Positive control system and method for verifying a positive control of a container closure integrity test

Abstract

The present invention claims a positive control system (1) for container closure integrity (CCI) testing, comprising a container (3) and an adapter. The container (3) has a hollow interior (31), an opening (35), and a rim (331) surrounding the opening (35). The adapter (2) has a first coupling structure (21) configured to connect to a flow reduction holder (4) and a second coupling structure (22). The second coupling structure (22) of the adapter (2) is vacuum-tightly bonded to the rim (331) of the container (3). The adapter (2) is configured such that the interior (31) of the container (3) is accessible from the first coupling structure (21).

Description

[Technical Field]

[0001] The present invention relates to a positive control system for container closure integrity (CCI) testing and a method for validating the respective CCI test method. [Background technology]

[0002] A positive control generally refers to a control of the integrity of a container or package that has an intentional or known leak. Positive controls are used to better understand the measurement system. In contrast, a negative control refers to a control of the integrity of a container or package that does not have a known leak, i.e., a container or package that is typically assembled using commonly processed components.

[0003] The container or package to be controlled is typically in the form of primary packaging, such as the primary packaging of a drug or pharmaceutical or chemical. Examples of such primary packaging are commonly used vials, cartridges, or syringes.

[0004] The integrity of a container or package generally refers to the ability to keep contents inside the respective container or package and harmful environmental contaminants outside the respective container or package.

[0005] A leak is typically perceived as a hole or crack of a specific diameter and length. Leakage is a measure of the gas flow (typically mass or volume) through a leak path under specific conditions. When the pressure in a 1 liter sealed container rises or falls by 1 mbar in 1 second, the leakage is 1 [mbar x 1 / s].

[0006] A commonly used CCI test method is the differential pressure (DP) method. This method is a pneumatic method with permanent or non-permanent leaks. It requires a headspace or vaporizing liquid. The DP method allows for immediate testing.

[0007] During pneumatic testing, the sample is typically placed in a sealed chamber. Either a vacuum or pressure is then applied to the chamber. An appropriate sensor is used to monitor the pressure conditions within the chamber. As gas exchange with the sample occurs, the pressure conditions change, signaling a leak.

[0008] Other known CCI testing methods include head space analysis (HSA), mass spectrometry (MS) and high voltage laser diode (HVLD).

[0009] Systems used for positive control in CCI tests usually require relatively complex setups, which can be tedious to construct and may involve specific structures that may not adequately represent the vessels being tested. Furthermore, known positive control procedures are destructive, resulting in damage to the specific structures.

[0010] Therefore, there is a need for a system and / or method that allows for improved positive control of CCI testing. Summary of the Invention

[0011] According to the present invention, this need is solved by a positive control system as defined by the features of independent claim 1 and a method as defined by the features of independent claim 13. Preferred embodiments are the subject of the dependent claims.

[0012] In one aspect, the present invention is a positive control system for container closure integrity (CCI) testing, comprising a container and an adapter. The container has a hollow interior, an opening, and a rim surrounding the opening. The adapter comprises a first coupling structure configured to be connected to a flow reducer holder and a second coupling structure. The second coupling structure of the adapter is vacuum-tightly adhered to the rim of the container. The adapter is configured such that the interior of the container is accessible from the first coupling structure, thereby allowing the interior of the container to be fluidly connected to or accessed by the flow reducer, particularly when connected to the first coupling structure.

[0013] The term "integrity" of a container or package refers to the ability to keep the contents inside the respective container or package and harmful environmental contaminants outside the respective container or package. In particular, when the contents are drug substances or similar pharmaceuticals or chemicals, integrity can relate to keeping the contents sterile inside the container or package. Furthermore, the contents may include a combination of a substance, such as a drug substance, and a gas, such as nitrogen. Environmental contaminants may include microorganisms, reactive gases, and other materials.

[0014] The container may in particular be a pharmaceutical container, i.e. a container or primary packaging configured to contain a drug substance. Typically, the pharmaceutical container makes it possible to keep the drug substance in a protected, sterile environment.

[0015] As used herein, the term "drug" relates to a therapeutically active agent, also commonly referred to as an active pharmaceutical ingredient (API), as well as combinations of two or more such therapeutically active agents. The term also encompasses diagnostic or imaging agents that must be administered to a patient in liquid form, such as contrast agents (e.g., MRI contrast agents), tracers (e.g., PET tracers), and hormones.

[0016] As used herein, the term "drug substance" relates to a drug as defined above that has been made into or reconstituted in a form suitable for administration to a patient. For example, a drug substance may further comprise excipients and / or other auxiliary ingredients in addition to the drug. Particularly preferred drug substances in the context of the present invention are drug solutions, especially solutions for oral administration, injection, or infusion.

[0017] The term "drug product" relates to a final product comprising a drug substance or drugs. In particular, a drug product may be a ready-to-use product having a drug substance in an appropriate dose and / or in an appropriate form for administration. For example, a drug product may include an administration device such as a pre-filled syringe.

[0018] The positive control system according to the invention makes it possible to achieve high quality and reliable CCI tests, which may in particular be physical CCI (pCCI) tests.

[0019] For example, a positive control system allows for the reuse of the components involved, particularly the container-adapter assembly, so that accurate original volume and leakage can be maintained and reused. More specifically, the same leakage can be used for multiple test methods, enabling increased quality in testing container integrity. Advantageously, a positive control system can be used with multiple deterministic leak testing methods compliant with Chapter 1207.2 of the United States Pharmacopeia. For example, a positive control system can be used with multiple deterministic leak testing methods, including laser-based gas headspace analysis, mass extraction, pressure decay, tracer gas detection vacuum or sniffing mode, and vacuum decay. Furthermore, a positive control system can prevent the need for a container dummy, which typically increases the complexity of CCI positive control.

[0020] Preferably, the positive control system includes a flow reducer holder that is securely connected to the first coupling structure of the adapter and configured to accommodate a flow reducer. The flow reducer can be any structure or element suitable for reducing gas flow to a predetermined extent. For example, the flow reducer can be a compound having through-holes with specific hole dimensions.

[0021] In a preferred embodiment, the flow reduction holder is a microcapillary holder. Such a microcapillary holder can effectively hold a microcapillary to accurately mimic an appropriate degree of leakage. A microcapillary may also be included in a positive control system.

[0022] As used herein, the term "microcapillary" refers to a microtube or micropipette suitable for simulating a single orifice defect. Microcapillaries may be formed of glass or any suitable plastic material and may have diameters ranging from about 0.1 μm to about 500 μm, more specifically from about 2 μm to about 9 μm. Diameters up to about 10 μm or 15 μm may be appropriate for helium leak testing. Diameters up to about 150 μm or about 30 μm may be appropriate for vacuum or pressure decay testing. Microcapillaries are typically used in place of smaller diameter, shorter leak paths when performing tests dependent on gas flow measurements.

[0023] The microcapillary holder may comprise a body having an elongated portion configured to securely connect to a first coupling structure of an adapter. The elongated portion may function as a coupling portion for the adapter, if present. Accordingly, the elongated portion may comprise a taper at its free end that allows for convenient coupling to another structure. The elongated portion of the body may be tapered toward a longitudinal end to efficiently facilitate efficient coupling with the adapter.

[0024] The elongated portion or body may have an outer diameter in the range of about 4 mm to about 9 mm, or in the range of about 5.5 mm to about 7.5 mm, or in the range of about 6 mm to about 7 mm. Such elongated portions may be beneficial in many applications and / or for efficient handling of immobilized microcapillaries.

[0025] Thereby, the body of the micro-capillary holder preferably comprises a periphery and a duct, the duct of the body extending through the elongated portion, the duct of the body being dimensioned to receive the micro-capillary.

[0026] The term "lateral circumference" in relation to a microcapillary holder may refer to the outer boundary of the body transverse to the longitudinal axis, which may also include portions of the body that are of increased diameter compared to the elongated portion.

[0027] The ducts may be embodied in the form of straight holes configured to precisely surround each microcapillary tube so as not to allow any gas flow between the outer wall of the microcapillary tube and the inner surface of the duct. The ducts may surround the microcapillary tube over substantially the entire length of the microcapillary tube. Typically, only one end of the microcapillary tube protrudes slightly into the cavity of the head portion of the holder.

[0028] The duct may be sized to hold the micro-capillary when received therein, thereby ensuring a secure attachment of the micro-capillary, preventing breakage or damage to the micro-capillary during use.

[0029] The duct may have an inner diameter of about 0.5 mm to about 3 mm, or about 1 mm to about 2 mm, or about 1.5 mm, which allows for efficient and safe holding and positioning of microcapillary tubes, which are widely used in CCI tests.

[0030] Furthermore, the ducts may have lengths ranging from about 0.5 cm to about 5 cm, or from about 1.5 cm to about 3.5 cm, or from about 2 cm to about 3 cm. Such ducts allow the microcapillary tubes to be securely held over a substantial length. In this way, secure holding can be achieved.

[0031] The body of the microcapillary holder preferably includes a through-channel extending between the periphery and the duct. Such a through-channel of the microcapillary holder allows adhesive to be applied or provided to the microcapillary within the duct, thereby firmly securing the microcapillary within the duct. In this way, the microcapillary can be handled safely and efficiently during CCI or pCCI testing, and more reliable results can be achieved.

[0032] The through channel in the body of the microcapillary holder preferably opens at the side periphery and the duct, so that the through channel is conveniently accessible so that adhesive can be efficiently applied to securely fix the microcapillary placed in the duct.

[0033] The through channel of the body of the microcapillary holder is preferably essentially perpendicular to the longitudinal axis of the elongated portion of the body of the microcapillary holder, which orientation is particularly advantageous for efficient application of adhesive material.

[0034] The through channel of the body may have an inner diameter ranging from about 0.5 mm to about 3 mm, or from about 1 mm to about 2 mm, or about 1.5 mm, such dimensions allowing for efficient delivery of adhesive through the through-hole to micro-capillaries disposed within the duct.

[0035] The above dimensions of the elongated portion, duct and / or through channel have proven to be particularly beneficial for commonly used microcapillary tubes, particularly for (p)CCI testing.

[0036] The body of the micro-capillary holder preferably includes a head portion from which the elongated portion extends, whereby the head portion preferably has a cavity into which the duct opens. The cavity may be provided to accommodate the filter unit. In this way, the cavity may surround, support and protect the filter unit.

[0037] The cavity preferably transitions into the duct via a tapered section. In this way, a smooth insertion of the microcapillary into the duct can be achieved. In particular, the risk of damaging the microcapillary during introduction into the duct can be reduced. Furthermore, the gas flow can be improved.

[0038] Preferably, the microcapillary holder comprises a nut having a first mounting structure, and the head portion of the body of the microcapillary holder has a second mounting structure corresponding to the first mounting structure of the nut, so that the nut can be attached to the head of the body by interaction of the first and second mounting structures. Hereby, the first and second mounting structures can be embodied as threads or bayonet closures, etc. In this way, a very tight and releasable attachment of the filter unit is possible.

[0039] Preferably, the micro-capillary holder comprises a filter unit arranged in a cavity in the head portion of the body so that the duct is covered, and the filter unit is preferably locked in the cavity in the head portion of the body by a nut, which ensures that gas flows through the filter and thus prevents, for example, contaminants from accessing the micro-capillary.

[0040] The filter unit may be locked into a cavity in the head portion of the body by a nut, in this way the tight and releasable fit may be further improved.

[0041] A first gasket may be disposed between the filter unit and the head portion of the body. Advantageously, the first gasket is an O-ring. Additionally, a second gasket may be disposed between the filter unit and the nut. Advantageously, the second gasket is an O-ring. O-rings have been shown to provide a very reliable and tight seal.

[0042] It should be noted that the positive control system with the nut can also be applied to permeability measurements. In this case, the dimensions of the microcapillary holder and the nut may differ from those used when performing CCI tests. In particular, the duct may be somewhat larger or smaller. Also, in such cases, a through channel for the adhesive is not required, especially if a microcapillary is not used due to the reduced flow rate.

[0043] Preferably, the adapter has a sealing device configured to seal the connection between the first coupling structure and the flow reduction holder, whereby the sealing device of the adapter preferably comprises at least one O-ring, and the first coupling structure of the adapter preferably comprises at least one circumferential recess configured to receive the at least one O-ring.

[0044] Preferably, the positive control system comprises a microcapillary adhesive configured to be supplied into the through channel of the body of the microcapillary holder when the microcapillary is received in the duct of the body of the microcapillary holder, thereby fixing the microcapillary within the duct of the body of the microcapillary holder.

[0045] Preferably, the second connecting structure of the adapter is vacuum-tightly bonded to the edge of the container with a vial adhesive. The vial adhesive and the microcapillary adhesive may be the same. For example, an epoxy adhesive may be suitable for both.

[0046] Preferably, the adapter is made of metal, preferably stainless steel, as such a metal adapter makes it possible to provide sufficient robustness and sterility.

[0047] As mentioned above, the container may be a container for a drug substance, particularly a liquid drug substance. For example, the container may be a syringe, such as a staked-in needle (SIN) or a prefilled syringe (PFS), a cartridge, or a vial.

[0048] As used herein, the term "vial" can refer to a vial in the literal sense, i.e., a relatively small container or bottle often used to store a medicine or drug or substance in liquid, powder, or encapsulated form. A vial can be made of glass or plastic, e.g., a sterilizable material such as cyclic olefin polymer (COP) or polypropylene. It typically includes a cover or cap containing a seal, such as a rubber stopper or septum, that is designed to be punctured for many applications.

[0049] In particular, the container is preferably a vial, which has a head with a rim and an opening extending from the rim of the head to the interior of the vial. The vial can have a neck and a body, and the opening including the rim is located in the head and opens to the interior of the body through the neck and head. The adapter is then configured to be connected to the rim of the head of the vial. In an advantageous embodiment, the head has a typical diameter, such as a diameter of 13 mm or 20 mm.

[0050] In particular, the vial is preferably made of a light-transmitting material such as glass, which allows the interior of the vial to be observed as it is being processed, for example by optical inspection.

[0051] Preferably, the second coupling structure of the adapter comprises a circumferential recess configured to surround the edge of the head of the vial. The recess may be formed by a circumferential groove or notch provided in the longitudinal or axial end of the adapter. In this way, a safe and sound connection between the adapter and the container can be established.

[0052] In another aspect, the invention is a method for positively controlling a container closure integrity (CCI) test, the method including obtaining a positive control system as described above, supplying a tracer gas to an interior of a container of the positive control system, securely connecting a first coupling structure of an adapter of the positive control system to a flow reduction holder, and applying a deterministic leak test method to positively control the physical container closure integrity of the positive control of the container of the positive control system having the tracer gas therein and the flow reduction holder securely connected to the first coupling structure of the adapter.

[0053] The method according to the invention and its preferred embodiments described below make it possible to achieve the effects and benefits mentioned above in relation to the positive control system according to the invention and its preferred embodiments, in particular the method according to the invention makes it possible to improve the positive control and to provide a reliable validation of the CCI test.

[0054] Preferably, the deterministic leakage test method complies with Chapter 1207.2 of the United States Pharmacopoeia, providing an approved positive control that can be used to validate the CCI test and receive formal approval.

[0055] Preferably, the deterministic leak testing method includes at least two of the following: laser-based gas headspace analysis, mass extraction, pressure decay, tracer gas detection vacuum mode, and vacuum decay. This combination of recognized testing methods allows for particularly high quality and reliability of CCI testing. Furthermore, the method allows for the reuse of the same single container-adapter assembly, which can help improve test parameters by controlling variables in ways not previously possible by eliminating certain phenomena related to part-to-part variability.

[0056] Preferably, the method further includes obtaining a microcapillary, wherein the flow reduction holder is a microcapillary holder; placing the microcapillary within a duct in a body of the microcapillary holder; and supplying a microcapillary adhesive within a through channel in the body of the microcapillary holder. [Brief explanation of the drawings]

[0057] The positive control system according to the invention and the method according to the invention are explained in more detail below by way of exemplary embodiments and with reference to the accompanying drawings, in which: FIG. [Figure 1] 1 is a cross-sectional view of an adapter of a first embodiment of a positive control system according to the present invention. [Figure 2] 2 is a partial cross-sectional and partial side view of a portion of a vial of the positive control system of FIG. 1. [Figure 3] FIG. 2 is a cross-sectional view of the positive control system of FIG. 1. [Figure 4] FIG. 10 is a cross-sectional view of an adapter of a second embodiment of a positive control system according to the present invention. [Figure 5] FIG. 5 is a cross-sectional view of the positive control system of FIG. 4. DETAILED DESCRIPTION OF THE INVENTION

[0058] In the following description, certain terminology is used for convenience and is not intended to limit the invention. The terms "right," "left," "up," "down," "under," and "above" refer to directions in the figures. The use of terms includes the explicitly mentioned terms as well as their derivatives and terms with similar meanings. In addition, spatially relative terms such as "beneath," "below," "lower," "above," "upper," "proximal," and "distal" may be used to describe the relationship of one element or feature shown in the figures to another element or feature. These spatially relative terms are intended to encompass various positions and orientations of the device during use or operation in addition to the positions and orientations shown in the figures. For example, if a device in the figures were inverted, elements described as "below" or "below" other elements or features would now be "above" or "above" the other elements or features. Thus, the exemplary term "below" can encompass both upward and downward positions and orientations. The device may be otherwise oriented (rotated 90 degrees or at other orientations), and the spatially relative descriptors used herein may be interpreted accordingly. Similarly, descriptions of movement along and about various axes include various particular device positions and orientations.

[0059] To avoid repetition in the figures and descriptions of various aspects and exemplary embodiments, it should be understood that many features are common to many aspects and embodiments. If an aspect is omitted from a description or figure, this does not mean that the aspect is missing from an embodiment incorporating that aspect. Rather, the aspect may be omitted for purposes of clarity and to avoid redundant description. In this context, the following applies to the remainder of this specification: for clarity of the drawings, if a figure includes a reference sign that is not described in the directly relevant part of the specification, reference is made to the preceding or subsequent part of the specification. Furthermore, for clarity, if not all features of a part in a drawing are labeled with a reference sign, reference is made to other drawings showing the same part. Like numbers in two or more figures represent the same or similar elements.

[0060] 1 shows an adapter 2 of a first embodiment of a positive control system 1 according to the present invention. The adapter 2 has a generally elongated shape and extends rotationally symmetrically along a longitudinal axis 24. It has an axial bore forming a first coupling structure 21 towards its upper or proximal end. The first coupling structure 21 comprises two circumferential recesses 231 axially spaced apart in the sealing device 23.

[0061] Towards the bottom or distal end, the adapter 2 has a flange-like portion that establishes a second joining structure 22. The second joining structure 22 has a circumferential notch 221 with a recess 222 that opens into the bottom or distal end of the adapter 2. Inside the recess 222, a vial adhesive 5 is disposed.

[0062] The adapter 2 is made of stainless steel.

[0063] Figure 2 shows vial 3 of positive control system 1, with the right half shown in cross section. Vial 3 is a 20 mm glass vial. It has a body 34 with a hollow interior 31, a head 33, and a neck 32 between the body 34 and the head 33. The neck 32 and head 33 have an opening 35 through which the interior 31 of the body 34 is accessible. The opening 35 opens upward and is defined by a periphery 331 that surrounds the opening 35.

[0064] 3 shows the assembled positive control system 1. The adapter 2 is placed face down on the vial 3, so that the rim 331 and the entire head 33 of the vial 3 are received within the recess 222 of the second connecting structure 22. The vial adhesive 5 is spread around the head 33 so that the second connecting structure 22 is vacuum-tightly adhered to the rim 331 of the vial 33.

[0065] The first coupling structure 21 of the adapter receives the microcapillary holder 4 as a flow reduction holder. The microcapillary holder 4 has an elongated portion 41 that is introduced into the first coupling structure 21 of the adapter 2. The sealing device 23 has two O-rings 232, each housed in one of the recesses 231. The O-rings 232 are compressed between the lateral periphery of the elongated portion 41 of the microcapillary holder 4 and the inner boundary of the first coupling structure 21 of the adapter 2, so that the microcapillary holder 4 is firmly connected to the first coupling structure 21 of the adapter 2.

[0066] The microcapillary holder 4 further comprises a head portion 44 located above the adapter 2, from which an elongated portion 41 extends downward into the first coupling structure 21 of the adapter 2. A duct 42 passes vertically through the microcapillary holder 4, and a through channel 43 extends between the lateral periphery of the microcapillary holder 4 and the duct 41. More specifically, the through channel 43 opens at the lateral periphery and at the duct 41 and is essentially perpendicular to the longitudinal axis of the elongated portion 41.

[0067] The head portion 44 of the microcapillary holder 4 has a cavity 49 into which the duct 41 opens. More specifically, the cavity 49 transitions into the duct 41 via a tapered section.

[0068] The microcapillary holder 4 further includes a nut 45, a filter unit 46, and two O-rings 47. The filter unit 46 is placed in a cavity 49 above one of the O-rings 47. The nut 45 has an internal thread as a first mounting structure and is screwed onto the head portion 44, which has a corresponding external thread as a second mounting structure, so that the cavity 49 is closed. The other of the two O-rings is placed between the nut 45 and the filter unit 46. By tightening the nut 45 onto the head portion 44, the filter unit 46 is locked between the two O-rings 47 and tightly fastened.

[0069] The microcapillary holder 4 receives the microcapillary 6. In particular, the microcapillary 6 is inserted vertically into the duct 42. A microcapillary adhesive 48 is provided in the duct 41 through a through channel 43, thereby vacuum-tightly fixing the microcapillary in the microcapillary holder 4.

[0070] FIG. 4 shows an adapter 20 of a second embodiment of a positive control system 10 according to the present invention. The adapter 20 is embodied similarly to the adapter 1 shown in FIGS. 1-3, but is designed to be attached to a smaller vial 30, i.e., a 13 mm vial. The adapter 20 has a generally elongated shape and extends rotationally symmetrically along a longitudinal axis 240. It has an axial bore forming a first coupling structure 210 toward its upper or proximal end. The first coupling structure 210 includes two circumferential recesses 2310 spaced axially apart from each other in the closure 230.

[0071] Towards the bottom or distal end, adapter 20 has a flange-like portion that establishes second joining structure 220. In particular, the flange-like portion forms a step on the interior of adapter 20. In this step, vial adhesive 50 is placed.

[0072] 5 shows a second positive control system 10, which, except for its dimensions, is designed similarly to the first positive control system 1 of FIGS. 1-3. Notably, other than the adapter 20, the positive control system 10 includes structurally identical elements to the positive control system 1. More specifically, the positive control system includes a microcapillary holder 40 including a head portion 440 having a cavity 490, an elongated portion 410, a duct 420 for receiving a microcapillary 60, a through channel 430, a nut 450, a filter unit 460, two O-rings 470, and a microcapillary adhesive 480, as well as a vial 30 having a body 340 with a hollow interior 310, a head 330, a neck 320, and an opening 350 with a periphery 3310.

[0073] 5, to be vacuum-tightly adhered to the vial, the adapter 20 is placed over the vial 30 such that the head 330 of the vial 30 is received within the second coupling structure 220. This causes the vial adhesive 50 to spread around the head 330 of the vial 30, locking the vial 30 to the adapter 20.

[0074] The present specification and the accompanying drawings, which illustrate aspects and embodiments of the present invention, should not be construed as limiting the scope of the claims, which define the protected invention. In other words, while the present invention has been illustrated and described in detail in the drawings and the foregoing description, such illustration and description should be considered illustrative or exemplary, rather than limiting. Various mechanical, compositional, structural, electrical, and operational changes may be made without departing from the spirit and scope of the specification and claims. In some instances, well-known circuits, structures, and techniques have not been shown in detail so as not to obscure the invention. Accordingly, it will be understood that those skilled in the art may make changes and modifications within the scope and spirit of the following claims.

[0075] Furthermore, the present disclosure encompasses all additional features that may not be described in the above or following description but are individually shown in the drawings. Also, individual alternatives to the embodiments and individual alternatives to those features described in the drawings and specification may be discarded from the subject matter of the present invention or disclosed subject matter. The present disclosure includes subject matter consisting of, and comprising, the features defined in the claims or exemplary embodiments.

[0076] Furthermore, in the claims, the word "comprising" does not exclude other elements or steps, and the indefinite articles "a" or "an" do not exclude a plurality. A single unit or step may fulfill the functions of several features recited in a claim. The fact that certain measures are recited in mutually different dependent claims does not indicate that a combination of these measures cannot be advantageously used. The terms "essentially," "about," "approximately," and the like, in connection with an attribute or value specifically define that very attribute or exactly that value as well. The term "about" in the context of a given numerical value or range refers, for example, to a value or range that is within 20%, within 10%, within 5%, or within 2% of the given value or range. Components described as being coupled or connected may be directly coupled electrically or mechanically or indirectly coupled via one or more intermediate components. Any reference signs in the claims should not be construed as limiting the scope.

Claims

1. A positive control system (1;10) for container closure integrity (CCI) testing, comprising: a container (3; 30) having a hollow interior (31; 310), an opening (35; 350) and a rim (331; 3310) surrounding said opening (35; 350); an adapter (2; 20) having a first coupling structure (21; 210) and a second coupling structure (22; 220) configured to be connected to a flow reduction holder (4; 40); Equipped with the second coupling structure (22; 220) of the adapter (2; 20) is vacuum-tightly bonded to the edge (331; 3310) of the container (3; 30); the adapter (2; 20) is configured such that the interior (31; 310) of the container (3; 30) is accessible from the first coupling structure (21; 210); Positive control system (1;10) for container closure integrity (CCI) testing.

2. 2. A positive control system (1; 10) as described in claim 1, comprising a flow reducer holder (4; 40) firmly connected to the first connecting structure (21; 210) of the adapter (2; 20) and configured to accommodate a flow reducer (6; 60).

3. 3. A positive control system (1; 10) according to claim 2, wherein said flow reduction holder (4; 40) is a microcapillary holder (4; 40).

4. A positive control system (1; 10) as described in claim 2 or 3, wherein the adapter (2; 20) has a sealing device configured to seal the connection between the first connecting structure (21; 210) and the flow reduction holder (4; 40).

5. 5. A positive control system (1; 10) according to claim 4, wherein the sealing device of the adapter (2; 20) comprises at least one O-ring (232; 2320).

6. 6. A positive control system (1; 10) as described in claim 5, wherein the first coupling structure (21; 210) of the adapter (2; 20) comprises at least one circumferential recess (231) configured to accommodate the at least one O-ring (232; 2320).

7. A positive control system (1; 10) according to any one of claims 1 to 6, wherein the second connecting structure (22; 220) of the adapter (2; 20) is vacuum-tightly adhered to the edge (331; 3310) of the container (3; 30) by a vial adhesive (5; 50).

8. A positive control system (1; 10) according to any one of claims 1 to 7, wherein the adapter (2; 20) is made of metal.

9. 9. A positive control system (1; 10) according to claim 8, wherein the adapter (2; 20) is made of stainless steel.

10. A positive control system (1; 10) according to any one of claims 1 to 9, wherein the container (3; 30) is a vial having a head (33; 330) with the edge (331; 3310) and the opening (35; 350) extending from the edge (331; 3310) of the head (33; 330) to the interior (31; 310) of the vial (3; 30).

11. 11. A positive control system (1; 10) according to claim 10, wherein the vial (3; 30) is made of a light-transmitting material such as glass.

12. A positive control system (1; 10) according to any one of claims 1 to 11, wherein the second connecting structure (22; 220) of the adapter (2; 20) comprises a circumferential recess (232; 2320) configured to surround the edge (331; 3310) of the head (33; 330) of the vial (3; 30).

13. 1. A method for positive control of a container closure integrity (CCI) test, comprising: Obtaining a positive control system (1; 10) according to any one of claims 1 to 12, supplying a tracer gas into the interior (31; 310) of the vessel (3; 30) of the positive control system (1; 10); Firmly connecting the first coupling structure (21; 210) of the adapter (2; 20) of the positive control system (1; 10) to a flow reduction holder (4; 40); applying a deterministic leak test method to positively control the physical container closure integrity of the container (3; 30) of the positive control system (1; 10), the container (3; 30) having the tracer gas therein (31; 310) and the flow reduction holder (4; 40) firmly connected to the first coupling structure (21; 210) of the adapter (2; 20); 1. A method for positively controlling a container closure integrity (CCI) test, comprising:

14. 14. The method of claim 13, wherein the deterministic leak test method is a method in accordance with Chapter 1207.2 of the United States Pharmacopeia.

15. 15. The method of claim 13 or 14, wherein the deterministic leak testing method comprises at least two of a laser-based gas headspace analysis method, a mass extraction method, a pressure decay method, a tracer gas detection vacuum mode method, and a vacuum decay method.

16. obtaining a microcapillary, said flow rate reduction holder (4; 40) being a microcapillary holder (4; 40); placing said microcapillary in a duct (42; 420) in the body of said microcapillary holder (4; 40); - providing a micro-capillary adhesive in a through channel (43; 430) of the body of the micro-capillary holder (4; 40); The method according to any one of claims 13 to 15, comprising:

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