Method for filling at least one degassed formulation into a container and formulation filling device - Patents.com

Abstract

A formulation filling apparatus 110 for filling at least one formulation into a container is proposed, the formulation filling apparatus 110 comprising: a) at least one formulation preparation apparatus 112 configured to prepare a liquid formulation; b) at least one filling station 114 for filling the liquid formulation into a container, the filling station 114 being fluidly coupled to the formulation preparation apparatus; and c) at least one degassing apparatus 116, the degassing apparatus 116 being fluidly interposed between the formulation preparation apparatus 112 and the filling station 114, the degassing apparatus 116 comprising at least one membrane 118 for at least partially separating at least one gas from the liquid formulation.

Description

[Technical field]

[0001] The present invention relates to a pharmaceutical formulation filling apparatus, a method for filling at least one formulation into a container, a method for improving the accuracy of the filling weight of a liquid formulation in a container, a method for improving the stability of at least one oxygen-sensitive active pharmaceutical ingredient in a liquid formulation, and a method for reducing polysorbate aggregate formation in a liquid formulation. The apparatus and method of the present invention can be used, by way of example, for filling liquid pharmaceutical or pharmaceutical products into containers such as in vials, syringes, or ampoules. However, other fields of application that include a step of bottling a liquid and further require the removal of one or several gases from the liquid to be bottled are also feasible. [Background technology]

[0002] Liquid solutions may contain gases in a dissolved state or as bubbles or microbubbles. In many fields dealing with liquids, the removal of gases from liquids is a common problem, since the presence of bubbles can interfere with certain processes or requirements, for example in quality control, where vials can be erroneously rejected because bubbles are mistaken for particles during visual inspection. Different devices and methods are commonly used to remove or reduce the amount of gas in a solution. Thus, for example to produce high purity purified water for pharmaceutical use, different methods and devices are used to reduce the amount of CO2 dissolved in water, including the use of chemicals such as NaOH, which can convert CO2 into carbonates that can then be removed, for example by reverse osmosis. To address the problem of removing one or several gases from a liquid solution, membrane-based modules such as LiquiCel® membrane contactors may be used. Membrane-based methods and devices for the removal of gases from liquids are a commonly used solution in a wide range of fields, for example in the field of water treatment, chromatography, the beverage industry, the coating and paint industry, and in the production of high purity purified water for pharmaceutical use.

[0003] Pharmaceutical or pharmaceutical products must also comply with numerous safety regulations. Thus, the presence of particles in liquid formulations must usually be prevented to reduce potential risks to users of such products. Therefore, vials filled with such products are usually periodically visually inspected for the presence of particles using fully automated or semi-automated systems, since the presence of particles may constitute a risk to potential future users. In general, said systems often cannot distinguish between particles and bubbles. Thus, the presence of bubbles in a formulation filled in a container may lead to incorrect sorting of the container, since bubbles may easily be mistaken for particles that may constitute a potential danger to future users.

[0004] The pharmaceutical filling apparatus and methods known in the art for filling at least one pharmaceutical formulation into a container usually include a degassing step of the bulk solution of the pharmaceutical formulation, which usually relies on the application of a vacuum. Despite the advantages of the methods and apparatuses known in the art, there remain many challenges that must be addressed. Thus, after the degassing step, the bulk solution is usually transferred to the filling apparatus by using nitrogen gas, which usually results in a new input of gas, such as nitrogen. However, the gas content in the liquid formulation may lead to a low accuracy of the filling weight of the liquid formulation contained in a container, such as a syringe or a vial. Furthermore, the apparatus and methods known in the art are often incomplete and ineffective. Moreover, they are usually time-consuming, since they generally constitute a separate, non-continuous step that is performed in addition to the filling process. Moreover, the static degassing of the bulk solution usually does not completely remove the dissolved gas present in the solution. Summary of the Invention [Problem to be solved by the invention]

[0005] It is therefore an object of the present invention to provide a formulation filling apparatus, a method for filling at least one formulation into a container, and a method for improving the accuracy of the fill weight of a liquid formulation in a container, which at least partially avoid the drawbacks and disadvantages of known methods and apparatuses of a similar type known in the art. In particular, it is desirable to improve the yield of containers filled with a liquid formulation. [Means for solving the problem]

[0006] This problem is solved by a method for filling at least one formulation into a container, a formulation filling device, a method for improving the accuracy of the filling weight of a liquid formulation in a container, a method for improving the stability of at least one oxygen-sensitive active pharmaceutical ingredient in a liquid formulation, and a method for reducing polysorbate aggregate formation in a liquid formulation, with the features of the independent claims. Advantageous embodiments, which can be realized alone or in any combination, are recited in the dependent claims.

[0007] As used below, the words "have", "comprise" or "include" or any grammatical variation of any of them are used non-exclusively. Thus, these words can describe both the absence of further features in the entity described in this context, as well as the presence of one or more further features, in addition to the features introduced by these words. As an example, "A has B", "A comprises B" and "A includes B" can describe both the absence of other elements in A besides B (i.e., the situation where A consists solely and exclusively of B), and the presence of one or more further elements in entity A besides B, such as element C, elements C and D, or further elements.

[0008] It should further be noted that the words "at least one," "one or more," or similar expressions indicating that a feature or element may be present once or more than once, are typically used only once when introducing each feature or element. In the following, in most cases, when referring to each feature or element, the words "at least one" or "one or more" will not be repeated, notwithstanding that each feature or element may be present once or more than once.

[0009] Furthermore, as used below, the terms "preferably", "more preferably", "particularly", "more particularly", "specifically", "more specifically", or similar terms are used with any feature without limiting alternative possibilities. Thus, features introduced by these terms are optional features and are not intended to limit the scope of the claims in any way. The invention is to be carried out by using alternative features, as will be recognized by those skilled in the art. Similarly, features introduced by "in an embodiment of the invention" or similar expressions are intended to be optional features, without any limitations regarding alternative embodiments of the invention, without any limitations regarding the scope of the invention, and without any limitations regarding the possibility of combining the features introduced in such a way with other optional or non-optional features of the invention.

[0010] In a first aspect of the present invention, a formulation filling apparatus for filling at least one formulation into a container is disclosed. The formulation filling apparatus comprises at least one formulation preparation apparatus, the formulation preparation apparatus configured to prepare and / or store a liquid formulation. The formulation filling apparatus further comprises at least one filling station for filling the liquid formulation into the container, the filling station being fluidly connected to the formulation preparation apparatus. The formulation filling apparatus further comprises at least one degassing apparatus, the degassing apparatus being fluidly interposed between the formulation preparation apparatus and the filling station, the degassing apparatus comprising at least one membrane for at least partially separating at least one gas from the liquid formulation.

[0011] The term "drug product" as used herein is a broad term and is to be given its ordinary and customary meaning to those skilled in the art, and is not to be limited to any special or customized meaning. The term may specifically refer, without limitation, to a solution, liquid, or suspension that can be used as a drug, or that can be used or prepared in the process of making a drug or drug product, or that can be used or prepared as an intermediate stage, precursor, or compound of a drug or drug product. Thus, the drug product may be used, for example, as part of or in connection with the treatment, prevention, prophylaxis, or diagnostic analysis of a disease. The drug product may specifically include at least one gas, such as at least one gas dissolved in the solution, liquid, or suspension of the drug product.

[0012] The term "filling device" as used herein is a broad term and is to be given its ordinary and customary meaning to one of ordinary skill in the art and is not to be limited to any special or customized meaning. The term may specifically refer, without limitation, to a device configured to dispense, expel, or direct any solution, liquid, or suspension into a receptacle or container.

[0013] The term "container" as used herein is a broad term and is to be given its ordinary and customary meaning to one of ordinary skill in the art, and is not to be limited to any special or customized meaning. The term may specifically refer, without limitation, to any container or receptacle configured to hold at least one liquid, such as, for example, a vial, particularly a glass vial, a syringe, or an ampoule.

[0014] The term "drug product preparation device" as used herein is a broad term and is to be given its ordinary and customary meaning to those skilled in the art, and is not to be limited to any special or customized meaning. The term may specifically refer to, without limitation, a device configured for use in the process of making, manufacturing, processing, or storing a drug product. By way of example, the drug product preparation device may comprise at least one of a mixing vessel, a reactor, an agitator or stirrer, a storage vessel, a tank, a transport vessel, such as a drug product transport vessel, and / or any other device suitable for use in the context of drug product preparation, drug product storage, and / or drug product transport.

[0015] The term "filling station" as used herein is a broad term and is to be given its ordinary and customary meaning to those skilled in the art, and is not to be limited to a special or customized meaning. The term may specifically refer, without limitation, to an apparatus that may be part of a filling device as defined above and that is suitable for filling at least one formulation into a container. The filling station may be or comprise at least one liquid handling device configured to fill, dispense or meter the formulation into the container. Thus, by way of example, the filling station may comprise at least one of a dispenser, a nozzle, a valve, etc. The filling station may further comprise at least one filling line. The filling station may be configured to fill multiple containers sequentially and / or in parallel. By way of example, the filling station may comprise N nozzles or dispensers for simultaneously filling a batch of N containers with the formulation, followed by a subsequent batch of N containers with the formulation, etc.

[0016] The term "fluidically coupled" as used herein is a broad term and is to be given its ordinary and customary meaning to those skilled in the art, and is not to be limited to any special or customized meaning. The term may specifically, without limitation, refer to a first device and a second device that are connected such that any fluid or any liquid can be moved or transferred from the first device to the second device and / or vice versa.

[0017] The term "degassing device" as used herein is a broad term and is to be given its ordinary and customary meaning to those skilled in the art, without being limited to any special or customized meaning. The term may specifically, without limitation, refer to a device configured to at least partially separate at least one gas from a liquid conducted through the degassing device. Various physical principles may be used therein to separate the gas. By way of example, the degassing device may comprise at least one degassing device based on permeation, as outlined in more detail below. However, other principles may also be used.

[0018] The term "fluidically interposed" as used herein is a broad term and is to be given its ordinary and customary meaning to those skilled in the art, and is not to be limited to any special or customized meaning. The term may specifically, without limitation, refer to a device connected to at least one first device and at least one second device such that any fluid or any liquid may be movable or transferable from the first device to the second device through the device that is fluidly interposed between the first device and the second device.

[0019] The term "membrane" as used herein is a broad term and is to be given its ordinary and customary meaning to those skilled in the art, and is not to be limited to a special or customized meaning. The term may specifically, without limitation, refer to a three-dimensional object having a dimension in a first extension direction that is less than the dimensions in the second and third extension directions of the device, such that the shape of the object may be described as a layer or sheet-like, and the layer or sheet-like object is configured to at least partially delimit or delineate a first space or compartment that bounds the object. Specifically, the layer or sheet-like object may be configured to separate the first space or compartment from a second space or compartment. Specifically, the dimension in the first extension direction may be described as the thickness of the membrane. In particular, the membrane may be configured to delimit or delineate a first space or compartment in at least one extension direction of the first space or compartment. While at least partially delimiting or delineating a first space or compartment, the membrane may also at least partially connect the first space or compartment to a second space or compartment by having selective permeability under certain conditions, which may comprise, for example, a pressure difference between the pressure in the first space or compartment and the pressure in the second space or compartment. Said conditions may further include other parameters, such as, for example, the temperature of the membrane and / or the temperature of the first space or compartment and / or the temperature of the second space or compartment, or the flow rate through the first compartment. While the membrane may be a selective permeability membrane that may allow the passage of certain molecules, such as molecules of nitrogen gas or other gases, in at least one direction, the membrane may be specifically a non-porous membrane and may prevent the mixing, in particular uncontrolled mixing, of the contents or substances in the first space or compartment with the contents or substances in the second space or compartment.

[0020] The term "at least partially separating off at least one gas from the liquid drug product" as used herein is a broad term and is to be given its ordinary and customary meaning to those skilled in the art, and is not to be limited to any special or customized meaning. The term may specifically, without limitation, refer to at least partially removing or directing at least one gas away from the liquid drug product so as to reduce the amount of gas that can be dissolved in the liquid drug product.

[0021] The degassing device comprises at least one membrane. The membrane may be a non-porous membrane. In one embodiment, the membrane may comprise at least one of the following materials: polydimethyldioxane (PDMS), cellulose acetate (CA), polysulfone (PS), polyethersulfone (PES), polyacrylonitrile (PAN), polyvinylidene fluoride (PVDF), polypropylene (PP), polyethylene (PE), polyvinyl chloride (PVC), polytetrafluoroethylene (PTFE), and silicone. In a preferred embodiment, the membrane comprises silicone. In particular, the membrane may have a thickness of 25 μm to 200 μm, preferably 25 μm to 100 μm, even more preferably 40 μm to 70 μm, and most preferably 55 μm. The term "thickness" may in particular refer to the dimension of the membrane in the direction of extension. The degassing device may in particular be configured such that the liquid formulation contacts the membrane on a first side and the opposing second side of the membrane is exposed to a lower pressure than the first side to apply a pressure difference to the membrane. Thus, the pressure difference may be the difference between the magnitude of the pressure on the first side and the magnitude of the pressure on the second side. In particular, the pressure difference on the membrane may be 0.1 bar to 3.0 bar, preferably 0.6 to 1.0 bar, more preferably 0.8 bar. Furthermore, the degassing device may comprise at least one vacuum source or vacuum port for applying a vacuum to the second side. In particular, the vacuum source may comprise at least one pump, such as a suction pump. By way of example, the pump may comprise at least one positive displacement pump, such as one or more of a rotary vane pump, a lobe pump, and the like. In particular, the absolute value of the vacuum applied to the second side may be between 0.010 bar and 0.900 bar, preferably between 0.010 bar and 0.020 bar, more preferably 0.015 bar. The term "vacuum" as used herein is a broad term and is to be given its ordinary and customary meaning to those skilled in the art, and is not to be limited to any special or customized meaning. The term may specifically refer, without limitation, to reduced pressure, low pressure, partial vacuum, or negative pressure.Thus, a space, chamber or compartment to which a vacuum is applied may have a lower pressure than another space, chamber or compartment to which a vacuum is not applied. Specifically, the formulation may have an absolute pressure in the degassing device of between 0.1 bar and 3.0 bar, preferably between 0.6 bar and 1.0 bar, more preferably 0.8 bar.

[0022] In particular, the degassing device may comprise at least one hollow fiber membrane module comprising a plurality of hollow fibers formed at least in part by membranes. The term "hollow fiber" as used herein is a broad term and is to be given its ordinary and customary meaning to those skilled in the art, and is not to be limited to any special or customized meaning. The term may specifically refer, without limitation, to a tube, tubule, or capillary that at least partially defines or comprises an interior space or lumen. In particular, the interior space or lumen of a hollow fiber may also be referred to as the interior of the hollow fiber. In particular, the hollow fiber may have an inner diameter and an outer diameter, with the inner diameter having a value of 50 μm to 800 μm, preferably a value of 150 μm to 250 μm, and more preferably a value of 190 μm, and the outer diameter having a value of 75 μm to 900 μm, preferably a value of 150 μm to 450 μm, and more preferably a value of 300 μm. In particular, the membrane thickness may be 55 μm, the hollow fiber inner diameter may be 190 μm, and the hollow fiber outer diameter may be 300 μm. Furthermore, the plurality of hollow fibers of the hollow fiber membrane module may comprise from 30 hollow fibers to 30,000 hollow fibers.

[0023] The number of hollow fibers of a hollow fiber membrane module may depend in particular on the size of the hollow fiber membrane module, in particular on the total membrane area, i.e. on the sum of the membrane areas of all hollow fibers in the hollow fiber membrane module and / or on the cross-sectional area of ​​the hollow fiber membrane module, which may be perpendicular to the main direction of extension, in particular to the length, of the hollow fiber membrane module.

[0024] For example, the fiber count per unit membrane area is 1.0 to 4.0 fibers / cm 2 , for example 1~3fibers / cm 2 , preferably 1 to 1.5 fibers / cm 2 , and more preferably 1.26 to 1.42 fibers / cm 2 Additionally or alternatively, the number of hollow fibers per unit of cross-sectional area of ​​the hollow fiber membrane module, specifically, the fiber count, may be in the range of 40 cm -2 ~500cm -2 , for example 42cm -2 ~483cm -2 20cm etc. -2 ~800cm -2 It could be.

[0025] Furthermore, the length of the hollow fibers may also depend on the size of the hollow fiber membrane module, specifically, the length of the hollow fiber membrane module. The hollow fibers may have a length of 10 cm to 16 cm. In particular, the degasser may be or comprise a PermSelect® silicone membrane module available from MedArray, Inc. (Ann Arbor, Michigan, 48108, USA), such as hollow fiber membrane module PDMSXA-2500 and / or hollow fiber membrane module PSMSXA-1.0.

[0026] By way of example, hollow fiber membrane modules available from MedArray, Inc. (Ann Arbor, Michigan, USA, 48108) may be used. A summary of exemplary embodiments of membrane modules available from this supplier and their characteristics are shown in Table 1.

[0027] [Table 1]

[0028] The hollow fibers may specifically form a fiber bundle. The term "fiber bundle" as used herein is a broad term and is to be given its ordinary and customary meaning to those skilled in the art, and is not limited to any special or customized meaning. The term may specifically, without limitation, refer to, for example, a plurality of fibers combined or held together to achieve a common alignment and / or orientation of the fibers. In particular, the fiber bundle may be embedded in a seal at both ends. Furthermore, the ends of the fiber bundle may be connected to a connection port. The term "connection port" as used herein is a broad term and is to be given its ordinary and customary meaning to those skilled in the art, and is not limited to any special or customized meaning. The term may specifically, without limitation, refer to any device configured to hold or receive at least one end of at least one fiber bundle for directly or indirectly joining, associating, or connecting the end of the fiber bundle to a further element or component. The hollow fiber membrane module may further comprise at least one housing having hollow fibers disposed therein. Additionally, the hollow fiber membrane module may comprise at least one fiber inlet port connected to a first end of the hollow fibers, at least one fiber outlet port connected to a second end of the hollow fibers, and at least one housing inlet port and at least one housing outlet port, both of which are connected to at least one interior space within the housing between the hollow fibers and the wall of the housing.

[0029] The term "fiber entry port" as used herein is a broad term and shall be given its ordinary and customary meaning to those skilled in the art, and shall not be limited to any special or customized meaning. The term may specifically, without limitation, refer to any device configured to hold or receive a first end of a fiber bundle for directly or indirectly joining, relating or connecting the first end of the fiber bundle to a further element or component, such as a preparation device, so that a fluid, particularly a gas or liquid, may be introduced into the fibers through the fiber entry port. In particular, when the fluid is a gas, the fiber entry port may also be used as a fiber exit port. Thus, as further described below, a vacuum may be applied to the interior of the hollow fibers by connecting one or both of the fiber entry port and the fiber exit port to a suction device. The term "fiber exit port" as used herein is a broad term and shall be given its ordinary and customary meaning to those skilled in the art, and shall not be limited to any special or customized meaning. The term may specifically, without limitation, denote any device configured to hold or receive a second end of a fiber bundle for directly or indirectly joining, relating or connecting the first end of the fiber bundle to a further element or component, e.g. a filling station, so that a fluid, in particular a gas or liquid, contained within the hollow fibers of the fiber bundle can be conveyed out of the hollow fibers via the fiber outlet port. In particular, a connection port connected to one end of the fiber bundle can be realized as a fiber inlet port and a connection port at the other end of the fiber bundle can be realized as a fiber outlet port. Furthermore, the fiber inlet port and / or the fiber outlet port can also be used as a vacuum port.

[0030] The term "housing entry port" as used herein is a broad term and shall be given its ordinary and customary meaning to those skilled in the art, and shall not be limited to a special or customized meaning. The term may specifically, without limitation, refer to any device configured to directly or indirectly join, associate, or connect the interior space of the housing to a further element or component, such as a preparation device, such that a fluid, particularly a gas or liquid, may be introduced into the interior space of the housing through the fiber entry port. In particular, when the fluid is a gas, the housing entry port may also be used as a housing exit port. Furthermore, the housing entry port and / or the housing exit port may also be used as a vacuum port. Thus, as further described below, a vacuum may be applied to the interior space by connecting one or both of the housing entry port and the housing exit port to a suction device. The term "housing exit port" as used herein is a broad term and shall be given its ordinary and customary meaning to those skilled in the art, and shall not be limited to a special or customized meaning. The term specifically refers, without limitation, to an internal space of the housing such that a fluid, particularly a gas or liquid, contained within the internal space of the housing can be conveyed out of the internal space of the housing through the housing outlet port. Wow The term may refer to any device configured to join, associate, or couple, directly or indirectly, to an element or component comprising, for example, a filling station.

[0031] The hollow fiber membrane module is i) the fiber inlet port may be fluidly connected, directly or indirectly, to a formulation preparation device and the fiber outlet port may be fluidly connected, directly or indirectly, to a filling station; or ii) the housing inlet port may be fluidly connected, directly or indirectly, to a dosage form preparation device, and the housing outlet port may be fluidly connected, directly or indirectly, to a filling station; The filling station may be fluidly interposed between the formulation preparation device (e.g., the dispensing area) and the filling station in a manner selected from the group consisting of:

[0032] In particular, option i) is selected and one or both of the housing inlet port and the housing outlet port can be connected to a suction device, such as, for example, a vacuum pump, specifically for applying a vacuum to the interior space of the housing. Furthermore, option ii) is selected and one or both of the fiber inlet port and the fiber outlet port can be connected to a suction device, specifically for applying a vacuum to the interior of the hollow fibers.

[0033] The pharmaceutical formulation filling apparatus includes at least one membrane. Specifically, the membrane may include at least one material selected from the group consisting of polydimethyldioxane (PDMS), cellulose acetate (CA), polysulfone (PS), polyethersulfone (PES), polyacrylonitrile (PAN), polyvinylidene fluoride (PVDF), polypropylene (PP), polyethylene (PE), polyvinyl chloride (PVC), polytetrafluoroethylene (PTFE), and silicone, but preferably, the membrane includes silicone. Furthermore, the degassing device may have at least one inlet port connected to the pharmaceutical formulation preparation apparatus and at least one outlet port connected to the filling station. Furthermore, the degassing device may be interposed, specifically, fluidly interposed, between the pharmaceutical formulation preparation apparatus and the filling station in an in-line manner. Thus, degassing of the liquid formulation may be performed as a step in a series of consecutively executable steps in the process of filling the liquid formulation into the container. The pharmaceutical formulation filling apparatus may further include at least one in-line filtering device fluidly interposed between the pharmaceutical formulation preparation apparatus and the filling station. In particular, the in-line filtering device may comprise a sterile filter. The in-line filtering device may further comprise a pre-filter, in particular a pre-filter for reducing bioburden. Furthermore, the degassing device may be at least partially sterilizable. In particular, the degassing device may be at least partially sterilizable by at least one of the following means: gamma radiation; beta radiation; steam; autoclaving; sterilization in place, sometimes abbreviated as SIP. In particular, the membrane of the degassing device may be sterilizable. Furthermore, at least one of the following elements that may form part of the degassing device may be sterilizable: hollow fibers, sealing, connection ports, housing, fiber inlet ports, fiber outlet ports, housing inlet ports, housing outlet ports. Preferably, all the elements of the degassing device may be sterilizable. Furthermore, the sterilization step of the above elements may be carried out in particular as sterilization in place. Thus, the areas in contact with the formulation may be sterilizable without substantial dismantling of the formulation preparation device.The formulation filling apparatus may further comprise at least one transfer system configured to transfer the formulation from the formulation preparation apparatus to the filling station. The at least one transfer system may be or comprise at least one pressure transfer system having at least one gas source, the pressure transfer system configured to transfer the formulation from the formulation preparation apparatus to the filling station by pressure. In particular, the gas source may provide nitrogen. Additionally or alternatively, the at least one transfer system may be or comprise at least one pump. Furthermore, the pressure for transferring the formulation from the formulation preparation apparatus to the filling station may be between 0.8 bar and 1.0 bar. This pressure may in particular be an absolute pressure.

[0034] The pharmaceutical filling machine comprises at least one filling station. The filling station, in particular the filling line, may in particular comprise at least one inspection device for optically inspecting the containers after filling with the liquid formulation. The filling station, in particular the filling line, may further comprise at least one selection device with at least one controller for automatically identifying defective containers and for automatically removing defective containers. In particular, the inspection device may comprise at least one camera and at least one image recognition device. Furthermore, the filling station, in particular the filling line, may further comprise at least one closing station for closing the containers, for example by means of at least one stopper. The closing station may further comprise at least one crimping station for fixing the stopper, for example by means of crimping. Additionally or alternatively, other devices for closing the containers may be used and applied to the containers, in particular by means of the closing station, such as caps, in particular that may comprise or be formed of plastic and / or aluminum, for example Plascap® manufactured by Daikyo Seiko. Furthermore, the closing station may in particular comprise a sealing station, for example for sealing ampoules.

[0035] The formulation filling apparatus comprises at least one formulation preparation device. The formulation preparation device may be configured to prepare a liquid formulation from at least two components. The formulation preparation device may specifically comprise at least one mixing container for mixing at least two components of the formulation. The mixing container may comprise at least one stirring device for stirring the formulation. The formulation preparation device may further comprise at least one storage container that may be fluidly connected to the filling station. The storage container may specifically comprise at least one temperature adjustment device for either or both cooling or heating the formulation. The storage container may specifically comprise at least one gas source for supplying at least one shielding gas into the storage container and for storing the formulation under the shielding gas. In particular, the gas source may comprise at least one nitrogen source.

[0036] The at least one formulation filled into the container by the formulation filling device may have a viscosity of 0.2 mPa·s to 30 mPa·s, preferably 1 mPa·s to 20 mPa·s, more preferably 1 mPa·s to 5 mPa·s, and most preferably 1 mPa·s to 1.5 mPa·s. The at least one membrane of the formulation filling device may have a contact area for contacting the formulation, the size of the contact area being 10 cm 2 ~5m 2 , preferably 0.5m 2 ~1.5m 2 and more preferably the size of the contact area is 1 m 2 The formulation filling apparatus may be configured to direct the formulation through the degassing device at a rate of 5 L / h to 150 L / h, preferably 60 L / h to 100 L / h, more preferably 70 L / h to 90 L / h. In particular, the formulation may have a temperature of 0°C to 25°C, preferably 0 to 8°C or 15 to 25°C, more preferably 2 to 8°C or 18 to 24°C.

[0037] By way of example, for the exemplary embodiment of the hollow fiber membrane module in Table 1 above, the following flow rates shown in Table 2 may be used:

[0038] [Table 2]

[0039] The formulation filling apparatus may further comprise a coupling bow having at least one first coupling access and at least one second coupling access, wherein the degassing apparatus is fluidly connectable to the formulation preparation apparatus via the first coupling access and the degassing apparatus is fluidly connectable to the filling station via the second coupling access. In particular, the degassing apparatus may be fluidly connectable to the formulation preparation apparatus directly or indirectly via the first coupling access and the degassing apparatus may be fluidly connectable to the filling station directly or indirectly via the second coupling access. In case of a direct fluid connection between the degassing apparatus and the first coupling access and / or the second coupling access, the degassing apparatus may be directly attached to the first coupling access and / or the second coupling access, respectively. In case of an indirect fluid connection between the degassing apparatus and the first coupling access and / or the second coupling access, the degassing apparatus may be attached to the first coupling access and / or the second coupling access, respectively, via at least one further element, such as a tube, a hose or a pipe. The term "fluidically connectable" as used herein is a broad term and is to be given its ordinary and customary meaning to those skilled in the art, and is not to be limited to a special or customized meaning. The term may specifically refer, without limitation, to a first device and a second device that are capable of connecting the first device and the second device in such a way that any fluid or any liquid may be movable or transportable from the first device to the second device and / or vice versa. Within the scope of the present invention, the terms "fluidically connected" and "fluidically coupled" may be used interchangeably.

[0040] The coupling bow may further comprise at least one holder for mounting the degassing device. Additionally or alternatively, the formulation filling apparatus, in particular the formulation preparation apparatus and / or the filling station, may comprise a holder for mounting the degassing device. In particular, the holder may be configured to removably receive the degassing device.

[0041] In a second aspect of the present invention, a method for filling at least one formulation into a container is disclosed. The method comprises the steps disclosed below. The steps can be specifically carried out in a given order. However, different orders are also possible. The method can comprise additional steps not mentioned. Furthermore, it is also possible to repeatedly carry out one or more of the method steps. Furthermore, two or more of the method steps can be carried out in a time-overlapping manner or simultaneously.

[0042] The method comprises the following steps: A) providing at least one formulation filling device configured to fill at least one liquid formulation into a container, the method comprising: providing at least one formulation preparation device configured to prepare a liquid formulation; providing at least one filling station for filling a liquid formulation into a container, the at least one filling station being fluidly connected to the formulation preparation device; Providing at least one degassing device fluidly interposed between the formulation preparation device and the filling station, the at least one degassing device comprising at least one membrane for separating at least one gas from the liquid formulation. The steps include: B) directing the formulation from the formulation preparation device to a filling station, the formulation being at least partially degassed as it passes through the degassing device; and C) filling the at least partially degassed formulation into a container by a filling station. Includes.

[0043] In particular, step B) of the method comprises: applying a pressure differential across the membrane using a degassing device such that the liquid formulation contacts the membrane on a first side and an opposing second side of the membrane is exposed to a lower pressure than the first side; It may further include.

[0044] In particular, the degasser provided in method step A) may be configured to apply a pressure difference to the membrane by comprising at least one vacuum source or vacuum port for applying a vacuum to the second side. The degasser may further comprise at least one hollow fiber membrane module comprising a plurality of hollow fibers, the hollow fibers being at least partially formed by the membrane. The hollow fibers may form a fiber bundle.

[0045] Furthermore, step B) specifically includes: directing the formulation from the formulation preparation device to a filling station, at least in part, by using at least one of a transport gas stream and a pump; may include.

[0046] In particular, the transport gas may be nitrogen. For the description of possible embodiments and the definition of the apparatus used in the method, reference may be made to the embodiments, definitions and descriptions as described above or further below. In particular, the drug product filling apparatus provided in method step A) may be a drug product filling apparatus as described above or further below. Nevertheless, other embodiments are also feasible.

[0047] The method may include improving the accuracy of the fill weight of a liquid formulation in a container. Improving the accuracy of the fill weight of a liquid product in a container may include preparing at least one liquid formulation, degassing the liquid formulation by at least partially separating at least one gas from the liquid formulation by using a degassing device, the degassing device comprising at least one membrane, and filling the degassed liquid formulation into the container.

[0048] The method may further include improving the stability of at least one oxygen-sensitive active pharmaceutical ingredient in the liquid formulation. Improving the stability of the oxygen-sensitive active pharmaceutical ingredient in the liquid formulation may include preparing at least one liquid formulation comprising at least one oxygen-sensitive active pharmaceutical ingredient. Furthermore, improving the stability of the oxygen-sensitive active pharmaceutical ingredient in the liquid formulation may include degassing the liquid formulation by partially separating at least one gas from the liquid formulation by using a degassing device, the degassing device comprising a membrane.

[0049] The method may further comprise the step of reducing polysorbate aggregate formation in the liquid formulation. The reduction of polysorbate aggregate formation in the liquid formulation may comprise the step of preparing at least one liquid formulation, the liquid formulation comprising at least one oxygen-sensitive active pharmaceutical ingredient, specifically a protein, and at least one polysorbate. Furthermore, the reduction of polysorbate aggregate formation in the liquid formulation may comprise the step of degassing the liquid formulation by at least partially separating at least one gas from the liquid formulation by using a degassing device, the degassing device comprising a membrane.

[0050] In a third aspect of the present invention, a method for improving the accuracy of the filling weight of a liquid formulation in a container is disclosed. The method includes the steps disclosed below. The steps can be specifically performed in a given order. However, different orders are also possible. The method can include additional steps not mentioned. Furthermore, it is also possible to repeatedly perform one or more of the method steps. Furthermore, two or more of the method steps can be performed in a time-overlapping manner or simultaneously.

[0051] The method comprises the following steps: I. Preparing at least one liquid formulation; II. Degassing the liquid formulation by at least partially separating at least one gas from the liquid formulation by using a degasser, the degasser comprising at least one membrane; III. Filling the degassed liquid formulation into a container Includes.

[0052] For possible definitions of most of the terms used herein, reference may be made to the disclosure of the formulation filling apparatus or method for filling at least one formulation into a container as disclosed above or in more detail below.

[0053] The term "increasing" as used herein is a broad term and is to be given its ordinary and customary meaning to one of ordinary skill in the art, and is not to be limited to a special or customized meaning. The term may specifically, without limitation, denote that a characteristic number or value characterizing a particular property of an object or process is greater when using the described method compared to using another method.

[0054] Thus, to quantify the accuracy of the fill weight, the nominal fill weight of the liquid formulation in the container is compared to the actual fill weight, which may generate information about the deviation, such as generating a standard deviation. The lower the deviation, the higher the accuracy of the fill weight may be. By comparing the deviation of a liquid formulation filled by using the method according to the present invention with that filled into a container by using a conventional method, in particular a method that does not include the method step II. of degassing the liquid formulation, a reduction in the deviation and thus an improvement in the fill weight may be identified, in particular when the methods are identical except for the degassing step.

[0055] The method of improving the accuracy of the fill weight of a liquid formulation in a container may specifically include using a degassing device and / or a formulation filling device as described above and / or further below.

[0056] [Table 3]

[0057] Table 3 displays exemplary characteristic properties of containers filled with a liquid formulation by a conventional pharmaceutical filling machine or by an exemplary embodiment of a pharmaceutical filling machine according to the invention comprising a PDMSXA-1.0 hollow fiber membrane module by MedArray, Inc. For each condition displayed by the rows of Table 3, at least 2900 containers were filled with a liquid formulation. The displayed data has been generated by first using a conventional pharmaceutical filling machine and then modifying the conventional pharmaceutical filling machine by implementing modifications such as the use of a degassing device to generate a pharmaceutical filling machine according to the invention. Parameter set 1 and parameter set 2 correspond to parameters used for the conventional pharmaceutical filling machine. Since the data is acquired continuously in time, a significant amount of one or more gases may still be present in the pharmaceutical filling machine during the measurements displayed as parameter set 1, for example. The degassing effect thus increases over time as visible during the measurements of parameter set 2, for example, compared to parameter set 1. Modifications to the drug product filling equipment for parameter set 3, including slowing down the squeezer of the drug product preparation equipment dosing tube, may contribute to further improving the fill weight accuracy and further decreasing the number of containers rejected due to particle detection. Modifications to the drug product filling equipment for parameter set 4, including using tubing with a diameter of 3 mm instead of 5 mm and increasing the ventilation cycle, may further improve the fill weight accuracy while slightly increasing the number of containers rejected due to particle detection and the number of containers rejected due to bubble detection. The standard deviation may be referred to as σ in Table 3.

[0058] In a fourth aspect of the present invention, a method for improving the stability of at least one oxygen-sensitive active pharmaceutical ingredient in a liquid formulation, particularly in a liquid formulation in a container, is disclosed. In particular, the oxygen-sensitive active pharmaceutical ingredient moiety can be or include a protein. The method includes the steps disclosed below. The steps can be specifically performed in a given order. Nevertheless, a different order is also possible. The method can include additional steps not mentioned. Furthermore, it is also possible to repeatedly perform one or more of the method steps. Furthermore, two or more of the method steps can be performed in a time-overlapping manner or simultaneously.

[0059] The method comprises the following steps: a. Preparing at least one liquid formulation comprising at least one oxygen-sensitive pharmaceutical active moiety; and β. Degassing the liquid formulation by at least partially separating at least one gas from the liquid formulation by using a degasser, the degasser comprising at least one membrane. Includes.

[0060] For possible definitions of most of the terms used herein, reference may be made to the disclosure of the formulation filling apparatus or method for filling at least one formulation into a container as disclosed above or in more detail below.

[0061] The term "liquid drug product" used in the context of the method for improving the stability of an oxygen-sensitive active pharmaceutical ingredient may specifically refer to a liquid product that includes a formulation and a solvent. The formulation contained in the liquid formulation may be an oxygen-sensitive active pharmaceutical ingredient, such as at least one protein, or an active pharmaceutical ingredient that includes at least one protein, or may include at least one oxygen-sensitive active pharmaceutical ingredient, specifically at least one protein. However, the liquid formulation may also include a protein for other purposes, for example as a stabilizer or carrier of the formulation. The method for improving the stability of at least one oxygen-sensitive active pharmaceutical ingredient in the liquid formulation may particularly include a step of improving the stability of a protein that the liquid formulation may include for the purpose of stabilizing or carrying the formulation. The method for improving the stability of at least one oxygen-sensitive active pharmaceutical ingredient in the liquid formulation may also include a step of improving the stability of a protein that the liquid formulation may include for other purposes.

[0062] The term "oxygen-sensitive active pharmaceutical ingredient" as used herein is a broad term and is to be given its ordinary and customary meaning to those skilled in the art, and is not to be limited to any special or customized meaning. The term may specifically refer, without limitation, to an ingredient that may form part of a formulation and contribute to the proper functioning of the formulation, for example, by mediating the medical effect of the formulation, by contributing to the medical effect of the formulation, or by mediating a contribution to the quality of the formulation that supports its proper functioning, such as the stability or shelf life of the formulation. An active pharmaceutical ingredient is specifically susceptible to oxidation, which may change its chemical nature, its chemical structure, or one or more of its chemical, physical, or biological properties. Additionally or alternatively, an active pharmaceutical ingredient may be oxygen sensitive in the sense that one or more of the chemical, physical, or biological properties or characteristics of the active pharmaceutical ingredient are affected by the presence of oxygen.

[0063] The term "stability of an oxygen-sensitive active pharmaceutical ingredient" as used herein is a broad term and is to be given its ordinary and customary meaning to those skilled in the art, and is not to be limited to any special or customized meaning. The term may specifically, without limitation, refer to the ability of an oxygen-sensitive active pharmaceutical ingredient, such as a protein, to maintain its structural and / or functional integrity.

[0064] The structural integrity of oxygen-sensitive active pharmaceutical ingredients such as proteins can be affected by degradation processes, i.e. oxygen-sensitive active pharmaceutical ingredients, particularly proteins, can be degraded in whole or in part. Such degraded oxygen-sensitive active pharmaceutical ingredients, particularly proteins, are usually characterized by a disturbance in the primary structure, for example accompanied by a lower molecular weight. Furthermore, degradation products, such as shorter proteins or peptides, can usually be generated as degradation products.

[0065] The structural integrity of oxygen-sensitive active pharmaceutical ingredients, particularly proteins, can be determined by various suitable methods well known to those skilled in the art.Usually, structural integrity can be determined by analyzing at least one oxygen-sensitive active pharmaceutical ingredient, particularly at least one protein, or a liquid formulation containing a sample thereof, by spectroscopic methods such as mass spectrometry (MS) or NMR spectroscopy.Furthermore, protein separation methods such as gel electrophoresis, such as polyacrylamide gel electrophoresis (PAGE), or chromatography, such as size exclusion or molecular sieve chromatography, can be applied.

[0066] Besides or in addition to structural integrity, the functional integrity of oxygen-sensitive active pharmaceutical ingredients, especially proteins, may also be affected. Thus, oxygen-sensitive active pharmaceutical ingredients, especially proteins, with impaired functional integrity cannot express their normal biological functions. Functional integrity may also be affected by degradation processes, i.e., the degradation of oxygen-sensitive active pharmaceutical ingredients, especially proteins, usually further leads to the loss of their function. Furthermore, functional integrity as meant herein also encompasses other causes that lead to impaired function of oxygen-sensitive active pharmaceutical ingredients, especially proteins, such as impaired folding and impaired post-translational modifications, such as impaired glycosylation, phosphorylation, or myristylation. Usually, the quaternary, tertiary, and / or secondary structure of oxygen-sensitive active pharmaceutical ingredients, especially proteins, may be impaired in such cases.

[0067] There are also various suitable methods well known to those skilled in the art for determining the functional integrity of oxygen-sensitive active pharmaceutical ingredients, particularly proteins. It will be understood that the suitable method in this sense depends on the nature of the oxygen-sensitive active pharmaceutical ingredient, particularly proteins. In the case of enzymes, for example, a suitable method for determining functional integrity can be an assay that measures enzyme activity. In the case of growth factors, cytokines, or other stimulants, a suitable method can be an assay that measures the ability of a compound to stimulate or prevent a biological response. Furthermore, the immunological properties of oxygen-sensitive active pharmaceutical ingredients, particularly proteins, can also be determined by immunological methods such as antibody binding assays or affinity chromatography.

[0068] Under "increasing the stability of at least one oxygen-sensitive active pharmaceutical ingredient" it is understood that the structural and / or functional integrity of the oxygen-sensitive active pharmaceutical ingredient, in particular a protein, is maintained over an extended period of time and / or under conditions that are less favorable for the stability of the oxygen-sensitive active pharmaceutical ingredient, in particular a protein, as compared to a standard, such as, for example, heat, acidic or basic pH, or oxidizing or reducing conditions.

[0069] The improvement in the stability of oxygen-sensitive active pharmaceutical ingredients, such as proteins, by applying the method of the present invention presented herein can be determined by comparing the stability of the oxygen-sensitive active pharmaceutical ingredient, particularly proteins, in a sample of a liquid formulation treated by the method of the present invention, i.e. the structural and / or functional integrity of the oxygen-sensitive active pharmaceutical ingredient, particularly proteins, with the stability of the oxygen-sensitive active pharmaceutical ingredient, particularly proteins, in a control liquid formulation, e.g. a sample of a liquid formulation not treated by the method of the present invention. A successful treatment will be accompanied by an improvement in the stability of the oxygen-sensitive active pharmaceutical ingredient, particularly proteins, in the treated sample relative to the control sample. Typically, such a comparison of stability determinations can be performed at various times after treatment in the future, e.g. time-resolved measurements.

[0070] Thanks to the method of the present invention, the stability of oxygen-sensitive active pharmaceutical ingredients, especially proteins, in liquid formulations can be significantly improved, which can result, for example, in better storage or transport capabilities for said formulations.

[0071] Methods for improving the stability of oxygen-sensitive active pharmaceutical ingredients, particularly proteins, in liquid formulations may include using a degassing device and / or formulation filling device as described above and / or further below.

[0072] The method comprises the following steps: γ. Filling the degassed liquid formulation into at least one container It may further include.

[0073] In a fifth aspect of the present invention, a method for reducing the formation of polysorbate aggregate formation in a liquid formulation, particularly in a liquid formulation in a container, is disclosed. The method includes the steps disclosed below. The steps may be specifically performed in a given order. However, different orders are also possible. The method may include additional steps not mentioned. Furthermore, it is also possible to repeatedly perform one or more of the method steps. Furthermore, two or more of the method steps may be performed in a time-overlapping manner or simultaneously.

[0074] The method comprises the following steps: X. Preparing at least one liquid formulation, the liquid formulation comprising at least one oxygen-sensitive active pharmaceutical ingredient, particularly a protein, and at least one polysorbate; and Y. Degassing the liquid formulation by at least partially separating at least one gas from the liquid formulation by using a degasser, the degasser comprising at least one membrane. Includes.

[0075] For possible definitions of most of the terms used herein, reference may be made to the disclosure of the formulation filling apparatus or method for filling at least one formulation into a container as disclosed above or in more detail below.

[0076] The term "polysorbate" as used herein is a broad term and is to be given its ordinary and customary meaning to those skilled in the art, and is not to be limited to any special or customized meaning. The term may specifically, without limitation, refer to a group of non-ionic surfactants that are usually used as emulsifiers. Polysorbates are derived from sorbitan ethoxylates by esterification with fatty acids. Polysorbates are usually used in pharmaceutical or food preparations. Typical examples of polysorbates include, but are not limited to, polysorbate 20, polysorbate 40, polysorbate 60, and polysorbate 80.

[0077] The term "polysorbate aggregate" as used herein is a broad term and is to be given its ordinary and customary meaning to those skilled in the art, and is not to be limited to any special or customized meaning. The term may specifically, without limitation, refer to an accumulation of polysorbate molecules. The polysorbate aggregate may be detected, for example, in a solution containing polysorbate stored at room temperature.

[0078] The term "reducing the formation of polysorbate aggregate formation" as used herein is a broad term and is to be given its ordinary and customary meaning to those skilled in the art, and is not limited to any special or customized meaning. The term may specifically refer, without limitation, to the fact that the number of aggregates formed by or containing polysorbate molecules and / or the ability of polysorbate molecules to form or contribute to the formation of aggregates containing polysorbate molecules in a liquid formulation is reduced compared to a control agent after applying the method. A typical control agent in this sense may be a liquid formulation that has not been treated by the method of the present invention.

[0079] Experimental techniques for determining aggregate formation typically involve spectroscopic techniques such as optical spectroscopy and light scattering, or size exclusion chromatography.

[0080] The reduced formation of polysorbate aggregate formation by applying the methods of the invention presented herein can be determined by comparing the number of polysorbate aggregates formed in a sample of a liquid formulation treated by the methods of the invention with the number of polysorbate aggregates formed in a control liquid formulation, e.g., a sample of a liquid formulation not treated by the methods of the invention. A successful treatment will be accompanied by a reduction in aggregates in the treated sample relative to the control sample. Typically, such comparisons of polysorbate aggregate determinations can be performed at various future time points after treatment, e.g., with time-resolved measurements.

[0081] Thanks to the method of the present invention, the formation of unfavorable polysorbate aggregates in liquid formulations is significantly reduced. decrease This can result in, for example, better storage and handling capabilities for the formulation, as well as better biocompatibility.

[0082] Methods for reducing the formation of polysorbate aggregate formation in liquid formulations may include using degassing equipment and / or formulation filling equipment as described above and / or further below.

[0083] The method comprises the following steps: Z. Filling the degassed liquid formulation into at least one container It may further include.

[0084] The proposed methods and apparatus, in particular a pharmaceutical filling apparatus, a method for filling at least one formulation into a container and a method for improving the accuracy of the filling weight of a liquid formulation in a container, offer numerous advantages over known methods and apparatus of a similar type.

[0085] In particular, the proposed method and device may reduce the amount of gas dissolved or contained in the liquid formulation. The proposed method and device may thus reduce or inhibit the presence, formation or nucleation of gas bubbles in the formulation, in particular in the formulation filled in the container. Gas bubbles contained in the formulation in the container may be erroneously identified as particles, for example, by optical inspection of the container after filling the container with the liquid formulation. This may lead to erroneous identification of the filled container as defective, and thus, as rejected, for example, by a fully or partially automated inspection machine. The proposed method and device may reduce erroneous identification of the filled container as rejected due to the presence of bubbles and improve the yield by at least partially separating at least one gas from the liquid formulation. Furthermore, the proposed method and device may reduce the need, expense and / or cost of steps or measures required to identify containers filled with formulations that have been erroneously separated. Thus, the proposed method and device removes gas bubbles that may be mistaken for particles during visual inspection. or This reduction can improve the yield of containers filled with the liquid formulation.

[0086] Furthermore, the proposed method and apparatus may be less time consuming than known methods and apparatus, since the proposed method and apparatus may be performed continuously, such as in-line, as part of filling the container with the liquid formulation and not as a separate step as is common for similar types of methods and apparatus known in the art. Furthermore, the proposed method and apparatus may eliminate one or several steps, such as, for example, temporary storage of the container filled with the formulation, which may take several hours or even days before optical inspection can be performed. Thus, the proposed method and apparatus may reduce the cost, time, and / or labor involved in the process of filling the container with the liquid formulation. Thus, the efficiency of filling the container with the liquid drug may be improved.

[0087] Moreover, it may be possible that the proposed method and device may be more effective in separating at least one gas from liquid formulation than the similar type of method and device known in the art.In particular, since gas may be directly separated from liquid formulation before formulation is filled into container, it may be possible that the proposed method and device may completely or partially avoid the new transfer or release of at least one gas into liquid formulation after using the proposed device or after carrying out the proposed method.In particular, the new contact of liquid formulation with gas, for example with nitrogen gas, may be avoided.

[0088] Moreover, it may be possible that at least partially separating at least one gas from the liquid formulation may not have any effect on the concentration of the formulation, particularly on the concentration of one or some active ingredients of the liquid formulation.Alternatively, the effect that at least partially separating at least one gas from the liquid formulation may have on the concentration of the formulation, particularly on the concentration of one or some active ingredients of the liquid formulation, may be negligible.Furthermore, it may be possible that the degassing device may only contain materials approved for use in the manufacture of formulations, particularly formulations approved by the Food and Drug Administration.

[0089] Furthermore, it may be possible that the proposed method of filling at least one liquid formulation into a container, the proposed method of improving the accuracy of the filling weight of the liquid formulation in the container, and / or the proposed formulation filling device may improve the accuracy of the filling weight of the liquid formulation in the container compared to similar types of methods and devices known in the art. Evidence may be seen, for example, in the experimental data displayed in Table 3. The improved accuracy compared to similar types of conventional methods and devices may in particular be due to at least partially separating at least one gas from the liquid formulation, since the presence of gas, for example in the form of bubbles, may for example reduce the fraction of the liquid formulation contained in a given volume.

[0090] Furthermore, it may be possible that the proposed method and device may contribute to the stability of the liquid formulation, in particular to at least one active ingredient of the liquid formulation, in particular by at least partially separating at least one gas from the liquid formulation. This may be because, as suggested, for example, by Giannos et al. (Giannos SA, Kraft ER, Zhao ZY, Merkley KH, Cai J., "Formulation Stabilization and Disaggregation of Bevacizumab, Ranibizumab and Aflibercept in Dilute Solutions." Pharm Res. 2018 Feb 28;35(4):78.doi:10.1007 / sl 1095-018-2368-7), the presence of microbubbles may cause or support the formation of aggregates of molecules, in particular molecules that act as active ingredients of the formulation, such as proteins, protein fragments, antibodies, and antibody fragments. A further contribution to the stability of the liquid formulation, in particular to at least one active ingredient of the liquid formulation, in particular to proteins, may be due to the fact that degassing the liquid formulation may avoid or at least partially reduce the formation of aggregates of polysorbate that may be present in the liquid formulation.

[0091] Furthermore, it may be possible that the proposed method and apparatus may reduce the time interval required to fill any number of containers, such as a batch or lot, with a liquid formulation, in particular with a degassed liquid formulation, or to fill a certain volume of degassed formulation into a container. This may be because the proposed method and apparatus may make long degassing steps redundant, in particular degassing steps that cannot be performed in-line but must be performed as a separate, non-continuous step in addition to the filling process. Thus, the proposed method and apparatus may be less time consuming than methods and apparatus known in the art.

[0092] In summary, without excluding further possible embodiments, the following embodiments can be envisaged.

[0093] Embodiment 1: A formulation filling apparatus for filling at least one formulation into a container, comprising: a) at least one formulation preparation device configured to prepare a liquid formulation; b) at least one filling station for filling a liquid formulation into a container, the filling station being fluidly connected to the formulation preparation device; and c) at least one degassing device, the degassing device being fluidly interposed between the formulation preparation device and the filling station, the degassing device comprising at least one membrane for at least partially separating at least one gas from the liquid formulation. A pharmaceutical filling apparatus comprising:

[0094] Embodiment 2: The formulation filling apparatus of embodiment 1, wherein the membrane has a thickness of 25 μm to 200 μm, preferably 25 μm to 100 μm, more preferably 40 μm to 70 μm, and most preferably 55 μm.

[0095] Embodiment 3: The formulation filling apparatus of embodiment 1 or 2, wherein the degassing device is configured such that the liquid formulation contacts the membrane on a first side and an opposing second side of the membrane is exposed to a lower pressure than the first side to apply a pressure differential across the membrane.

[0096] Embodiment 4: A formulation filling apparatus of embodiment 3, wherein the pressure difference across the membrane is between 0.1 bar and 3.0 bar, preferably between 0.6 bar and 1.0 bar, more preferably 0.8 bar.

[0097] Embodiment 5: The pharmaceutical filling apparatus of embodiment 3 or 4, wherein the degassing device comprises at least one of a vacuum source or a vacuum port for applying a vacuum to the second side.

[0098] Embodiment 6: The formulation filling apparatus of any one of embodiments 1 to 5, wherein the formulation has an absolute pressure in the degassing apparatus of from 0.1 bar to 3.0 bar, preferably from 0.6 bar to 1.0 bar, more preferably 0.8 bar.

[0099] Embodiment 7: The pharmaceutical filling apparatus of any one of embodiments 1-6, wherein the degassing apparatus comprises at least one hollow fiber membrane module comprising a plurality of hollow fibers, the hollow fibers being at least partially formed by the membranes.

[0100] Embodiment 8: The pharmaceutical filling apparatus of embodiment 7, wherein the hollow fibers form a fiber bundle.

[0101] Embodiment 9: The pharmaceutical filling apparatus of embodiment 8, wherein the fiber bundle is embedded within the sealing at both ends.

[0102] Embodiment 10: The pharmaceutical filling apparatus of embodiment 8 or 9, wherein an end of the fiber bundle is connected to a connection port.

[0103] Embodiment 11: The pharmaceutical filling apparatus of any one of embodiments 7-10, wherein the hollow fiber membrane module comprises at least one housing, the housing having hollow fibers disposed therein.

[0104] Embodiment 12: The pharmaceutical filling apparatus of embodiment 11, wherein the hollow fiber membrane module comprises at least one fiber inlet port connected to a first end of the hollow fiber, at least one fiber outlet port connected to a second end of the hollow fiber, and at least one housing inlet port and at least one housing outlet port, both of which are connected to at least one internal space within the housing between the hollow fiber and the wall of the housing.

[0105] Embodiment 13: A hollow fiber membrane module comprising: i) the fiber inlet port is fluidly connected, directly or indirectly, to a dosage form preparation device and the fiber outlet port is fluidly connected, directly or indirectly, to a filling station; or ii) the housing inlet port is fluidly connected, directly or indirectly, to a dosage form preparation device, and the housing outlet port is fluidly connected, directly or indirectly, to a filling station. 13. The formulation filling apparatus of embodiment 12, fluidly interposed between the formulation preparation apparatus and the filling station in a manner selected from the group consisting of:

[0106] Embodiment 14: The pharmaceutical filling apparatus of embodiment 13, wherein option i) is selected and one or both of the housing inlet port and the housing outlet port are connected to a suction device, specifically a suction device for applying a vacuum to the interior space.

[0107] Embodiment 15: The formulation filling apparatus of embodiment 13 or 14, wherein option ii) is selected and one or both of the fiber inlet port and the fiber outlet port are connected to a suction device, in particular a suction device for applying a vacuum to the interior of the hollow fiber.

[0108] Embodiment 16: The pharmaceutical filling apparatus of any one of embodiments 1 to 15, wherein the membrane comprises at least one material selected from the group consisting of polydimethyldioxane (PDMS), cellulose acetate (CA), polysulfone (PS), polyethersulfone (PES), polyacrylonitrile (PAN), polyvinylidene fluoride (PVDF), polypropylene (PP), polyethylene (PE), polyvinyl chloride (PVC), polytetrafluoroethylene (PTFE), and silicone, preferably wherein the membrane comprises silicone.

[0109] Embodiment 17: The formulation filling apparatus of any one of embodiments 1-16, wherein the degassing apparatus has at least one inlet port connected to the formulation preparation apparatus and at least one outlet port connected to the filling station.

[0110] Embodiment 18: The formulation filling apparatus of any one of embodiments 1 to 17, wherein the degassing apparatus is in-line and interposed between the formulation preparation apparatus and the filling station.

[0111] Embodiment 19: The formulation filling apparatus of any one of embodiments 1-18, further comprising at least one in-line filtering device fluidly interposed between the formulation preparation apparatus and the filling station.

[0112] Embodiment 20: The pharmaceutical filling apparatus of embodiment 19, wherein the in-line filtering device comprises a sterile filter and, optionally, a pre-filter for reducing bioburden.

[0113] Embodiment 21: The pharmaceutical filling apparatus of any one of embodiments 1 to 20, wherein the degassing device is at least partially sterilizable.

[0114] Embodiment 22: The formulation filling apparatus of any one of embodiments 1 to 21, further comprising at least one transfer system configured to transfer the formulation from the formulation preparation apparatus to the filling station, the transfer system having at least one of a gas source, a pump.

[0115] Embodiment 23: The formulation filling apparatus of embodiment 22, wherein the pressure for transferring the formulation from the formulation preparation apparatus to the filling station is between 0.8 bar and 1.0 bar.

[0116] Embodiment 24: The formulation filling apparatus of any one of embodiments 1 to 23, wherein the filling station further comprises at least one inspection device for optically inspecting the container after filling with the liquid formulation.

[0117] Embodiment 25: The pharmaceutical filling apparatus of embodiment 24, wherein the filling station further comprises at least one selection device having at least one controller for automatically identifying defective containers and for automatically removing defective containers.

[0118] Embodiment 26: The pharmaceutical filling apparatus of embodiment 24 or 25, wherein the inspection device comprises at least one camera and at least one image recognition device.

[0119] Embodiment 27: A pharmaceutical filling device according to any one of embodiments 1 to 26, wherein the filling station further comprises at least one closing station for closing the container by at least one of a stopper, a cap, in particular a Plascap®, a sealing.

[0120] Embodiment 28: A pharmaceutical filling apparatus according to embodiment 27, wherein the closure station further comprises at least one crimping station for fastening at least one of a stopper, a cap, in particular a Plascap®, a seal, for example by crimping.

[0121] Embodiment 29: The formulation filling apparatus of any one of embodiments 1 to 28, wherein the formulation preparation apparatus is configured to prepare a liquid formulation from at least two components.

[0122] Embodiment 30: The formulation filling apparatus of any one of embodiments 1 to 29, wherein the formulation preparation apparatus comprises at least one mixing container for mixing at least two components of the formulation.

[0123] Embodiment 31: The formulation filling apparatus of embodiment 30, wherein the mixing vessel comprises at least one stirring device for stirring the formulation.

[0124] Embodiment 32: The formulation filling apparatus of any one of embodiments 1 to 31, wherein the formulation preparation apparatus comprises at least one of a storage container, a transport container, and the storage container and / or the transport container are fluidly connected to the filling station.

[0125] Embodiment 33: The formulation filling apparatus of embodiment 32, wherein the storage container comprises at least one temperature regulating device for one or both of cooling or heating the formulation.

[0126] Embodiment 34: The formulation filling apparatus of embodiment 32 or 33, wherein the storage container comprises at least one gas source for supplying at least one shielding gas into the storage container and for storing the formulation under the shielding gas.

[0127] Embodiment 35: The pharmaceutical filling apparatus of embodiment 34, wherein the gas source comprises at least one nitrogen source.

[0128] Embodiment 36: A formulation filling apparatus of any one of embodiments 1 to 35, wherein the formulation has a viscosity of 0.2 mPa·s to 30 mPa·s, preferably 1 mPa·s to 20 mPa·s, more preferably 1 mPa·s to 5 mPa·s, and most preferably 1 mPa·s to 1.5 mPa·s.

[0129] Embodiment 37: At least one membrane has a contact area for contacting the formulation, the size of the contact area being 10 cm 2 ~5m 2 , preferably 0.5m 2 ~1.5m 2 and more preferably the size of the contact area is 1 m 2 The formulation filling apparatus of any one of embodiments 1 to 36,

[0130] Embodiment 38: The formulation filling apparatus of any one of embodiments 1 to 37, wherein the formulation filling apparatus is configured to direct the formulation through the degassing device at a rate of between 5 L / h and 150 L / h, preferably between 60 L / h and 100 L / h, and more preferably between 70 L / h and 90 L / h.

[0131] Embodiment 39: The formulation filling apparatus of any one of embodiments 1 to 38, wherein the formulation has a temperature between 0°C and 25°C.

[0132] Embodiment 40: The pharmaceutical formulation filling apparatus of any one of embodiments 1 to 39, wherein the pharmaceutical formulation filling apparatus further comprises a coupling bow having at least one first coupling access and at least one second coupling access, and wherein the degassing apparatus is fluidly connectable to the pharmaceutical formulation preparation apparatus directly or indirectly via the first coupling access, and the degassing apparatus is fluidly connectable to the filling station directly or indirectly via the second coupling access.

[0133] Embodiment 41: The pharmaceutical filling apparatus of embodiment 40, wherein the coupling bow further comprises at least one holder for mounting a degasser.

[0134] Embodiment 42: A method of filling at least one formulation into a container, comprising the steps of: A) providing at least one formulation filling device configured to fill at least one liquid formulation into a container, the step of providing the formulation filling device comprising: providing at least one formulation preparation device configured to prepare a liquid formulation; providing at least one filling station for filling a liquid formulation into a container, the filling station being fluidly coupled to a formulation preparation device; Providing at least one degassing device fluidly interposed between the formulation preparation device and the filling station, the degassing device comprising at least one membrane for separating at least one gas from the liquid formulation. including, steps; B) directing the formulation from the formulation preparation device to a filling station, the formulation being at least partially degassed as it passes through the degassing device; and C) filling the at least partially degassed formulation into a container by a filling station. The method includes:

[0135] Embodiment 43: Step B) comprises: applying a pressure differential across the membrane using a degassing device such that the liquid formulation contacts the membrane on a first side and an opposing second side of the membrane is exposed to a lower pressure than the first side; 43. The method of embodiment 42, further comprising:

[0136] Embodiment 44: The method of embodiment 43, wherein the degassing device is configured to apply a pressure differential across the membrane by comprising at least one of a vacuum source or a vacuum port for applying a vacuum across the second membrane.

[0137] Embodiment 45: The method of any one of embodiments 42 to 44, wherein the degassing device comprises at least one hollow fiber membrane module comprising a plurality of hollow fibers, the hollow fibers being at least partially formed by the membranes.

[0138] Embodiment 46: The method of embodiment 45, wherein the hollow fibers form a fiber bundle.

[0139] Embodiment 47: Step B) Conducting the formulation from the formulation preparation device to a filling station by at least partially using a transport gas flow. The method further comprising:

[0140] Embodiment 48: The method of embodiment 47, wherein the transport gas is nitrogen.

[0141] Embodiment 49: The method of any one of embodiments 42-48, wherein the dosage form filling apparatus of any one of embodiments 1-41 is used.

[0142] Embodiment 50: The method of any one of embodiments 42-49, wherein the accuracy of the fill weight of the liquid formulation in the container is improved.

[0143] Embodiment 51: The method of any one of embodiments 42 to 50, wherein the stability of at least one oxygen-sensitive active pharmaceutical ingredient in the liquid formulation is improved.

[0144] Embodiment 52: The method of any one of embodiments 42 to 51, wherein polysorbate aggregate formation in the liquid formulation is reduced.

[0145] Embodiment 53: A method for improving the accuracy of the fill weight of a liquid formulation in a container, the method comprising: I. Preparing at least one liquid formulation; II. Degassing the liquid formulation by at least partially separating at least one gas from the liquid formulation by using a degasser, the degasser comprising at least one membrane; III. Filling the degassed liquid formulation into a container A method comprising:

[0146] Embodiment 54: The method of embodiment 53, wherein the method comprises using a degassing device as described in any one of embodiments 1 to 41.

[0147] Embodiment 55: The method of embodiment 53 or 54, wherein the method comprises using the dosage form filling device of any one of embodiments 1 to 41.

[0148] Embodiment 56: A method for improving the stability of at least one oxygen-sensitive active pharmaceutical ingredient, particularly a protein, in a liquid formulation, particularly a liquid formulation in a container, comprising: a. Preparing at least one liquid formulation, the liquid formulation comprising at least one oxygen-sensitive active pharmaceutical ingredient, in particular a protein; and β. Degassing the liquid formulation by at least partially separating at least one gas from the liquid formulation by using a degasser, the degasser comprising at least one membrane. A method comprising:

[0149] Embodiment 57: The method of embodiment 56, wherein the method comprises using a degassing device as described in any one of embodiments 1 to 41.

[0150] Embodiment 58: The method of embodiment 56 or 57, wherein the method comprises using the dosage form filling device of any one of embodiments 1 to 41.

[0151] Embodiment 59: γ. Filling the degassed liquid formulation into at least one container 59. The method of any one of embodiments 56-58, further comprising:

[0152] Embodiment 60: A method of reducing polysorbate aggregate formation in a liquid formulation, particularly in a liquid formulation in a container, the method comprising: X. Preparing at least one liquid formulation, the liquid formulation comprising at least one oxygen-sensitive active pharmaceutical ingredient, in particular a protein, and at least one polysorbate; and Y. Degassing the liquid formulation by at least partially separating at least one gas from the liquid formulation by using a degasser, the degasser comprising at least one membrane. A method comprising:

[0153] Embodiment 61: The method of embodiment 60, wherein the method comprises using a degassing device according to any one of embodiments 1 to 41.

[0154] Embodiment 62: The method of embodiment 60 or 61, wherein the method comprises using the dosage form filling device of any one of embodiments 1 to 41.

[0155] Embodiment 63: Z. Filling the degassed liquid formulation into at least one container The method of any one of embodiments 60-62, further comprising: [Brief description of the drawings]

[0156] Further optional features and embodiments shall be disclosed in more detail in the following description of the embodiments, preferably with reference to the dependent claims, in which each optional feature may be realized alone and in any possible combination, as recognized by a person skilled in the art. The scope of the present invention is not limited by the preferred embodiments. The embodiments are illustrated diagrammatically in the figures, in which identical reference symbols in these figures represent identical or functionally equivalent elements.

[0157] [Figure 1A] FIG. 1 shows a cross-sectional view of a pharmaceutical filling apparatus equipped with a coupling bow. [Figure 1B] FIG. 2 shows a cross-sectional view of the degassing device inserted into the holder of the coupling bow. [Figure 2A] 1 shows an exploded view of the degassing device. [Figure 2B] 1 shows a detailed view of the hollow fibers of the fiber bundle provided in the degassing device. [Diagram 3] 1 shows a further view of the degassing device. [Figure 4] 1 shows an experimental setup for testing the ability of the degasser to separate oxygen from liquid formulations. [Figure 5A] FIG. 2 shows a measurement diagram showing the oxygen content in the formulation as a function of time for different flow rates of the formulation. [Figure 5B] FIG. 2 shows a measurement diagram showing the oxygen content in the formulation as a function of time for different flow rates of the formulation. [Figure 5C] FIG. 2 shows a measurement diagram showing the oxygen content in the formulation as a function of time for different flow rates of the formulation. [Figure 5D] FIG. 1 shows a measurement diagram showing the oxygen separation efficiency as a function of the flow rate of the formulation. [Figure 6] 1 illustrates a method for filling a formulation into a container. [Figure 7] A method for improving the accuracy of the fill weight of a liquid formulation in a container is presented. [Figure 8] A method for improving the stability of oxygen-sensitive active pharmaceutical ingredients in liquid formulations is presented. [Figure 9]A method for reducing the formation of polysorbate aggregates in a liquid formulation is disclosed. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0158] FIG. 1A illustrates a cross-sectional view of a formulation filling apparatus 110 configured to fill at least one liquid formulation into a container. The formulation filling apparatus 110 includes at least one formulation preparation apparatus 112 configured to prepare a liquid formulation. The formulation filling apparatus 110 further includes at least one filling station 114 for filling the liquid formulation into the container, the filling station 114 being fluidly coupled to the formulation preparation apparatus 112, as also depicted in FIG. 1A. As further shown in FIG. 1A, the formulation filling apparatus 114 further includes at least one degassing apparatus 116, the degassing apparatus 116 being fluidly interposed between the formulation preparation apparatus 112 and the filling station 114. The degassing apparatus 116 includes at least one membrane 118 for at least partially separating at least one gas from the liquid formulation. As also shown in FIG. 1A, the formulation filling apparatus 110 may further include a coupling bow 120 having at least one first coupling access 122 and at least one second coupling access 124, wherein the degassing apparatus 116 may be fluidly connectable to the formulation preparation apparatus 112 via the first coupling access 122 and the degassing apparatus 116 may be fluidly connectable to the filling station 114 via the second coupling access 124.

[0159] 1B shows a detailed view of the coupling bow 120. As can be seen, the degasser 116 may be fluidly connected to the first coupling access 122 by a first flexible tube 126, and the degasser 116 may be fluidly connected to the second coupling access 124 by a second flexible tube 128. Thus, the degasser 116 may be indirectly fluidly coupled to the formulation preparation device 112 and the filling station 114, but the indirect fluid connection with the formulation preparation device 112 may be established by at least the first coupling access 122 and the first flexible tube 126, and the indirect fluid connection with the filling station 114 may be established by at least the second coupling access 124 and the second flexible tube 128. The coupling bow 120 may further comprise at least one holder 130 for mounting the degasser 116. Additionally or alternatively, the formulation filling apparatus 110, particularly the formulation preparation apparatus 112 and / or the filling station 114, may comprise a holder 130 for mounting the degasser 116 (not shown). In particular, the holder 130 may be configured to removably receive the degasser 116, for example as shown in FIG. 1B. In particular, the degasser may be or comprise a PermSelect® silicone membrane module available from MedArray, Inc. (Ann Arbor, Michigan, 48108, USA), such as the hollow fiber membrane module PDMSXA-2500 and / or the hollow fiber membrane module PSMSXA-1.0.

[0160] FIG. 2A shows an exploded view of the degasser 116. The degasser 116 comprises at least one membrane 118 for separating gas from the liquid formulation. In particular, the membrane may comprise at least one material selected from the group consisting of polydimethyldioxane (PDMS), cellulose acetate (CA), polysulfone (PS), polyethersulfone (PES), polyacrylonitrile (PAN), polyvinylidene fluoride (PVDF), polypropylene (PP), polyethylene (PE), polyvinyl chloride (PVC), polytetrafluoroethylene (PTFE), and silicone, preferably, the membrane comprises silicone. In particular, the membrane may have a thickness of 25 μm to 100 μm, preferably 40 μm to 70 μm, more preferably 55 μm. As depicted in FIG. 2A, the degasser 116 may comprise at least one hollow fiber membrane module 132 comprising a plurality of hollow fibers 134, the hollow fibers 134 being at least partially formed by the membrane 118. Specifically, the hollow fibers 134 may have an inner diameter and an outer diameter, the inner diameter having a value between 50 μm and 800 μm, preferably between 150 μm and 250 μm, more preferably between 190 μm, and the outer diameter having a value between 75 μm and 900 μm, preferably between 150 μm and 450 μm, more preferably between 300 μm. In particular, the membrane thickness may be 55 μm, the inner diameter of the hollow fibers 134 may be 190 μm, and the outer diameter of the hollow fibers 134 may be 300 μm. The hollow fibers 134 may at least partially define or comprise an interior space or lumen 135. In particular, the interior space or lumen 135 of the hollow fibers 134 may be referred to as the interior of the hollow fibers 134. Furthermore, the plurality of hollow fibers 134 of the hollow fiber membrane module 132 may comprise a number of hollow fibers 134 between 30 and 30,000. The number of hollow fibers 134 in a hollow fiber membrane module 132 may depend in particular on the size of the hollow fiber membrane module 132, in particular on the total area of ​​the membranes 118, i.e. on the sum of the areas of the membranes 118 of all the hollow fibers 134 in the hollow fiber membrane module 132, and / or on the cross-sectional area of ​​the hollow fiber membrane module 132, which may be perpendicular to the main direction of extension of the hollow fiber membrane module 132, in particular to its length.

[0161] For example, the fiber count per unit area of ​​the membrane 118 is between 1.0 and 4.0 fibers / cm 2 , for example 1~3fibers / cm 2 , preferably 1 to 1.5 fibers / cm 2 , and more preferably 1.26 to 1.42 fibers / cm 2 Additionally or alternatively, the number of hollow fibers per unit of cross-sectional area of ​​the hollow fiber membrane module 132 may be in the range of 134 The number of fibers, specifically, the fiber count, is 40 cm -2 ~500cm -2 , for example 42cm -2 ~483cm -2 20cm etc. -2 ~800cm -2 In particular, the number of hollow fibers 134 per unit of cross-sectional area of ​​the hollow fiber membrane module 132 may be 20 cm -2 ~800cm -2 , preferably 40cm -2 ~570cm -2 It could be.

[0162] Furthermore, the hollow fibers 134 may have a length of 10 cm to 16 cm, preferably 10 cm to 15 cm, more preferably 10 cm to 12 cm. Furthermore, the hollow fiber membrane module 132 may have a length of 10 cm to 16 cm, preferably 10 cm to 16 cm, more preferably 11 cm to 15 cm, most preferably 14 cm. FIG. 2A further shows that the hollow fibers 134 may specifically form a fiber bundle 136. In particular, the fiber bundle 136 may be embedded in a sealing 138 at both ends. Furthermore, the ends of the fiber bundle 136 may be connected to a connection port 140 as shown in FIG. 2A. The hollow fiber membrane module 132 may further include at least one housing 142, the housing 142 having the hollow fibers 134 disposed therein. Additionally, the hollow fiber membrane module 132 may include at least one fiber inlet port connected to a first end of the hollow fibers, at least one fiber outlet port connected to a second end of the hollow fibers, and at least one housing inlet port and at least one housing outlet port, both of which may be connected to at least one interior space within the housing between the hollow fibers and the housing wall.

[0163] A fluid, particularly a gas or liquid, can be introduced into the fiber through the fiber inlet port. In particular, when the fluid is a gas, the fiber inlet port can also be used as the fiber outlet port. Thus, a vacuum can be applied to the interior of the hollow fiber by connecting one or both of the fiber inlet and outlet ports to a suction device, as described further below.

[0164] A fluid, particularly a gas or liquid, may be introduced into the interior space of the housing through the fiber inlet port. In particular, when the fluid is a gas, the housing inlet port may also be used as the housing outlet port. Thus, a vacuum may be applied to the interior space by connecting one or both of the housing inlet port and the housing outlet port to a suction device, as described further below.

[0165] Fluids, particularly gases or liquids, contained in the interior space of the housing can be conveyed out of the interior space of the housing via the housing outlet port.

[0166] FIG. 2B shows a detailed view of the hollow fibers 134 of the fiber bundle 136 that the degasser 116 comprises. The degasser 116 may be particularly configured such that the liquid formulation contacts the membrane at a first side 144 and an opposing second side 146 of the membrane 118 is exposed to a lower pressure than the first side 144 to apply a pressure differential to the membrane 118. Thus, the pressure differential may be the difference between the magnitude of the pressure on the first side 144 and the magnitude of the pressure on the second side 146. Specifically, the pressure differential across the membrane 118 may be between 0.1 bar and 3.0 bar, preferably between 0.6 bar and 1.0 bar, and more preferably 0.8 bar. Additionally, the degasser 116 may comprise at least one vacuum source (not shown) or vacuum port 148 for applying a vacuum to the second side 146. Specifically, the vacuum source may comprise at least one pump. In particular, the absolute value of the vacuum applied to the second side 146 may be 0.010-0.900 bar, preferably 0.010-0.020 bar, and more preferably 0.015 bar. In FIG. 2B, the solid arrow indicates the direction of movement of the liquid formulation that may enter the degasser 116 via the fiber inlet port 150 to be guided through the hollow fibers 134 to be at least partially degassed. As indicated by the solid arrow, the liquid formulation may then be at least partially degassed and exit the hollow fiber membrane module 132 via the fiber outlet port 152. Thus, the connection port 140 connected to one end of the fiber bundle 136 may be realized as the fiber inlet port 150, and the connection port 140 at the other end of the fiber bundle 136 may be realized as the fiber outlet port 152. Furthermore, the fiber inlet port 150 may be connected to a formulation preparation device and the fiber outlet port may be connected to a filling station (not shown in FIG. 2B). The dashed arrows indicate the direction of movement of at least one gas separated from the liquid formulation by the degasser 116. In particular, the formulation in the degasser 116 may have an absolute pressure of 0.1 bar to 3.0 bar, preferably 0.6 bar to 1.0 bar, and more preferably 0.8 bar.Additionally, the hollow fiber membrane module 132 may include at least one housing inlet port and at least one housing outlet port, both of which are connected to at least one interior space 154 within the housing 142 between the hollow fibers 134 and a wall 156 of the housing 142.

[0167] 3 shows a further view of the degasser 116. The degasser 116 is fluidly interposed between the formulation preparation apparatus 112 and the filling station 114. Specifically, the hollow fiber membrane module 132 includes: i) the fiber inlet port 150 may be fluidly connected, directly or indirectly, to the formulation preparation device 112 and the fiber outlet port 152 may be fluidly connected, directly or indirectly, to the filling station 114; or ii) the housing inlet port may be fluidly connected, directly or indirectly, to a drug formulation preparation device, and the housing outlet port may be fluidly connected, directly or indirectly, to a filling station (not shown); The fluid may be fluidly interposed between the formulation preparation device 112 and the filling station 114 in a manner selected from the group consisting of:

[0168] FIG. 3 shows a cross-sectional view of option i), with particular attention to the degasser 116. As shown in FIGS. 3 and 2B, the connection port 140 connected to one end of the fiber bundle 136 may be realized as a fiber inlet port 150, and the connection port 140 at the other end of the fiber bundle 136 may be realized as a fiber outlet port 152. Again, the dashed arrows indicate the direction of movement of at least one gas separated from the liquid formulation by the degasser 116. In the case depicted in FIG. 3, the liquid formulation flows through the lumen 135 of the hollow fiber 134, and the gas separated from the liquid formulation may be discarded via the vacuum port 148. If option ii) is chosen (not shown), the liquid formulation may flow through the interior space 154 of the housing 142. Thus, in the case of option ii), the vacuum port 148 shown in FIG. 3 may be used as the housing inlet port and the housing outlet port, respectively, and the connection port 140 may be used as the vacuum port 148. The further opening 157 may remain closed in both option i) and option ii).

[0169] 4 shows an experimental setup 158 for testing the ability of the degassing device 116 to separate oxygen, an exemplary gas, from a liquid formulation. The experimental setup 158 comprises the degassing device 116 fluidly interposed between a reservoir 160 of the liquid formulation and a collection vessel 162. Nitrogen gas is directed to the reservoir via at least one nitrogen supply tube 163 to generate the pressure required to deliver the formulation to the degassing device 116 via at least one delivery tube 164. The pressure of the nitrogen in the nitrogen supply tube 163 is adjustable by a pressure reducer 165. A flow meter 166 determines the volumetric flow rate of the formulation per time unit via the delivery tube 164. A pressure transmitter 168 monitors the pressure in the delivery tube 164. The degassing device 116 is further connected to the collection vessel 162 via at least one receiving tube 170 which directs the at least partially degassed formulation to the vessel 162. An oxygen sensor 172 connected to an oximeter 173 determines the oxygen content of the at least partially degassed liquid formulation in the receiving tube 170. A vacuum is applied by at least one vacuum pump 174 in conjunction with at least a peristaltic pump 176 such that the second side 146 of the membrane 118 is exposed to a lower pressure than the first side 144 of the membrane 118. The experimental apparatus 158 further comprises a vacuum controller 178, a vacuum reservoir 180, and a power supply 182. The experimental apparatus 158 may comprise additional elements not shown in FIG. 4 and / or not mentioned or described.

[0170] Further experimental equipment 158, not shown, is used to investigate and / or evaluate further aspects of the formulation filling apparatus. In particular, the effect of the degassing apparatus on the concentration of at least one active ingredient of the liquid formulation may be investigated, for example, by using a cold trap that may capture recovered water.

[0171] 5A, 5B, and 5C show a plot of the oxygen content (in %) 184 of the liquid formulation on the left x-axis as a function of time (in seconds) 186. The starting value of the oxygen content therein is arbitrarily set to 100%. The time points at which the vacuum is applied are separated by a vertical line. The right x-axis shows the oxygen content (in mg / L) 188. All of FIGS. 5A, 5B, and 5C represent experimental setups with a vacuum of 100 mbar applied to the second side of the membrane 118 and different flow rates of 10 L / h (5A), 20 L / h (5B), and 40 L / h (5C). The plots in FIGS. 5A, 5B, and 5C show the decrease in the oxygen content of the liquid formulation as a function of time for all flow rates. FIG. 5D shows the oxygen separation efficiency 190 as a function of the volumetric flow rate of the formulation (in L / h), showing an oxygen separation efficiency of approximately 80% to 90% depending on the volumetric flow rate.

[0172] In a second aspect of the present invention, a method for filling at least one formulation into a container is disclosed. The method includes the steps disclosed below. The steps can be specifically carried out in a given order. However, different orders are also possible. The method can include additional steps that are not mentioned. Furthermore, it is also possible to repeatedly carry out one or more of the method steps. Furthermore, two or more of the method steps can be carried out in a time-overlapping manner or simultaneously.

[0173] As shown in FIG. 6 , the method includes, in a first step A) (method step 194), a step of providing at least one formulation filling apparatus 110 configured to fill at least one formulation into a container, the step of providing the formulation filling apparatus including at least the substeps of providing at least one formulation preparation apparatus 112 configured to prepare a liquid formulation (substep 196), providing at least one filling station 114 for filling the liquid formulation into the container, the filling station being fluidly connected to the formulation preparation apparatus 112 (substep 198), and providing at least one degassing apparatus 116 fluidly interposed between the formulation preparation apparatus 112 and the filling station 114, the degassing apparatus 116 comprising at least one membrane 118 for separating at least one gas from the liquid formulation (substep 200). The method further includes, in a second step B) (method step 202), directing the formulation from the formulation preparation device 112 to a filling station 114, where the formulation is at least partially degassed upon passing through the degassing device 116. The method further includes, in a third step C) (method step 204), filling the at least partially degassed formulation into a container by the filling station 114.

[0174] The method may include further steps not shown in the figures. In particular, method step B) (method step 202) may further include using a degasser to apply a pressure differential to the membrane 118, with the liquid formulation contacting the membrane at the first side 144 and the opposing second side 146 of the membrane 118 being exposed to a lower pressure than the first side 144. In particular, the degasser 116 provided in step A) may be configured to apply a pressure differential to the membrane 118 by comprising at least one vacuum source or vacuum port 148 for applying a vacuum to the second side 146. The degasser 116 may comprise at least one hollow fiber membrane module 132 comprising a plurality of hollow fibers 134, the hollow fibers 134 being at least partially formed by the membrane 118.

[0175] The hollow fibers 134 may form a fiber bundle 136. Furthermore, step B) may specifically include directing the formulation from the formulation preparation device 112 to the filling station 114, at least in part by using a transport gas stream and / or a pump. In particular, the transport gas may be nitrogen. Furthermore, the formulation filling device 110 provided in step A) (method step 194) may specifically be a formulation filling device 110 as described above or further below. Nevertheless, other embodiments are also possible.

[0176] In a third aspect of the present invention, a method for improving the accuracy of the filling weight of a liquid formulation in a container is disclosed. The method includes the steps disclosed below. The steps can be specifically performed in a given order. However, different orders are also possible. The method can include additional steps that are not mentioned. Furthermore, it is also possible to repeatedly perform one or more of the method steps. Furthermore, two or more of the method steps can be performed in a time-overlapping manner or simultaneously.

[0177] As shown in Figure 7, the method comprises in a first step I. (method step 205) preparing at least one liquid formulation. The method further comprises in a second step II. (method step 206) degassing the liquid formulation by at least partially separating at least one gas from the liquid formulation by using a degasser 116, the degasser 116 comprising at least one membrane 118. The method further comprises in a third step (method step 207) filling the degassed liquid formulation into a container.

[0178] In a fourth aspect of the present invention, a method for improving the stability of an oxygen-sensitive active pharmaceutical ingredient, such as a protein, in a liquid formulation, particularly in a liquid formulation in a container, is disclosed. The method includes the steps disclosed below. The steps may be specifically performed in a given order. However, a different order is also possible. The method may include additional steps not mentioned. Furthermore, it is also possible to repeatedly perform one or more of the method steps. Furthermore, two or more of the method steps may be performed in a time-overlapping manner or simultaneously.

[0179] As shown in FIG. 8, the method includes in a first step α. (method step 208) preparing at least one liquid formulation, the liquid formulation comprising at least one oxygen-sensitive active pharmaceutical ingredient, such as a protein. The method further includes in a second step β. (method step 210) degassing the liquid formulation by at least partially separating at least one gas from the liquid formulation by using a degassing device, the degassing device comprising at least one membrane. The method may further include in a third step (method step 212) filling the degassed liquid formulation into at least one container. The method may specifically include using a degassing device as described above or further below. Furthermore, the method may specifically include using a formulation filling device as described above or further below.

[0180] In the fifth aspect of the present invention, a method for reducing the formation of polysorbate aggregate formation in a liquid formulation, particularly in a liquid formulation in a container, is described. The method includes the steps disclosed below. The steps can be specifically performed in a given order. However, different orders are also possible. The method can include additional steps that are not mentioned. Furthermore, it is also possible to repeatedly perform one or more of the method steps. Furthermore, two or more of the method steps can be performed in a time-overlapping manner or simultaneously.

[0181] As shown in FIG. 9, the method includes in a first step (method step 214) preparing at least one liquid formulation, the liquid formulation comprising at least one oxygen-sensitive active pharmaceutical ingredient, such as a protein, and at least one polysorbate. The method further includes in a second step (method step 216) degassing the liquid formulation by at least partially separating at least one gas from the liquid formulation by using a degassing device, the degassing device comprising at least one membrane. The method may further include in a third step (method step 218) filling the degassed liquid formulation into at least one container. The method may further include using a degassing device, specifically as described above or further described below. Additionally, the method may specifically include using a formulation filling device, specifically as described above or further described below. [Explanation of symbols]

[0182] 110 Pharmaceutical filling equipment 112 Pharmaceutical preparation equipment 114 Filling Station 116 Deaeration device 118 Membrane 120 Coupling Bow 122 First Coupling Access 124 Second coupling access 126 First flexible tube 128 Second flexible tube 130 Holder 132 Hollow fiber membrane module 134 Hollow Fiber 135 lumens 136 Fiber bundle 138 Ceiling 140 Connection Port 142 Housing 144 First side of membrane 146 Second side of membrane 148 Vacuum Port 150 Fiber Inlet Port 152 Fiber Exit Port 154 Interior Space 156 Wall 157 Further Openings 158 Experimental Equipment 160 Storage Tank 162 Collection container 163 Nitrogen supply pipe 164 Delivery tube 165 Pressure Reducer 166 Flow meter 168 Pressure Transmitter 170 Receptor Tube 172 Oxygen Sensor 173 Oxygen Meter 174 Vacuum Pump 176 Peristaltic Pump 178 Vacuum Controller 180 Vacuum Storage Tank 182 Power supply 184 Oxygen content (unit: %) 186 Time (unit: seconds) 188 Oxygen content (unit: mg / L) 190 Oxygen separation efficiency 192 Volumetric flow rate (unit: L / h) Providing at least one formulation filling device configured to fill at least one liquid formulation into the container. 196 Providing at least one formulation preparation device configured to prepare a liquid formulation. 198. Providing at least one filling station for filling a liquid formulation into a container, the filling station being fluidly connected to a formulation preparation device. 200 Providing at least one degasser fluidly interposed between the formulation preparation device and the filling station, the degasser comprising at least one membrane for separating at least one gas from the liquid formulation. 202. A step of directing a formulation from a formulation preparation device to a filling station, the formulation being at least partially degassed as it passes through a degassing device. 204 filling the at least partially degassed formulation into the container by a filling station. 205 preparing at least one liquid formulation 206 Degassing the liquid formulation by at least partially separating at least one gas from the liquid formulation by using a degasser, the degasser comprising at least one membrane. 207 Filling the degassed liquid preparation into a container 208. A method for preparing at least one liquid formulation, the liquid formulation comprising at least one oxygen-sensitive active pharmaceutical ingredient. 210 Degassing the liquid formulation by at least partially separating at least one gas from the liquid formulation by using a degasser, the degasser comprising at least one membrane. 212 Filling the degassed liquid formulation into at least one container. 214. Preparing at least one liquid formulation, the liquid formulation comprising at least one oxygen-sensitive active pharmaceutical ingredient and at least one polysorbate. 216 Degassing the liquid formulation by at least partially separating at least one gas from the liquid formulation by using a degasser, the degasser comprising at least one membrane. 218 Filling the degassed liquid formulation into at least one container.

Claims

1. A formulation filling apparatus (110) for filling at least one liquid formulation into a container, comprising: a) at least one formulation preparation device (112) configured to prepare said liquid formulation, said formulation preparation device (112) comprising at least one mixing vessel for mixing at least two components of the formulation; b) at least one filling station (114) for filling the liquid formulation into the container, said filling station (114) being fluidly connected to said formulation preparation device (112), said filling station (114) further comprising at least one inspection device for optically inspecting the container after filling with the liquid formulation; c) at least one degasser (116), said degasser (116) fluidly interposed between said formulation preparation device (112) and said filling station (114), said degasser (116) comprising at least one membrane (118) for at least partially separating at least one gas from said liquid formulation, said membrane (118) being a non-porous membrane, said degasser (116) comprising at least one hollow fiber membrane module (132) comprising a plurality of hollow fibers (134), said hollow fibers (134) being at least partially formed by said membrane (118), said hollow fibers being sterilizable; and d) at least one in-line filtering device fluidly interposed between said formulation preparation device (112) and said filling station (114), said filtering device comprising a sterile filter; A pharmaceutical filling apparatus (110) comprising:

2. 2. The formulation filling apparatus of claim 1, wherein the degassing device is configured such that the liquid formulation contacts the membrane on a first side and an opposing second side of the membrane is exposed to a lower pressure than the first side, thereby applying a pressure differential to the membrane.

3. The pharmaceutical filling apparatus (110) of claim 2, wherein the degassing apparatus (116) comprises at least one of a vacuum source or a vacuum port (148) for applying a vacuum to the second side (146).

4. The pharmaceutical filling apparatus (110) of any one of claims 1 to 3, wherein the hollow fibers (134) form a fiber bundle (136).

5. 5. The pharmaceutical formulation filling apparatus (110) of claim 4, wherein an end of the fiber bundle (136) is connected to a connection port (140) for fluidly connecting the end of the fiber bundle (136) to the pharmaceutical formulation preparation apparatus (112), the filling station (114), or a suction device.

6. 6. The pharmaceutical filling apparatus (110) of any one of claims 1 to 5, wherein the hollow fiber membrane module (132) comprises at least one housing (142), the housing (142) having the hollow fibers (134) disposed therein.

7. 7. The pharmaceutical filling apparatus (110) of claim 6, wherein the hollow fiber membrane module (132) comprises at least one fiber inlet port (150) connected to first ends of the hollow fibers (134), at least one fiber outlet port (152) connected to second ends of the hollow fibers (134), and at least one housing inlet port and at least one housing outlet port, both of which are connected to at least one interior space (154) within the housing (142) between the hollow fibers (134) and a wall (156) of the housing (142).

8. The hollow fiber membrane module (132) comprises: i) the fiber inlet port (150) is fluidly connected to the formulation preparation device (112) and the fiber outlet port (152) is fluidly connected to the filling station (114); or ii) the housing inlet port is fluidly connected to the formulation preparation device (112) and the housing outlet port is fluidly connected to the filling station (114).

8. The drug product filling apparatus (110) of claim 7, fluidly interposed between said drug product preparation apparatus (112) and said filling station (114) in a manner selected from the group consisting of:

9. 9. The pharmaceutical filling machine (110) of claim 8, wherein option i) is selected and one or both of the housing inlet port and the housing outlet port are connected to a suction device.

10. 10. The pharmaceutical filling apparatus (110) of claim 8, wherein option ii) is selected and one or both of the fiber inlet port and the fiber outlet port are connected to a suction device.

11. 11. The pharmaceutical formulation filling apparatus (110) of claim 1, wherein the degassing device (116) has at least one inlet port connected to the pharmaceutical formulation preparation device and at least one outlet port connected to the filling station (114).

12. 1. A method for filling at least one liquid formulation into a container, comprising the steps of: A) providing at least one formulation filling device (110) configured to fill at least one liquid formulation into a container, the step of providing said formulation filling device (110) comprising: providing at least one formulation preparation device (112) configured to prepare said liquid formulation, said formulation preparation device (112) comprising at least one mixing vessel for mixing at least two components of the formulation; providing at least one filling station (114) for filling the liquid formulation into the container, the filling station being fluidly connected to the formulation preparation device (112), the filling station (114) further comprising at least one inspection device for optically inspecting the container after filling with the liquid formulation; providing at least one degasser (116) fluidly interposed between said formulation preparation apparatus (112) and said filling station (114), said degasser (116) comprising at least one membrane (118) for separating at least one gas from said liquid formulation, said membrane (118) being a non-porous membrane, said degasser (116) comprising at least one hollow fiber membrane module (132) comprising a plurality of hollow fibers (134), said hollow fibers (134) being at least partially formed by said membrane (118), said hollow fibers being sterilizable; providing at least one in-line filtering device fluidly interposed between said formulation preparation device (112) and said filling station (114), said filtering device comprising a sterile filter; the steps of: B) directing the liquid formulation from the formulation preparation device (112) to the filling station (114), wherein the liquid formulation is at least partially degassed upon passing through the degassing device (116); and C) filling the at least partially degassed liquid formulation into the container by the filling station (114). The method includes:

13. The method according to claim 12, wherein a pharmaceutical filling device according to any one of claims 1 to 11 is used.

14. 14. The method of claim 12 or 13, wherein the accuracy of the fill weight of the liquid formulation in the container is improved.

15. The method of any one of claims 12 to 14, wherein the stability of at least one oxygen-sensitive active pharmaceutical ingredient in the liquid formulation is improved.

16. The method of any one of claims 12 to 15, wherein polysorbate aggregate formation in the liquid formulation is reduced.

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