WO2024083794A1 - Bouchon de lyophilisation comprenant une membrane - Google Patents
Bouchon de lyophilisation comprenant une membrane Download PDFInfo
- Publication number
- WO2024083794A1 WO2024083794A1 PCT/EP2023/078781 EP2023078781W WO2024083794A1 WO 2024083794 A1 WO2024083794 A1 WO 2024083794A1 EP 2023078781 W EP2023078781 W EP 2023078781W WO 2024083794 A1 WO2024083794 A1 WO 2024083794A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- stopper
- water vapor
- vial
- permeable membrane
- lyophilization
- Prior art date
Links
- 239000012528 membrane Substances 0.000 title claims abstract description 99
- 238000004108 freeze drying Methods 0.000 title claims description 47
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 90
- 229920000295 expanded polytetrafluoroethylene Polymers 0.000 claims description 20
- 238000000034 method Methods 0.000 claims description 12
- 239000000203 mixture Substances 0.000 claims description 12
- -1 bromobutyl Chemical group 0.000 claims description 10
- 229920001971 elastomer Polymers 0.000 claims description 10
- 229920000642 polymer Polymers 0.000 claims description 8
- 239000008194 pharmaceutical composition Substances 0.000 claims description 7
- 230000035699 permeability Effects 0.000 claims description 6
- 239000004721 Polyphenylene oxide Substances 0.000 claims description 5
- 238000001125 extrusion Methods 0.000 claims description 5
- 229920000570 polyether Polymers 0.000 claims description 5
- 238000003860 storage Methods 0.000 claims description 4
- 239000013543 active substance Substances 0.000 claims description 3
- 238000000748 compression moulding Methods 0.000 claims description 3
- 229920002943 EPDM rubber Polymers 0.000 claims description 2
- 244000043261 Hevea brasiliensis Species 0.000 claims description 2
- 229920002614 Polyether block amide Polymers 0.000 claims description 2
- 239000012190 activator Substances 0.000 claims description 2
- 229910052782 aluminium Inorganic materials 0.000 claims description 2
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 claims description 2
- 229920005557 bromobutyl Polymers 0.000 claims description 2
- 229920005549 butyl rubber Polymers 0.000 claims description 2
- 229920005556 chlorobutyl Polymers 0.000 claims description 2
- 150000002148 esters Chemical class 0.000 claims description 2
- 239000000945 filler Substances 0.000 claims description 2
- 229920003049 isoprene rubber Polymers 0.000 claims description 2
- 229920003052 natural elastomer Polymers 0.000 claims description 2
- 229920001194 natural rubber Polymers 0.000 claims description 2
- 239000000049 pigment Substances 0.000 claims description 2
- 239000004014 plasticizer Substances 0.000 claims description 2
- 239000003381 stabilizer Substances 0.000 claims description 2
- 150000003673 urethanes Chemical class 0.000 claims description 2
- 238000011109 contamination Methods 0.000 description 18
- 238000012792 lyophilization process Methods 0.000 description 16
- 238000007789 sealing Methods 0.000 description 15
- 239000007789 gas Substances 0.000 description 10
- 230000035515 penetration Effects 0.000 description 10
- 238000011049 filling Methods 0.000 description 5
- 230000008569 process Effects 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- 239000010410 layer Substances 0.000 description 4
- 229920003023 plastic Polymers 0.000 description 4
- 239000004033 plastic Substances 0.000 description 4
- 239000005020 polyethylene terephthalate Substances 0.000 description 4
- 229920000139 polyethylene terephthalate Polymers 0.000 description 4
- 230000001954 sterilising effect Effects 0.000 description 4
- 238000004659 sterilization and disinfection Methods 0.000 description 4
- 238000000859 sublimation Methods 0.000 description 4
- 230000008022 sublimation Effects 0.000 description 4
- 239000004698 Polyethylene Substances 0.000 description 3
- 239000004743 Polypropylene Substances 0.000 description 3
- 239000011248 coating agent Substances 0.000 description 3
- 230000007423 decrease Effects 0.000 description 3
- 239000011521 glass Substances 0.000 description 3
- 238000003780 insertion Methods 0.000 description 3
- 230000037431 insertion Effects 0.000 description 3
- 239000012633 leachable Substances 0.000 description 3
- 238000011169 microbiological contamination Methods 0.000 description 3
- 229920001343 polytetrafluoroethylene Polymers 0.000 description 3
- 239000004810 polytetrafluoroethylene Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 238000013022 venting Methods 0.000 description 3
- 241000894006 Bacteria Species 0.000 description 2
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 2
- XECAHXYUAAWDEL-UHFFFAOYSA-N acrylonitrile butadiene styrene Chemical compound C=CC=C.C=CC#N.C=CC1=CC=CC=C1 XECAHXYUAAWDEL-UHFFFAOYSA-N 0.000 description 2
- 229920000122 acrylonitrile butadiene styrene Polymers 0.000 description 2
- 239000004676 acrylonitrile butadiene styrene Substances 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 238000003490 calendering Methods 0.000 description 2
- 150000005829 chemical entities Chemical class 0.000 description 2
- 238000000576 coating method Methods 0.000 description 2
- 238000010276 construction Methods 0.000 description 2
- 239000012632 extractable Substances 0.000 description 2
- 238000011194 good manufacturing practice Methods 0.000 description 2
- 239000004700 high-density polyethylene Substances 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 239000000314 lubricant Substances 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 244000005700 microbiome Species 0.000 description 2
- 239000000825 pharmaceutical preparation Substances 0.000 description 2
- 229920000728 polyester Polymers 0.000 description 2
- 229920000573 polyethylene Polymers 0.000 description 2
- 229920001155 polypropylene Polymers 0.000 description 2
- 229920002635 polyurethane Polymers 0.000 description 2
- 239000004814 polyurethane Substances 0.000 description 2
- 229920005573 silicon-containing polymer Polymers 0.000 description 2
- 239000002356 single layer Substances 0.000 description 2
- 238000010254 subcutaneous injection Methods 0.000 description 2
- 239000007929 subcutaneous injection Substances 0.000 description 2
- IAYPIBMASNFSPL-UHFFFAOYSA-N Ethylene oxide Chemical compound C1CO1 IAYPIBMASNFSPL-UHFFFAOYSA-N 0.000 description 1
- 241000233866 Fungi Species 0.000 description 1
- 241000700605 Viruses Species 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- 230000004888 barrier function Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 229920001577 copolymer Polymers 0.000 description 1
- 238000012864 cross contamination Methods 0.000 description 1
- 239000002274 desiccant Substances 0.000 description 1
- 229940126534 drug product Drugs 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 229920002313 fluoropolymer Polymers 0.000 description 1
- 239000004811 fluoropolymer Substances 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 230000005251 gamma ray Effects 0.000 description 1
- 239000003292 glue Substances 0.000 description 1
- 231100001261 hazardous Toxicity 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- 230000036512 infertility Effects 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 238000003475 lamination Methods 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 229940126601 medicinal product Drugs 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 230000000813 microbial effect Effects 0.000 description 1
- 238000013508 migration Methods 0.000 description 1
- 230000005012 migration Effects 0.000 description 1
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 1
- 244000052769 pathogen Species 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 229940127557 pharmaceutical product Drugs 0.000 description 1
- 229920005644 polyethylene terephthalate glycol copolymer Polymers 0.000 description 1
- 239000011148 porous material Substances 0.000 description 1
- 239000012602 primary packaging material Substances 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 239000005361 soda-lime glass Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000003466 welding Methods 0.000 description 1
Classifications
-
- F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
- F26—DRYING
- F26B—DRYING SOLID MATERIALS OR OBJECTS BY REMOVING LIQUID THEREFROM
- F26B5/00—Drying solid materials or objects by processes not involving the application of heat
- F26B5/04—Drying solid materials or objects by processes not involving the application of heat by evaporation or sublimation of moisture under reduced pressure, e.g. in a vacuum
- F26B5/06—Drying solid materials or objects by processes not involving the application of heat by evaporation or sublimation of moisture under reduced pressure, e.g. in a vacuum the process involving freezing
Definitions
- Lyophilization Stopper comprising a membrane
- the present invention is directed to a lyophilization stopper comprising a water vapor- permeable membrane.
- Lyophilization i.e. freeze-drying
- the solvent is removed by sublimation.
- several containment systems are known in the prior art.
- WO 2019/012512 A1 describes a container that has been designed to protect product from contamination during lyophilization.
- the container has at least one water vapor- permeable side through which water vapor can escape during lyophilization.
- a container is unsuitable for long-term storage, as water can re-hydrate the product in the container in a humid environment.
- such a container is unsuitable for easy handling, as a needle pierceable region for reconstitution is missing.
- Vials with rubber stoppers are commonly used, wherein the stopper has a first configuration that allows the sublimation of the solvent and a second configuration for sealing the vial with the stopper.
- the product itself may potentially be hazardous and may contaminate the process facility.
- Such a risk of contamination is in particular worrisome for crosscontamination between batches of different products, wherein trace amounts of a first product may cross-contaminate a batch of a second product. It is, in particular for lyophilization in vials, a drawback that contamination can occur when the stopper is the above-mentioned first configuration and the vial is not yet sealed.
- Lyophilization products are especially concerned given the need for the vial to be partially open (“preplugged") during the lyophilization process in order to allow the water that sublimates during the process to escape the vial.
- the lyophilization can take several days in those products that require long freeze-drying cycles, thereby increasing the risk for contamination.
- a stopper comprising a stopper body and a water vapor-permeable membrane.
- this stopper allows the sublimation of solvent, such as water, during a lyophilization process while at the same time providing a barrier that lowers the risk of contamination.
- the membrane used in the stopper of the present invention is permeable to water vapor, thereby allowing the water that sublimates during the lyophilization process to escape the vial.
- the membrane used in the stopper of the present invention is furthermore impermeable to liquid water and impermeable to microorganisms, thereby reducing, preferably avoiding the risk of contamination such as microbiological contamination with microorganisms, such as bacteria, viruses, and fungi, in particular bacteria, of the lyophilized product.
- the stopper of the present invention can maintain the container closure integrity (CCI) of the prior art container systems.
- the stopper can be used with a vial for ready-to-use formulations, wherein the stopper can be pierced by a needle without interference of the water vapor-permeable membrane.
- the invention relates to a kit of parts comprising the stopper of the present invention, a lyophilization container, and preferably a cap assembly.
- the present invention relates to the use of the stopper of the present invention for lyophilization.
- the present invention relates to a method for preparing the stopper of the present invention, comprising the steps of
- Figure 1 depicts the cross section of a prior art two-legged stopper 2.
- the stopper 2 comprises a stopper head 4, and two stopper legs 6 that are essentially orthogonal to main surface area 7 of the stopper head 4.
- the stopper comprises an outer surface 3 and an inner surface 5.
- the stopper comprises a vent passageway 9.
- the two stopper legs form a vent area 8 on the outer surface 9 of the stopper through which gases can flow when the stopper is partially inserted into a vial.
- Figure 2 depicts the top view of a stopper, wherein stopper head 4 comprises a needle penetration region 10. This region is in the center of the main surface area of the stopper head. The needle penetration region allows the piercing of the stopper with a needle for reconstitution and removal of the reconstituted product without having to remove the stopper.
- Figure 3 shows the cross section of a two-legged stopper 12 of the present invention, wherein the stopper body 12 comprising a stopper head 4 and two stopper legs 6 that are essentially orthogonal to the stopper head, wherein the two stopper legs form a vent area, and the vent area is covered by a water vapor-permeable membrane 14.
- the vent area is completely covered by the water vapor-permeable membrane 14.
- the water vapor-permeable membrane 14 is connected to the surface of the stopper legs 6.
- Figure 4 depicts the cross section of a two-legged stopper 22 of the present invention, wherein the water vapor-permeable membrane 14 does only partially cover the vent area 8.
- the stopper is inserted into the vial so that the area not covered by the water vapor- permeable membrane is inside the vial.
- Figure 5 depicts the cross section of a two-legged stopper 32 of the present invention, wherein the water vapor-permeable membrane 16 is essentially orthogonal to the stopper legs 6 and the vent area 8.
- Figure 6 depicts a three-dimensional view of a two-legged stopper of the present invention comprising a stopper head 4 and two stopper legs 6 that are essentially orthogonal to the stopper head, wherein the two stopper legs form a vent area, and the vent area is covered by a water vapor-permeable membrane 14.
- the stopper legs 6 comprise nubs 18 that fasten the stopper and prevent the stopper from slipping off.
- Figure 7 depicts the cross section of a bunker stopper 42 of the present invention, wherein the vent area of the stopper 8 is completely covered by the water vapor- permeable membrane 16.
- Figure 8 depicts the cross section of a bunker stopper 52 of the present invention, wherein the stopper comprises a sealing ring 19.
- the sealing ring 19 is ring shaped and surrounds stopper legs 6.
- the sealing ring facilitates fastening of the stopper in the “open” configuration and stabilizes the legs of the stopper.
- the sealing ring prevents microcanals or crevices between the stopper and the vial from forming in the open configuration and helps to stabilize the legs during the insertion of the stopper into a vial.
- the sealing ring further minimizes contamination during lyophilization.
- the term “pharmaceutical” refers to compositions, wherein the active ingredient fulfils all necessary pharmaceutical standards/monographs of the LISP-NF (United States Pharmacopoeia National Formulary) or Ph. Eur. (European Pharmacopoeia) reference standard with regard to purity of the active ingredient and/or amount of pathogens and/or bacterial contamination.
- the term “stopper body” refers to the part of the stopper of the present invention not comprising a water vapor-permeable membrane.
- stopper generally refers to a device for closing a container or vial.
- stopper head refers to the part of the stopper body that is configured to not be inserted into the lyophilization vial.
- the stopper head has a larger diameter than the stopper leg and a larger diameter than the vial opening.
- stopper leg refers to the part of the stopper body that is configured to be pushed into the lyophilization vial.
- the stopper leg preferably protrudes essentially orthogonal to the main surface area of the stopper head.
- water vapor-permeable refers to a water vapor permeability of 1000 g/m 2 /24 h or more.
- essentially orthogonal refers to an angle of 70° to 110°.
- essentially parallel refers to an angle of -20° to +20°.
- wt.-% refers to the amount of the respective ingredient by weight based on the total amount of the element it refers to, unless noted otherwise.
- a stopper leg means one stopper leg or more than one stopper leg.
- vent area is to be understood as the area on the outer surface of the stopper of a vent passageway.
- the vent passageway is a passageway for gas that goes through the stopper and is used for venting gas during the lyophilization process.
- the vial is "pre-plugged" when the stopper is not completely inserted into the vial. With conventional stoppers, this configuration leaves vent areas allowing water vapor resulting from sublimation to escape the vial during lyophilization.
- the stopper is a lyophilization stopper.
- the stopper is a stopper for lyophilization, i.e. the stopper is for sealing and venting a lyophilization container, preferably a vial.
- the stopper of the present invention is a vial stopper.
- the stopper of the present invention is a two-legged stopper, a three-legged stopper or an Igloo stopper.
- These stoppers are commercially available, e.g. from West Pharmaceutical Services Inc. or DWK life Sciences Co. Ltd.
- a two-legged stopper of the prior art is schematically depicted in Figures 1 and 2.
- Igloo stoppers comprise a vent area comprising one vent portion through which gas can be removed during the lyophilization process.
- Two-legged stoppers comprise a vent area consisting of two vent portions through which gas can be removed during the lyophilization process.
- Three-legged stopper comprise a vent area consisting of three vent portions through which gas can be removed during the lyophilization process. These stoppers are typically sold having an outer diameter of the stopper leg of e.g. 12 mm, 13 mm, 15 mm or 20 mm. These stoppers are advantageous due to the large vent area that allows efficient and fast lyophilization. In addition, such stoppers are compatible with automated loading unloading systems (ALUS). The compatibility with automated systems, such as ALUS, is beneficial, since the use of automated systems increases production efficiency and further minimizes the risk of contamination before and after freeze-drying.
- ALUS automated loading unloading systems
- the stopper of the present invention is a bunker stopper.
- a bunker stopper is schematically depicted in Figure 7.
- Bunker stoppers comprise a vent area on the stopper leg, preferably near the stopper head. In the present invention, the vent area is completely covered by the water vapor-permeable membrane.
- the bunker stopper In the pre- plugged state, the bunker stopper is configured so that the water vapor-permeable membrane is not in the vial and is not in contact with the surface of the vial. After lyophilization, the bunker stopper is fully inserted so that the vent area and the water vapor-permeable membrane is inside the vial and the vial is sealed by the stopper.
- vent area is near the stopper head to minimize the amount of surface exposed to the outside in the pre-plugged state to further minimize the risk of contamination.
- This configuration is particularly preferred, as there is even less risk of contamination, as there is no contact point between the water vapor-permeable membrane and the vial’s surface in the pre-plugged state.
- the bunker stopper is configured in that the water-vapor permeable membrane is essentially orthogonal to the stopper head and/or the needle penetration area.
- the stopper body comprises a stopper head.
- the stopper head is configured to prevent the stopper from sliding or falling into a vial.
- the stopper head comprises a main surface area. Said main surface area is preferably circular.
- the stopper head preferably comprises a needle penetration region, i.e. a needle pierceable area.
- the needle penetration area is configured so that a needle can penetrate through the stopper. This region is preferably centrally located on the stopper head, i.e. the stopper comprises a centrally located needle penetration region. This is useful for reconstituting the lyophilized product and emptying the vial without removing the stopper.
- the stopper comprises a vent passageway for venting gas during the lyophilization process.
- the stopper body may further comprise a stopper leg that protrudes essentially orthogonal to the main surface area of the stopper head.
- the leg is configured to be inserted into the vial.
- the leg is configured to span a vent area on the outer surface of the stopper that allows gas to flow through the vent passageway through the stopper when the stopper is only partially inserted into a vial.
- the water vapor-permeable membrane is not parallel to the main surface area of the stopper head or the needle penetration area. It is preferred that the water vapor- permeable membrane is essentially orthogonal, i.e. horizontal, to the main surface area of the stopper head and/or the needle penetration area. In an embodiment, the water vapor-permeable membrane covers the vent passageway.
- the water vapor- permeable membrane is placed in the path of any gas traveling through the vent passageway. It is preferred that the water vapor-permeable membrane completely or partially covers the vent area.
- the stopper of the present invention is a lyophilization vial stopper comprising a stopper body and a water vapor-permeable membrane, wherein the water vapor-permeable membrane comprises ePTFE, the stopper body comprises a vent passageway, and the water vapor-permeable membrane covers the vent passageway.
- the stopper comprises nubs and/or recesses. Nubs and/or recesses facilitate fastening of the stopper to the vial and prevent the stopper from slipping off the vial. When the stopper is inserted into the vial, the stopper needs to be in a proper position. The nubs and/or recesses prevent angled or misplaced positioning of the stopper.
- the stopper comprises a sealing ring.
- the sealing ring facilitates fastening of the stopper in the “open” configuration and stabilizes the legs of the stopper.
- the sealing ring prevents microcanals between the stopper and the vial from forming in the open configuration and helps to stabilize the legs during the insertion of the stopper into a vial.
- the sealing band comprises preferably the same rubber as the stopper.
- the stopper does not comprise any moving parts.
- the absence of moving parts leads to a more stable and reliable stopper.
- the absence of moving parts decreases the probability of errors due to malfunctioning of the moving parts during the lyophilization process. As many lyophilized products are complex molecules that are difficult to manufacture, even a small decrease in errors during the lyophilization process results in substantial cost savings.
- the stopper of the present invention comprises a stopper body that is laminated with a fluoropolymer or a silicone polymer.
- a laminated stopper can reduce the migration of leachables from the stopper and can facilitate the insertion of the stopper into the vial.
- the water vapor-permeable membrane comprises expanded polytetrafluoroethylene (ePTFE) and/or a polymer selected from the group consisting of polyether esters, polyether amides, polyether urethanes, and mixtures thereof. It is preferred that the water vapor-permeable membrane comprises ePTFE. In an embodiment, the membrane comprises 50 to 100 wt.-% of ePTFE, preferably 70 to 100 wt.-% of ePTFE, and more preferably 90 to 100 wt.-% of ePTFE. In an embodiment, the water vapor-permeable membrane consists of ePTFE.
- Extractables are chemical entities that may be released from container systems under stressed conditions with various solvents.
- Leachables are chemical entities that can migrate from the container system into the drug product under standard conditions.
- ePTFE is obtained by the steps of extrusion of a PTFE resin with a lubricant, usually a naptha solvent. After extrusion to provide a film, the film is calendared, dried to evaporate the lubricant and subsequently expanded (either uniaxially or biaxially) at elevated temperatures, to provide a ePTFE membrane. Such a ePTFE membrane is porous.
- the expanded polytetrafluoroethylene is an uniaxially expanded membrane.
- An uniaxially expanded membrane is obtainable by calendaring in the machine direction (MD).
- the expanded polytetrafluoroethylene is a biaxially expanded membrane.
- a biaxial expanded membrane is obtainable by calendaring in the machine direction (MD) and in transverse or cross direction (CD).
- the ePTFE membrane preferably has a microstructure of nodes and fibrils, wherein the fibrils connect the nodes.
- the water vapor-permeable membrane comprises a polyether polyester copolymer or a polyester polymer. Such membranes are commercially available as Sympatex® and FuturelightTM.
- the water vapor-permeable membrane is a polyurethane. Suitable polyurethanes are described in US 6,790,926 B1.
- the water vapor-permeable membrane has a thickness of 0.1 to 500 pm, preferably of 1 to 200 pm, more preferably of 5 to 100 pm.
- the processing can be difficult and the stability of the membrane suffers.
- the thickness of the membrane exceeds 500 pm, the water vapor permeability may decrease leading to a less efficient lyophilization process.
- the water vapor-permeable membrane has a water vapor permeability of 1000 to 65000 g/m 2 /24 h, preferably of 3000 to 50000 g/m 2 /24 h. The water vapor permeability can be measured according to ASTM E-96-95, procedure B.
- the water vapor-permeable membrane has a water vapor permeability of 500 to 100000 g/m 2 /24 h, of 2000 to 40000 g/m 2 /24 h or of 4000 to 20000 g/m 2 /24 h.
- the membrane can comprise one or more layers.
- the membrane consists of a single layer.
- the membrane consists of a single layer and the membrane comprises 70 to 100 wt.-% expanded polytetrafluoroethylene.
- the membrane is a multi-layer construction, comprising, two, three, four or more layers. The layers can be attached to each other by lamination.
- the membrane comprises polyethylene, polyethylene terephthalate, and/or mixtures thereof.
- the stopper body comprises a rubber.
- the rubber is selected from the group consisting of natural rubber, isoprene rubber, ethylene propylene diene rubber, butyl rubber, bromobutyl rubber, chlorobutyl rubber and mixtures thereof as well as copolymers thereof.
- the rubber stopper may be coated by a hydrophobic coating agent, such as silicone polymers or may contain a desiccant.
- a hydrophobic coating agent such as silicone polymers or may contain a desiccant.
- the rubber stopper is coated with a polytetrafluoroethylene (PTFE) coating. The coating is preferable on the inside of the stopper.
- PTFE polytetrafluoroethylene
- the stopper body comprises a filler, an accelerator, an activator, a plasticizer, a pigment, and/or a stabilizer.
- the stopper is sterile in accordance with the European Pharmacopoeia 5.1.1, edition 10.0, 2019.
- the invention relates to a kit of parts comprising the stopper of the present invention, a lyophilization container, and preferably a cap assembly.
- the lyophilization container is a vial.
- the vial can be a plastic or a glass vial. Examples for glass are soda-lime glass and borosilicate.
- the vial has a hole opening with an inner diameter of 5 to 100 mm, preferably of 10 to 50 mm.
- the stopper has an outer diameter that is slightly larger of the inner diameter of the vial.
- the outer diameter of the stopper refers to the diameter of the portion of the stopper that is inserted into the vial, i.e.
- the outer diameter does not refer to the diameter of the stopper head.
- the outer diameter of the stopper refers to the outer diameter of the stopper legs, i.e. the portion of the stopper that is inserted into the vial.
- a rubber stopper with an outer diameter of e.g. 13 mm can be used.
- the stopper is configured to have
- the water vapor can vent through the vent area.
- the vent area is completely covered by the water vapor-permeable membrane.
- This configuration is used during the lyophilization process. Usually, this configuration is achieved by inserting the stopper into an intermediate position into the vial.
- the vial is hermetically sealed by the stopper. This position is used for storage. Usually, this configuration is achieved by inserting the stopper further into the vial until the stopper head touches the vial.
- the water vapor-permeable membrane is configured to substantially only cover the area on the outer surface of the stopper in the first position that allows water vapor through, i.e. the water vapor-permeable membrane covers the opening of the stopper body (the vent area), when inserted into the vial.
- the water vapor-permeable membrane is not coated continuously over the surface of the stopper body or the stopper leg.
- the stopper is configured so that the stopper body can be pierced to reconstitute the lyophilized product by a needle without piercing the water vapor-permeable membrane.
- the water-permeable membrane is not connected in such a way to the stopper body that the water vapor-permeable membrane can be pierced by a needle.
- the water-permeable membrane is not essentially parallel to the main surface area of the stopper head.
- the water vapor-permeable membrane is parallel to the main surface area of the stopper head and is pierced when the lyophilized product is reconstituted.
- the membrane may be damaged, in particular if the membrane is too thin.
- this configuration wherein the water-permeable membrane is not parallel to the main surface area of the stopper head, improves safety during reconstitution. In case the needle penetration region on the stopper head as well as the water-vapor-permeable membrane need both to be pierced, then the different pressure required to pierce the membrane and to withdraw the needle from the membrane may surprise the user and lead to slipping off and other accidents.
- the vent area that is covered by the water vapor-permeable membrane has a large surface area and therefore results in a time-efficient lyophilization process. It is preferred that the vent area has a surface of 0.01 cm 2 to 10 cm 2 , of 0.05 cm 2 to 5 cm 2 , of 0.1 cm 2 to 5 cm 2 , of 0.25 cm 2 to 5 cm 2 , of 0.5 cm 2 to 5 cm 2 , of 0.75 cm 2 to 5 cm 2 , of 1 cm 2 to 4 cm 2 , or of 1 .5 cm 2 to 3 cm 2 . It is to be understood that the surface area of the vent area corresponds to the surface of the membrane which completely covers the vent area.
- the membrane of the present invention likewise has a surface area of preferably 0.01 cm 2 to 10 cm 2 , of 0.05 cm 2 to 5 cm 2 , of 0.1 cm 2 to 5 cm 2 , of 0.25 cm 2 to 5 cm 2 , of 0.5 cm 2 to 5 cm 2 , of 0.75 cm 2 to 5 cm 2 , of 1 cm 2 to 4 cm 2 , or of 1 .5 cm 2 to 3 cm 2
- the kit of parts of the present invention comprises a cap system.
- the cap system also known as crimp seal, can comprise a metal seal, such as aluminum, and preferably a polymer button, and is configured to surround both the stopper and a neck of the vial in a sealed position.
- the cap system comprises a plastic cap, the plastic cap preferably comprising polypropylene.
- the cap comprises a polymer selected from the group of PE (polyethylene), PET (polyethylene terephthalate), PETG (polyethylene terephthalate glycol), PEHD (polyethylene high-density), PP (polypropylene), ABS (acrylonitrile butadiene styrene) polymer, and mixtures thereof.
- Cap systems act as an additional seal (the contact between stopper and vial acting as the primary seal) and are advantageous for further sealing the vial and increasing the container closure integrity (CCI).
- CCI container closure integrity
- the stopper of the present invention is used for lyophilization.
- the stopper is used to lyophilize a pharmaceutically active agent or a pharmaceutical composition, which typically comprises one or more pharmaceutically acceptable excipients besides the pharmaceutically active agent(s).
- the use of the stopper comprises the step of filling a pharmaceutical composition in a syringe, cartridge, vial or container.
- the stopper can then be inserted into the syringe, cartridge, vial or container so that gas can vent through the vent passageway.
- the syringe, cartridge, vial or container is hermetically sealed with the stopper.
- a cap system is additionally used for sealing the syringe, cartridge, vial or container.
- the pharmaceutical composition can be reconstituted with solvent prior to use. This allows for the administration by intravenous infusion or injection as well as subcutaneous injection. However, it is also possible to provide the pharmaceutical composition as a suspension which is used for subcutaneous injection.
- the invention relates to a method for preparing the stopper of the present invention, the method comprising the steps of
- connection of the water-vapor permeable membrane to the stopper body can be achieved by welding at elevated temperatures to fuse the water-vapor permeable membrane and the stopper body.
- the water vapor-permeable membrane and the stopper body may be connected using a glue.
- the method further comprises the step of
- the stopper and/or the pharmaceutical composition is sterile in accordance with the European Pharmacopoeia 5.1.1, edition 10.0, 2019.
- the composition is sterile, i.e. it contains less than 10' 4 wt.-% of nonsterile material, such as microbial contamination. Sterility of the composition can be ensured by a number of processes, such as thermal, chemical, and radiation steps.
- the stopper complies with the good manufacturing practice (GMP) standard for primary packaging materials for medicinal products DIN EN ISO 15378.
- the stopper is a stopper for a vial, preferably a glass or plastic vial. Any composition contained in the vial may be removed from the vial by puncturing the stopper with a needle.
- stoppers according to the present invention comprising an ePTFE membrane with conventional stoppers (not comprising a membrane) in terms of their ability to evacuate different volumes of water during a freeze-drying cycle.
- Vials were filled with different filling volume of water (2 mL and 5 mL) and stoppered with a stopper in accordance with the present invention or without a stopper. The vials were then lyophilized using the following freeze-drying cycle, launched in the 100ST freeze dryer (Table 1):
- Vials were filled with different filling volume of water (2 mL and 5 mL) and either (i) stoppered with a stopper in accordance with the present invention, comprising an ePTFE membrane covering the vent area using different surface areas between 3.14 mm 2 and 176.63 mm 2 (Vials 1-7, 11-17); or (ii) not stoppered and used as open vials without a stopper (Vials 8-10, 18-20). The vials were then lyophilized using the freeze-drying cycle according to Example 1.
- the amount of lyophilized water was measured by measuring the weight of the vial before the lyophilization cycle and after the lyophilization cycle.
- the results of the lyophilization cycle are stated in Table 2 below.
- the ePTFE membrane is capable of evacuating the sublimated water produced by lyophilization.
- stoppers of the present invention have a similar capacity to evacuate water than open vials.
- stoppers of the present invention offer the additional advantage that it will not be necessary to modify established freeze-drying cycles for existing pharmaceutical products, at the same time dramatically reducing the risk of microbiological contamination.
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- Engineering & Computer Science (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Molecular Biology (AREA)
- Mechanical Engineering (AREA)
- General Engineering & Computer Science (AREA)
- Medical Preparation Storing Or Oral Administration Devices (AREA)
- Closures For Containers (AREA)
Abstract
L'invention concerne un bouchon comprenant un corps de bouchon et une membrane perméable à la vapeur d'eau.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP22202491.1 | 2022-10-19 | ||
EP22202491.1A EP4357709A1 (fr) | 2022-10-19 | 2022-10-19 | Bouchon de lyophilisation comprenant une membrane |
Publications (1)
Publication Number | Publication Date |
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WO2024083794A1 true WO2024083794A1 (fr) | 2024-04-25 |
Family
ID=83899427
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/EP2023/078781 WO2024083794A1 (fr) | 2022-10-19 | 2023-10-17 | Bouchon de lyophilisation comprenant une membrane |
Country Status (2)
Country | Link |
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EP (1) | EP4357709A1 (fr) |
WO (1) | WO2024083794A1 (fr) |
Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5522155A (en) * | 1994-08-19 | 1996-06-04 | W. L. Gore & Associates, Inc. | Vented vial method of minimizing contamination of freeze-dried products |
US5596814A (en) * | 1995-11-06 | 1997-01-28 | W. L. Gore & Associates, Inc. | Vented vial stopper for processing freeze-dried products |
US6790926B1 (en) | 1998-10-21 | 2004-09-14 | Sympatex Technologies Gmbh | Water vapor permeable thermoplastic polyurethane film |
WO2007127286A2 (fr) * | 2006-04-24 | 2007-11-08 | Medical Instill Technologies, Inc. | dispositif de lyophilisation perméable aux aiguilles et refermable de façon étanche par laser et procédé associé |
US20090175315A1 (en) * | 2005-04-26 | 2009-07-09 | John Jeffrey Schwegman | Wireless temperature sensing system for lyophilization processes |
WO2013164422A2 (fr) * | 2012-05-03 | 2013-11-07 | Schott Ag | Procédé et dispositif pour manipuler des récipients et des substances contenues dans ces récipients pour des applications médicales, pharmaceutiques ou cosmétiques |
WO2019012512A1 (fr) | 2017-07-14 | 2019-01-17 | 4D Pharma León, S.L.U. | Procédé de lyophilisation de produit |
-
2022
- 2022-10-19 EP EP22202491.1A patent/EP4357709A1/fr active Pending
-
2023
- 2023-10-17 WO PCT/EP2023/078781 patent/WO2024083794A1/fr unknown
Patent Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5522155A (en) * | 1994-08-19 | 1996-06-04 | W. L. Gore & Associates, Inc. | Vented vial method of minimizing contamination of freeze-dried products |
US5596814A (en) * | 1995-11-06 | 1997-01-28 | W. L. Gore & Associates, Inc. | Vented vial stopper for processing freeze-dried products |
US6790926B1 (en) | 1998-10-21 | 2004-09-14 | Sympatex Technologies Gmbh | Water vapor permeable thermoplastic polyurethane film |
US20090175315A1 (en) * | 2005-04-26 | 2009-07-09 | John Jeffrey Schwegman | Wireless temperature sensing system for lyophilization processes |
WO2007127286A2 (fr) * | 2006-04-24 | 2007-11-08 | Medical Instill Technologies, Inc. | dispositif de lyophilisation perméable aux aiguilles et refermable de façon étanche par laser et procédé associé |
WO2013164422A2 (fr) * | 2012-05-03 | 2013-11-07 | Schott Ag | Procédé et dispositif pour manipuler des récipients et des substances contenues dans ces récipients pour des applications médicales, pharmaceutiques ou cosmétiques |
WO2019012512A1 (fr) | 2017-07-14 | 2019-01-17 | 4D Pharma León, S.L.U. | Procédé de lyophilisation de produit |
Also Published As
Publication number | Publication date |
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EP4357709A1 (fr) | 2024-04-24 |
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