WO2023154725A1

WO2023154725A1 - Helium leak test fixture

Info

Publication number: WO2023154725A1
Application number: PCT/US2023/062177
Authority: WO
Inventors: James McCAW; Len Takudzwa MAGARA; Alexander LYNESS
Original assignee: West Pharmaceutical Services, Inc.
Priority date: 2022-02-08
Filing date: 2023-02-08
Publication date: 2023-08-17

Abstract

Helium leak detection apparatus and method of helium leak detection are described. The apparatus is used with a container having a sealing member arranged to seal a first external access point. The apparatus includes a fitting that encloses at least a portion of the container and a holder that holds the sealing member of the container in place when a differential pressure is applied across the sealing member. The differential pressure can be applied across the seal to detect a fault in the seal.

Description

Helium Leak Test Fixture

Cross Reference to Related Applications

This application claims the benefit of U.S. Provisional Patent App. No. 63/307,689, filed February 8, 2022, the disclosure of which is hereby incorporated by reference herein.

Technical Field

Methods and systems disclosed herein relate to testing containers using helium leak detection. In particular, the various embodiments disclosed herein are directed to apparatuses and methods for testing the seal integrity of open systems, such as syringes, or closed systems, such as vials.

Background

Sealed containers, such as those used in medical applications, are often tested to ensure the integrity of their seal. Measuring container closure integrity (CCI) is important in, for example, ensuring that contents of a vial or a syringe remain sterile.

A container such as a vial may be filled with drug product and a cap crimped onto its neck to close and maintain a seal. Once crimped, a vial is considered a closed system — it is sealed and only opened to extract drug product. In this way, material is only able to enter or exit the container as a result of a leak in the container. Testing the integrity of a seal of a closed system is done by examining the entire package to determine a leak. This is suitable where a closed system has only one seal - since any leak detected can be determined to be a fault with the particular seal.

A syringe, in contrast to a standard vial only having one seal, serves a dual purpose: to store and deliver drug product as one device/system. Within a syringe, the plunger has a dual function where it maintains the container closure integrity (CCI) within the fixed volume (typically a barrel), as well as pushes drug product out of the container once the user has overcome the break loose extrusion forces. Syringes have one end from which they are filled and then sealed, while the other end has a luer-lock or needle or another port to allow delivery of drug out of the barrel. With dual seals and ports of entry/exit, any CCI test must test each seal and isolate any fault with them, enabling finer control over the CCI of the system. Finer control would allow for more robust design and testing of the container improving product development efficiency and efficacy.

There is therefore a need for a system and method for testing of individual seals in a container.

Furthermore, emerging gene and cell-based therapies are required to be stored at low (-80°C) and cryogenic (-196°C) temperatures, respectively. To develop containers suitable for these conditions first requires test fixtures that can replicate these extreme environments. It is thus important to have a test apparatus and method which is capable of isolating individual seals to ascertain CCI for the more complex containers, such as those with multiple openings, at extreme temperatures.

The various embodiments disclosed herein provide a helium leak test apparatus and method for testing one or more individual seals within an open system. The various embodiments invention also provide an approach for simulating the extreme temperature cycles that containers in advanced therapies experience when they are tested for CCI.

Summary

A helium leak detection apparatus for use with a container is presented. The container has a plurality of external access points, which means that it has more than one port of entry/exit. This makes the container an open system. The container also has a sealing member, which is arranged to seal one of the external access points. The apparatus also has a fitting, for example, a vacuum fitting, that encloses at least a portion of the container. Importantly, the apparatus comprises a holder which holds in place the sealing member of the container when a differential pressure is applied across the sealing member. Optionally, the container is an injector device and the sealing member is a moveable plunger. For example, when the container is a syringe, the holder can be arranged to hold the syringe’s plunger, thus preventing it from falling off when vacuum is pulled from underneath the fitting.

Optionally, the fitting may be a quick clamp vacuum fitting. Optionally, applying a differential pressure comprises creating a vacuum at either a first side of the sealing member or a second side of the sealing member. That is, in the example of a syringe, vacuum can be created on either side of the plunger.

Optionally, the holder comprises a stem that mates with a corresponding recess of the sealing member, thereby holding in place the sealing member when the differential pressure is applied. For example, the stem can have a screw-thread that can cooperate with the internal screw- thread of the recess in the sealing member.

Optionally, the holder may have one or more vent holes to allow gas particles, for example, helium, to be vented from the side of the holder that is closest to the sealing member of the container to the other side of the holder which is furthest from the sealing member. This means that any helium leaks can be vented from the holder and detected by the detector.

Optionally, the apparatus has a perimeter ring that surrounds the exterior perimeter of the holder. The apparatus may also have a clamp, which is arranged to hold the fitting, the perimeter ring and the holder in place with respect to the container. The clamp may also engage the perimeter ring when the clamp is in a closed position.

Optionally, the perimeter ring can have a mesh that engage the side of the holder that is furthest from the sealing member. Optionally, the perimeter ring may be a stainless steel ring.

Optionally, the apparatus may have a connector ring that is located between the sealing member and the holder.

Optionally, the apparatus may comprise a freezing jacket. The freezing jacket provides the desired ambient environment to test the containers as needed. For example, it simulates the low temperatures that containers are typically exposed to for certain applications. The freezing jacket houses the fitting, and the holder, enclose the plurality of external access points, and provide a desired temperature for the container. The freezing jacket may also house a clamp. An aspect of the freezing jacket is the ability to control the temperature of the test fixture and container such that CCI is tested in conditions in which they would be exposed to when used in, for example, gene therapy applications. Optionally, the container may have a tube, for example, a syringe’s tube, which is connected to a different external access point to the one that the sealing member seals. The differential pressure may then be applied through the tube.

Optionally, the freezing jacket can have an inlet for letting in super-cooled fluid. The freezing jacket can also have coils wound around its perimeter to aid in thermal energy transfer. The super-cooled fluid passes through the wound coils and thus lowers the temperature of the container by thermal energy transfer. The freezing jacket has the ability to control the temperature by either increasing or decreasing the flow rate and purity or concentration of the super-cooled fluid, for example, ethanol in ethanol/water mixture. It will be appreciated that any other liquid or gas may be used to perform this cooling function. This provides the flexibility to modulate the freezing point by altering the concentration of pure ethanol within the mixture while freezing it.

Optionally, the freezing j acket may have an outer shell that insulates the freezing jacket. A lid on this first outer shell covers the top section of the shell. There is also an opening in the lid, which is connected via a tube to a different external access point to the one that the sealing member seals. For example, when the container is a syringe, the syringe’s tube connects the tip of the syringe to the opening in the lid.

Optionally, an alternative configuration for the freezing jacket is one where the jacket has an inner lining containing an absorbent material for absorbing the cooling fluid that passes through the inlet. Such a freezing jacket would be suitable for applications that require cryogenic temperatures, where a cooling fluid such as liquid nitrogen may be used. When a cooling fluid such as liquid nitrogen is deposited or poured onto the absorbent material of the inner lining, it creates an extremely cold temperature environment. In this way, the contents of the freezing jacket (i.e., the test fixture and container) can be kept at around -196°C when performing CCI testing for the container. The freezing jacket may also have a neck tube that is connected to the opening in the lid and which is connected to a different external access point to the one that the sealing member seals via the syringe’s tube. In such a configuration, the differential pressure may be applied via the neck tube. Optionally, the freezing j acket allows gas particles to be vented away from the container from the side of the holder that is closest to the sealing member to the side that is furthest away from the sealing member. Therefore, any helium leaks can be vented away and detected.

Optionally, the differential pressure may be applied via the neck tube of the freezing jacket.

A method for helium leak detection is presented. The method comprises providing a container having a plurality of external access points and a sealing member arranged to seal a first external access point of the plurality of the external access points. The method also comprises providing a fitting configured to enclose at least a portion of the container and a holder configured to hold in place the sealing member of the container when a differential pressure is applied across the sealing member. Finally, the method comprises applying a differential pressure across the sealing member in order to detect a fault in the seal.

Optionally, the container is an injector device and the sealing member is a moveable plunger.

Optionally, the fitting may be a quick clamp vacuum fitting.

Optionally, the applying a differential pressure comprises creating a vacuum at either a first side of the sealing member or a second side of the sealing member.

Optionally, the holder may have one or more vent holes to allow gas particles, for example, helium, to be vented from the side of the holder that is closest to the sealing member to the other side of the holder which is furthest from the sealing member.

Optionally, the method comprises providing a perimeter ring that surrounds the exterior perimeter of the holder. The method may also comprise providing a clamp, which is arranged to hold the fitting, the perimeter ring and the holder in place with respect to the container. The clamp may also engage the perimeter ring when the clamp is in a closed position. Optionally, the perimeter ring can have a mesh that engage the side of the holder that is furthest from the sealing member. Optionally, the perimeter ring may be a stainless steel ring.

Optionally, the apparatus may have a connector ring that is connected with the sealing member and the holder.

Optionally, the method may comprise providing a freezing jacket. The freezing jacket houses the fitting, and the holder, enclose the plurality of external access points, and provide a desired temperature for the container.

Optionally, the container may have a tube, for example, a syringe’s tube, which is connected to a different external access point to the one that the sealing member seals. The differential pressure may then be applied through the tube.

Optionally, the freezing jacket can have an inlet for letting in super-cooled fluid. The freezing jacket can also have coils wound around its perimeter to aid in thermal energy transfer. The super-cooled energy passes through the wound coils and thus lowers the temperature of the container by thermal energy transfer.

Optionally, an alternative configuration for the freezing jacket is one where the jacket has an inner lining containing an absorbent material for absorbing the cooling fluid that passes through the inlet. The freezing jacket may also have a neck tube that is connected to the opening in the lid and which is connected to a different external access point to the one that the sealing member seals via the syringe’s tube. In such a configuration, the differential pressure may be applied via the neck tube. Optionally, the freezing j acket allows gas particles to be vented away from the container from the side of the holder that is closest to the container to the side that is furthest away from the container.

Brief Description of the Figures

Embodiments will now be described with reference to a number of non-limiting examples, as shown in the following figures, in which:

Figure 1 shows a schematic example of a helium leak detection system for testing the container closure integrity (CCI) of a test object;

Figures 2A - 2C shows a typical seal for a vial;

Figures 3A and 3B shows an open system such as a syringe;

Figure 4 shows a typical seal for a syringe shown in Figures 3 A and 3B;

Figure 5A and 5B show examples of existing setups for testing vials and syringes;

Figure 6 A shows depicts a schematic diagram of novel apparatus for testing the CCI of an open system according to an embodiment;

Figure 6B shows an exploded image of the syringe, plunger and holder of Figure 6A;

Figures 6C and 6D show examples of how a holder may be arranged to hold a plunger in place;

Figure 7A shows a cross-sectional view of an example design of the holder;

Figure 7B shows a top view and a bottom view of a holder;

Figures 8A - 8D show how the apparatus may be held together with a clamping mechanism; Figure 8E shows a schematic diagram of a clamp with a fitting;

Figures 9 A - 9C show a freezing jacket that is arranged to provide a desired temperature for a testing fixture and container;

Figure 10 shows an apparatus with a freezing jacket that is arranged to provide cryogenic temperatures for a testing fixture and container; and

Figure 11 shows a method for detecting leaks in a container with more than one external access point.

Detailed description

Embodiments will now be described in the context of a number of exemplary systems and methods. Those skilled in the art will understand that the devices and methods described herein and illustrated in the accompanying drawings are non-limiting exemplary embodiments and that modifications may be made to the described embodiments without departing from the scope of the invention. The features illustrated or described in connection with one exemplary embodiment may be combined with features of other embodiments, or features and/or steps described herein may be replaced with structurally similar and/or functionally equivalent means or steps. Such modifications and variations are included within the scope of the present disclosure.

Moreover, the skilled person will understand that relative terminology used in the following description is used for convenience only, and is not intended to be limiting on the scope of the invention. For example, the terms such as “lower”, “upper”, “top”, and “bottom” designate directions in the drawings to which reference is made. These terms are not intended to be limiting on the orientation of devices described herein. The terms “comprising” and “including” are used to refer to non-exhaustive lists of components or steps, and devices or methods according to the invention may include additional features or steps not listed in the claims or description. With reference to Figure 1, system 100 depicts a schematic example of a helium leak detection system for testing the CCI of a test object 101. Helium is an inert gas with a small atomic size, which means that it passes easily through leaks, thus making it an ideal choice for leak detection. The test object 101 may be filled with helium and is sealed prior to being placed in chamber 102. Chamber 102 can be evacuated with a vacuum pump. By connecting the chamber 102 to a helium detector 103, such as the HLD PD03 by Agilent™, the SIMS 1915+ by Leak Detection Associates™ or HD1 by Vaseco ^M. Helium that is leaked from test object 101 is detected by the helium detector 103, and the level of detected helium is measured. Depending on the application, different thresholds for the volume of detected helium may be used to indicate a leak.

For example, the isolated part of the container can observe around a 1 atm pressure differential. Once pumped down, the instrument starts to detect a leak rate of helium over time. If the container has a leak, helium will travel from the 1 atm helium of the upper fixture to the lower pressure (1 atm pressure differential) through the defect. The leaking helium will then be detected by the detector.

Depending on the test method, apparatus and desired specimen, a target leak rate will have different thresholds. Helium’s detection range lies between 10'² and 10'¹³ Pa-m³/s. As an example, a container with a seal tolerance of 0.8 microns is considered to be “gas tight” when the leak rate is less than around 10'⁹ mbar 1/s. Therefore, depending on the target application, the user can specify the target leak rate and associated setup conditions to achieve that leak rate sensitivity.

Referring back to Figure 1, the test object 101 can be a vial such as the one shown in Figures 2A - 2C, or a syringe, as shown in Figures 3 A, 3B and 4, although it can be any sealed object. Sealing, as referred to here, means closed in a way that prevents the flow of fluids such as helium and air into and out of the container. A seal is therefore arranged to seal an aperture in a body. Leakage, as referred to here, is a flow of fluid, for example helium, from a higher pressure area to a lower pressure area through a fault in an assembly or manufactured part of the container, for example, test object 101.

With reference to Figures 2 A - 2C, it shows a typical seal for a vial 201, comprising a rubber stopper 202 and an aluminium cap 203. The rubber stopper is configured to close an opening of the vial 201. Here, there are two sealing surfaces: the primary seal 204 and the secondary seal 205. The rubber stopper’s interference with the neck of the vial 201, provides a secondary seal 205, and the mechanical force used in crimping the aluminium cap 203 over the vial 201 provides the primary seal 204. These sealing surfaces create a fixed volume which becomes closed if crimping is performed correctly. The primary seal 204 and the secondary seal 205 are two constituent parts of a single seal around the orifice of the vial.

A vial is classified and tested as a “closed system” - meaning it is completely sealed and only opened to extract the contents - for example a drug product. Testing closed systems is relatively straightforward, since if a leak is detected, it is highly likely that the seal is deficient.

By contrast, a syringe, such as those shown in Figures 3A, 3B and 4, can be classified as an open system since it has more than one orifice/point of entry. As such, present CCI testing can be difficult, as one can only determine whether or not the entire package is leaking instead of being able to test individual seals and ascertain the root cause and mitigate or redesign to account for the problem. Examples of a typical syringe are shown in Figures 3A and 3B. Syringes serve a dual purpose: to store and deliver drug product as one device/system. Within a syringe, the plunger has a dual function where it maintains the container closure integrity (CCI) within the fixed volume (typically a barrel), as well as pushes drug product out of the container once the user has overcome the break loose extrusion forces.

Syringes have one end from which they are filled and then sealed, while the other end has a luer lock or needle or another port to allow delivery of drug out of the barrel. With dual seals and ports of entry/exit, the user must test each seal and isolate them, enabling finer control over the CCI of the system. Finer control allows for more robust design and testing of the container improving product development efficiency and efficacy. Within cell and gene therapy, this would be critical as the therapies are of high value and testing for maintaining CCI must occur at extreme temperatures. It is advantageous to have a test apparatus and method which is capable of isolating individual seals ascertaining CCI for complex containers at extreme temperatures.

With reference to Figures 3A and 3B, syringes typically have one end - labelled orifice 301 - from which they are filled. Orifice 301 may have a luer lock tip cap 305, as shown in Figure 3B or a needle tip cap 303, as shown in Figure 3 A, or other ports, to allow delivery of drug out of the barrel 304 of the syringe. The luer lock tip cap 305 and the needle tip cap 303 (or other ports) provide a leak tight seal prior to drug delivery.

With reference to Figures 3A and 3B, a second opening - orifice 302 - is sealed via a plunger 306. This seal is only breached once the drug is to be injected into the patient. In having multiple seals and ports of entry/exit, the user can more easily test each seal and isolate them from each other, giving finer control over the CCI of the entire system.

With reference to Figure 4, a typical seal for a syringe comprises a plunger 401 with multiple sealing ribs 402, 403. The plunger 401 is located with the barrel 404 of a syringe, and has an outer dimension that is arranged to closely match that of the interior of the barrel. The sealing rib 402402 is located toward a front end of the plunger, that is, the sealing rib is located towards the end of the plunger that comes into contact with a drug product present in the syringe. The sealing rib 402 is formed around a circumference of the plunger and is used to create the seal and has a thickness to create enough resistive force to seal the barrel 404. The sealing rib 403 is used to support and stabilise the plunger 401 as it travels through the barrel 404. The plunger 401 typically has a two-fold use: it is used to seal the container when in storage, and also used to push drug product forward and express it out of the syringe when being advanced in the barrel 404.

With reference to Figure 5, it depicts examples of existing setups for testing test objects such as vials and syringes. In Figure 5 A, the test object is a sealed vial 501, which is inverted and placed inside a vacuum fitting chamber 502. Similarly, Figure 5B shows a syringe 503 placed inside a vacuum fitting chamber 504, where vacuum is typically pulled from underneath the vacuum fitting chambers 502, 504. A problem with such a setup is that helium detection testing is only possible for the entire container as a closed system.

With reference to Figure 6A, it depicts a schematic diagram of an apparatus 600 for testing the CCI of an open system according to an embodiment. Of course, the apparatus can also be used for testing a closed system. An open system is a system that comprises more than one access point such as an orifice or a point of entry. Although the apparatus 600 is described in relation to testing a syringe, a person skilled in the art will understand that apparatus 600 may be used for any container with a sealing member and more than one access point. Syringe 601 is an example of an open system, with two orifices. A sealing member 602, for example, a moveable plunger 602, provides a seal for the syringe 601, as described with reference to Figure 4. In general, a sealing member may be a component that seals an opening in the container by providing a physical barrier to prevent fluid to pass from one side of the container to another side of the container. In addition, apparatus 600 comprises a fitting that encloses at least a portion of the syringe 601. Importantly, apparatus 600 also comprises a holder, such as holder

603, which is arranged to hold the plunger 602 in place when a differential pressure is applied across the plunger 602 during testing of the seal. That is, the holder is integrated into the fitting.

Applying a differential pressure may comprise actively altering the pressure at one side of the seal such that it is different from a pressure at the other side of the seal.

The purpose of the fitting is to hold the container in place as the differential pressure is applied. For example, the fitting may fit tightly around the container. The fitting can be vacuum fitting

604, for example, a quick clamp vacuum fitting. The fitting can be adapted to connect to a pump, such as a vacuum pump, that applies the differential pressure. The use of the fitting provides the benefit of keeping components of apparatus 600 tightly packed as well as sealing the joining sections so that they are not exposed to external temperature environment, thus minimizing potential leak paths at connection points or joints between tubing which can be a potential source of gas leak.

Figure 6B depicts an exploded image of the syringe 601, plunger 602 and holder 603. Optionally, the holder can extend (at least partially) through the syringe 601 to hold the plunger 602 in place, as will be described further, below. The container may also have a tube, such as syringe with tube 601a, shown in the figure. The purpose of this tube is to provide a conduit through which a differential pressure may be applied to a second external access point of the container. In the case of a syringe with tubing, the tube allows for a differential pressure to be applied so as to test the integrity of the needle tip cap or luer lock cap at the tip of the syringe. It is noted that the tubing is placed on top of/connected to the syringe during tests, as a flow conduit/pathway.

Optionally, when applying the differential pressure, a vacuum can be created at either the first side or the second side of the sealing member (e.g., plunger 602). Holder 603 ensures that the sealing member 602 is kept in place, i.e., does not fall off, or out of the barrel, in the case of a syringe plunger, when vacuum is pulled on the vacuum fitting and a differential pressure is applied across the sealing member 602 from either the first or the second side.

Optionally, the syringe 601 can be held in place via a clamp on its upper surface. The syringe could be fixtured by a clamp such a toggle clamp as known in the art, which requires minimal surface area, but has a 90 degree motion which pushes the syringe down into the holder and holds it in compression.

Figures 6C and 6D depict examples of how a holder 603 may hold the plunger 602 in place.

With reference to Figure 6C, a conforming connector ring 605 may be seated on the holder surface between the syringe flange and the holder. The connector ring 605 may be used to block potential leak pathways between the holder 603 to the sealing member 602, which, in Figure 6C, is a plunger 602. In this case, the syringe 601 extends (at least partially) through the holder 603 and connector ring 605 encircles the syringe such that the connector ring 605 is connected with the holder 603 and the syringe 601. Put another way, the holder comprises a collar which encircles part of the syringe 601. The holder 603 may comprise a stem which abuts the plunger 602 so as to hold it in place. The collar of the holder may be arranged to fit around, or encircle the vacuum fitting (not shown in Figure 6C). The conformable connector ring is compressed by inserting the syringe into the holder and when clamped and under compression provides a face seal which allows gas flow only in the desired direction and reduces the susceptibility to a leak at the connection point between the plunger and holder. For example, the connector ring can be an o-ring, which is used to provide a face or axial seal as it is compressed. In the configuration of Figure 6C, the syringe can be clamped to the holder to keep it in place. For example, this can be done via a vacuum clamp such as syringe clamp, shown in Figure 6D and Figures 8A, 8C, as described below.

With reference to Figure 6D, the holder 603 may extend (at least partially) through the syringe and it may comprise a stem 606, where the stem 606 mates with a recess in the sealing member 602. For example, the stem can comprise an external screw-thread that cooperates with another screw-thread that is within the sealing member’s recess. In this way, the sealing member is held in place when a differential pressure is applied across it in either direction. Alternatively, the holder may be arranged so as to cooperate with the sealing member so as to form an interference fit when they are brought together, thereby maintaining the holder and the sealing member in a fixed relationship during the testing process, when the apparatus is subject to the forces that will result from the application of the differential pressure to the sealing member.

By employing the holder, pressure may be applied on one or both sides of the sealing member, while maintaining a closed volume through the sealing member (e.g., the plunger). That is, gas can be vented and/or drawn from one or both directions.

With reference to Figure 7A, it illustrates cross-sectional and transparent views of an example design of the holder 603. As can be seen, the holder 603 comprises vent holes 603v that allow gas particles to be vented from the top of the holder, i.e., the side that is closest to the container, to the bottom of the holder, i.e. the side that is furthest from the container. The vent holes 603v are channels which extend from one side of the holder to another side located away from a seal being tested. The vent holes are encapsulated by the container (e.g., barrel of syringe), which allows any potential leaks to be measured as air is vented downwards. Figure 7A shows that the holder comprises a stem, for engaging a sealing member, as described herein. The vent holes 603 v may be located within a plurality of support columns 603 s, which provide the holder with structural strength. It is noted that the rest of the connections to the container/sealing member must not introduce a leak pathway. The syringe and sealing members will be dimensioned smaller than the location of the vent holes 603v. Thus the vent holes are at a location separate from the assembled syringe, holder and plunger. This is akin to a car keeping its passengers “sealed” even though the AC can allow desired air in while the external weather (rain, snow etc) represents the vent holes. The vent holes need to be dimensioned so as not to influence the test setup but only allow for venting in the event of a leak. The vent holes are typically of a diameter of around 1mm. For clarity these are vent holes outside the test part rather than the flow holes used for the test part.

In the event of a leak, as a differential pressure is applied across the sealing member, for example, when vacuum is pulled at the bottom of the holder (the side that is furthest from the container), the presence of the vent holes allows the vacuum to create a negative pressure at the sealing member. This, in turn, allows for helium gas, leaking from the container, to be directed through the vent holes and down the holder to a detector, where the leak may be detected. Although four vent holes are shown in the figure, the holder may comprise one or more vent holes. Additionally, the holder may comprise support columns 603s. Figure 7B illustrates a top view (where the holder is closest to the container) and a bottom view (where the holder is furthest from the container) of the holder 603.

Figures 8A - 8D show how apparatus 600 may comprise a clamping mechanism for holding the container and the test fixture together.

With reference to Figures 8 A and 8C, as described above, apparatus 600 may have a perimeter ring 607 that surrounds the external perimeter of the holder 603. The apparatus may also have a clamp 608 that holds the vacuum fitting 604, the perimeter ring 607, and the holder 603 in place with respect to the syringe. The clamp 608 may be arranged to engage the perimeter ring 607 when the clamp is in a closed position, as shown in Figures 8A and 8C.

With reference to Figure 8E, a schematic diagram of a clamp 608 with a fitting 604 is shown.

As can be seen in the figure, the clamp 608 comprises two hinged components, 608B and 608C, which are coupled together via a hinge 608a at their first ends. The two components tightly encircle the fitting 604 and are arranged to be coupled together at their second ends by a coupling means. The coupling means can, for example, be a screw or a quick clamp mechanism 608d. A quick clamp can open and close easily and quickly, thus facilitating frequent assembly and disassembly. The holder may be installed in apparatus 600 before the apparatus is clamped together. In this way, the same surface remains exposed to the ambient environment, regardless of whether or not the holder is in position. The top surface where the syringe tip is capped will be exposed to the ambient environment. For this embodiment where the ambient environment is controlled, this ensures that the syringe is not insulated against the temperature changes and thus can reach the desired temperature for the test.

In the configuration shown in Figure 8A, the holder 603 does not extend through the clamp base. An aspect of this arrangement is that it reduces the exposure of the holder 603 to temperature variations when apparatus 600 goes through different temperature cycles. This, in turn, ensures that the holder 603 maintains the required fit with the plunger and syringe, ensuring that that the plunger 602 does not fall out and/or that CCI is not lost as a result of a faulty fit or connection. In the configuration of Figure 8 A, the perimeter ring 607 has a mesh that engages the bottom of the holder, i.e., the side of the holder that is furthest from the syringe 601, to hold it in place and allow for the passage of any leaked gas from the seal (if faulty) through the vent holes and outward towards the detection apparatus (not shown). The perimeter ring 607 is shown in Figure 8B and may be made of stainless steel. The mesh reduces the susceptibility of the perimeter ring to loosening when apparatus 600 is used in low temperatures, while allowing for gas that is vented through the vent holes to pass through the ring and be measured in the event of a leak.

With reference to Figure 8C, it shows an alternative arrangement of the holder with respect to the clamp. In this arrangement, the holder 603 has a holder trunk 603a that extends through the clamp 608 and plunger 602 sits within the clamp 608. In order to allow the holder trunk 603a to extend through the clamp, the perimeter ring is an O-ring without a mesh, as shown in Figure 8D. In the embodiment comprising the trunk, the holder 603 is not required to be held in place by the mesh of the O-ring, so no mesh is required. The holder 603 may also include an optional stem extension that extends from stem 606. The stem extension mimics the tip of a plunger rod and preferably fills most, if not all, of the internal cavity of the plunger 602 to provide a rigid internal support for the plunger. This may be preferred for certain leak testing in order to obtain a more accurate measurement of the performance of the plunger. If the stem extension is not present, the plunger may collapse/compress under vacuum to an extent that is unlikely to occur than if a plunger rod was present resulting in different sealing performance.

In the configurations of Figures 8A and 8C, the small vent holes within the holder 603 allow gas to be vented away from the apparatus while the rest of the connections must not introduce a leak pathway. That is, the only way for gas to be vented away from the container is the small vent holes. In these configurations, there are four vent holes which will be encapsulated by the barrel of the syringe. This allows any potential leaks to be measured as the air is vented downwards and away from the seal towards a gas detector. The vent holes need to be dimensioned so as not to influence the test setup but only allow for venting in the event of a leak. It will be appreciated that more or fewer vent holes may be provided as long as a measurable amount of gas can pass through the holder and be measured.

In this way, apparatus 600 enables the testing of an open system with more than one point of access. Although the configurations of apparatus 600 shown in Figures 6 - 8 depict a system where the sealing member that is being isolated and tested is plunger 602, it is to be understood that apparatus 600 can be used in the same way to test a syringe’s tip cap, such as those shown in Figure 3A and 3B. It is also to be understood that apparatus 600 can also be used to test a variety of container geometries and configurations, including vials, cartridges and syringes, and the holder 603 may be arranged to hold the corresponding sealing member in place.

Although described with particular reference to Figures 7A, 7B and 8A to 8C, it is to be understood that the various embodiments described herein comprise vent holes which allow for gas to be vented from one side of the holder located at the seal or sealing member in question, and the other side of the holder, where leaked gas from a potentially leaky seal may be detected as described herein.

Freezing Jacket

As noted above, gene and cell-based therapies are required to be stored at low (-80°C) and cryogenic (-196°C) temperatures, respectively. However, existing test setups do not allow for testing at different temperatures as they are limited to the ambient environment around the existing equipment. To be able to accurately test CCI for containers used in such applications, it is paramount that test fixtures can replicate these extreme environments. It is thus important to have a test system and method which is capable of isolating individual seals in a container to ascertain CCI for the more complex containers, such as those with multiple openings, at extreme temperatures.

With reference to Figures 9 - 10, a novel setup is presented that simultaneously tests a container's seal integrity whilst allowing for finer control of the test environment to generate much lower temperatures (-20°C down to -196°C) and therefore simulate a cryogenic temperature cycle. The containers being tested should ideally be empty before they are sealed. A small amount of helium is injected into the container prior to sealing. In this way, helium leaks may be detected should the seal(s) be faulty. In these figures, the apparatus includes the integration of a freezing jacket, which provides the desired ambient environment to test the containers as needed. The test fixture and container of apparatus 600, discussed above, is housed within this jacket, and this enables a user to test a container's individual seals at temperatures below freezing. It should be appreciated that the test fixture of any of the embodiments of apparatus 600 described above may be used with a freezing jacket. Figure 9A depicts a perspective view of a freezing jacket 900 that is arranged to provide a desired temperature from room temperature to around -100°C for the container that is placed inside it. The freezing jacket 900 houses, that is to say substantially surrounds or encloses, the vacuum fitting 604, and the holder 603 and encloses the external access points of a container such as a syringe 601, as shown in Figure 9C. The freezing jacket may also house the clamp 608.

With reference to Figure 9B, which shows a cross-section of the freezing jacket 900 with no apparatus 600 present; the freezing jacket 900 uses convective heat transfer to lower the temperature of the test fixture’s ambient environment in a controllable way. The freezing jacket 900 has a first inlet 902 through which a super-cooled fluid is received. The super-cooled fluid can, for example, be a mixture of ethanol and water. The super-cooled fluid is passed in through the first inlet 902 and then travels via tightly wound coils 908 to transfer thermal energy away from the interior of the jacket causing the temperature of the test fixture and the container of apparatus to be lowered. An aspect of freezing jacket 900 is the ability to control the temperature by either increasing or decreasing the flow rate and purity or concentration of the super-cooled fluid, for example, ethanol, in the bath. For example, when the super-cooled liquid is 100% ethanol, the freezing point of the super-cooled fluid is around -115°C while a mixture including 80% ethanol and 20% water would have a freezing point of around -59°C. Therefore, this provides the flexibility to modulate the freezing point by altering the concentration of pure ethanol within the mixture while freezing it.

The freezing jacket also has an outer shell that further insulates the jacket, and a lid 905 on the outer shell to cover the top of the shell. The lid has an opening (a hole) 901 on a top surface, and a tube 906 connects the opening 901 to the interior of the freezing jacket 900. The other end of the tube 906 can be connected to the second access point of the container in the apparatus. When the container is syringe 601 , the syringe’ s tube 601a can be arranged to extend through tube 906 and the opening 901 without the need for an additional tube 906. This is shown in Figure 9C. The freezing jacket 900 also has another opening 907 in its base to allow gas or air flow from the interior of the helium leak test set up. Optionally, a fixture 904 such as an L-shaped mount bracket may be used to seat the holder in place.

With reference to Figure 9C, it shows a cross-sectional view of the freezing jacket 900 with the test fixture and container placed inside the freezing jacket 900. Although a particular configuration of the test set up is shown in conjunction with a syringe, it is to be understood that the other configurations (as shown, for example, in Figures 6D, 8A and 8C) are also possible. That is, the freezing jacket shown in Figure 9C can be used in a similar manner with a holder that does not extend through the clamp, such as the one shown in Figure 8 A. If a holder 603, such as the one in Figure 8A is used, it may be necessary to use a connector, such as the bottom vacuum fitting 604, that can seal the perimeter of the steel mesh O-ring and extend down through the opening 907 of the freezing jacket 900. A fixture, similar to fixture 904, may be inserted in the annular space around the bottom vacuum fitting 604 that extends through the opening 907 to ensure a seal around the outer surface of the vacuum fitting 604 and the inner surface of the opening 907. Of course, it is also possible to use the setup shown in Figure 9C to carry out CCI testing for containers other than a syringe. A pressure differential can be applied either from the top of the freezing jacket through tube 601a, or it can be applied from the base of the freezing jacket through hole 907 and/or holder 603 in the manner described above.

In order to simulate operating conditions with a temperature lower than -100°C, such as those used in cryogenic applications, it is preferable to use a freezing jacket with a cooling fluid such as liquid nitrogen. This is shown in Figure 10, which shows a cross section of a freezing jacket apparatus. With reference to Figure 10, apparatus 600 comprises a freezing jacket arranged such that the fitting, the clamp, the holder and the container may be placed inside freezing jacket 1000 via either the lid 905 or through the removable base. The freezing jacket 1000 of apparatus 600 has one or more inlets 1004 that allow passage of cooling fluid such as liquid nitrogen into the freezing jacket. Freezing jacket 1000 may also include an inner lining 1007 in communication with the one or more inlets 1004 that contains absorbent material for absorbing the cooling fluid. When a cooling fluid such as liquid nitrogen is deposited or poured via the one or more inlets 1004 onto the absorbent material of the inner lining 1007, it creates an extremely cold temperature environment within the freezing jacket. In this way, the contents of the freezing jacket (i.e., the test fixture and container) can be kept at operating temperatures at or below freezing, e.g., less than or equal to approximately -20° C, -40° C, -80° C, -120° C, -180° C, or -196° C, when performing CCI testing for the container.

Insulation 1005 insulates the freezing jacket while a lid 1003 covers the top section of the freezing jacket. There is an opening 1001 in lid 1003, which is connected to a neck tube 1002 that extends through the lid 1003. In the example of Figure 10, the container is syringe 601, where syringe tube 601a extends through the neck tube 1002 from the exterior of the freezing jacket to the syringe’s second external access point, i.e., the syringe tip.

In a similar manner described in relation to freezing jacket 900, freezing jacket 1000 has an opening in its base that allows gas or air flow from the helium leak test set up. The freezing jacket 1000 ensures that the container and test fixture in apparatus 600 are kept at cryogenic temperatures, while the holder ensures that the sealing member is kept in place when a differential pressure is applied across it. The differential pressure can be applied via either the opening in the base of freezing jacket or via neck tube 1002, which provides further flexibility when testing the container for CCI. For example, gas particles, e.g., helium and air, can be vented away from the bottom of the holder 603 through the opening in the base of the freezing jacket 1000, while the differential pressure is applied via the top of the holder 603.

It is noted that the holder can pass through the freezing jacket, as shown, for example, in Figure 9C, or it can be enveloped within the freezing jacket, as depicted in Figure 10. The latter configuration provides better temperature control as the whole test fixture is encompassed by the freezing jacket.

It is to be understood that although freezing jackets 900 and 1000 are described in relation to a container with more than one external access point, such as a syringe, they can equally be used to test CCI for closed systems such as vials in low temperatures. In a scenario where the freezing jacket is used in conjunction with a closed system, the freezing jacket may be modified by eliminating or sealing the opening 109 in Figure 9A and the tube 906 in Figure 9B, so that the jacket is only open at one end through hole 907. The closed system, e.g., a vial, may then be loaded into the jacket to reduce its temperature prior to applying a vacuum through the hole 907. A fitting, such as vacuum fitting chamber 502 in Figure 5A for holding the vial upsidedown, may be placed over the hole 907. A fixture, similar to the one in Figure 9C, may also be used to maintain the vial fitting within or above the hole 907.

Method of detecting faults in a seal

With reference to Figure 11, method 1100 can be used to detect leaks in a container with more than one external access point, using the test fixture of apparatus 600, described in the embodiments above. At step 1101, a container is provided. The container is an open system, such as syringe 601, in that it has more than one external access point. The container also has a sealing member, such as plunger 602 that is arranged to seal one of the external access points. Examples of a typical syringe are shown in Figures 3A and 3B. Syringes serve a dual purpose: to store and deliver drug product as one device/ system. Within a syringe, the plunger has a dual function where it maintains the container closure integrity (CCI) within the fixed volume (typically a barrel), as well as pushes drug product out of the container once the user has overcome the break loose extrusion forces. Syringes have one end from which they are filled and then sealed, while the other end has a luer lock or needle or another port to allow delivery of drug out of the barrel. With dual seals and ports of entry/exit, the user must test each seal and isolate them, enabling finer control over the CCI of the system.

At step 1102, a fitting such as vacuum fitting 604 is provided. The fitting encloses at least a portion of the container. The purpose of the fitting is to hold the container in place as the differential pressure is applied. For example, the fitting may fit tightly around the container. The fitting can be vacuum fitting 604, for example, a quick clamp vacuum fitting. The fitting can be adapted to connect to a pump, such as a vacuum pump, that applies the differential pressure. The use of the fitting provides the benefit of keeping components of apparatus 600 tightly packed so that they are not exposed to external temperature environment, which can be a potential source of gas leak.

Importantly, at step 1103, a holder, such as holder 603, is provided to hold in place the sealing member of the container when a differential pressure is applied across the sealing member. Holder 603 ensures that the plunger is kept in place, i.e., does not fall off, when vacuum is pulled on the vacuum fitting from either the first or the second side. A connector ring may be connected with the holder 603 and the sealing member 602, which, in Figure 6C, is a plunger 602. In this case, the syringe 601 extends (at least partially) through the holder 603 and connector ring 605 encircles the syringe such that the connector ring 605 is connected with the holder 603 and the plunger 602.

Apparatus 600 may have a perimeter ring 607 that surrounds the external perimeter of the holder 603. The apparatus may also have a clamp 608 that holds the fitting 604, the perimeter ring 607, and the holder 603 in place with respect to the container (e.g., syringe). The clamp 608 may be arranged to engage the perimeter ring 607 when the clamp is in a closed position. The clamp 608 comprises two hinged components, 608b and 608c, which are coupled together via a hinge 608a at their first ends. The two components tightly encircle the fitting 604 and are arranged to be coupled together at their second ends by a coupling means. The coupling means can, for example, be a screw or a quick clamp mechanism 608d. A quick clamp can open and close easily and quickly, thus facilitating frequent assembly and disassembly. The holder may be installed in apparatus 600 before the apparatus is clamped together.

The holder 603 may extend (at least partially) through the syringe and it may comprise a stem 606, where the stem 606 mates with a recess in the sealing member 602. For example, the stem can comprise an external screw-thread that cooperates with another screw-thread that is within the sealing member’s recess. In this way, the sealing member is held in place when a differential pressure is applied across it. Alternatively, the holder may be arranged so as to cooperate with the sealing member so as to form an interference fit when they are brought together, thereby maintaining the holder and the sealing member in a fixed relationship during the testing process, when the apparatus is subject to the forces that will result from the application of the differential pressure to the sealing member.

The holder 603 may or may not extend through the clamp base. When the holder does not extend through the clamp base, the perimeter ring 607 has a mesh that engages the bottom of the holder, i.e., the side of the holder that is furthest from the syringe 601. When the holder 603 extends through the clamp 608, the plunger 602 sits within the clamp 608. In order to allow the holder to extend through the clamp, the perimeter ring is an O-ring without a mesh.

Small vent holes within the holder 603 allow air to vented away from the apparatus while the rest of the connections must not introduce a leak pathway. These vent holes which are encapsulated by the barrel of the syringe. This allows any potential leaks to be measured as the air is vented downwards. The vent holes need to be small enough so as not to influence the test setup but only allow for venting in the event of a leak. It will be appreciated that more or fewer that four vent holes may be provided as long as a measurable amount of gas can pass through the holder and be measured. Once this test set up is in place, a differential pressure is applied across the sealing member to detect a fault in the seal. In the event of a leak, as a differential pressure is applied across the sealing member, for example, when vacuum is pulled at the bottom of the holder (the side that is furthest from the container), the presence of the vent holes allows the vacuum to create a negative pressure at the sealing member. This, in turn, allows for helium gas, leaking from the container, to be directed through the vent holes and down the holder to a detector, where the leak may be detected.

Fault detection can be done using helium leak detection methods that are known in the art. As an example, in “outside/in” helium leak detection, vacuum is pulled on the container being tested or it is pulled through the part, helium is sprayed in miniscule amounts on the lowest seal integrity or leaking areas of the part. The vacuum pulls it through if there is a leak and the detector can identify and quantify the amount of helium coming through.

Another type of helium leak test is inside/out leak detection, i.e., a sniffer helium leak detector. In this scenario, the part or container is pressurized with helium, if there is a leak, the helium will pass through it. This helium is then detected on the side with atmospheric pressure and the leak location will be found. The sniffer method is not as effective as that of the outside in since there’s atmospheric helium with a concentration of approximately 5ppm.

Helium leak detection tests involve pressurizing a fixed volume to around 1 atmosphere, followed by measuring the leak rate up to around 2-micron level of sensitivity and/or down to a leak rate of IxlO'¹⁰ mbar 1/s.

The test fixture (the holder, rings, clamp, etc) in apparatus 600 and the freezing jacket may be manufactured via machining metal components combined with plastic and nylon materials known to perform at extremely low temperatures. Electromechanical and thermal inserts as well as joining/fastening components may be included with the refrigerant/freezing fluid reservoir allowing circulation to ensure that the freezing jacket 900 remains at a desired temperature.

For testing samples at cryogenic temperatures, the freezing jacket 1000 contains hydroscopic absorbent material (such as Aerogel, Cabot Corp) in inner lining 1007 that would be charged with liquid nitrogen before use and then placed over the test fixture. An aspect of the various embodiments disclosed herein is that they can be used to test open system containers, used for storing and delivering next generation therapeutics, such as gene- and cell-based therapies, which are required to be stored at low (-80°C) and cryogenic (-196°C) temperature. The holder allows for the test fixture to test more complex containers, sealed components and new configurations at extreme temperatures.

The various embodiments also provide an enabling technology which allows testing and evaluation of more complex and novel container systems, such as cartridges, syringes and unique container systems to be invented for gene- and cell-based therapies. When a container has multiple seals and ports of entry/exit, the user can more easily test each seal and isolate them from each other, giving finer control over the CCI of the entire system. Having this finer control allows for more robust design and manufacturing of components, as this makes it possible to take a more targeted approach to problem solving and design of the container, thus improving overall design and testing efficiency and efficacy. It is advantageous to have a test method which is capable of isolating individual seals within a container and ascertaining CCI for devices and/or products to be used within the advanced therapy space as the freezing jacket ensures allows the seals to be tested at very low temperatures.

It will be appreciated by those skilled in the art that changes could be made to the embodiments described above without departing from the broad inventive concept thereof. It is understood, therefore, that this invention is not limited to the particular embodiments disclosed, but it is intended to cover modifications within the spirit and scope of the present invention as defined by the disclosure herein.

Claims

1. A helium leak detection apparatus for use with a container comprising a sealing member arranged to seal a first external access point, the apparatus comprising: a fitting configured to enclose at least a portion of the container; and a holder configured to hold the sealing member of the container in place when a differential pressure is applied across the sealing member.

2. The apparatus of claim 1, wherein the differential pressure is applied by a vacuum at either a first side of the sealing member or a second side of the sealing member.

3. The apparatus of claim 1, wherein the holder comprises a stem configured to mate with a corresponding recess of the sealing member, to hold the sealing member in place when the differential pressure is applied.

4. The apparatus of claim 3, wherein the stem comprises an external screw-thread arranged to cooperate with an internal screw thread within the recess.

5. The apparatus of claim 1, wherein the holder is configured to at least partially extend through the container to hold the sealing member in place.

6. The apparatus of claim 1, wherein the holder comprises one or more vent holes configured to allow gas to be vented from a first side of the holder proximal to the sealing member to a second side of the holder distal to the sealing member.

7. The apparatus of claim 6, further comprising: a first ring configured to surround an exterior perimeter of the holder; and a clamp configured to hold the fitting, the first ring, and the holder in place with respect to the container, wherein the clamp is further arranged to engage the first ring when the clamp is in a closed position.

8. The apparatus of claim 7, further comprising a second ring located between the sealing member and the holder.

9. The apparatus of claim 7, further comprising a first ring configured to surround an exterior perimeter of the holder, wherein the clamp is arranged to engage the first ring when the clamp is in a closed position, and wherein the first ring further comprises a mesh arranged to engage a second side of the holder distal to the container.

10. The apparatus of claim 1, wherein the container is an injector device and the sealing member is a moveable plunger.

11. The apparatus of claim 1, further comprising a freezing jacket configured to: house the fitting and the holder; enclose the first external access point; and set the container to a predetermined temperature.

12. The apparatus of claim 11, wherein the freezing jacket comprises: a first inlet; and a wound coil configured for thermal energy transfer, wherein the freezing jacket is configured to receive a super-cooled fluid through the first inlet and wound coils to lower the temperature of the container by way of thermal energy transfer.

13. The apparatus claim 11 , wherein the freezing j acket comprises: a first outer shell configured to insulate the freezing jacket; a first lid on the first outer shell configured to cover a top section of the first outer shell; and a first opening in the first lid, the first opening enabling a second external access point to be connected to a first conduit that passes through the first opening.

14. The apparatus of claim 11, wherein the freezing jacket further comprises: a second inlet configured to allow a passage of a cooling fluid; an inner lining containing an absorbent material configured to absorb the cooling fluid; a second outer shell configured to insulate the freezing jacket; a second lid on the second outer shell configured to cover a top section of the second outer shell; a second opening in the second lid; and a second conduit connected to the second opening and configured to be connected to a second external access point via a first conduit.

15. The apparatus of claim 14, wherein the differential pressure is applied via the second conduit.

16. The apparatus of claim 14, wherein gas is vented from the container from a first side of the holder to a second side of the holder.

17. The apparatus of claim 16, wherein the differential pressure is applied via the second side of the holder.

18. The apparatus of claim 1, wherein the container comprises a first conduit connected to a second external access point, wherein the differential pressure is applied through the first conduit.

19. A helium leak detection method, the method comprising: providing a container comprising a seal for a first external access point; providing a fitting configured to enclose at least a portion of the container; providing a holder configured to hold the seal of the container in place when a differential pressure is applied across the seal; and applying the differential pressure across the seal to detect a fault in the seal.