Control of buffer preparation process

Abstract

The present invention relates to 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 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. A plurality of settings is provided (S13) to one or more control systems of one or more automated processes. The invention also relates to a buffer tool configured to execute the computer-implemented method, a buffer management system comprising the buffer tool, and a computer-readable storage medium (25) storing thereon a computer program that, when executed in the buffer tool, causes 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 (buffer). Background Art

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

[0003] A buffer solution is an aqueous solution that includes a mixture of an acid, a base, and possibly a salt and water for injection (WFI). The mixture includes a weak acid and its conjugate base or a weak base and its conjugate acid that are mixed during the control process.

[0004] The property of a buffer is that when a small amount of strong acid or base is added to the 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 nearly 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 precision of the buffer solution.

[0005] A buffer solution with a desired pH and optionally a desired ionic strength can be prepared by calculating the necessary amounts of buffer components and mixing them. The mixing of these components can be performed in a preparation system that serves as a buffer kitchen or as a chromatography system. An example of such a system is developed by GE Healthcare Avant and BioProcess Inline Conditioning (IC) systems. Avant is a buffer mixing device that can prepare buffer solutions from stock solutions using a quaternary valve. IC is a buffer mixing device with several pumps for different components. A buffer management system for inline buffer preparation using concentrated single-component stock solutions of acids, bases, salts, and WFI has been put into operation. The use of concentrates significantly reduces the buffer volume, thereby saving floor space and storage tank volume. Many different buffers can be prepared from the same set of concentrates, thus streamlining buffer preparation. For the precision of the formulation and the consistency between preparations, it is possible to select different feedback modes characterized by built-in dynamic control functionality. Such an inline buffer preparation system (also called an inline conditioning system) can be used for buffer preparation but also serves as a chromatography system.

[0006] Chromatography is a technique for separating chemical and biological substances. In liquid chromatography, a buffer solution is an essential component of the process. It is important to use liquids with precisely known compositions and / or other properties (such as pH, ionic strength, etc.) in chromatography. There may also be a need to vary the composition of the liquid over time. Such a composition and its variations can be obtained by mixing or blending two or more liquids with each other using a mixing system.

[0007] A buffer solution with desired properties can be prepared, for example, by using commercially available software to calculate the necessary amounts of buffer components and mixing them. Buffer mixing devices are well known and are disclosed, for example, in the following background art patent applications / patents, which are incorporated herein by reference in their entirety: EP 2269055 A1, US 9446329 B2, US2011 / 0039712 A1, WO 2009 / 131524A1, US 9327212 B2, US2012 / 0217192 A1, EP 2480943 A1, WO2011 / 037530A1, EP 2585887 A1, US2013 / 0081703 A1, and WO 2011 / 162666 A1. Although the background art includes software solutions for calculating the relative concentrations of the different components of relatively simple mixtures of weak acids (or bases) and weak bases (or acids) based on pH (such as those defined in EP 2269055 A1), there is still a need to control the preparation of buffers with more complex properties. Conventional software solutions do not support the preparation of such complex buffers (such as buffers including additional components and salts). And although there are buffer mixing devices that can be used to obtain the relative concentrations using feedback control for a particular run (such as those defined in EP 2269055 A1), the use of such more complex buffers still requires tools to analyze the information obtained from such results of controlling new runs with similar but different control parameters. Examples of such control parameters are buffer concentration, salt and additive concentration, and the concentration and volume of the stock solutions. Other examples of relevant parameters are pH, the flow rate of the prepared buffer, the flow rate range of the pumps used in the system, or in the case of a quaternary valve, the range of the relative partitioning of the valve, and the selection of key parameters among interrelated parameters such as conductivity and concentration.

[0008] Therefore, there is a need for methods and tools for calculating the necessary amounts and setting these calculated values for buffer solution generation, for example, for buffer solutions with complex properties that are combinations of different strong electrolytes (such as salts and fully dissociated even strong acids or bases) or weak electrolytes (such as partially ionized buffer substances) or combinations thereof. Summary of the Invention

[0009] An object of the present disclosure is to alleviate, mitigate 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, where the liquid mixture includes an acid and its conjugate base or a base and its conjugate acid.

[0011] The computer-implemented method includes obtaining the composition for the 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 prompting information about a plurality of properties of the liquid mixture. In response to receiving the information about the plurality of properties and applying at least one software-implemented algorithm to determine the composition for the liquid mixture to be prepared.

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

[0014] According to some embodiments, determining the plurality of settings for controlling the preparation of the liquid mixture includes retrieving information about a selected automated process of the one or more automated processes. The control mode of the control system of the selected automated process can be determined; the automated 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 can include programming of a quaternary valve of the chromatography system.

[0017] According to some embodiments, determining the 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 the corresponding pumps used in the automated process.

[0018] In some embodiments, determining the 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 the satisfaction of the one or more boundary conditions. The boundary conditions can include the minimum and / or maximum flow rates of the corresponding pumps used in the automated process and one or more of the acid stock volume and the base stock 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 comprises an acid and its conjugate base or a base and its conjugate acid. The buffer tool comprises a user interface, a control system interface, and a processing circuitry. The processing circuitry 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 the buffer tool, causes the execution 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 the preparation of 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 aspects disclosed above enable the preparation of a liquid mixture based on an expected pH and / or ionic strength and buffer capacity, for example according to buffer type, buffer concentration, and / or salt concentration. Based on the expected pH of the liquid mixture and optionally also on the expected ionic strength and buffer capacity, the present invention provides settings for the preparation of a liquid mixture having the expected pH, ionic strength, and buffer capacity.

[0023] The aspects disclosed above provide improvements in the preparation of a liquid mixture (e.g., buffer preparation) because the exact composition is first calculated and then fed for subsequent use in an automated process for preparing the liquid mixture in a single step. Thus, the aspects disclosed above provide an automatic calculation of the molar formulation, stock concentration, and appropriate pump settings based on the pumps available in the system. The aspects disclosed above 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 laboratory utensils.

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

[0025] The present invention facilitates determination of the relative composition ratios of a liquid mixture (e.g., a buffer) that includes two or more buffering species and is generally considered a multi-buffer-species liquid. Thus, in accordance with some embodiments, two or more stock solutions can be prepared, where the stock solutions include different buffering species. In alternative embodiments, a stock solution including multiple buffering species can 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 to scale, emphasis instead being placed upon illustrating example embodiments.

[0027] Figure 1 is a flowchart showing 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 shows a system for preparing or generating a buffer solution.

[0033] Figure 6 shows a system for generating a buffer solution in accordance with one or more embodiments of the present disclosure.

[0034] Figure 7 shows on-demand generation of a buffer solution for a container in accordance with one or more embodiments of the present disclosure.

[0035] Figure 8 shows on-demand generation of a buffer solution for a container in accordance with one or more embodiments of the present disclosure.

[0036] Figure 9 shows a control unit in accordance with one or more embodiments of the present disclosure.

[0037] Figure 10 shows a flowchart of a computer-implemented method in accordance with one or more embodiments of the present disclosure.

[0038] Figure 11 shows a representation of an operating space in accordance with one or more embodiments of the present disclosure.

[0039] Figure 12 Table showing exemplary target properties of the target buffer solution.

[0040] Figure 13 Table showing exemplary system properties of the generation system.

[0041] Figure 14 Table showing exemplary system and / or component configurations.

[0042] Figure 15 Table showing exemplary target properties of the target buffer solution.

[0043] Figure 16 Table showing exemplary system and / or component configurations.

[0044] Figure 17 Representation of the operating space, combination process, in accordance with one or more embodiments of the present disclosure. Detailed Description

[0045] This application relates 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 relates 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 hereof, and in which are shown by way of illustration specific embodiments which may be practiced. The embodiments are described in sufficient detail to enable those skilled in the art to practice the embodiments, and it is to be 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. Accordingly, the following detailed description is not to be taken as limiting the scope of the invention.

[0047] The terms used herein are only for the purpose of describing particular aspects of the present disclosure and are not intended to limit the invention. As used in this specification, the term "comprise / comprising" is used to specify the presence of the stated features, integers, steps, or components, but does not preclude 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 also intended to include the plural forms unless the context clearly dictates otherwise.

[0048] In the context of the present disclosure, a buffer is a component or compound that takes the form of a liquid mixture and maintains a nearly constant pH value regardless of the addition of large amounts 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. To prepare such a liquid mixture (i.e., a buffer solution), the amounts of the weak acid / base and its conjugate base / acid, as well as the salt solution, are calculated as molar values or so-called molar formulations. From these molar values, the volumes required from the corresponding stock solutions or stock concentrations can in turn be calculated. Stock solutions of acids and bases can be prepared to known concentrations by diluting the weighted amounts of buffer salts to the measured volumes and controlling the flow rates from the stock solutions and water to the common mixing point of the buffer.

[0049] The preparation of the liquid mixture can be carried out in a preparation system that serves 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 that includes one or more chromatography columns). For example, a buffer preparation device having optional storage tanks / sacks for formulating buffers.

[0050] Examples of such systems or buffer preparation devices are those developed by GE Healthcare Avant and BioProcess Inline Conditioning (IC) systems. Avant is a buffer mixing device that uses a multi-port valve (e.g., a quaternary valve that allows the automatic mixing of four different components / fluids) from stock components. The use of the multi-port valve enables the flow control of multiple fluids / components to be mixed. IC is a buffer mixing device having several pumps for different fluids / components.

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

[0052] In the present disclosure, the terms "container" or "reservoir" will be referred to interchangeably to denote a receptacle suitable for holding fluids.

[0053] In the present disclosure, the terms "processing circuitry" and "processing component" will be referred to interchangeably.

[0054] In the present disclosure, the terms "composition" and "formulation" of a liquid mixture will be referred to interchangeably to denote the proportions of the respective components in the mixture that result in the target buffer solution.

[0055] In the present disclosure, the terms "preparation" and "generation" will be interchangeably referred to 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 formulation, giving the correct proportions of the respective ingredients, and producing the target buffer solution. The preparation of the buffer solution typically involves using concentrated stock solutions of single components, hydrochloric acid, bases, and water for injection (WFI), and may also include various additives (such as urea, polysorbate, and glycerol).

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

[0057] In the present disclosure, the terms "control system" and "control unit" will be interchangeably referred to, representing a device including processing circuitry and a memory that contains instructions executable by the processing circuitry to perform any of the steps or methods described herein, typically controlling the preparation / generation of the buffer solution in an automated process.

[0058] In the present disclosure, the terms "properties of the liquid mixture" and "target characteristics of the target buffer solution" will be interchangeably referred to, representing the expected properties or characteristics of the liquid mixture / buffer solution to be prepared.

[0059] In the present disclosure, the term "fluid source" represents 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" represents a generation system that generates a target buffer solution according to user demand, typically arranged at or geographically close to the location of a chromatography device. In the present disclosure, the term "on-demand buffer solution generation system" is used interchangeably with the "generation system".

[0061] In the present disclosure, the term "operating space" refers to the space formed by bounds within which a buffer generation system can be operated given a plurality of operating parameters such as pump flow rate, tubing size, and component concentration. In other words, the operating space can be considered an abstraction of a multi-dimensional space within which the parameters that control the generation of the buffer solution can be varied and will cause an on-demand system for generating the buffer solution to generate a target buffer solution. For example, a plurality of possible configurations of the system characteristics and component characteristics of an on-demand buffer solution generation system will achieve a given target characteristic of the target buffer solution to be generated by the generation system. In other words, any configuration selected from a large number of possible configurations can be used to generate a target buffer solution type.

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

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

[0064] In the present disclosure, the term "system characteristic" defines the properties of an on-demand buffer solution generation system, such as pump flow rate range, tubing size, and container volume.

[0065] In the present disclosure, the term "component characteristic" defines the properties of the components used to generate the buffer solution, such as component concentration and component type, such as acid, base, or salt.

[0066] In the present disclosure, the term "outer operating bounds" 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 gives a system configuration including component concentration. In one example, such outer operating bounds are given by boundary conditions. Examples of such boundary conditions include the maximum / minimum acid reserve volume, maximum / minimum base reserve volume, maximum / minimum flow rate, and one or more of the maximum / minimum flow rates of the respective pumps used in an automated process.

[0067] The present invention is useful for determining the relative component proportions of a liquid mixture, such as a buffer, that includes two or more buffer species, typically considered 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 including different buffer species. In alternative embodiments, a stock solution is provided that includes at least two (such as three, four, or more) buffer species.

[0068] The present invention is useful for determining the relative component proportions of a buffer species, in which, in addition to the buffer species, there is one or more non-buffer salts and additives.

[0069] The buffer tool controls the IC system to operate as a buffer kitchen or as a chromatography system. The tool is capable of controlling the generation of a method for controlling a buffer or for operating an entire production process including a 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, the buffer control provides the generation of a method for operating an actual chromatography. The control provides process optimization and process development as well as providing validated production of biopharmaceuticals.

[0070] Figure 1 is a flowchart showing an example method step for controlling the preparation of a liquid mixture performed, for example, in a buffer tool as disclosed, for example, in Figure 2 The liquid mixture includes an acid and its conjugate base or a base and its conjugate acid. As disclosed in FIG. 3, the buffer tool can be included in a buffer management system.

[0071] In an optional initial step, the 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 can be implemented in a computer-implemented buffer tool having a user interface as disclosed in Figure 4 where traffic light colors are preferably used to indicate the satisfaction, partial satisfaction, and non-satisfaction of the set conditions. Information related to controlling the preparation of a liquid mixture in one or more automated processes can include process information related to one or more automated processes presented in part 2 of the buffer tool interface as shown in Figure 4 The information can also include providing access to at least one computer-implemented algorithm presented in part 3 of the buffer tool interface as disclosed in

[0072] The algorithm can be applicable to determining the composition of the liquid mixture. It can be at least partially by means of Figure 4 as disclosed in part 3 of the buffer tool interface. The computer-implemented algorithm can be applicable to determining the composition of the liquid mixture. It can be at least partially by means of Figure 4Parts 2 and 3 of the user interface disclosed therein prompt user information to receive information. In one implementation of the computer-implemented method, 4 questions need to be answered in the tool: "Use pH feedback?", "Combination type of buffer?", "Salt?", and "Which is important for the process - concentration or conductivity?", that is, the information requested by prompting user information through the buffer tool interface. Information can also be received in part by retrieving information from a 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 can be retrieved include buffer systems, pH, salt types, additive types, flow rates, buffer volumes, process step times, molar formulations, etc., as well as information that can be automatically retrieved by prompting user information or as a combined operation that initiates an automatic retrieval in response to receiving the 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) includes the following steps: retrieving S11 the predetermined composition of the liquid mixture to be prepared, that is, information on the target buffer solution or target characteristics that define the target buffer and / or the characteristics of such a target buffer. In response to receiving an identifier of the liquid mixture (such as a buffer name), in-depth information related to the characteristics of the buffer can be retrieved from a database including library information defining a large number of buffer solutions or calculated from parameters retrieved during the execution of the computer-implemented method as described above. Thus, information related to the relative proportions of the stock concentrations to be included in the liquid mixture can be retrieved, for example, via wired or wireless communication from a database associated with the buffer tool or accessible from the buffer. Information on the relative proportions can also be directly entered into 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 its conjugate base (or vice versa), this composition will also, in most cases, include the concentrations of salts, water, and / or other additives. Such other additives include, for example, detergents that can contribute to protein stability and urea that can contribute to protein instability. In the context of buffer preparation, additives mainly consist of neutral molecules, while 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 on multiple attributes of the liquid mixture via a user interface or a liquid mixture composition interface, such as Figure 4presented by part 1 of the buffer tool interface as shown. Examples of such properties include at least one of liquid mixture type, liquid mixture concentration, and liquid mixture density and liquid mixture conductivity. The liquid mixture pH can be determined as a function of the conductivity and concentration of the buffer solution. However, the liquid mixture pH can also represent a preset property of the liquid to be prepared.

[0075] In response to receiving information on multiple properties, the composition of the S11b liquid mixture can be determined by applying at least one software-implemented algorithm, such as using a molar concentration calculation or a molar mass calculation algorithm as shown in part 3 of the buffer tool interface as shown. Figure 4 presented by part 3 of the buffer tool interface as shown.

[0076] According to some embodiments, obtaining the composition of the S11 liquid to be prepared includes running experiments on a chromatography device. The step of obtaining the S11 composition includes obtaining design of experiments (DoE) data, where 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 a design range. The method can further include, for example, running a first set of experiments using the chromatography device. In an example, the experiments are run by continuously providing each buffer composition mixed according to each unique formulation indicated by the DoE data as the sole input to the chromatography device. The method can further include obtaining experiment result (RoE) data as the output of 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 can further include obtaining a first objective function. In an embodiment, the first objective function can depend at least on the pH value and the conductivity value. The method can further include selecting a second subset from the set of buffer compositions and / or from the total set of buffer compositions whose corresponding pH value optimizes the first objective function. Optionally, the method further includes determining one or more buffer composition formulations for chromatography of a chemical sample as the unique formulation corresponding to the second subset. In an embodiment, the method further includes obtaining experiment prediction (PoE) data, where the PoE indicates at least the predicted pH value and the predicted conductivity value of each buffer composition of the total set of buffer compositions. Additional details regarding obtaining the composition of the buffer solution can be found in the previously incorporated WO2018229271.

[0077] When the buffer tool has received information related to the target buffer, i.e., when information related to the expected composition of the liquid mixture has been retrieved in the buffer tool, the next step involves 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 about the selected automated process for the preparation of the liquid mixture, such as whether the automated process is a buffer kitchen process or a chromatography system process. The settings may also include: control mode, molar formulation, and other settings associated with attributes such as solution concentration, solution type, volume; properties directly related to formulating 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 concentrated solutions can be prepared without solubility problems. According to some embodiments, determining the 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, with the buffer tool, all the settings required to control buffer preparation in the subsequently selected automated process can be determined. According to some embodiments, determining includes determining the control mode of the automated process, and wherein the control mode is used to operate the automated process. Such control modes include flow feedback, pH feedback, and / or conductivity feedback in accordance with a selected combination. Examples are disclosed in the following prior patent applications / patents, which are hereby incorporated by reference in their entirety: US 9446329 B2; US2011 / 0039712A1; EP 2269055 A1; WO 2009 / 131524 A1; US 9327212 B2; US2012 / 0217192 A1; EP2480943A1; WO 2011 / 037530 A1; EP 2585887 A1; US2013 / 0081703 A1; WO 2011 / 162666A1. The buffer tool will implement the calculation of all the settings required to operate an in-line regulation system as a buffer kitchen or as a chromatography system. It can provide settings as a molar formulation when using flow feedback, for example, provide settings for controlling the quaternary valve of a chromatography system when running Avant, and / or provide settings regarding which control mode to use based on preferences for controlling conductivity and / or pH. Thus, one or more control systems will be determined to receive the settings required in the expected target buffer.

[0078] According to some embodiments, the buffer tool is also capable of providing the functionality to determine whether a target buffer can be produced given the available stock concentrations and stock volumes in a given subsequent automated process. This can be done by Figure 4Part 4 of the buffer tool interface shown directly provides the stock concentration. However, the stock solution availability can also be automatically retrieved from an associated application that provides browsing 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 for the corresponding settings from one or more control systems and verifying the satisfaction of the one or more boundary conditions. Examples of such boundary conditions include one or more of the acid stock volume, base stock volume, minimum flow rate, and maximum flow rate of the corresponding pumps used in the automated process. Refer to Figure 4 the illustration in, the base pump flow rate and the base pump final concentration are examples of unfilled boundary conditions, which can be indicated in red or any other suitable signal color according to the color version if not filled. If the target buffer cannot be produced, the system can 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 volume of each stock solution required can be calculated. In the case where the same stock solution can be used to produce several buffers, information related to the requirement of each stock solution for each buffer and the total amount required for each stock solution can be provided.

[0079] As an end step, to initiate the actual preparation of the liquid mixture, the method includes, for example, providing a plurality of settings to one or more control systems of one or more automated processes in a process control interface. Thus, the buffer tool provides the settings required for the control system to operate subsequent automated processes, such as a buffer kitchen or a chromatography system. The buffer tool can generate settings for a specific buffer or for the entire production process including chromatography steps.

[0080] According to some embodiments, providing a plurality of settings to one or more control systems of one or more automated processes includes providing a plurality of settings to the control system when each boundary is satisfied. 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 satisfied, providing a plurality of settings to one or more control systems of 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 for the alternative liquid mixture to 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, the automated process for preparing the liquid mixture (i.e., the target buffer solution) may be monitored by sensors, for example to determine the pH level 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 as to obtain a buffer solution with the expected characteristics.

[0082] According to some embodiments, the buffer tool enables the selection and optimization of multiple stock concentrations for a process. One or more buffer formulations for preparing the corresponding liquid mixture may be selected from a database including buffer formulations. For example, a user selects several buffer formulations based on criteria (or tags) such as the process running on a system, buffer properties (e.g., pH, buffer concentration), or the type of stock solution. The buffer tool will retrieve the formulations for selecting one or more stock solutions based on boundary conditions, where the boundary conditions include the volume required for the corresponding stock solution for preparing the liquid mixture based on the retrieved buffer formulation. For each selected stock solution, the buffer tool determines the minimum number of stock concentrations of the one or more retrieved buffer formulations. It is also possible that the software suggests potential optimization possibilities based on, for example, a standard of <3 - 5 different concentrations for one 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 may present several different options that the user can select to implement in all / some of the selected buffer formulations. For example, options that are incompatible with the system settings due to boundary conditions (e.g., pump size and pump size combinations) may also be visible and may be excluded. After the optimization operation, the one or more buffer formulations are updated with the stock concentrations selected from the determined minimum number of stock concentrations.

[0083] Figure 2 Schematically shows an example of a buffer tool 20, which includes: a liquid mixture composition interface 21, such as Figure 4 shown in parts 1 - 4 of Figure 4 the result part; and a processing circuitry 23. The processing circuitry 23 is configured to determine settings for controlling the preparation of a liquid mixture in one or more automated processes in response to obtaining the composition of the liquid mixture to be prepared, and to provide multiple settings to one or more control systems of the one or more automated processes. The buffer tool may be applicable to provide settings for a variety of automated processes, for example for preparing liquid mixtures in buffer kitchen applications or in chromatography systems.

[0084] As Figure 2 Figure 2 Further shown herein, the present disclosure also relates to a computer-readable storage medium 25 storing thereon a computer program that, when executed in the buffer agent tool 20, causes the execution of any of the above-described method aspects.

[0085]

[0085] FIG. 3a shows a block diagram of a buffer agent management system 10 for controlling the preparation of a liquid mixture, where the liquid mixture includes an acid and its conjugate base or a base and its conjugate acid. The buffer agent management system is configured to use inline buffer agent preparation of the above-described buffer agent tool and is configured to perform the above-described method. The buffer agent management system 10 includes one or more automated process arrangements 40 for the preparation of the liquid mixture (i.e., buffer solution) and one or more control systems 30 for controlling the one or more automated processes. The preparation of the liquid mixture may involve using single-component concentrated stock solutions of hydrochloric acid, a base, and water for injection (WFI). The use of concentrates is beneficial in reducing the buffer agent volume and saving storage tank volume and occupied space. Additionally, many different buffer agents can be prepared from the same set of concentrates, thus further streamlining buffer agent preparation. For the accuracy of the formulation and consistency between preparations, it is possible to use a feedback mode that includes built-in dynamic control functionality.

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

[0087]

[0087] In the example embodiment shown in FIG. 3b, the buffer agent tool may support a scaling operation for scaling the liquid mixture preparation operation from a laboratory scale to a large industrial scale, e.g., from the liquid mixture preparation environment in Avant to large-scale liquid mixture preparation in a BioProcess Inline Conditioning (IC) system. Avant is a buffer agent mixing arrangement that can prepare buffer solutions from stock solutions using a quaternary valve, i.e., mainly for preparing laboratory-scale amounts of liquid mixtures, while IC is a buffer agent mixing arrangement that uses multiple pumps for different components.

[0088] Referring to Figure 3b, for example, the parameter settings for the laboratory-scale preparation of a liquid mixture in an Avant environment are determined in a buffer tool and provided (1) to the control system 30 of 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 using the buffer tool in conjunction with the Avant arrangement, Avant can perform a rough check to achieve the determination of the desired settings, for example, by allowing multiple runs in Avant while adjusting one or more parameters during each run. Thus, the Avant arrangement can help define the parameters for the large-scale production of buffer solutions. In the settings disclosed in Figure 3b, the buffer tool is used to determine the parameter settings, which are provided (1) to the control system, for example, in a data message. The control system continues to regulate the automated process in the Avant system by providing (2) control parameters from the control system to 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 provide feedback data, reports, and results to the control software and / or the buffer tool. Thus, the laboratory-scale arrangement (such as Avant) can generate data, which is provided (3) to the control software or the 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 the results and data from the laboratory-scale arrangement into parameter settings suitable for a larger-scale arrangement (such as 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 for new runs, or it can produce buffers for validating biopharmaceutical production in the system. The method implemented by the buffer tool will not only enable the control of buffer production in the buffer kitchen but also be applicable to chromatographic processes.

[0090] When the buffer tool is applied to develop the parameter settings for a laboratory-scale process, the tool implements the calculation of the molar formulation, the definition of which stock concentrations to use, and the appropriate pump settings. The feedback of these parameter settings can then be used to improve the generation of input data for operating the large-scale system. By allowing feedback data to be provided (7) from the large-scale arrangement 40b (such as an IC arrangement) to the control system 30 or the buffer tool 20, the feedback loop from the large-scale arrangement 40b will further enhance the improvement.

[0091] Thus, the disclosed buffer tool is applicable in multiple use cases, such as supporting the preparation of liquid mixtures for buffer / process development or industrial buffer / biopharmaceutical production in laboratory-scale setups or industrial large-scale setups. Additionally, the buffer tool is configured to allow for the scaling up and down of controlled processes. In the above use cases, the buffer tool has been applied with good results to buffer kitchen processes or chromatography processes.

[0092] In the scaling-up scenario, a laboratory-scale setup is initially used to determine the appropriate liquid mixture preparation process. Avant is used to define the molar formulation and optimize the liquid mixture process; traveling between the laboratory-scale setup during the determination of this liquid mixture process provides information (1)-(3). The scaling-up process is then carried out in a large-scale setup and further developed by providing information (4)-(7) between the buffer tool 20 for liquid mixture preparation, the control system 30, and the large-scale setup 40b.

[0093] In the scaling-down or change process, for example when a change in production is needed and a new process is to be verified, settings are retrieved from the large-scale setup and provided as information (7) to the buffer tool 20 or the control system (30), thereby determining the laboratory-scale settings such that the scaling-down process can be run and verified in a laboratory environment before running the industrial-scale process. Support for this type of scaling up and down is automated by the proposed buffer tool.

[0094] Those skilled in the art will also know that the feedback structure supports the simulation of liquid mixture preparation results, for example in order to obtain outputs related to buffer quality from the buffer tool, using the buffer calculator in the buffer tool to obtain theoretical results that can be compared with the actual results from liquid mixture preparation runs, or using information that can be stored as a built-in database in the buffer tool to determine the expected conductivity.

[0095] In an industrial large-scale context, the buffer management system implements a fully automated process for liquid mixture preparation, whereby the liquid mixture can be produced when needed and verified at the formulation point. The increased dynamics in the control of buffer preparation increase the precision of pH and / or conductivity.

[0096] Figure 4 An exemplary buffer tool interface is disclosed, which includes: a liquid mixture composition interface, divided into four parts, namely, parts 1-4; and a process control interface, presented as a result section.

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

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

[0099] Thus, the buffer agent tool will generate the multiple settings required for the control system to operate the automated process for the preparation of the target buffer agent. The buffer agent tool is capable of generating methods for producing a single buffer solution and also generating methods for operating the entire production process (such as a production process including a chromatography step).

[0100] According to some embodiments, there is provided a buffer agent management system 10 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. As can be seen from Figure 5 the selection of ingredients is mixed to generate the buffer solution. The buffer solution is provided at a specific flow rate (e.g., liters per second) at the outlet port PO. The ingredients generally include acid, base, salt, and water for injection WFI. Other ingredients can be added, such as urea, polysorbate, and glycerol.

[0102] Typically, WFI is provided by a main pump that is coupled to a container and a main pipe. The other end of the main pipe is coupled to an output port PO. The output port PO can include any combination of valves, adapters, fluid output members, or couplings (such as quick couplings to hoses or other tubular structures). System characteristics such as the size of the main pipe and the operating range of the main pump (e.g., flow rate) limit the operating space of the system with respect to the flow rate of the buffer solution (e.g., maximum flow rate).

[0103] The type of buffer solution to be prepared or generated will, for example, determine compositional 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 typically determined by defining the recipe of the target buffer solution. In other words, the operating space of the system is limited by the choice of components or stock solutions (e.g., choice of stock solution concentration).

[0104] Each of the components will be stored in a container and will be fed to the main pipe for mixing into the buffer solution by a component pump via a component pipe. Each component must be fed to the main pipe at a specific flow rate to generate a specific type of buffer solution. Thus, system characteristics such as the size of the component pipe 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., maximum flow rate of the generated buffer solution). This will thus 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 compositional characteristics can be used to generate, for example, a specific target buffer solution at a specific target flow rate, at a specific target pH, and with a specific target total volume. This large number of possible configurations of system characteristics and compositional characteristics can be regarded as the operating space of the system. In other words, any configuration selected from the large number of possible configurations can be used to generate the target buffer solution type.

[0106] In one example, to generate a specific buffer solution, 10 liters of acid at a specific concentration will be required, or alternatively 20 liters of acid at 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 choice of container and pump characteristics. Thus, a choice must be made between system characteristics and compositional characteristics, and both examples fall within the operating space of the system for the specific target buffer solution.

[0107] Figure 6A system 10 for generating a buffer solution according to 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, such as including component pipes CP1 - CP4 and a main pipe MP. In one embodiment, the fluid network includes a first pump P1 that is fluidly coupled to a first container C1, for example, through a first component pipe CP1. The first container C1 is configured to hold a salt solution FL1. The first pump P1 is configured to transfer the fluid FL1 from the first container C1 to an output port PO.

[0108] Additionally or alternatively, the fluid network further includes a second pump P2 that is fluidly coupled to a second container C2, for example, through a second component pipe CP2. The second container C2 is configured to hold an alkali 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 includes a third pump P3 that is fluidly coupled to a third container C3, for example, through a third component pipe 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 includes a fourth pump P4 that is fluidly coupled to a fourth container C4, for example, through a fourth component pipe CP4. The fourth container C4 is configured to hold water for injection FL4. The fourth pump P4 is configured to transfer the fluid FL4 from the fourth container C4 to the output port PO.

[0111] Additionally or alternatively, the fluid network further includes one or more additional pumps (not shown), each pump being fluidly coupled to a corresponding container (not shown) through a corresponding component pipe (not shown). The containers are configured to hold additives, such as urea, polysorbate, and glycerol. Each of the one or more pumps is configured to transfer the fluid from the corresponding container to the output port PO.

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

[0113] Each of the component pipes CP1 - CP4 is generally arranged with an inlet at one end (e.g., at the bottom of the corresponding containers C1 - C4) and is coupled to the corresponding pumps P1 - P4 at the other end.

[0114] The container may optionally be a single-use container or a reusable container. A single-use container has the advantage of not requiring cleaning, while a reusable container has 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 includes control units CU 30, 810, 910. The control unit generally includes a buffer tool 20 and a control system 30. The buffer tool 20 includes circuitry (the circuitry includes processing circuitry 512) and a memory 515, the memory 515 containing instructions executable by the processing circuit 512, wherein the control units CU 30, 810, 910 are communicatively coupled to each of the pumps P1 - P4, whereby the generation system 10 (the generation system 10 includes the control units CU 30, 810, 910) is configured to perform any of the method steps described herein. With respect to Figure 9 The control units CU 30, 810, 910 are further described.

[0118] In one embodiment, the system as described in any of the preceding claims further includes one or more sensors S1, S2, the sensors S1, S2 being configured to measure the properties of the generated buffer solution. The control units CU 30, 810, 910 are 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 sensors for performing measurements on the buffer solution may be used. Figure 7 Illustrated is the generation of a buffer solution for a container by the system 10 in accordance with one or more embodiments of the present disclosure. In one embodiment of the present disclosure, the generation of the buffer solution typically occurs just prior to a chromatographic run. In other words, the type of buffer solution required for a particular chromatographic run is generated in a timely manner to commence the chromatographic run. The generated buffer solution is temporarily stored in a fluid source (e.g., a single-use container or a reusable container). For example Figure 6 the container shown in

[0119] Figure 8 Illustrated is the generation of a buffer solution for a chromatographic device in accordance with one or more embodiments of the present disclosure. In one embodiment, the generation of the buffer fluid is performed concurrently with the chromatographic run. That is, the generation system 10 directly feeds the generated buffer solution into the chromatographic device 800 via an output port PO.

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

[0121] The chromatography device 800 may further include a control unit 810 that includes circuitry (e.g., a processor) and a memory. The memory may contain instructions executable by the processing circuitry, whereby the control unit 810 and / or the chromatography device may be operable 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 generation system 10. With respect to Figure 9 the control unit 810 of the generation system 10 is further described.

[0122] The chromatography device 800 optionally may include a separator 870 that is coupled to the fluid outlet of the column 841 and is coupled to a selection of any of a UV sensor 831, a conductivity sensor 832, and an outlet valve 820. The separator 870 may be configured to direct the fluid received from the column 841 to any 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 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 is configured to measure a quantitative metric (e.g., the UV light absorbance of the fluid) provided by the separator 870. The chromatography device 800 may further include a conductivity sensor 832 that is communicatively coupled to the control unit 810 and is configured to measure a quantitative metric (e.g., the 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 metric to the control unit 810 as a control signal containing measurement data.

[0124] The chromatography device 800 may further include an outlet valve 820 that is 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, fractionation of the eluent is performed.

[0125] Figure 9 Illustrated are control units CU 30, 810, 910 according to one or more embodiments of the present disclosure. The control units CU 30, 810, 910 may take the form of, for example, an electronic control unit, a server, an on-board computer, a fixed computing device, a laptop computer, a tablet computer, a handheld computer, a wrist-worn computer, a smartwatch, a smartphone, or a smart TV. The control units CU 30, 810, 910 may include processing circuitry 912 that is communicatively coupled to a transceiver 904 configured for wired or wireless communication. The control units CU 30, 810, 910 may further include at least one optional antenna (not shown in the figures). The antenna may be coupled to the transceiver 904 and is configured to transmit and / or emit and / or receive wired or wireless signals in a communication network (such as Wi-Fi, Bluetooth, 3G, 4G, 5G, etc.). In one example, the processing circuitry 912 may be any selection of processing circuitry and / or a central processor and / or a processor module and / or multiple processors configured to cooperate with each other. Additionally, the control units CU 30, 810, 910 may further include a memory 915. The memory 915 may include, for example, hard RAM, a disk drive, a floppy disk drive, a flash drive, or other removable or fixed media drives 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 circuitry 912 is optionally communicatively coupled to any selection of the transceiver 904, the memory 915, one or more sensors S1 and S2 (such as a pH sensor and a conductivity sensor S2). The control units CU 30, 810, 910 may be configured to send / receive control signals directly to / from any of the above units or to an external node, or to send / receive control signals via a wired and / or wireless communication network.

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

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

[0128] In one or more embodiments, the control units CU 30, 810, 910 may further include an input device 917 configured to receive an input or indication from a user and send a user input signal indicative of the user input or indication to the processing circuitry 912.

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

[0131] In another embodiment, the control units CU 30, 810, 910 may further include and / or be coupled to one or more additional sensors (not shown in the figures), the sensors being configured to receive and / or obtain and / or measure a physical property related to the generating system 10 and send one or more sensor signals indicative of the physical property of the generating system 10 to the processing circuitry system 912. For example, a temperature sensor that measures the ambient air temperature.

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

[0133] Figure 10The flowchart 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 executed 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 for holding components FL1-FL4 of the buffer solution; pumps P1-P4 for transferring fluid from each of the fluid containers C1-C4; a pipeline fluidly coupling each of the pumps to an output port PO of the generation system 10; and a control unit CU 810 communicatively coupled to each of the pumps P1-P4. Relatively Figure 6 The generation system 10 is further described. The method includes: Step 1010: Obtain first input data indicating target characteristics of a target buffer solution to be generated by the generation system 10. The first input data can be received from an input device 917 and / or retrieved from a memory 915, and / or received in a signal / message from another unit (e.g., from a server or a cloud server) via a communication network.

[0134] The first data can 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, as described further with respect to Figure 2 Further description.

[0135] In one embodiment, the target buffer solution that causes the determination of the operating space is defined by target characteristics. In one embodiment, the target characteristics indicate a selection of any one of a target buffer solution type, a target total generation volume of the buffer solution, 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.

[0136] Additionally or alternatively, the target characteristics indicate the flow rate of the generated buffer solution at the output port PO.

[0137] Additionally or alternatively, the target characteristics indicate the concentration of the generated buffer solution.

[0138] Step 1020: Obtain second input data indicating system characteristics of the generation system. The second input data can be received from an input device 917 and / or retrieved from a memory 915, and / or received in a signal / message from another unit (e.g., a server or a cloud server) via a communication network.

[0139] In one embodiment, the nature of the generation system 10 that causes the determination of the operating space is defined by system characteristics. In one embodiment, the system characteristics indicate the selection of the flow rate range of the pump, the volume of the component container, and the pipe size of the generation system 10. It is to be understood that the present disclosure is not limited to the above characteristics, but may also indicate the characteristics of other components (such as sensors, filters, etc.).

[0140] Step 1030: Obtain third input data, where the third input data indicates the component 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 (such as a server or cloud server) via a communication network.

[0141] In one embodiment, the nature of the components that are used to generate the buffer solution and cause the determination of the operating space is defined by component characteristics. In one embodiment, the component characteristics indicate the selection of either the concentration or the solubility of the components of the buffer solution.

[0142] In one example, obtaining the first, second, and third input data includes prompting information about multiple attributes of the liquid mixture / buffer solution. In response to receiving the information about the multiple attributes and applying at least one software-implemented algorithm (such as an algorithm for molar concentration calculation or molar mass calculation) to determine the composition of the liquid mixture to be prepared. The attributes of the liquid mixture / buffer solution may include at least one of the liquid mixture type / target buffer type, the liquid mixture concentration / target buffer concentration, the liquid mixture density / target buffer density, and the liquid mixture conductivity / target buffer type conductivity.

[0143] Step 1040: Determine the operating space by calculating the external 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 multiple system characteristics, where the third input data is obtained by selecting from multiple component characteristics.

[0144] Determining the operating space may include, for example, determining a plurality of settings for controlling the preparation of the liquid mixture in one or more automated processes, as Figure 2 further described in.

[0145] In one example, an outer operating limit is calculated by retrieving one or more predetermined boundary conditions for any of the first data and / or the second data and / or the third data, and selecting an outer operating limit that can be verified using the one or more boundary conditions. The boundary conditions can include one or more of a minimum and / or maximum acid reserve volume of a corresponding pump used in an automated process, a minimum and / or maximum base reserve volume, and a minimum and / or maximum flow rate. With respect to Figure 1 and Figure 2 Verification is further described with reference to FIG. 3b.

[0146] In one example, a user provides input data indicating a target buffer type of acetate, a target total volume of 1000 liters of the resulting buffer solution, a target pH of 4.3, a target pH of the resulting buffer solution of 4.3, and a target buffer concentration of 100 mM (millimoles). 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 storage tanks can be compared with the estimated volumes, and a subset of containers selected from the list of available containers that can accommodate the required volumes can be determined.

[0147] In another example, the user further provides input data indicating the component concentrations of base FL2 and acid FL3, a main pipe size of one (1) inch, and a flow rate of the generation system of 200 liters per hour. The generation system then determines an operating space indicating possible pumps to be used based on the estimated flow rates of different pumps P1 - P4 (e.g., an estimated flow rate range of 15 - 600 liters per hour for the first pump P1, an estimated flow rate range of 4 - 180 liters per hour for the second pump P2, an estimated flow rate range of 4 - 180 liters per hour for the third pump P3, and an estimated flow rate range of 45 - 200 liters per hour for the fourth pump P4). That is, a list of available pumps can be compared with the estimated flow rates, and a subset of pumps selected from the list of available pumps that can accommodate the required flow rates can be determined.

[0148] In some embodiments, the Debye - Hückel equation (which is further described in US9446329 B2 and is incorporated herein by reference in its entirety) is used to calculate the proportions of the components required to generate the buffer solution.

[0149] In one embodiment, obtaining the first input data further includes: receiving user input indicating a target property, where the target property at least indicates a target buffer solution type, a target concentration of the generated buffer solution, and a target total generated volume of the buffer solution; using the Debye-Hückel equation or its software-implemented algorithm to calculate other target properties, where the other target properties include the flow rate of the components obtained using a formulation defining the target buffer solution type.

[0150] Additionally or alternatively, this embodiment may further include determining the formulation of the buffer solution by evaluating an equation. The evaluation equation includes: determining the ionic size parameter a in the Debye-Hückel equation based on the weighted average ionic size of all species contributing to the ionic strength of the generated buffer solution, with the ionic strength of each species used 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 ionic size parameter a; and calculating other target properties indicating the flow rate of the components using the ratios of the components and the maximum flow rate obtained based on the pipe size of the generation system 10.

[0151] Additionally or alternatively, this embodiment may further include: determining the formulation of the buffer solution by obtaining the composition of the liquid to be prepared, including, for example, prompting information about multiple properties of the liquid mixture / buffer solution by means of a user interface or a liquid mixture composition interface, such as Figure 4 presented by part 1 of the buffer tool interface as shown. Examples of such properties include at least one of the liquid mixture / buffer solution type, the liquid mixture / buffer solution concentration, the liquid mixture / buffer solution density, and the liquid mixture / buffer solution conductivity. The liquid mixture pH can be determined as a function of the conductivity and concentration of the buffer solution. However, the liquid mixture pH can also represent a preset property of the liquid to be prepared. In response to receiving information about the multiple properties, the composition of the liquid mixture / buffer solution can be determined by applying at least one software-implemented algorithm, such as using the molar concentration calculation or molar mass calculation algorithm shown in part 3 of the buffer tool interface as shown in Figure 4 .

[0152] Additionally or alternatively, this embodiment may further include determining a formulation of a buffer solution by running an experiment on a chromatography device. The step of obtaining the composition of S11 then includes obtaining design of experiments (DoE) data, where the DoE data indicates a set of buffer compositions and corresponding unique formulations. The DoE data may 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 a design range. The method may further include, for example, running a first set of experiments using the chromatography device. In an example, the experiments are run by continuously providing, as the sole input to the chromatography device, each buffer composition mixed according to each unique formulation indicated by the DoE data. The method may further include obtaining result of experiment (RoE) data as an output from the first set of experiments. In an embodiment, the RoE data indicates a set of buffer compositions and / or at least the pH value of each buffer composition of 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 from the set of buffer compositions and / or from the total set of buffer compositions whose corresponding pH values optimize the first objective function. Optionally, the method further includes determining one or more buffer composition formulations for chromatography of a chemical sample as the unique formulations corresponding to the second subset. In an embodiment, the method further includes obtaining predicted outcome of experiment (PoE) data, where the PoE indicates at least the predicted pH value and the predicted conductivity value of each buffer composition of the total set of buffer compositions. Additional details regarding obtaining the composition of the buffer solution can be found in the previously incorporated WO2018229271.

[0153] Additionally or alternatively, the operating space is further presented as a representation and, for example, displayed to a user of the generation system 10. In this embodiment, the method further includes: presenting a representation 1100 indicating the operating space, and controlling the displays 818, 918 to display the representation 1100 to the user of the generation system. The display may be the display 918 included in or arranged in the generation system 100 or the display 818 included in or arranged in the chromatography device. With respect to Figure 11 further describe the representation 1100.

[0154] Depending on which aspects the user is going to focus on, the operating space may be defined by calculating different outer operating limits.

[0155] This has the advantage of improving perception and reducing the time for a user to understand information and react to it, such as to arrive at a viable configuration of the generation system 10. The representation 1100 may be adapted to visually show the operating space, thereby adapting the presentation to human physiology. For example, by presenting a set of adjacent units in a grid, thereby allowing the user's visual system to automatically group the units / elements into a pattern representing the operating space, see for example Gestalt theory.

[0156] In one embodiment, the operating limits indicate the pH of the generated buffer solution for each of a plurality of combinations of the concentrations of the components of the buffer solution.

[0157] The selection of the concentrations of the components is very important and extremely important for the process.

[0158] In one embodiment, the operating limits indicate the flow rate ranges of one or more pumps having system characteristics that fall within the determined operating space.

[0159] In one embodiment, the operating limits indicate the volume ranges of one or more containers having system characteristics that fall within the determined operating space.

[0160] In one embodiment, the operating limits indicate the volume range or concentration range of the components required to generate the buffer solution.

[0161] Any number of operating limits may be used and combined to form the operating space.

[0162] In some embodiments, the method further includes using control parameters to control the generation system 10, the control parameters being derived or assigned using the operating space. In this embodiment, the method further includes assigning control parameters for controlling the generation system 10 to operate within the determined operating space, and using the assigned control parameters to control the generation system 10.

[0163] In other words, the assigned control parameters or a plurality of settings are provided to one or more control systems 30, 810, 910 of one or more systems 10 running an automated process. The assigned control parameters may include one or more reserve concentrations and / or one or more pump settings for the respective pumps used in the automated process. Information on the selected automated process and / or the assigned control parameters of one or more automated processes is further retrieved / received by the control systems 30, 810, 910. The control mode of the control systems 30, 810, 910 for the selected automated process may be determined; the automated process is run by the control systems 30, 810, 910 using the control mode. The control mode includes one or more of flow feedback, pH feedback, and conductivity feedback. The automated process may be run as a buffer kitchen or as a chromatography system. When run as a chromatography system, the control mode may include programming of the quaternary valve of the chromatography system.

[0164] In one example, the control parameters for the dispensing control generation system 10 to operate within the determined operating space include selecting containers from a subset of containers as described above, where the containers are selected from a list of available containers that can accommodate the required volume, and the volume of the selected containers is assigned as a control parameter. For example, by pausing the generation of the buffer solution after the container has been emptied or when the container is empty or substantially empty.

[0165] Control parameters can be assigned within the operating space / operating limits by receiving from the user parameter values that fall within the operating space / operating limits.

[0166] Control parameters can be assigned within the operating space / operating limits by optimizing or evaluating an objective function to assign parameters that fall within the operating space / operating limits. The objective function, for example, has a low cost for available containers or components, and a higher cost for containers or components that need to be ordered or otherwise obtained. The volume of the container or the concentration of the component representing the lowest cost can be assigned.

[0167] In one example, the control parameters for the dispensing control generation system 10 to operate within the determined operating space include controlling pumps P1 - P3 to a specific flow rate, where the specific flow rate depends on the concentration of the components held in the corresponding containers C1 - C4. That is, when a first concentration of the component is selected, the pumps are controlled to a first flow rate, and when a concentration of the component that is half of the first concentration is selected, the pumps are controlled to a flow rate that is twice the first flow rate.

[0168] Figure 11 A representation 1100 of an operating space according to one or more embodiments of the present disclosure is shown. An example of the representation is shown as a two - dimensional grid having two axes. The grid can represent the pH value on one axis and a combination of the concentrations of the components of the buffer solution on the other axis. If the corresponding combination of the pH value and concentration of the component does not represent a valid combination for generating the target buffer solution, the box on the grid is shown as empty.

[0169] In one embodiment, a computer program is provided and includes computer - executable instructions for causing control units 30, 810, 910 to perform any of the method steps described herein when the computer - executable instructions are executed on the processing circuitry included in the control units 30, 810, 910.

[0170] In one embodiment, a computer program product is provided and includes a computer - readable storage medium having embodied therein the above - described computer program.

[0171] A first exemplary embodiment of the present disclosure is provided below. In this example, an appropriate hardware system and appropriate stock solutions for a process are determined.

[0172] Figure 12 Table 1200 showing exemplary target characteristics of the target buffer solution. The table shows in the first column an index identifying the type of the target buffer solution. The table shows in the second column the name of the target buffer solution. The table shows in the third column the target pH of the buffer solution. The table shows in the fourth column the target salt concentration of the buffer solution. The table also shows in the fifth column the target flow rate of the buffer solution.

[0173] The information in the table forms the first input data of the target characteristics, i.e., the buffer concentration, pH, salt concentration, and the maximum and minimum flow rates of the target buffer.

[0174] Based on the target flow rate of the buffer solution in the first input data, the customer needs a 1” system or a one (1) inch pipe size, thereby providing a flow rate range of 200 - 2000 liters per hour for target process 1 or the process used in this example to generate the target buffer solution. In other words, it is expected that the minimum flow rate falls within the flow rate range of the system using one-inch pipes.

[0175] Figure 13 Table 1300 showing exemplary system characteristics of the generation system. The second input data can then be regarded as a selection among 8 system configurations of the pumps shown in Table 1300 or 1×2×2×2 different combinations.

[0176] The third input data indicates the compositional characteristics 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).

[0177] It is generally advantageous for the user of the generation 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 pumps should be as small as possible. In this first example, 5 different possible stock concentrations of the acid and base have been considered, resulting in 25 different combinations.

[0178] In this example, the molar formulation (the molar concentration of the acid or the relative component ratio and the molar concentration of the base in each of the buffer solutions of the first input data) is calculated using the method described in US9446329B2 based on the solution of the Debye - Hückel equation, where the ionic size parameter a in Debye - Hückel is calculated as the weighted average ionic size of all species contributing to the ionic strength of the generated buffer solution, and the ionic strength of each species is used as the weighting parameter in the Debye - Hückel equation (or the application US12 / 988553 which is incorporated herein by reference in its entirety).

[0179] The molar formulation of each component is then used in the following equations to obtain all 25 combinations of the stock solutions and the pump flow rates of the acid and base pumps for the 8 combinations of pumps: Acid flow rate = (Molar concentration of acid / Stock concentration of acid) × Target buffer solution flow rate Base flow rate = (Molar concentration of base / Stock concentration of base) × Target buffer solution flow rate The results of the final selection of the pump combinations that give the highest volume reduction are provided in Table 1400.

[0180] Figure 14 Table 1400 showing exemplary system and / or component configurations. The first three columns include information similar to the columns shown in Figure 12 Table 1200 therein, i.e., target buffer type, target buffer flow rate, and component concentration. In the fourth column, the external operating limits of 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 as shown.

[0181] The results of Process 1 in this first example show that this customer requires a 1" piping system with a maximum capacity of 2000 L / h and sizes 3 of pump A (P3) and pump B (P2) in order to be able to produce all the expected buffers on an IC system. Systems with other pump sizes will not give the customer the same overall volume reduction.

[0182] A second exemplary embodiment of the present disclosure is provided below. In this second example, the appropriate hardware systems and the determination of the stock solution establishment for two processes are shown. In this example, the system will be used to run Process 1 in Example 1 as well as a second process (denoted herein as Process 2) The list of target buffer solutions for Process 1 is the same as in Example 1 and Figure 12 as shown.

[0183] The list of target buffer solutions for Process 2 is shown in Figure 15 Table 1500.

[0184] Figure 15 Table 1500 showing exemplary target characteristics of the target buffer solutions. The table shows in the first column an index identifying the target buffer solution type. The table shows in the second column the target buffer solution name. The table shows in the third column the target pH of the buffer solution. The table shows in the fourth column the target salt concentration of the buffer solution. The table also shows in the fifth column the target flow rate of the buffer solution.

[0185] The calculation process for Process 2 is similar to that for Process 1 provided in Example 1 above.

[0186] Figure 16Table 1600 showing a demonstration 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 sizes 3 of pumps A (P3) and B (P2) in order to be able to produce all the expected buffers on a production system. The stock solution with the highest possible concentration is provided in Figure 16 Table 1600.

[0187] The same process can then be repeated for any other production processes 3, 4, etc. The method can then display the hardware requirements for the individual processes as well as all the processes in combination.

[0188] Figure 17 Representation 1700 of a combined process showing the operating space according to one or more embodiments of the present disclosure. This overlay will show whether the requirements are covered by one system size or whether the customer requires a different size system.

[0189] In other words, the operating spaces of two or more processes overlap, thus forming a combined operating space when the operating spaces are stacked on top of each other.

[0190] In an embodiment, the communication network communicates using wired or wireless communication technologies, which may include local area network (LAN), metropolitan area network (MAN), global system for mobile communications (GSM), enhanced data GSM environment (EDGE), universal mobile telecommunications system, long term evolution, high speed downlink packet access (HSDPA), wideband code division multiple access (W-CDMA), code division multiple access (CDMA), time division multiple access (TDMA), Wi-Fi, voice over Internet protocol (VoIP), LTE advanced, IEEE802.16m, WirelessMAN-Advanced, evolved high speed packet access (HSPA+), 3GPP long term evolution (LTE), mobile WiMAX (IEEE 802.16e), ultra mobile broadband (UMB) (previously evolved data optimized (EV-DO) Rev.C), fast low latency access with seamless handover orthogonal frequency division multiplexing (Flash-OFDM), high capacity space division multiple access and mobile broadband wireless access (MBWA) (IEEE 802.20) systems, high performance radio metropolitan area network (HIPERMAN), wavelength division multiple access (BDMA), worldwide interoperability for microwave access (Wi-MAX), and ultrasonic communication, etc., but is not limited thereto.

[0191] In addition, those skilled in the art should know that the control units CU 30, 810, 910 may include the necessary communication capabilities in the form of, for example, functions, components, units, elements, etc. for implementing the present solution. Examples of other such components, units, elements, and functions are: processors, memories, buffers, control logics, encoders, decoders, rate matchers, de-rate matchers, 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., which are arranged appropriately together for implementing the present solution.

[0192] In particular, the processing circuitry and / or processing components of the present disclosure may include one or more instances of processing circuitry, processor modules, and multiple processors, central processing units (CPUs), processing units, processing circuitry, processors, application specific integrated circuits (ASICs), microprocessors, field programmable gate arrays (FPGAs), or other processing logics configured to cooperate with each other and capable of interpreting and executing instructions. Thus, the expressions "processing circuitry" and / or "processing components" may represent a processing circuitry system including multiple processing circuits, such as any one, part, or all of the above-mentioned processing circuitry systems. The processing components may further perform data processing functions for data input, output, and processing, including data buffering and device control functions, such as user interface control, etc.

[0193] The description of the example embodiments provided herein is given for the purpose of illustration. This description is not intended to be exhaustive or to limit the example embodiments to the precise forms disclosed; modifications and variations are possible in light of the above theory, or may be obtained from the practice of various alternatives of the provided embodiments. The examples described herein are selected and described so as to illustrate the principles and nature of the various example embodiments and their practical applications, so that those skilled in the art can utilize the example embodiments in various ways and with various modifications as are suitable for the particular use contemplated. The features of the embodiments described herein may be combined in 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 combination with each other.

[0194] In general, 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 in which it is used.

[0195] Reference is made herein to various embodiments. However, those skilled in the art will know that many variations of the described embodiments still fall within the scope of the claims.

[0196] For example, the method embodiments described herein disclose exemplary methods through steps performed in a certain order. However, it should be 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 though they are described as being performed sequentially. Therefore, the steps of any method disclosed herein need not be performed in the exact order disclosed, unless the steps are explicitly described as being after or before another step and / or it is implied that a step must be after or before another step.

[0197] It should also be noted that in the description of the embodiments, the division of functional blocks into specific units is not intended to be restrictive at all. On the contrary, these divisions are merely examples. A functional block described herein as a single unit may be divided into two or more units. In addition, functional blocks described herein as being implemented as two or more units may be combined into fewer (e.g., single) units.

[0198] Any feature of any one of the embodiments disclosed herein may be suitably applied to any other embodiment. Similarly, any advantage of any one of the embodiments may be applied to any other embodiment, and vice versa.

[0199] In the drawings and the 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 purposes of limitation.

[0200] Therefore, it should be understood that the details of the embodiments are merely examples presented for the convenience of description, and all variations falling within the scope of the claims are intended to be included therein.

Claims

1. 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 comprising: - obtaining the composition of the liquid mixture to be prepared; - determining a plurality of settings for controlling the preparation of the liquid mixture in one or more automated processes; and - providing the plurality of settings to one or more control systems of the one or more automated processes; and - controlling the preparation of the liquid mixture based on the plurality of settings; - wherein determining the plurality of settings for controlling the preparation of the liquid mixture includes: retrieving information on a selected automated process of the one or more automated processes; determining one or more stock concentrations; determining one or more pump settings for corresponding pumps used in the automated process; retrieving one or more boundary conditions for the corresponding settings from the one or more control systems; and verifying satisfaction of the one or more boundary conditions, wherein 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 automated process, an acid stock volume, and a base stock volume.

2. The method according to claim 1, wherein, Obtaining the composition of the liquid to be prepared further includes: - prompting information on a plurality of properties of the liquid mixture, and - in response to receiving the information on the plurality of properties, determining the composition of the liquid mixture to be prepared by applying at least one software-implemented algorithm.

3. The method according to claim 1, wherein Obtaining the composition of the liquid to be prepared further includes: obtaining design of experiments (DoE) data, wherein the DoE data indicates a set of buffer compositions and corresponding unique formulations, running a first set of experiments, obtaining experiment result of experiment (RoE) data as an output from the first set of experiments, and obtaining the composition by selecting a buffer composition from the set of buffer compositions that optimizes an objective function of the corresponding buffer properties.

4. The method according to claim 2 or 3, wherein, The properties include at least one of a liquid mixture type, a liquid mixture concentration, a liquid mixture density, and a liquid mixture conductivity, and wherein the software-implemented algorithm is an algorithm for molar concentration calculation or molar mass calculation.

5. The method according to any one of claims 1-4, wherein Determining the plurality of settings for controlling the preparation of the liquid mixture includes determining a control mode for a control system of the selected automated process, and wherein the control mode is used to run the automated process.

6. The method according to claim 5, wherein, The control mode includes flow feedback.

7. The method according to claim 5 or 6, wherein The control mode includes pH feedback.

8. The method according to any one of claims 5 to 7, wherein, The control mode further includes conductivity feedback.

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

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

11. The method according to any one of the preceding claims, further comprising: - retrieving one or more buffer formulations for preparing a corresponding liquid mixture from a database comprising buffer formulations, - selecting one or more stock solutions based on the boundary conditions, wherein the boundary conditions include the volume required from the corresponding stock solutions for preparing the liquid mixture based on the retrieved buffer formulations, - For each selected stock solution, determine the minimum number of stock concentrations for one or more buffer formulations retrieved, and - Update the one or more buffer formulations with the stock concentrations selected from the determined minimum number of stock concentrations.

12. The method according to claim 11, 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 according to claim 11, wherein, Providing the plurality of settings to 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 when at least one boundary condition cannot be satisfied, and - Providing the plurality of settings for the alternative liquid mixture to the one or more control systems.

14. The method according to any one of the preceding claims, further comprising: - Receiving feedback sensor data from the one or more automated processes, - Determining at least one adjustment setting for controlling the preparation of the liquid mixture in the one or more automated processes; and - Providing the adjusted setting to the one or more control systems of the one or more automated processes.

15. A buffer tool 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 buffer tool comprising: - A liquid mixture composition interface - A process control interface, and - A processing circuitry configured to implement the method according to any of the preceding claims.

16. A buffer management system 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 buffer management system comprising: - One or more automated process arrangements for the preparation of the liquid mixture; - One or more control systems for controlling the one or more automated processes; and - A buffer tool according to claim 15.

17. The buffer management system according to claim 16, wherein, The buffer management system is a chromatography system.

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