Patent Description:
More precisely, the invention relates to the field of bags for biopharmaceutical fluid content.

In recent years, bags have been increasingly proposed for containing, transporting, transforming or transferring biopharmaceutical fluid content. These bags are replacing the rigid stainless steel tanks that were previously used for these functions. These flexible bags, which can hold from one liter to one thousand liters, are often referred to as "single-use" because once they have been used they are not processed for reuse as tanks are, but are discarded.

The term "biopharmaceutical fluid" is understood to mean culture media, cell cultures, buffer solutions, artificial nutrition liquids, any fluid resulting from biotechnology, a pharmaceutical fluid, or more generally a fluid intended for use in the medical field.

The integrity of the bag is important to ensuring its use under proper conditions. A defect in its integrity can mean a leak and therefore a loss of product contained in the bag, which can be undesirable from an economic point of view. But more importantly, a loss of integrity implies that the contents of the bag may have been contaminated by the outside environment, and in this case it is the entire product contained in the bag, as well as any product resulting from the use of the bag, which is potentially contaminated and may need to be discarded. Great effort is therefore made to guarantee the integrity of the bag.

There are several categories of technologies for testing bag integrity. According to a first technology, the bag manufacturer can apply an integrity test after manufacture and before any delivery, storage, or use of the bag. One problem is that such an integrity test does not take into account the subsequent conditions of delivery, storage, or use of the bag, and may therefore be overengineered for the subsequent conditions of delivery, storage, or use of the bag. Moreover, since the test is overengineered, it can introduce defects into a bag that did not have any before the test and thus increase the risk of loss of integrity, which is even worse.

Another technology consists of monitoring the integrity of the bag until just before its use. This makes it possible for the integrity test to cover the storage and delivery stages, which are subsequent to its manufacture, until it is used. It is known to contain the bag in an outer pouch, the space between the bag and the outer pouch containing a colorimetric detection layer capable of detecting the possible presence of a tracer gas within the space. One problem with this technology, however, is that it is quite expensive and makes it complex to use the bag.

Another technology consists of testing the integrity of the bag after use. However, one problem is that if this test reveals a defect in its integrity, all production carried out using the bag is potentially contaminated and may have to be thrown away for safety. In addition, the test can damage an intact bag and detect an integrity defect due to the test itself, which is also unfortunate.

Whatever test is used, there is also the issue of the test revealing an integrity defect in absolute terms, but which is not problematic for the application. Such is the case, for example, if the test reveals a certain porosity in the film of the bag, but the porosity by itself is not an issue for the application.

A problem therefore arises related to the importance of offering bag users greater certainty regarding the integrity of their bags.

Further prior art can be found in <CIT> and <CIT>. <CIT> describes methods and systems for assessing the integrity of porous materials, such as membranes that may be used in filtration devices. The method involves applying a differential pressure across the material.

The present invention is defined by the independent claims <NUM> and <NUM>.

Optional features are recited in the dependent claims.

A description of the invention is given below.

According to a first aspect, the object of the invention is a method for characterization of a calibrated defect of a film of a bag for biopharmaceutical fluid, the method being as defined in claim <NUM>.

With these arrangements, the characteristics of the films are determined beforehand.

It is thus possible to determine which critical levels of defect are likely to lead to leakage in a bag composed of the film.

According to one embodiment, the characteristics of the fluid stresses comprise one or more of:.

According to one embodiment, the characteristics of the bag film sample (<NUM>) provided with a calibrated defect comprise one or more of:.

According to one embodiment, a calibrated defect is applied to the bag film sample.

According to one embodiment, the calibrated defect applied to the bag film sample is measured.

According to one embodiment, the leak test includes the application of a column of fluid of known height, known viscosity, known temperature, under known ambient conditions, to a bag film sample of known material, known thickness, known defect, for a known duration, and the detection over time of the passage of said fluid through said bag film sample.

According to another aspect, the invention relates to a method for building a database, wherein the above method for characterization is implemented for different bag film samples provided with calibrated defects and for various controlled fluid stresses.

According to another aspect, the invention relates to a system for characterization of a calibrated defect of a film of a bag for biopharmaceutical fluid, the system being as defined in claim <NUM>.

According to another aspect, the invention relates to a computerized method for obtaining characteristics of a film for a bag for biopharmaceutical fluid content, the computerized method is as defined in claim <NUM>.

According to another aspect, not forming part of the claimed invention, there is a computerized method for characterization of a bag for biopharmaceutical fluid content, the bag comprising at least one film, wherein,.

According to embodiments, the computerized method may be as defined in any of the claims <NUM>-<NUM>.

The figures of the drawings are now briefly described.

In the figures, the same reference number designates identical or similar elements.

The following is a detailed description of several embodiments of the invention, with examples and with reference to the drawings.

An example of a leak test conducted on a film sample is first described.

As can be seen in <FIG>, the leak test device <NUM> comprises a housing <NUM>. The housing <NUM> is in two parts. The housing <NUM> comprises an upper part 2a and a lower part 2b. The terms "upper" and "lower" are used in reference to the vertical direction, which is the direction of gravity. The present description is given by considering a functional orientation of the leak test device even if the leak test device could be placed in a different orientation, in particular when not in use. Furthermore, it is not impossible for the described leak test device, or variants thereof, to be functionally used in a different orientation than the one shown.

The two parts 2a, 2b of the housing are assembled together so as to define an interior space receiving the film to be tested <NUM>. In practice, the two parts 2a, 2b of the housing are removably assembled one to the other, so that they can alternatively be placed in a disassembled configuration for installation of the film to be tested in the leak test device and in an assembled configuration for the actual test. In the example shown, the two parts 2a, 2b of the housing are removably assembled to one another by screwing. Other removable assembly technologies could be considered.

Thus, the film to be tested <NUM> separates the leak test device into two regions: an upstream region and a downstream region. According to the principle of the leak test, the upstream region comprises a fluid in contact with the test film, and the downstream region comprises a detector for detecting the presence of fluid from the upstream region in the downstream region. In the orientation shown for the leak test device, the film to be tested is placed horizontally, the upstream region being located above the test film <NUM> and the downstream region being located below the test film <NUM>. Gravity can thus be used for the leak test.

The upper part 2a of the housing comprises a cover <NUM> and a tube <NUM> provided with a lower end flange <NUM>. In the present case, these two functions are fulfilled by two separate parts connected to one another in a fluidtight manner. Thus, in the present application, when the term "fluidtight" is used, this refers to impermeability to the fluid used during the leak test under normal conditions for implementing the leak test. For example, in the present embodiment, an O-ring seal <NUM> is provided between the lower end flange <NUM> and the cover <NUM>. The cover <NUM> enables a mechanical connection of the upper part 2a of the housing <NUM> to the lower part 2b of the housing <NUM>. The tube <NUM> comprises two ends 5a, 5b, for example opposite one another. End 5a can be fluidly connected in a fluidtight manner to a source of fluid. End 5b faces the test film <NUM> in the test configuration. The cover <NUM> has a through opening <NUM>, for example central in its upper face, for the passage of the tube <NUM> through the cover <NUM>.

The tube <NUM> is graduated and/or may be connected in a fluidtight manner to a graduated tube <NUM>. In the present case, a graduated tube <NUM> is connected in a fluidtight manner to the tube <NUM>. The graduated tube <NUM> comprises two ends 13a, 13b, for example opposite ends. End 13a can be fluidly connected in a fluidtight manner to a source of fluid. End 13b is fluidly connected in a fluidtight manner to the upper end 5a of the tube <NUM>. The graduated tube <NUM> is graduated so as to display the volume of fluid contained in the space above the test film <NUM> at the graduation level corresponding to the upper level of the fluid.

The lower part 2b of the housing <NUM> comprises a cover <NUM>. The cover <NUM> enables a mechanical connection of the lower part 2b of the housing <NUM> to the upper part 2a of the housing <NUM>. For example, in the example shown, covers <NUM> and <NUM> have complementary threads. The upper face 7a of cover <NUM> has a through-opening <NUM>. In the exemplary embodiment shown, the upper face 7a of cover <NUM> comprises a central pocket <NUM> carrying pins <NUM> and defined by a peripheral shoulder <NUM>. The through-opening <NUM> is arranged in the central pocket <NUM>. A tapered conical tube <NUM> (visible before assembly in <FIG>) extends downward from the through-opening <NUM>. The lower part 2b of the housing <NUM> also comprises a rigid support <NUM>. The support <NUM> has a planar upper face 9a. The support <NUM> is for example made of metal or plastic. For example, the support <NUM> is removably mounted on cover <NUM>. For example, the support <NUM> is carried by pins <NUM> projecting from the upper face 7a of cover <NUM>, so that the support <NUM> is laterally held by the peripheral shoulder <NUM>. The support <NUM> has a through-opening <NUM> that is aligned, in the assembled configuration, with the through-opening <NUM> in the upper face 7a of cover <NUM>.

The lower part 2b of the housing <NUM> also comprises a detector <NUM>. The detector <NUM> is a consumable part replaced after each leak test. It is therefore removably assembled to cover <NUM>. The detector <NUM> is arranged beneath the through-opening <NUM> in the upper face 7a of cover <NUM>. In particular, the tapered conical tube <NUM> concentrates any fluid flowing from the through-opening <NUM> in the direction of a localized area of the detector <NUM>. If necessary, the detector <NUM> is not part of the housing <NUM> but is arranged under the housing <NUM>, the latter having a through-opening between the test film <NUM> and the detector <NUM>. The detector <NUM> is, for example, contained in a container <NUM> assembled to cover <NUM>.

The leak test device <NUM> may operate as follows.

As represented in <FIG>, the test film <NUM> is installed in the leak test device <NUM>. To do so, if the leak test device <NUM> is assembled, the upper part 2a is disassembled from the lower part 2b. As represented in <FIG>, the tapered conical tube <NUM> is installed in the lower part 2b. The detector <NUM> is placed in the container <NUM>, and the container <NUM> is assembled to cover <NUM>. If the support <NUM> is a removable support, as represented in <FIG>, it is installed on cover <NUM>. The through-opening <NUM> of the upper face 7a of cover <NUM> and the through-opening <NUM> of the support <NUM> are then aligned.

The test film sample <NUM> is then placed on the support <NUM>, as represented in <FIG>. The test film <NUM> has an inside surface intended to be placed in contact with the biopharmaceutical fluid and an opposite outside surface. The test film <NUM> is placed in the leak test device in the orientation corresponding to its future use: the inside surface facing the source of fluid and the outside surface facing the detector. The diameter of the test film sample <NUM> is smaller than the inside diameter of the housing <NUM>. It has a diameter greater than the diameter of the support <NUM>. The outside surface of the test film sample <NUM> is then resting on the support <NUM> and the peripheral shoulder <NUM>.

As represented in <FIG>, the housing <NUM> is now assembled. The upper part 2a and the lower part 2b are assembled in a fluidtight manner. For example, a seal <NUM> is applied to the inside face of the test film sample <NUM>, in particular on the peripheral portion of said film. The seal <NUM> is for example integral with the upper part 2a of the housing. It is for example shaped as an annular ring. The seal <NUM> is interposed between the test film <NUM> and the lower end flange <NUM> of the tube <NUM>. Upon assembly of the housing <NUM>, the seal <NUM> is compressed between the tube <NUM> and the film <NUM>, and the O-ring seal <NUM> is compressed between the cover <NUM> and the tube <NUM>. The peripheral portion of the test film sample <NUM> is then interposed (vertically) between the peripheral shoulder <NUM> and the seal <NUM>. The test film sample <NUM> is then held in place in the housing <NUM>. Alternatively, the detector <NUM> may also be assembled to the cover <NUM> at this stage, as shown in <FIG>. The detector <NUM> is then facing the test film sample <NUM>.

The graduated tube <NUM> visible in <FIG> is assembled to the tube <NUM> in a fluidtight manner.

The upper end 13a of the graduated tube <NUM> is fluidly connected to a source of fluid, and a determined quantity of fluid is placed in the graduated tube by means of a pump (not shown). In a variant, a determined quantity of fluid is manually poured into the graduated tube <NUM>. We now have the configuration of <FIG>.

After a predetermined time, a result of the leak test is determined. A result of the leak test may for example be in Boolean form, namely whether or not the test film <NUM> leaks. To do so, for example, the detector <NUM> is observed directly.

If necessary, a result of the leak test may be quantitative, meaning it includes information on the nature of the leak. At this stage, this means quantifying the level of fluidtightness.

If necessary, these measurements are repeated over time, characterizing the fluidtightness over time.

According to one embodiment of the invention, a database of leak test results is constructed for bag films having different characteristics, exhibiting calibrated defects, and subjected to various mechanical conditions exerted by fluids of diverse mechanical characteristics.

Preferably, the set of tests is carried out with the same leak test device, such as the one presented above, for better reproducibility of results.

Each element of the database can be characterized by two or more of the following characteristics (characteristics either of the film or of the fluid stresses, and result of the test):.

In practice, leak tests, for example as described above, are carried out for a test film sample having a control calibrated defect.

The control defect comprises, for example, one or more through-holes of controlled shape and/or dimensions, created in the test film <NUM> beforehand. In a prior defect creation step, a LASER beam is used, for example controlled to produce a controlled hole in the test film <NUM>. The characteristics of the LASER beam used to form the defect may be sufficient to characterize the defect. Alternatively, following the generation of the defect, observation of the film is performed (for example by microscopy) in order to characterize the defect.

In practice, when performing a leak test, the identity of the constituent material of the film is indicated in the database (the identity may for example correspond to a commercial name of the film, with no need to specify all the film characteristics which can be very complex).

The thickness of the film is also indicated in the database, which may be intrinsic to the film identity.

The transverse dimensions of the film may also be provided. However, this information can be standardized for the test in question.

A control defect is created in the film, and the characteristics of the control defect are indicated in the database.

The test film <NUM> is installed in the test device <NUM>.

The fluid stresses exerted by the fluid are characterized. The test fluid is characterized. The identity of the test fluid is therefore indicated in the database (the identity may for example correspond to a commercial name for the fluid, with no need to specify all the fluid characteristics which can be very complex).

The mechanical characteristics of the test fluid are also indicated in the database, for example such as its viscosity, as described by the supplier of the fluid or as determined by an ad hoc test. The temperature of the fluid at the time of the test can also be entered.

A pressure is applied on the film sample. According to one embodiment, a predetermined volume of fluid is placed in the test device, and the volume in question is indicated in the database. This volume is measured, for example, using the graduated tube. The volume of liquid corresponds to the pressure exerted on the film sample. According to another example, additional pressurizing means could be used to pressurize the liquid. These may include, for example, pressurizing gas applied at a predefined pressure above the liquid, or a mechanical pressuring device such as a piston applying a force on the liquid. In any case, the pressure applied on the film sample is measured or estimated and recorded.

The ambient temperature at the time of the test may also be entered. The leak test is carried out, and the result of the test is recorded in the database. In particular, in spite of the presence of a defect in the film, the leak test may be positive (no leak is detected) for the application conditions. Such is the case if the defect is so slight that, considering the hydrostatic pressure exerted on the film and the viscosity of the fluid, the fluid does not pass through the defect. In such case, one could also consider the film having such a defect as remaining intact, despite the presence of a defect.

Numerous tests are carried out, varying the above parameters in order to construct the database. In particular, the test can also be carried out for film samples having no defects. <FIG> shows an example composition of the database. For each test, the following are recorded: the size of the hole in microns, the thickness of the film in microns, the viscosity of the test liquid, the film surface tension (determined from the volume of the fluid), the duration of the test in hours, the Boolean result of the leak test, and the moment at which a leak is detected in hours.

Records in the database can be entered through any known means such as user-machine interfaces, keyboard, joystick, mouse, keypad, touchscreen, microphone, voice recognition software.

As represented in <FIG>, a programmable machine <NUM> is provided, comprising a computer <NUM> configured to implement a predictive engine. The computer <NUM> has access to the database <NUM> described above, possibly via a network <NUM>. The computer <NUM> also has access to a memory <NUM> storing input data. The memory <NUM> may also be accessible to the computer <NUM> via a network <NUM>. The input data may in particular comprise information relating to a planned use of the bag. The information relating to the planned use may include characteristics (viscosity, temperature, maximum volume (or maximum pressure), etc.) of the biopharmaceutical fluid to be contained in the bag, mechanical conditions of the bag use, duration of the bag use, the intended application (or applications), and the level of fluidtightness required for the bag. The intended applications are for example chosen from the following list: "mixing, culture, transport, storage", which exert different stresses, particularly mechanical, on the bag.

The predictive engine will determine one or more sets of film characteristics that best match the need expressed by the information concerning the intended use. For example, the predictive engine uses a cost function to identify the elements of the database that best meet the need. The different parameters can be assigned different weights in the cost function. For example, failure to meet the required level of fluidtightness can generate a significant cost in the cost function. In particular, the predictive engine makes it possible to determine, for a given type of film, which is the most severe defect that is admissible without loss of fluidtightness.

According to one embodiment, a user is provided with a programmable device <NUM> provided with an interface <NUM>. The programmable device <NUM> may be connected to the computer <NUM> via the network <NUM>, or may access it locally. If necessary, the programmable device <NUM> comprises the memory <NUM> but alternatively the memory <NUM> may be accessed by the programmable device <NUM> via the network <NUM>. The interface <NUM> allows the user to enter the information relating to an intended use of the bag, which is then stored in the memory <NUM>. The interface <NUM> also makes it possible to display the results of the determination made by the computer <NUM>. It should be noted that the programmable device <NUM> may communicate, to the programmable device <NUM>, only some of the characteristics of the database elements which are selected by the predictive engine in response to the input information.

The programmable device <NUM> and the programmable machine <NUM> can therefore each have communication devices (not shown) capable of establishing communication between them via a network <NUM>.

According to one exemplary embodiment, the programmable device <NUM> comprises a processor <NUM> executing a computer program enabling the user to access the service. The computer program causes a number of drop-down menus to be displayed on the interface <NUM>. The computer program may in particular comprise an authentication system making it possible to verify that the user has authorization to access the service. The computer program may in particular comprise an input system querying the user on the intended use of the bag and requesting, for example:.

Once the input is completed, the data are stored in the memory <NUM> and sent to the computer <NUM>.

As explained above, the computer <NUM> determines an element, or a small number of elements, best suited to the entered needs.

The programmable device <NUM> then obtains, from the database <NUM>, information relating to the determined element or small number of elements, in particular at least the following for an element: the identity, the thickness of the film, and the characteristic of the maximum admissible defect and associated level of fluidtightness. This information may be displayed on the interface <NUM>.

If the user so wishes, a bag having the characteristics of the selected element is then manufactured, in particular in terms of volume, film material, film thickness; or a corresponding previously manufactured bag is selected for sending to the user.

If, after use of the bag, the end user performs a bag integrity test as is known in the art, and this test reveals a defect in the film, the defect detected during the final integrity test can be compared to the maximum admissible defect determined before use, in order to assess whether this defect is representative of a loss of integrity of the bag.

<FIG> now shows another embodiment of the system. According to this embodiment, a plurality of leak test devices <NUM> are provided in parallel. In the present example, five leak test devices <NUM> are provided in parallel. This enables to ensure that ambient conditions when performing tests are similar. In this example, it is also shown a pressuring device <NUM> applying controlled gas pressure to each of the test devices through a connecting manifold <NUM> and individual connecting tubes <NUM>. However, the other pressurizing technologies described above for the first embodiment can also be used when a plurality of leak test devices <NUM> are used in parallel.

Claim 1:
A method for characterization of a calibrated defect of a film of a bag for biopharmaceutical fluid, wherein said method comprises the following steps:
a film sample (<NUM>) provided with a calibrated defect is installed in a test device (<NUM>), a leak test is applied to the film sample (<NUM>) provided with a calibrated defect, in the test device (<NUM>), by applying controlled fluid stresses to the film sample (<NUM>) provided with a calibrated defect,
wherein the leak test includes placing the film sample (<NUM>) in a housing (<NUM>) of the test device (<NUM>), the housing (<NUM>) comprising an upper part (2a) and a lower part (2b) which are detachable from one another, between which the film sample (<NUM>) is held in a fluidtight manner, the upper part (2a) of the housing being connected in a fluidtight manner to a column of fluid to enable the application of a fluid to a first face of the film sample (<NUM>), a second face of the film sample (<NUM>), opposite the first side, facing a detector (<NUM>),
wherein a result of the leak test is measured, and characteristics of the film sample (<NUM>) provided with a calibrated defect, characteristics of the controlled fluid stresses, and the result of the leak test are recorded in a database (<NUM>).