Product formulation in biomanufacturing

Abstract

A method for combining solutions includes: receiving a flowing first solution comprising a biological product and directing the flowing first solution along a flow path, where the flow path includes a dilution location at which a dilution device is in fluid communication with the flow path; introducing a second solution into the flowing first solution at the dilution position to form a flowing third solution; measuring the biological product in the flowing first solution at a location upstream of the dilution location; measuring the biological product in the flowing third solution at a position downstream of the dilution position; determining a relative relationship between the measured values of the biological product at the upstream location and the downstream location or between values derived from the measured values of the biological product; and adjusting a flow rate of at least one of the first solution and the second solution based on the relative relationship.

Description

[0001] Cross - reference to related applications

[0002] This application claims priority to U.S. Provisional Patent Application No. 63 / 414,452, filed on October 7, 2022, the entire content of which is incorporated herein by reference. Technical Field

[0003] This disclosure relates to generating product formulations in a variety of manufacturing processes, including continuous biomanufacturing. Background Art

[0004] Continuous biomanufacturing processes can be used to generate a wide variety of therapeutically effective products. Typically, such products are obtained in solution after being produced in a bioreactor and optionally after one or more purification steps or other steps have taken place. The final product is then formulated according to the established specifications, and formulation typically involves adjusting the concentration of the product and optionally other components in the solution to match the previously established specifications. Excipient solutions can be used for the purpose of adjusting the product solution to match the specifications. Summary of the Invention

[0005] Some existing batch product formulation processes use volume - flow - based methods to add excipient solutions. Typically, such processes use a single flowmeter or other volume - measuring device to control the addition rate of the excipient solution during the formulation step. In contrast, this disclosure features methods and systems in which multiple measurements of the biomanufacturing process solution are performed. In particular, measurements are made both upstream and downstream of a location along the solution flow path, and the upstream and downstream measurement results are used to control the addition of the excipient solution to ensure that the final product formulation is consistent with the specifications previously established for one or more products in the process solution. By using two measurements, upstream and downstream, improved product quality can be achieved, and in particular, the methods and systems described herein are compatible with a variety of product purification steps that may be difficult to implement in a conventional product formulation workflow due to the relatively low volume flow rate of the product - containing solution and the time - dependent variations in the composition of the product - containing solution.

[0006] In a first aspect, the present disclosure features methods that include: receiving a first solution flowing including a biological product and guiding the flowing first solution along a flow path, where the flow path includes a dilution location at which a dilution device is in fluid communication with the flow path; introducing a second solution into the flowing first solution at the dilution location to form a flowing third solution; measuring the biological product in the flowing first solution at a location upstream of the dilution location; measuring the biological product in the flowing third solution at a location downstream of the dilution location; determining a relative relationship between the measured values of the biological product at the upstream location and the downstream location or values derived from the measured values of the biological product; and adjusting the flow rate of at least one of the first solution and the second solution based on the relative relationship.

[0007] Embodiments of these methods may include any one or more of the following features.

[0008] Measuring the biological product at the upstream location may include obtaining a measured value of a parameter of the first solution. The measured value of the parameter may be the refractive index of the first solution and / or the conductivity of the first solution and / or the absorbance of the first solution and / or the transmittance of the first solution and / or the reflectance of the first solution and / or the concentration of the biological product in the first solution.

[0009] The measured value of the parameter may be measured at a single wavelength. The single wavelength may be within the ultraviolet spectral region, or the visible spectral region, or the infrared spectral region.

[0010] Measuring the biological product at the upstream location may include obtaining a plurality of measured values of the first solution. The plurality of measured values may correspond to spectral information of the first solution at a plurality of wavelengths. These methods may include analyzing the spectral information to determine a value derived from the spectral information. Analyzing the spectral information may include using a calibrated chemometric model to determine a value derived from the spectral information.

[0011] The value derived from the spectral information may be the concentration of the biological product in the first solution, or a quantity related to the concentration of the biological product in the first solution. The spectral information may include the infrared spectrum of the first solution and / or the ultraviolet spectrum of the first solution and / or the Raman scattering spectrum of the first solution.

[0012] These methods may include measuring the attenuated total reflection of incident infrared light to obtain the infrared spectrum. These methods may include measuring the refractive index of the first solution by measuring the attenuated total reflection of incident infrared light from the first solution.

[0013] Measuring the biological product at the downstream location can include obtaining a measured value of a parameter of the third solution. The measured value of the parameter of the third solution can include at least one of the group consisting of: the refractive index of the third solution; the conductivity of the third solution; the absorbance of the third solution; the transmittance of the third solution; the reflectivity of the third solution; and the concentration of the biological product in the third solution.

[0014] The measured value of the parameter of the third solution can be measured at a single wavelength. The single wavelength can include a wavelength within the ultraviolet spectral region, the visible spectral region, or the infrared spectral region.

[0015] Measuring the biological product at the downstream location can include obtaining a plurality of measured values of the third solution. The plurality of measured values can correspond to spectral information of the third solution at a plurality of wavelengths.

[0016] The methods can include analyzing the spectral information to determine a value derived from the spectral information. Analyzing the spectral information can include using a calibrated chemometric model to determine a value derived from the spectral information.

[0017] The value derived from the spectral information can be the concentration of the biological product in the third solution, or a quantity related to the concentration of the biological product in the third solution. The spectral information can include at least one of the group consisting of the infrared spectrum of the third solution, the ultraviolet spectrum of the third solution, and the Raman scattering spectrum of the third solution. The methods can include measuring attenuated total reflection of incident infrared light to obtain the infrared spectrum. The methods can include measuring the refractive index of the third solution by measuring the attenuated total reflection of incident infrared light from the third solution.

[0018] Measuring the biological product at the upstream position may include obtaining at least one of a measured value of a parameter of the first solution and spectral information of the first solution, measuring the biological product at the downstream position may include obtaining at least one of a measured value of a parameter of the third solution and spectral information of the third solution, and the at least one of the measured value of the parameter of the first solution and the spectral information of the first solution may be measured using a measurement technique different from the at least one of the measured value of the parameter of the third solution and the spectral information of the third solution. The at least one of the measured value of the parameter of the first solution and the spectral information of the first solution may include information of a different type from the at least one of the measured value of the parameter of the third solution and the spectral information of the third solution. The at least one of the measured value of the parameter of the first solution and the spectral information of the first solution and the at least one of the measured value of the parameter of the third solution and the spectral information of the third solution may each independently be selected from the group consisting of: refractive index; conductivity; absorbance; transmittance; reflectance; concentration of the biological product; infrared spectrum; ultraviolet spectrum; and Raman scattering spectrum.

[0019] Measuring the biological product at the upstream position may include obtaining at least one of a measured value of a parameter of the first solution and spectral information of the first solution, measuring the biological product at the downstream position may include obtaining at least one of a measured value of a parameter of the third solution and spectral information of the third solution, and the at least one of the measured value of the parameter of the first solution and the spectral information of the first solution and the at least one of the measured value of the parameter of the third solution and the spectral information of the third solution may be measured using a common measurement technique. The at least one of the measured value of the parameter of the first solution and the spectral information of the first solution and the at least one of the measured value of the parameter of the third solution and the spectral information of the third solution may each independently be selected from the group consisting of: refractive index; conductivity; absorbance; transmittance; reflectance; concentration of the biological product; infrared spectrum; ultraviolet spectrum; and Raman scattering spectrum.

[0020] The second solution may not include the biological product. The flow rate of the flowing first solution along the flow path may be less than 2 mL / min. (For example, less than 1 mL / min).

[0021] Determining the relative relationship between the measured values of the biological product at the upstream location and at the downstream location or between values derived from the measured values of the biological product may include: obtaining a first value related to the concentration of the biological product in the first solution or a quantity related to the concentration of the biological product at the upstream location; obtaining a second value related to the concentration of the biological product in the third solution or a quantity related to the concentration of the biological product at the downstream location; calculating a comparison quantity based on the first value and the second value; and adjusting the flow rate of at least one of the first solution and the second solution based on the comparison quantity. The comparison quantity may be the ratio of the first value and the second value. The comparison quantity is a mathematical function of the first value and the second value.

[0022] These methods may include adjusting the flow rate of at least one of the first solution and the second solution until the value of the relative relationship is within a target value range. These methods may include adjusting the flow rate of at least one of the first solution and the second solution until the value of the comparison quantity is within a target value range.

[0023] The biological product may be a protein. The protein may be an antibody, an antibody fragment, or may include a portion of an antibody. The biological product in the first solution may be a drug substance, and the third solution may be a drug product.

[0024] The biological product may be a first biological product, the dilution location may be a first dilution location, and the flow path may include a second dilution location downstream of the first dilution location, and these methods may include: introducing a fourth solution into the flowing third solution at the second dilution location to form a flowing fifth solution, wherein the second dilution location is downstream of the location where the first biological product is measured in the flowing third solution; measuring a second biological product in the flowing fifth solution at locations upstream and downstream of the second dilution location; determining the relative relationship between the measured values of the second biological product at the upstream location and at the downstream location or between values derived from the measured values of the second biological product; and adjusting the flow rate of at least one of the third solution and the fourth solution based on the relative relationship of the second biological product.

[0025] Measuring the second biological product at a location downstream of the second dilution location may include obtaining a measured value of a parameter of the fifth solution. The measured value of the parameter of the fifth solution may include at least one of the group consisting of: the refractive index of the fifth solution; the conductivity of the fifth solution; the absorbance of the fifth solution; the transmittance of the fifth solution; the reflectance of the fifth solution; and the concentration of the second biological product in the fifth solution.

[0026] The measured value of the parameter of the fifth solution can be measured at a single wavelength. The single wavelength can include wavelengths within the ultraviolet spectral region, the visible spectral region, or the infrared spectral region.

[0027] Measuring the second biological product at a position downstream of the second dilution position can include obtaining a plurality of measured values of the fifth solution. The plurality of measured values can correspond to spectral information of the fifth solution at a plurality of wavelengths.

[0028] These methods can include analyzing the spectral information of the fifth solution to determine a value derived from the spectral information. Analyzing the spectral information of the fifth solution can include using a calibrated chemometric model to determine a value derived from the spectral information. The value derived from the spectral information can be the concentration of the second biological product in the fifth solution, or a quantity related to the concentration of the second biological product in the fifth solution.

[0029] The spectral information of the fifth solution can include at least one of the group consisting of the infrared spectrum of the fifth solution, the ultraviolet spectrum of the fifth solution, and the Raman scattering spectrum of the fifth solution. These methods can include measuring the attenuated total reflection of incident infrared light to obtain the infrared spectrum of the fifth solution. These methods can include measuring the refractive index of the fifth solution by measuring the attenuated total reflection of incident infrared light from the fifth solution.

[0030] The biological product can be measured at positions upstream and downstream of the dilution position by measuring different types of spectral information corresponding to the respective first solution and third solution. The measured value of the second biological product or the value derived from the measured value of the second biological product at the upstream position and the downstream position can be of different types.

[0031] These methods can include using different measurement techniques to obtain the measured value of the second biological product or the value derived from the measured value of the second biological product at the upstream position and the downstream position.

[0032] The fourth solution may not include the second biological product. The fourth solution may not include the first biological product.

[0033] The flowing first solution can be received from a purification unit of a biomanufacturing system. The purification unit can include a tangential flow filtration unit.

[0034] The measured value of the parameter of the first solution can be the osmolarity of the first solution. The measured value of the parameter of the third solution can be the osmolarity of the third solution. Measuring the biological product at the upstream position can include obtaining the osmolarity value of the first solution, and measuring the biological product at the downstream position can include obtaining the osmolarity value of the third solution.

[0035] These methods can include adjusting the flow rate of the second solution based on the relative relationship. The relative relationship can be the ratio of the osmolarity values of the first solution and the third solution. Unless otherwise explicitly stated, embodiments of these methods can also include any other features described herein and can include any combination of features, including combinations of features described separately in different embodiments.

[0036] In another aspect, the present disclosure features systems that include: a flow channel that includes an inlet; a fluid reservoir connected to the flow channel at a dilution location; at least one flow regulator connected between the fluid reservoir and at least one of the dilution location and between the inlet and the dilution location; a first sensor positioned at an upstream location between the inlet of the flow channel and the dilution location; a second sensor positioned at a downstream location between the outlet of the flow channel and the dilution location; and a controller connected to the first sensor, the second sensor, and the regulator, wherein the first sensor is configured to measure a biological product in a first solution flowing into the inlet, wherein the fluid reservoir is configured to introduce a second solution into the flow channel at the dilution location to form a flowing third solution, wherein the second sensor is configured to measure the biological product in the flowing third solution; and wherein the controller is configured to: determine a relative relationship between the measured values of the biological product at the upstream location and the downstream location or values derived from the measured values of the biological product; and adjust the at least one regulator based on the relative relationship to control the flow rate of at least one of the first solution and the second solution.

[0037] Embodiments of these systems can include any one or more of the following features.

[0038] The first sensor can be configured to obtain measured values of parameters of the first solution. The first sensor can be a refractive index sensor configured to measure the refractive index of the first solution. The first sensor can be a conductivity sensor configured to measure the conductivity of the first solution. The first sensor can be an absorbance sensor configured to measure the absorbance of the first solution. The first sensor can be a transmittance sensor configured to measure the transmittance of the first solution. The first sensor can be a reflectance sensor configured to measure the reflectance of the first solution. The first sensor can be a concentration sensor configured to measure the concentration of the biological product in the first solution.

[0039] The first sensor can be configured to measure the value of the parameter at a single wavelength. The single wavelength can be within the ultraviolet spectral region, or within the visible spectral region, or within the infrared spectral region.

[0040] The first sensor can be configured to obtain a plurality of measured values of the first solution. The plurality of measured values can correspond to spectral information of the first solution at a plurality of wavelengths. The controller can be configured to analyze the spectral information to determine a value derived from the spectral information. The controller can be configured to analyze the spectral information by using a calibrated chemometric model to determine a value derived from the spectral information. The value derived from the spectral information can be the concentration of the bioproduct in the first solution, or a quantity related to the concentration of the bioproduct in the first solution.

[0041] The first sensor can be configured to obtain the infrared spectrum and / or the ultraviolet spectrum and / or the Raman scattering spectrum of the first solution. The first sensor can be configured to measure the attenuated total reflection of incident infrared light to obtain the infrared spectrum. The first sensor can be configured to measure the refractive index of the first solution by measuring the attenuated total reflection of incident infrared light from the first solution.

[0042] The second sensor can be configured to obtain measured values of the parameter of the third solution. The second sensor can be configured to measure at least one of the group consisting of: the refractive index of the third solution; the conductivity of the third solution; the absorbance of the third solution; the transmittance of the third solution; the reflectance of the third solution; and the concentration of the bioproduct in the third solution.

[0043] The second sensor can be configured to measure the value of the parameter of the third solution at a single wavelength. The single wavelength can include wavelengths within the ultraviolet spectral region, visible spectral region, or infrared spectral region.

[0044] The second sensor can be configured to obtain a plurality of measured values of the third solution. The plurality of measured values can correspond to spectral information of the third solution at a plurality of wavelengths. The controller can be configured to analyze the spectral information to determine a value derived from the spectral information. The controller can be configured to analyze the spectral information by using a calibrated chemometric model to determine a value derived from the spectral information. The value derived from the spectral information can be the concentration of the bioproduct in the third solution, or a quantity related to the concentration of the bioproduct in the third solution.

[0045] The second sensor can be configured to obtain spectral information including at least one of the group consisting of an infrared spectrum of the third solution, an ultraviolet spectrum of the third solution, and a Raman scattering spectrum of the third solution. The second sensor can be configured to measure attenuated total reflection of incident infrared light to obtain the infrared spectrum. The second sensor can be configured to measure the refractive index of the third solution by measuring the attenuated total reflection of incident infrared light from the third solution.

[0046] The first sensor and the second sensor can be configured to measure biological products in the first solution and the third solution using different measurement techniques. At least one of the measured value of the parameter of the first solution and the spectral information of the first solution can include information of a different type from at least one of the measured value of the parameter of the third solution and the spectral information of the third solution. At least one of the measured value of the parameter of the first solution and the spectral information of the first solution and at least one of the measured value of the parameter of the third solution and the spectral information of the third solution can each independently be selected from the group consisting of: refractive index; conductivity; absorbance; transmittance; reflectance; concentration of the biological product; infrared spectrum; ultraviolet spectrum; and Raman scattering spectrum.

[0047] The first sensor and the second sensor can be configured to measure biological products in the first solution and the third solution using a common measurement technique. At least one of the measured value of the parameter of the first solution and the spectral information of the first solution and at least one of the measured value of the parameter of the third solution and the spectral information of the third solution can each independently be selected from the group consisting of: refractive index; conductivity; absorbance; transmittance; reflectance; concentration of the biological product; infrared spectrum; ultraviolet spectrum; and Raman scattering spectrum.

[0048] The second solution may not include the biological product.

[0049] The first sensor and the second sensor can be of different types.

[0050] The controller can be configured to determine the relative relationship between the measured values of the biological product at the upstream location and the downstream location or between values derived from the measured values of the biological product by: obtaining a first value related to the concentration of the biological product in the first solution or a quantity related to the concentration of the biological product; obtaining a second value related to the concentration of the biological product in the third solution or a quantity related to the concentration of the biological product; calculating a comparison quantity based on the first value and the second value; and adjusting the at least one regulator based on the comparison quantity to control the flow rate of at least one of the first solution and the second solution. The controller can be configured to calculate the comparison quantity as the ratio of the first value and the second value. The controller can be configured to calculate the comparison quantity as a mathematical function of the first value and the second value.

[0051] The controller can be configured to adjust the at least one regulator to control the flow rate of at least one of the first solution and the second solution until the value of the relative relationship is within a target value range. The controller can be configured to adjust the at least one flow regulator to control the flow rate of at least one of the first solution and the second solution until the value of the comparison quantity is within a target value range.

[0052] The biological product can be a protein. The protein can be an antibody, an antibody fragment, or can include a portion of an antibody.

[0053] The biological product in the first solution can be a drug substance, and the third solution can be a drug product.

[0054] These systems can include a purification unit for use in a biomanufacturing system, wherein the purification unit is in fluid communication with the inlet. The purification unit can include a tangential flow filtration unit.

[0055] Unless otherwise explicitly stated, embodiments of these systems can also include any other features described herein and can include any combination of features, including combinations of features described separately in different embodiments.

[0056] In another aspect, the present disclosure features methods that include: receiving a flowing first solution containing a biological product and guiding the flowing first solution along a flow path, wherein the flow path includes a dilution location at which a dilution device is in fluid communication with the flow path; introducing a second solution into the flowing first solution at the dilution location to form a flowing third solution; measuring a value of an attribute of the second solution at a location upstream of the dilution location; measuring a value of an attribute of the third solution at a location downstream of the dilution location; determining a relative relationship between the measured attribute values of the second solution and the third solution; and adjusting the flow rate of the second solution based on the relative relationship.

[0057] Examples of these methods may include any one or more of the following features.

[0058] The measured value of the property of the second solution may be the osmolarity of the second solution. The measured value of the property of the second solution may be the refractive index of the second solution. The measured value of the property of the second solution may be the conductivity of the second solution. The measured value of the property of the second solution may be the absorbance of the second solution. The measured value of the property of the second solution may be the transmittance of the second solution. The measured value of the property of the second solution may be the reflectivity of the second solution.

[0059] The measured value of the property of the second solution may be measured at a single wavelength. Measuring the value of the property of the second solution may include obtaining a plurality of measured values of the second solution. The plurality of measured values may include spectral information of the second solution at a plurality of wavelengths.

[0060] These methods may include analyzing the spectral information to determine the value of the property of the second solution. Analyzing the spectral information may include using a calibrated chemometric model to determine the value of the property of the second solution. The value of the property may be the osmolarity of the second solution.

[0061] The spectral information may include the Raman scattering spectrum of the second solution. The spectral information may include the infrared spectrum of the second solution. The spectral information may include the ultraviolet spectrum of the second solution.

[0062] The measured value of the property of the third solution may be the osmolarity of the third solution. The measured value of the property of the second solution may be the osmolarity of the second solution, and the measured value of the property of the third solution may be the osmolarity of the third solution. The measured value of the property of the third solution may be at least one of the group consisting of: the refractive index of the third solution; the conductivity of the third solution; the absorbance of the third solution; the transmittance of the third solution; and the reflectivity of the third solution.

[0063] The measured value of the property of the third solution may be measured at a single wavelength. Measuring the value of the property of the third solution may include obtaining a plurality of measured values of the third solution. The plurality of measured values may include spectral information of the third solution at a plurality of wavelengths. These methods may include analyzing the spectral information to determine the value of the property of the third solution. Analyzing the spectral information may include using a calibrated chemometric model to determine the value of the property of the third solution. The value of the property may be the osmolarity of the third solution.

[0064] The spectral information may include the Raman scattering spectrum of the third solution. The spectral information may include the infrared spectrum of the third solution. The spectral information may include the ultraviolet spectrum of the third solution.

[0065] The values of the properties of the second solution and the third solution may be measured using different measurement techniques. The properties of the second solution and the third solution for which values are measured may be different.

[0066] The second solution may not include the biological product. The flow rate of the flowing first solution along the flow path may be less than 2 mL / min.

[0067] Determining the relative relationship between the measured property values of the second solution and the third solution may include calculating a comparison quantity between these measured property values. The comparison quantity may be a ratio of these measured property values. The comparison quantity may be a mathematical function of these measured property values.

[0068] The methods may include adjusting the flow rate of the second solution until the value of the relative relationship is within a target value range. The methods may include adjusting the flow rate of the second solution until the value of the comparison quantity is within a target value range.

[0069] The biological product may be a protein. The protein may be an antibody, an antibody fragment, or a part of an antibody. The biological product in the first solution may be a drug substance, and the third solution may be a drug product.

[0070] Unless otherwise explicitly stated, embodiments of these methods may also include any other features described herein and may include any combination of features, including combinations of features described separately in different embodiments.

[0071] In another aspect, the present disclosure features systems that include: a flow channel having an inlet; a fluid reservoir connected to the flow channel at a dilution location; at least one flow regulator connected between the fluid reservoir and the dilution location; a first sensor positioned between the fluid reservoir and the dilution location; a second sensor positioned at a downstream location between the outlet of the flow channel and the dilution location; and a controller connected to the first sensor, the second sensor, and the flow regulator, wherein the flow channel is configured to receive a flowing first solution containing a biological product through the inlet, wherein the fluid reservoir is configured to introduce a second solution into the flow channel at the dilution location to form a flowing third solution, wherein the first sensor is configured to measure an attribute value of the second solution, wherein the second sensor is configured to measure an attribute value of the third solution, and wherein the controller is configured to determine a relative relationship between the measured attribute values of the second solution and the third solution and to adjust the at least one flow regulator based on the relative relationship to control the flow rate of the second solution.

[0072] Embodiments of these systems may include any one or more of the following features.

[0073] The first sensor may be a Raman scattering sensor configured to measure Raman scattered light from the second solution. The first sensor may be a refractive index sensor configured to measure the refractive index of the second solution. The first sensor may be a conductivity sensor configured to measure the conductivity of the second solution. The first sensor may be an absorbance sensor configured to measure the absorbance of the second solution. The first sensor may be a transmittance sensor configured to measure the transmittance of the second solution. The first sensor may be a reflectance sensor configured to measure the reflectance of the second solution.

[0074] The first sensor may be configured to obtain a plurality of measured values of the second solution. The plurality of measured values may include spectral information of the second solution at a plurality of wavelengths. The controller may be configured to analyze the spectral information to determine the measured attribute value of the second solution. The controller may be configured to analyze the spectral information by using a calibrated chemometric model to determine the measured attribute value of the second solution based on the spectral information. The first sensor may be configured to obtain a Raman scattering spectrum of the second solution.

[0075] The second sensor can be a Raman scattering sensor configured to measure Raman scattered light from the third solution. The second sensor can include at least one of the group consisting of: a refractive index sensor configured to measure the refractive index of the third solution; a conductivity sensor configured to measure the conductivity of the third solution; an absorbance sensor configured to measure the absorbance of the third solution; a transmittance sensor configured to measure the transmittance of the third solution; and a reflectance sensor configured to measure the reflectance of the third solution.

[0076] The second sensor can be configured to obtain a plurality of measured values of the third solution. The plurality of measured values can include spectral information of the third solution at a plurality of wavelengths. The controller can be configured to analyze the spectral information to determine a measured property value of the third solution based on the spectral information. The controller can be configured to analyze the spectral information by using a calibrated chemometric model to determine the measured property value of the third solution. The second sensor can be configured to obtain a Raman scattering spectrum of the third solution.

[0077] The first sensor and the second sensor can be configured to measure property values of the second solution and the third solution using different measurement techniques. The properties of the second solution and the third solution for which values are measured can be different. The second solution may not include the biological product. The first sensor and the second sensor can be of different types.

[0078] The controller can be configured to: calculate a comparison quantity based on the measured property values of the second solution and the third solution; and adjust the at least one regulator based on the comparison quantity to control the flow rate of the second solution. The controller can be configured to calculate the comparison quantity as a ratio of the measured property values. The controller can be configured to calculate the comparison quantity as a mathematical function of the measured property values.

[0079] The controller can be configured to adjust the at least one regulator to control the flow rate of the second solution until the value of the relative relationship is within a target value range. The controller can be configured to adjust the at least one flow regulator to control the flow rate of the second solution until the value of the comparison quantity is within a target value range.

[0080] The biological product can be a protein. The protein can be an antibody, an antibody fragment, or a portion of an antibody. The biological product in the first solution can be a drug substance, and the third solution can be a drug product.

[0081] The systems can include a purification unit, wherein the purification unit is in fluid communication with the inlet. The purification unit can include a tangential flow filtration unit.

[0082] Unless otherwise explicitly stated, embodiments of these systems may also include any other features described herein and may include any combination of features, including combinations of features described separately in different embodiments. As used herein, the terms "excipient" and "excipient solution" may be used interchangeably to refer to a substance that is typically (although not always) in liquid form (i.e., pure liquid, solution composed of one or more solvents and one or more dissolved substances, homogeneous or heterogeneous suspension of one or more components in one or more solvents) and is typically added to a solution to form a final product solution. Typically, although not always, the solution to which the excipient is added contains one or more products from a biomanufacturing operation, and adding the excipient does not change the chemical properties of the one or more products in the final product solution. The excipient may contain, for example, one or more substances that help to stabilize, encapsulate, and / or deliver the one or more products in the final product solution. Typically, although not always, the substances in the excipient do not chemically react with the one or more products in the solution to which the excipient is added. The excipient may be added to the product-containing solution, for example, to adjust the properties of the one or more products in the final product solution to match the formulated specifications of the final product solution. Examples of substances that may be present in the excipient include, but are not limited to, buffers, preservatives, fillers, chelating agents, colorants, stabilizers / scavengers, and solvents.

[0083] As used herein, the terms "regulator" and "flow regulator" refer to any device or device component that can be adjusted to regulate the flow of fluid in a conduit. Many different types of fluid valves are widely commercially available and can be used as flow regulators. Further, a variety of pumps are electronically controllable and have an adjustable pumping rate to regulate the flow of fluid through them. Additionally, many other devices that respond to an active control signal (e.g., an electronic signal) can act as flow regulators. Typically, a flow regulator operates by adjusting the cross-sectional area of an orifice within the flow regulator, or by adjusting the pumping rate, or both, to control the flow of fluid through the flow regulator.

[0084] As used herein, a "mathematical function" corresponding to a comparison quantity is a function of two variables and yields an output value representing the relative quantity values of the two variables. For example, the mathematical function may be the ratio of the values of the two variables, where the value of the ratio represents the relative quantity values of the two variables. More generally, a mathematical function corresponding to a comparison quantity may have any functional form that yields an output value (which can be used as a feedback metric to adjust the relative flow of fluid), as will be discussed in more detail below. Examples of such functions include, but are not limited to, logarithmic functions, exponential functions, power law functions, polynomial functions, hyperbolic functions, and any combination of these functions.

[0085] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the subject matter of this disclosure, suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control. In addition, these materials, methods, and examples are illustrative only and not intended to be limiting.

[0086] Details of one or more embodiments are set forth in the following drawings and description. Other features and advantages will be apparent from the specification, drawings, and claims. BRIEF DESCRIPTION OF THE DRAWINGS

[0087] Figure 1 is a schematic diagram showing a method of adding an excipient to a product-containing solution in a regulated manner.

[0088] Figure 2 is a schematic diagram showing another method of adding an excipient to a product-containing solution in a regulated manner.

[0089] Figure 3 is a schematic diagram of an example system for formulating a product in a biomanufacturing operation.

[0090] Figure 4 is a flowchart showing a series of example steps that can be performed to implement controlled product formulation.

[0091] Figure 5 is a schematic diagram of another example system for formulating a product in a biomanufacturing operation.

[0092] Figure 6 is a schematic diagram of an example of a multi-stage system for formulating a product in a biomanufacturing operation.

[0093] Figure 7 is a graph showing a product formulation operation during a portion of a 30-day period.

[0094] Figure 8 is a graph showing the time variation of multiple measured quantities during product formulation.

[0095] Figure 9A is a graph showing the measured values of the protein product concentration in the final formulation over time when using two different excipient addition control strategies.

[0096] Figure 9BIt is a graph showing the measured values of the osmolality of the final formulation changing over time when using two different excipient control strategies.

[0097] Figure 10 It is a schematic diagram of an example of the controller of the system described herein.

[0098] Like reference numerals indicate like elements in the various figures. Detailed Description

[0099] Introduction

[0100] Batch manufacturing operations have traditionally been used to prepare a wide variety of biological products, including therapeutic agents and other pharmaceutical substances. More recently, continuous biomanufacturing processes have replaced conventional batch methods because continuous operation offers significant improvements over batch processes. For example, for obtaining the same product yield over time, continuous biomanufacturing operations can typically be carried out in smaller vessels compared to batch operations. The smaller processing volumes handled in such vessels can reduce mixing times and / or eliminate mixing hardware (such as impellers) from the vessels. Furthermore, the absence of mechanical disturbances to the solution within the manufacturing vessel that would otherwise be caused by the mixing hardware can lead to improved product quality as eddies and mechanical shear forces are reduced.

[0101] When compared to batch operations, continuous biomanufacturing operations can also reduce the residence time of the product within the vessel. Product quality attributes and other properties as well as manufacturing conditions can be measured in real time or near real time, and this information can be used to dynamically adjust the conditions during the manufacturing operation in ways that would be more difficult or even incompatible for batch operations. As a result, product yields can be increased, and product batches with more predictable consistency can be produced.

[0102] Biomanufacturing operations typically involve a series of complex operations. The product is produced in a bioreactor and then extracted for further processing. Typically, the post-extraction processing steps include purification in a multi-column chromatography system, buffer and salt adjustment, further refinement via multi-column chromatography, single-stage or multi-stage tangential flow filtration, and one or more ultrafiltration and diafiltration steps.

[0103] An important aspect of continuous biomanufacturing operations involves product formulation, which typically occurs after the above stages have been carried out. Product formulation generally involves adjusting the properties of the product-containing solution to match the established specifications that will result in the final formulation of the product solution (e.g., formulated drug substance). For example, the product-containing solution can be adjusted such that the concentration of one or more products within the solution matches the specifications of the solution in the final formulation. Alternatively or additionally, the product-containing solution can be adjusted such that the concentration of one or more additional substances (such as, but not limited to, fillers, buffers, chelating agents, preservatives, colorants, stabilizers / scavengers, and other delivery agents) in the final product solution matches the specifications. As a further alternative or additionally, the product-containing solution can be adjusted such that one or more physical or chemical properties of the solution (such as, but not limited to, pH, viscosity, phase attributes, osmolarity, surface tension) match the specifications.

[0104] The product formulation process typically involves adding one or more excipient solutions ("excipients") to the product-containing solution to form the final product solution. Excipients can include substances intended to be added to the final product solution to adjust the substance concentration and / or properties of the final product solution. Excipients can include one or more solvents to adjust the concentration of the product in the final product solution. For example, by volumetrically adding a solvent via excipient addition, the concentration of the product in the final product solution can be decreased to match the established specifications of the product formulation.

[0105] In continuous biomanufacturing operations, the product formulation process occurs continuously; that is, the product-containing solution is adjusted in real time to produce the final product solution. A variety of methods can be used to determine the amount of excipient to add to the product-containing solution to produce a final product solution that is consistent with the target specifications. For example, in some methods, volumetric flow measurements are used to regulate the addition of excipient to the product-containing solution.

[0106] Figure 1 is a schematic diagram showing a method of adding excipient to the product-containing solution in a regulated manner. In Figure 1 , a product-containing solution 112 is obtained from a purification unit 102 (e.g., a single-pass tangential flow filtration unit). The product-containing solution 112 flows through a flow meter 104 that measures the volumetric flow rate of the solution 112. The solution 112 flows into a fluid junction 118.

[0107] The excipient 114 is stored in a reservoir 110 and is pumped by a pump 108 through a second flow meter 106. The flow measurements from flow meters 104 and 106 are used to regulate the flow rate at which the pump 108 delivers the excipient 114. The excipient 114 is delivered to the fluid junction 118 where the excipient is combined with the product-containing solution 112 to form the final product solution 116.

[0108] In Figure 1 the method shown, the volumetric flow rate of the product-containing solution 112 is used to adjust the flow rate of the excipient 114 to adjust the properties of the final product solution 116. For example, if it is desired to reduce the concentration of the product in solution 112 in the final product solution 116, an appropriate amount of excipient is continuously added to solution 112 based on the volumetric flow rate of solution 112 to achieve the desired dilution of solution 112, thereby producing a final product solution 116 in which the concentration of the product in solution 116 matches the target specification of the product concentration.

[0109] When the flow rate of solution 112 is large enough such that the flow meter 104 can accurately measure the flow rate, Figure 1 the method shown is effective. However, for some biomanufacturing operations, the flow rate of solution 112 (and the corresponding flow rate of excipient 114 measured by flow meter 106) may be low enough that accurate measurement of the flow rate becomes more difficult. For example, when the purification unit 102 is a single-pass tangential flow filtration unit, the flow rate of solution 112 leaving the filtration unit may typically be less than 2 mL / min. Under these conditions, the flow rate of excipient 114 to be added to solution 112 may be even lower, e.g., less than 0.3 mL / min. Commercially available flow meters typically have relatively high measurement errors at flow rates less than about 1 mL / min. Thus, Figure 1 the method shown is prone to errors caused by both the measurement of the flow rate of solution 112 and the measurement of the flow rate of excipient 114. These errors make it difficult to accurately add excipient 114 to solution 112 to achieve the target specification and, in some cases, result in unacceptable variability. Due to these limitations, unacceptable fluctuations in the osmolality and product concentration in the final product solution 116 have been experimentally observed.

[0110] An alternative method for regulating the addition of excipient to a product-containing solution is shown in Figure 2 . Figure 2 Certain components in Figure 1 are similar to components in Figure 2 and are labeled with the same reference numerals. In

[0111] The reservoir 110 contains an excipient 114 that is pumped out of the reservoir 110 by a pump 108 and delivered into a fluid junction 118. The excipient 114 is mixed with a solution 112 in the fluid junction 118 to produce a final product solution 116 that contains the same product as the solution 112. Based on the flow rate of the solution 112 measured by a flow meter 104 and the assumed concentration of the product in the solution 112, an appropriate flow rate of the excipient 114 is determined such that after the excipient is added to the solution 112 in the junction 118, the concentration of the product in the solution 116 will match the target specification of the solution 116.

[0112] A sensor 202 is positioned to measure the concentration of the product in the solution 116 after the excipient 114 is added. The flow rate of the excipient 114 is then adjusted via an adjustment of the pump 108 using the measured concentration of the product in the solution 116. In this way, the excipient flow rate can be controlled to adjust even closer to the target concentration of the product in the solution 116.

[0113] However, Figure 2 The method shown is based on the assumption that when the solution 112 exits the filtration unit 102, the concentration of the product in the solution 112 is relatively constant over time. In practice, this assumption may not hold in many cases. In particular, due to upstream variations in other processing and / or purification steps, the concentration of the product in the solution 112 may vary significantly over time. In some cases, it has been experimentally observed that when the concentration of the product in the solution 112 varies significantly, a single sensor 202 may not be sufficient to ensure that the target specification of the product concentration in the solution 116 is achieved.

[0114] The present disclosure features methods and systems that can be used to achieve improved control of product formulation steps in continuous biomanufacturing operations. In particular, these methods and systems use ratio-based control strategies and multiple sensor measurements to mitigate the effects of flow rate and product concentration variability on excipient addition control. By measuring the product-containing solution both before and after excipient addition, the resulting control method can dynamically adapt to a wide variety of process variations. Additionally, many different types of sensors can be used, enabling the implementation of robust control strategies to ensure that many different types of target specifications can be achieved for product formulations.

[0115] Product Formulation Control Method and System

[0116] Figure 3FIG. 0 is a schematic diagram showing an example of a system 300 configured to formulate a product-containing solution into a final product solution that achieves the target specifications (i.e., one or more target properties) of the final product solution. The system includes a flow meter 302, a first sensor 304, a fluid junction 306, a second sensor 308, a pump 310, a reservoir 312, and a controller 326. The controller 326 is connected to and communicates with the flow meter 302, sensors 304 and 308, and pump 310. The conduits 314, 316, and 318 establish the flow paths of the solution in the system 300.

[0117] As Figure 3 shown, the system 300 is configured to add excipients to the product-containing solution as described above. The excipients (represented by arrow 322) are contained in the reservoir 312 and are pumped by the pump 310 to the fluid junction 306. The product-containing solution (represented by arrow 320) enters the system 300 from an upstream source (e.g., a filtration unit, a conduit, or another component or stage of a continuous biomanufacturing system) and is mixed with the excipients 322 in the fluid junction 306. The resulting final product solution (represented by arrow 324) exits the fluid junction 306 into a conduit from which it is further transported to another part of the continuous biomanufacturing system, or for quality control verification or packaging.

[0118] The system 300 includes two sensors 304 and 308 located upstream and downstream, respectively, of the location where the solution 320 and the excipients 322 are combined. During operation of the system 300, the controller 326 receives measurements from the flow meter 302 and sensors 304 and 306 and determines the appropriate flow rate of the excipients 322 to ensure that the properties of the final product solution 324 match the target specifications of the final product solution. The controller 326 transmits control instructions to adjust the pump 310 to control the flow rate at which the excipients 322 are pumped into the fluid junction 306 for mixing with the solution 320.

[0119] As described above, excipient addition in a continuous biomanufacturing process typically occurs after the product has been produced and purified as part of the product formulation process. The specific nature of the excipient depends on the specifications of the final product formulation. In a typical product formulation process, for example, the excipient includes a concentrated buffer that is added in an amount sufficient to match the target specifications of the final product formulation. Since a continuous biomanufacturing process typically produces a product-containing solution at a relatively low flow rate, the addition of the excipient is also typically carried out at a low flow rate (e.g., 10% to 20% of the flow rate of the product-containing solution 320). As previously discussed, flow meters are prone to errors at the typical flow rates of such processes, making volume-flow-based control methods inaccurate. Further, the components and their concentrations of the product-containing solution can vary over time, and a single measurement feedback control strategy for excipient addition often fails to adequately respond to such changes, resulting in product formulations that are outside the specifications from time to time.

[0120] In contrast, the control method implemented by the controller 326 uses both pre-excipient and post-excipient measurements of the solution (i.e., upstream and downstream of the fluid junction 306) to dynamically control the flow rate of the excipient 322 and thereby ensure that the final product solution 324 matches the target specifications, even when the characteristics of the product-containing solution 320 (such as the concentration of the product therein) vary over time (e.g., when upstream process conditions change). The product formulation process implemented by the system 300 responds to such changes in an automated manner.

[0121] Specifically, since the sensors 304 and 308 are not flow meters, the measurements of the solution they provide are accurate even when the solution flow rate is very low (or even when the solution is not flowing at all). Thus, the control methods described herein are not prone to the errors typically caused by using flow meters at low solution flow rates. Further, since the control method relies on the ratio of the measurements, changes in the composition of the product-containing solution are reflected in both of these measurements, and thus the ratio of the measurements is insensitive to such changes.

[0122] Figure 4 is a flowchart showing a set of example steps that can be used to implement the control methods described herein. In step 402, the flow rate (F) of the product-containing solution 320 is measured by the flow meter 302. Then, in step 404, the controller 326 receives this measurement information and determines an initial set point (I sp ) for the flow rate of the excipient as follows:

[0123]

[0124] The dilution factor is a constant value pre-determined based on the expected composition of the product-containing solution 320 and the excipient 322. Then, the controller 326 adjusts the flow rate of the excipient 322 to this value by transmitting appropriate control instructions to the pump 310.

[0125] In step 406, measured values (M i ) of the product-containing solution 320 and the final product solution 324 are obtained by sensors 304 and 308 respectively. f ) Generally, these measured values can correspond to a wide variety of different types of measurement results. In some embodiments, for example, these measured values correspond to the measurement results of the concentrations of the components (e.g., the concentration of the product in these solutions) in the product-containing solution 320 and the final product solution 324.

[0126] The controller 326 receives these measured values and determines the ratio R of the measured values in step 408 as follows:

[0127]

[0128] Then, in step 410, the controller 326 determines the value of the adjustment factor α of the flow rate of the excipient 322 based on the ratio R of the measured values and the set point S of the target value representing the ratio of the measured values of the product-containing solution 320 and the final product solution 324. As an example, if the measured values of the two solutions represent the concentrations of the components (such as the product) in the solutions, the set point S represents the target value of the ratio of the concentrations of this component in the product-containing solution 320 and the final product solution 324. Then, the adjustment factor α is calculated as follows:

[0129]

[0130] where J is an adjustable parameter. The value of J is typically selected such that if R > S, then the value of α > 1, and if R < S, then the value of α < 1.

[0131] Next, in step 412, the controller 426 adjusts the flow rate of the excipient 322 entering the fluid junction 306 based on the adjustment factor α. To perform this adjustment, the controller 426 scales the initial set point I sp of the flow rate of the excipient 322 sp by the adjustment factor. Then, the controller 426 transmits appropriate control instructions to the pump 310 to adjust the flow rate of the excipient 322 to this scaled value.

[0132] In decision step 414, if the product formulation is complete, control passes to step 416 where the process terminates. However, if the product formulation is not complete, control returns to step 406 where further measurements of the product-containing solution 320 and the final product solution 324 are obtained via sensors 304 and 308 respectively, and a new value of the adjustment factor α is determined, and the flow rate of the excipient 322 is further adjusted based on the new value of the adjustment factor α. In this way, when the product-containing solution 320 enters the system 300, the control method dynamically responds to changes in the composition and other characteristics of the product-containing solution.

[0133] In system 300, pump 310 serves as a flow regulator to adjust the flow rate of excipient 322 into junction 306. Pump 310 receives control signals from controller 326 that regulate the throughput of pump 310. Generally, pump 310 can be implemented as any of a variety of adjustable pumps that respond to an external control signal. Alternatively or additionally, a flow regulator can be implemented in system 300 as a controllable valve that receives control signals from controller 326 and responds to those control signals. For example, a constant flow pump or a variable flow pump can be used in combination with a valve as a flow regulator in system 300 to adjust the flow rate at which the excipient 322 is introduced into junction 306. More generally, any combination of pumps, valves, and other flow restricting and / or flow regulating components can be used to regulate the flow rate of excipient 322 as long as the combination provides an adjustable flow rate. In the following discussion, the term "flow regulator" is used to refer to all such combinations of components that allow control of fluid flow.

[0134] In the foregoing description of system 300, controller 326 uses a flow regulator to adjust the flow rate of excipient 322. However, in some embodiments, controller 326 can adjust the flow rate of solution 320 into junction 306 as an alternative to adjusting the flow rate of excipient 322. In the above control method, the relative flow rates of the product-containing solution and the excipient are adjusted. This adjustment can be performed by maintaining the flow rate of either solution constant and adjusting the flow rate of the other solution.

[0135] To adjust the flow rate of solution 320 into junction 306, a flow regulator (e.g., corresponding to any of the combinations of components discussed above) can be positioned between the inlet of the system and junction 306. Figure 5FIG. 0 is a schematic illustration of an example of a system 500 that includes a flow regulator 502 positioned to regulate the flow of solution 320 into junction 306. The flow regulator 502 is connected to the controller 326 and adjusts the flow of solution 320 in response to a control signal from the controller 326. The flow regulator 502 can be implemented as, for example, a valve (where solution 320 is already flowing therethrough), a pump, a combination of one or more pumps and one or more valves, or any other combination of components that controllably regulates the flow of solution 320.

[0136] Further, in some embodiments, the systems described herein can actively regulate the flow of both solution 320 and excipient. As described above, the relative flow of these solutions is the basis of the control method. Thus, the methods described herein can be implemented by systems that include a flow regulator (e.g., the flow regulator 502 in Figure 5 positioned to regulate the flow of solution 320 into junction 306) and a flow regulator (e.g., where the pump 310 is located in Figure 3 ) positioned to regulate the flow of excipient 322 into junction 306.

[0137] As discussed above, various different types of measurements can be made by sensors 304 and 308. In some embodiments, the measurements correspond to the measurement of the concentration or amount of components in solutions 320 and 324 that are not present in the excipient. For example, the component can be a product that is produced during a continuous biomanufacturing process. Such products can include, but are not limited to: proteins and their fragments, antibodies and their fragments, enzymes (e.g., therapeutic enzymes), blood factors, bispecific antibodies, nanobodies, and viral vectors.

[0138] In some embodiments, the measurements correspond to measurements related to the measurement of the concentration or amount of components in solutions 320 and 324. For example, the measurements can correspond to physical or chemical properties of the solutions, such as, but not limited to, absorbance, transmittance, reflectance, refractive index, light scattering intensity, conductivity, fluorescence intensity, and Raman scattering intensity related to the presence of components in solutions 320 and 324.

[0139] More generally, in certain embodiments, the measured values correspond to measurements of some property of solutions 320 and 324 for which target specifications have been established in the target formulation. Such properties can include, but are not limited to, pH, viscosity, conductivity, and osmolality. Such properties can also include, but are not limited to, product quality attributes, including any product quality attributes described in U.S. Patent Application Publication No. US2019 / 0272894, the entire content of which is incorporated herein by reference. Chemometric-based methods (such as those described in U.S. Patent Application Publication No. US 2019 / 0272894) can be used to determine the values of product quality attributes from the corresponding spectral information.

[0140] Sensors 304 and 308 can generally be implemented in a variety of different configurations. In certain embodiments, sensors 304 and 308 can be sensors that measure optical and / or non-optical parameters (e.g., absorbance, transmittance, reflectance, fluorescence, refractive index, Raman scattering intensity, conductivity) of solutions 320 and 324. Some sensors are configured to measure the values of these measured quantities at a single wavelength (e.g., single-point measurement) or at multiple wavelengths (e.g., spectral measurement or multi-point measurement). Sensors that make optical measurements at multiple wavelengths are generally referred to herein as "spectral sensors".

[0141] Sensors configured to measure optical parameters can obtain measurement results in various wavelength regions, including but not limited to the ultraviolet region (e.g., between 150 nm and 400 nm), the visible region (e.g., between 400 nm and 780 nm), and the infrared region (e.g., between 780 nm and 3 μm).

[0142] In some embodiments, sensors 304 and 308 are implemented as the same type of sensor. However, more generally, sensors 304 and 308 do not need to be the same type of sensor and can be implemented as different types of sensors that measure different quantities to obtain information about solutions 320 and 324. For example, sensor 304 can measure the UV absorbance of solution 320, while sensor 308 can measure the fluorescence of solution 324. As another example, sensor 304 can measure infrared absorbance or transmittance at multiple wavelengths, while sensor 308 can measure Raman scattering intensity at multiple wavelengths. As yet another example, sensor 304 can measure refractive index, while sensor 308 can measure ultraviolet transmittance at a single wavelength. The foregoing are merely examples, and it should be understood that in particular embodiments of the control methods described herein, sensors 304 and 308 can generally be selected in any combination to measure any of the above quantities at one or more identical or different wavelengths.

[0143] Sensors suitable for measuring each of the above different parameters are commercially available. To measure the refractive index, sensors 304 and / or 308 can be implemented as, for example, a Pall mPath refractometer (available from Pall Corporation, New York, NY). To measure absorbance or transmittance in the ultraviolet region of the spectrum, sensors 304 and / or 308 can be implemented as, for example, an Optek AF46 sensor (available from Optek International, Largo, FL) or a PendoTECH UV photometer (available from PendoTECH, Princeton, NJ). Alternatively, to measure absorbance or transmittance, sensors 304 and / or 308 can be implemented as a variable path length spectrometer, such as a FlowVPE system (available from Repligen Corporation, Waltham, MA). To measure Raman scattering intensity, sensors 304 and / or 308 can be implemented as a MarqMetrix system (available from MarqMetrix, Seattle, WA).

[0144] The foregoing examples of sensors are not exhaustive, and in general, the control methods described herein can be implemented with a variety of different sensor types that measure many different properties of the measurement solutions 320 and 324. Preferably, the sensors used to implement the control method obtain measurement values in real time or near real time (e.g., obtain individual measurement values within a time window of 30 s or less).

[0145] In the embodiments described above in connection with Figure 3 and Figure 4 the flow rate of the excipient 322 is adjusted according to the measurement values obtained from sensors 304 and 308. However, more generally, the flow rate of solution 320 can be adjusted in addition to or in place of the adjustment of the flow rate of excipient 322. To adjust the flow rate of solution 320, a flow rate regulator (such as an adjustable valve) can be positioned upstream of the fluid junction 306, and the controller 326 can transmit appropriate control instructions to the flow rate regulator to adjust the flow rate of solution 320 into the fluid junction 306. By controlling the flow rate of excipient 322, controlling the flow rate of solution 320, or controlling the flow rates of both excipient 322 and solution 320, the controller 326 can adjust the properties of the final product solution 324. Thus, any of these different flow rate adjustments can be used in the control methods described herein.

[0146] In some embodiments, sensor 304 and / or 308 obtain single-point measurement results of solution 320 and / or 324. Such measurement results can directly correspond to the physical or chemical properties of the solution (e.g., such measurement results can directly correspond to the concentration of components in the solution and can be transmitted to controller 326 as concentration values). Alternatively, such measured values can be converted by controller 326 into measurement results of the physical or chemical properties of the solution. For example, the physical or chemical properties of the solution can be calculated by controller 326 as a mathematical function of the measured values of the solution. The mathematical function can generally take a variety of forms. For example, the value of the physical or chemical property of the solution can be determined as a linear or non-linear mathematical function of the measured values obtained for the solution. The non-linear function can be any one of a variety of different function types, including but not limited to exponential functions, logarithmic functions, polynomial functions, hyperbolic functions, and combinations of any two or more function types.

[0147] In certain embodiments, sensor 304 and / or 308 obtain multi-point measurement results of solution 320 and / or 324. Such measurement results can include, for example, measurement results at different times, which can be averaged, integrated, or otherwise combined to obtain an output measurement result that is transmitted to controller 326. Alternatively or additionally, such measurement results can include measured values at a plurality of different wavelengths, i.e., spectral measurement results.

[0148] In the case of obtaining spectral measurement values, the physical or chemical properties of the solution can be calculated as a mathematical function of the measured values at different individual wavelengths. Such mathematical functions can include a plurality of dependent variables corresponding to two or more of the spectral measurement values and can be a linear or non-linear function of each of the plurality of dependent variables, as described above.

[0149] In some embodiments, in the case of obtaining spectral measurement values by sensor 304 and / or 308, chemometric-based methods can be used to obtain the values of the properties of the solution from which these measurement values are obtained. Chemometric-based methods can generally be applied to a wide variety of different types of measurement values and can be used to determine the values of many different types of solution properties. Chemometric-based methods are described, for example, in U.S. Patent Application Publication No. US2022 / 0101953, the entire content of which is incorporated herein by reference.

[0150] It should also be noted that while Figure 3 and Figure 4Disclosed are control methods that can be implemented to ensure that the final product solution 324 matches the target specifications of certain parameters, such as product concentration or amount, or another physical or chemical property of solution 324. However, the control methods can be implemented in multiple stages continuously to ensure that the output solution matches the target specifications of multiple parameters. For example, solution 324 can be directed to another system similar to system 300, where solution 324 serves as the product-containing solution.

[0151] Figure 6 is a schematic diagram of an example of system 600 that includes two stages, each of which implements the control methods described herein. The first stage 650 includes components similar to those of system 300. Generally, the first stage 650 can include any one of different combinations of the features, embodiments, and examples described above.

[0152] Solution 324 exits the first stage 650 and enters the second stage 660, which includes a fluid junction 606, a third sensor 608, a pump 610, and a fluid reservoir 612 containing a second excipient 622. The pump 610 and the fluid reservoir 612 are connected to the fluid junction by a conduit 618.

[0153] During operation of system 600, the first stage 650 functions as described above to produce a solution 324 that matches the target specifications of a particular property or component, such as a first product present in solution 324. Solution 324 enters the second stage 660, which also functions as described above, but introduces the second excipient 622 into solution 324. The sensor 608 measures the solution after the excipient 622 has been added, and the measured value is transmitted to the controller 326. The controller 326 adjusts the relative flow rates of the excipient 622 and solution 324 into the fluid junction 606 to ensure that solution 624 matches another target specification, i.e., different from the target specification of the first stage 650. As an example, the first stage 650 and the second stage 660 can operate to ensure that the concentrations of two different products initially present in solution 320 match the target specifications in solution 624. As another example, the first stage 650 and the second stage 660 can operate to ensure that the concentration of the product and another chemical or physical property of solution 624 match the target specifications.

[0154] Typically, both the first stage 650 and the second stage 660 can include any of the components, embodiments, and examples described herein, including any of the flow regulators and sensors (and their different combinations) described, such as the flow regulators and sensors. These two stages can adjust any combination of the different components and properties of the incoming solution 320. Further, in certain embodiments, some of the components described herein may be omitted. For example, in system 600, sensor 608 serves as a downstream sensor in the second stage 660, while sensor 308 serves as a downstream sensor in the first stage 650 and as an upstream sensor in the second stage 660. Alternatively, in some embodiments, the second stage 660 can include another sensor positioned between sensor 308 and fluid junction 606, which is connected to controller 326 and serves as an upstream sensor in the second stage 660. This additional sensor can be any of the different types of sensors described herein.

[0155] The systems described herein are not limited to only two stages as Figure 6 shown. Typically, the system can include any number (e.g., two or more, three or more, four or more, five or more, six or more, eight or more, ten or more, or even more) of stages arranged in sequence. By implementing sequential stages similar to system 600, multiple target specifications can be met.

[0156] Hardware and Software Implementations

[0157] Figure 10 An example of controller 326 that can be used with the systems and methods disclosed herein is shown. Controller 326 can include one or more processors 1002, a memory 1004, a storage device 1006, and an interface 1008 for interconnection. Processor 1002 can process instructions for execution within the controller, including instructions stored in memory 1004 or on storage device 1006. For example, the instructions can direct processor 1002 to perform any of the analysis steps and control steps disclosed herein.

[0158] Memory 1004 can store executable instructions for processor 1002, information about system parameters (such as excitation wavelength and detection wavelength), and measured image information. Storage device 1006 can be a computer-readable medium, such as a floppy disk device, a hard disk device, an optical disk device, or a tape device, a flash memory or other similar solid-state memory device or device array (including devices in a storage area network or in other configurations). Storage device 1006 can store instructions that can be executed by processor 1002 as described above, as well as any other information that can be stored by memory 1004.

[0159] In some embodiments, the controller 326 may include a graphics processing unit to display graphical information (e.g., using a GUI or a text interface) on an external input / output device such as the display 1016. The graphical information may be displayed by a display device (e.g., a CRT (cathode ray tube) or an LCD (liquid crystal display) monitor) for displaying any information disclosed herein, such as measured and calculated spectra and images. A user may use an input device (e.g., a keyboard, a pointer device, a touch screen, a voice recognition device) to provide input to the controller 326. In some embodiments, one or more such devices may be part of the controller 326.

[0160] The user of any system described herein may provide various different types of instructions and information to the controller 326 via an input device. The instructions and information may include, for example, the target specifications of any formulated substances produced via biomanufacturing operations and systems, information about excipients, information and selections of measured values, and calibration information for any components of the systems and any method steps described herein. The controller 326 may use any of these various types of information to perform the methods and functions described herein. It should also be noted that any of these types of information may be stored (e.g., in the storage device 1006) and called by the controller 326 when needed.

[0161] The methods and the respective steps disclosed herein may be implemented by the controller 326 by executing instructions in one or more computer programs executable and / or interpretable by the controller 326. These computer programs (also referred to as programs, software, software applications, or code) include machine instructions for a programmable processor and can be implemented in a high-level procedural language and / or an object-oriented programming language, and / or in assembly / machine language. For example, a computer program may include instructions that may be stored in the memory 1004, the storage unit 1006, and / or on a tangible computer-readable medium and executed by the processor 1002 as described above. As used herein, the term "computer-readable medium" refers to any computer program product, device, and / or apparatus (e.g., a disk, an optical disk, a memory, a programmable logic device (PLD), an ASIC, and an electronic circuit system) for providing machine instructions and / or data to a programmable processor, including a machine-readable medium that receives the machine instructions.

[0162] By executing the instructions described above, which may optionally be part of controller 326, the controller can be configured to implement any one or more of the various steps described in connection with any of the control methods described herein. For example, controller 326 can receive measured values from sensors and flow meters, calculate any of the quantities described herein (as well as other quantities), determine actions based on the quantities and other decision metrics, and transmit control instructions to components of any of the systems described herein.

[0163] Applications

[0164] Although the control methods described herein are particularly applicable to the formulation process in a continuous biomanufacturing operation, they can also be applied to the product formulation process in other biomanufacturing operations (such as batch operations) as well. Further, while the control methods are described herein in the context of the product formulation process, these methods can also be applied to additional upstream steps in a biomanufacturing operation (e.g., prior to product formulation). For example, these methods can be applied to the addition of salts, solvents, detergents, and other reagents and the dilution of process fluids, and more generally to any operation or step in which target specifications for an output solution or fluid stream have been established.

[0165] For example, in some embodiments, the control methods described herein can be applied to an intermediate process (e.g., a process implemented after extraction of a product from a bioreactor but prior to product formulation) in which the process fluid is diluted to reduce the concentration of components in the fluid. Any of the various types of measured values described above can be used to regulate the relative flow rates of the fluids to effect the dilution. These measured values can be related to the product in the fluid, or they can be corrected with another non-product substance in the fluid since all components of the fluid are similarly diluted by the addition of another fluid. The fluid added for dilution purposes can contain any of the components described herein in connection with excipients, and in addition to diluting the process fluid, additional components can be added to the process fluid. For example, the added solution can contain one or more salts such that the process fluid is simultaneously diluted and its salt content increased by using the methods and systems described herein. As another example, the fluid added to the process fluid can contain a detergent that is added to the process fluid along with the dilution.

[0166] The foregoing dilution operations can be implemented at multiple different levels of a biomanufacturing operation. For example, dilution can be used as a load adjustment step during a purification operation to ensure that a chromatography system is adequately loaded but not overloaded. The dilution operation can also be implemented as a pre-operation for other unit operations (such as a polishing step and a filtration step).

[0167] Examples

[0168] Example 1: Continuous Biomanufacturing

[0169] The above-described control method is implemented for a 30-day period in a continuous biomanufacturing operation conducted in a 500 L bioreactor. The operation produces a process fluid containing a protein product, and the protein concentration in the final product solution is adjusted to match the target specification.

[0170] Figure 7 is a graph showing the performance of the control method during a portion of the 30-day period. In Figure 7 , trace 702 corresponds to the target concentration of protein in the final product solution, and trace 704 corresponds to the measured protein concentration in the solution. As Figure 7 shown, the measured protein concentration generally matches the target protein concentration until the time corresponding to the vertical line, at which point the measured concentration of protein is less than the target concentration. If the flow rate of the excipient (trace 708) is maintained at the flow rate determined based on the volumetric flow measurement (e.g., determined only based on the flow rate measured by flow meter 302), the flow rate of the excipient represented by trace 706 will always be too large, and the protein concentration in the final product solution will always be too low.

[0171] However, by implementing the control method described herein, the measured protein concentration was successfully adjusted. In Figure 7 , at the time indicated by the vertical line, the adjustment factor α (trace 710) calculated by controller 326 decreased, and thus controller 326 reduced the flow rate of the excipient added to the product-containing solution. Accordingly, within 30 minutes of the initial deviation of the protein concentration from the target concentration, the measured concentration 704 of protein in the final product solution increased to match the target protein concentration 702.

[0172] Figure 8 is a graph showing the time variation of multiple measured quantities during a product formulation process implemented with the control method described herein. In Figure 8 , trace 802 shows the measured protein concentration in the solution before the addition of the excipient (e.g., measured by sensor 304), trace 804 shows the measured protein concentration in the solution after the addition of the excipient (e.g., measured by sensor 308), and trace 806 shows the measured protein concentration in the product formulation. Trace 808 shows the measured flow rate of the product-containing solution (e.g., measured by flow meter 302), and trace 810 shows the flow rate of the excipient added to the product-containing solution. It is apparent from the figure that each of these quantities has a measurable fluctuation over time. Nevertheless, as shown by trace 806 corresponding to the concentration of protein in the product formulation, the control method is able to compensate for these temporal fluctuations, resulting in a final formulation in which the protein concentration remains substantially constant over the time window shown in the figure.

[0173] Figure 9A shows the control strategy (solid circles) using only the measured volumetric flow rate of the product-containing solution as described above in connection with Figure 1 and the measured values of the protein product concentration in the final product solution over time when using the control method (shaded circles) described in connection with Figure 3 and Figure 4 . Figure 9B shows the control strategy (solid circles) using only the measured volumetric flow rate of the product-containing solution as described above in connection with Figure 1 and the measured values of the osmolality of the final product solution over time when using the control method (shaded circles) described in connection with Figure 3 and Figure 4 . From the data shown in these figures, it is evident that by using the dual-sensor control method described herein, the fluctuations in both the protein concentration and the osmolality of the final product solution are significantly reduced, with a change of less than 5% over the time window shown in the figures, as compared to fluctuations in the measured values of the protein concentration and osmolality greater than 20% observed when using the control strategy based only on the measured volumetric flow rate of the product-containing solution.

[0174] Example 2: Osmolality-Based Control

[0175] In this example, the measurement results of osmolality are used to control the excipient addition during the biomanufacturing process. Osmolality is a typical critical quality attribute during formulation because it provides confirmation of the solute content and can be used to detect deviations in compounding. As used herein, osmolality is defined as the total concentration of all osmotically active dissolved solutes present in a given volume of solution. Osmolality can be measured by an osmometer that determines the freezing point of an aqueous solution having one or more dissolved solutes. Since dissolved solutes lower the freezing point of the corresponding pure solvent, osmolality can be determined by measuring the freezing point of the solution.

[0176] Conventional osmolality measurements are performed offline because the solution is frozen during the process. Therefore, in order to implement an osmolality-based control strategy in continuous biomanufacturing, a sensor capable of measuring osmolality at a high measurement frequency (e.g., in real-time or near real-time and without freezing the solution) is desirable.

[0177] Raman spectroscopy has been widely used in bioprocessing and has previously been used for both upstream and downstream applications. Raman spectroscopy provides measurements of inelastic light scattering of a sample, which is typically excited with light (e.g., laser) in the visible, near-infrared, or near-ultraviolet range. The Raman scattered light is typically energy-shifted relative to the excitation light, and the energy shift provides insight into the vibrational modes of the sample. By resolving the frequency of the Raman scattered light (e.g., by directing the scattered light through a monochromator and spatially separating the frequencies of the scattered light to be detected by a detector), various sample properties can be determined, including but not limited to the type and / or concentration of various components of the sample.

[0178] Raman scattering measurements can be performed quickly and are therefore very suitable for implementation in any of the methods described herein. As previously mentioned, multiple process parameters can be extracted from the Raman spectrum using univariate or multivariate analysis techniques. These process parameters can be used for automated recipe progression and / or closed-loop control in any of the aforementioned methods.

[0179] In this example, a Raman scattering sensor is used to obtain the measurement results of Raman scattering intensity, and the osmotic pressure molarity of the solution containing the product is quantitatively measured in the predefined target osmotic pressure molarity range in the continuous preparation excipient addition step. In order to evaluate the effectiveness of the control based on osmotic pressure molarity using Raman scattering, the Raman activity of each expected formulation component (e.g., mAb protein, excipient 1, excipient 2) of the solution containing the product is expected to be observed during normal processing. Test solutions of each formulation component, as well as excipient buffers and target formulation drug substances are prepared in water at several concentration levels. Each of these target solutions is then measured with a Raman spectrometer (obtained from MarqMetrix, Seattle, Washington) with a 180uL flow cell. The laser power of the spectrometer is 450mW, and the exposure time is optimized to achieve a detector saturation level between 50% and 80%. Select the number of scans to reach sufficient spectral quality and desired measurement time. In considering the control methods described herein, various measurement conditions were selected to achieve a measurement time of 20 seconds or less.

[0180] The acquired Raman spectra are superimposed to identify which formulation components are visible within the measurement wavelength range. A target spectrum for the formulated product (e.g., drug substance) is constructed based on the identified Raman visible components. It was observed that the Raman scattering method is capable of measuring the following types of formulation components: stabilizing salts and osmotic pressure regulators (i.e., arginine); sugars; cryoprotectants; and lyophilization excipients (i.e., sucrose).

[0181] Other formulation components are less visible in the measured Raman spectra. These include surfactants (i.e., PS80) and chelating agents (i.e., EDTA). Without being bound by theory, these components may be less visible due to their relatively low target concentrations in the product-containing solution.

[0182] To develop a Raman model for osmolarity measurement to enable monitoring and automated feedback control as described herein, a calibration data set of Raman spectra and offline reference measurements was obtained by creating a synthetic flow path that mimics unit operation conditions. The flow path starts with a solution of high concentration buffer and protein and, over time, a solution of excipient buffer is added in incremental steps. While the flow path is running, Raman spectra from 25 to 3500 cm -1 are obtained under conditions similar to those described above. Offline samples are also collected and their osmolarity is tested using an osmometer by conventional measurement.

[0183] The model was developed using multivariate modeling software by first trimming the spectra to the spectral regions previously identified during measurement of the test solution. After spectral trimming, preprocessing was applied by using first derivative, Savitzky-Golay smoothing, and standard normal variate (SNV) normalization. The preprocessed spectra were matched to the offline reference measurements and a PLS model for osmolarity was created. The latent variables of each model were selected based on leave-one-out cross-validation and selection of the minimum root mean square error for calibration and cross-validation. Typically, the models selected for use have low root mean square errors for calibration and cross-validation and have R 2 and Q 2 values greater than 90%, indicating the ability to accurately estimate new data. In addition, the models selected cover a range of osmolarity values expected to be encountered during continuous formulation operations, thus helping to ensure that the model will not have to predict osmolarity values by extrapolation outside the calibration range (e.g., the range of osmolarity values is 60 to 700 mOsm / kg H2O and the target osmolarity is 383 mOsm / kg H2O).

[0184] For process control of the continuous formulation of the product, Raman spectra were obtained by using a MarqMetrix Raman spectrometer as a sensor. The spectrometer includes a 180 uL flow cell connected to the MarqMetrix Raman kit. The Raman spectral information obtained by the sensor was sent to synTQ (Process Analytical Technology Data Management Tool) using the OPC communication protocol. The tool uses The QP converts Raman spectral information into osmolality values. These values are transmitted by the synTQ tool to control the hardware of the system and are input into the corresponding loop of a proportional-integral-derivative (PID) controller for process control.

[0185] In this example, Raman measurements are obtained from the product-containing solution immediately after excipient addition to continuously measure osmolality and product concentration. When controlling using the osmolality determined by Raman at this step, the setpoint value of the target osmolality is input into the controller, and a feedback loop using PID-based control is used to adjust the flow rate of the excipient pump. During operation, the performance of the model is evaluated by periodically removing and analyzing offline samples and comparing the online and offline measurement results. The performance of the model is evaluated by calculating the root mean square error of prediction (RMSEP). If the RMSEP is below 5 mOsm / kg H2O, the Raman-based osmolality prediction is considered acceptable. Nevertheless, based on typical historical process variations during formulation, an RMSEP of up to 20 mOsm / kg H2O is also considered acceptable.

[0186] In many embodiments, the process control methods described herein involve determining the ratio of the measurement results of a specific property value and adjusting the relative flow rates of the excipient and / or product solution based on the measurement result ratio. Control based on the osmolality ratio as described above was also tested in this example.

[0187] Typically, when an excipient is added to a product-containing solution as part of a product formulation, the excipient buffer is concentrated at a specific ratio relative to the final product stream. Since this ratio of the excipient is fixed, the ratio of the osmolality of the excipient buffer to the post-excipient product stream will also be at the same value. By continuously determining the osmolality of the excipient buffer and the post-excipient product stream based on Raman measurements using a stoichiometric model of the two solutions, the ratio of the osmolality values of the excipient buffer and the post-excipient product stream is used to adjust the flow rate of the excipient pump.

[0188] Similar to the methods described herein for controlling based on property value ratios such as protein concentration ratios, an adjustment factor of buffer:product is continuously calculated to adjust the excipient pump flow rate for process control. If the adjustment factor < 1, the excipient pump flow rate is decreased to bring the product stream closer to the target osmolality value, and vice versa for an adjustment factor > 1.

[0189] It should be noted that in some embodiments, if the protein makes a significant contribution to the osmolarity value of the post-excipient product-containing solution, the baseline value of the protein osmolarity can be subtracted from the post-excipient osmolarity determined as described above, or a third measurement of the osmolarity of the pre-excipient product-containing solution can be obtained, and this osmolarity value can be continuously subtracted based on the performance of the previous unit operations. The osmolarity value of the pre-excipient product-containing solution can generally be obtained using any method described herein, including by performing Raman scattering measurements and applying a multivariate model to the obtained Raman spectral information to extract the osmolarity value.

[0190] Raman scattering measurements can generally be used to obtain the osmolarity value of any solution in a continuous biomanufacturing system. In this example, Raman scattering measurements were used to measure the osmolarity of the post-excipient solution, the pre-excipient solution, and the excipient buffer solution. However, it should be understood that Raman scattering measurements can also be used to obtain osmolarity measurements of other process solutions, and these other process solutions include, but are not limited to, process solutions generated after one or more filtration, dilution, blending, separation, and / or purification steps. Such solutions can include, for example, filtrate solutions, elution solutions from chromatography columns, solutions obtained from mixing vessels, solutions obtained from centrifuges, and solutions obtained from process sampling at many different locations in the biomanufacturing system.

[0191] As described above, osmolarity is a typical critical quality attribute during formulation and can be used to detect deviations in compounding. In this example, Raman scattering measurements were used to measure osmolarity. However, other types of measurements and corresponding sensors can also be used to obtain the osmolarity measurements for use in the methods described herein. For example, infrared and / or ultraviolet absorbance or reflectance measurements can be used to obtain the spectrum of a solution, and a method based on multivariate chemometrics can be applied to the spectrum to obtain the osmolarity value. As another example, a conductivity sensor can be used to measure the conductivity of a solution, and the osmolarity value of the solution can be determined based on the measured conductivity.

[0192] In this example, process control is performed by measuring the osmolality of the excipient solution and the post-excipient solution to perform ratio-based adjustment of the excipient flow rate. It should be noted that while osmolality is a useful property for feedback control, measurements of any other property of the excipient solution and the post-excipient solution described herein can also be used to perform ratio-based adjustment of the excipient flow rate in the same manner. That is, adjusting the excipient flow rate based on the ratio of the property values of the excipient solution and the post-excipient solution is not limited to the osmolality property, but can also be performed based on measurements of a variety of different property values of the solution, including but not limited to any property generally described herein.

[0193] Other embodiments

[0194] Although this disclosure describes specific embodiments, these should not be construed as limitations on the scope of the disclosure, but rather as descriptions of features in certain embodiments. Features described in the context of separate embodiments can generally also be combined and implemented in a single embodiment. Conversely, the various features described in the context of a single embodiment can also be implemented separately or in any suitable sub-combination in multiple embodiments. Additionally, although the features may have been described above as being present in certain combinations and even initially claimed as such, one or more features from the claimed combination can generally be deleted from the combination, and the claimed combination can relate to a sub-combination or a variation of a sub-combination.

[0195] Except for the embodiments explicitly disclosed herein, it will be understood that various modifications can be made to the described embodiments without departing from the spirit and scope of the disclosure. Accordingly, other embodiments fall within the scope of the appended claims.

Claims

1. A method, comprising: Receiving a first flowing solution containing a biological product and guiding the first flowing solution along a flow path, wherein the flow path includes a dilution location at which a dilution device is in fluid communication with the flow path; Introducing a second solution into the first flowing solution at the dilution location to form a third flowing solution; Measuring the biological product in the first flowing solution at a location upstream of the dilution location; Measuring the biological product in the third flowing solution at a location downstream of the dilution location; Determining a relative relationship between the measured values of the biological product at the upstream location and the downstream location or values derived from the measured values of the biological product; and Adjusting the flow rate of at least one of the first solution and the second solution based on the relative relationship.

2. The method according to claim 1, wherein, Measuring the biological product at the upstream location includes obtaining a measured value of a parameter of the first solution.

3. The method according to claim 2, wherein, The measured value of the parameter is the refractive index of the first solution.

4. The method according to claim 2, wherein, The measured value of the parameter is the conductivity of the first solution.

5. The method according to claim 2, wherein, The measured value of the parameter is the absorbance of the first solution.

6. The method according to claim 2, wherein, The measured value of the parameter is the transmittance of the first solution.

7. The method according to claim 2, wherein The measured value of the parameter is the reflectivity of the first solution.

8. The method according to claim 2, wherein, The measured value of the parameter is the concentration of the biological product in the first solution.

9. The method according to claim 2, wherein, The measured value of the parameter is measured at a single wavelength.

10. The method according to claim 9, wherein, The single wavelength is within the ultraviolet spectral region.

11. The method according to claim 9, wherein, The single wavelength is within the visible spectral region.

12. The method according to claim 9, wherein, The single wavelength is within the infrared spectral region.

13. The method according to claim 1, wherein, Measuring the biological product at the upstream location includes obtaining a plurality of measured values of the first solution.

14. The method according to claim 13, wherein, The plurality of measured values includes spectral information of the first solution at a plurality of wavelengths.

15. The method according to claim 14, the method further comprising analyzing the spectral information to determine a value derived from the spectral information.

16. The method according to claim 15, wherein, Analyzing the spectral information includes using a calibrated chemometric model to determine a value derived from the spectral information.

17. The method according to claim 15, wherein, The value derived from the spectral information is the concentration of the biological product in the first solution or a quantity related to the concentration of the biological product in the first solution.

18. The method according to claim 14, wherein The spectral information includes the infrared spectrum of the first solution.

19. The method according to claim 14, wherein, The spectral information includes the ultraviolet spectrum of the first solution.

20. The method according to claim 14, wherein, The spectral information includes the Raman scattering spectrum of the first solution.

21. The method according to claim 18, the method further comprising measuring the attenuated total reflection of incident infrared light to obtain the infrared spectrum.

22. The method according to claim 3, the method further comprising measuring the refractive index of the first solution by measuring the attenuated total reflection of incident infrared light from the first solution.

23. The method according to claim 1, wherein, Measuring the biological product at the downstream location includes obtaining a measured value of a parameter of the third solution.

24. The method according to claim 23, wherein The measured value of the parameter of the third solution includes at least one of the group consisting of: the refractive index of the third solution; the conductivity of the third solution; the absorbance of the third solution; the transmittance of the third solution; the reflectivity of the third solution; and the concentration of the biological product in the third solution.

25. The method according to claim 23, wherein, The measured value of the parameter of the third solution is measured at a single wavelength.

26. The method according to claim 25, wherein, The single wavelength includes a wavelength within the ultraviolet spectral region, visible spectral region, or infrared spectral region.

27. The method according to claim 1, wherein, Measuring the biological product at the downstream location includes obtaining a plurality of measured values of the third solution.

28. The method according to claim 27, wherein, The plurality of measured values includes spectral information of the third solution at a plurality of wavelengths.

29. The method of claim 28, the method further comprising analyzing the spectral information to determine a value derived from the spectral information.

30. The method according to claim 29, wherein, Analyzing the spectral information includes using a calibrated chemometric model to determine a value derived from the spectral information.

31. The method according to claim 29, wherein, The value derived from the spectral information is the concentration of the biological product in the third solution, or a quantity related to the concentration of the biological product in the third solution.

32. The method according to claim 28, wherein, The spectral information includes at least one of the group consisting of an infrared spectrum of the third solution, an ultraviolet spectrum of the third solution, and a Raman scattering spectrum of the third solution.

33. The method of claim 32, the method further comprising measuring attenuated total reflection of incident infrared light to obtain the infrared spectrum.

34. The method of claim 24, the method further comprising measuring the refractive index of the third solution by measuring attenuated total reflection of incident infrared light from the third solution.

35. The method of claim 1, wherein: Measuring the biological product at the upstream location includes obtaining at least one of a measured value of a parameter of the first solution and spectral information of the first solution; Measuring the biological product at the downstream location includes obtaining at least one of a measured value of a parameter of the third solution and spectral information of the third solution; and At least one of the measured value of the parameter of the first solution and the spectral information of the first solution is measured using a measurement technique different from that of at least one of the measured value of the parameter of the third solution and the spectral information of the third solution.

36. The method according to claim 35, wherein, At least one of the measured value of the parameter of the first solution and the spectral information of the first solution includes information of a different type from that of at least one of the measured value of the parameter of the third solution and the spectral information of the third solution.

37. The method according to claim 35, wherein, At least one of the measured value of the parameter of the first solution and the spectral information of the first solution and at least one of the measured value of the parameter of the third solution and the spectral information of the third solution are each independently selected from the group consisting of: refractive index; conductivity; absorbance; transmittance; reflectance; concentration of the biological product; infrared spectrum; ultraviolet spectrum; and Raman scattering spectrum.

38. The method of claim 1, wherein: Measuring the biological product at the upstream location includes obtaining at least one of a measured value of a parameter of the first solution and spectral information of the first solution; Measuring the biological product at the downstream location includes obtaining at least one of a measured value of a parameter of the third solution and spectral information of the third solution; and At least one of the measured value of the parameter of the first solution and the spectral information of the first solution and at least one of the measured value of the parameter of the third solution and the spectral information of the third solution are measured using a common measurement technique.

39. The method according to claim 38, wherein, The measured value of the parameter of the first solution and at least one of the spectral information of the first solution, and the measured value of the parameter of the third solution and at least one of the spectral information of the third solution are each independently selected from the group consisting of: refractive index; conductivity; absorbance; transmittance; reflectance; the concentration of the biological product; infrared spectrum; ultraviolet spectrum; and Raman scattering spectrum.

40. The method according to claim 1, wherein The second solution does not include the biological product.

41. The method according to claim 1, wherein, The flow rate of the flowing first solution along the flow path is less than 2 mL / min.

42. The method according to claim 41, wherein, The flow rate is less than 1 mL / min.

43. The method according to claim 1, wherein, Determining a relative relationship between the measured values of the biological product at the upstream position and the downstream position or between values derived from the measured values of the biological product includes: Obtaining a first value related to the concentration of the biological product in the first solution or a quantity related to the concentration of the biological product at the upstream position; Obtaining a second value related to the concentration of the biological product in the third solution or a quantity related to the concentration of the biological product at the downstream position; Calculating a comparison quantity based on the first value and the second value; and Adjusting the flow rate of at least one of the first solution and the second solution based on the comparison quantity.

44. The method according to claim 43, wherein, The comparison quantity is the ratio of the first value and the second value.

45. The method according to claim 43, wherein, The comparison quantity is a mathematical function of the first value and the second value.

46. The method according to claim 1, the method further comprising adjusting the flow rate of at least one of the first solution and the second solution until the value of the relative relationship is within a target value range.

47. The method according to claim 43, the method further comprising adjusting the flow rate of at least one of the first solution and the second solution until the value of the comparison quantity is within a target value range.

48. The method according to claim 1, wherein, The biological product is a protein.

49. The method according to claim 48, wherein, The protein is an antibody, an antibody fragment, or includes a part of an antibody.

50. The method according to claim 1, wherein, The biological product in the first solution is a drug substance, and wherein the third solution is a drug product.

51. The method according to claim 1, wherein, The biological product is a first biological product, the dilution position is a first dilution position, and wherein the flow path includes a second dilution position downstream of the first dilution position, the method further comprising: Introducing a fourth solution into the flowing third solution at the second dilution position to form a flowing fifth solution, wherein the second dilution position is located downstream of the position where the first biological product is measured in the flowing third solution; Measuring a second biological product in the flowing fifth solution at positions upstream and downstream of the second dilution position; Determining a relative relationship between the measured values of the second biological product at the upstream position and the downstream position or between values derived from the measured values of the second biological product; and Adjusting at least one of the flow rate of the third solution and the flow rate of the fourth solution based on the relative relationship of the second biological product.

52. The method according to claim 51, wherein, Measuring the second biological product at a position downstream of the second dilution position includes obtaining the measured value of the parameter of the fifth solution.

53. The method according to claim 52, wherein, The measured values of the parameters of the fifth solution include at least one of the group consisting of: the refractive index of the fifth solution; the conductivity of the fifth solution; the absorbance of the fifth solution; the transmittance of the fifth solution; the reflectivity of the fifth solution; and the concentration of the second biological product in the fifth solution.

54. The method according to claim 52, wherein, The measured values of the parameters of the fifth solution are measured at a single wavelength.

55. The method according to claim 54, wherein, The single wavelength includes wavelengths within the ultraviolet spectral region, the visible spectral region, or the infrared spectral region.

56. The method according to claim 51, wherein, Measuring the second biological product at a position downstream of the second dilution position includes obtaining a plurality of measured values of the fifth solution.

57. The method according to claim 56, wherein, The plurality of measured values includes spectral information of the fifth solution at a plurality of wavelengths.

58. The method according to claim 57, the method further comprising analyzing the spectral information of the fifth solution to determine a value derived from the spectral information.

59. The method according to claim 58, wherein, Analyzing the spectral information of the fifth solution includes using a calibrated chemometric model to determine a value derived from the spectral information.

60. The method according to claim 58, wherein, The value derived from the spectral information is the concentration of the second biological product in the fifth solution, or a quantity related to the concentration of the second biological product in the fifth solution.

61. The method according to claim 57, wherein, The spectral information of the fifth solution includes at least one of the group consisting of the infrared spectrum of the fifth solution, the ultraviolet spectrum of the fifth solution, and the Raman scattering spectrum of the fifth solution.

62. The method according to claim 61, the method further comprising measuring the attenuated total reflection of incident infrared light to obtain the infrared spectrum of the fifth solution.

63. The method according to claim 53, the method further comprising measuring the refractive index of the fifth solution by measuring the attenuated total reflection of incident infrared light from the fifth solution.

64. The method according to claim 1, wherein The biological product is measured at positions upstream and downstream of the dilution position by measuring different types of spectral information corresponding to the respective first solution and third solution.

65. The method according to claim 51, wherein, The measured values of the second biological product or the values derived from the measured values of the second biological product at the upstream position and the downstream position are of different types.

66. The method according to claim 51, the method comprising using different measurement techniques to obtain the measured values of the second biological product or the values derived from the measured values of the second biological product at the upstream position and the downstream position.

67. The method according to claim 51, wherein, The fourth solution does not include the second biological product.

68. The method according to claim 67, wherein, The fourth solution does not include the first biological product.

69. The method according to claim 1, wherein Receiving the flowing first solution from a purification unit of a biomanufacturing system.

70. The method according to claim 69, wherein, The purification unit includes a tangential flow filtration unit.

71. A system, comprising: A flow channel, the flow channel including an inlet; A fluid reservoir, the fluid reservoir connected to the flow channel at a dilution position; At least one flow regulator, the at least one flow regulator connected between at least one of the fluid reservoir and the dilution position, and the inlet and the dilution position; A first sensor, the first sensor positioned at an upstream position between the inlet of the flow channel and the dilution position; A second sensor, the second sensor positioned at a downstream position between the outlet of the flow channel and the dilution position; And A controller, the controller connected to the first sensor, the second sensor, and the flow regulator, Wherein, the first sensor is configured to measure a biological product in a first solution flowing into the inlet; Wherein, the fluid reservoir is configured to introduce a second solution into the flow channel at the dilution position to form a flowing third solution; Wherein, the second sensor is configured to measure the biological product in the flowing third solution; and Wherein, the controller is configured to: Determine a relative relationship between measured values of the biological product at the upstream position and the downstream position or values derived from the measured values of the biological product; and Adjust the at least one flow regulator based on the relative relationship to control the flow rate of at least one of the first solution and the second solution.

72. The system according to claim 71, wherein, The first sensor is configured to obtain a measured value of a parameter of the first solution.

73. The system according to claim 72, wherein, The first sensor is a refractive index sensor configured to measure the refractive index of the first solution.

74. The system according to claim 72, wherein, The first sensor is a conductivity sensor configured to measure the conductivity of the first solution.

75. The system according to claim 72, wherein, The first sensor is an absorbance sensor configured to measure the absorbance of the first solution.

76. The system according to claim 72, wherein, The first sensor is a transmittance sensor configured to measure the transmittance of the first solution.

77. The system according to claim 72, wherein, The first sensor is a reflectance sensor configured to measure the reflectance of the first solution.

78. The system according to claim 72, wherein, The first sensor is a concentration sensor configured to measure the concentration of the biological product in the first solution.

79. The system according to claim 72, wherein, The first sensor is configured to measure the value of the parameter at a single wavelength.

80. The system according to claim 79, wherein, The single wavelength is within the ultraviolet spectral region.

81. The system according to claim 79, wherein, The single wavelength is within the visible spectral region.

82. The system according to claim 79, wherein, The single wavelength is within the infrared spectral region.

83. The system according to claim 71, wherein, The first sensor is configured to obtain a plurality of measured values of the first solution.

84. The system according to claim 73, wherein, The plurality of measured values includes spectral information of the first solution at a plurality of wavelengths.

85. The system according to claim 74, wherein, The controller is configured to analyze the spectral information to determine a value derived from the spectral information.

86. The system according to claim 85, wherein The controller is configured to analyze the spectral information by using a calibrated chemometric model to determine a value derived from the spectral information.

87. The system according to claim 85, wherein, The value derived from the spectral information is the concentration of the biological product in the first solution or a quantity related to the concentration of the biological product in the first solution.

88. The system according to claim 84, wherein, The first sensor is configured to obtain an infrared spectrum of the first solution.

89. The system according to claim 84, wherein, The first sensor is configured to obtain an ultraviolet spectrum of the first solution.

90. The system according to claim 84, wherein, The first sensor is configured to obtain a Raman scattering spectrum of the first solution.

91. The system according to claim 88, wherein, The first sensor is configured to measure attenuated total reflection of incident infrared light to obtain the infrared spectrum.

92. The system according to claim 73, wherein, The first sensor is configured to measure the refractive index of the first solution by measuring attenuated total reflection of incident infrared light from the first solution.

93. The system according to claim 71, wherein, The second sensor is configured to obtain a measured value of a parameter of the third solution.

94. The system according to claim 93, wherein, The second sensor is configured to measure at least one of the group consisting of: the refractive index of the third solution; the conductivity of the third solution; the absorbance of the third solution; the transmittance of the third solution; the reflectance of the third solution; And the concentration of the biological product in the third solution.

95. The system according to claim 93, wherein, The second sensor is configured to measure the value of the parameter of the third solution at a single wavelength.

96. The system according to claim 95, wherein, The single wavelength includes a wavelength within the ultraviolet spectral region, visible spectral region, or infrared spectral region.

97. The system according to claim 71, wherein, The second sensor is configured to obtain a plurality of measured values of the third solution.

98. The system according to claim 97, wherein The plurality of measured values includes spectral information of the third solution at a plurality of wavelengths.

99. The system according to claim 98, wherein, The controller is configured to analyze the spectral information to determine a value derived from the spectral information.

100. The system according to claim 99, wherein, The controller is configured to analyze the spectral information to determine a value derived from the spectral information by using a calibrated chemometric model.

101. The system according to claim 99, wherein, The value derived from the spectral information is the concentration of the biological product in the third solution, or a quantity related to the concentration of the biological product in the third solution.

102. The system according to claim 98, wherein, The second sensor is configured to obtain spectral information including at least one of the group consisting of an infrared spectrum of the third solution, an ultraviolet spectrum of the third solution, and a Raman scattering spectrum of the third solution.

103. The system according to claim 102, wherein, The second sensor is configured to measure attenuated total reflection of incident infrared light to obtain the infrared spectrum.

104. The system according to claim 94, wherein, The second sensor is configured to measure the refractive index of the third solution by measuring the attenuated total reflection of incident infrared light from the third solution.

105. The system according to claim 71, wherein The first sensor and the second sensor are configured to measure the biological product in the first solution and the third solution using different measurement techniques.

106. The system according to claim 105, wherein, At least one of the measured value of the parameter of the first solution and the spectral information of the first solution includes information of a different type from at least one of the measured value of the parameter of the third solution and the spectral information of the third solution.

107. The system according to claim 105, wherein, At least one of the measured value of the parameter of the first solution and the spectral information of the first solution and at least one of the measured value of the parameter of the third solution and the spectral information of the third solution are each independently selected from the group consisting of: refractive index; conductivity; absorbance; transmittance; reflectance; concentration of the biological product; infrared spectrum; ultraviolet spectrum; and Raman scattering spectrum.

108. The system according to claim 71, wherein, The first sensor and the second sensor are configured to measure the biological product in the first solution and the third solution using a common measurement technique.

109. The system according to claim 108, wherein, At least one of the measured value of the parameter of the first solution and the spectral information of the first solution and at least one of the measured value of the parameter of the third solution and the spectral information of the third solution are each independently selected from the group consisting of: refractive index; conductivity; absorbance; transmittance; reflectance; concentration of the biological product; infrared spectrum; ultraviolet spectrum; and Raman scattering spectrum.

110. The system according to claim 71, wherein, The second solution does not include the biological product.

111. The system according to claim 71, wherein, The first sensor and the second sensor are of different types.

112. The system according to claim 71, wherein, The controller is configured to determine a relative relationship between the measured values of the biological product at the upstream position and the downstream position or between the values derived from the measured values of the biological product by: Obtaining a first value or a quantity related to the concentration of the biological product in the first solution; Obtaining a second value or a quantity related to the concentration of the biological product in the third solution; Calculating a comparison quantity based on the first value and the second value; And Adjusting the at least one regulator based on the comparison quantity to control the flow rate of at least one of the first solution and the second solution.

113. The system according to claim 112, wherein, The controller is configured to calculate the comparison quantity as the ratio of the first value and the second value.

114. The system according to claim 112, wherein, The controller is configured to calculate the comparison quantity as a mathematical function of the first value and the second value.

115. The system according to claim 71, wherein, The controller is configured to adjust the at least one regulator to control the flow rate of at least one of the first solution and the second solution until the value of the relative relationship is within a target value range.

116. The system according to claim 112, wherein, The controller is configured to adjust the at least one flow regulator to control the flow rate of at least one of the first solution and the second solution until the value of the comparison quantity is within a target value range.

117. The system according to claim 71, wherein, The biological product is a protein.

118. The system according to claim 117, wherein, The protein is an antibody, an antibody fragment, or includes a part of an antibody.

119. The system according to claim 71, wherein, The biological product in the first solution is a drug substance, and wherein the third solution is a drug product.

120. The system according to claim 71, the system further comprising a purification unit for use in a biomanufacturing system, wherein, The purification unit is in fluid communication with the inlet.

121. The system according to claim 120, wherein, The purification unit includes a tangential flow filtration unit.

122. The method according to claim 2, wherein The measured value of the parameter of the first solution is the osmolarity of the first solution.

123. The method according to claim 23, wherein The measured value of the parameter of the third solution is the osmolarity of the third solution.

124. The method according to claim 1, wherein, Measuring the biological product at the upstream position includes obtaining the osmolarity value of the first solution, and wherein measuring the biological product at the downstream position includes obtaining the osmolarity value of the third solution.

125. The method according to claim 124, the method including adjusting the flow rate of the second solution based on the relative relationship.

126. The method according to claim 124, wherein The relative relationship is the ratio of the osmolarity values of the first solution and the third solution.

127. A method, including: Receiving a flowing first solution containing a biological product and guiding the flowing first solution along a flow path, wherein the flow path includes a dilution position at which a dilution device is in fluid communication with the flow path; Introducing a second solution into the flowing first solution at the dilution position to form a flowing third solution; Measuring the value of the property of the second solution at a position upstream of the dilution position; Measuring the value of the property of the third solution at a position downstream of the dilution position; Determining a relative relationship between the measured property values of the second solution and the third solution; and Adjusting the flow rate of the second solution based on the relative relationship.

128. The method according to claim 127, wherein, The measured value of the property of the second solution is the osmolarity of the second solution.

129. The method according to claim 127, wherein, The measured value of the property of the second solution is the refractive index of the second solution.

130. The method according to claim 127, wherein, The measured value of the property of the second solution is the conductivity of the second solution.

131. The method according to claim 127, wherein, The measured value of the property of the second solution is the absorbance of the second solution.

132. The method according to claim 127, wherein, The measured value of the property of the second solution is the transmittance of the second solution.

133. The method according to claim 127, wherein, The measured value of the property of the second solution is the reflectance of the second solution.

134. The method according to claim 127, wherein, The measured value of the property of the second solution is measured at a single wavelength.

135. The method according to claim 127, wherein Measuring the value of the property of the second solution includes obtaining a plurality of measured values of the second solution.

136. The method according to claim 135, wherein, The plurality of measured values includes spectral information of the second solution at a plurality of wavelengths.

137. The method according to claim 136, the method further including analyzing the spectral information to determine the value of the property of the second solution.

138. The method according to claim 137, wherein, Analyzing the spectral information includes using a calibrated chemometric model to determine the value of the property of the second solution.

139. The method according to claim 138, wherein, The value of the property is the osmolarity of the second solution.

140. The method according to claim 136, wherein, The spectral information includes the Raman scattering spectrum of the second solution.

141. The method according to claim 136, wherein, The spectral information includes the infrared spectrum of the second solution.

142. The method according to claim 136, wherein, The spectral information includes the ultraviolet spectrum of the second solution.

143. The method according to claim 127, wherein, The measured value of the property of the third solution is the osmolarity of the third solution.

144. The method according to claim 127, wherein, The measured value of the property of the second solution is the osmolarity of the second solution, and the measured value of the property of the third solution is the osmolarity of the third solution.

145. The method according to claim 127, wherein, The measured value of the property of the third solution includes at least one of the group consisting of: the refractive index of the third solution; the conductivity of the third solution; the absorbance of the third solution; the transmittance of the third solution; and the reflectivity of the third solution.

146. The method according to claim 127, wherein, The measured value of the property of the third solution is measured at a single wavelength.

147. The method according to claim 127, wherein, Measuring the value of the property of the third solution includes obtaining a plurality of measured values of the third solution.

148. The method according to claim 147, wherein, The plurality of measured values includes spectral information of the third solution at a plurality of wavelengths.

149. The method according to claim 148, the method further comprising analyzing the spectral information to determine the value of the property of the third solution.

150. The method according to claim 149, wherein, Analyzing the spectral information includes using a calibrated chemometric model to determine the value of the property of the third solution.

151. The method according to claim 150, wherein, The value of the property is the osmolarity of the third solution.

152. The method according to claim 148, wherein, The spectral information includes the Raman scattering spectrum of the third solution.

153. The method according to claim 148, wherein, The spectral information includes the infrared spectrum of the third solution.

154. The method according to claim 148, wherein, The spectral information includes the ultraviolet spectrum of the third solution.

155. The method according to claim 127, wherein, The values of the properties of the second solution and the third solution are measured using different measurement techniques.

156. The method according to claim 155, wherein, The properties of the second solution and the third solution for which values are measured are different.

157. The method according to claim 127, wherein, The second solution does not include the biological product.

158. The method according to claim 127, wherein The flow rate of the flowing first solution along the flow path is less than 2 mL / min.

159. The method according to claim 127, wherein, Determining the relative relationship between the measured property values of the second solution and the third solution includes calculating a comparison quantity between these measured property values.

160. The method according to claim 159, wherein, The comparison quantity is the ratio of these measured property values.

161. The method according to claim 159, wherein, The comparison quantity is a mathematical function of these measured property values.

162. The method according to claim 127, the method further comprising adjusting the flow rate of the second solution until the value of the relative relationship is within a target value range.

163. The method according to claim 159, the method further comprising adjusting the flow rate of the second solution until the value of the comparison quantity is within a target value range.

164. The method according to claim 127, wherein, The biological product is a protein.

165. The method according to claim 164, wherein, The protein is an antibody, an antibody fragment, or includes a part of an antibody.

166. The method according to claim 127, wherein, The biological product in the first solution is a drug substance, and wherein the third solution is a drug product.

167. A system, comprising: A flow channel, the flow channel including an inlet; A fluid reservoir, the fluid reservoir being connected to the flow channel at a dilution position; At least one flow regulator, the at least one flow regulator being connected between the fluid reservoir and the dilution position; A first sensor, the first sensor being positioned between the fluid reservoir and the dilution position; A second sensor, the second sensor being positioned at a downstream position between the outlet of the flow channel and the dilution position; And A controller, which is connected to the first sensor, the second sensor, and the flow regulator, wherein the flow channel is configured to receive a first flowing solution including a biological product through the inlet; wherein the fluid reservoir is configured to introduce a second solution into the flow channel at the dilution position to form a third flowing solution; wherein the first sensor is configured to measure an attribute value of the second solution; wherein the second sensor is configured to measure an attribute value of the third solution; and wherein the controller is configured to: determine a relative relationship between the measured attribute values of the second solution and the third solution; and adjust the at least one flow regulator based on the relative relationship to control the flow rate of the second solution.

168. The system according to claim 167, wherein, The first sensor is a Raman scattering sensor configured to measure Raman scattering light from the second solution.

169. The system according to claim 167, wherein, The first sensor is a refractive index sensor configured to measure the refractive index of the second solution.

170. The system according to claim 167, wherein, The first sensor is a conductivity sensor configured to measure the conductivity of the second solution.

171. The system according to claim 167, wherein, The first sensor is an absorbance sensor configured to measure the absorbance of the second solution.

172. The system according to claim 167, wherein, The first sensor is a transmittance sensor configured to measure the transmittance of the second solution.

173. The system according to claim 167, wherein, The first sensor is a reflectance sensor configured to measure the reflectance of the second solution.

174. The system according to claim 167, wherein, The first sensor is configured to obtain a plurality of measured values of the second solution.

175. The system according to claim 174, wherein, The plurality of measured values includes spectral information of the second solution at a plurality of wavelengths.

176. The system according to claim 175, wherein, The controller is configured to analyze the spectral information to determine the measured attribute value of the second solution.

177. The system according to claim 176, wherein, The controller is configured to analyze the spectral information by using a calibrated chemometric model to determine the measured attribute value of the second solution according to the spectral information.

178. The system according to claim 175, wherein, The first sensor is configured to obtain a Raman scattering spectrum of the second solution.

179. The system according to claim 167, wherein, The second sensor is a Raman scattering sensor configured to measure Raman scattering light from the third solution.

180. The system according to claim 167, wherein, The second sensor includes at least one of the group consisting of: a refractive index sensor configured to measure the refractive index of the third solution; a conductivity sensor configured to measure the conductivity of the third solution; an absorbance sensor configured to measure the absorbance of the third solution; a transmittance sensor configured to measure the transmittance of the third solution; and a reflectance sensor configured to measure the reflectance of the third solution.

181. The system according to claim 167, wherein, The second sensor is configured to obtain a plurality of measured values of the third solution.

182. The system according to claim 181, wherein, The plurality of measured values includes spectral information of the third solution at a plurality of wavelengths.

183. The system according to claim 182, wherein, The controller is configured to analyze the spectral information to determine the measured attribute value of the third solution according to the spectral information.

184. The system according to claim 183, wherein, The controller is configured to analyze the spectral information by using a calibrated chemometric model to determine the measured attribute value of the third solution.

185. The system according to claim 182, wherein, The second sensor is configured to obtain a Raman scattering spectrum of the third solution.

186. The system according to claim 167, wherein, The first sensor and the second sensor are configured to use different measurement techniques to measure the attribute values of the second solution and the third solution.

187. The system according to claim 186, wherein, The attributes of the second solution and the third solution for which values are measured are different.

188. The system according to claim 167, wherein, The second solution does not include the biological product.

189. The system according to claim 67, wherein, The first sensor and the second sensor are of different types.

190. The system according to claim 67, wherein The controller is configured to: calculate a comparison quantity based on the measured property values of the second solution and the third solution; and adjust the at least one regulator based on the comparison quantity to control the flow rate of the second solution.

191. The system according to claim 190, wherein, The controller is configured to calculate the comparison quantity as a ratio of the measured property values.

192. The system according to claim 190, wherein, The controller is configured to calculate the comparison quantity as a mathematical function of the measured property values.

193. The system according to claim 167, wherein, The controller is configured to adjust the at least one regulator to control the flow rate of the second solution until the value of the relative relationship is within a target value range.

194. The system according to claim 190, wherein, The controller is configured to adjust the at least one flow regulator to control the flow rate of the second solution until the value of the comparison quantity is within a target value range.

195. The system according to claim 167, wherein, The biological product is a protein.

196. The system according to claim 195, wherein, The protein is an antibody, an antibody fragment, or includes a part of an antibody.

197. The system according to claim 167, wherein, The biological product in the first solution is a drug substance, and wherein the third solution is a drug product.

198. The system according to claim 167, the system further comprising a purification unit, wherein, The purification unit is in fluid communication with the inlet.

199. The system according to claim 198, wherein, The purification unit includes a tangential flow filtration unit.

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