Patent Description:
Liquid medicaments, such as insulin or heparin or other liquid medicaments such as vaccines that for instance require administering by way of injection, are typically provided and stored in vitreous cartridges, such as carpules, vials or ampoules. With regard to the type of medicament, the material of the cartridge or container has to be inert. Therefore, cartridges made of glass are nowadays typically used for storing and distributing such medicaments.

Glass cartridges comprising a vitreous body of e.g. cylindrical geometry may become subject to fracture if not handled appropriately. In the event of undue care, glass cartridges may break. Even though in industrial filling and packaging processes, glass cartridges or vitreous bodies are generally handled with due care, occasional breakage of particular cartridges may not be entirely prevented. In case a glass cartridge is damaged, respective glass splinters may distribute and the medicament contained in the cartridge may contaminate the environment, in particular neighboring cartridges. In the event, a single glass cartridge is damaged in an industrial manufacturing line, it may become necessary that an entire charge of cartridges has to be visually inspected or discarded at high cost.

In addition, the quality of vitreous barrels or glass cartridges provided form a supplier may be subject to inevitable variations that arise from the glass production or manufacturing process of the respective cartridges.

Macroscopic glass breakage may occur due to a singular or due to repeated impact with a particular force or due to repeated and accumulated enlargement of macroscopic defects, the latter of which are not easily detectable. In typical production or assembly processes, a particular glass cartridge may be exposed to a series of low sized mechanical impacts. Any of these impacts alone does not yet lead to a macroscopic glass breakage. But accumulation of successive impact events may constantly lower the cartridge's integrity. This accumulation of mechanical microcracks or mechanical impact can be denoted as glass memory effect.

Especially with drug delivery devices that are initially equipped with a vitreous cartridge the cartridge has to be assembled in the delivery device during assembly thereof. There, the filled cartridge is inevitably subject to further handling. In a final step of device assembly or during packaging of the device the cartridge may be subject to further mechanical impact which may not damage the cartridge right away but which may harm its integrity on a long term scale. Typically, vitreous cartridges to accommodate a liquid medicament are sealed by e.g. a pierceable septum. In the production and assembly environment not only the vitreous body of the cartridge but also the seal may be subject to almost non-detectable defects that might be uncritical initially. However, such minor damages to the vitreous body, to the seal or to the connection of seal and body may harm the closure integrity of such cartridges on a long term scale.

There exist various methods of testing or determining the glass integrity during or prior to a mass-production, mass-assembly or filling process. Typically, the integrity of a vitreous body can be measured with a selection of tools by applying mechanical stress to the glass body from outside with a well-defined force until the glass body breaks or bursts.

Document <CIT> discloses a method for determining a bond integrity of a sealed package having a lid bonded to a container rim by detecting flaws in the bond between the lid and the container. Document <CIT> relates to an integrated apparatus and method for inspection of a container adapted to hold a pressurized gas.

With known non-destructive and non-invasive testing methods, such as optical inspection methods, minor damages, such as micro cracks or similar defects are hardly visible or detectable, e.g. due to low contrast or unfavorable optical inspection conditions. Furthermore, with optical inspection methods the medicament contained in the cartridge is subject to irradiation, which either may harm the medicament or which limits the spectral range of applicable electromagnetic waves. Moreover, some medicaments are light sensitive and have to be stored in colored or dyed cartridges that are generally rather unfavorable and disadvantageous to apply an optical inspection procedure.

It is therefore an object of the present invention to provide an improved method of testing the mechanical integrity of a cartridge containing a medicament, to provide a respective testing arrangement and to provide a drug delivery device equipped with such a cartridge and being particularly designed and configured for application of the testing method. The method of testing should be particularly applicable to inspect cartridges already assembled inside a drug delivery device. The method of testing should be highly reliable and should be adaptable to a mass assembly process, wherein each drug delivery device equipped with a cartridge is inspectable in regard of the cartridge's mechanical integrity.

The method of testing and the testing arrangement as well as the modified drug delivery device should be non-invasive and should be substantially inert to the medicament contained inside the cartridge. Moreover, the method of testing, the testing arrangement as well as the drug delivery device should support a precise detection of minor damages and defects not only of the vitreous barrel of the cartridge but also of further cartridge components, such as a proximal or distal seal thereof. In addition, the invention aims to provide a method of testing and a testing arrangement that allows for minimally or non-invasive inspection of cartridges filled with a medicament with a high degree of reproducibility.

In a first aspect the invention relates to a method of testing the mechanical integrity of a cartridge in accordance to the features of independent claim1. Here, the cartridge contains a medicament, typically a liquid medicament or at least a component of a liquid medicament. The cartridge containing the medicament is arranged inside a drug delivery device, such as an injection device, in particular inside a pen-injector. The method comprises the steps of acoustically stimulating the cartridge, measuring of the cartridge's acoustic response to the acoustic stimulation and comparing the acoustic response with a standard response or reference response of an intact cartridge.

Based on the comparison of the acoustic response with a standard response, the mechanical integrity of the cartridge is determined. Acoustically stimulating the cartridge comes along with acoustically exciting the cartridge, typically, by applying sound or sound waves to the cartridge. By exposing the cartridge with acoustic signals the cartridge is stimulated to vibrate and to acoustically respond to the acoustic stimulation. Cartridges of equal and standardized geometry as they are typically used in a mass manufacturing and mass assembly process of drug delivery devices exhibit a characteristic acoustic response. By measuring the acoustic response and by comparing the measured acoustic response with a standard or reference response even cartridges only exhibiting minor defects or damages can be precisely detected and identified in a very precise and reliable way.

Applying acoustic waves or sound waves to the cartridge, i.e. exposing the cartridge to a particular and predefined acoustic signal, leads to an acoustic stimulation of the cartridge and hence to a particular resonance of the cartridge. Measuring of the cartridge's acoustic response therefore corresponds to measuring of the cartridge's acoustic resonance to a particular acoustic stimulation. Comparing a measured resonance or resonance spectrum with a standard resonance or resonance spectrum allows to distinguish damaged cartridges from undamaged and intact cartridges. Sound propagation inside a vitreous barrel of a cartridge, through a distal or proximal seal of the cartridge as well as sound propagation through an interface of vitreous cartridge and distal or proximal seal strongly depends on the integrity of the vitreous barrel itself, the integrity of the proximal and/or distal seal as well as on the integrity of a connection of respective seals with the vitreous body. Assuming that either one of cartridge, seal or connection of cartridge and seal is subject to a defect or malfunction, this will have a measurable and detectable influence on the acoustic response of the cartridge in general.

By measuring and comparing of the cartridge's acoustic response not only damaged cartridges may be distinguished from intact cartridges but also a particular type of damage, e.g. a crack or a microcrack of the vitreous body of the cartridge, of the seal or of the connection of seal and body may each lead to different and distinguishable acoustic responses so that by measuring and analyzing the acoustic response of the cartridge it may already be determined and distinguished whether it is the vitreous body, the seal or the connection of vitreous body and seal which is subject to a damage or malfunction. In this way, the method of acoustically stimulating the cartridge and measuring of its acoustic response to the stimulation not only allows to qualitatively distinguish damaged and intact cartridges but also provides a quantitative approach, what kind of damage is actually present.

The method of testing the mechanical integrity is easily applicable in a mass manufacturing and mass assembly process, so that every drug delivery device is easily inspectable after termination of the assembly process. The acoustic stimulation and acoustic response analysis can be easily conducted at the end of an assembly and packaging process. In this way, even damages that may occur during assembly of the cartridge inside the drug delivery device and/or during packaging of the cartridge in a secondary packaging, such as a card box or other secondary containers can be precisely detected.

In this way, a risk of delivery of damaged cartridges to the market can be further reduced. In effect, patient safety can be further enhanced. The method of acoustic stimulation and acoustic response analysis is also beneficial in that the cartridges and/or the drug delivery devices assembled with respective cartridges do not necessarily have to be arranged in a particular orientation compared to the source of the acoustic stimulation and/or with regard to a detector for measuring the cartridge's acoustic response. Since sound propagation is rather undirected and since the acoustic stimulation as well as the acoustic response are rather omnipresent a relative positioning of an acoustic source, of an acoustic detector and of the drug delivery device with its cartridge is rather uncritical. The method of acoustic stimulation and acoustic response analysis is therefore easily implementable in a mass manufacturing and mass assembly process for drug delivery devices.

A probe, typically an acoustic probe, which is at least operable to emit acoustic signals is brought in indirect contact with the cartridge for indirectly acoustically simulating the cartridge.

The cartridge is indirectly acoustically from outside the housing by means of the probe and an indirect coupling. The indirect coupling is configured for sound guiding and sound propagation between the probe and the cartridge. The indirect coupling also forms a mount for the cartridge inside the housing. Furthermore, the probe is coupled with a device component of the drug delivery device. The device component is in direct mechanical contact with the cartridge and the cartridge is axially and radially clamped inside the housing by the at least one device component.

The probe is at least configured as a transmitter to apply acoustic signals and acoustic waves to the cartridge. The probe may also be implemented as a transducer, which is operable to transmit and to emit acoustic waves and which is also operable to receive and to detect acoustic waves emanating from the cartridge being in direct or indirect contact with the probe. In embodiments, wherein the method of testing should be applied to drug delivery devices packed inside a secondary packaging, i.e., wherein the drug delivery device is located inside a box, the box or the packaging in general may comprise a further through opening through which the probe of a testing arrangement is insertable in order to gain direct access at least to the housing of the drug delivery device and/or to the cartridge located therein.

The device component of the drug delivery device is in direct mechanical contact with the cartridge. Here, the probe of a testing arrangement is coupled with the device component for indirectly acoustically stimulating the cartridge. There are at least some device components, which upon a final assembly of the drug delivery device are in direct mechanical contact with the cartridge. It is conceivable, that a housing component, such as a cartridge holder, is in direct mechanical contact with the cartridge assembled therein. The cartridge holder may comprise a particular support structure at an inside-facing sidewall portion or at a distal housing portion to directly engage with the cartridge.

The cartridge may be clamped or positively locked inside the cartridge holder, so that a tight fitting of cartridge and cartridge holder of the drug delivery device is attained. The cartridge holder then acts as an acoustic conductor or wave guide to transfer at least an acoustic stimulation from the probe to the cartridge. It is further conceivable, that the cartridge holder not only transfers acoustic waves towards the cartridge but that the cartridge holder also transfers and guides the cartridge's acoustic response back to the probe or to some other acoustic detector which is either in direct contact with the cartridge holder or which is arranged in a contactless configuration in regard to the cartridge holder.

There are some further device components, such as a piston rod, which may be in direct axial abutment with a piston, hence with a proximal seal of the cartridge in a state of final assembly of the drug delivery device. It is then conceivable, that an acoustic stimulation or excitation is transferred to the cartridge via the piston rod. In general, there are many different ways in order to establish a mechanical contact between the cartridge and at least one further device component. Depending on the particular arrangement of the cartridge inside the drug delivery device, a particular reference response of an intact cartridge may be previously recorded and stored and may serve as a kind of a fingerprint that is to be compared with acoustic responses of a series of cartridges to be inspected with the present method.

According to another embodiment the probe of the testing arrangement is coupled with a drug delivery device's housing. Here, the housing of the drug delivery device is acoustically coupled to the device component that is in direct mechanical contact with the cartridge. In this embodiment, a further indirect acoustic stimulation of the cartridge is attained. First, the probe acoustically stimulates the housing of the drug delivery device, which through its mechanical coupling with a device component acoustically stimulates the respective device component, which in turn, through its direct mechanical contact with the cartridge, acoustically stimulates the cartridge.

In the same or in a similar way, the acoustic response of the cartridge may be transferred to the housing, such that the acoustic response is detectable either directly with the probe or with a further detector being either in direct mechanical contact with the housing or being located outside the drug delivery device.

Acoustic stimulation and measuring or recording of the cartridge's acoustic response may take place at the same time or within overlapping time intervals. However, it is also conceivable, that the acoustic response is detected and analyzed with a certain time delay compared to the acoustic stimulation. In this way, not only the direct and instant response of the cartridge but also its resonating and acoustic damping as well as an after response can be detected and analyzed, which may be equally or additionally used to detect and to determine the integrity of a particular cartridge.

According to another embodiment, the acoustic stimulation comprises emitting of a series of acoustic signals of different frequency. Typically, a whole spectrum of stimulating frequencies is to be applied to the cartridge. Typically, the acoustic stimulation includes or comprises a whole spectrum of acoustic excitation frequencies. The acoustic stimulation may comprise a frequency sweep, wherein the frequency of an acoustic stimulation signal is either continuously modified or wherein the frequency is modified stepwise. The frequency range may include audible frequencies, such as a frequency spectrum ranging from <NUM> to <NUM>. Alternatively or additionally a series of different frequency spectra is applicable to acoustically stimulate the cartridge. Depending on the resonance behavior and the eigenfrequency of the cartridge and its cartridge components, such as barrel, distal and proximal seal, the stimulation frequencies may also include an ultrasound spectrum. Hence, frequencies of a frequency range larger than <NUM> and up to <NUM> or hundreds of kHz are equally applicable to acoustically stimulate the cartridge.

Making use of a whole spectrum of acoustic stimulating waves allows to acoustically inspect the cartridge not only in regard to a single and a particular acoustic wavelength but to a whole series of different wavelengths. Accordingly, the whole spectrum of the acoustic response can be inspected and exploited in order to compare the measured acoustic response with a standard or reference response of an intact cartridge. Analysis of a whole spectrum of the cartridge's acoustic response increases reliability and precision of the testing method in general.

According to a further embodiment, comparing of the acoustic response is conducted on the basis of a power spectrum of the measured acoustic response and on the basis of a power spectrum of a standard response or reference response of an intact cartridge. The power spectrum generally describes, how the variance of the response of the cartridge, in particular of an oscillation or resonance as a function of time is distributed over frequency components. Especially the analysis of the power spectrum of recorded or measured acoustic response of the cartridge is indicative of eventual damages or defects thereof.

The power spectrum is obtainable from the measured acoustic response, e.g. through recording the acoustic response by a microphone or some other sound transducer and by way of transferring the recorded acoustic response into respective electrical signals. These electrical signals may be sub-converted into digital signals. Moreover, the electrical signals representing the acoustic response of the cartridge may be subject to at least one or several filter functions. For providing and generating a power spectrum the electrical signals representing the acoustic response of the cartridge may be subject to a Fourier transformation, typically they may be subject to a fast Fourier transform (FFT) to be conducted by electronic components of a testing arrangement.

Based on the power spectrum further testing and comparing algorithms may be applied in order to compare the measured power spectrum with a reference power spectrum representing an intact cartridge. Here it is even conceivable, that a large series of standard responses are stored in a memory of the testing arrangement, wherein the standard responses may not only represent intact cartridges but also cartridges exhibiting a particular damage.

By comparing measured acoustic responses with recorded and stored reference responses representing intact or damaged cartridges, a respective decision can be made, whether the measured acoustic response matches with the response of an intact cartridge or with a response of a damaged cartridge. It is even conceivable, that the comparison provides only a certain likelihood of a damage and hence generates a probability whether or not the measured or recorded acoustic response represents a damaged or an intact cartridge. Based on a likelihood it is conceivable, that the method conducts further analysis of the measured acoustic response in order to determine and to distinguish whether the investigated cartridge comprises a damage or not.

It is even conceivable, that particular peaks in the power spectrum are representative for particular damages or defects of the cartridge. Hence, for detecting of a particular type of defect it may be already sufficient to record the power spectrum and to further analyze only a single or a few characteristic frequencies thereof in order to detect a damaged or defect cartridge.

According to another aspect the invention also relates to a drug delivery system in accordance with claim <NUM>. The drug delivery system comprises a drug delivery device for administering a liquid medicament and a probe of a testing arrangement. The drug delivery device may be implemented as an injection device, such as an injection pen. The drug delivery device comprises a housing and a cartridge filled with the medicament, wherein the cartridge, which comprises a vitreous barrel, is arranged inside the housing. In addition, the drug delivery device comprises an indirect coupling to acoustically stimulate the cartridge from outside the device by means of the probe of the testing arrangement, wherein the probe is at least operable to emit acoustic signals. The drug delivery device comprises an indirect coupling to acoustically couple cartridge and probe.

The indirect coupling is particularly designed and configured for sound guiding and sound propagation between the probe and the cartridge located inside the housing of the drug delivery device. The indirect coupling is particularly configured to provide optimized sound propagation and an acoustic coupling between the cartridge located inside the drug delivery device and the probe of the testing arrangement, which may be located outside the drug delivery device or which may only partially reach or extend into the drug delivery device.

The drug delivery device comprises a further device component extending through or outside the housing.

The drug delivery device therefore distinguishes from known and conventional drug delivery devices by its indirect acoustic coupling, which is particularly configured and designed to provide an acoustic bridge between the cartridge and the probe of the testing arrangement. Hence, the drug delivery device, its housing or particular device components thereof require a geometric or functional modification in order to act or to support the direct or indirect coupling of the drug delivery device.

The indirect coupling comprises at least one device component in direct contact with the cartridge and being in direct or indirect coupling with the housing or with the further device component. The indirect coupling is configured for sound guiding and sound propagation between the probe and the cartridge, wherein the indirect coupling forms a mount for the cartridge inside the housing and wherein the cartridge is axially and radially clamped inside the housing by the at least one device component.

The indirect coupling comprises at least one device component that is in direct contact with the cartridge. Here, the device component is further acoustically coupled to the housing. The device component is particularly mechanically or rigidly connected to the housing. It is even conceivable, that the device component is configured and designed as an integral component of the housing. For instance, the device component may comprise a piston rod in axial abutment with the cartridge. In other embodiments the device component may comprise a distal support to directly engage with the vitreous barrel of the cartridge.

Further embodiments of the indirect coupling include fasteners by way of which the cartridge is rigidly attached to the housing of the drug delivery device. The device component particularly serves to provide a well-defined fixing of cartridge and housing of the drug delivery device. The at least one device component is configured to clamp the cartridge inside the housing or to press-fit the cartridge inside the housing. By means of the acoustic stimulation and acoustic response analysis it could be even determined, whether the cartridge is subject to inadmissible tension or mechanical load in its assembly configuration inside the housing of the drug delivery device.

Applying a mechanical load, e.g. for clamping the cartridge may alter the acoustic response of the cartridge. This could result in a frequency shift in the power spectrum derived from the measured acoustic response of the cartridge. If a respective frequency shift should be above a predefined level or threshold, this could be a clear indication for that an intact cartridge is assembled in an inappropriate way inside the drug delivery device, in which the cartridge might be subject to inadmissible mechanical load.

According to a comparative example outside the claim scope the drug delivery device comprises a direct coupling comprising a through opening in the housing of the drug delivery device to receive the probe and to bring the probe in direct contact with the cartridge located inside the housing. The through opening in the housing may be provided by an inspection window of a cartridge holder or by a cartridge holder portion of the drug delivery device's housing. Moreover, the housing of the drug delivery device may comprise a separate through opening, particularly adapted and configured to receive the probe and to bring the probe in direct contact with the cartridge located inside the housing.

By inserting the probe through the housing's through opening, a direct mechanical contact between the probe and the cartridge can be established in order to acoustically stimulate the cartridge by means of the probe. In this way, acoustic stimulation and acoustic excitation of the drug delivery device or components thereof can be substantially reduced, thereby improving a contrast and/or a signal quality of the measurable acoustic response detectable by an acoustic sensor.

Furthermore and according to another embodiment it is conceivable, that the cartridge is mechanically engaged or connected with a sound absorbing or sound transferring medium. In particular, the cartridge may be assembled inside a mount equipped or provided with a particular sound absorbing or sound sensitive material. For instance, the cartridge may be mechanically coupled to a pouch or to a bag filled with a gel exhibiting a particular acoustic response or particular acoustic properties. For instance, the cartridge could be at least in sections coupled with or wrapped inside a gel coating or a gel cushion. In this way, even a mechanically contactless acoustic coupling of a probe located outside the drug delivery device and the cartridge in acoustic or mechanical contact with the gel material could be established. In particular, such a gel-containing mount of the cartridge can be easily acoustically stimulated by the probe thereby transferring respective acoustic signals to the cartridge in well-defined and reproducible way.

In this way a mount for the cartridge may form an indirect mechanical coupling to the probe even without establishing a specific mechanical contact between the probe and the housing of the drug delivery device.

The indirect coupling comprises at least one device component that is in direct contact with the cartridge and which is directly or indirectly coupled with the housing or with a further device component extending through or outside the housing. Here, it is particularly conceivable, that e.g. a piston rod is in direct contact with the cartridge. The piston rod may be further in direct or indirect but permanent mechanical contact with at least one further device component, such as a dose button. The dose button may be located at a proximal end of the housing of the drug delivery device. It may even protrude proximally from the proximal end of the housing. It is particularly conceivable, that the device component in direct contact with the cartridge does not itself protrude from the housing but that the particular device component in direct contact with the cartridge is mechanically connected with at least one or several further device component, wherein the further device component extends through and/or outside the housing of the drug delivery device. It would then be possible to mechanically connect the probe of the testing arrangement with this further device component in order to indirectly transfer an acoustic stimulation to the cartridge.

It is generally to be mentioned, that the drug delivery device is particularly configured and adapted to cooperate and to mate with a probe of the testing arrangement as described below in order to conduct the method of testing the mechanical integrity of the cartridge as further described above. Hence, any features, benefits and effects described in conjunction with the method of testing and/or with the testing arrangement equally apply to the drug delivery device and vice versa.

According another aspect the present disclosure also describes a testing arrangement for testing of the integrity of a cartridge containing a medicament. The cartridge is arranged inside a drug delivery device, such as an injection pen or other delivery devices, such as an infusion device, an infusion pump or an inhaler. Typically, the testing arrangement is configured for testing of a cartridge arranged inside a drug delivery device as described above.

The testing arrangement comprises a probe for acoustically stimulating the cartridge. The testing arrangement further comprises a sensor for measuring the cartridge's acoustic response to the acoustic stimulation induced by the probe. The testing arrangement further comprises at least a processor to compare the acoustic response with a standard response, hence with a reference response of an intact cartridge. The processor is further operable to determine the mechanical integrity of the cartridge on the basis of the comparison.

Generally, the testing arrangement is implementable in a mass manufacturing or mass assembly process, wherein the drug delivery device during its assembly is equipped with at least one cartridge. The testing arrangement is particularly operable to conduct the above described method of testing the mechanical integrity of a cartridge. The probe is particularly configured to get in direct contact with the cartridge or to get in direct mechanical contact with a device component, which itself is in direct contact with the cartridge. The geometry of the probe is particularly adapted to the geometry and shape of the drug delivery device and/or of the cartridge in order to directly or to indirectly stimulate the cartridge with acoustic waves.

In general, acoustic stimulation of the cartridge may also occur via sound propagation through air. Hence, the acoustic stimulation of the cartridge does not necessarily require to establish mechanical contact between the probe and the cartridge in a direct or indirect way. However, a direct contact of probe and cartridge or a sound-transferring contact between probe and cartridge via at least one device component seems to be beneficial for an effective stimulation and acoustic excitation of the cartridge. Damping losses as well as sound reflections on surfaces of the drug delivery device and its components can be reduced in this way.

According to anembodiment the probe is operable to stimulate the cartridge with a series of acoustic signals of different frequency. In particular, the probe is operable to apply a whole spectrum of acoustic signals to the cartridge. Typically, the probe is operable to emit a continuous or a discrete acoustic spectrum and to apply respective acoustic waves to the cartridge. In this way, the acoustic response of the cartridge can be inspected and detected over a comparatively large range of frequencies.

According to another descriptive example the processor of the testing arrangement is operable to generate a power spectrum of the cartridge's acoustic response. By means of a power spectrum generation, a precise and reliable analysis of the cartridge's acoustic response to a series of acoustic signals of different frequency can be conducted, which generally increases the precision and reliability of the testing results achievable with the testing arrangement. In addition, the processor is generally applicable not only to generate a power spectrum but also to conduct analogue digital conversion of recorded and measured acoustic signals as well as to apply at least one or a series of filter functions that may help to improve to identify the acoustic contribution of the cartridge in the acoustic response, recorded and measured by an acoustic detector, which inevitably also records and measures an acoustic response of the drug delivery device.

Since the drug delivery device may be composed to a large extent of plastic components, the acoustic response of the drug delivery device and/or of its components may drastically differ from the acoustic response of the cartridge, which typically comprises a vitreous cartridge sealed with elastomeric sealing members and which may be fastened to the cartridge by means of a metal cap or the like fasteners.

According to a further embodiment the probe is operable to emit acoustic signals and the probe is further operable to detect and to capture the cartridge's acoustic response. In this embodiment the probe is implemented as an acoustic transducer being operable to generate and to broadcast or to transmit acoustic signals as well as to measure and to capture acoustic signals, which typically emanate from the cartridge in response to the acoustic stimulation. The frequency range and the amplitude or power of the acoustic signals emitted and detected or captured by the probe strongly depend on the acoustic response characteristics, hence on the acoustic fingerprint of the cartridge.

It might be of particular benefit to make use of acoustic frequencies that are located outside the audible spectrum. In this way, persons located in direct vicinity to the testing arrangement may not be harmed or influenced by the operation of the testing arrangement. Moreover, operating the testing arrangement in a non-audible frequency range may be also beneficial for the detection and measuring of the cartridge's response. In this way, other audible noise, which is inevitably present in a production and assembly environment would then be outside the detection range or outside a spectral range of interest of the testing arrangement.

In this context it is to be mentioned, that the testing arrangement is closely correlated to the above described testing method and to the drug delivery device. Hence, any features, benefits and effects described in conjunction with the method of testing and/or with the testing arrangement equally apply to the drug delivery device and vice versa.

Insulin derivates are for example B29-N-myristoyl-des(B30) human insulin; B29-N-palmitoyl-des(B30) human insulin; B29-N-myristoyl human insulin; B29-N-palmitoyl human insulin; B28-N-myristoyl LysB28ProB29 human insulin; B28-N-palmitoyl-LysB28ProB29 human insulin; B30-N-myristoyl-ThrB29LysB30 human insulin; B30-N-palmitoyl- ThrB29LysB30 human insulin; B29-N-(N-palmitoyl-Y-glutamyl)-des(B30) human insulin; B29-N-(N-lithocholyl-Y-glutamyl)-des(B30) human insulin; B29-N-(w-carboxyheptadecanoyl)-des(B30) human insulin and B29-N-(w-carboxyheptadecanoyl) human insulin.

Hormones are for example hypophysis hormones or hypothalamus hormones or regulatory active peptides and their antagonists as listed in <NPL>, such as Gonadotropine (Follitropin, Lutropin, Choriongonadotropin, Menotropin), Somatropine (Somatropin), Desmopressin, Terlipressin, Gonadorelin, Triptorelin, Leuprorelin, Buserelin, Nafarelin, Goserelin.

Antibodies are globular plasma proteins (~150kDa) that are also known as immunoglobulins which share a basic structure. As they have sugar chains added to amino acid residues, they are glycoproteins. The basic functional unit of each antibody is an immunoglobulin (Ig) monomer (containing only one Ig unit); secreted antibodies can also be dimeric with two Ig units as with IgA, tetrameric with four Ig units like teleost fish IgM, or pentameric with five Ig units, like mammalian IgM.

It will be further apparent to those skilled in the art that various modifications and variations can be made to the present invention without departing from the spirit and scope of the invention. Further, it is to be noted, that any reference numerals used in the appended claims are not to be construed as limiting the scope of the invention.

In the following, an exemplary embodiment of the present invention is described in detail by making reference to the drawings, in which:.

In <FIG> a schematic perspective view of a drug delivery device <NUM> is provided. The drug delivery device <NUM> is configured as an injection device, in particular as a pen-type injector. The drug delivery device <NUM> comprises a body <NUM> acting or serving as a proximal housing component. Here, the body <NUM> of the drug delivery device <NUM> is of sleeve-like or tubular shape. At its distal and hence at its dispensing end, the drug delivery device <NUM> comprises a cartridge holder <NUM> having an inspection window <NUM> through which the content of a cartridge <NUM> located inside the cartridge holder <NUM> is visually inspectable. At its distal end the cartridge holder <NUM> comprises a threaded socket <NUM> configured to releasably engage with a correspondingly threaded needle assembly.

Mounting of a needle assembly, which is not illustrated, to the distal end of the cartridge holder <NUM> provides access to the interior of the cartridge <NUM> located and fixed inside the cartridge holder <NUM>. In this specific embodiment cartridge holder <NUM> and proximal body <NUM> might be non-detachably interconnected. In particular, the drug delivery device <NUM> may be configured as a disposable drug delivery device. After consumption of the content of a cartridge <NUM> the entire drug delivery device <NUM> is to be discarded. The disposable type of the drug delivery device <NUM> requires that the cartridge <NUM> filled with the medicament assembled inside the device <NUM> as it enters the market and as it is delivered to customers or patients.

The cartridge <NUM> is shown in more detail in <FIG>. For reasons of simplicity, the arrangement of housing <NUM> and cartridge holder <NUM> of the drug delivery device <NUM> is illustrated and represented by a rather generic housing <NUM> as it is shown in <FIG>. In this context it has to be further noted, that the illustration of a drug delivery device <NUM> according to <FIG> is only exemplary and that the present invention is universally applicable to a large variety of drug delivery devices of different type as well as to different shapes and geometries of housings <NUM> thereof. The representation of the drug delivery device <NUM> with a housing <NUM> as shown in <FIG> may include a single and unitary housing as well as a two-component housing as shown in <FIG> consisting of cartridge holder <NUM> and proximal housing component or body <NUM>.

As shown in more detail in <FIG>, the cartridge <NUM> located inside the housing <NUM> of the drug delivery device <NUM> comprises a barrel <NUM> of tubular shape. The barrel <NUM> is typically made of a vitreous material that is substantially inert in regard to the medicament contained inside the cartridge <NUM>. Typically, the barrel <NUM> is made of glass. The proximal end <NUM> of the barrel, i.e. the end that is located on a side opposite to a dispensing end of the cartridge <NUM> is effectively sealed by means of a piston <NUM> of elastomeric material. The piston <NUM> is displaceable in axial direction inside the cartridge <NUM>. The piston <NUM> is sealingly engaged with the inside-facing sidewall portion of the barrel <NUM>. The distal end <NUM> of the cartridge <NUM> comprises a stepped down neck portion <NUM>. The tubular-shaped barrel <NUM> comprises a distal shoulder part <NUM> forming the neck portion <NUM> and which shoulder part <NUM> may be of a conical or conical-like shape. The diameter-reduced distal end <NUM> of the cartridge <NUM> is sealed with a pierceable septum <NUM> that is mechanically fixed to the cartridge's distal end <NUM> by means of a cap <NUM>.

For dispensing and for injecting a medicament the needle assembly (not illustrated) is attached to the housing <NUM> of the drug delivery device thereby piercing the septum <NUM>, hence the distal seal <NUM> of the cartridge <NUM> in order to access the interior of the cartridge <NUM>. Applying a distally-directed pressure onto the piston <NUM>, e.g. by means of a piston rod, which may be represented by the device component <NUM> according to <FIG> the piston <NUM> is displaceable in distal direction, thereby increasing a fluid pressure inside the cartridge <NUM> to expel a predefined amount, hence a dose of the medicament by way of the fluid transferring connection of cartridge <NUM> and needle assembly.

The drug delivery device <NUM> may be equipped with a drive mechanism <NUM> as it is indicated with the drug delivery device <NUM> according to <FIG>. The drive mechanism <NUM> is operable to advance a piston rod in distal direction. The drive mechanism <NUM> is further operable to set a dose of variable size and to subsequently trigger or to conduct a dispensing action, by urging the piston rod in distal direction. The drive mechanism <NUM> typically comprises numerous mechanically interacting components. Moreover, the drive mechanism <NUM> typically comprises a dose dial <NUM>, by way of which a user may individually select and set a dose of variable size. The drive mechanism <NUM> may further comprise a dose button <NUM> by way of which the previously set dose of a medicament may be dispensed and injected in a controlled way. Typically, the dose dial <NUM> is actuated or rotated by a user in order to set a predefined dose of a medicament while the dose button <NUM> is configured to be depressed in distal direction in order to trigger a dose dispensing action.

In the following the method of testing the mechanical integrity of the cartridge <NUM> is described. The method as indicated by the flowchart according to <FIG> comprises a first step <NUM>, wherein an acoustic stimulation is applied to the cartridge <NUM>, typically by making use of a probe <NUM> of a testing arrangement <NUM> as shown in <FIG>. Thereafter, in step <NUM> the acoustic response of the cartridge <NUM> is recorded or measured, typically by making use of an acoustic sensor <NUM> or by the probe <NUM>. Thereafter in step <NUM>, the acoustic response, in particular the signals obtained via the probe <NUM> and/or via the sensor <NUM> are analyzed in order to determine in a final step <NUM> whether the inspected cartridge <NUM> is intact or exhibits a damage or defect.

Analyzing of the acoustic response includes a comparison of the acoustic response measured by the sensor <NUM> or probe <NUM> with a standard acoustic response of an intact cartridge, that serves as a reference response. In order to automatically conduct the method of testing the mechanical integrity of the cartridge <NUM> the testing arrangement <NUM> comprises an input/output port <NUM> that is connected with at least one of the probe <NUM> and the acoustic sensor <NUM>. The input/output port <NUM> is further connected with a processor <NUM> that is operable to conduct the analysis of the measured acoustic response of the cartridge <NUM>. Furthermore, the testing arrangement <NUM> is equipped with a storage <NUM>, in which at least one standard response or a respective reference response is stored for enabling a comparison of measured acoustic responses with typical responses of intact cartridges <NUM>.

A measured acoustic response <NUM> of a damaged cartridge <NUM> is exemplary illustrated in <FIG> representing a power spectrum of an acoustic response <NUM> of a cartridge <NUM> that has been exposed to an acoustic spectrum ranging from <NUM> to <NUM>. In the illustrated experiment the wave form of the acoustic stimulation is of sinusoidal type and the frequency spectrum was swept over a time interval of <NUM> seconds. The acoustic response <NUM> of the cartridge <NUM> as illustrated in <FIG> exhibits various distinct peaks <NUM> that are generally usable to characterize the mechanical integrity as well as a closure integrity of the cartridge <NUM>.

In <FIG>, a reference or standard response <NUM> is illustrated in a comparable power spectrum. Also the standard response <NUM> exhibits various distinct peaks <NUM> that substantially match with the peaks <NUM> of the acoustic response <NUM> according to <FIG>. IN the illustrated exampled the standard response <NUM> according to <FIG> exhibits specific peak <NUM> at about <NUM>, which has no corresponding equivalent or counterpart in the measured acoustic response <NUM> according to <FIG>. Since the measured acoustic response <NUM> of the inspected cartridge <NUM> is void of a distinct peak in the region of <NUM> this is a clear and unequivocal indication that the acoustic response <NUM> differs from the standard or reference response <NUM> thereby indicating, that the inspected cartridge has at least a small damage or defect.

For practical implementations of the method of testing and for deploying and installing the testing arrangement it is of particular benefit that the testing arrangement is sufficiently and precisely acoustically coupled with the drug delivery device <NUM> and/or with the cartridge <NUM> located therein. In <FIG> various approaches to establish a well-defined and reproducible acoustic coupling between the probe <NUM> and the cartridge <NUM> are illustrated. Here, one may distinguish between a direct coupling and an indirect coupling of probe <NUM> and cartridge <NUM>.

In the embodiment according in <FIG>, the housing <NUM> of the drug delivery device <NUM> comprises a through opening <NUM> in a sidewall portion through which the cartridge <NUM>, in particular its vitreous barrel <NUM> is directly accessible for the probe <NUM>. The probe is operable to transmit acoustic signals <NUM> in order to induce an acoustic response of the cartridge <NUM> revealing its mechanical integrity. Such a through opening <NUM> may be directly provided or may coincide with an inspection window <NUM> of a cartridge holder <NUM> as exemplary illustrated with the drug delivery device <NUM> according to <FIG>. In this embodiment, the geometry, hence the size and outer dimensions of the probe <NUM> match and correspond to the size of the through opening <NUM>. By means of this type of direct coupling <NUM> as indicated in <FIG>, the cartridge <NUM> can be unalterably and rather directly acoustically stimulated by means of the probe <NUM> that is typically implemented as an acoustic transducer. In this way probe <NUM> and cartridge <NUM> are mutually acoustically coupled via a direct coupling <NUM>.

In the embodiment according to <FIG>, an indirect coupling <NUM> between probe <NUM> and cartridge <NUM> is implemented. There, a device component <NUM>, e.g. in form of a piston rod is shown, which is in direct mechanical contact with the cartridge <NUM>. In an assembly configuration of the drug delivery device <NUM>, in particular of a disposable drug delivery device the device component <NUM>, e.g. the piston rod, is in direct abutment with at least the piston <NUM> of the cartridge <NUM>. It is then intended that the device component <NUM> is subject to acoustic stimulation or acoustic excitation. In this way, the device component <NUM> acts as an acoustic waveguide to provide an acoustic stimulation or acoustic excitation of the cartridge <NUM>.

As shown in <FIG>, acoustic stimulation of a piston rod may be conducted via a further device component <NUM>, e.g. configured as a dose button <NUM> located at a proximal end of the housing <NUM>. Such a device component <NUM> may be directly or indirectly but permanently engaged with a piston rod <NUM>. An acoustic stimulation of the dose button <NUM> then leads to a respective acoustic stimulation of the cartridge <NUM> when assembled inside the device and when in direct abutment with the piston rod <NUM>. The piston rod <NUM> and the dose button <NUM> are made of a particular ultrasound transmitting plastic material. Their acoustic impedance, in particular their ultrasonic impedance may mutually match.

In the further embodiment as shown in <FIG> the cartridge <NUM> is rigidly coupled or rigidly engaged with the housing <NUM>, e.g. by means of a device component <NUM> acting as a bearing to engage with the shoulder portion <NUM> of the cartridge's <NUM> distal end <NUM>. By means of the device component <NUM> or by means of several device components <NUM> extending inwardly from the housing <NUM> and directly engaging with the cartridge <NUM> a well-defined transfer of acoustic excitation of the housing towards and into the cartridge <NUM> can be provided. Typically, the cartridge <NUM> is tightly fitted or tightly engaged with the device components <NUM>. In the embodiment according to <FIG> it is intended, that the probe <NUM> is in direct mechanical contact with the housing <NUM> of the drug delivery device <NUM>.

The bearing and hence the device component <NUM> may be located inside a cartridge holder or cartridge holder section of the housing <NUM>, which is particularly configured to accommodate the cartridge <NUM>. The bearing <NUM> and at least a portion of the housing <NUM> may comprise a particular ultrasound transmitting plastic material. The plastic material may be provided with ultrasound transmitting particles embedded therein. Hence, in the bulk of the housing <NUM> and/or of the bearing <NUM> there may be embedded particular ultrasound transmitting particles. Such particles may exhibit a well-defined and pronounced acoustic response or resonance when exposed to ultrasound of a given frequency.

In the embodiment according to <FIG>, two annular-shaped device components <NUM> separated in axial direction are configured to serve as a mount for the cartridge <NUM> inside the housing <NUM> of the drug delivery device <NUM>. The device components <NUM> may act as O-rings and may serve to clamp and to rigidly fasten the cartridge <NUM> to the inside-facing sidewall portions of the housing <NUM>. In this way, another well-defined mechanical engagement and hence as respective acoustic coupling of housing <NUM> and cartridge <NUM> can be established.

In a similar way, <FIG> shows three device components <NUM> of knob-like or nipple-like shape that are arranged at an axial distance at selected portions or sections on the inside-facing portion of the housing's <NUM> sidewall. There, the device components <NUM> may serve to axially and radially clamp the cartridge <NUM> inside the housing <NUM>. Also in this way, a well-defined acoustic coupling between cartridge <NUM> and housing <NUM> can be established. Depending on the type of cartridge <NUM> and housing <NUM> as well as depending on the acoustic properties, in particular depending on the acoustic resonance of housing <NUM> and cartridge <NUM> an appropriate mutual clamping or mechanical coupling of cartridge <NUM> and housing <NUM> has to be selected in order to optimize the representation and detectability of defects or damages of the cartridge <NUM> on the basis of its acoustic response <NUM>.

In <FIG>, another embodiment is shown, wherein a device component <NUM> serves as a mount or as a receptacle for the cartridge <NUM>. The device component <NUM> may be provided with a particular sound or acoustically sensitive material, which exhibits a predefined acoustic absorption characteristics or acoustic transfer behavior. For instance, the device component <NUM> may be equipped with a particular gel or a granular component that is acoustically stimulatable from outside the drug delivery device <NUM> even without a direct mechanical contact between the probe <NUM> and the housing <NUM>. The device component <NUM>, in particular its gelly-, granular filling or coating material may provide acoustic amplification or acoustic attenuation of desired or undesired acoustic frequencies, respectively. Moreover, the device component <NUM> may be also in mechanical contact with the housing <NUM>. It may provide a well-defined and improved acoustic coupling of the cartridge <NUM> with the housing <NUM> of the drug delivery device <NUM>.

In further embodiments the device component <NUM> comprises a hermetic seal, e.g. a liquidproof and/or gas-proof plastic foil completely surrounding the cartridge <NUM>. The device component may provide an envelope and a closed shell for the cartridge <NUM> assembled therein. An interspace between the cartridge <NUM> and the device component, i.e. the plastic foil may be provided or may be completely filled with an ultrasound transmitting gel, thereby forming or constituting a gel pack.

The arrangement of a hermetic seal and an ultrasound transmitting gel for wrapping of the cartridge <NUM> inside the drug delivery device <NUM> provides several beneficial effects. By means of the surrounding gel, the cartridge <NUM> is mechanically suspended inside the drug delivery device <NUM>. In this way the cartridge is mechanically dampened. The gel embedding the cartridge <NUM> effectively provides mechanical shock absorption. The device and hence the cartridge will become less prone to mechanical shock.

Second, the gel provides thermal insulation for the cartridge. The relatively thick gel layer completely surrounding the cartridge <NUM> may act like a cool pack. The cartridge <NUM> assembled inside the device will heat much slower when the device is taken out of a refrigerated area. The device component <NUM>, i.e. the foil and the ultrasound transmitting gel provide a reduced thermal conductivity.

In addition, the cartridge <NUM> densely packed inside a foil envelope filled with an ultrasound transmitting gel is easily acoustically inspectable by means of a probe extending through or into a through opening <NUM> of the housing <NUM> of the drug delivery device <NUM>.

The device component <NUM> may also comprise a shrinking foil configured to provide a shrinking effect when the cartridge <NUM> and the gel are arranged inside an envelope formed by the foil. In this way the cartridge <NUM> can be densely packed inside the foil envelope and the ultrasound transmitting gel.

Instead of a gel pack it is also conceivable that the cartridge is embedded inside a layer or cladding made of or comprising an epoxy resin. Then the resin based cladding provides an acoustic coupling between the cartridge <NUM> and the housing <NUM> and/or the probe <NUM>.

Additionally or alternatively it is also conceivable to shrink the cartridge <NUM> inside a single or multiple layers of sound transmitting or sound-permeable foils. Such foils could be also adhesively attached to the outer circumference of the cartridge's barrel.

The various implementations as shown in <FIG> represent an indirect coupling <NUM> between the cartridge <NUM> and a probe <NUM> located outside the drug delivery device <NUM>. The indirect coupling <NUM> is of particular benefit for a mass manufacturing or mass assembly process since for testing the integrity of the cartridge <NUM> it is not necessary to establish a well-defined mechanical connection or contact between the probe <NUM> and the cartridge <NUM>.

This mechanical connection can be enhanced by an ultrasonic tip, e.g. made of metal. Furthermore, it is conceivable to embed at least one or several metal pieces inside the wrapped foil or gel pack. For instance, a metal piece could be arranged or attached to an inside facing portion of a foil envelope or gel pack. When a probe <NUM> or an ultrasonic tip is then brought in direct contact with an outer surface of the foil in an overlapping configuration with the metal piece an almost direct mechanical or acoustic coupling between the metal piece and the probe <NUM> can be obtained. Such a metal piece could be embedded in a layer of ultrasound transmitting gel. It is even conceivable that the metal piece is in direct contact with the cartridge <NUM>. Then, an ultrasound transmission from the probe <NUM> towards the cartridge <NUM> is even enhanced.

The probe <NUM> or the ultrasonic tip may also comprise a plastic component. It is conceivable that the through opening <NUM> is provided with a plastic component or with a particularly small sized gel pack configured for ultrasound transmission. The through opening <NUM> can be provided in a proximal housing component also accommodating a drive mechanism. Alternatively or additionally, the through opening may be provided in a distally located cartridge holder of the drug delivery device <NUM> configured and designed for accommodating the cartridge <NUM>.

Claim 1:
A method of testing the mechanical integrity of a cartridge (<NUM>) comprising a vitreous barrel (<NUM>) and containing a medicament and being arranged inside a housing (<NUM>) of a drug delivery device (<NUM>), the method comprising the steps of:
- bringing a probe (<NUM>) of a testing arrangement in indirect contact with the cartridge (<NUM>), wherein the probe (<NUM>) is configured to emit acoustic signals (<NUM>),
- indirectly acoustically stimulating the cartridge (<NUM>) from outside the housing (<NUM>) by means of the probe (<NUM>) and an indirect coupling (<NUM>), which is configured for sound guiding and sound propagation between the probe (<NUM>) and the cartridge (<NUM>), wherein the indirect coupling (<NUM>) forms a mount for the cartridge (<NUM>) inside the housing (<NUM>), wherein the probe (<NUM>) is coupled with a device component (<NUM>, <NUM>, <NUM>, <NUM>) of the drug delivery device, wherein the device component (<NUM>, <NUM>, <NUM>, <NUM>) is in direct mechanical contact with the cartridge (<NUM>) and wherein the cartridge (<NUM>) is axially and radially clamped inside the housing (<NUM>) by the at least one device component (<NUM>, <NUM>, <NUM>, <NUM>),
- measuring of the cartridge's (<NUM>) acoustic response (<NUM>) to the acoustic stimulation (<NUM>),
- comparing the acoustic response (<NUM>) with a standard response (<NUM>) of an intact cartridge (<NUM>), and
- determining the mechanical integrity of the cartridge (<NUM>) on the basis of the comparison.