Time pressure filling system for liquid formulations

Abstract

The present invention provides a time-pressure filling system for filling containers with at least one liquid formulation. [Solution] The time-pressure filling system comprises: A. at least one storage container for storing a liquid formulation; B. at least one surge container configured for single use and partially made from at least one rigid plastic material; C. at least one supply line for pressurizing the supply of the liquid formulation from the storage container to the surge container; D. at least one pressure control line for applying a control pressure to the surge container; E. at least one dispenser for distributing the liquid formulation into the container; F. at least one distribution line connecting the surge container to the dispenser; G. at least one pressure sensor for determining the pressure in the distribution line; and H. at least one valve for controlling the flow of the liquid formulation in the distribution line. Furthermore, a surge container and a time-pressure filling method for use in this system are disclosed.

Description

Technical Field

[0001] The present invention relates to a time-pressure filling system and a time-pressure filling method for filling at least one liquid formulation into a container. The time-pressure filling system comprises at least one surge container configured for single use. By way of example, the apparatus and method of the present invention can be used for filling medical and pharmaceutical products into containers such as vials, syringes, cartridges, ampoules, etc. Other applications including the process of bottling liquids are also achievable.

Background Art

[0002] In the field of filling liquid formulations into containers, the devices and methods known to those skilled in the art can include the use of a time-pressure filling approach. Without limiting the scope, the present invention can be specifically described with respect to the filling of liquid formulations. However, it should be noted that the present invention may also be used for filling other types of liquids into containers.

[0003] In a time-pressure filling system, the filled volume can be determined by opening a squeeze valve during a specific time interval while a constant pressure is applied to the liquid formulation. The filling volume per unit time can depend on the pressure applied, the time interval, and the elements used, specifically the diameter of the tube and / or the needle. Thus, the system must meet the requirements for applying and maintaining a constant pressure within the system. Thus, generally, stainless steel devices are used for this purpose.

[0004] For these time-pressure filling systems to be used with a wide range of different liquid formulations, particularly in multi-product filling lines, the systems must be thoroughly cleaned and sterilized. This presents a significant challenge, especially for pharmaceutical formulations such as liquid formulations for subcutaneous application and / or high-potency liquid formulations. The acceptable toxicological residual concentrations of liquid formulations filled after system cleaning are often below the analytical detection limit. Furthermore, analytical detection methods with sufficient sensitivity are rarely available.

[0005] Therefore, a major challenge is to provide a method and apparatus that enables the filling of a wide range of many different liquid formulations using the same pressure filling system at the same time, while ensuring the highest possible level of patient safety and avoiding any cross-contamination that may occur. [Overview of the project] [Problems that the invention aims to solve]

[0006] Therefore, it is desirable to provide a method and apparatus for addressing the aforementioned technical challenges in filling containers with at least one liquid formulation. Specifically, it is desirable to provide a method and apparatus that enables the filling of a wide range of many different liquid formulations using the same time-pressure filling system while ensuring the highest possible level of patient safety. Furthermore, a method and apparatus for overcoming the need for extensive cleaning of time-pressure filling systems is proposed. [Means for solving the problem]

[0007] This challenge is addressed by time-pressure filling systems and time-pressure filling methods for filling at least one liquid formulation according to the features of an independent claim. Advantageous embodiments, which can be realized individually or in any combination, are described in the dependent claims.

[0008] Where used below, the terms “have,” “equip,” or “include,” or any grammatical variations thereof, are used inclusively. Therefore, these terms may refer to both situations in which the entity described in this context has no further features beyond those introduced by these terms, and situations in which one or more additional features exist. For example, the expressions “A has B,” “A equips B,” and “A includes B” may both refer to situations in which A has no other elements besides B (i.e., A consists solely and exclusively of B), and situations in which entity A has one or more additional elements besides B, such as element C, elements C and D, or even further elements.

[0009] Furthermore, it should be noted that the terms “at least one,” “one or more,” or similar expressions indicating that a feature or element can exist one or more times are usually used only once when introducing each feature or element. In most cases below, when referring to each feature or element, the expressions “at least one” or “one or more” will not be repeated, despite the fact that each feature or element can exist one or more times.

[0010] Furthermore, where used below, the terms “preferably,” “more preferably,” “particularly,” “more especially,” “specifically,” “more specifically,” or similar terms are used in conjunction with any feature without limiting the possibility of alternatives. Thus, the features introduced by these terms are arbitrary features and are not in any way intended to limit the scope of the claims. The present invention may be implemented by using alternative features as will be recognized by those skilled in the art. Similarly, features introduced by “in embodiments of the present invention” or similar expressions are intended to be arbitrary features without limitation on alternative embodiments of the present invention, without limitation on the scope of the present invention, and without limitation on the possibility of combining such introduced features with other arbitrary or non-arbitrary features of the present invention.

[0011] In a first aspect of the present invention, a time pressure filling system is disclosed. The time pressure filling system is configured to fill a container with at least one liquid formulation. The time pressure filling system is A. At least one storage container for storing liquid formulations, B. At least one surge container, wherein the surge container is configured for single use and is made at least partially from at least one rigid plastic material, C. At least one supply line for supplying a liquid formulation from a storage container to a surge container under pressure, D. At least one pressure control line for applying a control pressure to the surge vessel, E. At least one dispenser for dispensing a liquid formulation into a container, F. At least one distribution line connecting the surge container to the dispenser, G. At least one pressure sensor for determining the pressure in the distribution line, H. comprising at least one valve for controlling the flow of liquid formulation through the distribution line.

[0012] As used herein, the term “time-pressure filling system” is a broad term and should be given its ordinary and customary meaning to those skilled in the art, and should not be limited to any special or customized meaning. Specifically, the term can refer to any system for distributing, releasing, or leading any liquid, such as a pure liquid, liquid mixture, solution, suspension, dispersion, or emulsion, into a receptacle or container, etc. A time-pressure filling system may be configured to control the volumetric flow rate of a liquid by applying pressure to the liquid and controlling the opening time of a valve. Thus, a time-pressure filling system can be configured to supply a predetermined amount of liquid by supplying the liquid through a line at a controlled or predetermined pressure and by opening a valve over a predetermined time span. Thus, a time-pressure filling system may comprise at least one element that contains a liquid and is configured to apply pressure to the sealed liquid. Furthermore, a time-pressure filling system may comprise at least one valve, the opening time of which can be controlled, as outlined in more detail below. The volumetric flow rate of the liquid may depend on the applied pressure, the valve opening time, and the dimensions or geometric shape of the valve, such as the diameter or cross-section of the valve. Therefore, a time-pressure filling system may be configured to control the volume of liquid filling into a receptacle or container. Furthermore, a time-pressure filling system may be configured to sequentially and / or in parallel filling multiple containers via at least one dispenser in at least one distribution line. For example, a time-pressure filling system may have N dispensers for simultaneously filling a batch of N containers with liquid, and then subsequent batches of N containers, and so on. A time-pressure filling system may be used to fill a container with a predetermined amount of liquid. Therefore, a time-pressure filling system can be used in industrial applications such as filling a container with at least one liquid formulation.

[0013] As used herein, the term “liquid formulation” is a broad term and should be given its ordinary and customary meaning to those skilled in the art, and should not be limited to any special or customized meaning. Specifically, the term can refer to, but is not limited to, liquids such as pure liquids, liquid mixtures, solutions, suspensions, dispersions, or emulsions, which may be available as a drug, or may be used or prepared in the process of manufacturing a drug or preparation, or may be used or prepared as an intermediate step as a precursor or compound of a drug or preparation. Thus, formulations may be used, for example, as part of, or in connection with, the treatment, prevention, or prophylaxis of a disease or diagnostic analysis.

[0014] As used herein, the term “container” is a broad term and should be given its usual customary meaning to those skilled in the art, and should not be limited to any special or customized meaning. Specifically, the term can refer to a receptacle adapted to contain, store, or transport one or more liquids, but not limited to these uses. Specifically, a container can be used in the field of pharmaceutical formulations and, therefore, adapted to contain, store, or transport one or more liquid formulations. For example, a container can be selected from the group consisting of vials, syringes, cartridges, and ampoules.

[0015] As used herein, the term “storage container” is a broad term and should be given its usual customary meaning to those skilled in the art, and should not be limited to any special or customized meaning. Specifically, the term can refer to a liquid reservoir having at least one outlet and at least one pressure supply. Furthermore, the storage container may be configured to store a predetermined amount of liquid, for example, one batch of liquid formulation. At least one outlet of the storage container may connect the storage container to a surge container via at least one supply line. At least one pressure supply of the storage container may be configured to pressurize the liquid stored in the storage container. Thus, the storage container may be further configured to pressurize the surge container by at least one supply line to fill it with liquid, particularly liquid formulation. The storage container may be made of a metal or metal alloy such as stainless steel, or at least partially made of at least one rigid plastic material such as polypropylene or polyethylene. Thus, the storage container may be configured for single use.

[0016] As used herein, the term “surge vessel” is a broad term and should be given its usual customary meaning to those skilled in the art, and should not be limited to any special or customized meaning. The term can, in particular, refer to any device configured to contain or store a liquid, the device having at least one supply pipe, at least one outlet connection branch, and at least one pressure control branch. The surge vessel is made at least partially from a rigid plastic material, such as at least one of polypropylene, polycarbonate, and polyethylene, and is configured for single use. Furthermore, the surge vessel may have a cylindrical shape. Thus, the surge vessel has rigid cylindrical vessel sidewalls, a rigid vessel bottom plate, and a rigid vessel top plate. Other options, such as conical or cubic shapes, are also feasible. At least one supply line of the surge vessel penetrates the rigid vessel bottom plate and has at least one portion that protrudes into the internal space of the surge vessel, for example, to a height of 0.25–0.75% of the height of the surge vessel, or to a height of half the height of the surge vessel. Furthermore, at least one supply line has at least one inlet connection branch that protrudes from the rigid container bottom plate outside the internal space for connecting the supply line to the supply pipe. Thus, the surge container may be configured to be filled with liquid from a storage container, such as a liquid formulation. Furthermore, at least a portion of the supply pipe protruding into the internal space of the surge container may be configured to allow a smooth, turbulent inflow of the incoming liquid. Furthermore, at least one outlet connection branch protrudes from the container bottom plate outside the internal space for connecting at least one distribution line. The surge container may have multiple outlet connection branches for connecting multiple distribution lines. The multiple outlet connection branches may have equal or different diameters. Furthermore, at least one pressure control branch protruding from the container top plate outside the internal space for connecting at least one pressure control line may be configured to apply a control pressure to the liquid stored in the surge container. Thus, the surge container may be configured to supply the liquid stored in the surge container, such as a liquid formulation, to the distribution lines, specifically in a pressurized manner.

[0017] As used herein, the term “single-use” is a broad term and should be given its usual and customary meaning to those skilled in the art, and should not be limited to any special or customized meaning. Specifically, the term can refer to, but not limited to, the characteristics of an element that is discarded at the end of its use. Specifically, the end of use can be determined by a predetermined range of use and / or a predetermined usage time. Thus, elements of a time-pressure filling system, such as at least one surge container configured for single use, can be discarded after their predetermined range of use and / or their predetermined usage time. For example, the predetermined range of use can refer to the amount of liquid filled, such as a batch of liquid formulation. Thus, elements configured for single use may be disposable elements, for example, by being made from disposable materials such as plastic materials, such as rigid plastic materials. Furthermore, elements configured for single use can be easily replaced and thus can be replaced with new elements after their predetermined range and / or usage time has expired. Thus, elements configured for single use may be connected to other elements by detachable connectors.

[0018] As used herein, the term “rigid plastic material” is a broad term and should be given its usual customary meaning to those skilled in the art, and should not be limited to any special or customized meaning. Specifically, the term can refer to thermoplastic polymers, but is not limited to them. Specifically, rigid plastic materials may be moldable at high temperatures and may solidify at the temperature of use, e.g., room temperature. Thus, rigid plastic materials may be rigid thermoplastic polymers in a solidified state. For example, rigid plastic materials may be or include at least one of polypropylene, polycarbonate, or polyethylene. Other options are also feasible. Furthermore, rigid plastic materials may be pressure-stable materials. Thus, rigid plastic materials may be configured to withstand overpressures of, for example, 50 to 5000 mbar, particularly 50 to 3000 mbar, and more specifically at least 50 mbar in the range of 50 to 1000 mbar, with dimensional changes of, for example, less than 20% in at least one dimension, without macroscopic deformation. Rigid plastic materials may be at least partially transparent to light, particularly in the visible and / or infrared spectral range.

[0019] As used herein, the term “supply line” is a broad term and should be given its usual and customary meaning to those skilled in the art, and should not be limited to any special or customized meaning. Specifically, the term can refer to a liquid transport tube configured to supply a liquid contained in a storage container to a surge container. Specifically, the liquid may be a liquid formulation. Furthermore, the supply line may include a pressure-stabilizing tube. Specifically, the supply line may be made entirely or partially from at least one plastic material and / or at least one metal-reinforced plastic material, such as at least one metal-braided reinforced plastic material. For example, the supply line may include one or more reinforced silicone tubes, such as a braided reinforced silicone tube or a platinum-reinforced silicone tube. Thus, the supply line may be configured to supply a liquid formulation from a storage container to a surge container in a pressurized manner.

[0020] As used herein, the term “pressurized method” is a broad term and should be given its usual and customary meaning to those skilled in the art, and should not be limited to any special or customized meaning. Specifically, the term can refer to a method of transporting a liquid, such as a liquid formulation, through one or more tubes, tubing, and / or containers by applying overpressure to the liquid, but is not limited to this. Specifically, a liquid formulation can be transported pressurized within a time-pressure filling system. Thus, pressure can be applied to the storage container to transport the liquid formulation from the storage container to the surge container. Furthermore, a control pressure can be applied to the surge container to supply the liquid formulation to at least one distribution line.

[0021] As used herein, the term “pressure control line” is a broad term and should be given its usual customary meaning to those skilled in the art, and not limited to any special or customized meaning. Specifically, the term may refer to a pressure-stabilizing tube configured to apply a control pressure to a surge vessel, but is not limited to that. Specifically, a pressure control line may include a reinforced silicone tube, such as a braided-reinforced silicone tube or a platinum-reinforced silicone tube. As used herein, the term “control pressure” is a broad term and should be given its usual customary meaning to those skilled in the art, and not limited to any special or customized meaning. Specifically, the term may refer to a pressure applied to a surge vessel, such as to drive and / or control time-pressure filling from the surge vessel. Specifically, the control pressure may be applied to the surge vessel to control the flow of a liquid formulation through at least one distribution line. The control pressure may be in the range of 50 to 1000 mbar, specifically 50 to 400 mbar.

[0022] As used herein, the term “dispenser” is a broad term and should be given its usual and customary meaning to those skilled in the art, and should not be limited to any special or customized meaning. Specifically, the term can refer to any device configured to dispense a liquid, such as a liquid formulation, into a container and / or receptacle, but not limited to these. Specifically, a dispenser may be a device configured to dispense a liquid, such as a liquid formulation, toward a container. For example, a dispenser may comprise a needle, nozzle, valve, or tap. A dispenser may be installed at the end of a distribution line. Thus, a dispenser may mark the filling point. Furthermore, a time-pressure filling system may comprise at least one dispenser for each distribution line connected to a surge container via at least one outlet connection branch.

[0023] As used herein, the term “distribution line” is a broad term and should be given its usual and customary meaning to those skilled in the art, and should not be limited to any special or customized meaning. Specifically, the term can refer to a liquid transport tube connecting at least one outlet connection branch of a surge vessel to at least one dispenser, but is not limited thereto. Specifically, a distribution line may be made entirely or partially from at least one plastic material and / or at least one metal-reinforced plastic material, such as at least one metal-braided reinforced plastic material. For example, a supply line may include one or more reinforced silicone tubes, such as a braided reinforced silicone tube or a platinum-reinforced silicone tube. Specifically, at least one distribution line may include at least one pressure-stabilizing tube, such as at least one reinforced silicone tube, such as a braided reinforced silicone tube or a platinum-reinforced silicone tube. Other options are also feasible.

[0024] As used herein, the term "pressure sensor" is a broad term and should be given its ordinary and customary meaning to those of ordinary skill in the art and should not be limited to a special or customized meaning. Specifically, but not limited thereto, this term can refer to a device configured to quantitatively or qualitatively evaluate the pressure of a liquid by, for example, generating at least one item of information indicating pressure, such as an electronic signal. Specifically, the pressure sensor may be configured to evaluate the pressure of a liquid formulation within a distribution line. Thus, the pressure sensor may be integrated into at least one distribution line. Further, the pressure sensor can determine the pressure of the liquid formulation in the flow of the liquid formulation within at least one distribution line. Thus, the pressure sensor may comprise at least one passage for the liquid formulation and at least one pressure-sensitive element. The pressure sensor may be included in the distribution line. Further, the pressure sensor can generate an electrical signal that correlates with the pressure of the liquid, specifically the liquid formulation, that can pass through the pressure sensor. The pressure sensor may be configured for single use, particularly by being made at least in part from at least one rigid plastic material.

[0025] As used herein, the term “valve” is a broad term and should be given its usual customary meaning to those skilled in the art, and should not be limited to any special or customized meaning. Specifically, the term can refer to any device configured to regulate, guide, and / or control the flow of a liquid by opening, closing, and / or partially obstructing a passage, etc. Specifically, the opening and closing of at least one valve in a time-pressure filling system may be configured to be time-controlled. In this context, the term “opening time” can refer to a time interval in which a valve may be open and thus allow a liquid to pass through the valve. The opening time of at least one valve in a time-pressure filling system may be controllable. For example, at least one valve included in a time-pressure filling system may be a squeeze valve, or may comprise one such valve. A squeeze valve may be configured to control the flow through a distribution line by compressing the tubing of the distribution line. Furthermore, a time-pressure filling system may comprise at least one valve for each distribution line. Thus, the opening times of multiple valves may be controllable separately and / or collectively.

[0026] At least one storage container and at least one surge container included in the time pressure filling system may be pressure stable containers. Further, at least one supply line, at least one pressure control line, and at least one distribution line may comprise pressure stable tubes. As used herein, the term "pressure stable" is a broad term and should be given its ordinary customary meaning to those skilled in the art and should not be limited to a special or customized meaning. Specifically, without limitation, this term can refer to a property that does not macroscopically deform when subjected to pressure. In particular, macroscopic deformation can refer to a deformation of 10% or less, specifically 5% or less, more specifically 1% or less of the initial size. The initial size can refer to the size of the pressure stable container and / or the pressure stable tube under ambient pressure conditions without additional pressure. Further, the pressure stable container and / or the pressure stable tube may not macroscopically deform under an applied pressure of up to 5000 mbar, particularly up to 3000 mbar, more specifically up to 1000 mbar.

[0027] As an example, the pressure stable tube can be or can include a reinforced silicone tube, specifically a braided reinforced silicone tube, more specifically a platinum reinforced silicone tube. As another example, at least one surge container may be at least partially made from a rigid plastic material. Thus, the components of the time pressure filling system may have pressure stability within a pressure range of 50 to 5000 mbar, specifically 50 to 3000 mbar, more specifically 50 to 1000 mbar.

[0028] As outlined above, the time-pressure filling system comprises at least one pressure sensor for determining the pressure in the distribution line. The at least one pressure sensor may be located in at least one distribution line. Alternatively and / or additionally, the at least one pressure sensor may also be located in a bypass of the distribution line. Thus, the pressure sensor can determine the pressure in an additional line that bypasses the distribution line. Furthermore, the pressure sensor may also be located at at least one branch of the distribution line. As another example, the pressure sensor may be located in a line parallel to the distribution line. The parallel line may also be another distribution line and / or an additional line designated to be used for determining the pressure by at least one pressure sensor.

[0029] The time-pressure filling system may optionally further comprise at least one manifold, specifically at least one manifold for single use. The term “manifold” as used herein is a broad term, and its usual customary meaning should be given to those skilled in the art, and should not be limited to any special or customized meaning. Specifically, the term can refer to a fluid or hydraulic component that controls or regulates fluid flow between various fluid components, such as being configured to distribute a liquid flow to multiple fluid components, including multiple distribution nozzles. Thus, a manifold can provide a fluid distribution system and / or a fluid switchboard. At least one manifold may be configured for single use, particularly by being made from at least one rigid plastic material. Furthermore, at least one manifold may provide at least one inlet port and multiple outlet ports. The multiple outlet ports may have a smaller diameter than the inlet port. For example, the diameter of the multiple outlet ports may be at least 0.9 times, particularly at least 0.8 times, and even at least 0.7 times smaller than the diameter of the inlet port. Furthermore, at least one manifold may be installed in at least one distribution line. Therefore, at least one manifold may be configured to control the filling volume of at least one distribution line by reducing the diameter of at least one distribution line.

[0030] Furthermore, the time-pressure filling system may include at least one sterile filter. At least one sterile filter may be included in one or both of the supply line and / or distribution line. At least one sterile filter may be installed in close proximity to the filling point. The term “sterilized filter” as used herein is a broad term and should be given its usual customary meaning to those skilled in the art, and should not be limited to any special or customized meaning. Specifically, the term can refer to an apparatus configured to at least partially sterilize a liquid by filtering at least partially microbial contamination. Specifically, the sterile filter may be or include a porous membrane. The porous membrane may have pores with a diameter or equivalent diameter of 0.2 μm or less, specifically 0.1 μm or less. Furthermore, the sterile filter may sterilize the liquid by filtering the liquid that has passed through the sterile filter. Thus, the sterile filter may be configured to prevent impurities such as bacteria from passing through the sterile filter.

[0031] As used herein, the term “proximity” is a broad term and should be given its usual customary meaning to those skilled in the art, and should not be limited to any special or customized meaning. Specifically, the term can refer to a specification of relative position, but is not limited to this. Specifically, the term “proximity” can refer to the position of at least one sterile filter placed near the filling point. For example, the position of at least one sterile filter in proximity to the filling point can refer to an absolute distance of 5 m or less, specifically 2 m or less, more specifically 1 m or less, and even 0.5 m or less from the sterile filter to the filling point. The absolute distance can be measured with respect to the distance the liquid formulation travels from the sterile filter to the filling point. As another example, the position of at least one sterile filter in proximity to the filling point can refer to a relative distance of 10% or less, specifically 5% or less, more specifically 1% or less. The relative distance can be measured by comparing the absolute distance from at least one sterile filter to the filling point with the total distance the liquid formulation travels from at least one storage container to the filling point. Furthermore, the specification of the position of at least one sterile filter close to the filling point can also refer to a comparison with a situation in which the sterile filter can be installed outside at least one isolator, in which case at least one sterile filter can be installed inside at least one isolator.

[0032] As used herein, the term “filling point” is a broad term and should be given its usual, customary meaning to those skilled in the art, and should not be limited to any special or customized meaning. Specifically, the term can refer to, but is not limited to, the place where a liquid is dispensed into a container. The dispensed liquid may be or contain a liquid formulation. Thus, a filling point can be marked by at least one dispenser dispensing a liquid formulation into a container.

[0033] Furthermore, components of the time-pressure filling system may be connectable via couplings, specifically via plug-in couplings, and more specifically via quick-release couplings. For example, at least one supply line may be connected via a quick-release coupling to the outlet of a storage container and the inlet connection branch of a surge container. In addition, at least one sterile filter included in one or both of the supply and / or distribution lines may be connectable via a quick-release coupling. As another example, at least one distribution line may be connected via a quick-release coupling to the outlet connection branch of a surge container and at least one dispenser. In addition, at least one manifold in at least one distribution line may be connectable via a quick-release coupling. At least one pressure sensor included in the time-pressure filling system may also be connectable via a quick-release coupling.

[0034] The time-pressure filling system may be further surrounded by at least one isolator. At least one isolator can provide a sterile perimeter for the time-pressure filling system. Furthermore, the isolator may have at least one sterile port, which may be configured to allow unidirectional and / or bidirectional exchange of components of the time-pressure filling system in a sterile manner. Thus, the time-pressure filling system can be assembled inside at least one isolator by couplings, specifically by plug-in couplings, and more specifically by quick-release couplings.

[0035] As used herein, the term “isolator” is a broad term and should be given its usual customary meaning to those skilled in the art, and should not be limited to any special or customized meaning. Specifically, the term can refer to a microbiologically sealed container, such as a box, configured to surround a sterile area. The container may be airtight and / or connected to the environment via one or more filter systems, such as one or more sterile filters. Thus, an isolator may specifically be a sterile isolator. As an example, an isolator may include a glove box, which is typically used to provide a small sterile environment, and / or a sterile box or sterile chamber. Specifically, an isolator may be configured to surround a sterile area by keeping the interior of the isolator sealed from the outside. Additionally or alternatively, an isolator may be a system including, or comprising, at least one restricted area barrier system (RABS), e.g., at least one sterile box surrounding a sterile area, and the restricted area barrier system may be located inside a sterile chamber. Furthermore, an isolator may have at least one sterile port configured to allow sterile access to the isolator. As used herein, the term “sterilization port” is a broad term and should be given its usual customary meaning to those skilled in the art, and should not be limited to any special or customized meaning. Specifically, the term can refer to any device configured to allow access to an isolator without affecting the sterile interior of the isolator, but not limited to such devices. Specifically, a sterilization port may be or comprise a system of airlocks. For example, a sterilization port may comprise at least two airlocks that can be opened and closed independently of each other. The two airlocks may be arranged to enclose an intermediate stage up to the interior of the isolator. By opening the first outer airlock and keeping the second inner airlock closed, the intermediate stage can be made accessible from outside the isolator.The intermediate stage can be made accessible from inside the isolator by opening the second internal airlock and keeping the external airlock closed. At least two more airlocks may be further configured to hermetically seal the intermediate stage from inside and / or outside the isolator. Furthermore, the sterilization port may be configured to sterilize the intermediate stage by flowing a sterilization gas, such as gaseous H2O2, through it. Other options for locating the sterilization port are also feasible.

[0036] Furthermore, the materials used in the time-pressure filling system may be configured to be sterilized by at least one of radiation sterilization or gas sterilization, for example, by gamma sterilization and / or sterilization by ethylene oxide. For example, at least one rigid plastic material may be configured to be sterilized in particular by gamma rays. As another example, at least one supply line, at least one distribution line, and at least one pressure control line, composed of reinforced silicone tubing, may be configured to be sterilized in particular by gamma rays.

[0037] Furthermore, the control pressure applied to the surge vessel may be in the range of 50 to 1000 mbar, specifically 50 to 400 mbar.

[0038] The time-pressure filling system according to the present invention may specifically include at least one surge vessel according to the present invention, such as one relating to any of the embodiments disclosed herein and / or as further disclosed below. Therefore, any embodiment of the surge vessel of the time-pressure filling system can be referred to the surge vessel disclosures given further below.

[0039] The time-pressure filling system may further comprise at least one control unit. Specifically, the control unit may be configured for at least one of the following: controlling the filling level of a surge vessel; controlling the control pressure applied to the surge vessel; and controlling the valve opening time. As used herein, the term “control unit” is broad and should be given its usual customary meaning to those skilled in the art, and not limited to any special or customized meaning. Specifically, the term may refer to, but not limited to, electronic devices configured, particularly by hardware and / or software programming, for controlling the functions of the time-pressure filling system. Specifically, the control unit may be a computer configured to receive signals, such as signals from at least one optical sensor and / or signals from at least one pressure sensor, and to further evaluate the received signals. For example, the control unit may be configured to evaluate signals from at least one optical sensor for detecting the filling level of a surge vessel. As another example, the control unit may be configured to evaluate signals from at least one pressure sensor for determining the pressure in at least one distribution line. Furthermore, the control unit may be configured to control the control pressure applied to the surge vessel and / or the pressure applied to the storage vessel in order to supply the liquid formulation to the surge vessel. Thus, the control unit may be configured to control the filling level of the surge vessel in the range of 30% to 60%. The control unit may be further configured to control the valve opening time. For example, the control unit may control the valve opening time in conjunction with the control pressure applied to the surge valve to control the filling volume of the liquid formulation into the vessel.

[0040] In further aspects of the present invention, a surge container for use in a time-pressure filling system is disclosed, such as for use in a time-pressure filling system according to any one of the embodiments disclosed above and / or any one of the embodiments disclosed in further detail below. The surge container is configured for single use. The surge container is made from at least partially at least one rigid plastic material. The surge container is a. Side wall of a rigid cylindrical container, b. Hard container bottom plate and c. Hard container top plate and d. At least one supply pipe penetrating the bottom plate of a rigid container, wherein the supply pipe has at least one portion protruding into the internal space of the surge container, and the supply pipe further has at least one inlet connecting branch portion protruding from the bottom plate outside the internal space for connecting a supply line to the supply pipe, e. At least one outlet connection branch protruding from the bottom plate of the container outside the internal space for connecting at least one distribution line, f. comprising at least one pressure control branch protruding from the upper plate of the container outside the internal space for connecting at least one pressure control line.

[0041] As used herein, the term “rigid cylindrical container sidewall” is a broad term and should be given its usual customary meaning to those skilled in the art, and should not be limited to any special or customized meaning. Specifically, the term can refer to any cylindrical enclosure of a surge container made from at least one rigid plastic material, but not limited to, but at least partially. Thus, the rigid cylindrical container sidewall may be at least partially transparent to light, particularly in the visible and / or infrared spectral range. The rigid cylindrical container sidewall may be configured to accommodate at least one optical sensor on the outside of the rigid cylindrical container sidewall, the optical sensor may be configured to detect the filling level of the surge container. Furthermore, the rigid cylindrical container sidewall may have a wall thickness of at least 0.5 mm, specifically at least 1 mm, e.g., 0.5 mm to 5 mm, e.g., 1.0 mm to 3 mm. Furthermore, the enclosure of the surge container may also have a shape other than cylindrical, such as a conical or cubic shape. Other options are also feasible.

[0042] As used herein, the term “rigid container base plate” is a broad term and should be given its usual customary meaning to those skilled in the art, and should not be limited to any special or customized meaning. Specifically, the term can refer to any enclosure at the bottom of a surge vessel, which is made at least partially from one rigid plastic material, but is not limited to this. The rigid container base plate comprises at least one outlet connection branch. As an example, the rigid container base plate may also comprise multiple outlet connection branches. The multiple outlet connection branches may have equal or different diameters. At least one outlet connection branch is configured to connect at least one distribution line to the surge vessel. Furthermore, the rigid container base plate may have a shape corresponding to the shape of the surge vessel. For example, if the surge vessel has a cylindrical shape, the rigid container base plate may have a circular shape. Other options are also feasible. Furthermore, the rigid container base plate comprises at least one supply pipe, as outlined in more detail below.

[0043] As used herein, the term “rigid container top plate” is a broad term and should be given its usual customary meaning to those skilled in the art, and should not be limited to any special or customized meaning. Specifically, the term can refer to any enclosure at the top end of a surge vessel, which is made of at least one rigid plastic material, but not limited to, in part. The rigid container top plate comprises at least one pressure control branch, as outlined below in more detail. Furthermore, the rigid container top plate may have a shape corresponding to the shape of the surge vessel. For example, if the surge vessel may have a cylindrical shape, the rigid container top plate may have a circular shape. Other options are also feasible.

[0044] As used herein, the term “supply tube” is a broad term and should be given its usual and customary meaning to those skilled in the art, and should not be limited to any special or customized meaning. Specifically, the term can refer to any device configured to connect at least one supply line to the internal space of a surge vessel, without limitation. For this purpose, the supply tube penetrates the rigid vessel bottom plate and further has at least one portion projecting into the internal space of the surge vessel, and at least one inlet connecting branch projecting from the rigid vessel bottom plate outside the internal space to connect a supply line to the supply tube. At least a portion of the supply tube may project into the internal space of the surge vessel up to half the height of the surge vessel. Thus, at least a portion of the supply tube projecting into the internal space of the surge vessel may be configured to allow a smooth and turbulent inflow of the incoming liquid. Furthermore, the supply tube may be made at least partially from at least one rigid plastic material.

[0045] As used herein, the term “internal space of a surge vessel” is a broad term and should be given its usual customary meaning to those skilled in the art, and should not be limited to any special or customized meaning. Specifically, the term can refer to the space enclosed by the rigid cylindrical vessel sidewalls, rigid vessel bottom plate, and rigid vessel top plate, but is not limited to these. Specifically, the internal space of a surge vessel may include the liquid stored in the surge vessel. Furthermore, at least one control pressure may be applied to the internal space of the surge vessel, and therefore to the liquid stored in the surge vessel. Specifically, the internal space of a surge vessel may include a volume of at least 0.5 liters, for example, a volume of 1 liter to 50 liters, for example, a volume of 1 liter to 10 liters, for example, a volume of 7 liters to 8 liters.

[0046] As used herein, the term “inlet connection branch” is a broad term and should be given its usual customary meaning to those skilled in the art, and not limited to any special or customized meaning. Specifically, the term can refer to a device configured to fluidically connect at least one supply line to at least one supply pipe, but not limited to this. In this context, the term “fluidically connected” can refer to a method of connecting the first and second devices such that any liquid can move or may move from the first device to the second device and / or vice versa. Furthermore, at least one inlet connection branch protrudes from the rigid container bottom plate outside the internal space of the surge vessel.

[0047] As used herein, the term “outlet connection branch” is a broad term and should be given its usual customary meaning to those skilled in the art, and should not be limited to any special or customized meaning. Specifically, the term can refer to a device configured to fluidly couple a surge vessel to at least one distribution line, but is not limited to this. For example, at least one outlet connection branch may be made at least partially from at least one rigid plastic material. As another example, at least one outlet connection branch may also be made at least partially from a metal or metal alloy such as stainless steel. Furthermore, at least one outlet connection branch protrudes from the rigid vessel bottom plate outside the internal space of the surge vessel. For example, a surge vessel may have multiple outlet connection branches protruding from the rigid vessel bottom plate outside the internal space. The multiple outlet connection branches may have equal or different diameters. At least one distribution line connected to an outlet connection branch may have a similar diameter to the outlet connection branch. Thus, the multiple distribution lines connected to each of the at least one outlet connection branch may have equal or different diameters.

[0048] As used herein, the term “pressure control branch” is a broad term and should be given its usual and customary meaning to those skilled in the art, and should not be limited to any special or customized meaning. Specifically, the term can refer to a device configured to connect at least one pressure control line to a surge vessel, but is not limited to this. The pressure control branch may be configured to connect the pressure control line so that a control pressure can be applied to the internal space of the surge vessel. Specifically, the pressure control branch may protrude from the rigid vessel top plate outside the internal space.

[0049] As described above, the surge container is made of at least partially one rigid plastic material. The at least one rigid plastic material may include at least one material selected from the group consisting of polypropylene, polyethylene, and polycarbonate. Furthermore, the at least one rigid plastic material may be at least partially transparent to light in particular in the visible and / or infrared spectral range. The term “transparent” as used herein is a broad term and should be given its usual customary meaning to those skilled in the art, and should not be limited to any special or customized meaning. Specifically, the term can refer to an optical property that refers to the ability to transmit at least partially light in the visible and / or infrared spectral range, but is not limited to this. Specifically, the at least one transparent rigid plastic material may exhibit transmission of light in the visible and / or infrared spectral range of at least 0.7, preferably at least 0.8, and even more preferably at least 0.9. Furthermore, the at least one rigid plastic material may transmit light at least one wavelength in the visible and / or infrared spectral range. As another example, a transparent, rigid plastic material may transmit light at wavelength intervals in the visible and / or infrared spectral range.

[0050] The surge vessel may further comprise at least one optical sensor. At least one optical sensor may be located outside the internal space of the surge vessel. Specifically, at least one optical sensor may be mounted on the outside of the rigid cylindrical vessel sidewall, for example, by using at least one connecting element. Furthermore, at least one optical sensor may specifically be sensitive in at least one of the visible and / or infrared spectral ranges. As used herein, the term “optical sensor” is a broad term and should be given its usual customary meaning to those skilled in the art, and should not be limited to any special or customized meaning. Specifically, the term may refer to an electronic device configured to detect light in the visible and / or infrared spectral ranges, but not limited to these. Specifically, the optical sensor may be sensitive to incident light and may generate an electronic signal corresponding to the intensity of the incident light. The electronic signal generated by at least one optical sensor may be evaluated by at least one control unit for detecting the fill level of the surge vessel. Alternatively and / or additionally, the optical sensor may be configured to detect the fill level of the surge vessel. Furthermore, the optical sensor may be sensitive to at least one specific wavelength of light in the visible and / or infrared spectral range. In addition, the optical sensor may also be sensitive to wavelength intervals in the visible and / or infrared spectral range.

[0051] As used herein, the term “visible spectral range” is a broad term and should be given its usual, customary meaning to those skilled in the art, and should not be limited to any special or customized meaning. Specifically, the term can refer to the wavelength interval of visible light, but is not limited to that. Specifically, the visible spectral range can refer to visible light having wavelengths from 380 nm to 760 nm. As used herein, the term “infrared spectral range” is a broad term and should be given its usual, customary meaning to those skilled in the art, and should not be limited to any special or customized meaning. Specifically, the term can refer to the wavelength interval of infrared light, but is not limited to that. Specifically, the infrared spectral range can refer to infrared light having wavelengths from 760 nm to 1 mm.

[0052] Furthermore, at least one optical sensor may be configured to detect the filling level of the surge vessel. Specifically, the surge vessel and / or time pressure filling system may include at least one control unit, which may be configured to detect the filling level by evaluating at least one signal generated by the optical sensor.

[0053] The rigid cylindrical sidewall of the surge vessel may have a wall thickness of at least 1 mm. Thus, the surge vessel can be pressure-stable within the specified pressure range. The surge vessel may further comprise a plurality of outlet connection branches. The plurality of outlet connection branches may have at least two diameters, and these at least two diameters may be equal or different. Thus, a time-pressure filling system comprising a surge vessel may be configured to fill a plurality of vessels. The plurality of vessels may be filled by using at least one manifold in at least one distribution line. As another example, the plurality of vessels may be filled by using a plurality of distribution lines connected to a plurality of outlet connection branches. The time-pressure filling system may further be configured to fill vessels of different sizes by using a plurality of distribution lines connected to a plurality of outlet connection branches having different diameters.

[0054] In a further aspect of the present invention, a time-pressure filling method for filling a container with at least one liquid formulation is disclosed. The time-pressure filling method specifically includes the following steps, which can be performed in a predetermined order. However, it should be noted that different orders are also possible. Furthermore, one or more of the method steps can be performed once or repeatedly. Furthermore, one or more of the method steps can be performed simultaneously or in a timely and overlapping manner. The method may include further method steps not described.

[0055] The time-pressure filling method is i. Specifically, to provide a time-pressure filling system according to the present invention, comprising at least one surge vessel according to the present invention, including one of the embodiments disclosed above and / or one of the embodiments disclosed below, which refers to a surge vessel, and including a time-pressure filling system according to the present invention, including one of the embodiments disclosed above and / or one of the embodiments disclosed below, ii. Supplying the liquid formulation from the storage container to the surge container using a pressurized method, iii. Controlling the pressure inside the surge vessel by applying a control pressure to the surge vessel, iv. Determining the pressure in the distribution line by using a pressure sensor, v. Dispensing a predetermined amount of liquid preparation into a container by controlling the opening time of a valve.

[0056] As used herein, the term “supply a liquid formulation” is a broad term and should be given its ordinary and customary meaning to those skilled in the art, and should not be limited to any special or customized meaning. Specifically, the term may refer to the supply of a liquid formulation and / or the transfer of a liquid formulation from a storage container to a surge container by pressurizing a storage container, but is not limited to these.

[0057] As used herein, the term “controlling the pressure in a surge vessel” is a broad term and should be given its usual customary meaning to those skilled in the art, and should not be limited to any special or customized meaning. Specifically, the term can refer to one or more of the following: evaluation, verification, maintenance, or setting of the pressure in a surge vessel. Specifically, the pressure in a surge vessel may be set by applying a control pressure to the surge vessel. The pressure applied thereto can be verified by determining the pressure in the distribution line using a pressure sensor, as will be described in more detail below. Furthermore, controlling the pressure in a surge vessel may also include adjusting the control pressure applied after determining the pressure in the distribution line. Thus, steps iii. and iv. may then be repeated until a predetermined pressure value in the distribution line is achieved.

[0058] As used herein, the term “determine pressure” is a broad term and should be given its usual customary meaning to those skilled in the art, and should not be limited to any special or customized meaning. Specifically, the term can refer to a qualitative and / or quantitative assessment of pressure in a liquid, but is not limited to this. Specifically, the term can refer to a qualitative and / or quantitative assessment of pressure in a liquid formulation within a distribution line. Thus, determining pressure may include using at least one pressure sensor. For example, at least one pressure sensor may be placed within at least one distribution line to determine the pressure of the liquid formulation within at least one distribution line. The result of determining pressure may be, or may include, at least one numerical value indicating the pressure of the liquid formulation within at least one distribution line.

[0059] As used herein, the term “distributing a predetermined amount of liquid formulation into a container” is a broad term and should be given its usual customary meaning to those skilled in the art, and should not be limited to any special or customized meaning. Specifically, the term can refer to the controlled release of a liquid formulation into a container via at least one dispenser, but is not limited to this. Specifically, the amount of liquid formulation distributed into a container can be controlled with respect to a predetermined filling volume. For example, the predetermined filling volume can depend on the container being filled and can range from 100 μl to 100 ml. The filling volume distributed into the container can depend on the control pressure applied to the surge vessel and the valve opening time. Thus, the volume distributed into the container can be controlled by controlling the opening time of at least one valve in at least one distribution line in combination with the control pressure applied to the surge vessel.

[0060] The time-pressure filling system may further comprise at least one control unit, which may be configured for at least one of the following: controlling the control pressure applied to the surge vessel and controlling the valve opening time. The control unit may further be configured to control the valve opening time to at least one time value in the range of 1 to 2000 ms, specifically 1 to 400 ms. Furthermore, the control unit may be configured to control the filling level of the surge vessel to at least one level value in the range of 30% to 60% of the maximum filling capacity of the surge vessel.

[0061] A time-pressure filling method may further include filling a batch of liquid formulation into a container. A batch of liquid formulation may be defined by a predetermined amount of liquid formulation, and the method may include replacing the surge container after filling the batch of liquid formulation into the container, and discarding the surge container. Furthermore, a time-pressure filling system may include multiple surge containers, which may be used successively for different batches, and used surge containers may be discarded.

[0062] In a further aspect of the present invention, the use of at least one of a time pressure filling system and a surge container is disclosed. At least one time pressure filling system and at least one surge container are used to fill a container with at least one of the following liquid formulations, namely, pharmaceuticals, steroid products, liquid formulations for subcutaneous application, liquid formulations for intravenous application, high-potency liquid formulations, and aqueous protein solutions such as antibody formulations.

[0063] A pressure-stable surge container can be realized by using at least one rigid plastic material, such as polypropylene and / or polyethylene, to construct the surge container, and the rigid container sidewalls may have a thickness of at least 1 mm. The rigid plastic material may also be transparent, and thus it may be possible to determine the filling level of the surge container by using at least one optical sensor. Determining the filling level can prevent overfilling of the surge container. Furthermore, a filling level in the range of 25% to 75%, particularly 30% to 60%, can ensure a sufficient residence time for the liquid in the surge container, such as a liquid formulation. During the residence time, the liquid, such as a liquid formulation, can release gases that are absorbed when pressure, such as the pressure applied to the liquid in the storage container, is applied to the liquid. The release of gases from the liquid can improve the filling accuracy of the time-pressure filling system.

[0064] The surge container may be cylindrical in shape to ensure a uniform pressure distribution within the internal space of the surge container. The supply line may have at least one portion protruding from a rigid container bottom plate configured to allow a smooth, turbulent inflow of the incoming liquid, such as a liquid formulation.

[0065] Liquids, such as liquid formulations, can be transported to and from a storage container via platinum-reinforced silicone tubing that can be connected to at least one inlet connection branch and / or at least one outlet connection branch. Specifically, braided reinforced silicone tubing can be used to prevent pressure loss in one or more supply or distribution lines.

[0066] Furthermore, the number and / or diameter of at least one connecting branch can be adjusted to the number and / or diameter of at least one distribution line, as well as a predetermined filling volume of liquid, such as a liquid formulation. The predetermined filling volume and / or filling rate may depend on the container being filled with the liquid, such as a liquid formulation. The predetermined filling volume may be in the range of 100 μl to 100 ml.

[0067] Furthermore, the time-pressure filling system may include at least one manifold configured to reduce the diameter of the tubing to improve the filling accuracy of liquids such as liquid formulations, at least one choke, and / or at least one adapter.

[0068] The control pressure may be applied to the pressure control branch of the rigid vessel upper plate via a pressure control line. The applied pressure can be determined in at least one distribution line using at least one pressure sensor. The pressure sensors may be integrated into at least one distribution line and may be configured for single use. The control unit can control the applied pressure within a predetermined pressure limit.

[0069] As described above, the time-pressure filling system may be completely or partially enclosed by at least one isolator. The components of the time-pressure filling system may be sterilized, for example, by using at least one of gamma rays and / or gaseous ethylene oxide, and transferred to the isolator via a sterilization port. The assembly of the components of the time-pressure filling system may be performed inside the isolator via couplings such as quick-release couplings.

[0070] The methods and apparatus according to the present invention offer many advantages over similar methods and apparatus known in the art. Specifically, the methods and apparatus according to the present invention can enable the use of a time-pressure filling system in a wide range of different liquid formulations, particularly in multi-product filling lines. The time-pressure filling system, in particular the surge container, may be configured for single use and therefore may be discarded after filling a batch of liquid formulations. Thus, by using a time-pressure filling system, specifically the surge container according to the present invention, the need for extensive cleaning of the time-pressure filling system can be eliminated. Therefore, the methods and apparatus according to the present invention can enable the filling of a wide range of many different liquid formulations using the same time-pressure filling system while enabling the highest possible level of patient safety and avoiding potential cross-contamination.

[0071] Furthermore, the assembly of the time-pressure filling system inside at least one isolator can provide easy handling for the operator and further offer advantages in compliance and product stability. Therefore, sterile filtration may be performed close to the filling point and thus comply with regulations and safety guidelines. In addition, the sterile filter may be installed inside at least one isolator and thus avoid the absorption of H2O2 into the liquid formulation by the decontamination process. This can further improve product safety.

[0072] The integration of time-pressure filling systems and / or surge vessels proposed herein may also be carried out on existing or established time-pressure filling systems that have previously been made from stainless steel. The automation of existing filling systems can be used without further adjustment. Only minor mechanical and electrical adjustments may be required. These adjustments may refer to extending the pressure supply to surge vessels configured for single use, and determining the pressure in the distribution line by using pressure sensors configured for single use.

[0073] To summarize without excluding further possibilities, the following embodiments may be considered.

[0074] Embodiment 1: A time pressure filling system for filling a container with at least one liquid formulation, A. At least one storage container for storing liquid formulations, B. At least one surge container, wherein the surge container is configured for single use and is made at least partially from at least one rigid plastic material, C. At least one supply line for supplying a liquid formulation from a storage container to a surge container under pressure, D. At least one pressure control line for applying a control pressure to the surge vessel, E. At least one dispenser for dispensing a liquid formulation into a container, F. At least one distribution line connecting the surge container to the dispenser, G. At least one pressure sensor for determining the pressure in the distribution line, H. A time-pressure filling system comprising at least one valve for controlling the flow of a liquid formulation through a distribution line.

[0075] Embodiment 2: The time-pressure filling system according to the prior embodiment, wherein at least one storage container and at least one surge container are pressure-stabilizing containers.

[0076] Embodiment 3: A time-pressure filling system according to any one of the prior embodiments, wherein at least one supply line, at least one pressure control line, and at least one distribution line comprises a pressure stabilizing tube.

[0077] Embodiment 4: A time-pressure filling system according to any one of the prior embodiments, wherein the pressure-stabilizing tube includes a reinforced silicone tube, specifically a braided reinforced silicone tube, and more specifically a platinum-reinforced silicone tube.

[0078] Embodiment 5: A time-pressure filling system according to any one of the three preceding embodiments, wherein the components of the time-pressure filling system are pressure-stable in a pressure range of 50 to 5000 mbar, specifically 50 to 3000 mbar, and more specifically 50 to 1000 mbar.

[0079] Embodiment 6: A time-pressure filling system according to any one of the preceding embodiments, wherein a pressure sensor is located in at least one distribution line.

[0080] Embodiment 7: A time pressure filling system according to any one of the prior embodiments, wherein the time pressure filling system comprises at least one manifold, specifically at least one manifold for single use, and the manifold provides one inlet port and a plurality of outlet ports.

[0081] Embodiment 8: A time-pressure filling system according to any one of the preceding embodiments, wherein the multiple outlet ports of the manifold have a smaller diameter than the inlet ports.

[0082] Embodiment 9: A time-pressure filling system according to any one of the two preceding embodiments, wherein at least one manifold is installed in at least one distribution line.

[0083] Embodiment 10: A time pressure filling system according to any one of the prior embodiments, wherein the time pressure filling system comprises at least one sterile filter in one or both of the supply line and the distribution line.

[0084] Embodiment 11: A time-pressure filling system according to a prior embodiment, wherein the sterilization filter is installed in close proximity to the filling point.

[0085] Embodiment 12: A time-pressure filling system according to any one of the prior embodiments, wherein the components of the time-pressure filling system are connectable via couplings, specifically via plug-in couplings, and more specifically via quick-release couplings.

[0086] Embodiment 13: A time-pressure filling system according to any one of the preceding embodiments, wherein the time-pressure filling system is surrounded by at least one isolator, such as a box isolator and / or a restricted area barrier system, and the isolator provides a sterile perimeter for the time-pressure filling system.

[0087] Embodiment 14: The time-pressure filling system according to the prior embodiment, wherein the isolator comprises at least one sterilization port, the sterilization port being configured to replace components of the time-pressure filling system in a unidirectional or bidirectional manner in a sterilization manner.

[0088] Embodiment 15: A time-pressure filling system according to any one of the prior embodiments, wherein the material used in the time-pressure filling system is configured to be sterilized by radiation, specifically by gamma rays.

[0089] Embodiment 16: A time pressure filling system according to any one of the prior embodiments, wherein the control pressure applied to the surge vessel is in the range of 50 to 1000 mbar, specifically 50 to 400 mbar.

[0090] Embodiment 17: A time pressure filling system according to one of the prior embodiments, comprising at least one surge vessel according to one of the following embodiments relating to a surge vessel.

[0091] Embodiment 18: A time-pressure filling system according to any one of the prior embodiments, wherein the time-pressure filling system further comprises at least one control unit, the control unit being configured specifically for at least one of: controlling the filling level of a surge vessel; controlling the control pressure applied to the surge vessel; and controlling the opening time of a valve.

[0092] Embodiment 19: A surge container for use in a time-pressure filling system, specifically for use in a time-pressure filling system according to any one of the preceding embodiments, wherein the surge container is configured for single use, the surge container is made at least partially from at least one rigid plastic material, and the surge container is a. Side wall of a rigid cylindrical container, b. Hard container bottom plate and c. Hard container top plate and d. At least one supply pipe penetrating the bottom plate of a rigid container, wherein the supply pipe has at least one portion protruding into the internal space of the surge container, and the supply pipe further has at least one inlet connecting branch portion protruding from the bottom plate outside the internal space for connecting a supply line to the supply pipe, e. At least one outlet connection branch protruding from the bottom plate of the container outside the internal space for connecting at least one distribution line, f. A surge vessel comprising at least one pressure control branch protruding from the upper plate of the vessel outside the internal space for connecting at least one pressure control line.

[0093] Embodiment 20: A surge container according to the prior embodiment, wherein at least one rigid plastic material comprises at least one material selected from the group consisting of polypropylene, polyethylene, and polycarbonate.

[0094] Embodiment 21: A surge container according to any one of the prior embodiments relating to a surge container, wherein the rigid plastic material is at least partially transparent to light in particular in the visible and / or infrared spectral range.

[0095] Embodiment 22: A surge vessel according to a prior embodiment, wherein the surge vessel comprises at least one optical sensor, the at least one optical sensor being located outside the internal space, specifically the optical sensor being mounted on the outside of the side wall of a rigid cylindrical vessel, and the optical sensor being sensitive in at least one of the visible spectral range and the infrared spectral range.

[0096] Embodiment 23: A surge vessel according to a prior embodiment, wherein at least one optical sensor is configured to detect the filling level of the surge vessel, specifically, the surge vessel and / or time pressure filling system may comprise at least one control unit, the control unit configured to detect the filling level by evaluating at least one signal generated by the optical sensor.

[0097] Embodiment 24: A surge container according to any one of the preceding embodiments, wherein the rigid cylindrical side wall has a wall thickness of at least 1 mm.

[0098] Embodiment 25: A surge container according to any one of the preceding embodiments, wherein the surge container comprises a plurality of outlet connection branches.

[0099] Embodiment 26: A surge container according to a prior embodiment, wherein a plurality of outlet connection branches have at least two diameters, and at least two of these diameters are equal to or different from each other.

[0100] Embodiment 27: A time pressure filling method for filling a container with at least one liquid formulation, i. Specifically, to provide a time-pressure filling system according to one of the prior embodiments relating to a time-pressure filling system, comprising at least one surge vessel according to one of the prior embodiments relating to a surge vessel, ii. Supplying the liquid formulation from the storage container to the surge container using a pressurized method, iii. Controlling the pressure inside the surge vessel by applying a control pressure to the surge vessel, iv. Determining the pressure in the distribution line by using a pressure sensor, A method comprising dispensing a predetermined amount of liquid formulation into a container by controlling the opening time of a valve.

[0101] Embodiment 28: The method according to the preceding embodiment, wherein the time pressure filling system further comprises at least one control unit, the control unit configured for at least one of controlling the control pressure applied to the surge vessel and controlling the opening time of a valve.

[0102] Embodiment 29: The method according to the prior embodiment, wherein the control unit is configured to control the valve opening time to at least one time value in the range of 1 to 2000 ms, specifically 1 to 400 ms.

[0103] Embodiment 30: The method according to any one of the two preceding embodiments, wherein the control unit is configured to control the filling level of the surge vessel to at least one level value within the range of 30% to 60% of the maximum filling capacity of the surge vessel.

[0104] Embodiment 31: A method according to any one of the preceding method embodiments, wherein a batch of liquid formulations is defined by a predetermined amount of liquid formulations, and the method comprises replacing a surge container after filling a bench batch of liquid formulations into a container, and discarding the surge container.

[0105] Embodiment 32: The method according to the preceding embodiment, wherein the time pressure filling system comprises multiple exploratory surge containers, the exploratory surge containers are used successively for different batches, and the used surge containers are discarded.

[0106] Embodiment 33: Use of at least one of a time pressure filling system according to any one of the prior embodiments relating to a time pressure filling system and a surge container according to any one of the prior embodiments relating to a surge container, for filling a container with at least one of a liquid formulation, i.e., a protein aqueous solution such as a pharmaceutical, a steroid product, a liquid formulation for subcutaneous application, a liquid formulation for intravenous application, a high-potency liquid formulation, or at least one antibody formulation solution. [Brief explanation of the drawing]

[0107] Further optional features and embodiments are disclosed in more detail in subsequent descriptions of embodiments, preferably in conjunction with dependent claims. Here, each optional feature may be implemented independently and in any viable combination, as will be understood by those skilled in the art. The scope of the present invention is not limited by preferred embodiments. Embodiments are schematically shown in the figures, where the same reference numerals in these figures refer to identical or functionally equivalent elements.

[0108] The diagram is as follows. [Figure 1] A schematic diagram shows an embodiment of a time-pressure filling system for filling a container with at least one liquid formulation. [Figure 2a] Embodiments of the surge container are shown in cross-sectional and perspective views. [Figure 2b] Embodiments of the surge container are shown in cross-sectional and perspective views. [Figure 2c] Embodiments of the surge container are shown in cross-sectional and perspective views. [Figure 2d] Embodiments of the surge container are shown in cross-sectional and perspective views. [Figure 2e] Embodiments of the surge container are shown in cross-sectional and perspective views. [Figure 3] A schematic diagram shows an embodiment of the manifold. [Figure 4]A flowchart shows an embodiment of a time-pressure filling method for filling a container with at least one liquid formulation. [Modes for carrying out the invention]

[0109] Figure 1 schematically shows an exemplary embodiment of a time-pressure filling system 110 for filling a container 111 with at least one liquid formulation. The container 111 is not shown in Figure 1. In this regard, you can refer to Figure 3, which will be described in more detail below.

[0110] The time-pressure filling system 110 comprises at least one storage container 112. The storage container 112 is configured to store a liquid formulation. The storage container 112 may have at least one outlet 113. Furthermore, the storage container 112 may be connected to at least one pressure supply unit 115.

[0111] The time-pressure filling system 110 further comprises at least one surge vessel 114. The surge vessel 114 can be connected to the storage vessel 112 via at least one supply line 116, which connects to an outlet 113, thereby fluidly connecting the surge vessel 114 to the storage vessel 112, and optionally via one or more connecting lines 119 and / or one or more valves 121. The supply line 116 is configured to supply a liquid formulation from the storage vessel 112 to the surge vessel 114 in a pressurized manner.

[0112] Furthermore, the time-pressure filling system 110, specifically the surge container 114, may be equipped with at least one optical sensor 117, which may be located outside the internal space 148 of the surge container 114. For example, the optical sensor 117 may be mounted on the outside of the surge container 114. The optical sensor 117 may be configured to detect the filling level of the surge container 114. To control the filling of the surge container 114, one or more of any valves 121 may be directly connected to the optical sensor 117. Alternatively, at least one valve 121 may be controlled by at least one control unit 123 of the time-pressure filling system 110 that can receive one or more sensor signals from at least one optical sensor 117.

[0113] The surge container 114 can be specifically embodied as a disposable component. Specifically, the surge container 114 is made from at least one rigid plastic material, at least in part. Exemplary embodiments of the surge container 114 are shown in Figures 2a to 2e and are described in further detail below.

[0114] The time-pressure filling system 110 further comprises at least one pressure control line 118. The pressure control line 118 is configured to apply a control pressure to the surge vessel 114. For this purpose, the pressure control line 118 can be connected to at least one further pressure supply unit 125, such as one or more of a pump, a pressure supply line, and / or a pressure controller. The pressure can be applied in a controlled manner. The control pressure applied to the surge vessel 114, in conjunction with the opening time of a distribution or filling valve such as a valve 126, can determine the filling volume of the liquid formulation, as will be disclosed in more detail below.

[0115] The time-pressure filling system 110 further comprises at least one dispenser 120 for dispensing liquid formulations into containers. Furthermore, the time-pressure filling system 110 comprises at least one distribution line 122. The distribution line 122 is configured to connect the surge container 114 to the dispenser 120. For example, the at least one dispenser 120 may be at least one needle or nozzle, or may comprise them, as outlined below in more detail with respect to Figure 3.

[0116] To determine the pressure in the distribution line 122, the time-pressure filling system 110 includes at least one pressure sensor 124. The pressure sensor 124 can be located entirely or partially within at least one distribution line 122. However, additionally or alternatively, the at least one pressure sensor 124 may also be located, for example, in a bypass of the distribution line 122, a branch of the distribution line 122, or in one or more parallel lines of the distribution line 122.

[0117] Furthermore, the time-pressure filling system 110 includes at least one valve 126, also called a distribution valve or dosing valve. The valve 126 is configured to control the flow of the liquid formulation through the distribution line 122 or a portion thereof. At least one valve 126 may be a squeeze valve or may include one. Specifically, the valve 126 may be a controllable valve such as an electronically controllable valve and / or a computer-controllable valve. Thus, for example, the opening time of the valve 126 may be controlled by the control unit 123.

[0118] The time-pressure filling system 110 may be further enclosed, fully or partially, by at least one isolator 128, such as a glove box and / or sterile container. The at least one isolator 128 may be configured to provide a sterile perimeter to the time-pressure filling system 110 or a portion thereof. Specifically, one or more, or even all, of the following components of the time-pressure filling system 110 may be located fully or partially within the sterile perimeter provided by the isolator 128: surge container 114, dispenser 120, distribution line 122, valve 126, pressure sensor 124, supply line 116, at least one sterile filter 130, further disclosed below, and manifold 134, further disclosed below. Other components, such as one or more, or even all, of the components of storage container 112 having at least one outlet 113, pressure supply section 115 and / or 125, valve 121, and connection line 119, may be located outside the sterile perimeter provided by the isolator 128.

[0119] Furthermore, the time-pressure filling system 110 may include at least one sterile filter 130, specifically inside at least one isolator 128. The sterile filter 130 may be included in either or both of the supply line 116 or the distribution line 122. Thus, the sterile filter 130 may be installed close to the filling point 132 of the dispenser 120. The sterile filter 130 may be configured for either or both filtering and / or sterilizing the liquid formulation. Furthermore, the time-pressure filling system 110 may further include at least one manifold 134, which is not shown in Figure 1. An exemplary embodiment of the manifold 134 is shown in Figure 3 and will be described in further detail below.

[0120] As described above, the time-pressure filling system 110 may be specifically embodied as a completely or partially disposable system. Therefore, several components of the time-pressure filling system 110, such as one or more or even all of the following components, may be made from one or more plastic materials: the surge container 114, the dispenser 120, the distribution line 122, the valve 126, the pressure sensor 124, the supply line 116, the sterilization filter 130 further disclosed below, and the manifold 134 further disclosed below. However, other components may be embodied as reusable components, such as components that are completely or partially made from one or more metallic materials, such as stainless steel. Therefore, for example, one or more or even all of the components of the storage container 112 having at least one outlet 113, the pressure supply section 115 and / or 125, the pressure control line 118, the valve 121, and the connection line 119 may be made from at least one metallic material, such as stainless steel. As shown in Figure 1, most metal components other than the pressure control line 118 may be located outside the isolator 128, and most disposable plastic components may be located inside the isolator 128. Specifically, the time pressure filling system 110 may include one or more interfaces 137 for establishing a releaseable connection between the reusable components and disposable components of the time pressure filling system 110. For example, at least one interface may be located between one or more of the connection line 119, outlet 113 or valve 121 and the supply line 116. Furthermore, at least one interface 137 may also be located between the pressure control line 118 and the surge vessel 114. Specifically, the interface may include at least one quick-release coupling. This allows disposable components of the time pressure filling system 110 to be quickly removed and replaced with new components.

[0121] Figures 2a to 2e show exemplary embodiments of the surge container 114 in various diagrams. Here, Figure 2a shows a cross-sectional view, Figure 2b shows a bottom view in the arrangement of Figure 1, Figure 2c shows a top view in the arrangement of Figure 1, and Figures 2d and 2e show different perspective views of the surge container 114.

[0122] The surge container 114 is made from at least one rigid plastic material, at least in part, and can therefore be specifically configured for single use. The surge container 114 comprises a rigid container side wall 138, a rigid container bottom plate 140, and a rigid container top plate 142. Figure 2b shows the rigid container bottom plate 140 in a plan view, and Figure 2c shows the rigid container top plate 142 in a plan view.

[0123] As shown in Figures 2a and 2e, the surge vessel 114 further comprises at least one supply pipe 144 that penetrates the rigid vessel bottom plate 140. The supply pipe 144 has at least one portion 146 that protrudes into the internal space 148 of the surge vessel 114. The supply pipe 144 further comprises at least one inlet connecting branch portion 150 that protrudes out of the vessel bottom plate 140 into the internal space 148 for connecting a supply line 116 to the supply pipe 144.

[0124] Furthermore, the surge vessel 114 includes at least one outlet connection branch 152. The surge vessel 114 may also include multiple outlet connection branches 152. As shown in Figure 2c, the multiple outlet connection branches 152 may all have the same diameter, or they may have different diameters, such as at least two different diameters or three or more different diameters, as in the illustrated embodiment. Thus, the diameter of the outlet connection branches 152 may generally be designed to be variable, and / or multiple outlet connection branches 152 with different diameters may be provided, and as a result, a variable diameter may be selected as needed for the situation.

[0125] At least one outlet connection branch 152 protrudes from the rigid container bottom plate 140 to the outside of the internal space 148 and is configured to connect at least one distribution line 122. If multiple connection branches 152 are provided, not all of them are necessarily used. Thus, the surge container 114 can be designed as a disposable, general-purpose component for multiple applications without the need to redesign the surge container 114 if connection branches 152 of different diameters are required. The connection branches 152 may be connected according to the requirements of each situation. Connection branches 152 that are not currently in use can simply be closed, for example, by using one or more valves, caps, stoppers, etc.

[0126] The surge vessel 114 may further comprise at least one pressure control branch 154, as particularly shown in Figures 2a and 2d. The pressure control branch 154 protrudes outward from the internal space 148 and is configured to be directly or indirectly connected to the pressure control line 118, for example, via at least one interface 137 in Figure 1.

[0127] As described above, the time pressure filling system 110, particularly within the distribution line 122 and / or within the dispenser 120, may comprise at least one manifold 134, such as a manifold 134 having a plurality of outlet ports 158. Figure 3 shows a schematic side view of an exemplary embodiment of the manifold 134. The manifold 134 may comprise at least one inlet port 156 that can be connected to the distribution line 122 or a first portion of the distribution line 122. Furthermore, the manifold 134 may comprise a plurality of outlet ports 158, the plurality of outlet ports 158 may have a smaller diameter than the inlet port 156. The outlet ports 158 may be directly connected to at least one dispenser 120 and / or connected to at least one second portion of the distribution line 122 directly or indirectly connected to the dispenser 120. Therefore, generally, the manifold 134 may be installed between at least one distribution line 122, for example, between the surge container 114 and the dispenser 120 in Figure 1, for example, between the surge container 114 and the pressure sensor 124, between the pressure sensor 124 and the valve 126, or between the valve 126 and the dispenser 120. Various options are feasible. Thus, the manifold 134 can be configured to control the filling volume in at least one distribution line 122, for example, by reducing the diameter of the distribution line 122, and / or to fill multiple containers 111 simultaneously. Furthermore, as described above, the manifold 134 can be made from at least one rigid plastic material and therefore can be configured for single use.

[0128] Figure 4 shows a flowchart of an exemplary embodiment of a time-pressure filling method for filling a container 111 with at least one liquid formulation, the method being indicated by reference numeral 160. The time-pressure filling method 160 specifically includes the following steps, which can be performed in a predetermined order. Furthermore, different orders are also possible. Two or more method steps may be performed entirely or partially simultaneously. Furthermore, one, two or more, or all method steps may be performed once or repeatedly. The time-pressure filling method 160 may include additional method steps that are not listed.

[0129] The time-pressure filling method 160 includes the following steps: i. To provide a time pressure filling system 110 that specifically comprises at least one surge container 114 (as indicated by reference numeral 162), ii. Supplying the liquid formulation from the storage container 112 (indicated by reference numeral 164) into the surge container 114 by pressurization, iii. Controlling the pressure inside the surge vessel 114 by applying a control pressure to the surge vessel 114 (indicated by reference numeral 166), iv. Determining the pressure in the distribution line 122 by using the pressure sensor 124 (indicated by reference numeral 168), and v. Dispensing a predetermined amount of liquid formulation into a container by controlling the opening time of valve 126 (indicated by reference numeral 170).

[0130] As outlined above, the time-pressure filling system 110 may further comprise at least one optical sensor 117 and at least one control unit 123. The control unit 123 may be configured to detect the filling level of the surge container 114 by evaluating at least one signal generated by the optical sensor 117. Thus, the control unit 123 may be configured to control the filling level of the surge container 114 to at least one level value within the range of, for example, 25 to 75% of the maximum filling capacity of the surge container 114, or 30 to 60%. Thus, the control unit 123 may be configured to perform step ii of the time-pressure filling method.

[0131] Furthermore, the control unit 123 can be configured to evaluate the signal generated by the pressure sensor 124 and thus determine the pressure in the distribution line 122. However, steps iii. and iv. of the time-pressure filling method 160 may include adjustment of the control pressure applied to the surge container 114. Thus, the control unit can be configured to control the applied control pressure to achieve a predetermined pressure value. Furthermore, the control unit 123 can be configured to control the opening time of the valve 126. Thus, a predetermined amount of liquid formulation can be distributed into the container.

[0132] The time-pressure filling method 160 may further include replacing the surge container 114 after filling a batch of liquid formulation into a container, for example, after filling a predetermined amount of liquid formulation into a container. The surge container 114 may then be discarded. To fill different batches, the time-pressure filling method 160 may include using multiple surge containers 114, particularly for different batches, one after the other. [Explanation of Symbols]

[0133] 110-hour pressure filling system 111 Container 112 Storage containers 113 Exit 114 Surge container 115 Pressure supply unit 116 Supply Line 117 Optical Sensors 118 Pressure control line 119 connection lines 120 Dispenser 121 valves 122 distribution lines 123 Control Unit 124 Pressure Sensor 125 Pressure supply unit 126 valves 128 Isolators 130 Sterilization Filters 132 Filling Point 134 Manifold 137 Interface 138 Rigid container side wall 140 Hard container bottom plate 142 Hard container top plate 144 Supply pipe 146 Supply pipe section 148 Interior space 150 Inlet connection branch 152 Outlet connection branch 154 Pressure control branch 156 Manifold Inlet Port 158 Manifold Outlet Port 160-hour pressure filling method We offer a 162-hour pressure filling system. 164. Supplying liquid formulations from storage containers to surge containers. 166 Controlling the pressure inside the surge vessel 168 Determine the pressure in the distribution line. 170 Dispense a predetermined amount of liquid preparation into the container.

Claims

1. A time pressure filling system (110) for filling a container (111) with at least one liquid formulation, A. At least one storage container (112) for storing the liquid formulation, B. At least one surge container (114), wherein the surge container (114) is configured for single use, and the surge container (114) is at least partially made from at least one rigid plastic material, C. At least one supply line (116) for supplying the liquid formulation from the storage container (112) to the surge container (114) in a pressurized manner, D. At least one pressure control line (118) for applying a control pressure to the surge container (114), E. At least one dispenser (120) for dispensing the liquid formulation into the container (111), F. At least one distribution line (122) connecting the surge container (114) to the dispenser (120), G. At least one pressure sensor (124) for determining the pressure in the distribution line (122), H. A time-pressure filling system (110) comprising at least one valve (126) for controlling the flow of the liquid formulation through the distribution line (122).

2. A surge container (114) for use in a time pressure filling system (110) according to claim 1, wherein the surge container (114) is configured for single use, the surge container (114) is made at least partially from at least one rigid plastic material, and the surge container (114) a. Rigid cylindrical container side wall (138) and b. Hard container bottom plate (140) and c. Hard container top plate (142) and d. At least one supply pipe (144) penetrating the rigid container bottom plate (140), wherein the supply pipe (144) has at least one portion (146) protruding into the internal space (148) of the surge container (114), and the supply pipe (144) further has at least one inlet connecting branch (150) protruding from the rigid container bottom plate (140) outside the internal space (148) for connecting a supply line (116) to the supply pipe (144), e. At least one outlet connection branch (152) protruding from the rigid container bottom plate (140) outside the internal space (148) to connect at least one distribution line (122), f. A surge vessel (114) comprising at least one pressure control branch (154) protruding from the rigid vessel upper plate (142) outside the internal space (148) to connect at least one pressure control line (118).

3. A time pressure filling method for filling a container (111) with at least one liquid formulation, i. To provide the time pressure filling system (110) described in claim 1, ii. Supplying the liquid preparation from the storage container (112) to the surge container (114) by pressurization, iii. Controlling the pressure inside the surge container (114) by applying a control pressure to the surge container (114), iv. Determining the pressure in the distribution line (122) by using the pressure sensor (124), v. A method comprising distributing a predetermined amount of the liquid preparation into the container (111) by controlling the opening time of the valve (126).

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