between the first pressure difference and the second pressure difference.

[0111] Then, as the final step 132 of the evaluation, the control unit compares the leakage ratio with a classified reference leakage ratio. If the evaluated leakage is classified as exceeding the maximum permissible leakage limit, the syringe 2 is rated as non-compliant or lacking sufficient closure integrity.

[0112] Figure 3 shows test measurements for different simulated leak types or defects under varying pressure differentials. In Figure 3, the dashed lines represent varying pressure differentials, with their absolute measurements plotted on the left axis of the vertical axis. The solid and dotted lines represent the gas flow rates for two simulated leak or defect types, for example, in the stopper of a syringe. Therefore, the corresponding gas flow rates are plotted on the right axis of the vertical axis. The horizontal axis depicts time.

[0113] More specifically, capillary-like defects are simulated using capillaries, where the length of the capillary is 600 times that of the orifice and the width is 7 times that of the orifice; for example, a capillary with an inner diameter of 15 µm and a length of 30 mm. Capillary-like defects are represented by solid lines. Furthermore, orifice-like defects are simulated using blind plates with drilled holes, where the thickness of the blind plate is approximately 25 times the diameter of the drilled hole; for example, the blind plate has a thickness of 50 µm and the drilled hole has a diameter of 2 µm. Orifice-like defects are represented by dashed lines.

[0114] As can be seen in Figure 3, although the flow rate of orifice-type defects increases more or less linearly with respect to the increased pressure difference, the flow rate of capillary-type defects increases disproportionately or exponentially with the increase in pressure difference.

[0115] Furthermore, as shown in Figure 3, the flow rates are approximately the same under a normally applied pressure differential of 1 bar (see approximately halfway down the axis of time plotted on the horizontal axis). Therefore, by considering a single pressure differential when evaluating the flow rates of a leak or defect, one can conclude that the leaks or defects are approximately the same or have approximately the same behavior. As can be seen from other flow measurements, such conclusions can be proven false, and it can be demonstrated that the two defects or leaks have substantially different structures (defect geometries) and therefore substantially different behaviors.

[0116] Therefore, when measuring the flow rate of a true defect under multiple increased pressure differentials, it is possible to assess whether the defect is more like an elongated geometry (capillary type) or a short geometry (orifice type). Multi-pressure differential measurements of flow rate allow for improved assessment or identification of the quality of defects or leaks compared to measuring flow rate under a single pressure differential.

[0117] Figure 4 also shows test measurements for different simulated leaks under varying pressure differentials. In Figure 4, the dashed lines represent varying pressure differentials, with their absolute measurements plotted on the left axis of the vertical axis. The solid and dotted lines represent gas flow rates for two simulated leak types, such as in the stopper of a syringe. Therefore, the corresponding normalized gas flow rates are plotted on the right axis of the vertical axis. The horizontal axis represents time.

[0118] More specifically, a single capillary-sample defect was simulated using a 30 mm long capillary with an inner diameter of 15 µm. A single capillary-sample defect is represented by a solid line. Furthermore, multiple capillary-sample defects were simulated using ten capillary tubes, each with a length of 25 mm and an inner diameter of 15 µm. Multiple capillary-sample defects are represented by dashed lines. It is important to note that the flow rate measurements of both defects were normalized by dividing the flow rate of the multiple capillary-sample defects by ten.

[0119] As can be seen in Figure 4, although the dimensions vary slightly due to different capillary lengths, the flow rates exhibit more or less the same behavior under different pressure differentials. Therefore, when measuring the flow rate of a real defect, it can be concluded that multiple defects (in this case, capillary samples) exist. Compared to measuring the flow rate under a single pressure differential, multi-pressure differential measurement of the flow rate allows for improved assessment or determination of the amount of defect or leakage.

[0120] The description and accompanying drawings illustrating aspects and embodiments of the invention should not be construed as limiting the scope of the claims defining the protected invention. In other words, while the invention has been described and illustrated in detail in the accompanying drawings and the foregoing description, such description and illustration are intended to be illustrative or exemplary rather than restrictive. Various mechanical, compositional, structural, electrical, and operational changes may be made without departing from the spirit and scope of this specification and the claims. In some cases, well-known circuits, structures, and techniques have not been shown in detail to avoid obscuring the invention. Therefore, it should be understood that changes and modifications can be made by those skilled in the art within the scope and spirit of the appended claims. In particular, the invention covers further embodiments having any combination of features from the different embodiments described above and below. For example, instead of determining the second leakage rate by means of steps 107 to 109 described above, the second leakage rate may also be extrapolated as specified in the description of the invention.

[0121] This disclosure also covers all other features shown in the figures. Although they may not be described in the preceding or following description, they are individual. Furthermore, single alternatives to the embodiments described in the figures and description, and single alternatives to their features, may be excluded from the subject matter of the invention or from the disclosed subject matter. This disclosure includes the subject matter consisting of features defined in the claims or exemplary embodiments, as well as the subject matter including said features. Additionally, this disclosure covers intermediate generalizations of features or groups of features of the embodiments described and illustrated in the figures. That is, specific features or groups of features disclosed in the figures, and associated portions described, may be combined with more general embodiments of the invention disclosed in the description of the invention. In particular, such specific features or groups of features may be provided in more general embodiments of the invention, independent of further specific features shown in the figures. For example, the piping shown and described in the associated portions of the figures may be implemented in a more general CCI test system of the invention or a preferred embodiment thereof, without the need for or implementation of other features. It should be understood that those skilled in the art can incorporate specific features from the description of the figures into embodiments described in the invention.

[0122] Furthermore, in the claims, the term "comprising / including" does not exclude other elements or steps, and the indefinite article "a / an" does not exclude multiple. A single unit or step can perform the function of several features listed in the claims. The mere fact that certain measures are listed in mutually different dependent claims does not suggest that a combination of these measures cannot be advantageous. Terms related to attributes or values, such as "substantially," "about," "approximately," etc., also precisely define the attribute or exact value, respectively. In the context of a given numerical value or range, the term "about" refers to a value or range, for example, within 20%, 10%, 5%, or 2% of a given value or range. Components described as coupled or connected may be electrically or mechanically coupled directly, or they may be indirectly coupled via one or more intermediate components. Any reference numerals in the claims should not be construed as limiting the scope.

Claims

1. A CCI test method for testing the physical container closure integrity of a container (2), the CCI test method comprising: Obtain a container (2) having a hollow interior (223), an outlet (221), an open end (222), and a plug (21) arranged to close the hollow interior (223); The first orifice, which is one of the outlet (221) of the container (2) and the opening end (222) of the container (2), is tightly connected to the test gas detector (11); The second orifice, which is the other of the outlet (221) of the container (2) and the opening end (222) of the container (2), is connected to the test gas supply unit (171); The test gas detector (11) is arranged to apply detector pressure at the first orifice; The test gas supply unit (171) is arranged to supply test gas to the second orifice at a first test gas pressure; While the test gas is supplied at the first test gas pressure, the test gas is measured at the first orifice by means of the test gas detector (11); The first leakage rate is determined based on the test gas measured at the first test gas pressure; as well as The second leakage rate was determined under the second pressure. The first pressure difference, which is the difference between the first test gas pressure and the detector pressure, is different from the second pressure difference, which is the difference between the second pressure and the detector pressure.

2. The CCI testing method according to claim 1, wherein the detector pressure is a pressure lower than atmospheric pressure.

3. The CCI testing method according to claim 1, wherein the test gas is helium.

4. The CCI testing method according to any one of the preceding claims, wherein determining the second leakage rate comprises: The test gas supply unit (171) is arranged to supply test gas to the second orifice at the second pressure; While providing test gas under the second pressure, the test gas is measured at the first orifice by means of the test gas detector (11); as well as The second leakage rate is determined based on the test gas measured at the second pressure.

5. The CCI testing method according to any one of the preceding claims, the CCI testing method comprising the 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 according to 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 test method according to claim 6, wherein the second pressure difference is about 1 bar.

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

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

10. The CCI testing method according to claim 8 or 9, wherein processing the at least two reference containers (2) comprises: For each of the at least two reference containers (2), The first reference orifice, which is the first of the outlet (221) of the reference container (2) and the opening end (222) of the reference container (2), is tightly connected to the test gas detector (11); The second reference port, which is the second of the outlet (221) of the reference container (2) and the open end (222) of the reference container (2), is connected to the test gas supply unit (171); The test gas detector (11) is arranged to apply the detector pressure at the first reference orifice; The test gas supply unit (171) is arranged to supply test gas to the second reference orifice at the first test gas pressure; While providing test gas at the first test gas pressure, the test gas is measured at the first reference orifice by means of the test gas detector (11); A first reference leakage rate is determined based on the test gas measured at the first test gas pressure; The test gas supply unit (171) is arranged to supply test gas to the second reference orifice at the second pressure; While providing test gas under the second pressure, the test gas is measured at the first reference orifice by means of the test gas detector (11); as well as A second reference leakage rate is determined based on the test gas measured at the second pressure.

11. The CCI testing method according to claim 3 or 4 and claim 6, wherein the first leakage rate is between a first reference leakage rate of one of the at least two reference containers and a first reference leakage rate of the other of the at least two reference containers.

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

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

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

15. The CCI testing method according to any one of the preceding claims, wherein the CCI testing method comprises: The step of calculating the leakage ratio between the first leakage rate and the second leakage rate; and / or The step of calculating the pressure ratio between the first pressure difference and the second pressure difference.

16. The CCI test method according to any one of the preceding claims, wherein the first pressure difference is less than the second pressure difference.

17. The CCI testing method according to any one of the preceding claims, the CCI testing method comprising: The test gas supply unit (171) is arranged to supply test gas to the second orifice at at least one additional test gas pressure; While providing test gas at each of the at least one additional test gas pressure, the test gas is measured at the first orifice by means of the test gas detector (11); and At least one additional leakage rate is determined based on the test gas measured at each of the at least one additional test gas pressure.

18. The CCI testing method according to any one of the preceding claims, wherein arranging the test gas supply (171) to provide test gas to the second orifice at a first test gas pressure comprises: The test gas pressure is adjusted to continuously increase from approximately the detection pressure to the test gas pressure.

19. A CCI testing system for controlling the physical container closure integrity of a container (2), the container having a hollow interior (223), an outlet (221), an open end (222), and a plug (21) configured to close the hollow interior (223), the CCI testing system comprising: A container retainer (13) is configured to tightly receive a first opening, the first opening being either the outlet (221) of the container (2) or the open end (222) of the container (2); Test gas supply unit (171), which includes test gas; A test gas detector (11) is tightly coupled to the container holder (13) to form a tight connection with the first orifice when the first orifice is received by the container holder (13); and A chamber (14), which is tightly connected to the container holder (13), to form a surrounding of a second opening when the first opening is received by the container holder (13), the second opening being the outlet (221) of the container (2) or the open end (222) of the container (2) not received by the container holder (13). The test gas supply unit (171) is coupled to the chamber (14) and configured to supply test gas into the chamber (14). The test gas supply unit (171) has a pressure regulator (15) to variably adjust the test gas pressure in the chamber (14) within a range between a minimum pressure and a maximum pressure. The test gas detector (11) is configured to apply detector pressure to the container holder (13), and the container holder (13) is configured to apply the detector pressure to the first orifice. The chamber (14) is configured such that when the first orifice is received by the container holder (13) and the test gas supply (171) supplies test gas into the chamber (14), the second orifice is exposed to the test gas pressure.

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