Low volume filling of liquids into containers

Abstract

A process for constructing a filling system for low-volume filling of a container with a liquid, the process comprising: (i) obtaining a plurality of liquid delivery devices configured to provide liquid from a reservoir to the container; (ii) simulating the operation of each of the liquid delivery devices by numerically modeling the flow pattern of the liquid (3) as it is being delivered by the liquid delivery device and determining a shear stress rate for each of the liquid delivery devices based on the modeled flow pattern; (iii) determining the suitability of each of the liquid delivery devices by comparing the liquid delivery operating parameters of the liquid delivery devices, including the determined shear stress rate; (iv) selecting the liquid delivery device having the highest determined suitability; and (v) installing the selected liquid delivery device in the filling system.

Description

[Technical Field]

[0001] The present invention relates to a process for constructing a filling system for low-volume filling of a liquid into a container, and to a computer-implemented method and respective computer programs for evaluating a liquid delivery device for a filling system for low-volume filling of a liquid into a container. [Background technology]

[0002] At an industrial level, filling small volumes of liquids with the desired accuracy, efficiency, and precision can be challenging. Particularly when it comes to relatively demanding liquids, such as pharmaceutical or drug substances, especially parenteral substances, filling small volumes can impose high demands on the filling procedure. This can lead to liquid properties, such as the viscosity or sensitivity of the associated drug to physical stress, making it difficult to efficiently fill small volumes with the desired accuracy.

[0003] For example, current intravitreal eye treatments for conditions such as wet age-related macular degeneration (AMD) or diabetic macular edema are typically filled in volumes greater than necessary due to the lack of filling systems capable of accurately and precisely filling the drug substance in industrial processes. This creates a need to ensure that sufficient amounts of drug substance are available for administration to patients. However, while overfilling is common, it also presents many disadvantages, such as dosing errors due to incorrect dosages, misuse of remaining product, or wasted drug substance. To address some of these disadvantages, prefilled syringes, filled with the desired fill volume in the range of 50 to 100 microliters (μl), are used as an alternative to vials.

[0004] More specifically, for example, in relation to intravitreal administration, the presence of particles on a visible and invisible scale can be a hindrance to the application of drug substances. Therefore, it is desirable to ensure the absence of such particles in the final product. However, particularly in relation to biological or biochemical agents, including antibodies, such as monoclonal antibodies, particle formation may occur during the filling of drug substances into vials or other containers. This may cause antibodies or other proteins to form particles or aggregates to a greater or lesser extent depending on the conditions to which the drug substances are exposed during filling, particularly while being pumped or similarly driven.

[0005] To identify a suitable filling system, particularly a suitable pump or similar liquid delivery device, it is common to compare various filling systems with one another. The resulting filled drug substance is then analyzed, for example, for the presence of particles. Because the formation of such particles can occur long after filling and can even be traced back to the filling system, the drug substance must be examined over time. Therefore, defining or setting up and building a filling system can be relatively laborious, time-consuming, and result in unnecessary waste.

[0006] Therefore, there is a need for a process or system that allows for the construction and specification of filling systems for filling low volumes of liquids, particularly liquid drug substances, in industrial processes. Summary of the Invention

[0007] According to the present invention, this need is solved by a process for constructing a filling system for low-volume filling of a container with a liquid, as defined by the features of independent claim 1, and a computer-implemented method for evaluating a liquid delivery device for a filling system for low-volume filling of a container with a liquid, as defined by the features of independent claim 13. Preferred embodiments are the subject of the dependent claims.

[0008] In one aspect, the invention is a process for constructing a filling system for low-volume filling of a container with a liquid, the process including the steps of: (i) obtaining a plurality of liquid delivery devices configured to provide a liquid from a reservoir to the container, (ii) simulating the operation of each of the liquid delivery devices by numerically modeling a flow pattern of the liquid as it is delivered by the liquid delivery device and determining a shear stress rate for each of the liquid delivery devices based on the modeled flow pattern, (iii) determining a suitability for each of the liquid delivery devices by comparing operating parameters of the liquid delivery of the liquid delivery devices, including the determined shear stress rate, (iv) selecting the liquid delivery device having the highest determined suitability, and (v) installing the selected liquid delivery device in the filling system.

[0009] The liquid may in particular be a liquid drug substance. The low volume filling may be under aseptic conditions, which is often necessary, in particular when liquid drug substances are involved.

[0010] The term "drug," as used herein, relates to a therapeutically active agent, also commonly referred to as an active pharmaceutical ingredient (API), as well as to combinations of multiple such therapeutically active substances. The term also encompasses diagnostic or imaging agents, such as contrast agents (e.g., magnetic resonance imaging (MRI) contrast agents), tracers (e.g., positron emission tomography (PET) tracers), and hormones, which must be administered to a patient in liquid form.

[0011] The term "drug substance", as used herein, relates to a drug, as defined above, that has been formed or reconstituted into a form suitable for administration to a patient. For example, apart from the drug, the drug substance may additionally comprise excipient ingredients and / or other auxiliary components. Particularly preferred drug substances in the context of the present invention are drug solutions, in particular solutions for administration by injection or infusion.

[0012] The drug substance can be a parenteral drug substance. More specifically, it can be an intravitreal drug substance, which is typically particularly sensitive to the presence of particles, aggregates, or other conditions. For example, the drug substance can be formulated for intravitreal treatment of ocular diseases such as wet age-related macular degeneration (AMD) or diabetic macular edema.

[0013] The drug substance can also be a biological or biochemical drug substance, or any high-concentration formulation. Such drug substances often include proteins, e.g., antibodies, such as monoclonal antibodies. Typically, such drug substances are administered in relatively small dosages or volumes. Also, such drug substances often have a relatively high viscosity and tend to be relatively resistant to mechanical stress.

[0014] The term "drug product" can refer to a single drug substance or a finished, final product containing multiple drug substances. In particular, a drug product may be a ready-to-use product having drug substances in an appropriate dosage and / or in a form suitable for administration. For example, a drug product may include an administration device such as a pre-filled syringe or the like.

[0015] As used herein, the term "low volume" refers to a relatively small volume of liquid to be filled. In particular, such a low volume can be the volume of a drug administered parenterally or intravitreally. Such a low volume can be less than about 200 microliters (μl), about 100 μl or less, or about 50 μl or less. In the context of a prefilled syringe, this low volume can be in the range of about 50 μl to about 100 μl.

[0016] The reservoir may be any containment or any other structure for holding a liquid. In particular, the reservoir may be embodied to make a liquid available. It may therefore comprise a tube, a pipe, a tank, any combination thereof, or the like.

[0017] The container can be any container suitable or desirable for further processing or handling of the liquid. Where the liquid is a drug substance, the container can be a vial, a dispensing device such as a syringe, or the like. In particular, the container can be a pre-filled syringe containing a predetermined dosage of the liquid drug substance.

[0018] The fluid delivery device can be a pump or pump-like device. For example, a pump suitable for dispensing low volumes of fluid can be a rotary piston pump, a radial peristaltic pump, or a linear peristaltic pump.

[0019] Acquiring multiple fluid delivery devices may involve having all of the relevant devices, or samples thereof, physically available or providing them. Additionally or alternatively, this may involve having data or information available or providing about a single physical device. For example, acquiring multiple fluid delivery devices may be embodied by providing a drawing or technical drawing for the device that allows for gathering all the information necessary for the simulation, such as dimensions and the like. Thus, acquiring multiple fluid delivery devices may also be referred to as acquiring information or data about the physical delivery devices. Typically, for this simulation, it is important to have at least information about the geometry of the fluid delivery devices.

[0020] Numerical modeling is a proven method used to solve theoretical fluid properties, allowing for efficient investigation of shear stress rates during fluid delivery through various fluid delivery devices.

[0021] The shear stress rate can be any measure or magnitude that indicates the degree of shear or shear stress to which the liquid is exposed in the liquid delivery device. It can be or include physical units, a numerical value made up of physical units or values, or the like. Furthermore, the shear stress rate can also be a cumulative shear stress rate that indicates the total shear stress to which the liquid is exposed while being provided, delivered, or processed by each liquid delivery device.

[0022] The appropriateness may be a cumulative appropriateness that indicates the total process of the liquid being provided by each liquid delivery device. The term "having the highest appropriateness" is not limited to having the highest numerical value or the like in relation to selecting a liquid delivery device. Instead, depending on the appropriateness determination applied, the highest appropriateness may also be represented by the lowest numerical value, color, sound, or any other scale or signal that allows for identification of the most appropriate liquid delivery device. The highest appropriateness may be a scale or magnitude that allows for ranking the associated liquid delivery devices. Appropriateness may alternatively be referred to as compatibility or applicability.

[0023] In the context of the present invention, apart from requirements such as fill accuracy, compatibility with cleaning-in-place / sterilization-in-place (CIP / SIP), and materials with low extractable and leachable profiles, the shear stress to which a liquid is exposed during filling has been found to have a significant impact on particle formation in the liquid during filling into containers. Shear stress is present in almost all bioprocesses, and it has been found to play a role in protein aggregation and denaturation, which may be sensitive to shear stress. Looking at the vast portfolio within the pharmaceutical industry, protein-based products account for a significant portion of their pipeline, both currently and in the future. This calls for the control and analysis of key parameters during aseptic filling, especially when it comes to direct administration to the human eye (intravitreal). In selecting the most appropriate liquid delivery device, it is important to understand how the device's filling mechanism can affect the stability of the liquid or drug substance.

[0024] The particles to be prevented in the liquid may be visible or may not be visible to the naked eye, i.e., smaller than about 2 microns. For example, in the field of pharmaceutical substances, especially intravitreal pharmaceutical substances, preventing the formation of such particles is extremely important. And, in particular, pharmaceutical substances containing proteins, such as antibodies, often have relatively low resistance to shear stress, and the shear stress to which these proteins are exposed can damage them, promoting the formation of particles, e.g., aggregates. Therefore, considering shear stress in the evaluation of a given environment allows for the efficient selection of the most appropriate liquid delivery device. More specifically, taking into account the shear stress rate determined by simulating the operation of the liquid delivery device allows for a particularly efficient, rapid, and resource-saving selection of the most suitable liquid delivery device for a particular low-volume filling procedure. In this way, filling equipment for filling containers with liquids on an industrial scale can be designed and configured economically and reliably.

[0025] Simulation of the technical process of the operation of a liquid delivery device, in particular numerical modeling of its flow pattern, allows for the qualification of the liquid delivery device, which serves as a basis for selecting the most appropriate liquid delivery device for a given situation. In this way, test cycles and stability studies are not required to select a liquid delivery device, which can prevent liquid waste in the test cycle and substantially improve the selection capability or efficiency. In particular, the greater the number of liquid delivery devices considered and / or the higher the value of the liquid to be filled, the more significant these effects can be.

[0026] Preferably, the operation of each of the liquid delivery devices is simulated by applying computational fluid dynamics (CFD). CFD, a branch of fluid dynamics, typically uses numerical analysis and data structures to analyze and solve problems related to fluid flow. Generally, computers are used to perform the calculations necessary to simulate the free stream flow of fluids and the interaction of fluids (liquids and gases) with surfaces defined by boundary conditions.

[0027] Thus, the CFD preferably includes Navier-Stokes equations, Euler equations, Stokes equations, potential equations, or a combination thereof, allowing for efficient and accurate modeling of the respective operation of the liquid delivery device.

[0028] Apart from the determined shear stress rate, the operational parameters may include parameters related to dosage accuracy, dosage rate, stability or robustness of the liquid delivery device, maintenance effort, suitability for cleaning-in-place / sterilization-in-place (CIP / SIP), or the like.

[0029] Preferably, simulating the respective operation of the liquid delivery device comprises defining the moving parts of the liquid delivery device as generic movable objects, whereby numerically modeling the flow pattern preferably comprises defining the displacement of the generic movable objects over time, such simulation allows to achieve relatively high processing speed and accuracy.

[0030] Preferably, simulating the operation of each of the liquid delivery devices comprises defining pressure boundary conditions at the liquid inlet of the liquid delivery device and at the liquid outlet of the liquid delivery device, in this way the limits of the simulation can be efficiently set to preferred ranges.

[0031] Preferably, the operational parameters include liquid properties, which can be used to efficiently simulate the operation of filling a container with a liquid, particularly since many filling systems are highly dependent on the properties of the liquid being filled, such a process allows for accurate simulation of a given situation.

[0032] Thereby, the liquid properties preferably include viscosity, which is often one of the key properties that influences the filling process, which may be particularly relevant for liquids with relatively high viscosity, for example, liquid drug substances that contain proteins.

[0033] Alternatively or additionally, the liquid properties preferably include an indicator of the liquid's sensitivity. The sensitivity of the liquid can also be conferred by a substance contained therein. This sensitivity can be an indicator of the threshold force that a component of the liquid, such as an antibody, can withstand without being damaged or injured. This sensitivity can also be referred to as the liquid's fatigue.

[0034] Preferably, the highest determined relevance is at or facilitated by the lowest shear rate. Such a process allows for simple and efficient implementation, suitable when shear rate is the most influential characteristic or parameter in determining a particular fluid delivery device.

[0035] Preferably, the liquid delivery device comprises a piston pump and / or a peristaltic pump, which may be particularly suitable for delivering small volumes of liquid with desired accuracy and power.

[0036] Preferably, acquiring the plurality of fluid delivery devices includes providing geometry data for each of the fluid delivery devices. Such acquiring step allows for efficient integration into numerical modeling. In particular, the geometry data can be directly used in numerical modeling.

[0037] Thus, simulating the operation of each of the fluid delivery devices preferably includes mapping the determined shear stress rates to the geometry of each of the fluid delivery devices as represented by the provided geometry data, such mapping enabling an efficient simulation.

[0038] Furthermore, simulating the operation of each of the fluid delivery devices preferably includes categorizing the determined shear stress rates and distributing these categorized shear stress rates, which again allows for an efficient simulation to be achieved.

[0039] Preferably, the elastic part of any one of the liquid delivery devices is simulated as an additional liquid having a relatively high viscosity. Such an elastic part can be silicone or similar tubing. For example, such tubing is often used in peristaltic pumps. By simulating the elastic part as an additional liquid, its properties, in particular its elasticity, can be efficiently modeled.

[0040] In another aspect, the invention is a computer-implemented method for evaluating fluid delivery devices for a filling system for low-volume filling of a container with a liquid, the computer-implemented method including: acquiring delivery device data for a plurality of fluid delivery devices configured to provide fluid from a reservoir to a container; evaluating the acquired delivery device data to simulate operation of each of the fluid delivery devices by numerically modeling a flow pattern of the fluid as it is delivered by the fluid delivery device and determining a shear stress rate for each of the fluid delivery devices based on the modeled flow pattern; determining a validity for each of the fluid delivery devices by comparing operating parameters of the fluid delivery of the fluid delivery devices, including the determined shear stress rate; and providing a validity indicator data signal representative of the fluid delivery device having the highest determined validity.

[0041] The term "computer" as used herein can refer to any suitable computing device, e.g., a laptop computer, a desktop computer, a server computer, a tablet, a smartphone, or the like. The term covers single devices as well as combined devices. The computer can be, for example, a distributed system, e.g., a cloud solution, with different tasks performed in different locations.

[0042] A computer may typically be associated with a processor or central processing unit (CPU), persistent data storage having, for example, a recording medium such as a hard disk, flash memory, or the like, random access memory (RAM), and read only memory (ROM). It may further have communications adapters, for example, a universal serial bus (USB) adapter, a local area network (LAN) adapter, a wireless LAN (WLAN) adapter, a Bluetooth adapter, or the like, and a physical user interface, for example, a keyboard, a mouse, a touch screen, a screen, a microphone, speakers, or the like. A computer may be embodied using a wide variety of components.

[0043] The term "data signal" as used herein can refer to a measurable or determinable physical quantity or unit, or a sequence of such quantities or units, configured to represent information or data. In particular, the signal can be a voltage or potential, sound pressure, electromagnetic wave, field force, a sequence thereof, or any combination thereof. It can be physically transferred via a point-to-point or point-to-multipoint communication channel. Such channels can be copper wires, optical fibers, wireless communication channels, storage media, and computer buses. In any case, the signal or data signal can be recordable or conceivable and can be unambiguously determined. Data signals can be binary data signals, digital electronic signals, electromagnetic signals, or combinations thereof. They can represent specific data specifically packaged according to a specific protocol. This data itself can be a digital bitstream or the like. It represents physical and / or logical conditions and changes or the like. It can be in a format that is accessible and evaluable, in particular, by a computer executing the method.

[0044] The term "represent" in reference to a signal or data signal may relate to the presence of information. This does not exclude that other information may also be included in the signal or data signal apart from the information explicitly stated. For example, a data signal may represent information by being adjusted in a particular manner so that the information can be recollected or determined from the data signal.

[0045] The computer-implemented method and preferred embodiments thereof described below enable the effects and benefits of the process and preferred embodiments of the present invention to be efficiently realized. In particular, the computer-implemented method can be embodied in a fully automated manner, achieving efficient and accurate operation with a high degree of capability.

[0046] Preferably, obtaining the sending device data includes receiving a device data signal for each of the sending devices.

[0047] Simulating the operation of each of the liquid delivery devices preferably comprises applying CFD, whereby the CFD preferably comprises the Navier-Stokes equations, the Euler equations, the Stokes equations, the potential equations, or a combination thereof.

[0048] Preferably, simulating the respective liquid delivery operation comprises defining a moving part of the liquid delivery device as a generic movable object, whereby numerically modelling the flow pattern preferably comprises defining a displacement of the generic movable object over time.

[0049] Preferably, simulating each operation of delivering liquid comprises defining pressure boundary conditions at the liquid inlet of the liquid delivery device and at the liquid outlet of the liquid delivery device.

[0050] Preferably, the operating parameters include liquid properties, whereby the liquid properties preferably include viscosity. Additionally or alternatively, the liquid properties preferably include an indicator of the sensitivity of the liquid.

[0051] Preferably, the highest determined relevance is or is facilitated by the lowest shear rate.The liquid delivery device preferably comprises a piston pump and / or a peristaltic pump.

[0052] Preferably, the feeding device data includes geometry data for each of the liquid feeding devices, whereby simulating the operation of each of the liquid feeding devices preferably includes mapping the determined shear stress rates to the geometry of each of the liquid feeding devices represented by the provided geometry data. Additionally or alternatively, simulating the operation of each of the liquid feeding devices preferably includes classifying the determined shear stress rates and distributing these classified shear stress rates.

[0053] Preferably, the elastic part of any one of the liquid delivery devices is simulated as a further liquid having a relatively high viscosity.

[0054] In yet another aspect, the invention is a computer program comprising instructions which, when executed by a computer, cause the computer to perform the computer-implemented method described above.

[0055] The computer program may be a computer program product comprising computer code means adapted to control a processor of a computer and, when executed on the computer, to perform the computer-implemented method described above or below, or any of its preferred embodiments. Furthermore, a computer-readable medium may be provided comprising instructions which, when executed by a computer, cause the computer to perform the method described above or below, or any of its preferred embodiments. The medium may be a storage medium, and may be a mobile or portable storage medium to allow convenient distribution. Alternatively, a data carrier signal carrying the computer program described hereinabove may be provided to allow transfer via the Internet or the like, or for other purposes. The computer program may also be referred to as or be included thereby as software.

[0056] The computer program according to the present invention and its preferred embodiments make it possible to efficiently realize the benefits and effects of the above-mentioned computer-implemented method and its preferred embodiments.

[0057] The invention will now be described in more detail by way of exemplary embodiments and with reference to the accompanying drawings in which: [Brief explanation of the drawings]

[0058] [Figure 1] FIG. 1 shows a flow scheme of a process embodiment according to the present invention in relation to a computer executing a computer program embodiment to perform a computer-implemented method embodiment according to the present invention. [Figure 2] FIG. 2 shows a schematic diagram of a piston pump associated with the process and computer-implemented method of FIG. [Figure 3] FIG. 3 shows a schematic diagram of a radial peristaltic pump associated with the process and computer-implemented method of FIG. [Figure 4] FIG. 4 shows a schematic diagram of a linear peristaltic pump associated with the process and computer-implemented method of FIG. [Figure 5] FIG. 5 illustrates a graphical validity indicator generated within the process and computer-implemented method of FIG. DETAILED DESCRIPTION OF THE INVENTION

[0059] Certain terminology is used in the following description for convenience and is not intended to limit the invention. The terms "right," "left," "up," "down," "under," and "above" refer to directions in the drawings. The terms include explicitly described terms, derivatives thereof, and terms of similar meaning. Spatially relative terms, such as "beneath," "below," "lower," "above," "upper," "proximal," and "distal," may also be used to describe the relationship of one element or feature to another, as shown in the drawings. These spatially relative terms are intended to encompass different positions and orientations of each device during use or operation, in addition to the positions and orientations shown in the drawings. For example, if a device in the figures is turned upside down, any elements described as "below" or "beneath" another element or feature would then be "above" or "over" that other element or feature. Thus, the exemplary term "below" can include both above and below positions and orientations. Devices may be oriented otherwise (rotated 90 degrees or at other orientations) and interpreted accordingly by the spatially relative descriptors used herein. Similarly, descriptions of movement along and about various axes include various particular device positions and orientations.

[0060] To avoid repetition in the drawings and descriptions of the various aspects and embodiments to facilitate understanding, it should be understood that many features are common to many aspects and embodiments. The omission of an aspect from a description or drawing does not imply that the aspect is missing from the embodiment incorporating that aspect. Instead, the aspect may be omitted for clarity or to avoid redundant description. In this context, the following also applies to other parts of this specification: for the sake of clarity of the drawings, if a drawing includes a reference sign that is not described in a directly related part of this specification, it is referred to a previous or subsequent description section. Furthermore, for clarity, if a drawing does not provide a reference sign for every feature of a part, it is referred to another drawing showing the same part. The same number in two or more drawings represents the same or similar elements.

[0061] 1 shows an embodiment of a process 1 for constructing a filling system for low-volume filling of a container with a liquid 3 according to the present invention. Process 1 relates to a computer executing an embodiment of a computer program 4 for executing an embodiment of a computer-implemented method according to the present invention.

[0062] The process 1 includes a step 12 of acquiring three pumps 11 as liquid delivery devices. The pumps 11 are configured to provide liquid from a reservoir to a container. More specifically, piston pump technical drawing data 111, radial peristaltic pump technical drawing data 112, and linear peristaltic pump technical drawing data 113, each represented by a data signal, are transferred to a computer via an interface 41 implemented by a computer program 4. Furthermore, liquid property data 31, including properties of the liquid 3, such as its viscosity and sensitivity, each represented by a data signal, are transferred to the computer via the interface 41.

[0063] In step 13 of process 1, which is implemented by computer program 4, the operation of each of the pumps 11 is simulated by numerically modeling the flow pattern of the liquid 3 as it is being pumped by the liquid delivery device and determining the shear stress rate for each of the pumps 11 based on the modeled flow pattern.

[0064] More specifically, the obtained technical drawing data 111, 112, 113 and the obtained liquid property data 31 are evaluated by a computer program to simulate the operation of each of the pumps 11 by applying computational fluid dynamics (CFD) to numerically model the flow pattern of the liquid 3 as it is being pumped by the pumps 11 and by determining the shear stress rate for each of the pumps 11.

[0065] In a first substep 131, the respective behavior of the pump 11 is modeled by defining the moving parts of the pump 11 as generic moving objects, whereby the displacement of the generic moving objects over time is defined.

[0066] In a second sub-step 132, pressure boundary conditions are defined at the liquid inlet of the pump 11 and at the liquid outlet of the pump 11. Furthermore, the determined shear stress rates are mapped to the respective geometry of the pump 11, represented by the technical drawing data 111, 112, 113. The determined shear stress rates are classified and the classified shear stress rates are distributed.

[0067] In step 14 of process 1, which is implemented by computer program 4, the adequacy of each of pumps 11 is determined by comparing the operating parameters of the pumping process of pumps 11. The operating parameters include the determined shear stress rate, the geometry of pump 11, and the liquid properties.

[0068] In step 15 of process 1 implemented by computer program 4, a suitability indicator data signal is provided. This suitability indicator data signal represents one of pumps 11 having the highest determined suitability. For example, such a suitability indicator data signal may be associated with a number, a graphical symbol, or the like, that allows an operator to identify the most appropriate pump 11.

[0069] In step 16 of process 1, the operator selects one of the pumps with the highest determined validity.

[0070] In step 17 of process 1, a selected one of the pumps 11 is installed in the filling system. In this way, the most appropriate filling system can be set up in a given situation in an efficient manner.

[0071] By way of example, the three pumps 11 involved in the process 1 and computer-implemented method shown in Figure 1 are described in more detail below. In particular, Figure 2 shows a rotary piston pump 21, depicted in four successive positions from left to right. The piston pump 21 has an essentially cross-shaped housing 212 with a liquid inlet on the left and a liquid outlet on the right. A rod-like piston 211 is received vertically in the housing 212.

[0072] In the leftmost view of Figure 2, the liquid inlet is open, allowing liquid 3 to flow from the reservoir into the interior 213 of the housing 212. As the arrow indicates, this liquid flow is induced by the piston 211 moving upward, which draws liquid 3 from the reservoir into the interior 213.

[0073] As the arrow in the second leftmost drawing in Figure 2 indicates, when the interior 213 of the housing 212 is filled, the piston 211 rotates 180 degrees about its longitudinal axis, closing the liquid inlet and instead opening the liquid outlet.

[0074] The piston then moves vertically downwards, as shown by the arrow in the second rightmost drawing of Figure 2, causing liquid 3 to be forced out of interior 213 and through the liquid outlet into the container.

[0075] Once the piston has moved fully downward, as shown by the arrow in the right-most drawing of Figure 2, it again rotates 180 degrees, causing the liquid outlet to close and the liquid inlet to open. The process can now begin again.

[0076] With each cycle of movement of the piston 211 as previously described herein, a precisely predetermined amount or dosage of liquid 3 is delivered and exits the liquid outlet. In this way, the liquid can be precisely dispensed into the container.

[0077] Piston pump 21 can be used specifically for high-precision aseptic filling because the fill volume can be adjusted very precisely. Piston pump 22 is limited to a defined range of dosages, and therefore, different pump sizes may be required if a specific range of fill volumes must be covered. In general, piston pumps are often used due to their high filling accuracy and precision, especially for low fill volumes, e.g., ≦0.3 ml.

[0078] Figure 3 shows a radial peristaltic pump 22. The radial peristaltic pump 22 includes tubing 221 with a liquid inlet on the left side and a liquid outlet on the right side, a housing 225, and a rotor 222. The housing 225 forms a stator with a semicircular counter pressure portion 224. The tubing 221 is located between the rotor 222 and the counter pressure portion 224. The counter pressure portion 224 is adjustable to accommodate the distance to the rotor 222, allowing for the use of tubing of various sizes. The rotor 222 includes three rollers 223 distributed at regular intervals around its circumference.

[0079] To pump liquid from the liquid inlet to the liquid outlet, rotator 222 rotates clockwise, causing rollers 223 to squeeze tubing 221 against counterpressure section 224, forcing liquid to move clockwise through tubing 221. The distance between rollers 223, the diameter of tubing 221, and the elasticity of tubing 222 enable radial peristaltic pump 22 to precisely pump a predetermined volume or dosage of liquid through the liquid outlet.

[0080] One advantage of the radial peristaltic pump 22 is the fact that the liquid only comes into direct contact with the tubing 222 and not with other parts of the pump 22. This allows for minimizing the presence of potential extractables, leachables, and particulates. However, the use of tubing materials that are suitable for an aseptic fill-finish process and therefore capable of being washed and sterilized at 121°C and 2 bar pressure can be highly important. Additionally, there are constraints regarding leachables, extractables, and particulates that must be considered.

[0081] 4 shows a linear peristaltic pump 23 having a housing 232, a counter pressure plate 234, and six linear piezoelectric actuators 233. Tubing 231 extends vertically between the piezoelectric actuators 233 and the counter pressure plate 234. The piezoelectric actuators 233 can move back and forth horizontally. The alternating movement of the piezoelectric actuators 233 pumps liquid from an upper liquid inlet of the tubing 231 to a liquid outlet of the tubing 231. More specifically, the linear peristaltic pump 23 can operate as described in WO2016 / 012567A1.

[0082] The fill capacity of the linear peristaltic pump 23 may be controlled by the amount of cycles, the number of displacing piezo actuators 233, the actuator size, the pre-compression of the tubing by the counter pressure plate 234, and the elasticity of the tubing 231. Compared to radial peristaltic pumps, the orthogonal motion and lack of a tangential force vector may result in less relative motion of the inner surface of the tubing, resulting in less material damage and less particle entrainment.

[0083] 5 shows a graphical plausibility indicator represented by the plausibility indicator data signal provided in step 15 above. More specifically, the velocity and shear rate during low-volume aseptic filling is simulated based on technical drawing data 111, 112, 113 for each one of the pumps 11. FIG. 5 shows the shear rate and corresponding fluid velocity for two successive motion states for different pumps 11. This analysis allows for estimation as to the shear rate level during low-volume filling depending on the pump type.

[0084] As can be seen in Figure 5, the shear rate in the radial peristaltic pump 22 is about 10 to 20 times higher compared to the piston pump 21. CFD analysis shows the highest shear rate from the linear peristaltic pump 23. This observation is based on the high fluid velocity induced by the rapid movement of the six piezo actuators 233 inside the linear peristaltic pump 23.

[0085] The present specification and accompanying drawings illustrating various aspects and embodiments of the present invention should not be construed as limiting the scope of the claims defining the protected invention. In other words, while the present invention has been shown and described in detail in the drawings and the foregoing specification, such illustrations and descriptions are to be considered as illustrative and for purposes of understanding only, and are not limiting in any way. Various mechanical, compositional, structural, electrical, and operational changes may be made without departing from the spirit and scope of the present specification and claims. In some instances, known circuits, structures, and techniques have not been shown in detail so as not to obscure the present invention. Accordingly, it should be understood that those skilled in the art may make modifications and variations within the scope and spirit of the following claims. In particular, the present invention encompasses additional embodiments that combine any of the features different from the embodiments described above and below. For example, the present invention may be implemented in an embodiment in which additional parameters, in addition to shear rate, are used in the simulation.

[0086] In fact, as experimentally verified, one particular protein-containing liquid used in pump 11 to validate the simulation showed the highest number of particles not visible to the naked eye after piston pump 21, despite the shear rate being higher than that of the other two pumps. Therefore, the effect of space on protein damage can be included in the simulation. In particular, this space provides a recirculation zone, and as a result, the liquid may undergo multiple pumping cycles. Therefore, it is desirable to include appropriate measures in the simulation. To achieve this, a parameter called "mean volume fatigue" can be involved. This allows for the prediction of the stress level to which a protein liquid formulation will be exposed at any point during aseptic filling over multiple pump cycles. Fatigue is a well-known parameter in materials science that describes the weakening of materials after repeated use or loading. Mean volume fatigue can indicate that after one filling cycle, the shear rate levels are comparable in all three pump types used in the above embodiment. By considering the recirculation zone inside the piston pump 21, the cyclic shear volume fraction is included in this calculation, which may indicate the cumulative average volume fatigue for the piston pump 21. This will result in the highest particle count and therefore the lowest validity.

[0087] The present disclosure also encompasses all additional features individually shown in the drawings, which may not be described in the above or following description. Furthermore, single alternatives to the embodiments and features described in the drawings and specification may be exempt from the subject matter of the present invention or the subject matter disclosed. The present disclosure includes subject matter that comprises the features defined in the claims or exemplary embodiments, as well as subject matter that includes such features.

[0088] Furthermore, in the claims, the term "comprising" does not exclude other elements or steps. The indefinite articles "a" or "an" do not exclude a plurality. A single unit or step may fulfill the functions of several features recited in the claims. The mere fact that certain measurements are recited in mutually different dependent claims does not indicate that a combination of those measurements cannot be used to advantage. Terms such as "essentially," "about," and "approximately" in connection with an attribute or value also specifically define that exact attribute or that exact value, respectively. The term "approximately" in the context of a given numerical value or range refers to a value or a range, for example, within 20%, within 10%, within 5%, or within 2% of the given value or range. Components described as joined or connected may be directly joined electrically or mechanically, or indirectly joined via one or more intermediate components. Any reference signs in the claims should not be construed as limiting the scope of the invention.

[0089] The computer program may be stored / distributed on a suitable medium, for example an optical storage medium or a solid-state medium provided together with or as part of other hardware, but may also be distributed in other forms, for example via the Internet or other wired or wireless telecommunication systems. In particular, for example, the computer program may be a computer program product stored on a computer-readable medium. In this medium, the computer program product may have computer-executable program code adapted to be executed to perform a specific method, for example, a method according to the present invention. Furthermore, the computer program may also be a data structure product or a signal for implementing a specific method, for example, a method according to the present invention.

Claims

1. 1. A process for constructing a filling system for low volume filling of a container with a liquid (3), comprising: obtaining a plurality of liquid delivery devices (21, 22, 23) configured to provide said liquid from a reservoir to said container; simulating the operation of each of the liquid delivery devices (21, 22, 23) by numerically modelling a flow pattern of the liquid (3) as it is being delivered by the liquid delivery devices (21, 22, 23) and determining a shear stress rate for each of the liquid delivery devices (21, 22, 23) based on the modelled flow pattern; determining the adequacy of each of the liquid delivery devices (21, 22, 23) by comparing operational parameters of the liquid (3) delivery of the liquid delivery devices (21, 22, 23), including the determined shear stress rate, the adequacy being a measure or signal that allows identification of the most suitable liquid delivery device; selecting the liquid delivery device (21, 22, 23) having the highest determined validity; installing the selected liquid delivery device (21, 22, 23) in the filling system; A process involving:

2. 2. The process of claim 1, wherein the operation of each of said liquid delivery devices (21, 22, 23) is simulated by applying computational fluid dynamics.

3. The process of claim 2, wherein simulating the operation of each of the liquid delivery devices (21, 22, 23) comprises defining a moving part of the liquid delivery device as a generic moving object.

4. The process of claim 3 , wherein numerically modeling the flow pattern includes determining the displacement of the generic movable object over time.

5. 5. The process according to claim 1, wherein simulating the operation of each of the liquid delivery devices (21, 22, 23) comprises defining pressure boundary conditions at the liquid inlets of the liquid delivery devices (21, 22, 23) and at the liquid outlets of the liquid delivery devices.

6. The process of claim 1 , wherein the operating parameters include liquid properties.

7. 7. The process of claim 1, wherein the highest determined relevance is the lowest shear stress rate.

8. 8. The process according to any one of claims 1 to 7, wherein the liquid delivery device (21, 22, 23) comprises a piston pump and / or a peristaltic pump.

9. 9. The process according to claim 1, wherein acquiring the plurality of liquid delivery devices (21, 22, 23) comprises providing geometry data (111, 112, 113) of each of the liquid delivery devices (21, 22, 23).

10. The process of claim 9, wherein simulating the operation of each of the liquid delivery devices (21, 22, 23) comprises mapping the determined shear stress rate to the geometry of each of the liquid delivery devices represented by the provided geometry data (111, 112, 113).

11. 11. The process of claim 9 or claim 10, wherein simulating the operation of each of the liquid delivery devices (21, 22, 23) comprises classifying the determined shear stress rates and distributing the classified shear stress rates.

12. 12. The process according to any one of claims 1 to 11, wherein the elastic part (221, 231) of any one of the liquid delivery devices (21, 22, 23) is simulated as a further liquid having a relatively high viscosity.

13. 1. A computer-implemented method for evaluating a liquid delivery device for a filling system for low volume filling of a container with a liquid (3), comprising: acquiring delivery device data (111, 112, 113) of a plurality of said liquid delivery devices (21, 22, 23) configured to provide said liquid (3) from a reservoir to said container; evaluating the obtained delivery device data (111, 112, 113) to simulate the operation of each of the liquid delivery devices (21, 22, 23) by numerically modeling a flow pattern of the liquid (3) while being delivered by the liquid delivery devices (21, 22, 23) and by determining a shear stress rate for each of the liquid delivery devices (21, 22, 23) based on the modeled flow pattern; determining the adequacy of each of the liquid delivery devices (21, 22, 23) by comparing operational parameters of the liquid (3) delivery of the liquid delivery devices (21, 22, 23), including the determined shear stress rate, the adequacy being a measure or signal that allows identification of the most suitable liquid delivery device; providing a validity indicator data signal representative of the fluid delivery device (21, 22, 23) having the highest determined validity; A method comprising:

14. 14. The computer-implemented method of claim 13, wherein obtaining the feeding device data (111, 112, 113) comprises receiving a device data signal for each of the feeding devices (21, 22, 23).

15. 15. A computer-implemented method according to claim 13 or claim 14, wherein the delivery device data (111, 112, 113) comprises geometry data of each of the liquid delivery devices (21, 22, 23).

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