Patent Application
20200249114
The invention relates to the field of methods for characterization of bags for biopharmaceutical fluid content.
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.
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, characterized in that said method comprises the following steps:
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 (3) 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 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 one embodiment, the leak test includes placing the bag film sample in a housing, the housing comprising an upper part and a lower part which are detachable from one another, between which the bag film sample is held in a fluidtight manner, the upper part 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 bag film sample, a second face of the bag film sample, opposite the first side, facing a detector.
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, characterized in that said system comprises:
According to one embodiment, the test device comprises a housing, the housing comprising an upper part and a lower part which are detachable from one another, between which the bag film sample is held in a fluidtight manner, the upper part 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 bag film sample, a second face of the bag film sample, opposite the first side, facing a detector of the measurement device.
According to another aspect, the invention relates to a computerized method for characterization of a bag for biopharmaceutical fluid content, the bag comprising at least one film, wherein,
According to another aspect, the invention relates to a computerized method for characterization of a bag for biopharmaceutical fluid content, the bag comprising at least one film, wherein,
According to another aspect, the invention relates to a computerized method for characterization of a bag for biopharmaceutical fluid content, the bag comprising at least one film, wherein,
According to one embodiment, said characteristics comprise a maximum admissible defect of the film.
According to one embodiment, the programmable machine and the computer communicate via a network.
According to another aspect, the invention relates to a computer program comprising instructions which, when the program is executed by a processor, cause the processor to implement the above method.
According to another aspect, the invention relates to a system for characterization of a bag for biopharmaceutical fluid content, the bag comprising at least one film, the system comprising:
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
The two parts 2a, 2b of the housing are assembled together so as to define an interior space receiving the film to be tested 3. 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 3 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 3 and the downstream region being located below the test film 3. Gravity can thus be used for the leak test.
The upper part 2a of the housing comprises a cover 4 and a tube 5 provided with a lower end flange 26. 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 27 is provided between the lower end flange 26 and the cover 4. The cover 4 enables a mechanical connection of the upper part 2a of the housing 2 to the lower part 2b of the housing 2. The tube 5 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 3 in the test configuration. The cover 4 has a through opening 6, for example central in its upper face, for the passage of the tube 5 through the cover 4.
The tube 5 is graduated and/or may be connected in a fluidtight manner to a graduated tube 13. In the present case, a graduated tube 13 is connected in a fluidtight manner to the tube 5. The graduated tube 13 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 5. The graduated tube 13 is graduated so as to display the volume of fluid contained in the space above the test film 3 at the graduation level corresponding to the upper level of the fluid.
The lower part 2b of the housing 2 comprises a cover 7. The cover 7 enables a mechanical connection of the lower part 2b of the housing 2 to the upper part 2a of the housing 2. For example, in the example shown, covers 4 and 7 have complementary threads. The upper face 7a of cover 7 has a through-opening 8. In the exemplary embodiment shown, the upper face 7a of cover 7 comprises a central pocket 22 carrying pins 11 and defined by a peripheral shoulder 23. The through-opening 8 is arranged in the central pocket 22. A tapered conical tube 24 (visible before assembly in
The lower part 2b of the housing 2 also comprises a detector 12. The detector 12 is a consumable part replaced after each leak test. It is therefore removably assembled to cover 7. The detector 12 is arranged beneath the through-opening 8 in the upper face 7a of cover 7. In particular, the tapered conical tube 24 concentrates any fluid flowing from the through-opening 8 in the direction of a localized area of the detector 12. If necessary, the detector 12 is not part of the housing 2 but is arranged under the housing 2, the latter having a through-opening between the test film 3 and the detector 12. The detector 12 is, for example, contained in a container 25 assembled to cover 7.
The leak test device 1 may operate as follows.
As represented in
The test film sample 3 is then placed on the support 9, as represented in
As represented in
The graduated tube 13 visible in
The upper end 13a of the graduated tube 13 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 13. We now have the configuration of
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 3 leaks. To do so, for example, the detector 12 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 3 beforehand. In a prior defect creation step, a LASER beam is used, for example controlled to produce a controlled hole in the test film 3. 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. This results in a calibrated 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 3 is installed in the test device 1.
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.
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
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 19 provided with an interface 20. The programmable device 19 may be connected to the computer 15 via the network 17, or may access it locally. If necessary, the programmable device 19 comprises the memory 18 but alternatively the memory 18 may be accessed by the programmable device 19 via the network 17. The interface 20 allows the user to enter the information relating to an intended use of the bag, which is then stored in the memory 18. The interface 20 also makes it possible to display the results of the determination made by the computer 15. It should be noted that the programmable device 14 may communicate, to the programmable device 19, 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 19 and the programmable machine 14 can therefore each have communication devices (not shown) capable of establishing communication between them via a network 17.
According to one exemplary embodiment, the programmable device 19 comprises a processor 21 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. 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 18 and sent to the computer 15. As explained above, the computer 15 determines an element, or a small number of elements, best suited to the entered needs.
The programmable device 19 then obtains, from the database 16, 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 20.
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.
For example, the leak test devices 1 shown on
| Number | Date | Country | Kind |
|---|---|---|---|
| 201741037624 | Oct 2017 | IN | national |
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/IB2018/000090 | 2/10/2018 | WO | 00 |
