Control of buffer preparation process

Abstract

The present invention relates to a computer-implemented method for controlling the preparation of a liquid mixture, the liquid mixture comprising an acid and its conjugate base or a base and its conjugate acid. The method comprises obtaining (S11) a composition for the liquid mixture to be prepared, and determining (S12) a plurality of settings for controlling the preparation of the liquid mixture in one or more automated processes. The plurality of settings are provided (S13) to one or more control systems of the one or more automated processes. The present invention also relates to a buffer tool configured to perform the computer-implemented method, a buffer management system comprising the buffer tool, and a computer-readable storage medium (25) on which a computer program is stored, which, when executed in the buffer tool, causes the execution of the computer-implemented method.

Description

Technical Field

[0001] The present disclosure relates to the field of bioprocessing and, more particularly, to the field of controlled preparation of liquid mixtures, such as buffers. Background Art

[0002] In the field of biological treatment, it is important to obtain liquids of precisely known composition in many cases. In many cases, the composition of the liquid should not only be precisely known and controlled at each moment, but also should change over time in a precise and controlled manner.

[0003] Buffer solution is an aqueous solution which includes a mixture of acid, base and possibly salt and water WFI for injection. The mixture includes a weak acid and its conjugate base or a weak base and its conjugate acid mixed in a controlled process.

[0004] The property of a buffer is that when a small amount of a strong acid or base is added to a buffer solution, there is only a slight effect on the pH of the buffer solution. Therefore, buffer solutions can be used as a means to maintain the pH at a near constant value in a large number of chemical applications, such as chromatography or other types of filtration operations. Feedback control can also be applied to maintain the desired accuracy of the buffer solution.

[0005] A buffer solution having a desired pH and optionally a desired ionic strength can be prepared by calculating the necessary amounts of the buffer components and mixing them. The mixing of these components can be performed in a preparative system used as a buffer kitchen or as a chromatography system. An example of such a system is the ÄKTA TM Avant and BioProcess Inline Conditioning (IC) systems. ÄKTA TM Avant is a buffer mixing device that can prepare buffer solutions from a stock solution using a quaternary valve. IC is a buffer mixing device with several pumps for different components. Buffer management systems for inline buffer preparation using concentrated single-component stock solutions of acids, bases, salts and WFI are already in operation. The use of concentrates significantly reduces buffer volume, saving floor space and tank volume. Many different buffers can be prepared from the same collection of concentrates, streamlining buffer preparation. For precision of formulation and consistency between preparations, it is possible to select different feedback modes featuring built-in dynamic control functionality. This type of inline buffer preparation system (also called inline regulation system) can be used for buffer preparation, but is also used as a chromatography system.

[0006] Chromatography is a technique for separating chemical and biological substances. In liquid chromatography, buffer solutions are essential components of the process. It is important to use liquids of precisely known composition and / or other properties (e.g., pH, ionic strength, etc.) in chromatography. There may also be a need to change the composition of a liquid over time. This composition and its variation can be obtained by mixing or blending two or more liquids with each other using a mixing system.

[0007] Buffer solutions with desired properties can be prepared by, for example, calculating the necessary amounts of buffer components using commercially available software and mixing them. Buffer mixing devices are well known, for example as disclosed in the following background patent applications / patents, which are incorporated by reference in their entirety: EP 2269055 A1, US 9446329 B2, US 2011 / 0039712 A1, WO 2009 / 131524 A1, US 9327212 B2, US 2012 / 0217192 A1, EP 2480943 A1, WO 2011 / 037530 A1, EP 2585887 A1, US 2013 / 0081703 A1, and WO 2011 / 162666 A1. Although the background technology includes software solutions for calculating the relative concentrations of different components of relatively simple mixtures of weak acids (or bases) and weak bases (or acids) according to pH (e.g., as defined in EP 2269055 A1), there is still a need to control the preparation of buffers of more complex nature. Conventional software solutions do not support the preparation of such complex buffers (e.g., buffers including additional ingredients and salts). And although there are buffer mixing devices (e.g., as defined in EP 2269055 A1) that can be used to obtain relative concentrations using feedback control of a specific run, the use of more complex buffers of this type still requires tools to analyze the information obtained from such results of controlling new runs using similar but different control parameters. Examples of such control parameters are buffer concentration, salt and additive concentrations, and the concentration and volume of stock solutions. Other examples of related parameters are pH, the flow rate of the prepared buffer, the flow rate range of the pump used in the system, or the range of the relative division of the valve in the case of a quaternary valve, and the selection of key parameters among the interrelated parameters such as conductivity and concentration.

[0008] Therefore, methods and tools are needed for calculating the necessary amounts and using these calculated settings for buffer solution generation, for example for buffer solutions of complex nature being a combination of different strong electrolytes (e.g. salts and fully dissociated even strong acids or bases) or weak electrolytes (e.g. partially ionized buffer substances) or combinations thereof. Summary of the invention

[0009] It is an object of the present disclosure to mitigate, alleviate or eliminate one or more of the above mentioned deficiencies in the art.

[0010] According to a first aspect, this is achieved by a computer-implemented method for preparing a liquid mixture, wherein the liquid mixture comprises an acid and its conjugate base or a base and its conjugate acid.

[0011] The computer-implemented method includes obtaining a composition for a liquid mixture to be prepared, and determining a plurality of settings for controlling the preparation of the liquid mixture in one or more automated processes. The plurality of settings are provided to one or more control systems of the one or more automated processes.

[0012] In some embodiments, obtaining the composition for the liquid to be prepared includes information indicating a plurality of properties of the liquid mixture. In response to receiving the information of the plurality of properties and applying at least one software-implemented algorithm, the composition for the liquid mixture to be prepared is determined.

[0013] According to some embodiments, the property of the liquid mixture includes liquid mixture type, liquid mixture concentration, and at least one of liquid mixture density and liquid mixture conductivity. The software implemented algorithm may be an algorithm for molarity calculation or molar mass calculation.

[0014] According to some embodiments, determining a plurality of settings for controlling the preparation of the liquid mixture includes retrieving information for a selected automatic process of the one or more automatic processes. A control mode of a control system of the selected automatic process may be determined; the automatic process operates using the control mode.

[0015] According to some embodiments, the control mode includes one or more of flow feedback, pH feedback, and conductivity feedback.

[0016] According to some embodiments, the automated process operates as a buffer kitchen or as a chromatography system. When operating as a chromatography system, the control mode may include programming of a quaternary valve of the chromatography system.

[0017] According to some embodiments, determining a plurality of settings for controlling the preparation of the liquid mixture further includes determining one or more stock concentrations, and determining one or more pump settings for corresponding pumps used in the automated process.

[0018] In some embodiments, determining a plurality of settings for controlling the preparation of the liquid mixture includes retrieving one or more boundary conditions of the corresponding settings from one or more control systems and verifying satisfaction of the one or more boundary conditions. The boundary conditions may include one or more of a minimum and / or maximum flow rate of a corresponding pump used in the automated process and an acid reserve volume, a base reserve volume.

[0019] According to a second aspect, the object of the present disclosure is achieved by a buffer tool for controlling the preparation of a liquid mixture, wherein the liquid mixture includes an acid and its conjugate base or a base and its conjugate acid. The buffer tool includes a user interface, a control system interface, and a processing circuit system. The processing circuit system is configured to perform the method according to the first aspect.

[0020] According to a third aspect, the object of the present disclosure is achieved by a computer-readable storage medium having stored thereon a computer program which, when executed in a buffer tool, causes the performance of the method according to the first aspect.

[0021] According to a fourth aspect, the object of the present disclosure is achieved by a buffer management system for controlling the preparation of a liquid mixture, wherein the liquid mixture comprises an acid and its conjugate base or a base and its conjugate acid. The buffer management system comprises: one or more automated processes for preparing the liquid mixture; one or more control systems for controlling the one or more automated processes; and a buffer tool according to the third aspect.

[0022] The above disclosed aspects enable the preparation of a liquid mixture based on an expected pH and / or ionic strength and buffer capacity, for example according to the type of buffer, buffer concentration and / or salt concentration. Based on the expected pH of the liquid mixture and optionally also based on the expected ionic strength and buffer capacity, the present invention provides settings for the preparation of a liquid mixture with an expected pH, ionic strength and buffer capacity.

[0023] The above disclosed aspects provide improvements in the preparation of liquid mixtures (e.g., in buffer preparation) because the exact composition is first calculated and put into use for the subsequent preparation of the liquid mixture in a single step. id Subsequent use in an automated process of the mixture. Thus, the above disclosed aspects provide for automatic calculation of molar formulas, stock concentrations, and appropriate pump settings based on the pumps available in the system. The above disclosed aspects for liquid preparation can be used, for example, in buffer / process development, buffer / biopharmaceutical production, and in automated dispensing devices for intelligent buffer preparation in microplates or other labware.

[0024] The present invention is useful for determining the relative composition ratios of buffering species where, in addition to the buffering species, one or more non-buffering salts and additives are present.

[0025] The present invention facilitates determining the relative composition ratios of a liquid mixture (e.g., a buffer) that includes two or more buffer species, generally referred to as multiple buffer species liquids. Thus, according to some embodiments, two or more stock solutions may be prepared that include different buffer species. In alternative embodiments, a stock solution including multiple buffer species may be provided. BRIEF DESCRIPTION OF THE DRAWINGS

[0026] The foregoing will be apparent from the following more particular description of example embodiments, as illustrated in the accompanying drawings, in which like reference characters refer to the same parts throughout the different views. The drawings are not necessarily drawn to scale, emphasis instead being placed upon illustrating example embodiments.

[0027] Figure 1 is a flow chart illustrating example method steps for controlling the preparation of a liquid mixture.

[0028] Figure 2 is a schematic diagram of a buffer tool.

[0029] FIG. 3a is an example schematic diagram of a buffer management system.

[0030] FIG. 3b is an example schematic diagram of a buffer management system.

[0031] Figure 4 is an example illustration of a user interface to a computer implemented buffer tool.

[0032] Figure 5 A system for preparing or generating a buffer solution is shown.

[0033] Figure 6 A system for generating a buffer solution according to one or more embodiments of the present disclosure is shown.

[0034] Figure 7 On-demand generation of buffer solutions for containers in accordance with one or more embodiments of the present disclosure is shown.

[0035] Figure 8 On-demand generation of buffer solutions for containers in accordance with one or more embodiments of the present disclosure is shown.

[0036] Fig. 9 A control unit according to one or more embodiments of the present disclosure is shown.

[0037] Fig.10 A flow chart illustrating a computer-implemented method in accordance with one or more embodiments of the present disclosure.

[0038] Fig.11 A representation of an operating space is shown in accordance with one or more embodiments of the present disclosure.

[0039] Fig.12 Table showing exemplary target properties of target buffer solutions.

[0040] Fig.13 A table showing exemplary system characteristics of the generation system.

[0041] Fig.14 Tables showing exemplary system and / or component configurations.

[0042] Fig.15 Table showing exemplary target properties of target buffer solutions.

[0043] Fig.16 Tables showing exemplary system and / or component configurations.

[0044] Fig.17 A representation of an operation space, a combination process, is shown in accordance with one or more embodiments of the present disclosure. DETAILED DESCRIPTION

[0045] This application is related to U.S. Patent Application No. US9327212, which is incorporated herein by reference in its entirety. This application further relates to European Patent Application No. EP2585887, which is incorporated herein by reference in its entirety. The present invention is related to PCT Application WO2018229271—METHOD AND APPARATUS FOR DETERMINING ONE OR MOREBUFFER COMPOSITION RECIPES, which is incorporated herein by reference in its entirety.

[0046] In the following detailed description, reference is made to the accompanying drawings which form a part of the description, in which specific embodiments that may be implemented are shown by way of illustration. These embodiments are described in sufficient detail to enable those skilled in the art to implement the embodiments, and it is understood that other embodiments may be utilized and that logical, mechanical and other changes may be made without departing from the scope of the embodiments. Therefore, the following detailed description is not to be construed as limiting the scope of the invention.

[0047] The terms used herein are only used to describe specific aspects of the present disclosure and are not intended to limit the present invention. When used in this specification, the terms "comprise" and "comprising" are used to specify the presence of the features, integers, steps or components, but do not exclude the presence or addition of one or more other features, integers, steps, components or groups thereof. As used herein, the singular forms "a", "an" and "the" are intended to include the plural forms as well, unless the context clearly indicates otherwise.

[0048] In the context of the present disclosure, a buffer is a component or compound that maintains a nearly constant pH value in the form of a liquid mixture, regardless of the addition of a large amount of acid and / or base. A buffer solution is an aqueous solution that includes a weak acid and its conjugate base or a weak base and its conjugate acid. In order to prepare such a liquid mixture (i.e., a buffer solution), the amount of the weak acid / base and its conjugate base / acid and the salt solution as a molar value or a so-called molar formula is calculated. From these molar values, the volume required from the corresponding stock solution or stock concentration can be calculated. A stock solution of an acid and a base can be prepared to a known concentration by diluting the weighted amount of the buffer salt to the measured volume and controlling the flow from the stock solution and water to the common mixing point of the buffer.

[0049] The preparation of the liquid mixture can be performed in a preparation system used as a buffer preparation system / buffer mixing system (also referred to herein as a buffer kitchen) or as a chromatography system (i.e., a buffer mixing system including (one or more) chromatography columns). Storage Buffer preparation device for bags.

[0050] An example of such a system or buffer preparation device is the ÄKTA TM Avant and BioProcess Inline Conditioning (IC) systems. ÄKTA TM Avant is a buffer mixing device that uses a multi-port valve (e.g. a quaternary valve that allows automatic mixing of four different components / fluids) from a stock component. The use of a multi-port valve enables flow control of multiple fluids / components to be mixed. IC is a buffer mixing device with several pumps for different fluids / components.

[0051] The "or" in this description and the corresponding claims is to be understood as a mathematical OR covering "and" and "or", rather than being understood as XOR ("exclusive or"). The indefinite article "a" in this disclosure and the claims is not limited to "one", but can also be understood as "one or more" (i.e., a plurality).

[0052] In this disclosure, reference will be made interchangeably to the term "container" or the term "reservoir" to denote a receptacle suitable for holding a fluid.

[0053] In this disclosure, reference will be made interchangeably to the term "processing circuitry" and the term "processing component."

[0054] In this disclosure, reference will be made interchangeably to the terms "composition" and "recipe" of a liquid mixture, referring to the proportions of the respective ingredients in the mixture that results in a target buffer solution.

[0055] In this disclosure, the terms "preparation" and "generation" will be referred to interchangeably in the context of preparing a liquid mixture, typically a buffer solution. In one example, preparing or generating a liquid mixture or buffer solution includes mixing the ingredients according to a recipe to give the correct proportions of the respective ingredients and producing the target buffer solution. The preparation of a buffer solution typically involves the use of concentrated stock solutions of the single ingredients, hydrochloric acid, a base, and water for injection (WFI), and may also include various additives (e.g., urea, polysorbate, and glycerol).

[0056] In the present disclosure, reference will be made interchangeably to the terms "settings for controlling preparation of a liquid mixture" and "assigned control parameters" to refer to settings and / or parameters used to configure and / or control preparation / generation of a liquid mixture / buffer solution.

[0057] In this disclosure, reference will be made interchangeably to the terms "control system" and "control unit" to refer to a device comprising a processing circuit system and a memory containing instructions executable by the processing circuit system to perform any of the steps or methods described herein, typically controlling the preparation / generation of buffer solutions in an automated process.

[0058] In the present disclosure, reference will be made interchangeably to the terms "property of the liquid mixture" and "target characteristic of the target buffer solution", meaning the desired property or characteristic of the liquid mixture / buffer solution to be prepared.

[0059] In the present disclosure, the term "fluid source" refers to a unit or arrangement capable of providing a fluid, such as a fluid container. In the following description, the fluid source will be described as a container, but any suitable fluid source may be used.

[0060] In the present disclosure, the term "on-demand buffer solution generation system" refers to a generation system that generates a target buffer solution according to user demand, and is usually arranged at the location of a chromatography device or geographically close to it. In the present disclosure, the term "on-demand buffer solution generation system" is used interchangeably with "generation system".

[0061] In the present disclosure, the term "operation space" refers to the space formed by limits within which a buffer generation system can be operated given a plurality of operating parameters (e.g., pump flow rates, pipe dimensions, and component concentrations). In other words, the operation space can be viewed as an abstraction of a multidimensional space within which the parameters controlling the generation of a buffer solution can be changed and will result in the generation of a target buffer solution by an on-demand system for generating a buffer solution. For example, the system characteristics and Element The multiple possible configurations of a feature will RealityThe given target characteristics of the target buffer solution generated by the generating system will now be described. In other words, any configuration selected from a large number of possible configurations can be used to generate the target buffer solution type.

[0062] In this disclosure, the term "buffer solution" refers to a fluid for use with a chromatography device, such as to suspend a sample prior to performing a chromatography procedure.

[0063] In the present disclosure, the term "target property" defines the property of a target buffer solution to be generated by an on-demand buffer solution generating system.

[0064] In this disclosure, the term "system characteristics" defines the properties of an on-demand buffer solution generating system, such as pump flow rate range, tubing dimensions, and vessel volumes.

[0065] In this disclosure, the term "ingredient characteristics" defines the properties of the ingredients used to generate the buffer solution, such as ingredient concentration and ingredient type, such as acid, base, or salt.

[0066] In the present disclosure, the term "external operating limits" defines the range of properties of the target buffer solution and / or the on-demand buffer solution generation system and / or the properties of the components used to generate the buffer solution. For example, the minimum and maximum pH of the generated buffer solution give the system configuration including the concentrations of the components. In one example, such external operating limits are given by boundary conditions. Examples of such boundary conditions include one or more of the maximum / minimum acid reserve volume, the maximum / minimum base reserve volume, the maximum / minimum flow rate, and the maximum / minimum flow rate of the corresponding pump used in the automatic process.

[0067] The present invention is useful for determining the relative proportions of components of a liquid mixture (e.g., a buffer) comprising two or more buffer species, generally considered to be a plurality of buffer species liquids. Thus, in one embodiment, the present invention is a method as described above, wherein two or more stock solutions are prepared, the stock solutions comprising different buffer species. In alternative embodiments, a stock solution comprising at least two (e.g., three, four or more) buffer species is provided.

[0068] The present invention is useful for determining the relative composition ratios of buffering species where, in addition to the buffering species, one or more non-buffering salts and additives are present.

[0069] The Buffer Tool will control the IC system to operate as a buffer kitchen or as a chromatography system. The tool can control one buffer or generate a method to run the entire production process including the chromatography step. The system controlled by the Buffer Tool can be used as a buffer kitchen or as a chromatography system. When used as a chromatography system, Buffer Control provides the generation of a method to run the actual chromatography. Control provides optimization of the process and process development as well as providing validation production of biopharmaceuticals.

[0070] Figure 1 is shown for controlling, for example, Figure 2 Flow chart of example method steps for preparation of a liquid mixture including an acid and its conjugate base or a base and its conjugate acid performed in the disclosed buffer tool.As disclosed in FIG3 , the buffer tool may be included in a buffer management system.

[0071] In an optional initial step, a computer-implemented method for controlling the preparation of a liquid mixture includes retrieving information related to controlling the preparation of a liquid mixture in one or more automated processes. The computer-implemented method may be implemented in a computer having a Figure 4 The present invention is implemented in a computer-implemented buffer tool of the user interface disclosed in , wherein traffic light colors are preferably used to indicate satisfaction, partial satisfaction, and non-satisfaction of set conditions. Information related to controlling the preparation of a liquid mixture in one or more automated processes may include, for example, Figure 4 Process information associated with one or more automated processes is presented in Section 2 of the Buffer Tool interface shown in FIG.

[0072] The information may also include information on Figure 4 The method of claim 1, wherein the algorithm is operable to access at least one computer-implemented algorithm as set forth in section 3 of the buffer tool interface disclosed in the present invention, wherein the computer-implemented algorithm is operable to determine the composition of the liquid mixture. Figure 4 Parts 2 and 3 of the user interface disclosed in the disclosure prompt the user to receive information. In one implementation of the computer-implemented method, four questions need to be answered in the tool: "Use pH feedback ”, “Combination type of buffer ","Salt and “Which is more important to the process—concentration or conductivity?” Information may also be received in part by retrieving information from the control system, from a database associated with the control system, or from a database associated with the buffer tool and including library information defining a large number of buffer solutions. Examples of other information that may be retrieved include buffer system, pH, salt type, additive type, flow rate, buffer volume, process step time, molar formula, etc., and may be requested by prompting the user for information. interest Or the information is automatically retrieved as a combined operation of initiating automatic retrieval in response to receiving prompted information.

[0073] In its most general form, a computer-implemented method for controlling the preparation of a liquid mixture (the liquid mixture includes an acid and its conjugate base or a base and its conjugate acid) comprises the following steps: retrieving S11 a predetermined composition of the liquid mixture to be prepared, i.e., information or target properties of a target buffer solution defining a target buffer and / or properties of such a target buffer. In response to receiving an identifier of the liquid mixture (e.g., a buffer name), in-depth information related to the properties of the buffer may be retrieved from a database including library information defining a large number of buffer solutions or calculated from parameters retrieved during execution of the computer-implemented method as described above. Thus, information related to the relative proportions of the reserve concentrations to be included in the liquid mixture may be retrieved, for example, by means of wired or wireless communication, from a database associated with a buffer tool or accessible from the buffer. Information on the relative proportions may also be directly input to the buffer tool in the user interface of the buffer tool. Although the liquid mixture in its most general composition may consist only of a composition including a weak acid and a conjugate base (or vice versa), the composition will in most cases also include concentrations of salts, water, and / or other additives. Such other additives include, for example, detergents that may contribute to protein stability and urea that may contribute to protein instability. In the context of buffer preparation, additives consist primarily of neutral molecules, whereas salts consist of charged particles used to control conductivity.

[0074] According to some embodiments, obtaining S11 the composition of the liquid to be prepared includes, for example, prompting S11a information of multiple properties of the liquid mixture by means of a user interface or a liquid mixture composition interface, for example Figure 4 Examples of such properties include liquid mixture type, liquid mixture concentration, and at least one of liquid mixture density and liquid mixture conductivity. The liquid mixture pH may be determined as a function of the conductivity and concentration of the buffer solution. However, the liquid mixture pH may also represent a preset property of the liquid to be prepared.

[0075] In response to receiving information of the plurality of attributes, an algorithm may be implemented by applying at least one software, such as using Figure 4 The composition of the S11b liquid mixture is determined using a molar concentration calculation or a molar mass calculation algorithm shown in section 3 of the Buffer Tool interface shown.

[0076] According to some embodiments, obtaining the composition of the liquid to be prepared in S11 includes running an experiment on a chromatographic device. The step of obtaining the composition of S11 includes obtaining experimental design DoE data, wherein the DoE data indicates a set of buffer compositions and corresponding unique formulas. The DoE data can be retrieved from a memory, for example. In an embodiment, the set of buffer compositions is selected as a subset of the total set of buffer compositions within the design range. The method may further include, for example, using a chromatographic device to run a first set of experiments. In an example, the experiment is run by continuously providing the buffer composition mixed according to each unique formula indicated by the DoE data as the only input to the chromatographic device. The method may further include obtaining experimental result RoE data as an output from the first set of experiments. In an embodiment, the RoE data indicates at least the pH value of each buffer composition of the set of buffer compositions and / or the total set of buffer compositions. Optionally, the method may further include obtaining a first objective function. In an embodiment, the first objective function may depend at least on the pH value and the conductivity value. The method may further include selecting a second subset of the first objective function whose corresponding pH value optimizes from the set of buffer compositions and / or from the total set of buffer compositions. Optionally, the method further comprises determining one or more buffer composition recipes for chromatography of the chemical sample as a unique recipe corresponding to the second subset. In an embodiment, the method further comprises obtaining experimentally predicted PoE data, wherein the PoE indicates at least a predicted pH value and a predicted conductivity value for each buffer composition of the total set of buffer compositions. Further details on obtaining the composition of the buffer solution can be found in previously included WO2018229271.

[0077] When the buffer tool has received information about the target buffer, that is, when information about the expected composition of the liquid mixture has been retrieved in the buffer tool, the next step includes determining S12 a plurality of settings for controlling the preparation of the liquid mixture in one or more automated processes. Such settings may include information of the selected automated process for the preparation of the liquid mixture, for example, the automated process is a buffer kitchen process or a chromatography system process. Settings may also include: control mode, molar formula, and other settings associated with properties, such as solution concentration, solution type, volume; properties directly related to the preparation of the buffer. Other properties such as density, conductivity, and solubility are useful characteristics of the stock solution (also known as the base solution) to ensure that a concentrated solution can be prepared without solubility problems. According to some embodiments, determining a plurality of settings may include determining one or more stock concentrations, and determining one or more pump settings for the corresponding pumps used in the automated process. Thus, by the buffer tool, all settings required for controlling the preparation of the buffer in the subsequently selected automated process may be determined. According to some embodiments, determining includes determining a control mode of the automated process, and wherein the automated process is run using the control mode. Such control modes include flow feedback, pH feedback, and / or conductivity feedback in a selected combination. Examples are disclosed in the following prior patent applications / patents which are incorporated by reference in their entirety: US 9446329 B2; US2011 / 0039712 A1; EP 2269055 A1; WO 2009 / 131524 A1; US ​​9327212 B2; US 2012 / 0217192 A1; EP 2480943 A1; WO 2011 / 037530 A1; EP 2585887 A1; US ​​2013 / 0081703 A1; WO 2011 / 162666 A1. The Buffer Tool will enable the calculation of all settings required to run the system as a buffer kitchen or as an inline regulation system for a chromatography system. It can provide the settings as a molar recipe when using flow feedback, e.g. when running ÄKTA TM Avant provides settings for controlling the quaternary valves of the chromatography system, and / or provides settings regarding which control mode to use based on a preference for controlling conductivity and / or pH. Thus, one or more control systems will be determined to receive the desired settings in the intended target buffer.

[0078] According to some embodiments, the buffer tool can also provide functionality to determine whether a target buffer can be produced given the stock concentration and stock volume available in the subsequent automated process. Figure 4Portion 4 of the buffer tool interface shown provides the stock concentrations directly. However, the stock solution availability may also be automatically retrieved from an associated application that provides a view of the stock solution availability. Thus, the step of determining a plurality of settings for controlling the preparation of the liquid mixture may further include retrieving one or more boundary conditions of the corresponding settings from one or more control systems, and verifying that the one or more boundary conditions are satisfied. Examples of such boundary conditions include one or more of the acid reserve volume, base reserve volume, minimum flow rate, and maximum flow rate of the corresponding pump used in the automated process. Figure 4 , the basic pump flow rate and the basic pump final concentration are examples of unfilled boundary conditions, which may be indicated in the color version using red or any other suitable signal color. If the target buffer cannot be produced, the system may automatically provide alternative stock concentrations to be selected based on the system properties / pump range. When determining the settings for producing the target buffer, i.e., when controlling the preparation of the liquid mixture, the required volume of each stock solution may be calculated. In the case where the same stock solution can be used to produce several buffers, information related to the need for each stock solution of each buffer and the total amount required of each stock solution may be provided.

[0079] As a final step, in order to initiate the actual preparation of the liquid mixture, the method comprises the step of providing S13 a plurality of settings to one or more control systems of one or more automated processes, for example in a process control interface. Thus, the settings required for the control system to run a subsequent automated process, for example as a buffer kitchen or as a chromatography system, are provided from the buffer tool. The buffer tool can generate settings for a specific buffer or for the entire production process including the chromatography step.

[0080] According to some embodiments, providing the plurality of settings to one or more control systems of the one or more automated processes includes providing the plurality of settings to the control systems when each boundary is met. However, as described, the buffer tool is also capable of determining that the target buffer cannot be produced, and when it is determined that the boundary conditions are not met, providing the plurality of settings to the one or more control systems of the one or more automated processes includes determining a plurality of settings for controlling the preparation of an alternative liquid mixture, and providing the plurality of settings of the alternative liquid mixture to the one or more control systems.

[0081] According to some embodiments, a buffer tool may be used to determine settings for a control system operating in a feedback mode. The method may then include receiving sensor data from one or more automated processes, determining at least one adjustment setting for controlling the preparation of a liquid mixture in one or more automated processes, and providing the adjustment setting to one or more control systems of the one or more automated processes. Thus, an automated process for preparing a liquid mixture (i.e., a target buffer solution) may be monitored by sensors, for example, to determine pH levels and conductivity associated with the buffer solution. If the characteristics of the buffer solution are not the expected characteristics, the flow rate of the solution from the container may be changed so that a buffer solution having the expected characteristics is obtained.

[0082] According to some embodiments, a buffer tool enables selection and optimization of multiple stock concentrations for a process. One or more buffer formulas for preparing a corresponding liquid mixture can be selected from a database including buffer formulas. For example, a number of buffer formulas are selected by a user based on criteria (or tags) such as processes running on a system, buffer properties (e.g., pH, buffer concentration), or types of stock solutions. The buffer tool uses the retrieved formulas in selecting one or more stock solutions based on boundary conditions, wherein the boundary conditions include the corresponding stock solutions for preparing the liquid mixture based on the retrieved buffer formulas. Solution required Volume. For each selected stock solution, the buffer tool determines the minimum number of stock concentrations for the retrieved one or more buffer recipes. It is also possible that the software suggests potential optimization possibilities based on, for example, criteria for <3-5 different concentrations for a stock solution. The optimization criteria can be set by the user, such as the concentration range of the stock solution to be optimized. The buffer tool can give the user several different options that can be selected to be implemented in all / some of the selected buffer recipes. For example, options that are incompatible with system settings due to boundary conditions (such as pump size and pump size combination) may also be visible and may be excluded. After the optimization operation, one or more buffer recipes are updated using a stock concentration selected from the determined minimum number of stock concentrations.

[0083] Figure 2 An example of a buffer tool 20 is schematically shown, and the buffer tool 20 includes: a liquid mixture forming an interface 21, such as Figure 4 As shown in parts 1-4; liquid mixture process control interface 22, for example Figure 4; and processing circuit system 23. Processing circuit system 23 is configured to determine settings for controlling the preparation of liquid mixtures in one or more automated processes in response to obtaining the composition of the liquid mixture to be prepared, and provide multiple settings to one or more control systems of the one or more automated processes. The buffer tool can be suitable for providing settings to a variety of automated processes, for example, for preparing liquid mixtures in buffer kitchen applications or in chromatography systems.

[0084] like Figure 2 As further shown in FIG. 1 , the present disclosure also relates to a computer-readable storage medium 25 having stored thereon a computer program that, when executed in the buffer tool 20, causes the performance of any of the above-described method aspects.

[0085] FIG3a shows a block diagram of a buffer management system 10 for controlling the preparation of a liquid mixture, wherein the liquid mixture includes an acid and its conjugate base or a base and its conjugate acid. The buffer management system is configured for inline buffer preparation using the above-mentioned buffer tool, and is configured to perform the above-mentioned method. The buffer management system 10 includes one or more automatic process arrangements 40 for the preparation of a liquid mixture (i.e., a buffer solution) and one or more control systems 30 for controlling one or more automatic processes. The preparation of the liquid mixture may involve the use of a single-component concentrated stock solution of hydrochloric acid, a base, and water for injection (WFI). The use of concentrates is beneficial to reducing the volume of the buffer and saving tank volume and occupied space. In addition, many different buffers can be prepared from the same collection of concentrates, thereby even further streamlining the buffer preparation. For the accuracy of the recipe and consistency between preparations, it is possible to use a feedback mode containing built-in dynamic control functionality.

[0086] According to some embodiments, one or more automated process arrangements include a chromatography system controlled by a control system 30. The buffer tool 20 is configured to provide a plurality of settings to the control system; the plurality of settings are determined to facilitate controlling the preparation of a liquid mixture in one or more automated processes.

[0087] In the example embodiment shown in FIG. 3 b , the buffer tool can support scaling operations for liquid mixture preparation operations from laboratory scale to large industrial scale, such as from ÄKTA TMThe liquid mixture preparation environment in Avant is transformed to the large-scale liquid mixture preparation in the BioProcess Inline Conditioning (IC) system. Avant is a buffer mixing arrangement that can prepare buffer solutions from stock solutions using quaternary valves, i.e., it is mainly used to prepare laboratory-scale quantities of liquid mixtures, while IC is a buffer mixing arrangement that uses multiple pumps for different components.

[0088] Referring to FIG. 3 b , parameter settings for laboratory scale preparation of a liquid mixture in an Avant environment are determined in a buffer tool, for example, and provided (1) to a control system 30 of the Avant, for example, in a data message. The parameters are used to determine and provide (2) control settings from the control system, for example, in a control message. In the context of the buffer tool being used in conjunction with the Avant arrangement, the Avant is able to perform a rough check to achieve determination of an ideal setting, for example, by allowing multiple runs in the Avant while adjusting one or more parameters during each run. Thus, the Avant arrangement can help define parameters for large-scale production of buffer solutions. In the arrangement disclosed in FIG. 3 b , the buffer tool is used to determine parameter settings, which are provided (1) to the control system, for example, in a data message. The control system proceeds with regulatory control of the automated process in the Avant system by providing (2) control parameters from the control system to the Avant, for example, in a control message. The laboratory scale arrangement Avant operates under the control of these control settings to provide a buffer solution. In addition to the buffer solution, the disclosed buffer management system is also configured to feed back data, reports, and results to the control software and / or the buffer tool. Thus, a lab-scale arrangement (eg Avant) may generate data which is provided (3) to the control software or buffer tool, for example in a data message. This data is further provided (4) to the buffer tool, for example in a data message.

[0089] In an example embodiment, the buffer tool is configured to convert results and data from a lab-scale arrangement into parameter settings suitable for a larger scale arrangement (e.g., an IC arrangement). The IC arrangement can be used for buffer process development, where it generates data that can be used in the buffer tool to perform new runs, or it can produce buffers for biopharmaceutical production in a validation system. The methods implemented by the buffer tool will not only enable control of buffer production in a buffer kitchen, but can also be used for chromatography processes.

[0090] When the buffer tool is applied to develop parameter settings for a laboratory scale process, the tool implements the calculation of the molar recipe, the definition of which reserve concentrations to use, and the appropriate pump settings. Feedback on these parameter settings can then be used to improve the generation of input data for running the large-scale system. By allowing feedback data to be provided (7) from the large-scale arrangement 40b (e.g., IC arrangement) to the control system 30 or buffer tool 20, the feedback loop from the large-scale arrangement 40b will further promote improvements.

[0091] Thus, the disclosed buffer tool is applicable in multiple use cases, such as supporting liquid mixture preparation for buffer / process development or industrial buffer / biopharmaceutical production in a lab-scale arrangement or in an industrial large-scale arrangement. In addition, the buffer tool is configured to allow scale-up and scale-down of controllable processes. In the above use cases, the buffer tool is applied to a buffer kitchen process or a chromatography process with good results.

[0092] In the scale-up scenario, the laboratory scale setup is initially used to determine the appropriate liquid mixture preparation process. Avant is used to define the molar recipe and optimize the liquid mixture process; Reality The laboratory scale arrangement provides (1)-(3) information. The scale-up process is then performed in a large-scale arrangement, and pass In liquid mixture Prepared for slow (4)-(7) information is provided between the injection tool 20, the control system 30 and the large-scale arrangement 40b for further development.

[0093] During a scale-down or change process, for example when a change in production needs to be made and the new process validated, the settings are retrieved from the large-scale arrangement and provided as information (7) to the buffer tool 20 or control system (30), whereby the laboratory scale settings are determined so that the scale-down process can be run and validated in a laboratory environment before running the industrial scale process. Support for this type of scale-up and scale-down is automated by the proposed buffer tool.

[0094] The technician will also be aware that the feedback structure supports simulation of liquid mixture preparation results, for example to obtain output from the buffer tool related to buffer quality, use the buffer calculator in the buffer tool to obtain theoretical results that can be compared with actual results from the liquid mixture preparation run, or use information that can be stored in the buffer tool as a built-in database to determine the expected conductivity.

[0095] In an industrial large scale context, a buffer management system enables a fully automated process for liquid mixture preparation, whereby liquid mixtures can be produced when needed and validated at the point of preparation. Increased control in buffer preparation dynamically increases the precision of pH and / or conductivity.

[0096] Figure 4 An example buffer tool interface is disclosed, comprising: a liquid mixture composition interface, divided into four sections, namely, sections 1-4; and a process control interface, presented as a results section.

[0097] In section 1, "Buffer Class", the buffer tool may prompt information on multiple properties of a liquid mixture. Examples of such properties include liquid mixture type, liquid mixture concentration, and at least one of liquid mixture density and liquid mixture conductivity. Liquid mixture pH may be determined as a function of the conductivity and concentration of the buffer solution. However, liquid mixture pH may also represent a preset property of the liquid to be prepared. Other properties relate to the type and concentration of salts and additives. In section 2, "Process Information", information related to the preparation of a liquid mixture in one or more automated processes may be prompted or presented after being retrieved from a control system or another associated system. Process information may include process information such as flow rate, buffer volume, and process step time. Based on the prompted information, a computer-implemented algorithm may be applied to perform molar concentration calculations or molar mass calculations to determine the composition of the liquid mixture. Available stock solutions may be retrieved, for example, from an automated process or from a control system of an automated process, and used to determine a reserve concentration for use during the preparation of the liquid mixture. Section 4 provides an example interface for determining such reserve concentrations.

[0098] The results section reflects a plurality of settings to be applied during control of one or more automated processes for the preparation of a liquid mixture, wherein the liquid mixture comprises an acid and its conjugate base or a base and its conjugate acid. Such results include flow rate settings to be applied to various pumps that provide acid, base, salt, additive, and water when the pump prepares the liquid mixture in the automated process and is connected to inlets B1 and A2.

[0099] Thus, the Buffer Tool will generate the multiple settings needed to control the system to run an automated process for target buffer preparation.The Buffer Tool is able to generate methods for producing single buffer solutions, but also methods to run an entire production process, such as one including a chromatography step.

[0100] According to some embodiments, a buffer management system 10 is provided in the form of a system for generating a buffer solution.

[0101] Figure 5 A system 10 for preparing or generating a buffer solution is shown. Figure 5It can be seen that the selection of ingredients is mixed to generate a buffer solution. The buffer solution is provided at a specific flow rate (e.g., liters / second) at the outlet port PO. The ingredients typically include acids, bases, salts, and water for injection WFI. Other ingredients such as urea, polysorbate, and glycerol may be added.

[0102] Typically, WFI is provided by a main pump that is coupled to a container and a main pipeline. The other end of the main pipeline is coupled to an output port PO. The output port PO may include any combination of a valve, an adapter, a fluid output member, or a coupling (e.g., to achieve a quick coupling to a hose or other tubular structure). System characteristics such as the size of the main pipeline and the operating range (e.g., flow rate) of the main pump limit the operating space of the system with respect to the flow rate (e.g., maximum flow rate) of the buffer solution.

[0103] The type of buffer solution to be prepared or generated will, for example, determine the composition characteristics, such as the number of components, the required volume of the components and / or the concentration of the components. The total generated volume of the buffer to be generated will, for example, determine the required volume of the components. The required volume of the components is usually determined by defining the recipe of the target buffer solution. In other words, the operating space of the system is limited by the selection of the components or stock solutions (e.g., the selection of the stock solution concentration).

[0104] Each of the components will be stored in a container and will be fed to the main pipeline for mixing into a buffer solution by a component pump via the component pipeline. Each component must be fed to the main pipeline at a specific flow rate to generate a specific type of buffer solution. Therefore, system characteristics such as the size of the component pipeline and the operating range of the component pump (e.g., flow rate range) limit the operating space of the system with respect to the flow rate of the buffer solution (e.g., the maximum flow rate of the generated buffer solution). Therefore, this will limit the characteristics of the buffer solution that can be generated, such as limiting the type of buffer solution that can be selected, and limiting the supported target flow rate of the generated buffer solution.

[0105] As can be understood from the above description, a large number of possible configurations of system characteristics and component characteristics can be used to generate, for example, a specific target flow rate, a specific target pH and a specific target total volume of a specific target buffer solution. This large number of possible configurations of system characteristics and component characteristics can be viewed as the operating space of the system. In other words, any configuration selected from a large number of possible configurations can be used to generate a target buffer solution type.

[0106] In one example, to generate a specific buffer solution, 10 liters of acid of a specific concentration will be required, or alternatively 20 liters of acid of half the concentration will be required. In this example, when comparing the 10 liter and 20 liter examples, the volume capacity of the component container holding the acid will have to be doubled, and the flow rate capacity of the component pump will have to be doubled. This can, for example, affect the selection of the characteristics of the container and the pump. Therefore, the choice must be made between the system characteristics and the component characteristics, and both examples fall within the operating space of the system for the specific target buffer solution.

[0107] Figure 6 A system 10 for generating a buffer solution in accordance with one or more embodiments of the present disclosure is shown. The on-demand buffer generation system 10 is configured to generate a buffer solution. The generation system includes a fluid network, for example, including component conduits CP1-CP4 and a main conduit MP. In one embodiment, the fluid network includes a first pump P1, which is fluidically coupled to a first container C1, for example, via a first component conduit CP1. The first container C1 is configured to hold a saline solution FL1. The first pump P1 is configured to transfer fluid FL1 from the first container C1 to an output port PO.

[0108] Additionally or alternatively, the fluid network further comprises a second pump P2, which is fluidically coupled to the second container C2, for example via a second component conduit CP2. The second container C2 is configured to hold a base solution FL2. The second pump P2 is configured to transfer the fluid FL2 from the second container C2 to the output port PO.

[0109] Additionally or alternatively, the fluid network further comprises a third pump P3, which is fluidically coupled to the third container C3, for example via a third component conduit CP3. The third container C3 is configured to hold an acid solution FL3. The third pump P3 is configured to transfer the fluid FL3 from the third container C3 to the output port PO.

[0110] Additionally or alternatively, the fluid network further comprises a fourth pump P4, which is fluidically coupled to a fourth container C4, for example via a fourth component conduit CP4. The fourth container C4 is configured to hold water for injection FL4. The fourth pump P4 is configured to transfer fluid FL4 from the fourth container C4 to the output port PO.

[0111] Additionally or alternatively, the fluid network further comprises one or more additional pumps (not shown), each pump being fluidically coupled to a corresponding container (not shown), for example, via a corresponding component conduit (not shown). The container is configured to hold an additive, such as urea, polysorbate, and glycerol. Each of the one or more pumps respective Configured to transfer fluid from the corresponding container to the output port PO.

[0112] Additionally or alternatively, the fluid network further includes couplings and / or conduits that fluidly couple each of the pumps P1-P4 to the output port PO of the generating system 10. The fluid network may, for example, include a main pump P4 configured to provide fluid FL4 (e.g., WFI) from the container C4 to the output port PO via one or more main conduits.

[0113] Each of the component conduits CP1-CP4 is typically arranged with an inlet at one end (eg, at the bottom of the corresponding container C1-C4), and is coupled to a corresponding pump P1-P4 at the other end.

[0114] The container may optionally be a single-use container or a reusable container. Single-use containers have the advantage of not requiring cleaning, while reusable containers have the advantage of economies of scale, i.e., if the generation of the buffer solution is repeated, it will be cheaper in the long run.

[0115] Additionally or alternatively, the on-demand system further includes a display 518 .

[0116] Additionally or alternatively, the on-demand system further includes an input device 517 .

[0117] Additionally or alternatively, the on-demand system further comprises a control unit CU 30, 810, 910. The control unit typically comprises a buffer tool 20 and a control system 30. The buffer tool 20 comprises a circuit system (the circuit system comprises a processing circuit system 512) and a memory 515, the memory 515 containing instructions executable by the processing circuit 512, wherein the control unit CU 30, 810, 910 is communicatively coupled to each of the pumps P1-P4, whereby the generating system 10 (the generating system 10 comprises the control unit CU 30, 810, 910) is configured to perform any of the method steps described herein. With respect to Fig. 9 The control unit CU 30 , 810 , 910 is further described.

[0118] In one embodiment, the system as claimed in any of the preceding claims further comprises one or more sensors S1, S2 configured to measure a property of the generated buffer solution. The control unit CU 30, 810, 910 is further communicatively coupled to each of the sensors S1, S2. The sensors may be configured to measure the pH and / or conductivity of the generated buffer solution. Any suitable sensor for performing measurements on the buffer solution may be used. Figure 7The system 10 is shown generating a buffer solution for a container according to one or more embodiments of the present disclosure. In one embodiment of the present disclosure, the generation of the buffer solution is typically performed just before a chromatographic run. In other words, the type of buffer solution required for a particular chromatographic run is generated in a timely manner to start the chromatographic run. The generated buffer solution is temporarily stored in a fluid source (e.g., a disposable container or a reusable container). For example Figure 6 The container shown in .

[0119] Figure 8 The generation of a buffer solution for a chromatography device according to one or more embodiments of the present disclosure is shown. In one embodiment, the generation of the buffer fluid is performed simultaneously with the chromatography run. That is, the generation system 10 feeds the generated buffer solution directly into the chromatography device 800 via the output port PO.

[0120] Figure 8 Further shown is a chromatography device 800 according to one or more embodiments of the present disclosure. The chromatography device 800 may generally include at least one inlet 855. The inlet may optionally be coupled to the generating system 10 and / or configured to hold a reservoir of a fluid (e.g., an eluent). The inlet 855 may be implemented, for example, as a tubular element (e.g., a tube or hose). The inlet 855 may be configured to be coupled to a column 841. The column 841 may be included in the chromatography device 800, or may be arranged outside the chromatography device 800.

[0121] The chromatographic device 800 may further include a control unit 810, which includes a circuit system (e.g., a processor) and a memory. The memory may contain instructions executable by the processing circuit system, whereby the control unit 810 and / or the chromatographic device may be operated to perform any of the steps or methods described herein. The control unit 810 may be independent and communicatively coupled or integrated with the control unit CU 810 of the generating system 10. Fig. 9 The control unit 810 of the generation system 10 is further described.

[0122] The chromatography apparatus 800 may optionally include a separator 870 coupled to the fluid outlet of the column 841 and coupled to a selection of any one of the UV sensor 831, the conductivity sensor 832, and the outlet valve 820. The separator 870 may be configured to direct the fluid received from the column 841 to any one of the UV sensor 831, the conductivity sensor 832, and the outlet valve 820. Optionally, the separator 870 may be communicatively coupled to the control unit 810 and perform the coupling of the fluid to any one of the UV sensor 831, the conductivity sensor 832, and the outlet valve 820 in response to one or more control signals from the control unit 810.

[0123] The UV sensor 831 may be communicatively coupled to the control unit 810 and configured to measure a quantitative measurement (e.g., UV light absorbance of the fluid) provided by the separator 870. The chromatography apparatus 800 may further include a conductivity sensor 832 communicatively coupled to the control unit 810 and configured to measure a quantitative measurement (e.g., conductivity of the fluid) provided by the separator 870. The UV sensor 831 and / or the conductivity sensor 832 may be further configured to provide the measured quantitative measurement to the control unit 810 as a control signal containing the measurement data.

[0124] The chromatography device 800 may further include an outlet valve 820 coupled to the separator 870. The outlet valve 820 may have one or more outlets or outlet ports 821-823 and is configured to provide the fluid provided by the separator 870 to the one or more outlets 821-823 in response to a control signal received, for example, from the control unit 810. In other words, a fractionation of the eluent is performed.

[0125] Fig. 9A control unit CU 30, 810, 910 according to one or more embodiments of the present disclosure is shown. The control unit CU 30, 810, 910 may take the form of, for example, an electronic control unit, a server, an onboard computer, a fixed computing device, a laptop computer, a tablet computer, a handheld computer, a wrist-worn computer, a smart watch, a smart phone, or a smart TV. The control unit CU 30, 810, 910 may include a processing circuit system 912, which is communicatively coupled to a transceiver 904 configured for wired or wireless communication. The control unit CU 30, 810, 910 may further include at least one optional antenna (not shown in the figure). The antenna may be coupled to the transceiver 904 and configured to transmit and / or transmit and / or receive wired or wireless signals in a communication network (e.g., Wi-Fi, Bluetooth, 3G, 4G, 5G, etc.). In one example, the processing circuit system 912 may be any one of the selections of the processing circuit system and / or a central processor and / or a processor module and / or a plurality of processors configured to cooperate with each other. In addition, the control unit CU 30, 810, 910 may further include a memory 915. The memory 915 may include, for example, a hard RAM, a disk drive, a floppy disk drive, a flash drive, or other removable or fixed media drive or any other suitable memory known in the art. The memory 915 may contain instructions executable by the processor to perform any of the steps or methods described herein. The processing circuit system 912 may optionally be coupled to the transceiver 904, the memory 915, and any one of the sensors S1 and S2 (e.g., a pH sensor and a conductivity sensor S2) in communication. The control unit CU 30, 810, 910 may be configured to send / receive control signals directly to any of the above-mentioned units or to an external node, or to send / receive control signals via a wired and / or wireless communication network.

[0126] Wired / wireless transceiver 904 and / or a wired / wireless communication network adapter may be configured to send / receive data values ​​or parameters as signals from processing circuitry 912 to other external nodes or from other external nodes to processing circuitry 912. For example, the measured pH or conductivity of a buffer solution or the generated volume.

[0127] In an embodiment, the transceiver 904 communicates with external nodes directly or via a wireless communication network.

[0128] In one or more embodiments, the control unit CU 30 , 810 , 910 may further include an input device 917 configured to receive input or instructions from a user and send a user input signal indicating the user input or instructions to the processing circuit 912 .

[0129] In one or more embodiments, the control unit CU 30, 810, 910 may further include a display 818, which is configured to receive a display signal indicating a rendered object (e.g., a text or graphical user input object) from the processing circuit 912, and display the received signal as an object (e.g., a text or graphical user input object).

[0130] In one embodiment, the display 818 is integrated with the user input device 917, and is configured to receive a display signal indicating a rendered object (e.g., a text or graphical user input object) from the processing circuit 912 and display the received signal as an object (e.g., a text or graphical user input object), and / or is configured to receive input or indications from a user and send a user input signal indicating the user input or indication to the processing circuit 912.

[0131] In another embodiment, the control unit CU 30, 810, 910 may further include and / or be coupled to one or more additional sensors (not shown in the figure), which are configured to receive and / or obtain and / or measure physical properties related to the generation system 10, and send one or more sensor signals indicating the physical properties of the generation system 10 to the processing circuit system 912. For example, a temperature sensor that measures the ambient air temperature.

[0132] In one or more embodiments, the processing circuit system 912 is further communicatively coupled to an input device 917 and / or a display 9818, 918 and / or additional sensors and / or relative Figure 6 Any of the units.

[0133] Fig.10 A flow chart of a computer-implemented method 1000 according to one or more embodiments of the present disclosure is shown. The computer-implemented method is configured to determine an operating space and is performed by an on-demand buffer solution generation / preparation system 10 configured to generate / prepare a buffer solution. The generation system 10 includes: a plurality of fluid containers C1-C4, which are used to hold components FL1-FL4 of the buffer solution; pumps P1-P4, which are used to transfer fluid from each of the fluid containers C1-C4; a pipeline, which fluidically couples each of the pumps to an output port PO of the generation system 10; and a control unit CU 810, which is communicatively coupled to each of the pumps P1-P4. Relative Figure 6 The generation system 10 is further described. The method comprises:

[0134] Step 1010: Get first input data indicating a target property of a target buffer solution to be generated by the generating system 10. The first input data may be received from the input device 917 and / or retrieved from the memory 915 and / or received in a signal / message from another unit (e.g., from a server or cloud server) via a communication network.

[0135] The first data may include the composition of the liquid mixture to be prepared and is obtained in a manner similar to how the composition of the liquid mixture to be prepared is obtained, such as with respect to Figure 2 Further description.

[0136] In one embodiment, the target buffer solution that causes the determination of the operating space is defined by a target characteristic. In one embodiment, the target characteristic indicates a selection of any one of a target buffer solution type, a target total generated volume of the buffer solution, and a target pH of the buffer solution, a target concentration of the buffer solution, a target flow rate of the buffer solution, and a target salt concentration of the buffer solution.

[0137] Additionally or alternatively, the target characteristic is indicative of a flow rate of the generated buffer solution at the output port PO.

[0138] Additionally or alternatively, the target characteristic is indicative of a concentration of the generated buffer solution.

[0139] Step 1020: Obtain second input data, the second input data indicating system characteristics of the generation system. The second input data may be received from the input device 917 and / or retrieved from the memory 915, and / or received in a signal / message from another unit (e.g., a server or a cloud server) via a communication network.

[0140] In one embodiment, the properties of the generating system 10 that result in the determination of the operating space are defined by system characteristics. In one embodiment, the system characteristics indicate the selection of flow rate ranges of pumps, volumes of ingredient containers, and pipe sizes of the generating system 10. It is to be understood that the present disclosure is not limited to the above-mentioned characteristics, but may also indicate characteristics of other components (e.g., sensors, filters, etc.).

[0141] Step 1030: Get third input data indicating the composition characteristics of the components used to generate the buffer solution. The third input data can be received from the input device 517 and / or retrieved from the memory 515, and / or received in a signal / message from another unit (e.g., a server or a cloud server) via a communication network.

[0142] In one embodiment, the properties of the components used to generate the buffer solution and cause the determination of the operating space are defined by component properties. In one embodiment, the component properties indicate a selection of any one of the concentration and solubility of the components of the buffer solution.

[0143] In one example, obtaining the first, second, and third input data includes prompting information about a plurality of properties of the liquid mixture / buffer solution. In response to receiving the information about the plurality of properties and applying at least one software-implemented algorithm (e.g., an algorithm for molar concentration calculation or molar mass calculation), the composition of the liquid mixture to be prepared is determined. The properties of the liquid mixture / buffer solution may include at least one of a liquid mixture type / target buffer type, a liquid mixture concentration / target buffer concentration, and a liquid mixture density / target buffer density and a liquid mixture conductivity / target buffer type conductivity.

[0144] Step 1040: Determine the operating space by calculating the outer operating limits of the generation of the buffer solution using the first input data, the second input data, and the third input data. Additionally or alternatively, the second input data is obtained by selecting from a plurality of system characteristics, wherein the third input data is obtained by selecting from a plurality of component characteristics.

[0145] Determining the operating space may, for example, include determining a plurality of settings for controlling the preparation of a liquid mixture in one or more automated processes, such as Figure 2 Further described in .

[0146] In one example, the external operating limit is calculated by retrieving one or more predetermined boundary conditions of any one of the first data and / or the second data and / or the third data, and selecting an external operating limit that can be verified using the one or more boundary conditions. The boundary conditions may include one or more of a minimum and / or maximum acid reserve volume, a minimum and / or maximum base reserve volume, and a minimum and / or maximum flow rate of the corresponding pump used in the automatic process. Figure 1 , Figure 2 and Figure 3b further describe the verification.

[0147] In one example, a user provides input data indicating a target buffer type of acetate, a target total volume of a generated buffer solution of 1000 liters, a target pH of 4.3, a target pH of a generated buffer solution of 4.3, and a target buffer concentration of 100 mM (millimolar). The generation system then determines an operating space indicating possible containers to be used based on an estimated base component volume of 29.4 liters, an estimated acid component volume of 35.3 liters, and an estimated salt component volume of 29.4 liters. That is, a list of available containers or tanks can be compared to the estimated volumes, and a determination can be made as to which of the possible containers or tanks can be used. adaptA subset of containers selected from the list of available containers of the requested volume.

[0148] In an additional example, the user further provides input data indicating the component concentrations of the base FL2 and the acid FL3, a main pipe size of one (1) inch, and a flow rate of the generation system of 200 liters / hour. The generation system then determines an operating space indicating possible pumps to be used based on the estimated flow rates of the different pumps P1-P4 (e.g., an estimated flow rate range of 15-600 liters / hour for the first pump P1, an estimated flow rate range of 4-180 liters / hour for the second pump P2, an estimated flow rate range of 4-180 liters / hour for the third pump P3, and an estimated flow rate range of 45-200 liters / hour for the fourth pump P4). That is, a list of available pumps can be compared to the estimated flow rates, and a subset of pumps selected from the list of available pumps that can accommodate the required flow rates is determined.

[0149] In some embodiments, the Debye-Hückel equation (which is further described in US Pat. No. 9,446,329 B2, which is incorporated herein by reference in its entirety) is used to calculate the proportions of the components required to generate the buffer solution.

[0150] In one embodiment, obtaining the first input data further includes: receiving user input indicating target characteristics, wherein the target characteristics indicate at least a target buffer solution type, a target concentration of the generated buffer solution, and a target total generated volume of the buffer solution; and calculating other target characteristics using the Debye-Hückel equation or a software-implemented algorithm thereof, wherein the other target characteristics include flow rates of components derived using a recipe defining the target buffer solution type.

[0151] Additionally or alternatively, this embodiment may further include determining a formulation of the buffer solution by evaluating an equation. The evaluation equation includes: determining an ion size parameter a in the Debye-Hückel equation based on a weighted average ion size of all species contributing to the ionic strength of the generated buffer solution, the ionic strength of each species being used as a weighting parameter in the Debye-Hückel equation; determining relative component ratios of components of the buffer solution based on the Debye-Hückel equation and the determined ion size parameter a; and calculating other target characteristics indicative of the flow rate of the components using the ratios of the components and a maximum flow rate derived based on the pipe size of the generating system 10.

[0152] Additionally or alternatively, this embodiment may further include: determining the recipe of the buffer solution by obtaining the composition of the liquid to be prepared includes prompting information about multiple properties of the liquid mixture / buffer solution, for example, by means of a user interface or a liquid mixture composition interface, such as Figure 4The pH of the liquid mixture may be determined as a function of the conductivity and concentration of the buffer solution. However, the pH of the liquid mixture may also represent a preset property of the liquid to be prepared. In response to receiving information of the plurality of properties, an algorithm may be implemented by applying at least one software, such as using a buffer solution such as Figure 4 The composition of the liquid mixture / buffer solution can be determined using the molar concentration calculation or molar mass calculation algorithm shown in Section 3 of the Buffer Tool interface shown in FIG.

[0153] Additionally or alternatively, this embodiment may further include determining the formulation of the buffer solution by running an experiment on a chromatographic device. The step of obtaining the S11 composition includes obtaining experimental design DoE data, wherein the DoE data indicates a set of buffer compositions and corresponding unique formulations. The DoE data can be retrieved from a memory, for example. In an embodiment, the set of buffer compositions is selected as a subset of the total set of buffer compositions within the design range. The method may further include, for example, using a chromatographic device to run a first set of experiments. In an example, the experiment is run by continuously providing the buffer composition mixed according to each unique formulation indicated by the DoE data as the only input to the chromatographic device. The method may further include obtaining experimental results RoE data as output from the first set of experiments. In an embodiment, the RoE data indicates at least the pH value of each buffer composition of the set of buffer compositions and / or the total set of buffer compositions. Optionally, the method may further include obtaining a first objective function. In an embodiment, the first objective function may depend at least on the pH value and the conductivity value. The method may further include selecting a second subset of the first objective function whose corresponding pH value optimizes from the set of buffer compositions and / or from the total set of buffer compositions. Optionally, the method further comprises determining one or more buffer composition recipes for chromatography of the chemical sample as a unique recipe corresponding to the second subset. In an embodiment, the method further comprises obtaining experimentally predicted PoE data, wherein the PoE indicates at least a predicted pH value and a predicted conductivity value for each buffer composition of the total set of buffer compositions. Further details on obtaining the composition of the buffer solution can be found in previously included WO2018229271.

[0154] Additionally or alternatively, the operation space is further presented as a representation and displayed, for example, to a user of the generation system 10. In this embodiment, the method further comprises:

[0155] presenting a representation 1100 indicating an operation space, and

[0156] The display 818, 918 is controlled to display the representation 1100 to a user of the generating system. The display may be a display 918 comprised by or arranged at the generating system 100 or a display 818 comprised by or arranged at the chromatographic device. Fig.11 Representation 1100 is further described.

[0157] Depending on which aspects the user is going to focus on, the operating space can be defined by calculating different outer operating limits.

[0158] This has the advantage of improving perception and reducing the time for the user to understand and react to the information, e.g. to arrive at a feasible configuration for generating system 10. Representation 1100 may be suitable for visually illustrating the operating space, thereby adapting the presentation to human physiology. For example, by presenting a set of adjacent cells in a grid, thereby allowing the user's visual system to automatically group the cells / elements into a pattern representing the operating space, see e.g. Gestalt theory.

[0159] In one embodiment, the operating limit indicates the pH of the resulting buffer solution for each of a plurality of combinations of concentrations of components of the buffer solution.

[0160] The choice of concentration of the ingredients is very important and critical to the process.

[0161] In one embodiment, the operating limits indicate a range of flow rates for one or more pumps having system characteristics that fall within the determined operating space.

[0162] In one embodiment, the operating limits indicate a volume range of one or more containers having system characteristics that fall within the determined operating space.

[0163] In one embodiment, the operating limits indicate the volume range or concentration range of the components required to generate the buffer solution.

[0164] Any number of operating limits may be used and combined to form an operating space.

[0165] In some embodiments, the method further comprises controlling the generation system 10 using control parameters derived or assigned using the operating space. In this embodiment, the method further comprises assigning control parameters that control the generation system 10 to operate within the determined operating space, and controlling the generation system 10 using the assigned control parameters.

[0166] In other words, the assigned control parameter or settings are provided to one or more control systems 30, 810, 910 of one or more systems 10 running the automated process. The assigned control parameters may include one or more reserve concentrations and / or one or more pump settings for corresponding pumps used in the automated process. 0 Further retrieve / receive selected automatic process information and / or assigned control parameters of one or more automatic processes. A control mode of the control system 30, 810, 910 of the selected automatic process may be determined; the automatic process is operated by the control system 30, 810, 910 using the control mode. The control mode includes one or more of flow feedback, pH feedback, and conductivity feedback. The automatic process may be operated as a buffer kitchen or as a chromatography system. When operated as a chromatography system, the control mode may include programming of a quaternary valve of the chromatography system.

[0167] In one example, dispensing control generating control parameters for operating the system 10 within the determined operating space includes selecting a container from a subset of containers as described above, the container being selected from a list of available containers that can accommodate the required volume, and dispensing the volume of the selected container as a control parameter, such as by pausing the generation of the buffer solution after the container is emptied or when the container is empty or substantially empty.

[0168] The control parameters may be allocated within the operating space / operating limits by receiving from a user an indication of parameter values ​​that fall within the operating space / operating limits.

[0169] The control parameters can be allocated within the operating space / operating limits by optimizing or evaluating an objective function to allocate parameters that fall within the operating space / operating limits. The objective function is, for example, a function that is proportional to the available container or Element Has a low cost, but has a higher cost for containers or ingredients that need to be ordered or otherwise obtained. Dispensable represent The volume of the container or concentration of the ingredient that provides the lowest cost.

[0170] In one example, the control parameters for dispensing control generating system 10 to operate within the determined operating space include controlling pumps P1-P3 to specific flow rates that depend on the concentration of the component held in the corresponding containers C1-C4. That is, when a first concentration of the component is selected, the pumps are controlled to No. A flow rate is selected, and when a concentration of the component half of the first concentration is selected, the pump is controlled to a flow rate twice the first flow rate.

[0171] Fig.11A representation 1100 of an operating space in accordance with one or more embodiments of the present disclosure is shown. An example of the representation is shown as a two-dimensional grid with two axes. The grid may represent pH values ​​on one axis and combinations of concentrations of components of a buffer solution on another axis. If the corresponding combination of pH values ​​and concentrations of the components does not represent a valid combination that can generate a target buffer solution, the box on the grid is shown as empty.

[0172] In one embodiment, a computer program is provided and includes computer executable instructions for causing the control unit 30, 810, 910 to perform any of the method steps described herein when the computer executable instructions are executed on processing circuitry contained in the control unit 30, 810, 910.

[0173] In one embodiment, a computer program product is provided and includes a computer-readable storage medium having the above-described computer program embodied therein.

[0174] A first exemplary embodiment of the present disclosure is provided below. In this example, a suitable hardware system and suitable stock solution set up for a process are determined.

[0175] Fig.12 Table 1200 showing exemplary target properties of a target buffer solution. The table shows an index identifying the target buffer solution type in a first column. The table shows the target buffer solution name in a second column. The table shows the target pH of the buffer solution in a third column. The table shows the target salt concentration of the buffer solution in a fourth column. The table also shows the target flow rate of the buffer solution in a fifth column.

[0176] The information in the table forms the first input data for the target properties, ie, buffer concentration, pH, salt concentration and maximum and minimum flow rates of the target buffer.

[0177] Based on the target flow rate of the buffer solution in the first input data, the customer requires a 1" system or one (1) inch pipe size, thereby providing a flow rate range of 200-2000 liters / hour for the target process 1, or the process used to generate the target buffer solution in this example. In other words, the expected minimum flow rate falls within the flow rate range of a system using one inch pipe.

[0178] Fig.13 Table 1300 showing exemplary system characteristics of the generated system. The second input data can then be viewed as a selection among the 8 system configurations or 1×2×2×2 different combinations of pumps shown in table 1300 .

[0179] The third input data indicates the identity of the components used to generate the buffer solution, or in Example 1, the concentrations of the stock solutions of the acid and base (the components used to generate the buffer solution).

[0180] It is generally advantageous for the user of the generating system that the stock solutions are as concentrated as possible within the solubility limits of the different components. This is because it gives a greater volume reduction. For the same reason, the pump should be as small as possible. In this first example, 5 different possible stock concentrations of acid and base have been considered, resulting in 25 different combinations.

[0181] In this example, the molar formula (the molar concentration or relative component ratio of the acid and the molar concentration of the base in each of the buffer solutions of the first input data) is calculated based on the solution of the Debye-Hückel equation using the method described in US9446329B2, wherein the ion size parameter a in the Debye-Hückel is calculated as the weighted average ion size of all species contributing to the ionic strength of the generated buffer solution, and the ionic strength of each species is used as a weighting parameter in the Debye-Hückel equation (or the application US12 / 988553 which is incorporated herein by reference in its entirety).

[0182] The molar formula of each component was then used in the following equation to obtain the pump flow rates for the acid and base pumps for all 25 combinations of stock solutions and 8 combinations of pumps:

[0183] Acid flow rate = (acid molar concentration / acid reserve concentration) × target buffer solution flow rate

[0184] Base flow rate = (base molar concentration / base reserve concentration) × target buffer solution flow rate

[0185] The results of the final selection of the combination of pumps that gave the highest volume reduction are provided in table 1400.

[0186] Fig.14 Table 1400 shows an exemplary system and / or component configuration. The first three columns include Fig.12 1200, i.e., target buffer type, target buffer flow rate, and component concentration. In the fourth column, the outer operating limits for the generation of the buffer solution are shown in the form of pump characteristics or sizes. Pump A represents the size of the acid pump, and Pump B represents the size of the base pump. In other words, Figure 6 Pumps P2 and P3 are shown.

[0187] The results for Process 1 in this first example indicate that this customer would need a 1" piping system with a maximum capacity of 2000 L / h and a size 3 for Pump A (P3) and Pump B (P2) to be able to produce all of the expected buffer on one IC system. Systems with other pump sizes would not give the customer the same overall volume reduction.

[0188] A second exemplary embodiment of the present disclosure is provided below. In this second example, determination of appropriate hardware systems and stock solution establishment for two processes is shown. In this example, the system will be used to run process 1 in Example 1 as well as a second process (represented herein as process 2)

[0189] The list of target buffer solutions for Process 1 is the same as in Example 1 and Fig.12 Same as shown.

[0190] The list of target buffer solutions for process 2 is in Fig.15 is shown in Table 1500.

[0191] Fig.15 Table 1500 showing exemplary target properties of a target buffer solution. The table shows an index identifying the target buffer solution type in a first column. The table shows the target buffer solution name in a second column. The table shows the target pH of the buffer solution in a third column. The table shows the target salt concentration of the buffer solution in a fourth column. The table also shows the target flow rate of the buffer solution in a fifth column.

[0192] The calculation process of process 2 is similar to that of process 1 provided in example 1 above.

[0193] Fig.16 Table 1600 shows an exemplary system and / or component configuration. The results of this second example indicate that this customer requires a 1" system with a maximum capacity of 2000 L / h and a size 3 for Pump A (P3) and Pump B (P2) to be able to produce all expected buffers on one production system. The stock solution with the highest possible concentration is Fig.16 is provided in Table 1600.

[0194] The same process can then be repeated for any other generation processes 3, 4 etc. The method can then display the hardware requirements for the individual processes as well as all the processes combined.

[0195] Fig.17 A representation 1700 of the combined process of operating spaces in accordance with one or more embodiments of the present disclosure is shown. This overlay will show whether the need is being sized by a system. Covered Or if the customer requires a different sized system.

[0196] In other words, the operation spaces of two or more processes overlap, thereby forming a combined operation space when the operation spaces are stacked on top of each other.

[0197] In an embodiment, the communication network communicates using wired or wireless communication technology, which may include a local area network (LAN), a metropolitan area network (MAN), a global system for mobile communications (GSM), an enhanced data GSM environment (EDGE), a universal mobile telecommunications system, long term evolution, a high speed downlink packet access (HSDPA), a wideband code division multiple access (W-CDMA), a code division multiple access (CDMA), a time division multiple access (TDMA), Bluetooth®, Zigbee®, Wi-Fi, voice over Internet protocol (VoIP), LTE Advanced, IEEE 802.16m, WirelessMAN-Advanced, Evolved High Speed ​​Packet Access (HSPA+), 3GPP Long Term Evolution (LTE), Mobile WiMAX (IEEE 802.16e), Ultra Mobile Broadband (UMB) (formerly Evolution-Data Optimized (EV-DO) Rev. C), Fast Low Latency Access with Seamless Handover Orthogonal Frequency Division Multiplexing (Flash-OFDM), High Capacity Spatial Division Multiple Access (iBurst®), and Mobile Broadband Wireless Access (MBWA) (IEEE 802.16e). The present invention may include at least one of IEEE 802.20) system, High Performance Radio Metropolitan Area Network (HIPERMAN), Wavelength Division Multiple Access (BDMA), Worldwide Interoperability for Microwave Access (Wi-MAX), and ultrasonic communication, but is not limited thereto.

[0198] Furthermore, the skilled person will appreciate that the control unit CU 30, 810, 910 may comprise necessary communication capabilities in the form of, for example, functions, components, units, elements, etc., for performing the present solution. Examples of other such components, units, elements and functions are: processors, memories, buffers, control logic, encoders, decoders, rate matchers, de-rate matching, mapping units, multipliers, decision units, selection units, switches, interleavers, de-interleavers, modulators, demodulators, inputs, outputs, antennas, amplifiers, receiver units, transmitter units, DSPs, MSDs, TCM encoders, TCM decoders, power supply units, power feeders, communication interfaces, communication protocols, etc., suitably arranged together for performing the present solution.

[0199] In particular, the processing circuit system and / or processing component of the present disclosure may include processing circuits, processor modules, and multiple processors configured to cooperate with each other, central processing units (CPUs), processing units, processing circuits, processors, application-specific integrated circuits (ASICs), microprocessors, field programmable gate arrays (FPGAs), or one or more instances of other processing logic that can interpret and execute instructions. Therefore, the expression "processing circuit system" and / or "processing component" may represent a processing circuit system including multiple processing circuits, such as any one, part, or all of the above-mentioned processing circuit systems. The processing component may further perform data processing functions for input, output, and processing of data, including data buffering and device control functions, such as user interface control, etc.

[0200] The description of the example embodiments provided herein is provided for ease of illustration. This description is not intended to be an exhaustive description or to limit the example embodiments to the precise form disclosed; modifications and variations are possible in light of the above theory or may be obtained from the practice of various alternatives to the provided embodiments. The examples described herein are selected and described in order to illustrate the principles and properties of the various example embodiments and their practical application so as to enable those skilled in the art to utilize the example embodiments in various ways and with various modifications as are suitable for the particular use under consideration. The features of the embodiments described herein may be combined in accordance with all possible combinations of buffer tools, buffer management systems, corresponding methods, and computer program products. It should be understood that the example embodiments described herein may be implemented in conjunction with each other.

[0201] Generally, all terms used herein are to be understood according to their ordinary meaning in the relevant technical field, unless a different meaning is explicitly given and / or implied by the context of its use.

[0202] Reference is made herein to various embodiments. However, those skilled in the art will appreciate numerous variations to the described embodiments that still fall within the scope of the claims.

[0203] For example, the method embodiments described herein disclose example methods by steps being performed in a certain order. However, it is understood that these sequences of events may occur in another order without departing from the scope of the claims. In addition, some method steps may be performed in parallel even if they are described as being performed sequentially. Therefore, the steps of any method disclosed herein do not have to be performed in the exact order disclosed unless a step is explicitly described as being performed after or before another step. Before and / or where it is implied that a step must follow or precede another step.

[0204] It should also be noted that in the description of the embodiments, the division of the functional block into specific units is not intended to be limiting at all. On the contrary, these divisions are just examples. The functional block described as a unit herein can be divided into two or more units. In addition, the functional block described as being implemented as two or more units herein can be merged into fewer (e.g., single) units.

[0205] Any feature of any one of the embodiments disclosed herein may be appropriately applied to any other embodiment. Likewise, any advantage of any one of the embodiments may be applicable to any other embodiment, and vice versa.

[0206] In the drawings and specification, exemplary aspects of the present disclosure are disclosed. However, many changes and modifications can be made to these aspects without substantially departing from the principles of the present disclosure. Therefore, the present disclosure should be regarded as illustrative rather than restrictive, and is not limited to the specific aspects described above. Accordingly, although specific terms are used, they are used only in a general and descriptive sense and not for limitation.

[0207] It should be understood, therefore, that the details of the described embodiments are merely examples set forth for the purpose of illustration, and that all changes coming within the scope of the claims are intended to be embraced therein.

Claims

1. A computer-implemented method for controlling the preparation of a liquid mixture comprising an acid and its conjugate base or a base and its conjugate acid, the method comprising: - obtaining the composition of the liquid mixture to be prepared; - determining a plurality of settings for controlling the preparation of said liquid mixture in one or more automated processes; as well as - providing said plurality of settings to one or more control systems of said one or more automatic processes, - wherein determining a plurality of settings for controlling the preparation of the liquid mixture comprises retrieving information of a selected automatic process of the one or more automatic processes, determining a control mode of a control system for the selected automatic process, and wherein the automatic process is run using the control mode, Wherein determining a plurality of settings for controlling the preparation of the liquid mixture further comprises: - retrieving one or more boundary conditions for the corresponding setting from said one or more control systems, and - verifying that one or more boundary conditions are met, Wherein providing the plurality of settings to one or more control systems of the one or more automated processes comprises: - determining a plurality of settings for controlling the preparation of the alternative liquid mixture when at least one boundary condition is not met, and - providing said plurality of settings of said alternative liquid mixtures to said one or more control systems, Wherein, determining a plurality of settings for controlling the preparation of the liquid mixture further comprises: - determining one or more reserve concentrations; and - determining one or more pump settings for a respective pump used in said automated process, The one or more boundary conditions include one or more of a maximum flow rate and a minimum flow rate of the corresponding pump used in the automatic process, an acid reserve volume, and an alkali reserve volume.

2. The method of claim 1, wherein: The composition of the liquid to be prepared comprises: - information indicating a plurality of properties of the liquid mixture, and - in response to receiving information of said plurality of properties, determining said composition for said liquid mixture to be prepared by applying at least one software implemented algorithm.

3. The method of claim 1, wherein: The composition of the liquid to be prepared comprises: obtaining design of experiments (DoE) data, wherein the DoE data indicates a set of buffer compositions and corresponding unique formulations, Run the first set of experiments, obtaining experimental result RoE data as output from said first set of experiments, and The composition is obtained by selecting a buffer composition from the set of buffer compositions whose corresponding buffer properties optimize the objective function.

4. The method of claim 2, wherein: The plurality of properties include liquid mixture type, liquid mixture concentration, and at least one of liquid mixture density and liquid mixture conductivity, and wherein the at least one software implemented algorithm is an algorithm for molar concentration calculation or molar mass calculation.

5. The method of claim 3, wherein: The plurality of properties of the liquid mixture include liquid mixture type, liquid mixture concentration, and at least one of liquid mixture density and liquid mixture conductivity, and wherein at least one software implemented algorithm is an algorithm for molar concentration calculation or molar mass calculation.

6. The method of claim 1, wherein: The control mode includes flow feedback.

7. The method of claim 6, wherein: The control mode includes pH feedback.

8. The method according to any one of claims 1 to 7, wherein: The control mode further includes conductance feedback.

9. The method according to any one of claims 1 to 7, wherein: The automated process operates as a buffer kitchen or as a chromatography system.

10. The method of claim 9, wherein: The control mode includes the programming of the quaternary valve of the chromatography system.

11. The method of claim 1, further comprising: - retrieving one or more buffer recipes for preparing the corresponding liquid mixture from a database comprising buffer recipes, - selecting one or more stock solutions based on the boundary conditions, wherein the boundary conditions include the volumes required from the respective stock solutions for preparing the liquid mixture based on the retrieved buffer recipe, - for each selected stock solution, determining the minimum number of stock concentrations for use with the retrieved buffer formulation or formulations, and - Updating said one or more buffer formulations with said stock concentration selected from said determined minimum number of stock concentrations.

12. The method of claim 1, wherein: Providing the plurality of settings to one or more control systems of the one or more automated processes includes providing the plurality of settings to the control systems when each boundary is satisfied.

13. The method of any one of claims 1 to 7, further comprising: - receiving feedback sensor data from said one or more automated processes, - determining at least one adjustment setting for controlling said preparation of said liquid mixture in one or more automated processes; as well as - providing the adjusted settings to said one or more control systems of said one or more automatic processes.

14. A buffer means for controlling the preparation of a liquid mixture comprising an acid and its conjugate base or a base and its conjugate acid, the buffer means comprising: -Liquid mixture composition interface -Process control interface, and - a processing circuit system configured to: ○ obtaining the composition of the liquid mixture to be prepared; o determining a plurality of settings for controlling said preparation of said liquid mixture in one or more automated processes; as well as o providing the plurality of settings to one or more control systems of the one or more automated processes, wherein determining a plurality of settings for controlling the preparation of the liquid mixture comprises retrieving information for a selected automatic process of the one or more automatic processes, determining a control mode for a control system of the selected automatic process, and wherein the automatic process is run using the control mode, Wherein determining a plurality of settings for controlling the preparation of the liquid mixture further comprises: - retrieving one or more boundary conditions for the corresponding setting from said one or more control systems, and - verifying that one or more boundary conditions are met, Wherein providing the plurality of settings to one or more control systems of the one or more automated processes comprises: - determining a plurality of settings for controlling the preparation of the alternative liquid mixture when at least one boundary condition is not met, and - providing said plurality of settings of said alternative liquid mixtures to said one or more control systems, Wherein, determining a plurality of settings for controlling the preparation of the liquid mixture further comprises: - determining one or more reserve concentrations; and - determining one or more pump settings for a respective pump used in said automated process, The one or more boundary conditions include one or more of a maximum flow rate and a minimum flow rate of the corresponding pump used in the automatic process, an acid reserve volume, and an alkali reserve volume.

15. A computer readable storage medium having stored thereon a computer program which, when executed in a buffer tool, causes the performance of the method of any one of claims 1-13.

16. A buffer management system for controlling the preparation of a liquid mixture comprising an acid and its conjugate base or a base and its conjugate acid, the buffer management system comprising: - one or more automated process arrangements for the preparation of the liquid mixture; - one or more control systems for controlling said one or more automated processes; as well as - Buffer means according to claim 14.

17. The buffer management system of claim 16, wherein: The buffer management system is a chromatography system.

18. A computer-implemented method for determining an operation space performed by a buffer solution generation system configured to generate a buffer solution, the generation system comprising a plurality of fluid sources for holding components of the buffer solution, a pump for conveying fluid from each of the fluid sources, a conduit fluidically coupling each of the pumps to an output port of the generation system, and a control unit communicatively coupled to each of the pumps, the method comprising: obtaining first input data indicating a target characteristic of a target buffer solution to be generated by the generating system, obtaining second input data, the second input data indicating a system characteristic of the generating system, obtaining third input data indicating component characteristics of components used to generate the buffer solution, determining an operating space by calculating an outer operating limit for the generation of the buffer solution using the first input data, the second input data, and the third input data, wherein the second input data is obtained by selecting from a plurality of system characteristics, and wherein the third input data is obtained by selecting from a plurality of component characteristics, assigning control parameters that control the generation system to operate within the determined operating space, and The generating system is controlled using the assigned control parameters.

19. The method of claim 18, wherein: Obtaining the first input data further comprises: receiving a user input indicating target characteristics, wherein the target characteristics indicate at least a target buffer solution type, a target concentration of a generated buffer solution, and a target total generated volume of the buffer solution, The Debye-Hückel equation is used to calculate additional target properties, wherein the additional target properties include flow rates of components derived using a recipe defining relative proportions of components of the target buffer solution type, the recipe being determined using the Debye-Hückel equation.

20. The method of claim 19, wherein: Determine that the formula comprises: determining an ion size parameter a in the Debye-Hückel equation based on a weighted average ion size of all species contributing to the ionic strength of the resulting buffer solution, the ionic strength of each species serving as a weighting parameter in the Debye-Hückel equation; determining the relative composition ratios of the components of the buffer solution based on the Debye-Hückel equation and the determined ion size parameter a; A further target characteristic indicative of the flow rate of the components is calculated using the ratios of the components and the flow rate of the buffer solution defined by a maximum flow rate derived based on the piping dimensions of the generation system.

21. The method of claim 18, wherein: Obtaining the first input data further comprises: obtaining design of experiments (DoE) data, wherein the DoE data indicates a set of buffer compositions and corresponding unique formulations, Run the first set of experiments, obtaining experimental result RoE data as output from said first set of experiments, The first input data is obtained by selecting a buffer composition and a corresponding unique formulation from the set of buffer compositions, the corresponding buffer properties of the set of buffer compositions optimizing an objective function.

22. The method of any one of claims 18 to 21, further comprising: presenting a representation indicative of the operation space, A display is controlled to display the representation to a user of the generation system.

23. The method of any one of claims 18 to 21, wherein: The target characteristic indicates any selection of a target buffer solution type, a target total generated volume of the buffer solution, and a target pH of the buffer solution, a target concentration of the buffer solution, a target flow rate of the buffer solution, and a target salt concentration of the buffer solution.

24. The method of any one of claims 18 to 21, wherein: The target characteristic is indicative of a flow rate of the generated buffer solution at the output port.

25. The method of any one of claims 18 to 21, wherein: The target property indicates the concentration of the resulting buffer solution.

26. The method of any one of claims 18 to 21, wherein: The system characteristics dictate the overall flow rate range and selection of piping sizes for the generating system.

27. The method of any one of claims 18 to 21, wherein: The compositional profile indicates any selection of concentration and solubility of the components of the buffer solution.

28. The method of any one of claims 18 to 21, wherein: The operating limits indicate the pH of a resulting buffer solution for each of a plurality of combinations of concentrations of the components of the buffer solution.

29. The method of any one of claims 18 to 21, wherein: The operating limits indicate a range of flow rates for one or more pumps having system characteristics that fall within the determined operating space.

30. The method of any one of claims 18 to 21, wherein: The operating limits indicate the volumes of the components required to generate the buffer solution.

31. A buffer generation system configured to generate a buffer solution, the generation system comprising: Fluid Networks, monitor, Input device, and a control unit comprising a circuit system, the circuit system comprising: processing circuitry, and a memory comprising instructions executable by the processing circuit system, wherein the control unit is communicatively coupled to each of the pumps, whereby the generating system is configured to perform a method as described in any of claims 1-13 and / or 18-30 when the instructions are executed by the processing circuit system.

32. The system of claim 31, wherein: The fluid network comprises: a first pump fluidically coupled to a first fluid source, the first fluid source being configured to hold a saline solution, the first pump being configured to transfer fluid from the first fluid source; a second pump fluidically coupled to a second fluid source, the second fluid source being configured to hold an alkaline solution, the second pump being configured to transfer fluid from the second fluid source; a third pump fluidically coupled to a third fluid source, the third fluid source being configured to hold an acid solution, the third pump being configured to transfer fluid from the third fluid source; a fourth pump fluidically coupled to a fourth fluid source, the fourth fluid source being configured to hold water for injection, the fourth pump being configured to transfer fluid from the fourth fluid source; and a conduit fluidically coupling each of the pumps to an output port of the generation system.

33. The system of any of claims 31-32, further comprising one or more sensors configured to measure a property of the generated buffer solution, wherein the control unit is communicatively coupled to each of the sensors.

34. A computer program product comprising computer executable instructions for causing a control unit to perform any of the method steps of claims 1-13 and / or 18-30 when the computer executable instructions are executed on processing circuitry comprised in the control unit.

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