Systems and devices for producing biological products and methods of using same

Abstract

Systems and devices for producing biological products and methods of using the same are provided. An example universal skid includes a rigid support and multiple flow channel hardware sets. Each flow channel hardware set couples with a respective one of multiple flow channels for a unit operation. The flow channel hardware sets allow the flow channels to operate in parallel or serially for continuous processing across the unit operations. An example modular assembly includes one or more disposable kits for one or more unit operations and a universal skid coupled with the one or more disposable kits. An example manufacturing system includes multiple modular assemblies coupled to each other, allowing continuous processing within each modular assembly and between modular assemblies, and fully continuous processing across multiple unit operations.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of priority to U.S. Provisional Application No. 63 / 410,878, filed September 28, 2022, and U.S. Provisional Application No. 63 / 415,099, filed October 11, 2022, the entire contents of which are incorporated herein by reference. [Background technology]

[0002]

[0003] The ramp-up of upstream processes in biopharmaceutical production is progressing rapidly, with downstream processes becoming a bottleneck in manufacturing schemes. Biomanufacturers are pursuing the development of continuous downstream processes to increase efficiency and flexibility, reduce product footprint and costs, and improve product consistency and quality. However, the implementation of continuous downstream operations is limited due to different and incompatible downstream unit operations (chromatography, inactivation, viral filtration, ultrafiltration / diafiltration), limited automation, limited operating ranges, large equipment size, increased service and maintenance costs, etc.

[0004] Therefore, there is a need for systems and devices for producing biological products, and methods of using the same, that address the above and other needs. Summary of the Invention [Means for solving the problem]

[0003] The present disclosure provides systems and devices for producing biological products, as well as methods of using the same. An example universal skid includes a rigid support and multiple flow channel hardware sets. Each flow channel hardware set is coupled to a respective flow channel for a unit operation. The multiple flow channel hardware sets enable continuous processing across one or more unit operations. An example modular assembly includes one or more disposable kits for one or more unit operations and a universal skid coupled to the one or more disposable kits. An example manufacturing system includes multiple modular assemblies coupled to each other, allowing continuous processing within each modular assembly, among the multiple modular assemblies, and fully continuous processing across multiple unit operations.

[0004] The foregoing features of the present disclosure will become apparent from the following detailed description of the disclosure taken in conjunction with the accompanying drawings. [Brief explanation of the drawings]

[0005] [Figure 1] FIG. 1 illustrates an example universal skid according to some embodiments. [Figure 2] FIG. 1 illustrates an example modular assembly according to some embodiments. [Figure 3A] FIG. 1 illustrates a perspective view of an example universal skid according to some embodiments. [Figure 3B] FIG. 3B is a rear view of the example universal skid of FIG. 3A. [Figure 3C] FIG. 3B is a left side view of the example universal skid of FIG. 3A. [Figure 3D] FIG. 3B is a right side view of the example universal skid of FIG. 3A. [Figure 3E] FIG. 3B is a front view of the example universal skid of FIG. 3A. [Figure 4A] FIG. 10 is a front view of another example universal skid according to some embodiments. [Figure 4B] 1 shows an example disposable kit for chromatography. [Figure 4C] 4B is a front view of an example modular assembly having the example universal skid of FIG. 4A combined with the example disposable kit of FIG. 4B. [Figure 5A] FIG. 1 is a perspective view of an example modular assembly for chromatography, according to some embodiments. [Figure 5B] FIG. 5B is a top view of the example modular assembly of FIG. 5A. [Figure 5C] FIG. 5B is a front view of the example modular assembly of FIG. 5A. [Figure 5D] FIG. 5B is a rear view of the example modular assembly of FIG. 5A. [Figure 5E] FIG. 5B is a right side view of the example modular assembly of FIG. 5A. [Figure 5F] FIG. 5B is a left side view of the example modular assembly of FIG. 5A. [Figure 6A] 1 is a piping and instrumentation diagram (P&ID) illustrating a modular assembly for chromatography, according to some embodiments. [Figure 6B] 1 is a P&ID showing a modular assembly for virus filtration, according to some embodiments. [Figure 6C] 1 is a P&ID showing a modular assembly for viral inactivation, according to some embodiments. [Figure 6D] 1 is a P&ID showing a modular assembly for ultrafiltration / diafiltration, according to some embodiments. [Figure 7] 1 is a P&ID illustrating another example universal skid according to some embodiments. [Figure 8A] 1 is a P&ID showing a modular assembly for chromatography, according to some embodiments. [Figure 8B] 1 is a P&ID showing a modular assembly for virus filtration, according to some embodiments. [Figure 8C]1 is a P&ID showing a modular assembly for viral inactivation, according to some embodiments. [Figure 8D] 1 is a P&ID showing a modular assembly for ultrafiltration / diafiltration, according to some embodiments. [Figure 9] FIG. 1 illustrates an example manufacturing system for continuous manufacturing, according to some embodiments. [Figure 10A] FIG. 1 illustrates an example implementation of a manufacturing system for a fed batch process, according to some embodiments. [Figure 10B] FIG. 1 illustrates an example implementation of a manufacturing system for a perfusion process, according to some embodiments. [Figure 10C] FIG. 1 illustrates an example implementation of a manufacturing system for a perfusion process, according to some embodiments. [Figure 11A] FIG. 1 shows a plot of absorbance values ​​versus time for each flow channel of an example modular assembly for chromatography. [Figure 11B] FIG. 1 shows plots of buffer and sample flow rates versus time for an example modular assembly for chromatography. [Figure 11C] FIG. 1 shows plots of pH value versus time for each flow channel of an example modular assembly for chromatography. [Figure 11D] FIG. 1 shows a plot of conductivity values ​​versus time for each flow channel of an example modular assembly for chromatography. [Figure 12A] FIG. 1 shows plots of pH values ​​versus time for each flow channel of an example modular assembly for viral inactivation. [Figure 12B] FIG. 1 shows a plot of flow rate versus time for the supply lines and each flow channel of an example modular assembly for viral inactivation. [Figure 13A] FIG. 1 shows a plot of conductivity values ​​versus time for each flow channel of an example modular assembly for ultrafiltration / diafiltration. [Figure 13B] FIG. 1 shows a plot of diavolume values ​​versus time for each flow channel of an example modular assembly for ultrafiltration / diafiltration. [Figure 13C] FIG. 1 shows a plot of flux values ​​versus time for each flow channel of an example modular assembly for ultrafiltration / diafiltration. DETAILED DESCRIPTION OF THE INVENTION

[0006] While various embodiments of the present disclosure have been shown and described herein, it will be apparent to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will occur to those skilled in the art without departing from the invention. It will be understood that various alternatives to the embodiments described in the present disclosure may be employed.

[0007] Reference will now be made in detail to certain exemplary embodiments according to the present disclosure, specific examples of which are illustrated in the accompanying drawings. Wherever possible, the same reference numbers will be used throughout the drawings to refer to the same or like parts.

[0008] As used in this specification and claims, the singular forms "a," "an," and "the" include plural references unless the context clearly dictates otherwise. As used herein, the terms "comprises" and / or "comprising" specify stated features, integers, steps, operations, elements, and / or components, but do not exclude the presence or addition of one or more other features, integers, steps, operations, elements, components, and / or groups thereof. As used herein, the term "and / or" includes any and all combinations of one or more of the associated listed items.

[0009] The section headings used herein are for organizational purposes only and should not be construed as limiting the subject matter described in any way. All documents or portions of documents cited in this application, including, but not limited to, patents, patent applications, articles, books, and treatises, are expressly incorporated herein by reference in their entirety for all purposes.

[0010] As used herein, unless specifically stated or clear from the context, the term "about" is understood to mean within normal tolerances in the art, for example, within two standard deviations of the mean. "About" can be understood to mean within 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.1%, 0.05%, or 0.01% of the stated value. Unless otherwise clear from the context, all numerical values ​​provided herein are modified by the term "about."

[0011] The present disclosure relates generally to the fields of biomanufacturing and bioprocessing. More specifically, the present disclosure relates to systems and devices for producing biological products (e.g., manufacturing systems and / or devices using universal skids) and methods of using the same.

[0012] Continuous manufacturing is a routine production method for industries such as petrochemical and food production. However, it has not been widely implemented in the biopharmaceutical industry. Because the technical needs of upstream and downstream development of biopharmaceuticals differ from those of other industries, experience with continuous downstream operations is limited. Therefore, there remains a need for systems that can accommodate different unit operations to provide continuous processing that offers steady-state operation, reduced equipment size, large-scale production, streamlined process flow, shorter cycle times, and / or reduced capital costs.

[0013] Embodiments of the present disclosure provide a universal skid (defined below) for accommodating different unit operations (defined below) and for integrating and / or connecting flow paths of the different unit operations to perform continuous processing (defined below). For example, the universal skid may include flow channel hardware sets (defined below) for supporting (via coupling, connecting, attaching, assembling, etc.) multiple flow channels of one or more disposable kits (defined below) for one or more unit operations. Each flow channel hardware set may support an individual flow channel (defined below). The flow channel hardware sets may be arranged in parallel, series, other suitable configurations, and / or various combinations thereof to enable the flow channels to operate in parallel, series, and / or some combination thereof. In some embodiments, the flow channel hardware sets may be identical or may have at least two of the same type of hardware components. In some embodiments, the flow channel hardware sets may be different. For example, one flow channel hardware set may include more hardware components than another flow channel hardware set.

[0014] In some embodiments, a flow channel hardware set may allow flow channels to operate in parallel, be switchable, and / or interchangeable. For example, if a flow channel hardware set for one flow channel is occupied (e.g., for processing a biological sample or for buffer flow), another flow channel hardware set may support additional flow channels to perform the same processing step in parallel (e.g., for the same unit operation) or to perform different processing steps in parallel (e.g., for a different unit operation). If the flow channel hardware configured for one flow channel is inoperative, that flow channel can be switched to another flow channel hardware set for processing. If a flow channel is inoperative, another flow channel can replace the inoperative flow channel by coupling to another flow channel hardware set. In this way, instead of batch processing, a universal skid may enable continuous processing between the inlets and outlets of a single universal skid and / or between the inlets and outlets of a disposable kit for a single unit operation. Examples of universal skids are described with respect to Figures 1-8. Instead of batch processing, a universal skid may also enable fully continuous processing and / or end-to-end continuous processing across multiple unit operations. An example of a universal skid is described with reference to FIGS.

[0015] In some embodiments, a flow channel hardware set may operate the flow channels in series to enable sequential processing across a particular unit operation and / or across multiple unit operations. For example, a flow channel may be coupled to a flow channel hardware set of a universal skid and operated in series to perform different processing steps so that fluids are processed for a particular unit operation and / or across multiple unit operations. In another example, a flow channel may be coupled to a flow channel hardware set of each of multiple universal skids and operated in series to allow fluids to flow through the flow channels in series for a particular unit operation and / or across multiple unit operations. In some embodiments, sequential processing across a particular unit operation and / or across multiple unit operations may be performed using a single universal skid or multiple universal skids based on serial and / or parallel flow channels.

[0016] In some embodiments, by enabling continuous processing for at least the specific unit operation and / or multiple unit operations described above, the universal skid can eliminate, reduce, or optimize (e.g., minimize) the hold-up volume at the specific unit operation and / or multiple unit operations, can eliminate, reduce, or optimize (e.g., minimize) the average residence time in one or more surge receptacles and / or one or more flow channels (defined below) used, and / or can eliminate, reduce, or optimize (e.g., minimize) the volume of one or more surge receptacles and / or one or more flow channels used. For example, the average residence time in one or more surge receptacles and / or one or more flow channels used can be less than about 30 minutes (e.g., from about 10 minutes to about 30 minutes). In another example, the average residence time in one or more surge receptacles and / or one or more flow channels can be less than about 60 minutes (e.g., from about 40 minutes to about 60 minutes). In some embodiments, the average residence time in one or more surge receptacles and / or one or more flow channels can be less than about 120 minutes. By reducing or limiting the average residence time, the hold-up volume and volume of one or more surge receptacles and / or one or more flow channels used can be reduced. Furthermore, by at least reducing the average residence time, the universal skid may allow for simultaneous delivery and receipt of flow by one or more surge receptacles and / or allow for more flexible use of surge receptacles (e.g., allowing for the use of surge receptacles of different quantities, different sizes, different configurations, or different volumes).

[0017] Embodiments of the present disclosure also provide a compact size manufacturing system in which different scale universal skids are combined with different disposable kits to perform continuous manufacturing across a variety of unit operations to produce a biological product (e.g., a recombinant protein or other suitable biological product) in an automated manner. An example manufacturing system is described with respect to Figures 9 and 10.

[0018] The present disclosure provides several technical advantages, including, but not limited to, one or more of the following: continuous processing of a single unit operation, fully continuous processing across multiple unit operations and / or end-to-end continuous processing, parallel processing, steady-state operation, reduced number of skids used, reduced number and volume of surge receptacles used, reduced average residence time of surge receptacles used, reduced hold-up volume, reduced overall size of biomanufacturing system / device, reduced capital costs, reduced service and maintenance, reduced complexity, simplified equipment qualification, simplified skid manufacturing, etc.

[0019] As used herein, a "unit operation" refers to a functional step that may be performed in a method for producing a biological product or a component of a system used in a process for producing a biological product. For example, a unit operation may include filtration (e.g., removal of contaminating bacteria, yeast viruses, or mycobacteria and / or specific substances from a fluid containing a recombinant therapeutic protein), capture, removal of an epitope tag, purification, retention or preservation, polishing, viral inactivation, adjustment of the ionic concentration and / or pH of a fluid containing a biological product, and removal of unwanted salts. Examples of unit operations may include methods and / or system components for chromatography (e.g., multi-column chromatography or other suitable chromatography), viral inactivation, viral filtration, ultrafiltration, diafiltration, ultrafiltration / diafiltration, formulation, sterile filtration, or another suitable functional step that may be performed in a method or system for producing a biological product, recombinant protein, etc.

[0020] As used herein, a "disposable kit" refers to a kit that provides a collection of consumable and / or disposable components for performing a particular unit operation. Examples of consumable and / or disposable components include one or more surge receptacles, one or more flow channel elements (e.g., tubing, fluid conduits, pipelines, etc.), one or more columns, one or more filters, one or more chambers, one or more pump heads, one or more sensors, or other suitable disposable and / or consumable components required to perform a particular unit operation.

[0021] As used herein, "universal skid" refers to a three-dimensional solid structure that can serve as a platform or support for various disposable kits for performing the various unit operations described herein. A universal skid can impart mobility to a manufacturing system or portion thereof if it includes one or more structures that enable movement (e.g., wheels, rollers, etc.). A universal skid can include pumps, valves, sensors, scales, regulators, flow meters, and / or other suitable hardware configured to support a disposable kit and / or to couple with disposable or consumable components of a disposable kit. A universal skid can be a single solid structure (e.g., all of its hardware components are mounted on the same cart). A universal skid can include multiple solid structures. For example, a universal skid can include multiple carts, each having some of the hardware components. All or some of the hardware components of a universal skid can be designed to support various disposable kits for the same or different unit operations. All or some of the hardware components of a universal skid can be permanently attached.

[0022] As used herein, a "flow channel" refers to a portion of the disposable kit described above. An example flow channel may include one or more columns, one or more filters (e.g., for purposes of ultrafiltration, diafiltration, sterile filtration, viral filtration, etc.), one or more viral inactivation chambers, flow path elements, other suitable disposable and / or consumable components associated with one or more unit operations, and / or some combination thereof.

[0023] As used herein, a "flow channel hardware set" refers to a set of hardware components of a universal skid that support a flow channel. Examples of a flow channel hardware set may include pumps, valves, sensors, mounting hardware, and / or other suitable hardware components for supporting a flow channel.

[0024] As used herein, "modular assembly" refers to an assembly having a universal skid coupled with one or more disposable kits for one or more unit operations. In some embodiments, a modular assembly can be an assembly having a universal skid coupled with disposable kits for a particular unit operation. In some embodiments, a modular assembly can be an assembly having a universal skid coupled with multiple disposable kits for multiple unit operations.

[0025] As used herein, a "surge receptacle" refers to a container that holds liquids and / or liquid mixtures to absorb or manage flow rate fluctuations from an upstream process and / or to maintain a more constant or consistent flow rate to a downstream process. For example, a surge receptacle may be located between two unit operations and / or at the downstream end of a supply line for a unit operation.

[0026] As used herein, "residence time" refers to the total time a fluid spends inside one or more surge receptacles and / or one or more flow channels. Residence time can be the volume of one or more surge receptacles and / or one or more flow channels divided by the flow rate. "Average residence time" refers to the average total time a fluid spends inside one or more surge receptacles and / or one or more flow channels over a given period of time.

[0027] As used herein, "continuous processing" or "continuous manufacturing" refers to a bioprocess in which a fluid is continuously fed through at least a portion of a modular assembly for a particular unit operation and / or in which a fluid flows and is processed continuously end-to-end through a modular assembly for a different unit operation. A unit operation is continuous if the corresponding modular assembly is capable of processing a continuous flow input over an extended period of time. A continuous unit operation has zero, reduced, or optimized (e.g., minimum) internal hold-up volume within the corresponding modular assembly and / or unit operation, zero, reduced, or optimized (e.g., minimum) average residence time of one or more surge receptacles and / or one or more flow channels used, and / or zero, reduced, or optimized (e.g., minimum) volume of one or more surge receptacles and / or one or more flow channels used. Output can be continuous or discrete, with small packets generated periodically. Fully continuous processing is continuous processing across all unit operations, e.g., allowing all unit operations in a process to operate simultaneously with consistent average material flow between all unit operations. (This can be achieved, for example, by connecting multiple universal skids in series.) An integrated (physically connected or coupled) modular assembly is fully continuous if it has zero, reduced, or optimized (e.g., minimum) hold-up volumes between and / or within the modular assemblies and / or multiple unit operations, zero, reduced, or optimized (e.g., minimum) average residence times of one or more surge receptacles used, and / or zero, reduced, or optimized (e.g., minimum) volumes of one or more surge receptacles and / or flow channels used.

[0028] As used herein, "biological product" refers to one of protein-based therapeutic agents, nucleic acid-based drug agents, and gene therapy drugs. Protein-based therapeutic agents may include at least one of proteins, peptides, antibodies, and enzymes. Nucleic acid-based drug agents may include at least one of DNA, plasmids, oligonucleotides, aptamers, DNAzymes, RNA aptamers, RNA decoys, microRNA fragments, small interfering RNA fragments, lipid nanoparticles, vaccines, cell therapies, etc.

[0029] As used herein, "recombinant protein" refers to an immunoglobulin, including an antibody or antibody fragment thereof, a protein fragment, an engineered protein, a blood factor, a nanobody, or an enzyme.

[0030] Universal skids and modular assemblies for a variety of unit operations Referring to the drawings, Figure 1 illustrates an example universal skid 100 of the present disclosure. The universal skid 100 includes a support 102, a plurality of pumps 104, a plurality of valves 106, a plurality of sensors 108, a surge receptacle support 110 for supporting a surge receptacle 120, a plurality of inlets 112, a plurality of outlets 114, and other hardware components 140 (e.g., regulators, flow meters, power sources, mounting hardware, a scale for measuring the weight of the surge receptacle 120, or other suitable hardware components for monitoring, measuring, supporting, coupling, connecting, and / or communicating with a disposable kit 130). The universal skid 100 can be further coupled with a disposable kit 130 to perform a particular unit operation. The disposable kit 130 can be easily assembled and / or disassembled from the universal skid 100, as further described with respect to Figures 2-8.

[0031] The support 102 (e.g., a hard casting, a movable cart, etc.) is configured to support the hardware components of the universal skid 100. The hardware components of the universal skid 100 may be attached to the support 102. The support 102 may also include one or more structures (e.g., wheels, rollers, etc.) that allow for movement.

[0032] The pump 104 is configured to pump / pressurize a liquid (e.g., a buffer solution) and / or a liquid mixture (e.g., a biological sample, a processed biological sample, waste, etc.). The pump 104 can communicate with a flow path element (e.g., a tube, a fluid conduit, a pipeline, etc.) of the disposable kit 130 by compressing the flow path element such that the liquid mixture is pressurized, thereby causing an output fluid flow from the pump 104. For example, pump 104A can be configured to pump / pressurize a buffer solution entering the universal skid 100 via inlet 112A (e.g., a location or means for entering the universal skid 100). Pump 104B can be configured to pump / pressurize a biological sample entering the disposable kit 130 from inlet 112B via valve 106C. The pump 104 can include various types of pumps for pumping / pressurizing a liquid or liquid mixture, such as a centrifugal pump, a peristaltic pump, a diaphragm pump, and / or other pumping mechanisms for pumping / pressurizing a liquid and / or a liquid mixture.

[0033] Valves 106 are configured to control the flow of fluids into and / or out of one or more components of the universal skid 100, the disposable kit 130, and / or another universal skid. For example, valve 106A may control the flow of fluid into surge receptacle 120 (e.g., biological sample entering universal skid 100 via inlet 112B) and / or another valve 106B, which controls the flow of fluid into pump 104B. Valve 106C may control the flow of fluid into disposable kit 130. Valve 106D may control the flow of fluids out of universal skid 100 via outlets 114A and 114B (e.g., outlet refers to a location or means for exiting universal skid 100).

[0034] The sensors 108 are configured to monitor the bioprocessing operation upstream and downstream of the outlet 114 and / or the inlet 112. Example sensors may include flow sensors, ultraviolet sensors, conductivity sensors, pH sensors, refractive index sensors, pressure sensors, or other suitable sensors for detecting data / signals related to the universal skid 100.

[0035] FIG. 2 illustrates an example modular assembly 200 of the present disclosure. The modular assembly 200 can be a universal skid 100 coupled (e.g., assembled, connected, attached, or inserted) with specific disposable kits 130 for chromatography (Chrom), viral inactivation (VI), viral filtration (VF), ultrafiltration / diafiltration (UF / DF), and other suitable unit operations. As shown in FIG. 2, for illustrative purposes, the modular assembly 200A is a universal skid 100 coupled with a specific disposable kit 130A for chromatography. It should be understood that the universal skid 100 can be coupled with one or more of any other disposable kits 130 (e.g., kits for VI, VF, or UF / DF) to form the modular assembly 200.

[0036] In some embodiments, a unit operation can be a component of a system used in a biomanufacturing process. Modular assembly 200 can be coupled to one or more components of one or more operational units. Examples of unit operations can include a unit operation having a bioreactor containing host cells producing, for example, a recombinant protein, a unit operation including one or more capture chromatography systems, a unit operation having one or more post-capture chromatography systems, a unit operation having an ultrafiltration system and a diafiltration system, unit operations between the above operational units (e.g., a subsystem for performing viral inactivation, a second subsystem for performing viral filtration, an in-line excipient for formulating a therapeutic agent), or some combination thereof.

[0037] FIG. 3A is a perspective view of an example universal skid 100. FIG. 3B is a rear view of the example universal skid 100 of FIG. 3A. FIG. 3C is a left side view of the example universal skid 100 of FIG. 3A. FIG. 3D is a right side view of the example universal skid 100 of FIG. 3A. The universal skid 100 may include a support 102, a pump 104, a valve 106, a sensor 108, a surge receptacle support 110 (as shown in FIG. 3B), an analyzer indicator transmitter 140A, and a scale 140B (as shown in FIG. 3B). As shown in FIG. 3B, the surge receptacle support 110 can support the surge receptacle 120 of the disposable kit 130. The scale 140B can measure the weight of the surge receptacle 120. In some embodiments (not shown), the universal skid 100 may include a timer for measuring the average residence time of the surge receptacle 120 and / or the flow channel.

[0038] The support 102 may be a movable cart having rollers 116. The universal skid 100 may be a single, solid, rigid structure. For example, all hardware components of the universal skid 100 may be attached to the support 102. In some embodiments, all or some of the hardware components of the universal skid 100 may be permanently attached to the support 102. In some embodiments, some hardware components may be removable from the support 102. Examples of hardware components of a universal skid are described with respect to FIG. 1.

[0039] The pumps 104 may include diaphragm pumps 104C and centrifugal pumps 104D. The diaphragm pumps 104 may be positive displacement pumps that use the reciprocating action of a rubber, thermoplastic, or Teflon diaphragm in combination with appropriate valves (check valves, butterfly valves, flap valves, or any other form of shut-off valve) on either side of the diaphragm to pump fluid. The centrifugal pumps 104D may be mechanical devices designed to move fluids through the transmission of rotational energy from one or more driven rotors.

[0040] The valve 106 may include a control valve 106E and a pressure control valve 106F. The control valve 106E, such as an on / off type control valve, can control the flow of the fluid. The pressure control valve 106F can control the pressure of the fluid.

[0041] The sensors 108 may include sensors 108A-108C that measure the power or intensity of ultraviolet (UV) radiation, pH, and conductivity in liquids (e.g., buffer solutions) and / or liquid mixtures (e.g., biological samples, processed biological samples, waste products, etc.), a pressure sensor 108D that monitors the pressure of the liquids and / or liquid mixtures, a flow sensor that measures the flow rate of the liquids and / or liquid mixtures, and other suitable sensors for detecting data / signals related to the universal skid 100. As shown in FIG. 3A, sensors 108A and 108B can be used to measure the UV, pH, and / or conductivity of the flow channel hardware set 310 (as shown in FIG. 3B). Sensor 108C can be used to measure the UV, pH, and / or conductivity of a supply line.

[0042] The analyzer indicator transmitter 140A can receive and analyze data from the sensor 108 and / or other hardware components.

[0043] FIG. 3E is a front view of the example universal skid 100 of FIG. 3A. A legend 300 is provided to indicate the symbols shown in FIGS. 3A-3E. As shown in FIG. 3E, the universal skid 100 can include two flow channel hardware sets 310A (dotted area) and 310B (dashed area) for sequential processing. As shown, each of the flow channel hardware sets 310 can include the same hardware components. For example, each of the flow channel hardware sets 310 can include multiple valves 106 (e.g., control valve 106E and pressure control valve 106F) and a sensor 108. The control valve 106E can control the flow of fluid into and / or out of one or more components of the respective flow channels coupled (e.g., inserted, connected, attached, or assembled) to each of the flow channel hardware sets 310. The pressure control valve 106F can control the pressure of the fluid flow within the respective flow channel. Sensors 108 may monitor ultraviolet (UV), pH and / or conductivity of each flow channel.

[0044] In some embodiments, each of the flow channel hardware sets 310 may include more or fewer hardware components than those shown in FIG. 3E . For example, each of the flow channel hardware sets 310 may further include an analyzer indicator transmitter 140A and / or other suitable hardware components (e.g., valves, regulators, pumps, sensors, etc.). In some embodiments (not shown), each of the flow channel hardware sets 310 may have different hardware components. For example, flow channel hardware set 310A may have more or fewer hardware components (e.g., may support hardware components and / or valves) than flow channel hardware set 310B. In some embodiments, all of the hardware components of the flow channel hardware set 310 may be coupled (e.g., inserted, connected, attached, or assembled) to a flow channel. In some embodiments, only some of the hardware components of the flow channel hardware set 310 may be coupled to a flow channel. For example, some unit operations (e.g., VF, UF / DF, VI) may not use a column. The hardware components of the flow channel hardware set 310 for connecting to a column may not be used. In some embodiments (not shown), the universal skid 100 may include three or more flow channel hardware sets 310 to support three or more flow channels.

[0045] The flow channel hardware set 310 enables sequential processing. In some embodiments, the flow channel hardware set 310 may enable flow channels to operate in parallel or serially to perform sequential processing across one or more unit operations. For example, a first flow channel hardware set 310A may be coupled to a first flow channel containing flow path elements and other suitable disposable and / or consumable components associated with a unit operation. The first flow channel may be a first part of a disposable kit for a unit operation, the first part being coupled to the first flow channel hardware 310A. For example, as shown in FIGS. 4A-4C, the first flow channel may have flow path element 420A and column 430A, with flow path element 420A connecting to column 430A. A second flow channel hardware set 310A may be coupled to a second flow channel. In some embodiments, the second flow channel may be a second part of a disposable kit for the same unit operation. For example, as shown in Figures 4A-4C, the second flow channel can have flow path element 420B and column 430B, with flow path element 420B connected to column 430B. The first flow channel can be used in a first location of a processing step of a particular unit operation (e.g., one of Chrom, VF, UF / DF, VI, and other suitable unit operations). The second flow channel can be used in a second location of the same processing step operated in the first flow channel. The second location can be different from the first location. The first location can refer to the location where first flow channel hardware 310A or the first flow channel is located. The second location can refer to the location where second flow channel hardware 310B or the second flow channel is located. The flow channel hardware set 310 can enable the first and second flow channels to operate in parallel, such that fluid flows sequentially through either the first flow channel or the second flow channel for a particular unit operation.

[0046] In some embodiments, the flow channel hardware set 310 can enable the first and second flow channels to operate in series, such that fluid flows sequentially through the first and second flow channels for a particular unit operation. For example, the output from the first flow channel can be the input to the second flow channel. The second flow channel can be used for a subsequent processing step for the particular unit operation (e.g., a different processing step than that operated in the first flow channel).

[0047] In this manner, the universal skid 100 may allow for continuous processing between the inlet and outlet of a single universal skid and / or between the inlet and outlet of a disposable kit for a single unit operation.

[0048] Additionally, the flow channel hardware set 310 may allow the flow channels to operate in parallel or serially to perform sequential processing across multiple unit operations. For example, a first flow channel hardware set 310A may be coupled to a first flow channel that can be used for a processing step of a first unit operation (e.g., one of Chrom, VF, UF / DF, VI, and other suitable unit operations). For example, the first flow channel may be part of a first disposable kit for the first unit operation. A second flow channel hardware set 310B may be coupled to a second flow channel that can be used for a processing step of a second unit operation (e.g., one of Chrom, VF, UF / DF, VI, and other suitable unit operations). For example, the second flow channel may be part of a second disposable kit for the second unit operation (e.g., one of Chrom, VF, UF / DF, VI, and other suitable unit operations). In some embodiments, the first unit operation may be the same as or different from the second unit operation. The flow channel hardware set 310 may allow the first and second flow channels to operate in parallel, such that fluid flows continuously through either the first or second flow channel. Thus, instead of batch processing, the parallel configuration of flow channels offers the advantage of continuous processing.

[0049] In some embodiments, the flow channel hardware set 310 can enable the first and second flow channels to operate in series, such that fluid flows sequentially into the first flow channel for a first unit operation and into the second flow channel for a second unit operation. For example, the output from the first flow channel for a first unit operation can be the input to the second flow channel for a second unit operation. By connecting the flow channels in series, at least two unit operations can be performed on the same universal skid, thereby minimizing the number of universal skids used. Connecting multiple universal skids in series enables fully continuous processing (connecting multiple unit operations in full). In this manner, a series configuration of flow channels and / or multiple universal skids provides the capability for fully continuous processing (connecting multiple unit operations in full) and / or end-to-end continuous processing across multiple unit operations. Thus, the universal skid 100 can enable the use of flow channels in both a parallel configuration as taught herein for continuous processing and a serial configuration as taught herein for fully continuous processing.

[0050] In some embodiments, a single universal skid 100 can be used for a single unit operation and / or multiple unit operations. For example, as described above, a flow channel hardware set 310 can be used for a specific unit operation or multiple unit operations. Disposable kits for a specific unit operation or multiple unit operations can be combined in whole or in part on a single universal skid 100.

[0051] In some embodiments, flow channel hardware set 310 may allow flow channels to operate in parallel, be switchable, and / or interchangeable. For example, when flow channel hardware set 310A is occupied (e.g., for processing a biological sample or for buffer flow), flow channel hardware set 310B can support flow channels to perform the same processing step in parallel (e.g., for the same unit operation) or different processing steps in parallel (e.g., for different unit operations), or vice versa. If flow channel hardware set 310A is inoperative, flow channel hardware set 310B can be used for processing, and vice versa. If a flow channel coupled to flow channel hardware set 310A is inoperative, another flow channel can be coupled to flow channel hardware set 310B to replace the inoperative flow channel, and vice versa.

[0052] In some embodiments, by enabling continuous processing for a particular unit operation and / or multiple unit operations as at least described above, the universal skid 100 can eliminate, reduce, or optimize (e.g., minimize) the hold-up volume of a particular unit operation and / or multiple unit operations, eliminate, reduce, or optimize (e.g., minimize) the average residence time in the surge receptacle 120 and / or each flow channel, and / or eliminate, reduce, or optimize (e.g., minimize) the volume of the surge receptacle 120 and / or each flow channel. For example, the average residence time in the surge receptacle 120 and / or each flow channel can be less than about 30 minutes (e.g., about 10 minutes to about 30 minutes). In another example, the average residence time in the surge receptacle 120 and / or each flow channel can be less than about 60 minutes (e.g., about 40 minutes to about 60 minutes). In some embodiments, the average residence time in the surge receptacle 120 and / or each flow channel can be less than about 120 minutes. Reducing or limiting the average residence time can reduce the holdup volume and volume of the surge receptacle 120. Additionally, due to at least the reduction in average residence time, the universal skid 100 can allow the surge receptacle 120 to simultaneously send and receive flows and / or allow for more flexible use of the surge receptacle 120 (e.g., allowing for the use of surge receptacles of different quantities, sizes, configurations, or volumes).

[0053] FIG. 4A is a front view of another example universal skid 100. A legend 400 is provided to indicate the symbols shown in FIG. 4A. The universal skid 100 may include valves 106, sensors 108 (e.g., two UV, pH, and conductivity sensors 108A and 108B for the flow channel hardware set 310 and one UV, pH, and conductivity sensor 108C for the supply line), pumps 104 (e.g., a diaphragm pump 104C and a centrifugal pump 104D), regulators 140C (e.g., a backpressure regulator), a surge receptacle support 110, and a scale 140B. Each of the flow channel hardware sets 310 may include multiple valves 106, regulators 140C, and sensors 108. Valves 160C can control fluid flow into the respective flow channels. Valves 160E can control fluid flow into and / or out of the respective columns 430. Regulator 140C can regulate the flow of fluid through each column 430. Sensors 108A, 108B can monitor the ultraviolet (UV), pH, and / or conductivity of each flow channel. In some embodiments, flow channel hardware set 310A (within the dotted area) can have more or fewer hardware components (e.g., can support more hardware components and / or valves) than flow channel hardware set 310B (within the dashed area). In some embodiments, all of the hardware components of flow channel hardware set 310B can be coupled (e.g., inserted, connected, attached, or assembled) to the flow channel. In some embodiments, only a portion of the hardware components of flow channel hardware set 310B can be coupled (e.g., inserted, connected, attached, or assembled) to the flow channel. In some embodiments (not shown), universal skid 100 can include more than two flow channel hardware sets to support more than two flow channels.

[0054] 4B is a front view of an example disposable kit 130A for chromatography. The disposable kit 130A includes flow path elements 420 (e.g., tubing, fluid conduits, pipelines, etc.), a column 430, a sensor 440, a surge vessel 120, and other suitable disposable and / or consumable components necessary to perform chromatography.

[0055] 4C is a front view of an example modular assembly 200A including the example universal skid 100 of FIG. 4A coupled with the example disposable kit 130A of FIG. 4B. As shown in FIG. 4C, a flow path element 420 is coupled (e.g., inserted, connected, attached, or assembled) with various valves 106. A column 430 is coupled with the universal skid 100 via mounting hardware (not shown) of the universal skid 100. A sensor 440 is coupled with the sensor 108. A surge receptacle 120 is disposed on a scale 140B. A first flow channel having a flow path element 420A connecting to column 430A can be coupled with flow channel hardware set 310A. A second flow channel having a flow path element 420B connecting to column 430B can be coupled with flow channel hardware set 310B.

[0056] As shown in FIGS. 4A-4C, the universal skid 100 allows flow channels to operate in parallel to perform sequential processing for chromatography. For example, a first flow channel hardware set 310A can be coupled to a first flow channel (e.g., a flow channel having flow path element 420A connecting to column 430A). A second flow channel hardware set 310B can be coupled to a second flow channel (e.g., a flow channel having flow path element 420B connecting to column 430B). The first flow channel can be used in a first position for a first processing step for chromatography. The second flow channel can be used in a second position for the same processing step. The first position can be different from the second position. The first position can refer to the position where the first flow channel hardware 310A or the first flow channel is located. The second position can refer to the position where the second flow channel hardware 310B or the second flow channel is located. The flow channel hardware set 310 may allow the first and second flow channels to operate in parallel, such that fluid flows sequentially through either the first or second flow channel for chromatography. In some embodiments (not shown), the flow channel hardware set 310 may allow the first and second flow channels to operate in series, such that fluid flows sequentially through the first and second flow channels for multi-column chromatography. For example, the first processing step may be different from the second processing step. The output of the first processing step may be the input of the second processing step, and vice versa.

[0057] Thus, by allowing the flow channels to be used in both parallel and serial configurations instead of batch processing, the universal skid 100 can enable continuous processing for chromatography between the inlet and outlet of the universal skid 100 and / or the inlet and outlet of the chromatography disposable kit 130. Additionally, the universal skid 100 can provide zero, reduced, or optimized (e.g., minimum) hold-up volume for chromatography, zero, reduced, or optimized (e.g., minimum) average residence time in the surge receptacle 120 and / or flow channels, and / or zero, reduced, or optimized (e.g., minimum) volume of the surge receptacle 120 and / or flow channels. For example, the average residence time in the surge receptacle 120 and / or flow channels can be less than about 30 minutes (e.g., about 10 minutes to about 30 minutes). In another example, the average residence time in the surge receptacle 120 and / or flow channels can be less than about 60 minutes (e.g., about 40 minutes to about 60 minutes). In some embodiments, the surge receptacle 120 and / or flow channel average residence time may be less than about 120 minutes. Reducing or limiting the average residence time may reduce the holdup volume and volume of the surge receptacle 120 and / or flow channel. Additionally, due to at least the reduced average residence time, the universal skid 100 may allow the surge receptacle 120 to simultaneously send and receive flows and / or may allow for more flexibility in the surge receptacle 120 (e.g., allowing for the use of surge receptacles of different quantities, sizes, configurations, or volumes).

[0058] FIG. 5A is a perspective view of an example modular assembly 200A for chromatography. FIG. 5B is a top view of the example modular assembly 200A of FIG. 5A. FIG. 5C is a front view of the example modular assembly 200A of FIG. 5A. FIG. 5D is a rear view of the example modular assembly 200A of FIG. 5A. FIG. 5E is a right side view of the example modular assembly 200A of FIG. 5A. FIG. 5F is a left side view of the example modular assembly 200A of FIG. 5A. By way of example, the modular assembly 200A can be a universal skid 100 coupled (e.g., inserted, connected, attached, or assembled) with a disposable kit 130A for chromatography. It should be understood that the modular assembly 200 can perform any other suitable unit operation when the universal skid 100 is combined with any other disposable kits 130 for that suitable unit operation (e.g., one or more kits for Chrom, VI, VF, UF / DF, or any other suitable unit operation). Examples are described with respect to Figures 6A-6D.

[0059] While the various example embodiments described herein have specific configurations (e.g., quantities, locations) of hardware components, those skilled in the art will understand, in light of this disclosure, that a universal skid can have a different configuration than the universal skid 100 shown in FIGS. 3-5 . Furthermore, those skilled in the art will understand, in light of this disclosure, that the hardware components of a flow channel hardware set for sequential processing can differ from the flow channel hardware set 310 shown in FIGS. 3 and 4 . In light of this disclosure, those skilled in the art will also understand that a universal skid can have three or more flow channel hardware sets for sequential processing, and that the hardware components of each of the flow channel hardware sets can differ. In light of this disclosure, those skilled in the art will also understand that a universal skid can, in some embodiments, have additional hardware components not explicitly described herein.

[0060] FIG. 6A is a piping and instrumentation diagram (P&ID) diagram illustrating a modular assembly 200A for chromatography. The modular assembly 200A may be the universal skid 100, as shown in FIGS. 3A-3E, coupled (e.g., assembled, connected, attached, or inserted) with a disposable kit 130A for chromatography. The hardware components of the universal skid 100 and disposable kit 130A may be represented using standard notation / symbols in P&ID software. For purposes of illustration and simplicity, one identical hardware component is labeled, while the other identical hardware component is not. As shown, the universal skid 100 may include pumps 104C, 104D, valves 106E, 106F, sensors 108A-108C, a surge receptacle support 110, and a scale 140B. Disposable kit 130A may include flow path element 420 (e.g., tubing, fluid conduit, pipeline, etc.), column 430, pressure sensor 440A, flow sensor 440B, surge vessel 120, and other suitable disposable and / or consumable components (not shown) necessary for performing chromatography. The dotted area may include first flow channel hardware set 310A coupled (e.g., assembled, inserted, connected, or attached) to first flow channel 460A. First flow channel hardware set 310A may include valves 106E, 106F and sensor 108A. First flow channel 460A may include flow path element 420A, pressure sensor 440A, and column 430A. The dashed area may include second flow channel hardware set 310B coupled (e.g., assembled, inserted, connected, or attached) to second flow channel 460B. Second flow channel hardware set 310B can include valves 106E, 106F and sensor 108B. Second flow channel 460B can include flow path element 420B, pressure sensor 440A and column 430B. In some embodiments, second flow channel hardware set 310B can further include valve 106E in dash-dotted region 320.Second flow channel 460B may further include flow path element 420B connecting dash-dotted region 320 and valve 106E in column 430B.

[0061] The first flow channel 460A can be used in a first position of a chromatographic processing step to process a biological sample received from a previous unit operation 500 (e.g., the same unit operation for Chrom or a different unit operation for VI, VF, UF / DF, etc.). The second flow channel 460B can be used in a second position of the same processing step operating on the first flow channel 460B. The first position can be different from the second position. The first position can refer to the position where the first flow channel hardware 310A or the first flow channel is located. The second position can refer to the position where the second flow channel hardware 310B or the second flow channel is located. The flow channel hardware set 310 can operate the first and second flow channels 460A, 460B in parallel, allowing fluid to flow sequentially through either the first flow channel 460A or the second flow channel 460B for chromatography. In some embodiments (not shown), the flow channel hardware set 310 can operate the first and second flow channels 460 in series, such that fluid flows sequentially through the first and second flow channels 460 for multi-column chromatography. For example, the output from the first flow channel 460A can be the input to the second flow channel 460B. The second flow channel 460B can be used for a subsequent processing step (e.g., a different processing step) for multi-column chromatography.

[0062] 6A, the combined output from the first flow channel 460A and the second flow channel 460B can be the input to a biological product or a subsequent unit operation 510 (e.g., the same unit operation for Chrom or a different unit operation for VI, VF, UF / DF, etc.). By allowing for the arrangement of at least the flow channels in a parallel or serial configuration, the flow channel hardware set 310 can enable continuous processing between the inlet and outlet of the universal skid 100 and / or the inlet and outlet of the disposable kit 130A for chromatography. Additionally, with continuous processing at least as described herein, the universal skid 100 can provide zero, limited, or optimized (e.g., minimum) hold-up volume for chromatography, zero, reduced, or optimized (e.g., minimum) average residence time in the surge receptacle 120 and / or the flow channel 460, and / or zero, reduced, or optimized (e.g., minimum) volume in the surge receptacle 120 and / or the flow channel 460. For example, the average residence time of the surge receptacle 120 and / or the flow channel 460 can be less than about 30 minutes (e.g., about 10 minutes to about 30 minutes). In another example, the average residence time of the surge receptacle 120 and / or the flow channel 460 can be less than about 60 minutes (e.g., about 40 minutes to about 60 minutes). In some embodiments, the average residence time of the surge receptacle 120 and / or the flow channel 460 can be less than about 120 minutes. Reducing or limiting the average residence time can reduce the holdup volume and volume of the surge receptacle 120 and / or the flow channel 460. Furthermore, by at least reducing the average residence time, the universal skid 100 can allow the surge receptacle 120 to simultaneously send and receive flows and / or allow for more flexible use of the surge receptacle 120 (e.g., allowing for the use of surge receptacles of different quantities, sizes, configurations, or volumes).

[0063] FIG. 6B is a P&ID illustrating a modular assembly 200B for VF. The modular assembly 200B may be the universal skid 100, as shown in FIG. 6A, coupled (e.g., assembled, connected, attached, or inserted) with a disposable kit 130B for VF. The hardware components of the universal skid 100 and the disposable kit 130B may be represented using standard notation / symbols in P&ID software. For purposes of illustration and simplicity, one identical hardware component is labeled, while the other identical hardware component is not. As shown, the disposable kit 130B may include flow path elements 420 (e.g., tubing, fluid conduits, pipelines, etc.), a VF filter 530, a pressure sensor 440A, a flow sensor 440B, a surge receptacle 120, and other suitable disposable and / or consumable components (not shown) necessary to perform VF. The dotted area may include first flow channel hardware set 310A coupled (e.g., assembled, inserted, connected, or attached) to first flow channel 560A. First flow channel hardware set 310A may include valves 106E, 106F and sensor 108A. First flow channel 560A may include flow path element 420A, pressure sensor 440A, and VF filter 530A. The dashed area may include second flow channel hardware set 310B coupled (e.g., assembled, inserted, connected, or attached) to second flow channel 460B. Second flow channel hardware set 310B may include valves 106E, 106F and sensor 108B. Second flow channel 560B may include flow path element 420B, pressure sensor 440A, and VF filter 530B. In some embodiments, the second flow channel hardware set 310B may further include valves 106E in the dash-dotted region 320, which are not used for VF.

[0064] The first flow channel 560A can be used for a VF processing step to process a biological sample received from a previous unit operation 540 (e.g., the same unit operation for VF or a different unit operation for VI, Chrom, UF / DF, etc.). The second flow channel 560B can be used for a second location of the same processing step operating on the first flow channel 560B. The first location can be different from the second location. The first location can refer to the location where the first flow channel hardware 310A or the first flow channel is located. The second location can refer to the location where the second flow channel hardware 310B or the second flow channel is located. The flow channel hardware set 310 can operate the first and second flow channels 560A, 560B in parallel, allowing fluid to flow sequentially through either the first flow channel 560A or the second flow channel 560B for VF. In some embodiments (not shown), the flow channel hardware set 310 can operate the first and second flow channels 560 in series, such that fluid flows sequentially through the first and second flow channels 560 for VF. For example, the output from the first flow channel 560A can be the input to the second flow channel 560B. The second flow channel 560B can be used for a subsequent processing step (e.g., a different processing step) of the VF.

[0065] As shown in Figure 6B, the combined output from the first flow channel 560A and the second flow channel 560B can be the biological product or input to the next unit operation 550 (e.g., the same unit operation for VF or a different unit operation for VI, Chrom, UF / DF, etc.). In this manner, by allowing at least the flow channels to be used in both parallel and serial configurations, the flow channel hardware set 310 can enable continuous processing between the inlet and outlet of the universal skid 100 and / or the inlet and outlet of the disposable kit 130B for VF. Additionally, continuous processing, at least as described herein, allows the universal skid 100 to zero, reduce, and / or optimize (e.g., minimize) the holdup volume for VF, to zero, reduce, or optimize (e.g., minimize) the mean residence time of the surge receptacle 120 and / or the flow channel 560, and / or to zero, reduce, or optimize (e.g., minimize) the volume of the surge receptacle 120 and / or the flow channel 560. For example, the average residence time of the surge receptacle 120 and / or the flow channel 560 can be less than about 30 minutes (e.g., about 10 minutes to about 30 minutes). In another example, the average residence time of the surge receptacle 120 and / or the flow channel 560 can be less than about 60 minutes (e.g., about 40 minutes to about 60 minutes). In some embodiments, the average residence time of the surge receptacle 120 and / or the flow channel 560 can be less than about 120 minutes. Reducing or limiting the average residence time can result in a reduction in the holdup volume and volume of the surge receptacle 120 and / or the flow channel 560. Furthermore, by at least reducing the average residence time, the universal skid 100 can allow the surge receptacle 120 to simultaneously send and receive flows and / or allow for more flexible use of the surge receptacle 120 (e.g., allowing for the use of surge receptacles of different quantities, different sizes, different configurations, or different volumes).

[0066] FIG. 6C is a P&ID illustrating a modular assembly 200C for a VI. The modular assembly 200C may be a universal skid 100, as shown in FIG. 6A, coupled (e.g., assembled, connected, attached, or inserted) with a disposable kit 130C for the VI. The hardware components of the universal skid 100 and the disposable kit 130C may be represented using standard notation / symbols in P&ID software. For purposes of illustration and simplicity, one identical hardware component is labeled, while the other identical hardware component is not. As shown, the disposable kit 130C may include flow path elements 420 (e.g., tubing, fluid conduits, pipelines, etc.), a vessel 630, a pressure sensor 440A, a flow sensor 440B, a surge vessel 120, and other appropriate disposable and / or consumable components (not shown) required to perform the VI. The dotted area may include a first flow channel hardware set 310A coupled (e.g., assembled, inserted, connected, or attached) with a first flow channel 660A. First flow channel hardware set 310A may include valves 106E, 106F, and sensor 108A. First flow channel 660A may include flow path element 420A, pressure sensor 440A, flow sensor 440B, and reservoir 630. The dashed area may include second flow channel hardware set 310B coupled (e.g., assembled, inserted, connected, or attached) to second flow channel 660B. Second flow channel hardware set 310B may include valves 106E, 106F, and sensor 108B. Second flow channel 660B may include flow path element 420B, pressure sensor 440A, and flow sensor 440B. In some embodiments, second flow channel hardware set 310B may further include valve 106E within dash-dotted area 320. As shown, some valves 106E of the first and second flow channel hardware sets 310 are not used for VI.

[0067] The first flow channel 660A can be used for a processing step of the VI to process a biological sample received from a previous unit operation 600 (e.g., the same unit operation for VI or a different unit operation for VF, Chrom, UF / DF, etc.). The output from the first flow channel 660A can be input to the second flow channel 660B. The second flow channel 660B can be used for a subsequent processing step (e.g., a different processing step) of the VI. The output from the second flow channel 660B can be input to a biological product or a next unit operation 610 (e.g., the same unit operation for VI or a different unit operation for VF, Chrom, UF / DF, etc.). In this manner, the flow channel hardware set 310 can operate the first and second flow channels 660 in series, allowing fluid to flow sequentially through the first and second flow channels 660 for the VI, thereby enabling continuous processing between the inlet and outlet of the universal skid 100 and / or the inlet and outlet of the disposable kit 130C for the VI. Additionally, through continuous processing at least as described herein, the universal skid 100 can eliminate, reduce, or optimize (e.g., minimize) the holdup volume for the VI, eliminate, reduce, or optimize (e.g., minimize) the average residence time in the surge receptacle 120 and / or the flow channel 660, and / or eliminate, reduce, or optimize (e.g., minimize) the volume of the surge receptacle 120 and / or the flow channel 660. For example, the average residence time in the surge receptacle 120 and / or the flow channel can be less than about 30 minutes (e.g., between about 10 minutes and about 30 minutes). In another example, the average residence time in the surge receptacle 120 and / or the flow channel can be less than about 60 minutes (e.g., between about 40 minutes and about 60 minutes). In some embodiments, the average residence time in the surge receptacle 120 and / or the flow channel can be less than about 120 minutes. Reducing or limiting the average residence time can reduce the hold-up volume and volume of the surge receptacle 120 and / or flow channel.Furthermore, by at least reducing the average residence time, the universal skid 100 may allow the surge receptacle 120 to simultaneously send and receive flows and / or allow for more flexible use of the surge receptacle 120 (e.g., allowing for the use of surge receptacles of different quantities, different sizes, different configurations, or different volumes).

[0068] FIG. 6D is a P&ID illustrating a modular assembly 200D for UF / DF. The modular assembly 200D may be a universal skid 100, as shown in FIG. 6A, coupled (e.g., assembled, connected, attached, or inserted) with a disposable kit 130D for UF / DF. The hardware components of the universal skid 100 and the disposable kit 130D may be represented using standard notation / symbols in P&ID software. For purposes of illustration and simplicity, one identical hardware component is labeled, while other identical hardware components are not. As shown, the disposable kit 130D may include flow path elements 420 (e.g., tubing, fluid conduits, pipelines, etc.), a UF / DF filter 690, a pressure sensor 440A, a flow sensor 440B, a diavolume sensor 440C, a surge receptacle 120, and other suitable disposable and / or consumable components (not shown) necessary to perform UF / DF. The diavolume sensor 440C can measure diavolume, which refers to the total buffer volume introduced into the operation during diafiltration divided by the initial retentate volume. The dotted area can include a first flow channel hardware set 310A coupled (e.g., assembled, inserted, connected, or attached) to the first flow channel 680A. The first flow channel hardware set 310A can include valves 106E, 106F, and a sensor 108A. The first flow channel 680A can include a flow path element 420A, a pressure sensor 440A, a flow sensor 440B, and a UF filter 690A. The dashed area can include a second flow channel hardware set 310B coupled (e.g., assembled, inserted, connected, or attached) to the second flow channel 680B. The second flow channel hardware set 310B can include valves 106E, 106F, and a sensor 108B. The second flow channel 680B can include a flow path element 420B, a pressure sensor 440A, a flow sensor 440B, and a DF filter 690B. In some embodiments, the second flow channel hardware set 310B can further include a valve 106E in the dash-dotted region 320.

[0069] The first flow channel 680A can be used for a UF / DF processing step to process a biological sample received from a previous unit operation 640 (e.g., the same unit operation for UF / DF or a different unit operation for VF, Chrom, VI, etc.). The output from the first flow channel 680A can be input to a second flow channel 680B. The second flow channel 680B can be used for a subsequent processing step (e.g., a different processing step) of the UF / DF. The output from the second flow channel 680B can be input to a biological product or a next unit operation 650 (e.g., the same unit operation for UF / DF or a different unit operation for VF, Chrom, VI, etc.). In this manner, the flow channel hardware set 310 allows the first and second flow channels 680 to operate in series such that fluid flows sequentially into the first and second flow channels 680 for UF / DF, thereby enabling sequential processing between the inlet and outlet of the universal skid 100 and / or the inlet and outlet of the disposable kit 130D for UF / DF. Additionally, sequential processing, at least as described herein, allows the universal skid 100 to zero, reduce, or optimize (e.g., minimize) the holdup volume for UF / DF, to zero, reduce, or optimize (e.g., minimize) the average residence time of the surge receptacle 120 and / or the flow channel 680, and / or to zero, reduce, or optimize (e.g., minimize) the volume of the surge receptacle 120 and / or the flow channel 680. For example, the average residence time in the surge receptacle 120 and / or flow channel 680 can be less than about 30 minutes (e.g., about 10 minutes to about 30 minutes). In another example, the average residence time in the surge receptacle 120 and / or flow channel 680 can be less than about 60 minutes (e.g., about 40 minutes to about 60 minutes). In some embodiments, the average residence time in the surge receptacle 120 and / or flow channel 680 can be less than about 120 minutes. Reducing or limiting the average residence time can reduce the holdup volume and volume of the surge receptacle 120 and / or flow channel 680.Furthermore, by at least reducing the average residence time, the universal skid 100 may allow the surge receptacle 120 to simultaneously send and receive flows and / or allow for more flexible use of the surge receptacle 120 (e.g., allowing for the use of surge receptacles of different quantities, different sizes, different configurations, or different volumes).

[0070] In some embodiments, the UF / DF processing step can be changed to a chromatography step by changing from UF / DF filter 690 to a chromatography membrane / resin. Thus, Figure 6D can also be a depiction of a series of sequential chromatography steps.

[0071] FIG. 7 is a P&ID illustrating another example universal skid 100 disclosed herein. The universal skid 100 includes valves 106, sensors 108 (e.g., UV, pH, and conductivity sensors 108A and 108B for flow channel hardware sets 310A and 310B, and UV, pH, and conductivity sensor 108C for supply lines), pump 104, and regulator 140C. Flow channel hardware set 310 is configured to support a flow channel. The universal skid 100 illustrated in FIG. 7 may have different quantities and locations of hardware components than the universal skid 100 illustrated in FIGS. 3-6.

[0072] FIG. 8A is a P&ID showing a modular assembly 200A for multi-column chromatography. The modular assembly 200A may be the universal skid 100 shown in FIG. 7 coupled (e.g., assembled, connected, attached, or inserted) with a disposable kit 130A for multi-column chromatography. FIG. 8B is a P&ID showing a modular assembly 200B for VF. The modular assembly 200B may be the universal skid 100 shown in FIG. 7 coupled with a disposable kit 130B for VF. FIG. 8C is a P&ID showing a modular assembly 200C for VI. The modular assembly 200C may be the universal skid 100 shown in FIG. 7 coupled with a disposable kit 130C for VI. FIG. 8D is a P&ID showing a modular assembly 200D for UF / DF. The modular assembly 200D can be a universal skid 100 as shown in Figure 7 combined with a disposable kit 130D for UF / DF. As shown, the disposable kit 130D can have three or more filters.

[0073] In some embodiments (not shown), the modular assembly 200 may be an assembly having a universal skid 100 coupled with multiple disposable kits for multiple, same or different, unit operations. For example, a first flow channel may include a first disposable kit (e.g., one of Chrom, VI, VF, UF / DF, etc.) for a first unit operation, and a second flow channel may be part of a second disposable kit for a second unit operation, which may be the same or different from the first unit operation. Both the first and second flow channels may be coupled with the universal skid 100.

[0074] It should be understood that the location and quantity of hardware components of the universal skid may differ from the universal skid 100 shown in Figures 3-8. It should also be understood that the hardware components of the flow channel hardware set 310 may differ from those shown in Figures 3-8. The hardware components of a first flow channel hardware set may differ from a second flow channel hardware set. It should also be understood that a universal skid may have more than two flow channel hardware sets for more than two flow channels. It should also be understood that different hardware components of a universal skid may be used for different unit operations. For example, components of a disposable kit may be coupled to all or some of the hardware components of a universal skid.

[0075] Manufacturing systems for continuous manufacturing FIG. 9 illustrates an example manufacturing system 900 for continuous manufacturing of the present disclosure. The manufacturing system 900 can include multiple modular assemblies 200(1)-200(N), each performing a specific unit operation based on a corresponding disposable kit 130(1)-130(N). In some embodiments, the multiple modular assemblies 200(1)-200(N) can be different from one another. In some embodiments, several of the modular assemblies 200(1)-200(N) can perform the same unit operation. Multiple modular assemblies can be coupled together, such as by coupling the output (e.g., outlet) of one modular assembly 200(1) to the input (e.g., inlet) of an adjacent modular assembly 200(2). The flow channel hardware set of the multiple modular assemblies may enable continuous processing within and between each of the multiple modular assemblies 200(1)-200(N), fully continuous and / or end-to-end processing from a starting modular assembly 200(1) to an ending modular assembly 200(N), fully continuous and / or end-to-end processing across multiple unit operations. The flow channel hardware set of the multiple modular assemblies may eliminate, reduce, or optimize (e.g., minimize) internal holdup volumes within the multiple modular assemblies, eliminate, reduce, or optimize (e.g., minimize) the average residence time of one or more surge receptacles and / or one or more flow channels used in the multiple modular assemblies, and / or eliminate, reduce, or optimize (e.g., minimize) the volume of one or more surge receptacles and / or one or more flow channels used in the multiple modular assemblies. For example, the average residence time of the one or more surge receptacles and / or one or more flow channels used can be less than about 30 minutes (e.g., about 10 minutes to about 30 minutes). In another example, the average residence time of the one or more surge receptacles and one or more flow channels used can be less than about 60 minutes (e.g., about 40 minutes to about 60 minutes).In some embodiments, the average residence time of the one or more surge receptacles and one or more flow channels used can be less than about 120 minutes. Reducing or limiting the average residence time can reduce the holdup volume and volume of the one or more surge receptacles and one or more flow channels used. Furthermore, at least reducing the average residence time can allow one or more surge receptacles to simultaneously send and receive flows and / or allow for more flexibility in the use of the one or more surge receptacles (e.g., allowing for the use of surge receptacles of different quantities, different sizes, different configurations, or different volumes).

[0076] 6A-6D, as described above, modular assemblies 200A-200D may couple an outlet (e.g., outlets 510, 550, 610, 650) of one modular assembly of modular assemblies 200A-200D with an inlet (e.g., outlets 500, 540, 600, 640) of another modular assembly of modular assemblies 200A-200D. For each modular assembly 200, flow channel hardware set 310 may enable continuous processing between the inlet and outlet of each modular assembly 200 and end-to-end continuous processing across a particular unit operation (e.g., Chrom, VF, VI, UF / DF). The flow channel hardware set 310 can eliminate, reduce, or optimize (e.g., minimize) the internal holdup volume within the corresponding modular assembly 200, can eliminate, reduce, or optimize (e.g., minimize) the mean residence time of the surge receptacle 120 and / or flow channel, and / or can eliminate, reduce, or optimize (e.g., minimize) the volume of the surge receptacle 120 and / or flow channel 460, 560, 660, 680. When modular assemblies 200A-200D are combined, the flow channel hardware set 310 can further enable continuous processing between multiple modular assemblies 200A-200D, end-to-end continuous processing from a starting modular assembly to an ending modular assembly, and end-to-end continuous processing across multiple unit operations (e.g., Chrom, VF, VI, UF / DF).

[0077] In some embodiments, multiple modular assemblies 200(1)-200(N) can be coupled together in series, e.g., one modular assembly can be directly coupled to another modular assembly. In some embodiments, multiple modular assemblies can be coupled together with other processing steps in between. For example, a modular assembly can be coupled to one or more processing steps before it is coupled to another modular assembly. In some embodiments, multiple modular assemblies 200(1)-200(N) of different scales (e.g., different liquid volume retention, modular assembly sizes, and / or hardware component quantities) can be used for different types of processes to process volumes ranging from small to large. Example implementations of manufacturing system 900 using modular assemblies 200(1)-200(N) at different scales are described with reference to FIGS. 10A-10C.

[0078] 10A illustrates an example implementation of manufacturing system 900A for a fed-batch process 1010 (e.g., a 2 kL fed-batch process at 5 g / L). Compared to conventional equipment 1000A, manufacturing system 900A uses modular assemblies of different scales (e.g., holding different liquid volumes, as shown in FIG. 10A) for continuous processing with fewer steps and less equipment, thereby reducing equipment size, service and maintenance, and capital costs, and can provide other technical advantages as described above.

[0079] 10B illustrates an example implementation of a manufacturing system 900B for a perfusion process 1020 (e.g., a 500 L perfusion process at 2.5 g / L / day). Compared to conventional equipment 1000B, manufacturing system 900B uses modular assemblies of different scales (e.g., holding different liquid volumes, as shown in FIG. 10B) to process continuously with fewer steps and less equipment and zero or minimal hold-up volume (e.g., time or intermediate storage). FIG. 10B also illustrates additional equipment that can be used to perform a fed-batch process 1010 in the same area (listed under "Storage"). To perform the fed batch process 1010, the manufacturing system 900B can use one additional piece of equipment: a 2000 L disposable mixer (“2 kL SUM”) 1004. In contrast, the conventional equipment 1000B requires two additional pieces of equipment: a 2000 L disposable mixer (“2 kL SUM”) 1004 and a chromatography kit (“Chrom”) 1002.

[0080] FIG. 10C illustrates an example implementation of a manufacturing system 900C for a perfusion process 1030 (e.g., a 500 L perfusion process at 0.5 g / L / day). Compared to the conventional equipment 1000C, the manufacturing system 900C uses modular assemblies of different scales (e.g., holding different liquid volumes, as shown in FIG. 10C) to process continuously with fewer steps and less equipment and zero or minimal hold-up volume (e.g., time or intermediate storage). FIG. 10C also illustrates additional equipment that can be used to perform the fed-batch process 1010 and the perfusion process 1020 in the same area (listed under "Storage"). To perform the fed-batch process 1010 and the perfusion process 1020, the manufacturing system 900C can use one additional piece of equipment: a 2000 L disposable mixer ("2 kL SUM") 1004. In contrast, conventional instrument 1000C requires five additional instruments: a 2000 L disposable mixer ("2 kL SUM") 1004, two 1000 L disposable mixers ("1 kL SUM") 1006, one 100 L disposable mixer ("100 L SUM") 1008, and a polishing chromatography kit ("PC") 1012.

[0081] FIG. 11A shows a plot 1100 of absorbance values ​​versus time for each flow channel of an example modular assembly for chromatography. These results can be obtained from a modular assembly 200A such as that shown in FIG. 6A based on data captured by sensors 108A and 108B. FIG. 11B shows a plot 1102 of buffer and sample flow rates versus time for an example modular assembly for chromatography. These results can be obtained from a modular assembly 200A such as that shown in FIG. 6A based on data captured by flow sensor 440B. FIG. 11B also illustrates how modular assembly 200A, operating using two flow channels 460 in parallel, allows for continuous flow of the inlet product stream. It should be understood that the same principles can be applied to operations where flow channels operate in parallel (such as VF or other filtration). FIG. 11C shows a plot 1104 of pH values ​​versus time for each flow channel of an example modular assembly for chromatography. These results can be obtained from modular assembly 200A as shown in FIG. 6A based on data captured by sensors 108A and 108B. FIG. 11D shows a plot 1106 of conductivity values ​​versus time for each flow channel of an example modular assembly for chromatography. These results can be obtained from modular assembly 200A as shown in FIG. 6A based on data captured by sensors 108A and 108B. All of the results in FIGS. 11A-11D demonstrate that the modular assembly can perform continuous processing for chromatography, as expected.

[0082] FIG. 12A shows a plot 1200 of pH values ​​versus time for each flow channel of an example modular assembly for VI. These results can be obtained from a modular assembly 200C, such as that shown in FIG. 6C, based on data captured by sensors 108A-108C. For example, the pH value of the supply line can be obtained using sensor 108C. The low and neutral pH values ​​can be obtained using sensors 108A and 108B. FIG. 12B shows a plot 1202 of flow rate versus time for the supply line and each flow channel of an example modular assembly for VI. These results can be obtained from a modular assembly 200C, such as that shown in FIG. 6C, based on data captured by flow sensor 440B of the supply line and each flow channel. All of the results in FIGS. 12A and 12B demonstrate that the modular assembly can perform continuous processing of VI, as expected.

[0083] FIG. 13A shows a plot 1300 of conductivity values ​​versus time for each flow channel of an example modular assembly for UF / DF. These results can be obtained from modular assembly 200D as shown in FIG. 6D based on data captured by sensors 108A-108B. FIG. 13B shows a plot 1302 of diavolume values ​​versus time for each flow channel of an example modular assembly for UF / DF. These results can be obtained from modular assembly 200D as shown in FIG. 6D based on data captured by diavolume sensor 440C. FIG. 13C shows a plot 1304 of flux values ​​versus time for each flow channel of an example modular assembly for UF / DF. These results can be obtained from modular assembly 200D as shown in FIG. 6D based on data acquired by flow sensor 440B. All of the results in FIGS. 13A-13C demonstrate that the modular assembly is capable of continuous UF / DF processing, as expected.

[0084] In some embodiments, the systems disclosed herein (e.g., universal skid 100, modular assembly 200, manufacturing system 900) are closed systems. Closed systems contain unit operations that are designed and operated to limit exposure to the outside environment. Materials can be introduced into the closed system, but additions must be made in a way that avoids exposure of the product to the indoor environment.

[0085] The systems described herein may also include fluid conduits disposed between the apparatus and the unit operations. Suitable fluid conduits may be polyethylene, polycarbonate, or plastic tubing. The fluid conduits may also include one or more of the following, in any combination: one or more in-line buffer conditioning reservoirs in fluid communication with the fluid conduit and positioned such that buffers stored in the in-line buffer conditioning reservoirs are added to the fluid present in the fluid conduit; and one or more filters disposed within the fluid conduit to filter (e.g., remove bacteria) the fluid present in the fluid conduit.

[0086] In some embodiments, the systems provided herein include a pump system, which may include one or more of the following: one or more pumps known in the art, one or more filters known in the art, and one or more UV detectors.

[0087] It should be understood that the operations and processes described above and illustrated in the figures may be performed or executed in any suitable order desired in various implementations. Additionally, in certain implementations, at least some of the operations may be performed in parallel. Furthermore, in certain implementations, fewer or more operations than those described may be performed.

[0088] In describing the example embodiments, specific terminology is used for the sake of clarity. For purposes of description, each specific term is intended to include all technical and functional equivalents that operate in a similar manner to accomplish at least a similar purpose. In addition, where a particular example embodiment includes multiple system elements, device components, or method steps, those elements, components, or steps may be replaced with a single element, component, or step. Similarly, a single element, component, or step may be replaced with multiple elements, components, or steps that serve the same purpose. Moreover, while example embodiments have been shown and described with reference to specific embodiments thereof, those skilled in the art will recognize that various substitutions and changes in form and detail may be made without departing from the scope of the present disclosure. Moreover, other embodiments, features, and advantages are within the scope of the present disclosure.

Claims

1. 1. A universal skid for processing one or more biological products, comprising: A rigid support; a plurality of flow channel hardware sets attached to the rigid support, each flow channel hardware set configured to couple with a respective one of the plurality of flow channels for one or more unit operations in the production process of the one or more biological products; wherein said plurality of flow channel hardware sets enable continuous processing across said one or more unit operations.

2. 10. The universal skid of claim 1, wherein the plurality of flow channel hardware sets each include at least two of the same type of hardware components and provide hardware support to enable a first flow channel associated with a first processing step of the one or more unit operations and a second flow channel associated with a second processing step of the one or more unit operations, arranged in a parallel or serial configuration.

3. 10. The universal skid of claim 1, wherein the multiple flow channel hardware set enables the multiple flow channels to operate in series for continuous processing across the one or more unit operations.

4. 10. The universal skid of claim 1, wherein the multiple flow channel hardware set enables the multiple flow channels to operate in parallel for sequential processing across the one or more unit operations.

5. 10. The universal skid of claim 1, wherein the multiple flow channel hardware set provides zero or optimized hold-up volume for the one or more unit operations.

6. 10. The universal skid of claim 1, wherein the plurality of flow channel hardware sets reduce average residence time in one or more surge receptacles or the plurality of flow channels used in each disposable kit coupled with the universal skid to facilitate the one or more unit operations.

7. The universal skid of claim 6 , wherein the average residence time in the one or more surge receptacles or the plurality of flow channels is less than about 30 minutes, less than about 60 minutes, or less than about 120 minutes.

8. The universal skid of claim 1 , wherein the plurality of flow channel hardware sets includes a plurality of sensors and a plurality of valves.

9. The universal skid of claim 1 further comprising a plurality of hardware components mounted to the rigid support, the hardware components including one or more pumps, valves, and sensors.

10. 10. The universal skid of claim 1, wherein the one or more unit operations comprise one or more processing steps or one or more system components for performing chromatography, viral inactivation, viral filtration, ultrafiltration, diafiltration, ultrafiltration / diafiltration, formulation, or sterile filtration.

11. 1. A modular assembly for processing one or more biological products, comprising: one or more disposable kits for one or more unit operations of the one or more biological product production processes, the one or more disposable kits including one or more surge receptacles and a plurality of flow channels; a universal skid configured to couple with the one or more disposable kits, a rigid support; and a plurality of flow channel hardware sets attached to the rigid support, each flow channel hardware set configured to couple with a respective one of the plurality of flow channels; Including universal skid and wherein said plurality of flow channel hardware sets enable continuous processing across said unit operations.

12. 12. The modular assembly of claim 11, wherein the plurality of flow channel hardware sets each include at least two of the same type of hardware components and provide hardware support to enable a first flow channel associated with a first processing step of the one or more unit operations and a second flow channel associated with a second processing step of the one or more unit operations, arranged in a parallel or serial configuration.

13. 12. The modular assembly of claim 11, wherein the plurality of flow channel hardware sets enable the plurality of flow channels to operate in series for sequential processing across the one or more unit operations.

14. 12. The modular assembly of claim 11, wherein the multiple flow channel hardware set enables the multiple flow channels to operate in parallel for sequential processing across the one or more unit operations.

15. The modular assembly of claim 11 , wherein the plurality of flow channel hardware sets reduce average residence time in the one or more surge receptacles or the plurality of flow channels.

16. 16. The modular assembly of claim 15, wherein the average residence time in the one or more surge receptacles or the plurality of flow channels is less than about 30 minutes, less than about 60 minutes, or less than about 120 minutes.

17. 12. The modular assembly of claim 11, wherein the unit operation comprises one or more functional steps or one or more system components for performing chromatography, viral inactivation, viral filtration, ultrafiltration, diafiltration, ultrafiltration / diafiltration, formulation, or sterile filtration.

18. 1. A manufacturing system for processing one or more biological products, comprising: A plurality of modular assemblies coupled together, each modular assembly performing one or more unit operations, the plurality of modular assemblies enabling continuous processing within each of the plurality of modular assemblies, continuous processing between the plurality of modular assemblies, continuous processing end-to-end across the plurality of modular assemblies, and fully continuous processing across a plurality of unit operations. each modular assembly including: one or more disposable kits for the one or more unit operations, the one or more disposable kits comprising one or more surge receptacles and a plurality of flow channels; a universal skid configured to couple with the one or more disposable kits, a rigid support; and a plurality of flow channel hardware sets attached to the rigid support, each flow channel hardware set configured to couple with a respective one of the plurality of flow channels; Including universal skid and wherein the plurality of flow channel hardware sets enable continuous processing across the one or more unit operations.

19. 20. The manufacturing system of claim 18, wherein the plurality of flow channel hardware sets each include at least two of the same type of hardware components and provide hardware support for enabling a first flow channel associated with a first processing step of the one or more unit operations and a second flow channel associated with a second processing step of the one or more unit operations, arranged in a parallel or serial configuration.

20. 20. The manufacturing system of claim 18, wherein the plurality of flow channel hardware sets enable the plurality of flow channels to operate in series for continuous processing across the one or more unit operations.

21. 20. The manufacturing system of claim 18, wherein the multiple flow channel hardware set enables the multiple flow channels to operate in parallel for sequential processing across the one or more unit operations.

22. 20. The manufacturing system of claim 18, wherein an output of one modular assembly of the plurality of modular assemblies is coupled to an input of an adjacent modular assembly of the plurality of modular assemblies such that fluid flows continuously and is processed end-to-end across the plurality of modular assemblies.

23. 20. The manufacturing system of claim 18, wherein the plurality of modular assemblies have different scales for holding different liquid volumes for sequential processing.

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