Real-time, non-destructive container closure integrity measurement method and measurement system

Abstract

Systems and methods for determining container closure integrity (CCI) in a container system are disclosed, the container system comprising a container, an elastomeric plug, and a retainer for holding the plug in place. The system and method involve providing a component within a seal assembly that is configured to sense the degree of compression of the elastomeric plug. In a first implementation, the elastomeric plug includes an embedded locating component embedded within an elastomeric material. The position of the locating component is sensed using a detection system, and the closure integrity is determined based on the position of the embedded component. In a second implementation, a force sensitive resistor is provided within the seal stack to measure the compression of the elastomeric plug. The compression of the elastomeric plug is associated with seal integrity.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit of and priority to U.S. Provisional Application Serial No. 62 / 796,886, filed on January 25, 2019, the entire contents of which are incorporated herein by reference. Technical Field

[0003] The present disclosure relates to systems and methods for determining container closure integrity (CCI) in a container system, which allow non-destructive CCI testing. More particularly, the present disclosure relates to systems and methods for determining the position and / or compression of an elastomeric plug in a sealed container system. Background Art

[0004] Pharmaceutical products are stored in a variety of container systems, including vials and drug reservoirs used with drug delivery devices. Closures for container systems should provide a barrier that protects the stability and sterility of the pharmaceutical product in the container system during its shelf life by preventing the intrusion of microorganisms, moisture, and gas into the interior volume of the container.

[0005] Container Closure Integrity (CCI) testing is used to evaluate the suitability of closure seals for use in container systems. Current CCI testing methods include microbial and dye intrusion testing, qualitative and quantitative headspace testing, vacuum or pressure decay testing, high voltage leak detection (HVLD), and helium leak detection.

[0006] However, these methods are limited by their destructive nature, the complex laboratory equipment required to perform the tests, and their unsuitability for certain drug types (eg, HVLD).

[0007] There is a need for improved CCI testing methods. Summary of the invention

[0008] Generally speaking, the present disclosure provides improved methods and systems for determining container closure integrity (CCI) by measuring compressive forces within a seal stack comprising a container rim, an elastomeric plug, and a retainer for pressing the plug against the rim of the container. In embodiments of the present invention, the seal stack preferably includes a sensor or detectable component disposed within the seal stack to directly measure the compression of the elastomeric plug, such that the CCI of the container can be measured in a non-destructive manner at different points during the shelf life of the product. For example, embodiments of the present invention can be used to determine the CCI of a container system at at least one of the following points during the use of the product: immediately after sealing, at the end of a production line, during or after the product is stored for a period of time, or at point-of-care.

[0009] In a first aspect, a method for determining container closure integrity in a container system is provided, the container system comprising a container, an elastomeric plug including an embedded locating feature, and a retainer for holding the plug in place, wherein the elastomeric plug is constrained between an edge of the container and the retainer to seal the container. The method comprises: (i) determining the position of the embedded locating feature using a detection system; and (ii) determining the container closure integrity based on the measured position of the embedded detectable feature. By sensing the position of the embedded locating feature within a seal stack formed by the elastomeric plug, the retainer, and the edge of the container, compression of the elastomeric plug can be determined. This in turn can be used to determine the seal integrity of the container system.

[0010] In some embodiments, the method may further include determining a degree of compression of the elastomeric plug based on the position of the embedded positioning component, and wherein the step of determining the container closure integrity is based on the determined degree of compression of the elastomeric plug.

[0011] Optionally, this includes correlating said degree of compression to a residual sealing force for said container system, wherein said step of determining container closure integrity is based on said residual sealing force.

[0012] In some embodiments, the method further comprises calibrating the detection system for detecting the position of the embedded locating feature for a predetermined container system configuration to correlate the detected position of the embedded locating feature with a residual sealing force for the predetermined container system configuration.

[0013] The embedded locating component may include a magnetic material (eg, a permanent magnet), and the step of determining the position of the embedded locating component may include detecting a magnetic field strength.

[0014] The detection system may include a sensor, wherein the sensor detects the magnetic field strength.

[0015] In some embodiments, the embedded positioning component includes a conductive material configured as a first capacitor plate in an electrical circuit, wherein the detection system includes a second capacitor plate in the electrical circuit, and wherein the step of determining the position of the embedded positioning component includes detecting a capacitance of the electrical circuit. The detection system may include a capacitive sensor, wherein the capacitive sensor measures the capacitance of the electrical circuit.

[0016] The second capacitor plate may be formed by a seal formed from an electrically conductive material. The method may include detecting a distance between the seal and the embedded positioning feature.

[0017] In any of the embodiments described in the Summary of the Invention, the container system may include a lid. The lid may optionally include at least a portion of the detection system. For example, the lid may be configured to form a capacitive circuit with a conductive positioning member, or the lid may include a sensor configured to sense magnetic field strength.

[0018] The cap may also include one or more of a microcontroller, a detection circuit, a wireless communication module, and a power source.The method may also include communicating data indicative of container closure integrity to a remote device for display.

[0019] In a second aspect, a method for determining container closure integrity (CCI) in a container system is provided, the container system comprising a container, an elastomeric plug, and a retainer for holding the plug in place, wherein the elastomeric plug is constrained between an edge of the container and the retainer to seal the container. The method according to the second aspect comprises: (i) measuring the resistance of a force-sensitive resistor disposed between the elastomeric plug and the edge of the container or the retainer with a detection system; (ii) determining the container closure integrity based on the measured resistance value.

[0020] The method may further include determining a residual sealing force based on the measured electrical resistance, wherein the step of determining container closure integrity is based on the residual sealing force.

[0021] Advantageously, the method further comprises: calibrating the detection system for a predetermined container system to correlate the measured resistance of the force sensitive resistor; and determining the container closure integrity based on the measured resistance. By calibrating the system, the measured value (e.g., the measured resistance value) can be directly equated to the CCI.

[0022] In some embodiments, the container system may include a lid, wherein the lid houses at least a portion of the detection system. For example, the lid may include a resistance meter that communicates with the force-sensitive resistor to measure the resistance of the force-sensitive resistor within the seal stack.

[0023] The cap may also include one or more of a microcontroller, a detection circuit, a wireless communication module, and a power source.The method may also include communicating data indicative of container closure integrity to a remote device for display.

[0024] In a third aspect, a method for configuring, verifying or monitoring a filling line for producing filled container systems is provided, the method comprising: (i) filling and sealing one or more container systems, the sealed container system comprising a filling container, an elastomeric plug including an embedded positioning component and a retainer for holding the plug in an appropriate position, wherein the elastomeric plug is confined between the edge of the container and the retainer to seal the container, wherein the method further comprises: (ii) determining the position of the embedded positioning component using a detection system; and (iii) determining the container closure integrity based on the measured position of the embedded detectable component.

[0025] The method according to the third aspect may further comprise any of the features described above with reference to the first aspect.

[0026] In a fourth aspect, a method of configuring, verifying or monitoring a fill line for producing filled container systems is provided, the method comprising: (I) filling and sealing one or more container systems, the sealed container systems comprising a filled container, an elastomeric plug and a retainer for holding the plug in place, wherein the elastomeric plug is constrained between a rim of the container and the retainer to seal the container, wherein the method further comprises:

[0027] (ii) measuring the resistance of a force sensitive resistor disposed between the elastomeric plug and the edge of the container or the retainer using a detection system; and (iii) determining the container closure integrity based on the measured resistance value.

[0028] The method according to the fourth aspect may further comprise any of the features described above with reference to the second aspect.

[0029] In a fifth aspect, a method for testing the CCI of a container system at the point of care is provided. The method according to the fifth aspect comprises: (i) using a detection system to determine the position of an embedded locating component within a container system, the container system comprising a container, an elastomeric plug, and a retainer that seals the plug to a rim of the container; and (ii) determining the container closure integrity based on the measured position of the embedded detectable component.

[0030] The method according to the fifth aspect may further comprise any of the features described above with reference to the first aspect.

[0031] In a sixth aspect, a method for testing the CCI of a container system at the point of care is provided. The method according to the sixth aspect comprises: (i) measuring the resistance of a force-sensitive resistor disposed between an elastomeric plug and a rim or retainer of a container with a detection system; (ii) determining the container closure integrity based on the measured resistance value.

[0032] The method according to the sixth aspect may further comprise any of the features described above with reference to the second aspect.

[0033] In a seventh aspect, a detection system for determining container closure integrity of a container system is provided, the container system comprising a container, an elastomeric plug comprising an embedded locating feature, and a retainer for retaining the plug in an appropriate position between the retainer and an edge of the container, the detection system comprising: a sensor configured to determine a position of the embedded locating feature within the container system; and a controller configured to determine the container closure integrity based on a measured position of the embedded locating feature. The detection system may include the container system.

[0034] The detection system may be included in the cap of the container system, or the detection system may be provided in an external reader. In some embodiments, the detection system may be included partially in the container system and partially in the cap or external reader.

[0035] The controller may be configured to determine a degree of compression of the elastomeric plug based on the position of the embedded positioning feature, and determine container closure integrity based on the determined degree of compression of the elastomeric plug.

[0036] In at least some embodiments, the controller is further configured to correlate the determined degree of compression to a residual sealing force for the container system and determine the container closure integrity based on the residual sealing force.

[0037] The controller may be calibrated for a predetermined container system configuration to detect the position of the embedded locating feature to correlate the detected position of the embedded locating feature with a residual sealing force for the predetermined container system configuration.

[0038] In some embodiments, the embedded positioning component includes a magnetic material, and wherein the sensor is configured to detect a magnetic field strength.

[0039] The sensor may be configured to measure the magnetic field strength.

[0040] The embedded positioning component includes a conductive material configured as a first capacitor plate in an electrical circuit, wherein the detection system includes a second capacitor plate in the electrical circuit, and wherein the controller is configured to determine the position of the embedded positioning component by detecting a capacitance of the electrical circuit.

[0041] A capacitive sensor may be configured to measure the capacitance of the circuit formed by the two capacitor plates.

[0042] In some embodiments, the second capacitor plate may be formed by a seal formed of a conductive material, and wherein the sensor is configured to detect a distance between the seal and the embedded positioning feature.

[0043] The container system may include a cover secured to the container system, wherein the cover includes at least a portion of the detection system.

[0044] In at least some embodiments, the cap includes one or more of a microcontroller, a detection circuit, a wireless communication module, and an optional power source. The wireless communication module can be configured to communicate data indicative of container closure integrity to a remote device for display.

[0045] In an eighth aspect, a detection system for determining container closure integrity of a container system is provided, the container system comprising a container, an elastomeric plug comprising a resistance sensor, a retainer for retaining the plug in an appropriate position between the retainer and an edge of the container, wherein a force sensitive resistor is positioned between the elastomeric plug and the retainer. The detection system comprises: a sensor configured to determine a resistance of the force sensitive resistor within the container system; a controller configured to determine the container closure integrity based on the measured resistance of the force sensitive resistor. The detection system may include the container system.

[0046] The detection system may be included in the cap of the container system, or the detection system may be provided in an external reader. In some embodiments, the detection system may be included partially in the container system and partially in the cap or external reader.

[0047] The controller may be configured to determine a degree of compression of the elastomeric plug based on a measured resistance of the force sensitive resistor, and to determine container closure integrity based on the determined degree of compression of the elastomeric plug.

[0048] In at least some embodiments, the controller is further configured to correlate the determined degree of compression to a residual sealing force for the container system and determine the container closure integrity based on the residual sealing force.

[0049] The controller may be calibrated for a predetermined container system configuration to correlate the measured resistance to the degree of plug compression, and determine a CCI residual sealing force for the predetermined container system configuration based on the measured resistance.

[0050] The container system may include a cover secured to the container system, wherein the cover includes at least a portion of the detection system.

[0051] In at least some embodiments, the cap includes one or more of a microcontroller, a detection circuit, a wireless communication module, and an optional power source. The wireless communication module can be configured to communicate data indicative of container closure integrity to a remote device for display.

[0052] In a ninth aspect, a container system including a sterile seal is provided, the container system comprising: a container; an elastomeric plug, the elastomeric plug including an embedded positioning component; and a retainer, the retainer being used to hold the plug in an appropriate position between the retainer and the edge of the container, wherein the embedded positioning system comprises: a magnetic material; or a conductive material.

[0053] The container system may also include a lid. The lid may include one or more of the following: a microcontroller; a detection circuit including a sensor for detecting the position of the embedded positioning component; a wireless communication module; and an optional power source. The wireless communication module may be configured to communicate data indicating the integrity of the container closure to a remote device for display.

[0054] The microcontroller may be configured to measure (and optionally store) magnetic field strength and / or capacitance values. The microcontroller may determine the CCI of the container based on the measured values ​​(and optionally the stored values), or the microcontroller may communicate the stored data to an external reader, which is configured to determine the CCI based on the received data.

[0055] Additionally or alternatively, the container system of the ninth aspect may further include any one of the features described above in conjunction with the seventh aspect.

[0056] In a tenth aspect, a container system including a sterile seal is provided, the container system comprising: a container; an elastomeric plug; and a retainer for holding the plug in an appropriate position, wherein the elastomeric plug is confined between an edge of the container and the retainer to seal the container; and a force-sensitive resistor disposed between the elastomeric plug and the edge of the container or the retainer.

[0057] The container system may also include a lid. The lid may include one or more of the following: a microcontroller; a detection circuit configured to measure the resistance of the force sensitive resistor; a wireless communication module; and an optional power source. The wireless communication module is configured to communicate data indicating the integrity of the container closure to a remote device for display.

[0058] The microcontroller may be configured to measure (and optionally store) the resistance of the force sensitive resistor. The microcontroller may determine the CCI of the container based on the measured (and optionally stored) resistance value, or the microcontroller may communicate the stored data to an external reader, which is configured to determine the CCI based on the received data.

[0059] Additionally or alternatively, the container system of the tenth aspect may further include any one of the features described above in conjunction with the ninth aspect.

[0060] In any of the above embodiments, the cover may further include a hinge. The hinge may include electrical contacts that provide contact between the microcontroller, at least one of the power source and the detection circuit, and at least one of the embedded positioning component and the force sensitive resistor:.

[0061] In an eleventh aspect, a lid for use in any of the above systems and methods is provided. The lid may include a detection circuit configured to determine the container closure integrity of the container system. The detection circuit may be configured to detect at least one of the following: a magnetic field strength of a magnetic element embedded in the elastomeric plug; a capacitance of a circuit including a conductive component disposed in the elastomeric plug as one plate of a capacitor; a resistance of a circuit including a force-sensitive resistor disposed in a seal stack of the container system.

[0062] By providing a cap configured to measure a physical quantity representative of compression of the elastomeric plug, a container system may be provided.

[0063] These and other advantages will be better understood from the following description. BRIEF DESCRIPTION OF THE DRAWINGS

[0064] Specific embodiments are described below in the detailed description by way of example only and with reference to the accompanying drawings, in which:

[0065] Figure 1 The overall workflow of some embodiments of the present invention is shown;

[0066] Figure 2A Shows an embedded conductive disk in a rubber stopper and a plastic cover housing containing additional electronics such as a battery, wireless communication device, or microcontroller;

[0067] Figure 2B An aluminum seal is shown that acts as one conductive plate of a capacitive sensor within a deformable elastomer and an embedded disk in a rubber stopper that acts as a second conductive plate of a capacitive sensor within a deformable elastomer;

[0068] Figure 3An embodiment is shown of an embedded conductive disk acting as one plate of a capacitor and an external conductive plate used to measure the distance between the two plates related to the compressive force.

[0069] Figure 4 A magnet embedded in an elastomeric plug is shown, emitting a varying magnetic field with varying depths.

[0070] Figure 5 A sample graph showing the depth of a magnet measured with a smartphone magnetometer, with varying thickness of rubber placed between the magnet and the sensor.

[0071] Fig. 6A A force sensitive resistor is shown placed between the plastic cover and above the plug;

[0072] Figure 6B Shown is a force sensitive resistor placed beneath an aluminum seal.

[0073] Fig. 7A shows a cross-sectional side view of a sealed container system;

[0074] Figure 7B Shows Fig. 7A A top view of a sealed container system;

[0075] Figure 8 A system for determining container closure integrity according to a first implementation is shown;

[0076] Fig. 9 A system for determining container closure integrity according to a second implementation is shown;

[0077] Fig.10 A system for determining container closure integrity according to a third implementation is shown;

[0078] Fig.11 A system for determining container closure integrity of a container system using an external detection system is shown;

[0079] Fig.12 A system for determining container closure integrity of a container system using a first detection system integrated into a cap is shown;

[0080] Fig.13 A system for determining container closure integrity of a container system including a second detection system integrated into a cap is shown;

[0081] Like reference numerals are associated with like features throughout the drawings. DETAILED DESCRIPTION

[0082] It will be understood that certain terms are used in the following detailed description for convenience and not limitation. The terms 'a / an' and 'the' should be interpreted as 'at least one'. The term 'comprising' will be understood as 'including but not limited to', such that a system or method including specific features or steps is not limited to only those listed features or steps, but may also include features or steps that are not listed.

[0083] Those skilled in the art will also appreciate that modifications may be made to the exemplary embodiments described herein without departing from the present invention. The structural features of the systems and devices described herein may be replaced with functionally equivalent parts. In addition, it will be appreciated that features from the embodiments may be combined with each other without departing from the present disclosure.

[0084] Generally speaking, the present invention includes an embedded sensor system that can provide assurance for container closure integrity (CCI) in a vial system to allow more efficient and faster measurements. The present invention can provide a real-time, non-destructive method for testing CCI when a drug is in a container system. The present invention includes a capacitance-based sensor, a magnetic-based sensor using a Hall effect sensor or a magnetometer, or a force-sensitive resistor (FSR). The capacitance sensor includes a conductive plate embedded in a rubber stopper and an aluminum seal used as a second conductive plate. The capacitance measured between the plates can be measured based on the distance between the plates, and can therefore be related to the residual sealing force (RSF) or crimp height of the vial to verify the container closure integrity. The magnetic sensor is composed of or includes an embedded magnet that emits a magnetic field based on the depth of the magnet in the stopper. The magnetic field can be sensed by an integrated Hall effect sensor or a magnetometer, or it can be sensed using a magnetometer in a smart phone. Finally, the percentage of compression within the elastomer can also be measured using an FSR, which can output a variable voltage based on the amount of force applied to the stopper.

[0085] Currently, the sealing and capping process for glass vials with rubber stoppers affects container closure integrity (CCI). Ensuring an ideal fit between all parts of the vial is essential to maintaining product sterility.

[0086] The present invention uses a capacitance meter, Hall effect sensor, magnetometer or force sensitive resistor (FSR) to measure the stack height of the seal relative to the rubber stopper. These methods will then be correlated to CCI values ​​calibrated and tested for these applications. The present invention allows for more efficient and faster screening to assess the seal quality of vials and therefore provides CCI assurance. The present invention uses a real-time, non-destructive method to measure RSF and correlate it to CCI. The real-time CCI measurement of the present invention will enable more efficient packaging and shipment verification. It will also provide end users with greater assurance of product safety, effectiveness and possibly even product authentication.

[0087] The solution includes a capacitive sensor that measures the stacking height of the seal and plug 204 on the vial container system 202 to ensure proper container closure integrity. The rubber plug 204 contains a conductive substrate 210 (a metal transparent conductive film (such as ITO or PEDOT), carbon nanotubes, graphene, etc.) that will act as one plate of a parallel capacitor, and a metal or other conductive seal 206 as the other plate of the parallel capacitor. The two plates 210, 206 can be connected to a microcontroller 216 and / or a battery 214 housed in the lid 250 of the container system. A second embodiment includes the use of an embedded magnet 410 in the elastomeric plug 404, and the use of a Hall effect sensor or magnetometer to measure the magnetic field that changes with the depth of the magnet 410 placed in the plug 404. A third embodiment includes the use of a force sensitive resistor (FSR) 620 to measure the compression percentage, and then correlate it with a reference value of CCI.

[0088] The above sensors are coupled to a microcontroller 216, 316, 416, which will perform the correlation and analysis of each output value with the CCI test value. The microcontroller output, including the verification of the CCI, can be wirelessly transmitted to a remote display (such as a smart phone, laptop or computer) and / or a cloud-based system (e.g., via Bluetooth low energy, RFID communication (such as near field communication) or Wi-Fi). Bluetooth low energy and Wi-Fi communication will require a power source 214, 414; however, RFID communication (e.g., near field communication (NFC)) does not require a power source. The overall workflow of the proposed invention is as follows Figure 1 shown.

[0089] The solution comprises two conductive parts 210, 206 separated by an elastomeric part 204 which is deformable to allow an increase and decrease in capacitance between the conductive parts 210, 206, such as Figure 2A and Figure 2B as shown. The two conductive components 210, 206 act as capacitive sensors that measure capacitance and transmit that value to a microcontroller 216 where the capacitance is analyzed and correlated to the compressive force applied to the elastomeric component 204. A battery 214 is used to supply power to the circuit, and this may include, for example, a flexible printed battery, a solar cell, or a lithium-ion battery. The output of the compressive force may be transmitted to a remote transceiver to alert a user that a particular residual sealing force is within a particular threshold or tolerance. Additionally, the two conductive plates 210, 206 of the capacitive sensor may be placed in separate components and a signal may only be read when the two plates are brought together. For example, one conductive plate 110a of the capacitive sensor may be embedded within a rubber stopper 204, while a second conductive plate may be an aluminum seal 206 that is typically placed on top of a vial container system, such as Figure 2A and Figure 2B Alternatively, Figure 3 As shown, plug 304 may include conductive member 310 and the second capacitor plate may be formed as plate 312 in the external reader system. Any additional electronics may be housed in the plastic cover 250 of the container system or in an external system that may scan the container system to determine container closure integrity.

[0090] A second embodiment of the present invention includes an embedded magnet 410 in an elastomeric plug 404 and a Hall effect sensor coupled to a microcontroller 416, wireless communications (such as Bluetooth Low Energy, RFID communications (e.g., Near Field Communications), Wi-Fi, Zigbee, etc.), and a power source 414. The Hall effect sensor may output a variable voltage in response to a magnetic field, which may increase or decrease depending on the depth of the magnet 410 in the elastomeric plug 404, such as Figure 4 The embedded magnet 410 may also be detected by a magnetometer, such as that included in a smartphone, so that the depth of the magnet 410 and therefore the amount of RSF may be easily detected by scanning the elastomeric plug 404 . Figure 5 An example graph of the output where a magnetometer is used is shown.

[0091] The present invention may also include a force sensitive resistor (FSR) 620 that may be placed below the flange of the plug to directly measure the RSF placed on the plug, as shown in Figure 6. The FSR sensor may analyze and communicate an output signal over time using similar communication techniques as listed above to verify CCI.

[0092] The present solution may allow for a more accurate, faster and more efficient measurement system to assess container closure integrity. The present invention minimizes the need for manual or visual inspection and thereby improves the accuracy of the measurement as well as the time required. The present invention may allow for the measurement of residual sealing force and the assessment of the crimping of the seal without having to use computer tomography or inspect the system with the human eye.

[0093] The present invention may also include the use of a transparent conductive layer, such as indium tin oxide coated glass, to act as one plate of the capacitive sensing element on the vial. The present invention may also be used in the crimp portion of the seal of the cartridge system.

[0094] The output voltage may also indicate the position of the elastomeric component, as the output voltage may be correlated to the breakaway force and the extrusion force, thereby signaling the position of the elastomeric component in the self-injection system.

[0095] Certain embodiments of the present invention may be compression molded into an elastomeric component or otherwise attached to surrounding components of a containment system by an injection molding process. Electronic components may be embedded in the elastomer using a two-step molding or incremental molding process. Packages for additional electronics such as leads, wiring, batteries, microcontrollers, etc. may be injection molded into secondary components of a containment system.

[0096] The present invention can be used to measure the residual sealing force to verify the container closure integrity, and can improve the current process to be faster and more efficient. For example, the rubber stopper can package the capacitive sensing element with a microcontroller, a battery, and a wireless communication device contained in the plastic cover of the container system. When the vial is subjected to a compressive force, the capacitive sensor warns the user when a specified residual sealing force or crimping height has been reached. Another example includes a rubber stopper with an embedded plate of a capacitive sensing element, which is scanned to engage with a second plate of the capacitive sensor. Then, the capacitance between the plates can be related to a specific distance, and therefore it can be estimated whether the vial has reached a sufficient crimping height.

[0097] The solution can also be used to track and trace container systems to prevent counterfeiting and verify the authenticity of the product. The invention can also be used to warn the user that the container system has been opened, punctured or used before.

[0098] This technology can be applied to any stopper and vial container system requiring container closure integrity. Such a system will provide container closure integrity assurance. The present invention can be used for cartridge systems including crimped seals.

[0099] Now refer to FIG. 7A to FIG. 13 To describe another specific implementation of the above invention.

[0100] Fig. 7A and Figure 7B A container system for containing a pharmaceutical substance is shown. Fig. 7A and Figure 7B The illustrated form of container system 700 may be implemented in conjunction with any of the embodiments described herein.Throughout the embodiments described herein, like reference numerals are used to refer to like parts.

[0101] Fig. 7A A side view of a container system 700 is shown, which includes a container 702 and an elastomeric plug 704 sealing the container 702. Fig. 7A The container 702 shown is a vial configured to hold a medication and may be formed of glass, plastic, or other suitable material. A retainer 706 secures the plug 704 in place and presses the plug 704 against a rim 708 of the container 702. Fig. 7AIn the illustrated embodiment, the retainer 706 takes the form of an aluminum seal crimped over the plug 704 and a flange formed with the edge 708 of the container 702. However, it will be appreciated that other materials may be used to form the sealing wrap. Alternatively (or additionally), the retainer 706 may take the form of a cap secured over the plug 704 and configured to press the plug 704 against the edge 708 of the container 702.

[0102] exist Fig. 7A In the illustrated embodiment, the embedded positioning member 710 is embedded in the elastomeric plug 704. In some implementations, which will be described in more detail below, the embedded positioning member 710 may be omitted, and the force-sensitive resistor may be positioned within the seal stack (the seal stack is formed by the rim, plug, and retainer of the container). In such embodiments, the force-sensitive resistor may be embedded within the elastomeric plug, or the force-sensitive resistor may be placed between the plug and the rim or retainer.

[0103] Figure 7B 7 shows a top view of the container system 700. Figure 7B As shown, the positioning component 710 (or force sensitive resistor, in embodiments employing this type of sensor) has an annular shape with an opening in the middle. The annular shape of element 710 allows the plug 704 to be pierced with a needle (not shown) to remove some or all of the contents of the container. Although the annular shape of element 710 (or force sensitive resistor, when in use) is useful for allowing access to the interior of the container via the plug, the annular shape is not required. In some embodiments (where the plug is not configured to be pierced), the element (or force sensitive resistor, when in use) may be formed as a disk. In other embodiments, multiple discrete elements (or force sensitive resistors, when in use) may be positioned around the periphery of the plug, or a single element (or force sensitive resistor, when in use) may be positioned at the periphery of the plug to allow access through Figure 7B The central area of ​​the plug is shown entering the interior of the container.

[0104] like Figure 7B As shown, the retainer 706 (formed as a crimped aluminum seal in this embodiment) extends over the positioning member 710. This ensures that the seal 706 and the element 710 overlap vertically in the seal stack, which allows the seal 706 and the element 710 to each act as a plate in a parallel plate capacitor (described in more detail below). Although Figure 7B Such a configuration is shown in , but overlap between seal 706 and element 710 is not present in all embodiments.

[0105] Figure 8A container system configuration 800 is shown, which is similar to the system 700 shown in Figure 7, and wherein the embedded positioning component 810 takes the form of a conductive material that is configured to act as a plate of a capacitor. The conductive material may include a metal transparent conductive film (such as ITO or PEDOT), a carbon nanotube, graphene, or other conductive materials. A detection system for detecting the position of the embedded positioning component 810 includes a second capacitor plate 812 connected to the conductive positioning component 810 via a power source 814. The detection system is configured as a capacitive sensor, wherein the capacitance reading of the circuit represents the distance D1 between the capacitor plates 810 and 812. The distance D1 between the capacitor plates 810 and 812 determines the position (e.g., distance D2) of the embedded positioning component 810 relative to the edge 808 of the container 802. This in turn provides a measurement of the compression of the plug 804, and thereby provides a measurement of the residual sealing force, which indicates the CCI.

[0106] like Figure 8 As shown, the detection system is configured to communicate with a controller 816 (e.g., a microcontroller configured to determine the distance D1 and determine the CCI based on the measurement). Figures 11 to 13 As will be appreciated from the description of the controller 816, the controller 816 can be an external component in communication with the detection system, which is configured to make electrical contact with an embedded positioning component disposed on the exterior of the container system. Alternatively, as will be explained in more detail below, the controller 816 can be integrated into the cover of the container system, which includes components that may include, but are not limited to, a microcontroller, a power source, and / or a communication module.

[0107] Fig. 9 Another container system 900 is shown in which an embedded positioning component 910 can be used to determine the closure integrity of the container system 900. Fig. 9 As shown, the container system 900 has Figure 8 A similar configuration is shown for container system 800. However, instead of measuring capacitance to determine distance D1 (and D2), Fig. 9 The embedded positioning component 910 is formed of a magnetic material (in one example, a permanent magnet), and the detection system is configured to measure the magnetic field strength of the embedded positioning component 910 to determine the distance D1. Fig. 9 In the illustrated embodiment, the detection system includes a magnetic field sensor 918, such as a Hall effect sensor or a magnetometer. Since the strength of a magnetic field varies with distance from a magnetic material, a magnetometer can be used to determine the distance D1 between the embedded locating member 910 and the sensor 918. This in turn can be used to determine the distance D2 between the embedded locating member 910 and the edge 908 of the container 902, and thereby determine the residual sealing force and CCI of the container system 900. Figure 8 As shown in the embodiment, Fig. 9 The controller 916 may be an external component that communicates with a detection system that senses the position of the embedded positioning component 910. Alternatively, as will be explained in more detail below, the controller may be integrated into the lid of the container system, which may include, but is not limited to, a microcontroller, a power source, and / or a communication module.

[0108] Fig.10 Another implementation of the present invention is shown, which includes a force sensitive resistor 1020 disposed within the seal stack (formed by the rim, plug and retainer of the container) of the container system 1000. Although the force sensitive resistor 1020 can be embedded within the elastomeric plug 1004 (similar to the positioning components 810, 910), Fig.10 The force sensitive resistor 1020 is shown disposed between the retainer 1006 and the plug 1004. Although not shown in the figures, the force sensitive resistor 1020 may also be disposed between the rim 1008 of the container 1000 and the plug 1004 to measure the compressive force within the seal stack.

[0109] Compared to measuring the position of embedded positioning components (such as in Figure 8 and Fig. 9 As in the embodiment shown), Fig.10 The illustrated embodiment is configured to directly measure the compressive force within the seal stack by placing a force sensor within the stack. The measured force within the stack represents the residual sealing force and, thereby, the CCI of the container 1002. Figure 8 and Fig. 9 Similar to the illustrated embodiment, the controller 1016 is operably connected to the sensor 1020. The controller 1016 can be an external component that communicates with a detection system configured to sense the resistance of the force sensitive resistor 1020 and relate it to the compressive force within the stack. Alternatively, as will be explained in more detail below, the controller can be integrated into the lid of the container system, which can include, but is not limited to, a microcontroller, a power source, and / or a communication module.

[0110] Fig.11 A container system 1100 is shown in which the container system 1100 is configured with a conductive embedded positioning member 1210 (similar to Figure 8 An embodiment of the configuration shown in FIG. Fig.11 As shown, in this embodiment, internal electrical connections 1122 connect embedded conductive positioning features 1110 with external electrical contacts 1124 on the exterior of holder 1106. External contacts 1124 are configured to contact reader contacts 1126 to form a reference Figure 8 For example, when the container 1102 passes by the reader contact 1126 while being moved on the conveyor, the reader contact 1126 is preferably configured to easily contact the external electrical contact 1124. Fig.11As shown, the reader contacts 1126 may take the form of a conductive elastic wire brush configured to contact the external contacts 1124 . Fig.11 The configuration shown may be particularly suitable for use in a filling facility in which a filling container system travels along a filling line in a direction into and / or out of the page, such as Fig.11 1104. The container 1102 is upright on the surface 1128 so that the position of the edge 1108 relative to the fixed capacitor plate 1112 of the detection system does not change with the passage of each container 1102. Since the position of the edge 1108 is known, changes in the measured capacitance between the plates 1110, 1112 can be attributed to changes in the compression of the plug 1104. This allows the detection circuit of the reader to be calibrated to relate the measured capacitance to the CCI for the passage of a container. Thus, Fig.11 The system can be used to measure and monitor the CCI of container systems on a filling line.

[0111] It will be appreciated that an embedded locating component (or force sensitive resistor, when such components are used) may be provided in each container leaving the filling line to provide assurance of the CCI of each individual container system. Alternatively, an embedded locating component (or force sensitive resistor, when such components are used) may be provided in a portion of the container system, which allows monitoring or statistical analysis of the performance of the sealing process of the container system.

[0112] although Fig.11 , but embodiments of the invention also include a container and a detection system configured to measure the capacitance between a first plate formed by the element and a second plate formed by the holder (e.g., where the holder is formed as an aluminum seal). In such embodiments, the external contact pads for the element are insulated from the conductive seal. The external contact pads may be as described above with reference to Fig.11 The detection system may further include a second contact pad (eg, in the form of a second wire brush, not shown) configured to contact the conductive seal.

[0113] In these embodiments, rather than measuring the distance D1 between the outer capacitor plate and the inner element, the distance D1 is the distance between the conductive retainer (eg, aluminum seal) and the embedded positioning component. It will be appreciated that this measurement also indicates the compression of the plug and thereby the CCI of the container.

[0114] In yet another embodiment, Fig.11 The detection system shown can be reconfigured to sense the distance between the magnetic positioning component and a magnetic field sensor (e.g., a Hall effect sensor), such as Fig. 9 As shown. It will be appreciated that it is not necessary to form a circuit between the embedded positioning component and the sensor. For this purpose, the Fig.11Contacts 1122, 21124, 1126 are shown.

[0115] Now turn to Fig.12 and Fig.13 In at least some embodiments, a detection circuit for sensing the position of the embedded positioning component or the resistance of the force sensitive resistor may be disposed in the cover.

[0116] First reference Fig.12 , the container system 1200 is similar to the above reference Fig. 7A and Figure 7B The container system is described and includes a container 1202, an elastomeric plug 1204, a positioning member 1210, and a retainer 1206 (shown as a crimped seal) that holds the plug 1204 in place against a rim 1208 of the container 1202.

[0117] The cap 1250 is placed over the seal stack of the container system 1200. The cap 1250 may be positioned on the container system 1200 by a push-fit arrangement, a bayonet arrangement, a threaded fit, or any other suitable mechanism for securing the cap 1250 to the container system 1200. Fig.12 In the illustrated embodiment, the embedded positioning component 1210 is a magnetic positioning component. The cover 1250 houses a magnetometer 1218 (e.g., a Hall effect sensor) for measuring the position of the magnetic element 1210, a power source 1214, and a microcontroller 1216 configured to determine the residual sealing force or CCI based on the measured position of the magnetic element 1210. The cover 1250 may include a display (not shown) configured to indicate the CCI. This is particularly useful for determining the CCI at the point of care (e.g., after the container system 1200 has been stored for a period of time and before delivering the drug).

[0118] Alternatively, the cover 1250 may include a communication module 1260 configured to communicate the measured values ​​(e.g., distance D1, residual sealing force, or qualitative and / or quantitative CCI estimation) for display on an external device. The external device may be, for example, a mobile phone running a compatible application or a mobile reader, which is configured to communicate wirelessly with the communication module 1260 of the cover 1250. This configuration is also particularly useful for determining the CCI of the container system 1200 at the point of care, after the container is stored for a period of time, and before the drug is delivered. It should be understood that the cover 1250 is preferably configured so that the position of the sensor 1218 (e.g., a Hall effect sensor) relative to the edge 1208 of the container 1202 is known (so that the distances D1 and D2 can be accurately determined). This can be achieved by controlling the position of the cover 1250 relative to the container system 1200 when the cover 1250 is fixed in place.

[0119] Fig.13Another embodiment of a cover 1350 including a microcontroller 1316 configured to detect CCI of a container system 1300 is shown. Fig.13 As shown, similar to Fig.12 The cover 1350 includes a microcontroller 1316, a power source 1314, and a communication module 1360. The container system 1300 is similar to the reference Fig. 7A and Figure 7B Describe the container system.

[0120] exist Fig.13 In the illustrated embodiment, the detection system is configured to determine the capacitance (similar to Fig. 9 configuration shown). Fig.13 In the illustrated embodiment, capacitor plate 1312 is shown as being in cover 1350, but as discussed above, a second capacitor plate may also be formed by retainer 1306 when retainer 1306 is configured as a conductive seal surrounding plug 1304 and cover 1350 may include suitable electrical contacts for contacting the conductive seal.

[0121] like Fig.13 As shown, cover 1350 also includes hinge 1370. Hinge 1370 supports electrical contacts 1322 (similar to Fig.11 The electrical contacts 1122 in the cover 1350 extend into the cover 1350 to form a circuit similar to Figure 8 The circuit is shown schematically.

[0122] It will be appreciated that the material and configuration of holder 1306 is configured to allow detection of distance D1 between plate 1312 and element 1310, wherein second capacitor plate 1312 is disposed in cover 1350. Similarly, the configuration and material for holder 1306 may be selected to allow holder 1306 to act as a second capacitor plate in the manner described above.

[0123] In each of the above embodiments, the retainer is shown as a crimped seal extending around the convex edge of the container. The crimped seal may be formed of aluminum or another metal or conductive material, or the seal may be formed of a polymer material suitably formed on a seal laminate.

[0124] The retainer may also be formed as a cap rather than a crimped or formed seal. For example, the retainer may be a nut configured to engage a complementary thread on the container. Other retainers configured to secure the plug to the edge of the container are also possible.

[0125] As reference Fig.12 and Fig.13The described cap arrangement may be combined with the seal-type retainer shown throughout the figures, or the cap itself, including the detection circuit, may be configured to press the plug against the rim of the container.

[0126] Of course, you will understand, Fig.13 The hinged cover arrangement shown may also be applied to a device configured to sense Fig.12 Describes the types of magnetic positioning components of the cover.

[0127] In any of the above embodiments, the detection circuit can be configured to be supplied with power using harvested energy, for example, the detection circuit can be configured for radio frequency (RF) harvesting. To this end, the power source described for each of the above systems may include an energy storage device (e.g., a battery) and / or an energy harvesting device (such as an antenna configured to receive RF energy from an external source and rectify it to generate the power required by the device). In addition to RF antennas, energy harvesting devices suitable for use in the above systems and methods may include solar cells, thermoelectric generators (TEGs), and kinetic energy harvesting devices.

[0128] In some embodiments, the energy harvesting device may be configured to charge a battery to supply power to one or more components of the device circuit. In other embodiments, the energy harvesting device may be configured to supply power directly to components of the system. For example, the above-mentioned sensors (capacitive sensors, magnetic field sensors, and force-sensitive resistor sensors) do not have large power consumption requirements. The current required for the operation of the sensors can be provided by the energy harvesting device (e.g., an RF antenna and an appropriate rectifier). In addition, since the communication module and / or integrated display do not have to be supplied with power at the same time as the sensors, the power requirements of the system can be minimized to allow the system to operate within the operating limits of the power supplied by the energy harvesting device.

[0129] although FIG. 7A to FIG. 13 The embodiments have been described in the context of a vial system having an opening for removing a drug, but the skilled person will appreciate that the invention described above can also be used in other drug containment solutions. For example, the embodiments described above can be included in a drug cartridge for a drug delivery device. In such embodiments, the detection circuit ( Figures 8 to 10 ) can be implemented in a drug delivery device to monitor and confirm the CCI of a drug container inserted therein.

[0130] Those skilled in the art will appreciate that changes may be made to the above-described embodiments without departing from the present invention. In particular, the method for determining the CCI of the above-described container system may also include the step of providing any of the features of the detection system or container system described in conjunction with the apparatus described herein. In addition, it will be understood that the features described in conjunction with one or more exemplary embodiments may be combined with the features described in conjunction with other embodiments. Furthermore, the components described herein may be replaced with components of similar structure or equivalent function. Such modifications are to be understood to fall within the scope of the present invention.

Claims

1. A method for determining container closure integrity in a container system, the container system comprising: container; an elastomeric plug including an embedded locating feature; a retainer for holding the elastomeric plug in place; and a cover comprising at least a portion of a detection system for detecting the position of the embedded locating feature, wherein the elastomeric plug is captured between an edge of the container and the retainer to seal the container, wherein the method comprises: Determine the position of the embedded positioning component using a detection system; Based on the determined position of the embedded locating feature, the container closure integrity of the container is determined.

2. The method as claimed in claim 1 further includes determining the degree of compression of the elastomeric plug based on the determined position of the embedded positioning component, and wherein the step of determining the closure integrity of the container is also based on the determined degree of compression of the elastomeric plug.

3. The method of claim 2, further comprising correlating the degree of compression to a residual sealing force for the container system, wherein determining the closure integrity of the container is also based on the residual sealing force.

4. The method of any one of claims 1 to 3 further comprises calibrating the detection system for detecting the position of the embedded positioning component for a predetermined container system configuration so as to associate the detected position of the embedded positioning component with a residual sealing force for the predetermined container system configuration.

5. The method of claim 1, wherein: The embedded positioning component includes a magnetic material, and Determining the position of the embedded positioning component includes detecting the magnetic field strength with a sensor of the detection system.

6. The method of claim 1, wherein: The embedded positioning component includes a first capacitor plate, The detection system includes a second capacitor plate, and Wherein determining the position of the embedded positioning component includes detecting the capacitance between the first capacitor plate and the second capacitor plate with a sensor.

7. The method of claim 6, wherein: The second capacitor plate includes a retainer, The holder is made of at least a conductive material, and The method also includes detecting a distance between the retainer and the embedded positioning feature.

8. The method of claim 1, wherein: The cover comprises: Microcontroller; Detection circuit; a wireless communication module; and Power source, The method also includes communicating data indicative of closure integrity of the container to a remote device.

9. A method for determining container closure integrity in a container system, the container system comprising: container; an elastomeric plug; a retainer for holding the elastomeric plug in place; and a cover comprising at least a portion of the detection system, wherein the elastomeric plug is captured between a rim of the container and the retainer to seal the container, the method comprising: measuring, with the detection system, the resistance of a force-sensitive resistor disposed between the elastomeric plug and the edge of the container or the retainer; and The closure integrity of the container is determined based on the measured electrical resistance.

10. The method of claim 9, further comprising: determining the residual sealing force based on the measured resistance, and Wherein determining the closure integrity of the container is also based on the residual sealing force.

11. The method of claim 9 or claim 10, further comprising calibrating the detection system for a predetermined container system to correlate the measured resistance of the force sensitive resistor; Wherein the closure integrity of the container is determined based on the measured resistance.

12. The method of claim 9, wherein: The cover comprises: Microcontroller; Detection circuit; a wireless communication module; and power source, and The method also includes communicating data indicative of closure integrity of the container to a remote device.

13. A method of configuring, verifying or monitoring a fill line for producing a filled container system, the container system comprising: container; an elastomeric plug including an embedded locating feature; a retainer for holding the elastomeric plug in place; and a cover comprising at least a portion of a detection system for detecting the position of the embedded locating feature, wherein the elastomeric plug is captured between an edge of the container and the retainer to seal the container, the method comprising: filling and sealing one or more of said container systems; Determining the position of the embedded positioning component using the detection system; Based on the determined position of the embedded locating feature, container closure integrity is determined.

14. A method of configuring, verifying or monitoring a fill line for producing a filled container system, the container system comprising: container; an elastomeric plug including an embedded locating feature; a retainer for holding the elastomeric plug in place; and a cover comprising at least a portion of a detection system for detecting the position of the embedded locating feature, wherein the elastomeric plug is captured between an edge of the container and the retainer to seal the container, the method comprising: filling and sealing one or more container systems; measuring the resistance of a force-sensitive resistor disposed between the elastomeric plug and the retainer with the detection system; The closure integrity of the container is determined based on the measured electrical resistance.

15. A detection system for determining container closure integrity of a container system, comprising: container; an elastomeric plug including an embedded locating feature; a retainer for retaining the elastomeric plug in place between the retainer and the rim of the container; and a cover comprising at least a portion of a detection system for detecting the position of the embedded positioning component, the detection system comprising: a sensor configured to determine a position of the embedded positioning component within the container; A controller is configured to determine a closure integrity of the container based on the determined position of the embedded locating feature.

16. The detection system of claim 15, wherein the controller is configured to: determining a degree of compression of the elastomeric plug based on the determined position of the embedded positioning component; and The closure integrity of the container is further determined based on the determined degree of compression of the elastomeric plug.

17. The detection system of claim 16, wherein the controller is further configured to: correlating the determined degree of compression to a residual sealing force for the container system; and The closure integrity of the container is also determined based on the residual sealing force.

18. A detection system as described in claim 17, wherein the controller is calibrated for a predetermined container system configuration to detect the position of the embedded positioning component to associate the determined position of the embedded positioning component with the residual sealing force for the predetermined container system configuration.

19. A detection system as claimed in any one of claims 15 to 17, wherein: The embedded positioning component includes a magnetic material, and The sensor is configured to detect a magnetic field strength.

20. The detection system according to any one of claims 15 to 17, wherein: The embedded positioning component includes a first capacitor plate, The detection system includes a second capacitor plate, and The controller is configured to determine the position of the embedded positioning component by detecting capacitance between the first capacitor plate and the second capacitor plate using a sensor.

21. The detection system of claim 20, wherein: the holder comprising the second capacitor plate, The holder further comprises a seal made of at least a conductive material, and The sensor is configured to detect a distance between the seal and the embedded positioning component.

22. The detection system of claim 19, wherein the cover comprises: Microcontroller; Detection circuit; Wireless communication module; as well as power source, and The wireless communication module is configured to communicate data indicative of closure integrity of the container to a remote device for display.

23. A container system comprising: Sterile seals; container; an elastomeric plug including an embedded locating component; a retainer for holding the elastomeric plug in place between the retainer and a rim of the container; as well as a cover, the cover comprising a detection circuit for detecting the position of the embedded positioning component; The embedded positioning component comprises: Magnetic materials; or Conductive material.

24. The container system of claim 23, wherein the lid further comprises: Microcontroller; Wireless communication module; as well as Power source, where: The wireless communication module is configured to communicate data indicative of closure integrity of the container to a remote device, and The detection circuit includes a sensor.

25. A container system comprising: Sterile seals; container; Elastomer plugs; a retainer for holding the elastomeric plug in place, wherein the elastomeric plug is captured between a rim of the container and the retainer to seal the container, a force sensitive resistor disposed between the elastomeric plug and the edge of the container or the retainer; as well as A cover is placed over the holder and includes a detection circuit.

26. The container system of claim 25, wherein: The cover also includes: Microcontroller; a wireless communication module; and Optional power source, wherein the wireless communication module is configured to communicate data indicative of closure integrity of the container to a remote device, and The detection circuit is configured to measure the resistance of the force sensitive resistor.

27. The container system of claim 25 or claim 26, wherein: The cover also includes a hinge, and The hinge includes internal electrical connections that provide contact between the microcontroller, the power source, and at least one of the detection circuit and the force sensitive resistor.

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