Patent Description:
In the use of pre-filled pharmaceutical containers, such as pre-filled medical syringes, pharmaceutical vials or cartridges, but also in other fields of uses of a container, tightness of the container is often essential for maintaining an integrity and/or a sterility of the container content. To ensure that a container provides sufficient tightness for a planned use, it is known to perform in advance a tightness test, also known as container closure integrity (CCI) test, on the same container or on another container of the same or a comparable type. Tightness tests may also provide criteria for classifying a container type corresponding to different tightness requirements.

A known method for determining a tightness of a container is the so-called dye solution tightness test, which is laid out in Annex H to Part <NUM> of the international standard ISO <NUM>, 3rd edition issued <NUM> April <NUM>. According to this standard, sub-assembled syringes which are filled with liquid and closed with a plunger stopper are submerged in a, normally aqueous, dye solution. After a depressurisation/ re-pressurisation cycle, the sub-assembled syringes are inspected for leakage by checking the presence or absence of ingress of the dye solution into the syringe. To this end, the dye solution together with the syringes submerged therein is placed in a vacuum chamber, which produces and holds a negative pressure of at least <NUM> mbar during a period of half an hour. In the case that a leak is present in one of the containers, a portion of the content inside the container, which is still at atmospheric pressure, will be pressed out through the leak. Afterwards, when the vacuum chamber becomes re-pressurized, a portion of the dye solution is pressed into the container through the leak by the ambient pressure to compensate for the volume of the content that previously had been pressed out. Such dye can subsequently be detected using optical or spectroscopic techniques.

In an alternative method, a transfer of gas is detected which takes place during a depressurisation/ re-pressurization cycle between air in a headspace of the container and a reference gas, for example, carbon dioxide, in the vacuum chamber. Since the reference gas is typically invisible, subsequent inspection of the container(s) is mostly performed by means of spectroscopy to thereby detect an anomalous gas composition or concentration of the reference gas in the headspace.

<CIT> relates to testing pressurized containers for leaks. Hood members, each having an open lower end, are conveyed above a heated bath and are partially immersed in the bath, thereby being sealed at their lower open end. Aerosol cans suspended in the hood members are raised in temperature by the bath below, in order to obtain a testing pressure within the cans. At a testing station each hood member is evacuated. The withdrawn air is tested by means of a gas detection apparatus to determine if gas has escaped from the relevant aerosol can.

<CIT> relates to leakage testing of a connection between a rubber stopper and a corresponding drug container. A drug container is provided with a communication opening for enabling fluid communication of an exterior of the drug container with the interior of the drug container apart from its dispensing opening. Either the exterior of the drug container or, alternatively, the interior of the drug container is exposed at least at a connection region of the drug container and the rubber stopper inserted into the dispensing opening of the drug container to a test medium. The rubber stopper is displaced relative to the drug container in an opening direction for a chosen distance with a displacement device, while measuring any presence of the test medium either in the interior or, alternatively, in the exterior of the drug container that has passed through the dispensing opening.

<CIT> relates to a portable automotive leak detector. A container of pressurized gas with an ultraviolet dye dispersed therein has an outlet to which a tubing is connected. An outlet port of the tubing is dimensioned to facilitate attachment to the vapor recovery system access port of an automotive vehicle. Preferably the gas is a vapor made visible by shining an ultraviolet light thereon.

<CIT> relates to a pharmaceutical container.

The method described in <CIT> requires an aerosol, or gaseous, content of the aerosol cans. Moreover, the method described in <CIT> requires providing a communication opening in the container apart from a dispensing opening of the container.

Also, known methods of determining a container tightness often require the provision of a vacuum chamber.

Furthermore, conventional tests often do not provide a reliable indication of a container tightness for many real-use scenarios, for example, pharmaceutical applications including extended storage periods of a container which has been pre-filled with an mRNA vaccine.

Therefore, a technique is desirable that avoids, or at least mitigates, at least one the aforesaid disadvantages.

Accordingly, there is provided methods according to claims <NUM>-<NUM>.

According to a first aspect, a method of determining a tightness of a container is provided as defined in claim <NUM>.

The container body and the at least one closure device may define a container volume of the container. The initial content of the container may be arranged in the container volume. The boundary of the container may be identical to a boundary of the container volume. As an alternative, the boundary of the container may extend at least partially outside the container volume.

The initial content may comprise gas, in particular air. In addition or as an alternative, the initial content may comprise a liquid different from the ambient liquid.

According to the claimed invention, providing the container having the initial content at the first temperature comprises conditioning the container to have the first temperature. Providing the container having the initial content at the first temperature may comprise conditioning the container such that the initial content of the container has the first temperature. In addition the method may further comprise conditioning the ambient liquid to have the second temperature during the first predetermined period of time.

Exposing the container to the ambient liquid may comprises immersing, preferably completely immersing, the container in the ambient liquid.

Determining the tightness of the container may comprise assessing the container regarding an amount of the ambient liquid which has entered into the container and/or assessing the ambient liquid regarding an amount of the initial content of the container which has entered into the ambient liquid. The assessing may be performed using microscopy and/or spectroscopy. The assessing may be performed manually and/or automatically.

The first temperature may be a temperature in a first temperature range and the second temperature may be a temperature in a second temperature range, the first temperature range and the second temperature range being non-overlapping.

A difference between the first temperature and the second temperature may be <NUM> degrees Celsius or more, more preferably <NUM> degrees Celsius or more, more preferably <NUM> degrees Celsius or more, more preferably <NUM> degrees Celsius or more, more preferably <NUM> degrees Celsius or more. In addition or as an alternative, a difference between the first temperature and the second temperature may be <NUM> degrees Celsius or less, more preferably <NUM> degrees Celsius or less, more preferably <NUM> degrees Celsius or less, more preferably <NUM> degrees Celsius or less. Further, in addition or as an alternative, a difference between the first temperature and the second temperature may be between <NUM> degrees Celsius and <NUM> degrees Celsius, more preferably between <NUM> degrees Celsius and <NUM> degrees Celsius, more preferably between <NUM> degrees Celsius and <NUM> degrees Celsius, more preferably between <NUM> degrees Celsius and <NUM> degrees Celsius.

The second temperature may be higher than the first temperature and the second temperature may be -<NUM> degrees Celsius or more, more preferably -<NUM> degrees Celsius or more, more preferably -<NUM> degrees Celsius or more, more preferably -<NUM> degrees Celsius or more, more preferably -<NUM> degrees Celsius or more, more preferably -<NUM> degrees Celsius or more, more preferably -<NUM> degrees Celsius or more, more preferably <NUM> degrees Celsius or more, more preferably <NUM> degrees Celsius or more, more preferably <NUM> degrees Celsius or more, more preferably <NUM> degrees Celsius or more, and/or less than or equal to <NUM> degrees Celsius, more preferably less than or equal to <NUM> degrees Celsius, more preferably less than or equal to <NUM> degrees Celsius.

Alternatively, the second temperature may be lower than the first temperature and the second temperature may be <NUM> degrees Celsius or less, preferably <NUM> degrees Celsius or less, more preferably <NUM> degrees Celsius or less, more preferably <NUM> degrees Celsius or less, more preferably -<NUM> degrees Celsius or less, more preferably -<NUM> degrees Celsius or less, more preferably -<NUM> degrees Celsius or less, more preferably -<NUM> degrees Celsius or less, more preferably -<NUM> degrees Celsius or less, more preferably -<NUM> degrees Celsius or less, more preferably -<NUM> degrees Celsius or less, more preferably -<NUM> degrees Celsius or less, more preferably -<NUM> degrees Celsius or less, more preferably -<NUM> degrees Celsius or less, and/or more than or equal to -<NUM> degrees Celsius, more preferably more than or equal to -<NUM> degrees Celsius, more preferably more than or equal to -<NUM> degrees Celsius.

The first predetermined period of time may be <NUM> minute or more, preferably <NUM> minutes or more, more preferably <NUM> hour or more, more preferably <NUM> hours or more, more preferably <NUM> hours or more, more preferably <NUM> hours or more, more preferably <NUM> hours or more, more preferably <NUM> hours or more, more preferably <NUM> hours or more, more preferably <NUM> hours or more. In addition or as an alternative, the first predetermined period of time may be <NUM> month or less, preferably <NUM> week or less, more preferably <NUM> days or less, more preferably <NUM> hours or less.

The ambient liquid and/or the initial content of the container may comprise an organic solvent and/or water, preferably an aromatic compound, organic acid, ether, ester, alkane, ketone, aldehyde or alcohol, more preferably H<NUM>C-(CH<NUM>)n-OH, where n is chosen from the range <NUM> to <NUM>, preferably <NUM> to <NUM>, more preferably <NUM> to <NUM>, more preferably methanol or ethanol, n-propanol or iso-propanol, diethyl ether or THF, n-butyl methyl ether, iso-butyl methyl ether, ethyl acetate, methyl acetate, benzene, toluene, ethylbenzene, mesitylene, p-xylene, m-xylene, o-xylene, acetone, butanone, formaldehyde, acetaldehyde, propionic aldehyde, propionic acid, acetic acid, formic acid, methyl tert-butyl ether.

A concentration of the organic solvent may be <NUM> weight percent or more, preferably <NUM> weight percent or more, more preferably <NUM> weight percent or more, more preferably <NUM> weight percent or more, more preferably <NUM> weight percent or more, more preferably <NUM> weight percent or more, more preferably <NUM> weight percent or more, wherein the concentration of the organic solvent is with respect to the total mass in the ambient liquid and/or the initial content, respectively. In addition or as an alternative, the concentration of the organic solvent may be <NUM> weight percent or less, preferably <NUM> weight percent or less, more preferably <NUM> weight percent or less with respect to the total mass in the ambient liquid and/or the initial content, respectively.

In addition or as an alternative, a concentration of the organic solvent may be <NUM> volume percent or more, preferably <NUM> volume percent or more, more preferably <NUM> volume percent or more, more preferably <NUM> volume percent or more, more preferably <NUM> volume percent or more, more preferably <NUM> volume percent or more, more preferably <NUM> volume percent or more, wherein the concentration of the organic solvent is with respect to the total volume in the ambient liquid and/or the initial content, respectively. In addition or as an alternative, the concentration of the organic solvent may be <NUM> volume percent or less, preferably <NUM> volume percent or less, more preferably <NUM> volume percent or less with respect to the total volume in the ambient liquid and/or the initial content, respectively.

The initial content of the container and/or the ambient liquid may comprise a dye. The dye may be an organic dye. The dye may comprise at least one aromatic moiety, preferably riboflavin, fluorescein or bromothymol blue, more preferably fluorescein.

The second temperature may be higher than the first temperature and the initial content of the container may comprise a dye. Alternatively, the second temperature may be lower than the first temperature and the ambient liquid may comprise a dye.

The method may further comprise, during the first predetermined period of time, applying a negative pressure to an environment of the ambient liquid, for example, when both the first and the second temperatures are close to a room temperature. The negative pressure may be produced at least partially be means of a vacuum pump acting on the environment of the ambient liquid. The method may further comprise, during or after the first predetermined period of time, releasing the negative pressure from the environment of the ambient liquid. However, applying a negative pressure is only optional, but not necessary in other embodiments of the method. In particular in embodiments, in which the second temperature is lower than the first temperature and the second temperature is -<NUM> degrees Celsius or less.

The method may further comprise, after the first predetermined period of time has lapsed and before determining a tightness of the container, conditioning the container during at least a second predetermined period of time such that a temperature of the container returns towards the first temperature.

The container may be a pharmaceutical container which has been closed and/or sealed, wherein determining the tightness of the container comprises determining a tightness of a closure and/or sealing of the container.

The container may be a vial, preferably closed by a stopper. Alternatively, the container may be a syringe, preferably closed on opposing sides by a tip cap and a plunger. Further alternatively, the container may be a cartridge, preferably closed by a stopper and a plunger.

The at least one closure device may constitute multiple boundaries of the container, the multiple boundaries arranged in a nested arrangement. Determining the tightness of the container may be based at least partly on a number of boundaries from among the multiple boundaries across which an amount of the ambient liquid and/or an amount of an initial content of the container has passed.

The method may further comprise using results of the determined tightness to evaluate the suitability of the container for the storage of a solution, preferably a pharmaceutical solution, preferably at low temperature and/or reduced pressure.

In addition or as an alternative, the method may further comprise connecting and/or linking results of the determined tightness to the container.

According to another aspect, a method of using results of a tightness determination to evaluate the suitability of a container for the storage of a solution, preferably a pharmaceutical solution, preferably at low temperature and/or reduced pressure, is provided. The results are obtainable by the method as presently provided.

The method may further comprise connecting and/or linking the results of the tightness determination to the container. The container may be a pharmaceutical container.

According to another aspect, a method is provided. The method comprises connecting and/or linking results of a tightness determination to a container, preferably a pharmaceutical container. The results are obtainable by the determining method as presently provided.

According to another aspect, a container is provided in combination with the method according to the claimed invention. The container comprises a container body and at least one closure device applied to the container body. The at least one closure device constitutes multiple boundaries of the container, the multiple boundaries arranged in a nested arrangement. The container is configured to fulfil a tightness criterion which is defined at least partly based on a number of boundaries from among the multiple boundaries across which an amount of the ambient liquid and/or an amount of an initial content of the container passes when using the method as presently provided.

Each of at least some of the multiple boundaries may be constituted by one of multiple sealing ribs of the closure device. The container may be considered to fail the tightness criterion when the amount of the ambient liquid and/or the amount of the initial content of the container passes across more than one of the multiple sealing ribs. As an alternative, the container may be considered to fail the tightness criterion when the amount of the ambient liquid and/or the amount of the initial content of the container passes across more than two, or, alternatively, more than a number larger than two, of the multiple sealing ribs.

Further details, advantages and objectives of the invention become apparent from the drawings and the detailed description. In the drawings, there is shown:.

<FIG> shows schematically and exemplarily a container <NUM>. The container comprises a container body <NUM> and a closure device <NUM>. The closure device <NUM> seals an opening <NUM> of the container body <NUM>. When the container body <NUM> is sealed by the closure device <NUM>, the container body <NUM> and the closure device <NUM> enclose a container volume <NUM> inside the container <NUM>. In the shown example, the closure device <NUM> is a stopper having a plug <NUM> which extends in the container body <NUM> in the region of the opening <NUM>. A container volume <NUM> of the container <NUM> is defined by a portion of the inner wall of the container body <NUM> and by an inner surface <NUM> of the plug <NUM>.

The container body <NUM> has a crown <NUM> which surrounds the opening <NUM> of the container <NUM>. The crown <NUM> serves for retaining a cap <NUM> of the stopper <NUM> in a sealing position of the stopper <NUM>. For this purpose, the cap <NUM> is crimped onto the crown <NUM>. In addition, a holding element <NUM> extends below an underside of the crown <NUM>.

The plug <NUM> is further provided with one or more sealing ribs <NUM> which extend along a side surface of the plug <NUM>. The one or more sealing ribs <NUM> serve for sealing a gap between the plug <NUM> and the inner wall of the container body <NUM> and/or for balancing a break-loose and/or gliding force of the plug <NUM> during opening and closing of the container <NUM>. For this purpose, the plug <NUM> preferably comprises elastic material.

Concerning maintenance of a sterility or an integrity of a container content, the container <NUM> has various structures which can potentially serve as a boundary of the container <NUM> which a content in the container volume <NUM> and/or an ambient substance at an outside of the container <NUM> must not transgress in order for the sterility or the integrity of the container and of its content to be preserved.

For example, in certain applications and/or implementations of the container <NUM> integrity of the container content may be seen as compromised or lost when a respective one of the following structures of the container <NUM> is transgressed either by the container content or an ambient substance: a seam between the inner wall of the container body <NUM> and the inner surface <NUM> of the plug <NUM>, a seam between the inner wall of the container body <NUM> and any one of the one or more sealing ribs <NUM>, a seam between an interior edge <NUM> of the crown <NUM> and an underside of the cap <NUM>, a seam between the holding element <NUM> and an outer surface of the container body <NUM>. In some examples, the various structures of the container <NUM> provide different degrees of tightness, and a boundary of the container <NUM> is chosen according to the structure providing the greatest tightness.

In the shown example, the container <NUM> comprises a pharmaceutical vial. In other examples, the container <NUM> comprises other types of containers, such as a medical syringe or a pharmaceutical cartridge. Furthermore, in other examples a container has other and/or additional structures than the shown container <NUM> which may serve as a boundary of the container concerning the maintenance of a sterility or an integrity of the container and/or its container content.

<FIG> shows schematically and exemplarily a setup <NUM> for determining a tightness of a container, at different stages. The setup <NUM> comprises an immersion arrangement <NUM> and a container <NUM> for use with the immersion arrangement <NUM>.

The container <NUM> comprises a container body <NUM> having two openings <NUM>-<NUM>, <NUM>-<NUM> arranged on different sides of the container body <NUM>. Each of the openings <NUM>-<NUM>, <NUM>-<NUM> is sealed by means of a closure device <NUM>-<NUM>, <NUM>-<NUM>. A container volume <NUM> of the container <NUM> is defined by a portion of the inner wall of the container body <NUM> and an inner surface of each of the closure devices <NUM>-<NUM>, <NUM>-<NUM>. Regarding the container <NUM>, especially the container body <NUM> and each of the closure devices <NUM>-<NUM>, <NUM>-<NUM> the previous description of the container <NUM> applies correspondingly, unless otherwise clear from the following description and the drawings.

In the shown example, the container <NUM> is a medical syringe or a pharmaceutical cartridge. A first opening <NUM>-<NUM> at a proximal end of the container body <NUM> is sealed by a closure device <NUM>-<NUM> in the form of a stopper consisting essentially of a plug. Similar to the plug <NUM>, the closure device <NUM>-<NUM> has one or more sealing ribs <NUM>-<NUM> along its side surface. A second opening <NUM>-<NUM> at a distal end of the container body <NUM> is arranged in a tip of the container <NUM>, and it is sealed by a closure device <NUM>-<NUM> in the form of a cap. Analogously to the example in <FIG>, the container <NUM> has structures which may serve as a boundary of the container <NUM> with respect to a sterility or an integrity of the container <NUM> or its content. In some examples, in the region of one or both of the closure devices <NUM>-<NUM>, <NUM>-<NUM> various structures are provided which can serve as a possible boundary of the container <NUM>. These structures include, for example, a seam between an inner wall of the container body <NUM> and an inner surface of the closure device <NUM>-<NUM>, a seam between an inner wall of the container body <NUM> and any one of the one or more sealing ribs <NUM>-<NUM>, a seam between an inner edge of the second opening <NUM>-<NUM> and an inner surface of the cap <NUM>-<NUM>, a seam between an outer surface of the container body <NUM> in the region of the second opening <NUM>-<NUM> and a rim of the cap <NUM>-<NUM>.

The container volume <NUM> comprises, preferably contains, an initial content, for example, a gas, such as air, or a liquid, such as a reference liquid or a testing liquid, or both liquid and gas.

The immersion arrangement <NUM> comprises an immersion device <NUM>. In the immersion device <NUM>, a reservoir is provided which in connection with determining a tightness of a container serves as an ambient liquid <NUM>. In the example of <FIG>, the immersion device <NUM> is shown as a simple tub. In other examples, the immersion device <NUM> further includes conditioning facilities, for example, for adjusting and holding a temperature of the ambient liquid <NUM> in accordance with an intended use for determining a tightness of a container as described below. In other examples, the immersion device <NUM> further comprises an arrangement for holding and moving one or more containers <NUM>, in particular, for charging the immersion device <NUM> and for reversibly immersing the one or more containers <NUM> in the ambient liquid <NUM>.

As shown in <FIG>), in a first example of the described process, the container volume <NUM> is provided to be entirely filled with gas, such as air. In addition, the container <NUM>, including the gas inside the container volume <NUM>, is conditioned to have a first temperature, for example, room temperature, around <NUM> degrees Celsius. Furthermore, the ambient liquid <NUM> is conditioned to have a second temperature significantly lower than the first temperature, for example, around -<NUM> degrees Celsius.

In some examples, the ambient liquid <NUM> comprises an organic solution having a freezing point significantly in the negative Celsius range. This enables a corresponding application of the described process with a second temperature in the negative Celsius range down until near the freezing point of the ambient liquid <NUM>. Furthermore, in some examples, the ambient liquid <NUM> comprises a dye which is present in the ambient liquid <NUM>, for example, in a resolved form. The dye solution comprises, preferably contains, in some example ethanol as a solvent in which fluorescein disodium is dissolved as dye, in a concentration of <NUM> gram per <NUM> litre.

As shown in <FIG>, in a next step, the container <NUM> is placed inside the ambient liquid <NUM>. Preferably, the container <NUM> is entirely submerged in the ambient liquid <NUM>. Whilst submerged in the ambient liquid <NUM>, the container <NUM> will gradually adopt a temperature at least close to the second temperature. In preferred examples, an absolute heat capacity of the container <NUM> is small relative to an absolute heat capacity of the ambient liquid <NUM>. In this way, temperature variations of the ambient liquid <NUM> due to the immersion of the container <NUM> can be kept minimal. When the temperature of the container <NUM> sinks due to the immersion in the ambient liquid <NUM>, a temperature of the gas in the container volume <NUM> will sink correspondingly. Hence, the gas in the container volume <NUM> will contract, and a gas pressure within the container volume <NUM> will drop below an ambient pressure which is constituted, for example, by the ambient air pressure plus a, mostly negligible, pressure caused by the column of ambient liquid above the container <NUM>. If the container <NUM> has a leak sufficiently large, parts of the ambient liquid <NUM> will be pressed into the container <NUM> via the leak by the excess pressure on the outside of the container <NUM>.

The container <NUM> remains in the ambient liquid <NUM> during at least a predetermined period of time. The period of time is chosen to allow that a temperature inside the container <NUM> comes close enough to the second temperature and that a transgression of liquid through a possible leak in the container <NUM> due to the pressure difference between the inside of the container <NUM> and an ambient pressure can take place. In some examples, the predetermined period of time is chosen to be ca. <NUM> minutes. In other examples, the predetermined period of time is chosen to be less or more than ca. <NUM> minutes.

<FIG>, shows schematically two possible outcomes once the container <NUM> has been removed from the ambient liquid <NUM>. In the upper example, i), an amount L of the ambient liquid is detected inside the container volume <NUM>. In particular, an amount L of ambient liquid <NUM> has transgressed a boundary of the container <NUM> in the region of the tip. This indicates the presence of a leak in the region of the tip of the container <NUM> under the conditions applied in previous stages a) and b). In the lower example, ii), no parts of the ambient liquid <NUM> are detected inside the container <NUM>. This indicates tightness of the container <NUM> under the conditions applied in previous stages a) and b).

Using an organic solution for the ambient liquid <NUM> allows for a second temperature in the range around -<NUM> to -<NUM> degrees Celsius, which overlaps with the range of storage temperatures, for example, of various vaccines. Hence, the process can be performed to determine a tightness of the container <NUM> at an intended temperature of use of the container <NUM> for relevant applications.

Furthermore, a pressure difference between the inside of the container <NUM> and an ambient pressure when the container <NUM> filled with a gas is immersed in the ambient liquid <NUM> can be roughly determined based on the equation for ideal gases. According to the equation, the pressure inside the container is linearly proportional to the temperature inside the container <NUM>. Accordingly, when the container <NUM> is assumed to be at atmospheric pressure and <NUM> degrees Celsius at the outset, immersing the container <NUM> in the ambient liquid <NUM> at -<NUM> degrees Celsius, for example, will lead to a temperature change from about <NUM> Kelvin to <NUM> Kelvin, leading to a pressure drop by about <NUM> mbar relative to atmospheric pressure. This corresponds also to the pressure requirements defined in the international standard ISO <NUM>, Part <NUM>, issued <NUM> April <NUM>, which demand a negative pressure of at least <NUM> mbar in order to ensure valid results.

Corresponding calculation for a second temperature at -<NUM> degrees Celsius still yields a pressure drop inside the container <NUM> by about <NUM> mbar. Though different from the international standard ISO <NUM> of <NUM>, meaningful results can still be expected for many relevant use cases also under such pressure conditions.

In some examples, after removing the container <NUM> from the ambient liquid <NUM> the container <NUM> is conditioned during at least another predetermined period of time prior to allow for its temperature to at least essentially return to the first temperature, before the container <NUM> is inspected for possible dye ingress.

In the above description, it has been assumed that the container <NUM> initially comprises, preferably contains, gas and that the second temperature, i.e., the temperature of the ambient liquid <NUM>, is less than a first temperature of the container <NUM> at the outset of the process, and that the content of the container <NUM> will be finally inspected concerning a dye ingress. However, in alternative examples of the method, the container <NUM> initially comprises, preferably contains, a liquid with a dye resolved therein. In some of these examples, the ambient liquid <NUM> has a second temperature which is higher than the first temperature of the container <NUM>. Immersing the container <NUM> in the ambient liquid <NUM> will correspondingly lead to an increase of pressure inside the container <NUM>. If the container <NUM> has a leak sufficiently large, parts of the dye solution thus will be pressed into the ambient liquid <NUM> via the leak by the excess pressure inside the container <NUM>. Determining the presence or absence of a leak in the container <NUM> is finally performed in this case based on an inspection of the ambient liquid <NUM> for portions of the dye solution that have egressed from the container <NUM>.

In some examples, the process at stage b) includes applying a negative pressure to an environment of the ambient liquid <NUM>. For example, the immersion arrangement <NUM> is configured for this purpose to at least partially evacuate a space of air above the ambient liquid <NUM> in the immersion device <NUM>. To this end, the immersion arrangement <NUM> comprises a vacuum pump in some examples. In other examples, the immersion device <NUM> is configured to be transferred, at least temporarily, into a vacuum chamber which is external to the immersion arrangement <NUM>. Applying a negative pressure to the environment of the ambient liquid <NUM> facilitates in some examples the adjusting of a pressure difference between an inside and an outside of the container <NUM>.

Furthermore, in applications of the setup <NUM> in which a difference between the first temperature and the second temperature is too small to generate a significant pressure difference between an inside and an outside of the container <NUM>, for example, when both the first and the second temperatures are close to a room temperature, applying a negative pressure to the environment of the ambient liquid <NUM> can be suited to produce a suitable pressure difference. A transfer of dye occurs, for example, from inside the container <NUM> to the ambient liquid during application of the negative pressure. In another example, a transfer of dye occurs from the ambient liquid into the container <NUM>, after a negative pressure has been applied for an extended period to the environment of the ambient liquid <NUM>, and has been transmitted via the ambient liquid <NUM> into the container <NUM>, and is then released. However, generating a suitable pressure difference by using a vacuum pump is not required in most examples of the system <NUM>, due to a pressure difference resulting from the difference between the first and the second temperatures, as described.

In addition or as an alternative, in some examples, the process at stage b) further includes, after exposing the container <NUM> to the second temperature in the ambient liquid <NUM> and before determining a tightness of the container <NUM> at stage c), conditioning the container <NUM> such that a temperature of the container <NUM> returns towards the first temperature. To this end, in some examples, the immersion device <NUM> with the container <NUM> placed therein is exposed to the first temperature in order for the ambient liquid <NUM> to gradually change its temperature from the second temperature towards the first temperature. In other examples, the container <NUM> is removed from the ambient liquid <NUM> and placed in another ambient liquid (not shown) at a temperature equal to the first temperature or at least closer to the first temperature. This causes a fast conditioning of the container <NUM>, since no heat transfer needs to take place on the ambient liquid <NUM>.

It has been found that fast conditioning of the container <NUM> from a lower second temperature towards a higher first temperature, especially by thawing from -<NUM> degrees Celsius to room temperature, poses higher stress on a tightness of the container <NUM> than a slow conditioning which occurs when conditioning the ambient liquid <NUM> as a whole. A possible reason is that the syringe body warms up faster than the stopper, which temporarily reduces a tightness of the container while a pressure difference between the inside and the outside of the container still exists.

By applying the described tightness test to a range of medical syringes, it has been found that an increased amount of siliconization, for example, as a layer of cured silicon oil, on the inner wall of the syringe body leads to improved tightness when using an uncoated stopper than with a silicon-coated stopper, in the case that fast conditioning of the syringe was performed from a lower second temperature, especially around minus <NUM> degrees Celsius, towards room temperature.

The following Table <NUM> contains the results of a container tightness test as described above which has been applied to syringe sets consisting of a predefined number of syringes (first column) and having varying syringe properties (second to fourth columns). The varying syringe properties include syringe sizes (second column), barrel siliconization compositions (third column), and amounts of siliconization applied (fourth column). In the last column, unless all syringes of a set have passed the tightness test (Result: OK), the number x of syringes that failed the test out of a given syringe set size y is indicated (Result: x/y fail). In all cases, an open end of the syringe barrel was closed using Datwyler FM257 stopper and the tip was closed using West <NUM> tip cap. In addition, in all cases a siliconization coating was applied to the syringe tip using Composition A, as described below.

Apart from a reference Composition C of pure silicone oil, the barrel siliconization compositions in Table <NUM> include Composition A and Composition B. For each of Compositions A and B, the following Table <NUM> contains the constituents and their functions as well as their respective concentrations in percentage by weight.

<FIG> shows schematically and exemplarily a flow diagram of a method <NUM> of determining a tightness of a container, for example a container such as container <NUM> or container <NUM>. The method <NUM> comprises providing a container having a first temperature, step <NUM>, wherein providing the container having the initial content at the first temperature comprises conditioning the container to have the first temperature. The method <NUM> further comprises exposing the container to an ambient liquid, for example, ambient liquid <NUM> shown in <FIG>, during a first predetermined period of time, wherein during the first predetermined period of time the ambient liquid has a second temperature different from the first temperature, step <NUM>. After the first predetermined period of time has lapsed, a tightness of the container is determined based on an amount of the ambient liquid and/or an amount of an initial content of the container having passed across a boundary of the container, step <NUM>.

<FIG> shows schematically and exemplarily a detail of a container <NUM> according to another example. The container <NUM> comprises a container body <NUM> having an opening <NUM> and a closure device <NUM> which seals the opening <NUM>. The closure device <NUM> is a stopper consisting essentially of a plug. Similar to the plug <NUM> and the closure device <NUM>-<NUM>, the closure device <NUM> has an inner surface <NUM> and three sealing ribs 438a, 438b, 438c along its side surface. As further shown in <FIG>, an amount L of an ambient liquid is found in spaces between the sealing ribs 438a, 438b, 438c.

<FIG> shows the container <NUM> after a process as described in connection with <FIG> and <FIG>. In the case shown in <FIG>, the amount L of the ambient liquid has not entered a container volume of the container <NUM>. In particular, the amount L has not transgressed a seam between the inner wall of the container body <NUM> and the inner surface <NUM> of the closure device <NUM>. Still, an integrity or a sterility of the container <NUM> or its content need to be regarded as compromised or lost in certain examples under the conditions applied during the process, for example, if the central sealing rib 438b, or even merely the outer sealing rib 438c, is transgressed. In such cases, the respective sealing rib 438b or 438c defines the boundary of the container <NUM> in the context of the tightness determination process.

Other examples of a closure device have more and/or other structures than the closure device <NUM> which may serve as boundaries of a container. In some examples the various structures of the closure device can be regarded as multiple boundaries that enclose one another in a nested manner. Furthermore, in different example applications, different ones of the multiple (possible) boundaries provided by a closure device are regarded as the boundary of the container when applying the technique described herein.

<FIG> shows schematically and exemplarily a flow diagram of a method <NUM>. The method <NUM> is a method of using results of a tightness determination to evaluate the suitability of a container for a storage of a solution, preferably a pharmaceutical solution, preferably at low temperature and/or reduced pressure. The results are obtained by a process as described above and below.

<FIG> shows schematically and exemplarily a flow diagram of a method <NUM>. The method <NUM> comprising using the results of a tightness determination obtainable by a method as described above and below to evaluate the suitability of a container for a storage of a solution, preferably a pharmaceutical solution, preferably at low temperature and/or reduced pressure, step <NUM>. In addition or as an alternative, the method <NUM> comprises connecting and/or linking the results of the tightness determination obtainable by as described above and below to a container, preferably a pharmaceutical container. In some examples, the method <NUM> is performed after execution of the method <NUM> as described above, involving the results obtained by the method <NUM>.

<FIG> shows schematically and exemplarily a container <NUM>. Similar to the container <NUM>, the container <NUM> comprises a container body <NUM> and a closure device <NUM>. Moreover, an inner surface <NUM> of the closure device <NUM> and a portion of an inner wall of the container body <NUM> define a container volume <NUM> of the container <NUM>. The closure device <NUM> comprises a plurality of sealing ribs 738a - 738d. Furthermore, the container body <NUM> has a crown having an inner edge <NUM>.

Claim 1:
Method (<NUM>) of determining a tightness of a container (<NUM>; <NUM>; <NUM>; <NUM>), the method comprising:
providing (<NUM>) a container (<NUM>; <NUM>; <NUM>; <NUM>) having an initial content at a first temperature, the container (<NUM>; <NUM>; <NUM>; <NUM>) comprising a container body (<NUM>; <NUM>; <NUM>; <NUM>) and at least one closure device (<NUM>; <NUM>-<NUM>, <NUM>-<NUM>; <NUM>; <NUM>) applied to the container body (<NUM>; <NUM>; <NUM>; <NUM>);
exposing (<NUM>) the container (<NUM>; <NUM>; <NUM>; <NUM>) to an ambient liquid (<NUM>) during a first predetermined period of time, wherein during the first predetermined period of time the ambient liquid (<NUM>) has a second temperature different from the first temperature, and
after the first predetermined period of time has lapsed, determining (<NUM>) a tightness of the container (<NUM>; <NUM>; <NUM>; <NUM>) based on an amount (L) of the ambient liquid (<NUM>) and/or an amount of the initial content of the container (<NUM>; <NUM>; <NUM>; <NUM>) having passed across a boundary (<NUM>, <NUM>, <NUM>; <NUM>; 438a - 438c; <NUM>, <NUM>, 738a - 738d) of the container (<NUM>; <NUM>; <NUM>; <NUM>),
characterized in that
providing (<NUM>) the container (<NUM>; <NUM>; <NUM>; <NUM>) having the initial content at the first temperature comprises conditioning the container (<NUM>; <NUM>; <NUM>; <NUM>) to have the first temperature.