EP2470147B1 - Bag for storing a therapeutic solution - Google Patents

Description

Field of the invention

The present invention relates to a therapeutic solution storage bag.

Technological background

By therapeutic solution is meant any type of product in liquid form used for a therapeutic purpose. These are usually blood components in liquid form, for example blood plasma, platelets, or a packed cell. These may be blood plasma derivatives, for example albumin or an immunoglobulin. It can also be medication solutions, or even nutritional solutions. It may be glucose solution for example at 5%, G5, or else saline solutions, especially isotonic solutions or a Ringer's solution. It may also be solutions prepared extemporaneously, in particular by adding a drug in a pocket containing a solution of a carrier fluid, typically for the treatment of intravenous diseases as for the treatment of cancer.

Storage bags are now an alternative to glass bottle packaging for biotechnology products. Commonly used in intravenous administration for infused solutes or for parenteral nutrition solutions or for blood, the flexible storage pouches have many advantages, in particular because of their lightness and their ease of handling.

Storage bags, like glass bottles, are subject to very demanding regulations, particularly with regard to their manufacture and traceability. The pockets must have an inscription providing information about the solution, safety elements such as, the name of the manufacturer, the expiry date, the lot number, the recipient or the name of the patient, including traceability of the solution. The pouches are usually packaged and sent to hospitals or to any recipient who can administer the solution to a patient. The patient can himself be a recipient and administer the solution.

The bags currently on the market have an inscription carried directly on a membrane delimiting a receiving compartment of the solution, as is the case of the Flexbumin ^® flexible pouch, flexible pouch containing human albumin, manufactured and marketed, particularly in Sweden, by Baxter. The inscription can also be worn by gluing a label on which it was previously written, printed and / or stamped, or by gluing a blank label on which one writes and / or stamps thereafter. The inscription can also be worn directly on the membrane by handwriting typically with a pen or pen or ink pad. This is particularly the case when the bag is used to administer an infusion to a patient. It may be that during the course of administration the contents of the bag are modified, for example by the addition of a drug, and that the nursing staff then wear a marker indicating the modification in question. quantity to be administered or the administration time to be respected.

However molecules in the ink and / or glue used can cross the membrane and migrate into the therapeutic solution. Such molecules may have toxicity to the recipient or alter the properties of the solution. Their presence is therefore undesirable and should be avoided. Moreover, the material constituting the membrane is likely to deteriorate when the inscription is made because molecules of the membrane can dissociate and contaminate the solution. This contamination of the solution and / or deterioration of the membrane may be particularly important in the case where a handwriting inscription is carried with a felt or pen directly on the membrane or on a blank label previously glued to the membrane. membrane.

Flexible storage pockets are described in the patent application WO 02/072429 and the patent US 4,654,240 from Baxter. The patent application WO 02/072429 discloses a flexible polymer pouch for storing a solution of peptides and / or proteins, as well as a method of introducing such a solution into a flexible polymer container. The manner of carrying an inscription on the storage bag is not mentioned in this document. The patent US 4,654,240 discloses a laminated film material for a flexible pouch capable of storing a product to be maintained and extracted under sterile conditions. The bag is optionally steam sterilized. The way of carrying an inscription on the storage pocket is not mentioned in this document either.

A solution to reduce the risk of contamination in the case where the inscription is carried on the membrane is to use a particular ink whose molecules pass through the membrane more difficult. However, such an ink is expensive. Moreover, this solution does not sufficiently reduce the risk of contamination because ink molecules continue to cross the membrane, and because the membrane can still be damaged. Finally, this solution does not respond to the risk of contamination related to the inscription carried by sticking a label. There is therefore a need to enhance the safety of the batches of therapeutic solution. The Applicant has surprisingly developed by the present invention a storage bag of a therapeutic solution, providing an improvement in the safety of the therapeutic solution, and allowing to carry an inscription while reducing the risk of contamination. .

Summary of the invention

The invention proposes a therapeutic solution storage pouch (10) comprising at least one solution receiving compartment (11) delimited by a multilayer membrane, and at least one appendage (13) in the extension of the multilayer membrane (12). and having an inscription zone (14), and an immunoglobulin, or albumin, in the compartment (11) of the pocket (10), characterized in that said pocket comprises a sealed and / or opaque outer envelope and in that the surface ratio of the appendix / storage pocket surface is between 0.20 and 0.35.

For this, the application describes a therapeutic solution storage bag comprising at least one membrane-delimited solution receiving compartment. The bag further comprises at least one appendage in the extension of the membrane and having a registration area.

• la membrane est transparente ;
• la membrane comprend un ou plusieurs orifices ;
• l'enveloppe externe est constituée d'un film multicouche contenant une couche d'aluminium entourée de part et d'autre d'une couche de plastique ;
• le compartiment a une capacité de contenance maximale comprise entre un millilitre et un litre, avantageusement comprise entre 5 et 500 millilitres, avantageusement comprise entre 10 et 500 millilitres, plus avantageusement comprise entre 20 et 200 millilitres, et encore plus avantageusement comprise entre 50 et 100 millilitres ;
• le compartiment contient une solution thérapeutique d'immunoglobuline G normale (IGNG).

In preferred embodiments, the storage bag further has one or more of the following features:

• the membrane is transparent;
• the membrane comprises one or more orifices;
• the outer envelope is made of a multilayer film containing an aluminum layer surrounded on either side of a plastic layer;
• the compartment has a capacity of maximum capacity of between one milliliter and one liter, advantageously between 5 and 500 milliliters, advantageously between 10 and 500 milliliters, more advantageously between 20 and 200 milliliters, and still more advantageously between 50 and 100 milliliters; milliliters;
• the compartment contains a therapeutic solution of normal immunoglobulin G (IGNG).

1. (i) formation simultanée de la membrane et de l'appendice,
2. (ii) formation du compartiment par soudure,
3. (iii) perforation de la poche de stockage et éventuellement formation de l'organe d'accrochage,
4. (iv) insertion d'orifices, et scellage des orifices.

The application also describes a method of manufacturing a therapeutic solution storage bag, previously described, comprising the steps of:

1. (i) simultaneous formation of the membrane and the appendix,
2. (ii) formation of the compartment by welding,
3. (iii) perforation of the storage bag and possibly formation of the attachment member,
4. (iv) insertion of orifices, and sealing of the orifices.

1. (i) remplissage de la poche de stockage avec une solution thérapeutique,
2. (ii) bouchage de la poche de stockage remplie par la solution thérapeutique par un organe d'obturation,
3. (iii) mirage de la poche de stockage remplie par la solution thérapeutique et fermée par l'organe d'obturation,
4. (iv) apposition d'inscriptions sur l'appendice de la poche de stockage contenant la solution thérapeutique, ainsi mirée,
5. (v) éventuellement suremballage de la poche de stockage contenant la solution thérapeutique par une enveloppe externe, et
6. (vi) éventuellement apposition d'inscriptions sur l'enveloppe externe contenant la poche de stockage.

The application also describes a method of manufacturing a therapeutic solution storage bag whose compartment contains a therapeutic solution or albumin or an immunoglobulin, previously described, comprising the steps of:

1. (i) filling the storage bag with a therapeutic solution,
2. (ii) clogging of the storage bag filled with the therapeutic solution by a closure member,
3. (iii) mirage of the storage bag filled with the therapeutic solution and closed by the closure member,
4. (iv) affixing inscriptions on the appendix of the storage bag containing the therapeutic solution, thus mirrored,
5. (v) optionally overpacking the storage bag containing the therapeutic solution with an outer envelope, and
6. (vi) possibly affixing inscriptions on the outer envelope containing the storage bag.

Optionally, the method further comprises a step of irradiating the storage bag before step (i) filling.

Brief description of the figures.

• figure 1, une vue d'une poche de stockage selon un mode de réalisation préféré de l'invention.

In the drawings, we provide:

• figure 1 , a view of a storage pocket according to a preferred embodiment of the invention.

DETAILED DESCRIPTION OF EMBODIMENTS OF THE INVENTION

Other characteristics and advantages of the invention will appear on reading the following detailed description of an embodiment of the invention, given by way of example only and with reference to the figure 1 .

The invention relates to a <a> page 4a. The pocket comprises at least one receiving compartment of the solution. The pocket also includes a membrane, the compartment being the space delimited by the membrane. The pocket also comprises at least one appendix in the extension of the membrane and having a registration area.

The membrane may consist of a single piece folded and / or welded so as to define the compartment. The membrane may also consist of an assembly of several parts welded together so as to define the compartment.

The compartment allows the reception of a volume of solution for its storage. The registration area allows for an inscription providing information relating to the pocket. This information includes but is not limited to one or more of the following: the contents of the solution, the solution producer and its logo, the solution vendor, the concentration of the solution, information about the hospital or the solution institution or recipient, the name of the patient. The information can be coded for example in the form of a barcode or datamatrix (dot matrix) therapeutic solution storage bag (10) comprising at least one solution receiving compartment (11) delimited by a multilayer membrane, and at least one appendage (13) in the extension of the multilayer membrane (12) and comprising a zone (14), and an immunoglobulin, or albumin, in the compartment (11) of the pocket (10), characterized in that said pocket comprises a sealed and / or opaque outer envelope and that the ratio surface of the appendix / surface storage pocket is between 0.20 and 0.35. or juxtaposed squares, equivalent to the bar code in two dimensions). The inscription may be carried, in a non-limiting manner, by writing by hand with ink on the appendix, by gluing or stapling a label on which was previously printed, handwritten, or stamped, or by gluing or stapling a blank label on which the inscription is subsequently handwritten or stamped.

The registration area is on the appendage in the extension of the membrane, it is possible to wear an inscription on the pocket with a reduced risk of contamination. Indeed, carrying an inscription on an area of an appendage in the prolongation of the membrane and not directly on the membrane in contact with the solution reduces the risk of deterioration of the membrane and migration of contaminating molecules towards the membrane. compartment.

In order to eliminate before the commercialization, the cases where a migration could have occurred, one carries out a stage of mirage normally. The term "mirage" refers to a visual inspection operation on containers intended to detect any contamination or other defects, such as particles, filling defects, pieces of plastic.

The invention is now described with reference to the figure 1 which has a view of a storage pocket 10 according to a preferred embodiment of the invention.

In this embodiment, the bag 10 comprises a compartment 11 for receiving solution delimited by a membrane 12. The bag 10 also comprises an appendage 13 in the extension of the membrane 12. In general, the appendix 13 is projecting of the membrane 12, but not necessarily in the axis or in the plane of the membrane 12. The appendix 13 comprises an inscription zone 14, which is separated from the membrane 12 in a separate zone. An inscription 15 providing information on the bag can be worn with a reduced risk of contamination.

In addition, in a preferred embodiment, the membrane 12 is transparent. This makes it possible to examine visually or by any other equivalent means a solution stored in the pocket 10. In fact, carrying an inscription on an area of an appendix in the extension of a transparent membrane and not directly on the membrane improves the effectiveness of the mirage, especially at the time of filling, because the membrane is blank, but also at the time of use by hospital staff to check the clarity of the solution to be infused.

There are standards in the medical field that require care providers to take certain precautionary measures before administering a therapeutic solution to a patient. An example of such a precautionary measure is the visual inspection operation which consists of several steps allowing the caregiver to visually verify that no deposit has formed or no impurity is present in a therapeutic solution before an infusion. The transparency of the membrane 12 thus allows the caregiver to take the precautionary measures requiring visual inspection of the solution stored in the pocket, such as in particular the verification of the color of the therapeutic solution or the presence of bacterial or particulate contamination in the patient. within the therapeutic solution to infuse 10.

The storage pockets on the market have an inscription on the membrane. However, in addition to the contamination problems associated with it, an inscription on the membrane is an inconvenience for the nursing staff when it wishes to take the precautionary measures mentioned above. An inscription on the membrane is also an inconvenience when the caregiver wishes to check the volume of solution contained in the compartment 11, for example to verify that an infusion is proceeding correctly. In addition, the presence of this inscription on the membrane is a hindrance during the operation of mirage therapeutic solutions.

In the pocket 10 shown in figure 1 , the inscription zone 14 is separated from the transparent membrane 12 . No registration thus hinders the eye, which facilitates and consequently speeds up the work of the nursing staff. The facilitation of the work of the nursing staff is of great importance especially in emergency care.

In another variant, the membrane 12 is not transparent, but rather opaque in order to protect the solution from light irradiation. This can be the case when the solution stored in the bag 10 is not directly administered, but taken for example by means of a syringe before being administered. In this case, the precautionary measures mentioned above can be taken after taking the solution from the syringe. It is also possible that the solution is administered from the bag 10 in this case of the opaque membrane.

The invention uses a surface ratio of the appendix / pocket storage area between 0.20 and 0.35, in particular between 0.25 and 0.30, in particular equal to 0.27.

The membrane 12 of the figure 1 comprises an orifice 16. The orifice 16 allows the injection into the compartment 11 of a solution for storage. The orifice 16 also allows the flow of a solution stored out of the compartment 11 for its administration by infusion to a patient. In the case of such use, the orifice 16 is connected to a conduit, not shown, administering the solution to a patient. Typically, the conduit connects the compartment 11 to a vein of the patient. The orifice 16 may also be used as an access route for taking a certain amount of solution using a syringe or other sampling tool. The orifice 16 may also be used as an access route for the injection of a given quantity of a medicament, for example for the treatment of cancer patients, for whom a solution of active principle is injected. in the pocket, possibly after reconstitution by the medical staff.

The membrane may also include several orifices. For example, the membrane may comprise two orifices: a first orifice for injecting the solution into the compartment for its storage, and a second orifice for the flow of the solution out of the compartment for its administration to a patient. In this case, a pocket comprising a plurality of orifices makes it possible to add elements to a solution stored in the pocket via the first orifice at the same time as the solution flows through the second orifice during the infusion.

The orifice 16 is advantageously located in an area opposite the appendix 13 with respect to the compartment 11. In this case, the appendix 13 may be provided with a fastening member 17, as is the case in the realization of the figure 1 . In this embodiment 1, the attachment member 17 consists of a hole passing through the appendix 13. This configuration is however not limiting. Indeed, a different number of holes can be made. Moreover, other types of attachment members, such as a magnet, a hook protruding from the appendix 13 or an adhesive can be used. Similarly, it is possible to have a pre-cut hook in Appendix 13, and can be unfolded to allow snapping.

The fastening member 17 makes it possible to suspend the pocket at a support preferably located at a height. Since the orifice 16 is situated in an area opposite the appendix 13 with respect to the compartment 11, the suspension of the pocket 10 by the fastening member 17 allows the solution to flow out of the compartment 11 through the orifice 16 under the effect of gravity. The bag 10 can thus be suspended over a patient and be used as an infusion bag. The term "zone opposite to the appendix to the compartment" means the zone of the membrane 12 the lowest when the bag is suspended by a fastening member 17 of Appendix 13.

In the case where the membrane 12 comprises a plurality of orifices, the orifice or the orifices intended for the flow of the solution out of the compartment 11 are situated in an area opposite to the appendix 13 with respect to the compartment 11, which ensures flow of the solution under the effect of gravity.

Alternatively, the flow of the solution is by means of a pump, or even by compression of the compartment 11, especially in the infusion assisted infusion mode. In this variant, the orifice 16 may as well be located in an opposite zone to the appendix 13 with respect to the compartment 11 as in another zone, the gravity being no longer necessary to ensure the flow of the solution.

The orifice 16 is provided with a closure member 18. This closure member makes it possible to prevent an undesired flow of the solution.

Typically, after the injection solution into the compartment 11 through port 16, we equip the orifice 16 of the shutter member 18, for example by welding a fixed part 19 of the closure member 18 of the contour of the orifice 16. When using the bag, for example for an infusion, is removed a removable portion 20 of the closure member 18 by breaking a breakable joint between the fixed part 19 and the part removable 20. Typically the joint is scored by a rotation of the movable part 20 relative to the fixed part 19. This mechanism is known as the English term "twist-off". A breakable joint allows rapid use of the pocket 10.

Configurations different from that shown may however be used for the closure member 18. For example, the fixed part 19 may be closed by the removable portion 20, or by another element, although it has been previously removed using for example a screw mechanism. This configuration makes it possible to close the orifice 16 despite a first beginning of flow of the solution. This configuration is of interest for example when it is desired to temporarily interrupt an infusion.

The membrane 12 is preferably made of a flexible material. It is advantageously a plastic material. PVC, polyethylene, polypropylene or any other material commonly used for producing flexible bags can be used. The thickness of the films is classic.

In a preferred embodiment, the membrane is made from polypropylene.

The flexibility of the pocket 10 allows easier storage of the pocket 10, a simpler waste disposal, as well as greater ease of use compared to rigid bottles. Moreover, the membrane being made of a flexible material, it is unbreakable. This avoids the problems of decontamination related to the use of glass vials.

The membrane 12 consists of multilayer films, in particular three-layer films, the constituent materials of the different layers having their own functions, for example a barrier (for example an oxygen barrier or an infusion product), a support, a binder between two layers, etc. ... A use of several layers makes it possible to further reduce the risk of contamination and to increase the resistance capabilities of the membrane 12, in particular to physical stresses and beta-ray irradiations. A use of three layers makes it possible to compromise between an increase in the resistance and the preservation of the transparency of the membrane 12.

The bag is placed in a removable outer envelope preferably waterproof. This outer shell has the advantage of constituting a physical barrier for the loss of water. In addition, this outer envelope, if it is opaque, protects the solution from denaturations that could be induced by light. Such an outer envelope is particularly advantageous in the case where the solution stored in the bag 10 is albumin or an immunoglobulin for example, particularly sensitive to light.

In the case of storage of an immunoglobulin, the immunoglobulin can be manufactured according to the method described in the documents FR-2824568-A1 and FR-2895263-A1 . It may be an intravenous immunoglobulin G (IVIG).

The outer casing may also consist of multilayer films, in particular three-layer films, the constituent materials of the different layers having their own functions, for example that of blocking the light, or that of ensuring a seal. The outer shell can be made of aluminum or plastic or a mixture of both. The outer casing may be thermoformed around the storage bag 10.

In a preferred embodiment of the invention, the outer envelope consists of a multilayer film containing an aluminum layer surrounded on both sides by a layer of plastic, for example polypropylene, which makes it gives special resistance to shocks, and is a barrier to light. According to a preferred embodiment of the invention, the outer envelope consists of a polyethylene layer, an aluminum layer and a polypropylene layer.

Typically, a storage bag 10 according to the invention is packaged in the outer envelope and then sent to a recipient. Before using the bag 10, the recipient removes the outer envelope. Thus, the envelope constitutes a additional protection until it is removed, i.e. until the use of the pocket 10.

The compartment 11 has a capacity of maximum capacity of between one milliliter and one liter, advantageously a capacity of maximum capacity of between 5 and 500 milliliters, advantageously between 10 and 500 milliliters, and still more advantageously between 20 and 200 milliliters, advantageously 50 and 100 milliliters. For example, the pouch has a capacity of up to 100 milliliters.

In the case where the membrane 12 is transparent thus allowing to examine the solution in the compartment 11 by eye , the invention is all the more interesting that the volume of the compartment 11 is small. In fact, in general, the smaller the volume of the compartment 11 , the smaller the surface of the membrane 12 , and the more an inscription on the membrane 12 constitutes an inconvenience.

The pocket 10 comprises a weld separating the membrane 12 from the appendix 13. In the case where the pocket is made of a flexible material and where it is filled with a solution, the weld gives a flexibility to the appendix 13 relative to the compartment 11 . This flexibility is useful especially in the case where several pockets storing a solution are stored in a storage box. Since the inscription 15 is on an inscription area 14 of Appendix 13, it is possible to identify a pocket without removing it from the box. The work of the nursing staff is thus facilitated.

In another embodiment not shown, the bag comprises a plurality of solution receiving compartments. A membrane delimits the compartments, and as in the embodiment of the figure 1 , an appendage is in the extension (projecting) of the membrane. Whether in this embodiment not shown or in the previous, several appendices may be in the extension of the membrane, one after the other or next to each other superimposed on each other. This allows to carry several inscriptions on the pocket. This allows for example to carry an inscription per compartment when the pocket comprises several compartments.

In the embodiment where the bag comprises several compartments, the bag may be provided with a mixer ensuring a mixture of the contents of the different compartments, the mixture then flowing through the orifice. The bag may also be provided with an orifice per compartment, a mixture then being provided by a mixer outside the bag.

The new flexible pouch is manufactured by any conventional method of manufacturing flexible pouches. In general, the compartment 11 is prepared by welding according to a predefined scheme, by welding a folded membrane on itself or two separate films. A cover is provided during the welding, conventionally. The welding can also be done in a conventional manner, by heat-sealing or ultrasound. The appendage in the extension (projecting) can be attached by welding on an already existing pocket, or on the contrary be obtained directly during manufacture. The folded membrane on itself can be continued to form the appendix; it is also possible that the two films are welded together to form the appendix, or that only one of the films is extended to form the appendix. According to one embodiment, the pouch comprises a weld 21 between separating the membrane of the appendix.

1. (i) Formation simultanée de la membrane et de l'appendice,
2. (ii) Formation du compartiment par soudure,
3. (iii) Perforation de la poche de stockage et éventuellement formation de l'organe d'accrochage,
4. (iv) Insertion d'orifices et scellage des orifices.

For example, a method of manufacturing a pouch may include the steps of:

1. (i) Simultaneous formation of the membrane and the appendix,
2. (ii) Formation of the compartment by welding,
3. (iii) perforation of the storage bag and possibly formation of the attachment member,
4. (iv) Inserting orifices and sealing the orifices.

1. (i) Remplissage de la poche de stockage avec une solution thérapeutique,
2. (ii) Bouchage de la poche de stockage remplie par la solution thérapeutique par un organe d'obturation,
3. (iii) Mirage de la poche de stockage remplie par la solution thérapeutique et fermée par l'organe d'obturation,
4. (iv) Apposition d'inscriptions sur l'appendice, de la poche de stockage contenant la solution thérapeutique, ainsi mirée,
5. (v) Eventuellement suremballage de la poche de stockage contenant la solution thérapeutique par l'enveloppe externe,
6. (vi) Eventuellement apposition d'inscriptions sur l'enveloppe externe contenant la poche de stockage.

The pouch packaging process comprises the following steps (after the last step of the pouch manufacturing process):

1. (i) Filling the storage bag with a therapeutic solution,
2. (ii) Clogging of the storage bag filled with the therapeutic solution by a closure member,
3. (iii) Mirage of the storage bag filled with the therapeutic solution and closed by the closure member,
4. (iv) Apposition of inscriptions on the appendix, of the storage bag containing the therapeutic solution, thus mirrored,
5. (v) Possibly overpacking the storage bag containing the therapeutic solution with the outer envelope,
6. (vi) Eventual affixing of inscriptions on the outer envelope containing the storage bag.

The method may include a step of irradiating the storage bag prior to step (i) of filling to sterilize the bag. Preferably, the irradiation is by beta 25 kilograys. The method may comprise an intermediate step of pasteurization and / or incubation of the storage bag containing the therapeutic solution, after the step (ii) of capping and before the step (iii) of candling of the storage bag. Advantageously, the method comprises an intermediate step of pasteurization and incubation between steps (ii) and (iii).

Examples

The following examples illustrate the invention without limiting it.

In the examples, the tested pouches conform to the figure 1 . These are pockets previously sterilized by β-irradiation, at 25 kGy. The membrane 12 is each time transparent, comprises an orifice 16 provided with a twist-off, and is a multilayer membrane consisting of three layers of polypropylene. The pouch 12 also comprises an outer casing made of a multilayer film containing an aluminum layer surrounded on either side by a plastic layer. The aluminum layer has a thickness of 8 μm. The layers surrounding the aluminum layer are polypropylene terephthalate and polypropylene and have a thickness of 12 microns and 75 microns respectively. The outer envelope (also called "overpouch" below and in the figures) is thus waterproof and opaque. The outer envelope has a width of substantially 160 mm and a length of substantially 270 mm. The compartment 11 has a capacity of maximum capacity substantially equal to 100 milliliters. In both cases also, pre-prints information on labels, and for each pocket, it then sticks a label on the registration area (14) of the appendix (13) in the extension of the membrane (12), and another label is glued to the outer envelope.

Example 1: Study of the stability of 20% albumin stored in test bags. 1. Material

In this test, 20% albumin is stored in the test bag compartment. The pockets are grouped into different batches independently controlled. Within a batch, the albumin volume is uniform and is substantially equal to 50 or 100 ml depending on the batch (hereinafter referred to as "lot in 50/100 ml presentation" depending on the capacity of the pockets of the lot in question).

• ECE 1 : température de +25°C ±2°C, humidité relative (HR) de 40% ±5%,
• ECE 2 : température de +40°C ±2°C, HR ≤ 25%.

The pouches are placed in controlled temperature and humidity chambers according to two sets of experimental conditions (ECE):

• ECE 1: temperature of + 25 ° C ± 2 ° C, relative humidity (RH) of 40% ± 5%,
• ECE 2: temperature + 40 ° C ± 2 ° C, RH ≤ 25%.

1. a) avant conditionnement (Tavc), i.e. au stade MPVP (Matière Première Vrac Purifiée : albumine stabilisée préchauffée),
2. b) après conditionnement (Tapc), i.e. après la répartition en poche,
3. c) après pasteurisation, incubation et conditionnement secondaire avec la surpoche (T0), et
4. d) tous les mois pendant six mois.

Pockets are collected at scheduled dates for analysis. These analyzes follow the following order:

1. a) before conditioning (Tavc), ie at the MPVP stage (purified bulk raw material: preheated stabilized albumin),
2. b) after conditioning (Tapc), ie after the pocket distribution,
3. c) after pasteurization, incubation and secondary conditioning with the overpouch (T0), and
4. d) every month for six months.

The analyzes can be classified according to three categories according to their characterization: qualitative, microbiological or functional. The qualitative characterization of the bags focuses on the appearance of the solution (color, degree of opalescence), pH, osmolality, concentration of polymers, aggregates, enzymatic degradation products, sodium , to the potential adsorption of the stabilizer sodium caprylate, to the study of the migration of the highly toxic component of the overpouch aluminum, to the study of the prekallikrein activator, to the observation of the presence of water between the membrane and the overpouch, to the extent of the extractable volume and the weight of the pocket to highlight a possible loss of water during storage. Microbiological characterization focuses on sterility. The functional characterization focuses on the total protein content (active ingredient content).

Table I groups the different analyzes and provides for each the method used and the acceptance criterion applied. <b><u> Table I: Analysis, Method and Application Criteria Applied </ u></b> Analysis Method Criteria of acceptance Aspect of the solution Ph.Eur 2.2.2 Ph.Eur 2.2.1 Virtually colorless, -Color yellow (J, JB≥JV3) - Degree of opalescence limpid pH Ph.Eur 2.2.3 6.7-7.3 Osmolality (mosmol / kg) Ph.Eur 2.2.35 200-300 Total protein (g / l) Ph.Eur 2.5.33 method 5 190-210 Polymers and aggregates (%) Ph.Eur 2.2.29 ≤5 Sodium caprylate (mg / g protein) Ph.Eur 2.2.28 12.80 - 16.80 Sodium (mmol / l) Ph.Eur 2.2.22 114-126 Degradation Products (%) Ph.Eur 2.2.29 ≤5 Extractable volume Ph.Eur 2.9.17 ≥ nominal volume Prekallikrein activator (Ul / ml) Ph.Eur 2.6.15 ≤35 Sterility Ph.Eur 2.6.1 Sterile Aluminum (μg / l) Ph.Eur 2.2.23 process I ≤200 Weight tracking of the pocket with reference overlay Weighing N / A Water between the membrane and the overpouch Visual observation N / A

The results obtained for each analysis are compared to the acceptance criteria of the product at each deadline. In addition, the evolution of the active ingredient content (total proteins) is studied by linear regression according to the ICH Q1A recommendations (from 5 deadlines). The absence of a linear regression (p ≥ 0.05) highlights the absence of a change in the results studied over time.

2. Results Lots ECE 1

Table II presents the results for a batch in 50ml presentation subjected to the set of conditions ECE 1, the batch being representative.

Whatever the batch and the presentation (50ml or 100ml), the total protein contents observed at each maturity are in accordance with the acceptance criterion.

The statistical analysis of the results shows the absence of a change in the total protein content as a function of the storage time for all the batches, except for one lot in the 100 ml presentation, for which a decrease in the total protein content is observed over time (existence of a linear regression, p <0.05). But this decrease has no impact on the quality of the product, given the conformity of the results obtained at each deadline.

Moreover, whatever the batch and the presentation (50ml or 100ml), the results obtained at each deadline are in conformity with the acceptance criteria, with the exception of the sterility of one of the batches in presentation 50 ml to l 6 month deadline. However, after investigation, the lack of observed sterility is probably linked to a leak in the pocket. Indeed, a sterility test performed on a pocket taken at a time close to 9 months gave a consistent result.

Also, whatever the batch and the presentation (50ml or 100ml), no evolution is observed after 6 months on the weight of the pockets (overpockets included) of reference, and no abnormal presence of water between the membrane and the overpouch has not been found.

Lots ECE 2

Table III presents the results for a batch in 100ml presentation subjected to the set of conditions ECE 2, the batch being representative.

Whatever the batch and the presentation (50ml or 100ml), the total protein contents observed at each maturity are in accordance with the acceptance criterion.

The statistical analysis of the results shows the absence of a change in the total protein content as a function of the storage time for all the batches, except for one batch in 50 ml presentation and one batch. in presentation 100 ml, for which a decrease in the total protein content is observed over time (existence of a linear regression, p <0.05). But this decrease has no impact on the quality of the product, given the conformity of the results obtained at each deadline.

Moreover, whatever the batch and the presentation (50ml or 100ml), the results obtained at each deadline are in conformity with the criteria of acceptance, with the exception of the sterility of one of the batches in presentation 100 ml at the expiry 6 months. But after investigation, the lack of sterility observed is probably related to a lack of waterproofness of the pocket. Indeed, a sterility test performed on a pocket taken at a time close to 9 months gave a consistent result.

Also, if water loss were to occur during storage, it would be confirmed by an increase in pH, osmolality and sodium content, which is not the case.

Conclusion

• pendant 6 mois à une température de 25 °C ± 2°C,
• pendant 6 mois à une température de 40°C ± 2°C.

The results obtained make it possible to conclude that the 20% albumin stored in the soft pouches tested, in 50ml and 100ml presentation, is stable:

• for 6 months at a temperature of 25 ° C ± 2 ° C,
• for 6 months at a temperature of 40 ° C ± 2 ° C.

Example 2: Study of the stability of IgNG (immunoglobulin G normal) 5% stored in test pockets 1. Material

The notations of Example 1 are repeated. The compartments of the bags are filled, manually with the aid of a peristaltic pump, with 50 ml of normal immunoglobulin G (IgNG) 5% manufactured according to the process described in the documents FR-2824568-A1 and FR-2895263-A1 , overcoated and stored under ECE 1 (ie 25 ° C ± 2 ° C RH = 40% ± 5%) or ECE 2 (ie 40 ° C ± 2 ° C RH ≤25%). At the same time, glass vials are filled with the same quantity and then stored under the same conditions for reference.

The analyzes carried out are primarily aimed at verifying the stability of 5% IgNG in the pockets and a possible loss of water during storage, resulting from the diffusion of water through the multilayer membrane of the pocket.

The analyzes are carried out at T0 and after storage for 1 month and 3 months, at 25 ° C. and 40 ° C. The methods used are those recommended by the European Pharmacopoeia with regard to the appearance of the solution (degree of opalescence and color), pH, osmolality, total protein content (HPSEC, Anti-Hbs activity, AAC ). In addition, the fragment assay (≤3%), the evaluation of the presence of visible and sub-visible particles, and the tween 80 assay are also performed. The aspect of the pocket (flexibility of the membrane, transparency, sealing of the welds, presence of water between membrane and overflow) is also followed.

Secondly, container / content interactions are evaluated.

For this, the extractables and relargables are dosed, according to the "guideline on plastic immediate packaging materials" (CPMP / QWP / 4359/03).

The extractables study is carried out with four extraction matrices (EPPI, NaOH, HCl and ethanol), at 100 ° C., for 5 hours. Only antioxidants are sought. This study being carried out on non-irradiated bags, a study on γ pockets radiated at 50 kGy is also conducted. EPPI is used as an extraction medium in this study.

The substances released from the pockets of IgNG stored for 3 months at 25 ° C and 40 ° C are assayed, in view of the results of the study extractables. The analyzes are of a semi-quantitative nature, which means that the assays have not been validated beforehand. For techniques requiring extraction (in dichloromethane) of potentially salted organic compounds (GC / MS and PTVGC / MS), the extraction yield may not be total and the values underestimated. On the other hand, by this semi-quantitative analysis, the response factor of the detected species is assumed equal to that of the internal standard, which is not always accurate.

2. Results Stability

Tables IV and V present the results of the stability study of the bags under the conditions ECE 1 and ECE 2 respectively, with each time the result of the references (glass bottles).

In general, the results show that IgNG is not destabilized in the pockets after 3 months at 25 ° C and 40 ° C, compared to storage in a glass bottle. The increase in the polymer and fragment content at 40 ° C. is comparable in the pockets and the glass bottles. The anti-HBS activity decreases in the same proportions in the pockets and glass vials. There is no clear evolution of the AAC, the different results being related to the variability of the test. In this study, the use of an all-aluminum overpouch proved effective in preventing water loss. Ig concentration and osmolality do not increase after 3 months of pocket storage with overpouch.

extractable

Regarding the study of extractables for non-irradiated bags, the main entities detected are Irganox 1076, Irganox 1010, Irganox 1330, Irgafos 168 and Irgafos 168 oxidized at concentrations below the limit of 1 ppm set by the Pharmacopoeia. European, for extractions in aqueous medium and at very low concentrations for extraction in ethanol. In the case of the γ -radiated pockets, volatile compounds by HS-GC / MS and semi-volatile by GC / MS, conventionally known as degradation products or solvents of the polymers have been identified.

leachables

Tables VI and VII below provide the evolution of the content of volatile compounds detected in pockets filled with 5% IgNG after storage for three months at 25 ° C. and 40 ° C. respectively. The values are expressed in ppb. <b><u> Table VI: Evolution of the content of volatile compounds at 25 ° C </ u></b> Time (months) 0 1 3 isobutylene 12 7 9 Cylcohexane 43 24 17 Ethyl acetate 0 170 180 Time (months) 0 1 3 isobutylene 12 8 12 Cylcohexane 43 17 14 Ethyl acetate 0 210 190 Acetone 0 0 5 tert-butanol 0 0 6

For the majority of compounds, the values detected are of the order of ppb and close to the detection limit of the method (5 ppb); the differences between the maturities are not significant. These are degradation products of polymers, identified in the study of extractables and solvents of the polymers used in the production of the bags. Only the evolution of the ethyl acetate content is significant. While this solvent is not initially detected, it is released after 1 month of storage, at concentrations that remain low.

Tables VIII and IX below provide the evolution of the content of volatile compounds detected in pockets filled with 5% IgNG, after storage for three months, at 25 ° C and 40 ° C respectively. The values are expressed in ppb. <b><u> Table VIII: Evolution of the content of semi-volatile compounds at 25 ° C </ u></b> Time (months) 0 1 3 2,4-di-tert-Butylphenol 25 240 200 Time (months) 0 1 3 2,4-di-tert-Butylphenol, 25 130 110 Benzyl alcohol, 0 0 11 Ethylhexanoic acid, 0 14 15 Unknown, 0 0 18 bislactone, 0 44 110 Tert-butyl-oxaspirodecadienedione, 0 20 40 (tert-butyl-hydroxyphenyl) propionic acid, 0 19 34

Again, for the majority of the compounds detected, the values are not significant and close to the limit of detection (10 ppb). Two compounds have significant levels after one month of storage: 2,4-di-terbutylphenol (CAS 96-76-4), a degradation product of antioxidants, very commonly found in plastic bags. It is irritating but not known to be carcinogenic. Bislactone (CAS 6607-34-7) is a release agent for which no toxicity data are available. Terbutylphenol has been identified in extractables while bislactone still appears only after long exposure.

With respect to the non-volatile compounds by PTV-GC / MS and LC / UV (antioxidants), the antioxidants identified in the extractables study were investigated. Their presence beyond the detection limit has not been demonstrated.

Conclusion

The results of the stability study show that IgNG is not destabilized in the Inerta 101 bags after 3 months at 25 ° C and 40 ° C, compared to storage in a glass bottle.

The study of the relargables shows the good chemical inertness of the Inerta 101 pocket. Only a solvent of the polymers, ethyl acetate and a degradation product of an antioxidant conventionally found in the plastic bags, terbutylphenol, have been detected at very low levels (of the order of ppb).

The use of the aluminum overpouch is effective in blocking the diffusion of water through the membrane. <u> TABLE II </ u> Analyzes Acceptance criteria Tave slap T0 1 month 2 months 3 months 4 months 6 months Aspect of the solution: degree of opalescence limpid limpid limpid limpid limpid limpid limpid limpid limpid Aspect of the color solution virtually colorless, yellow (J, JB ≥ JV3) JB3 JB3 JB3 JB3 JB3 JB3 JB3 JB3 Presence of water between pocket and overpouch N / A N / A N / A absence absence absence absence presence of a few drops absence pH 6.7-7.3 7.0 6.9 7.0 7.0 6.9 7.0 6.9 6.9 osmolality 200-300 mosmol / kg 218 220 221 219 219 220 219 222 Total protein 190-210 g / l 201 202 204 204 205 204 204 201 Sodium 114 -126 mmol / l 116 119 119 122 120 120 118 121 Degradation products ≤ 5% <5 <5 <5 <5 <5 <5 <5 <5 Sodium caprylate 12.80-16.80 mg / g prot. 15,30 14.62 14.20 15.17 14.76 15.19 14.84 15,03 Extractable volume ≥ 50 ml N / A N / A 51 N / A N / A 51 N / A 51 Polymers and aggregates ≤ 5% 4 4 4 4 4 4 4 4 Aluminum ≤ 200 μg / l N / A N / A <10 <10 <10 <10 <10 <10 Prekallikrein activator ≤ 35 VI / ml <1 <1 <1 <1 <1 <1 <1 <1 Sterility sterile N / A N / A sterile N / A N / A N / A N / A sterile Weight pocket of reference N / A N / A N / A 72.0 72.1 72.0 72.0 72.0 72.0 Analyzes Acceptance criteria Tave slap T0 1 month 2 months 3 months 4 months 6 months Aspect of the solution: degree of opalescence limpid limpid limpid limpid limpid limpid limpid limpid limpid Aspect of the solution: color virtually colorless, yellow (J, JB ≥ N3) JB3 JB3 JB3 JB3 JB3 JB3 JB3 JB3 Presence of water between pocket and overpouch N / A N / A N / A absence absence absence absence presence of a few drops absence pH 6.7-7,3 7.0 7.0 7.0 6.9 6.9 6.9 6.8 6.8 osmolality 200 - 300 mosmol / kg 218 221 220 220 219 222 220 222 Total protein 190-210 g / l 201 201 202 204 204 200 201 202 Sodium 114-126 mmol / l 116 118 117 118 118 120 120 120 Degradation products ≤ 5% <5 <5 <5 <5 <5 <5 <5 <5 Sodium caprylate 12.80 - 16.80 mg / g prot. 15,30 16.57 14.78 14.78 14.73 15.76 13.95 15.18 Extractable volume ≥ 100 ml N / A N / A 102 104 102 102 100 100 Polymers and aggregates ≤5% 4 4 4 45 5 5 5 5 Aluminum ≤200 μg / l N / A N / A <10 <10 <10 <10 <10 <10 Prekallikrein activator ≤ 35 IU / ml <1 <1 <1 <1 <1 <1 <1 <1 Sterility sterile N / A N / A sterile N / A N / A N / A N / A NR ⁽¹⁾ Weight pocket of reference N / A N / A N / A NR ⁽²⁾ NR ⁽²⁾ NR ⁽²⁾ NR ⁽²⁾ NR ⁽²⁾ NR ⁽²⁾ POCKETS Analyzes Specifications (Internal Standards) T0 T1 T3 Aspect of the solution - RAS Whitish particles * RAS pH 4.6-5.0 4.7 4.8 4.7 Osmolality, mosm / kg 270-330 310 311 311 Total protein, g / l 45-55 51 51 50 HPSEC % Polymers ≤ 1.00 <LOD ** <LOD ** <LOD ** % Dimer ≤8,0 6.25 6.37 5.34 % Monomers ≥ 90.0 93.46 93.26 94.22 % Fragments ≤ 0.70 0.29 0.37 0.44 Anti-HBs ≥ 0.03 IU / ml 4.33 4.10 3.92 AAC ≤ 50% 40% 40% 38% Dosage of tween 80 20.0-50.0 mg / l GLASS BOTTLES Analyzes Specifications (Internal Standards) T0 T1 T3 Aspect of the solution - RAS RAS RAS pH 4.6-5.0 4.7 4.7 4.6 Osmolality, mosm / kg 270-330 310 308 308 Total protein, g / l 45-55 50 50 49 HPSEC % Polymers ≤1,00 <LOD ** <LOD ** <LOD ** % Dimer ≤8,0 6.41 6.45 6.06 % Monomers ≥ 90.0 93.32 93.20 93.51 % Fragments ≤ 0.70 0.27 0.34 0.43 Anti-HBs ≥0.03 IU / ml 4.47 4.24 3.85 AAC ≤ 50% 42% 56% 39% Dosage of tween 80 20.0-50.0 mg / l * Probable microbial contamination during sample storage before analysis
** LOD = 0.0.5% POCKETS Analyzes Specifications (Internal Nornmes) T0 T1 T3 Aspect of the solution - RAS RAS RAS pH 4.6-5.0 4.7 4.7 4.7 Osmolality, mosm / kg 270-330 310 309 311 Total protein, g / l 45-55 51 50 49 HPSEC % Polymers ≤ 1.00 <LOD ** 0.07 0.21 % Dimer ≤8,0 6.25 5.31 5.32 % Monomers ≥ 90.0 93.46 93.74 92.63 % Fragments ≤ 0.70 0.29 0.89 1.84 Anti-HBs ≥ 0.03 IU / ml 4.33 3.60 2.78 AAC ≤ 50% 40% 42% 36% Dosage of tween 80 20.0-50.0 mg / l GLASS BOTTLES Analyzes Specifications (Internal Standards) T0 T1 T3 Aspect of the solution - RAS RAS Blackish particles * pH 4.6-5.0 4.7 4.7 4.7 Osmolality, mosm / kg 270-330 310 311 311 Total protein, g / l 45-55 50 50 50 HPSEC % Polymers ≤ 1.00 <LOD ** 0.08 0.29 % Dimer ≤8,0 6.41 5.89 5.82 % Monomers ≥90,0 93.32 93.17 92,09 % Fragments ≤0,70 0.27 0.86 1.79 Anti-HBs ≥ 0.03 IU / ml 4.47 3.41 2.76 AAC ≤ 50% 42% 53% 38% Dosage of tween 80 20.0-50.0 mg / l * Probable microbial contamination during sample storage before analysis
LOD = 0.05% **

Claims (6)

1. Bag (10) for storing therapeutic solution comprising:

   - at least one compartment (11) for receiving solution defined by a multilayer membrane, and

   - at least one appendage (13) forming an extension of the multilayer membrane (12) and comprising an inscription area (14), and

   - an immunoglobulin, or albumin, in the compartment (11) of the bag (10),

   characterized in that said bag comprises an outer impervious and/or opaque envelope and in that the appendage surface area/storage bag surface area ratio is comprised between 0.20 and 0.35.
2. Bag according to claim 1 in which the membrane is transparent.
3. Bag according to one of claims 1 to 2, in which the membrane comprises one or more ports (16).
4. Bag according to claim 3, in which the outer envelope is constituted by a multilayer film containing a layer of aluminium surrounded on both sides by a layer of plastic.
5. Bag according to any one of claims 1 to 4 in which the compartment has a maximum holding capacity comprised between one millilitre and one litre, advantageously comprised between 5 and 500 millilitres, advantageously comprised between 10 and 500 millilitres, more advantageously comprised between 20 and 200 millilitres, and even more advantageously comprised between 50 and 100 millilitres.
6. Bag according to claim 1 in which the immunoglobulin is normal immunoglobulin G (NIgG).

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