The invention concerns a device for filling sample bags and a method for depositing a measured volume in a sample bag. In particular, the invention is useful for accurately depositing a measured volume in a flexible 2D sample bag when taking in-process and product fluid samples during manufacture, testing, and quantifying of pharmaceutical compositions such as vaccines.

BACKGROUND OF THE INVENTION

Flexible 2D sample bags for taking in-process and product fluid samples in the biopharmaceutical environment such as the Flexboy ^® Bioprocessing bag manufactured by Sartorius Stedim Biotech and the BioProcess Container (BPC ^® ) manufactured by Thermo Scientific Hyclone are well known in the art. Such sample bags have a variety of advantages over rigid glass, stainless steel and plastic containers. For example, they are of low cost and as they are intended for single use, reduce the risk of cross-contamination from batch-to-batch and product-to-product. Furthermore, they are more ergonomically stored and therefore save space in storage and transport. Flexible 2D sample bags such as the Flexboy ^® have graduations on the bag indicating fill volume, however, due to the flexible nature of the bag and the three dimensional manner in which fluid enters the bag on filling, inaccuracies in the measured volume intended to be deposited in the bag can occur. Further, flexible 2D sample bags such as the BPC ^® are rated as to the volume they contain; however, in practice, these bags may retain more than the stated volume. As a result of these inaccuracies, excessive sample volumes need to be taken at each stage of product manufacture resulting in high wastage costs. It is, however, still desirable to use volume for the measurement of samples because of the greater accuracy compared to, for example, weight measurement. Therefore, a method of accurately depositing a measured volume in a flexible 2D sample bag, negating unwanted wastage costs, whilst retaining the advantages of the flexible 2D sample bag is warranted. The present invention provides a device and a method for improving the degree of accuracy on filling a flexible 2D sample bag thereby reducing wastage costs. The invention is particularly useful for manufacturing, testing, packaging and distributing pharmaceutical compositions such as vaccines.

DISCLOSURE OF THE INVENTION

The present invention provides a device for filling a sample bag as defined in appended claims 1 to 35 and a method for depositing a measure volume in a sample bag as defined in appended claims 36 to 45. The method of the invention can be used in methods of manufacturing, testing and quantifying pharmaceutical compositions as defined in claims 46 to 50.

The present invention provides a sample bag filling device comprising first and second walls connected so as to define a defined space, the device being designed to receive a sample bag such that the sample bag can be filled to a measured volume. In an aspect of the invention, a section of the first wall of the device may be transparent, preferably, the section of the first wall is flexible and preferably the flexible section of the first wall is flexible enough to allow manipulation of a sample bag contained within the device through applying a force to the flexible section, without permitting expansion of a bag contained within the device beyond the constraints of the front wall. The section of the first wall may be Perspex. Thus, it is possible for the user of the device to manipulate a sample bag contained within the device in order to remove bubbles and/or blockages that may occur on filling of a bag in the device, increasing the accuracy of filling.

In an aspect of the invention, at least one spigot or at least one hook may be attached to one of the first or second walls. Preferably, the spigot(s) of hook(s) are attached to the second wall. The spigot(s) or hook(s) may be specifically designed to accommodate a specific hanging feature of a specific design of sample bag.

The spigot(s) or hook(s) may be at an angle relative to the second wall so that a bag will hang from the spigots(s) or hook(s) in use of the device. Thus, a sample bag received within the device can be fixed within the device to facilitate consistent and reproducible filling of sample bags. The spigot(s) or hook(s) are preferably at an angle relative to the second wall which reduces tearing pressure when removing the bag from the device. The angle may be 10° or more preferably 15° or more preferably 20° or more preferably 25° or more preferably 30° or more preferably 35° or more preferably 40° or more preferably 45° relative to the second wall.

The first wall and/or the second wall may have a lip attached thereto, angled outwards from the wall. The lip can be unitary with the wall e.g. it can be formed by introducing a bend into the material which forms the wall. The lip(s) may be positioned at the edges of the wall(s) adjacent to the position where a sample bag is placed in the cavity in the device, in order to facilitate smooth placement of a sample bag within the cavity of the device. The spigot(s) or hook(s) can be on a lip rather than on a wall to avoid catching a bag when entering and exiting the device. In an aspect of the invention, the first and second walls of the device may be connected by four support pins. The four support pins are preferably attached adjacent to the four corners of the first and second walls. Alternatively, the first and second walls of the device may be connected by two opposing side walls. The opposing side walls may be parallel. One of the walls may be hinged thereby facilitating alternative means of access to the defined space. A releasable fastening may be included to fasten the hinged wall. Preferably, the releasable fastening comprises a magnet, or the releasable fastening comprises a clip. The clip may have a pressure rating of about 0.5 bar. Thus, a sample bag can be placed in the device through the front of the device, and the depth of the device remains fixed and constant when the wall is fastened shut.

In an aspect of the invention, the first wall may have graduations which indicate the measured volume deposited in the bag received in the device. The depth of the device is calibrated to restrict the expansion of a flexible sample bag placed in the device, such that when the sample bag is filled with fluid up to a graduation defining the required volume, the required volume has been accurately deposited in the sample bag. This reduces overfilling and therefore wastage costs when manufacturing, testing and quantifying pharmaceutical compositions such as vaccines. The device may be constructed so that the position of the first and second walls can be adjusted to alter the dimensions of the defined space, for example by moving the first and/or second walls along the support pins. In this case, the device would have graduations which indicate measured volumes corresponding to different dimensions of the defined space. The device may have a set of graduations pre-calibrated with particular relative positions of the first and second walls to allow the user to fill a variety of different sample bags with different maximum capacities to different volumes. The graduations may indicate volumes of from about 20mL up to the maximum capacity of the bag.

In an aspect of the invention, the device may comprise a further wall, the position of which can be adjusted to alter the dimensions of the defined space. In an embodiment where the device comprises a base, the base may be lowered to alter the capacity of the defined space of the device. In this embodiment, the device would comprise alternative graduations to indicate the volume of liquid deposited in a sample bag received in the device after adjustment of the position of the base.

In an aspect of the invention, the device will freely stand on a horizontal surface. In a further aspect the level of a fluid contained in a sample bag received in the device is perpendicular to the edges of the first and second walls of the device.

In an aspect of the invention, the device may comprise a support foot. This may be a single foot or a number of feet protruding from the bottom edges or base of the device.

The device may be attached to a stand. The stand may be attached to the base of the device.

In an aspect of the invention, the device may be manufactured using a material approved by the U.S. Food and Drug Administration (FDA) for pharmaceutical Good Manufacturing Practice (GMP), further described herein as a GMP suitable material. The GMP suitable material may be PTFE, or stainless steel, or acrylic. A main advantage of these materials is that they are easy to clean. It is desirable that the device is of solid structure to allow it to stand freely and retain its dimensions. Furthermore, it is desirable for the device to be lightweight in order to facilitate movement of the device. It is also desirable that the device is of low cost to fabricate. Furthermore, it is desirable that the device has smooth edges and/or no crevices in order to facilitate efficient and effective cleaning of the device.

The device of the present invention may have a sample bag received within the device. The sample bag may be a 2D flexible sample bag. The sample bag may contain a sample, which may be a measured volume of fluid. The fluid may be a vaccine.

In a second embodiment, the invention provides a method of depositing a measured volume in a sample bag comprising placing the bag in a sample bag filling device having a defined space and filling the bag, wherein the measured volume entered into the bag can be determined with reference to a reference part on the device. The sample bag filling device used in the method of the present invention may be the sample bag filling device of the present invention.

In an aspect of the invention, the bag may be viewed through a window in the bag filling device during filling of the bag. In a further aspect, filling may be terminated when the measured volume is deposited in the bag as determined by a graduation on the sample bag filling device. The measured volume may be that of a fluid and the filling is terminated when the measured volume is deposited in the bag as determined by aligning the level of the fluid with a graduation on the sample bag filling device. The depth of the device used in the method of the invention is calibrated to restrict the expansion of a flexible sample bag placed in the device, such that when the sample bag is filled with fluid up to a graduation defining the required volume, the required volume has been accurately deposited in the sample bag. This reduces overfilling and therefore wastage costs when manufacturing, testing and quantifying pharmaceutical compositions such as vaccines The depth of the device may be adjusted, allowing a variety of different sample bags with different maximum capacities to be filled to different volumes. In this case, the device would have alternative sets of graduations calibrated to indicate measured volumes corresponding to alternative depths of the device. The graduations may indicate volumes of from about 20mL up to the maximum capacity of the bag. In an aspect of the invention, any bubbles in the fluid deposited in the bag may be removed by manipulating the bag through application of a force to the window in the bag filling device, thus increasing accuracy and reproducibility of the measured volume deposited in the sample bag.

In an aspect of the invention, when filling the sample bag, the sample bag filling device is stood on a horizontal surface. The device may be configured so that the level of the fluid deposited in a sample bag received in the device is perpendicular to the edges of the first and second walls of the device. The sample bag may be removed from the device when the measured volume has been deposited in the bag.

In an aspect of the invention, the sample bag is releasably fastened to one or more spigots in the bag filling device. Thus, the sample bag can be fixed to the device to facilitate consistent and reproducible filling of the sample bag received within the device.

The sample bag of the present invention may be a 2D flexible sample bag. The method of the present invention is suitable for use in the manufacturing, testing and quantifying pharmaceutical compositions. The pharmaceutical compositions may be vaccines, or more preferably influenza vaccines.

The present invention also provides a method of manufacturing a pharmaceutical composition comprising a step of preparing measured samples of the vaccine according to the method of the present invention. The present invention also provides a method for preparing a pharmaceutical composition comprising the steps of; (a) manufacturing a bulk pharmaceutical composition; (b) preparing a sample of the bulk pharmaceutical composition according to the method of the present invention; (c) testing the sample for its acceptability for clinical use; and if the results from step (c) indicate that the pharmaceutical composition is acceptable for clinical use (d) preparing the pharmaceutical composition for use from the bulk .

The present invention also provides a method for preparing a pharmaceutical composition comprising the steps of; (a) manufacturing a bulk pharmaceutical composition; (b) preparing a sample of the bulk pharmaceutical composition according to the method of the present invention; (c) quantifying the sample to obtain a desired dilution factor; and (d) preparing the pharmaceutical composition for use from the bulk with the dilution factor obtained in step (c).

The pharmaceutical composition of the present invention may be a vaccine, or more specifically an influenza vaccine

BRIEF DESCRIPTION OF THE DRAWINGS

The present invention will be described in detail with reference to the accompanying drawings, which illustrate preferred embodiments of the invention, and are not to be construed as limiting the scope of the invention, wherein:

Fig. 1 is a perspective view of a 2D flexible sample bag suitable for use in the present invention;

Fig. 2 is a frontal view of one embodiment of a device according to the present invention; Fig. 3 is perspective view of the device of Fig. 2;

Fig. 4 is a perspective view of one embodiment of a device of the present invention wherein the front wall is hinged, illustrating the front wall in an open position; and

Fig. 5 is a perspective view of the device of Fig. 4 illustrating the front wall in a closed position.

DETAILED DESCRIPTION OF THE INVENTION

Fig. 1 provides an illustration of a 2D flexible sample bag 1 suitable for use in the device and method of the present invention. The sample bag 1 comprises a main body constructed from two flexible sheets 5 and 7 welded together so as to form a seal 9 around the perimeter of the bag which defines a cavity 11 therein. The bag also comprises mounting holes 13 and tubes 15 through which fluid can be deposited into the cavity 11 within the bag 1. The volume of fluid entered into the bag may be theoretically indicated by the graduations 17 printed on the front however, as previously described, these graduations can be inaccurate due to the flexible nature of the bag and the three dimensional manner in which fluid enters the bag on filling. Other bags suitable for use in the device and method of the present invention, not shown in Fig. 1, do not have graduations but instead come with a specified capacity. However such bags can often be filled with volumes larger than the specified capacity. Figures 2 and 3 provide illustrations of one embodiment of a device according to the present invention. The device 19 comprises a front wall 21 which is parallel to a rear wall 23 to which it is connected to by means of four support pins 25 which are adjacent to the four corners of the front 21 and rear 23 walls. Both the front and rear walls are manufactured from stainless steel. The front and rear walls have lips 24 and 26 at their top edges to facilitate smooth placement of a sample bag into the device. The front wall has a flexible window 27, manufactured from Perspex, through which a sample bag (not shown in figures 2 or 3) contained within the device 19 can be viewed.

The window 27 is flexible enough to allow manipulation of a bag contained within the device through applying a force to the window without permitting expansion of the bag contained within the device beyond the constraints of the front wall 21. The rear wall 23 comprises two spigots 29 on the lip part 26 of the wall, adjacent to the top of the wall, configured so as to be able to accept the complementary mounting holes 13 of a 2D sample bag such as that illustrated in Fig. 1. The spigots are at an angle of 45° from the plane of the rear wall to reduce tearing pressure when a sample bag (not shown in figures 2 or 3) is removed from the device. The bottom edges 31 and 33 of the front and back walls are aligned and horizontal to enable the device to stand on a horizontal surface. Graduations 35 on the front wall 21 of the device 19 indicate the volume of fluid, when entered into a sample bag such as that illustrated in Fig. 1, contained in the device 19. The depth of the device 19, as defined by the length of the support pins 25, is fixed such that the graduations 35 on the front wall 21 reflect the volume to which a sample bag contained within the device expands on filling, so that when the level of the meniscus of a fluid being entered into the bag reaches the, for example, 50 mL graduation, only 50 mL of fluid has been reliably entered into the bag.

In use of the device 19, the device is first placed on a horizontal surface. A sample bag such as that illustrated in Fig. 1 is then placed within the constraints of the front 21 and rear 23 walls and the support pins 25, through the top entry to the cavity 37, and fastened to the spigots 29 by using the mounting holes 13. Fluid is then deposited into the sample bag (not shown in Fig. 2 or 3) via tubes 15. Filling is continued until the level of the meniscus of the fluid entered into the bag reaches the graduation 35 indicating the required volume. If air bubbles are present in the fluid deposited within the bag, they can be removed my manipulating the bag through application of a force to the flexible window 27, retaining the accuracy of the measurement. Filling is terminated when the level of the meniscus of the fluid being deposited into the sample bag is level with the graduation indicating the required volume. After filling is terminated, the tubes of the sample bag are sealed and the bag is unhooked and removed from the device 19 via the top entry to the cavity 37.

Figures 4 and 5 provide an illustration of another embodiment of the device of the present invention. The device 38 comprises a front wall 39, a rear wall 41 , and two side walls 43 and 45. In the closed configuration of the device 38, as illustrated in figure 5, the front 39 and rear 41 walls are parallel, as are the two side walls 43 and 45. Side wall 45 is permanently attached to rear wall 41 and hinged to front wall 39 by way of hinges 47. Side wall 43 is permanently attached to front wall 39 and can be releasably attached by means of a clip 49 to the rear wall 41. The device can be opened by releasing clip 49 and rotating the front wall 39 about the hinge 47. The front wall 39 has a flexible window a 51 through which a sample bag (not shown in figures 4 or 5) contained within the device 38 can be viewed. The window 51 is flexible enough to allow manipulation of a bag contained within the device through application of a force to the window without permitting expansion of the bag contained within the device beyond the constraints of the front wall 39.

The rear wall 41 comprises two spigots 53 adjacent to the top two corners of the wall configured so as to be able to accept the complementary fastening or mounting holes of a 2D sample bag such as that illustrated in Fig. 1. The depth of the device 38, as defined by the width of the side walls 43 and 45, is fixed such that the graduations 55 on the front wall 39 reflect the volume to which a sample bag contained within the device expands on filling, so that when the level of the meniscus of a fluid being entered into the bag reaches the, for example, 50 mL graduation, only 50 mL of fluid has been reliably entered into the bag.

In use of the device 38, the device is opened by releasing clip 49 and rotating the front wall 39 about hinge mechanism 47. A sample bag such as that illustrated in Fig. 1 is then placed within the device and fastened to the hooks 53 on the rear wall of the device. The device is then closed by fastening clip 49. Fluid is then deposited into the sample bag (not shown in figures 4 or 5) via tubes 15. Filling is continued until the level of the meniscus of the fluid entered into the bag reaches the graduation 55 indicating the required volume. If air bubbles are present in the fluid deposited within the bag, they can be removed by manipulating the bag through application of a force to the flexible window 51 , retaining the accuracy of the measurement. Filling is terminated when the level of the meniscus of the fluid being deposited into the sample bag is level with the graduation indicating the required volume. After filling is terminated, the tubes of the sample bag are sealed, the device 38 is opened, and the sample bag is unhooked and removed from the device 38. It will be understood that the invention has been described above by way of example only and that modifications may be made whilst remaining within the scope of the invention as claimed.