Formulation kits, systems, and methods

Abstract

A formulation system comprising: a housing (12) having an interior space (34); an interface on an exterior surface of the housing for receiving a flow set (200); a first pump (36) for pumping a first fluid from a first source to a mixing chamber; a second pump (38) for pumping a second fluid from a second source to the mixing chamber (226); and one or more valves (44) for selectively controlling flow of the first fluid to the mixing chamber, flow of the second fluid to the mixing chamber, and flow of a mixed fluid from the mixing chamber to a collection vessel (270).

Description

Technical Field

[0001] The embodiments of the present invention generally relate to pharmaceutical formulation systems, and more specifically, to a formulation kit, system, and method for clinical and commercial production of nanoparticle drugs. Background Technology

[0002] Currently, there are large-scale pipelines (sometimes called R&D pipelines) of nanoparticle-based drugs in the fields of gene therapy, protein replacement, oncology indications (including cancer vaccines), and infectious disease vaccines. However, challenges in achieving reproducibility and scalability hinder the ability to bring these formulations to market and make them widely available.

[0003] In view of the above, there is an unmet need for a formulation system and method that maintains consistent quality properties throughout development and scaling up. Summary of the Invention

[0004] The following outlines certain embodiments that are proportionate in scope to the originally claimed subject matter. These embodiments are not intended to limit the scope of the claimed subject matter, but are merely intended to provide a brief overview of feasible embodiments. In fact, this disclosure may cover a variety of forms that may be similar to or different from the embodiments set forth below.

[0005] One aspect of this disclosure is a formulation system comprising: a housing having an internal space and an external surface; a first pump for pumping a first fluid from a first fluid source to a mixing chamber configured to receive the first fluid; a second pump for pumping a second fluid from a second fluid source to a mixing chamber configured to receive the second fluid; a mounting mechanism located on the external surface of the housing for receiving the first and second pumps; and an array of valves for selectively controlling the flow (sometimes referred to as flow rate) of fluids entering the mixing chamber from the first and second pumps to generate a mixed fluid, and for controlling the flow of the mixed fluid from the mixing chamber to a collection container.

[0006] On one hand, the formulation system also includes a third pump for pumping a third fluid from a third fluid source to a point downstream of the mixing chamber or for use in the prime (sometimes called a filling pump) formulation system.

[0007] In one aspect, the formulation system further includes: a first fluid source; a second fluid source; and a third fluid source, wherein the first fluid from the first fluid source comprises nucleic acids and an aqueous solution, wherein the second fluid from the second fluid source comprises a solvent and one or more lipids dissolved therein, and wherein the third fluid from the third fluid source comprises a diluent fluid.

[0008] On one hand, arrayed valves include pinch valves or diaphragm valves.

[0009] On one hand, the installation mechanism includes a first receiving seat for receiving a first pump head and a second receiving seat for receiving a second pump head.

[0010] On one hand, the first receiver and the second receiver each include a removable retaining clip for releasably retaining the first pump head and the second pump head in the first receiver and the second receiver, respectively.

[0011] On one hand, the formulation system also includes a cartridge (sometimes called a box) receiver, wherein the cartridge receiver includes a recess for receiving the mixing chamber.

[0012] On one hand, the formulation system also includes an outer casing located within the internal space, which is configured to receive a supply of compressed air.

[0013] On one hand, the formulation system also includes a venting mechanism, which includes an outlet located on the outer surface of the housing and a filter in fluid communication with the outlet.

[0014] On one hand, the formulation system also includes a control panel that is integrated with the housing and accessible from the outside of the housing.

[0015] In one aspect, the formulation system also includes at least one sensor configured to monitor one or more flow rates, wherein the at least one sensor is mounted within a cable that is movable between a sensing position and a retractable position; and wherein the housing includes a protective recess for receiving the end of the cable in the retractable position.

[0016] On the one hand, the first and second pumps are centrifugal pumps.

[0017] In one respect, the at least one sensor is a flow meter.

[0018] In one respect, the at least one sensor is a Coriolis flow meter.

[0019] On the one hand, the third pump is the peristaltic pump.

[0020] In one aspect, the formulation system also includes a flow kit comprising: a mixing chamber; a first pump head having one or more first inlets and a first outlet, the first pump head configured to engage with a first pump; a second pump head having one or more second inlets and a second outlet, the second pump head configured to engage with a second pump, wherein the mixing chamber includes a first chamber inlet fluidly connected to the first outlet of the first pump head, a second chamber inlet fluidly connected to the second outlet of the second pump head, and a chamber outlet; and a chamber outlet fluidly connected to the mixing chamber and configured for fluid connection to a collection container.

[0021] In one aspect, the formulation system also includes a tube array fluidly connected to a collection tube section, the tube array including a first flow path terminating in a waste outlet and a second flow path configured for fluid connection to at least one sensing device.

[0022] On the one hand, the third pump is installed below the first and second pumps.

[0023] On one hand, the formulation system also includes a calibration flow meter, which is configured to calibrate one or more ultrasonic flow meters.

[0024] One aspect of this disclosure includes a flow kit for a formulation system, comprising: a first pump head having one or more first inlets and a first outlet; a second pump head having one or more second inlets and a second outlet; a mixing chamber having a first chamber inlet fluidly connected to the first outlet of the first pump head, a second chamber inlet fluidly connected to the first outlet of the second pump head, and a chamber outlet; and a tube fluidly connected to the chamber outlet of the mixing chamber and configured as an outflow fluid connection from the mixing chamber to a collection container.

[0025] In one aspect, the flow kit includes: a first flow path formed by a first pump head, a second pump head, a tube, and an outlet fluid connector, and a second flow path including a dilution line and at least one sensing device and connected to the first flow path as an inlet fluid connector.

[0026] In one respect, the at least one sensing device is an ultrasonic flow meter.

[0027] On one hand, the second flow path includes an additional tube connected to the peristaltic pump.

[0028] On one hand, the second flow path includes a third pump head having a third inlet and a third outlet, wherein the third outlet of the third pump head is fluidly connected to the dilution line.

[0029] In one aspect, the flow kit further includes: a first pipe section fluidly connected to one or more first inlets of a first pump head, the first pipe section being configured for fluid connection to a first fluid source; and a second pipe section fluidly connected to one or more second inlets of a second pump head, the second pipe section being configured for fluid connection to a second fluid source.

[0030] In one aspect, the flow kit further includes: a third pipe section fluidly connected to one or more first inlets of a first pump head, the third pipe section being configured for fluid connection to a third fluid source; and a fourth pipe section fluidly connected to one or more second inlets of a second pump head, the fourth pipe section being configured for fluid connection to a fourth fluid source.

[0031] In one aspect, the flow kit also includes a fifth pipe section that is fluidly connected to a third inlet of a third pump head, the fifth pipe section being configured for fluidly connecting to a fifth fluid source.

[0032] On the one hand, a mobile kit is a disposable kit.

[0033] In one aspect, the flow kit also includes a first flow meter located between the first outlet of the first pump head and the inlet of the first chamber; and a second flow meter located between the first outlet of the second pump head and the inlet of the second chamber.

[0034] One aspect of this disclosure includes a formulation method comprising: attaching a flow kit to the outside of a formulation system, the flow kit having a first input line and a second input line, a formulation output line, and a mixing chamber including a first chamber inlet, a second chamber inlet, and a chamber outlet, wherein the first chamber inlet and the second chamber inlet are fluidly connected to the first input line and the second input line, and the chamber outlet is connected to the formulation output line; attaching a first fluid-containing source and a second fluid-containing source accordingly to the first input line and the second input line; attaching a collection container to the formulation output line; activating a first pump and a second pump to pump fluid from the first fluid-containing source and the second fluid-containing source into the mixing chamber to form a mixed fluid within the mixing chamber; and discharging a flow of the mixed fluid from the mixing chamber via the formulation output line into the collection container.

[0035] In one aspect, the formulation method further includes: a first input line, a second input line, and / or a formulation output line of a perfusion flow kit; and at least one flow meter calibrated and operatively connected to the first input line, the second input line, and / or the formulation output line.

[0036] On one hand, the first input line, the second input line, and / or the formulation output line of the perfusion flow kit are executed using a peristaltic pump.

[0037] On one hand, the first input line, second input line, or formulation output line of the perfusion flow kit includes switching one or more valves.

[0038] On one hand, the formulation method also includes purging flammable gases from the internal space of the formulation system before starting the first and second pumps.

[0039] On one hand, purging involves supplying compressed air to an outer enclosure within the interior space, which isolates any components that could generate sparks.

[0040] On the one hand, purging is automatically initiated before the first and second pumps are started, and / or purging is initiated after startup and when the pressure in the internal space is detected to drop below a threshold pressure.

[0041] On the one hand, the pumped fluid flow rate is approximately 6 to approximately 48 L / h.

[0042] On one hand, formulations are entered via a user interface, and these formulations are used to infuse and calibrate the formulation system.

[0043] On one hand, infusion involves setting one or more flow meters to the viscosity defined in the formulation.

[0044] On one hand, calibration includes running the first and second pumps at a predetermined flow rate specified in the formulation.

[0045] On the one hand, the output continues until the predetermined formulation volume is output.

[0046] On one hand, the formulation method includes opening one or more valves once a predetermined formulation volume is output via a formulation output line.

[0047] On one hand, the formulation method includes using an identifier associated with the flow kit to validate the flow kit.

[0048] On one hand, formulation methods include verifying whether the flow kit is compatible with the formulation.

[0049] On one hand, the formulation method includes pumping a buffer solution through a buffer line to dilute the mixed fluid output leaving the mixing chamber.

[0050] In one aspect, the formulation method includes flushing the first input line, second input line, and / or formulation output line of the flow kit after perfusing the first input line, second input line, and / or formulation output line of the flow kit. Attached Figure Description

[0051] The invention will be better understood by reading the following description of non-limiting embodiments with reference to the accompanying drawings, wherein: Figure 1 This is a first front elevation view of an exemplary formulation system with an exemplary flow kit installed.

[0052] Figure 2 yes Figure 1 A front perspective view of an exemplary formulation system.

[0053] Figure 3 yes Figure 1 Rear elevation view of an exemplary formulation system.

[0054] Figure 4 yes Figure 1 A second elevation view of an exemplary formulation system, depicted as without the exemplary flow kit installed.

[0055] Figure 5 yes Figure 4 A side elevation view of an exemplary formulation system.

[0056] Figure 6 yes Figure 1 A frontal transparent perspective view of a portion of an exemplary formulation system.

[0057] Figure 7 yes Figure 1 An exploded view of an exemplary valve in an exemplary formulation system.

[0058] Figure 8 yes Figure 7 A perspective view of the housing of an exemplary valve, depicting a safety lock in the open position.

[0059] Figure 9 yes Figure 7 A perspective view of the housing of an exemplary valve, depicting a safety lock in the closed / locked position.

[0060] Figure 10 yes Figure 1 An exploded view of an exemplary pump assembly of an exemplary formulation system.

[0061] Figure 11A This is an enlarged perspective view of an exemplary mounting mechanism for an exemplary pump assembly.

[0062] Figure 11B yes Figure 10 A perspective view of an exemplary locking mechanism of an exemplary pump assembly.

[0063] Figure 12A yes Figure 1 Enlarged perspective view of exemplary flow meters and exemplary flow sensors for exemplary formulation systems.

[0064] Figure 12B yes Figure 1 A second magnified perspective view of an exemplary flow meter and an exemplary flow sensor for an exemplary formulation system.

[0065] Figure 13 yes Figure 12A and 12B Enlarged perspective view of the cable holding / retracting port of the exemplary flow meter and exemplary flow sensor.

[0066] Figure 14 yes Figure 1 An enlarged perspective view of an exemplary venting mechanism of a formulation system.

[0067] Figure 15 yes Figure 1 A partial cross-sectional perspective view of an exemplary formulation system, including an exemplary purge chamber within the exemplary formulation system.

[0068] Figure 16 yes Figure 1A rear-view perspective view of the interior of an exemplary formulation system, including Figure 15 An exemplary purge box.

[0069] Figure 17 yes Figure 1 A detailed perspective view of an exemplary purge chamber of an exemplary formulation system, including Figure 15 An exemplary purge box.

[0070] Figure 18 Is with Figure 1 A perspective view of an exemplary flow kit used in conjunction with a formulation system.

[0071] Figure 19 yes Figure 18 An enlarged perspective view of a portion of an exemplary flow kit.

[0072] Figure 20 yes Figure 1 A schematic diagram of an exemplary formulation system.

[0073] Figure 21 It is used for depiction Figure 1 An exemplary graph illustrating the improved flow rate achieved by an exemplary formulation system.

[0074] Figure 22 It shows that it can be used Figure 1 A flowchart illustrating exemplary steps for preparing a product using an exemplary formulation system. Detailed Implementation

[0075] I. Introduction In one embodiment, a formulation system is provided. The formulation system includes: a housing having an internal space containing electrical, electromechanical, and mechanical components; and a purged and pressurized outer casing for housing non-Hazloc-rated (sometimes referred to as non-explosion-proof certified) electrical components; an interface located on the outer surface of the housing for receiving a flow kit; a first pump for pumping a first fluid from a first source bag to a mixing chamber; a second pump for pumping a second fluid from a second source bag to a mixing chamber; and an array of pinch valves for selectively controlling the flow of the first fluid to the mixing chamber, the flow of the second fluid to the mixing chamber, and the flow of the mixed fluid from the mixing chamber to a collection container.

[0076] In another embodiment, a flow kit for a formulation system is provided. The flow kit includes: a first pump head having a first inlet and an outlet; a second pump head having a first inlet and an outlet; a mixing chamber having a first inlet fluidly connected to the outlet of the first pump head, a second inlet fluidly connected to the outlet of the second pump head, and an outlet; and a collection tube section fluidly connected to the outlet of the mixing chamber and configured for fluid connection to a collection container.

[0077] In yet another embodiment, a formulation method includes: attaching a flow kit to the exterior of a formulation system housing, the flow kit having at least first and second fluid flow lines, a collection flow line, and a mixing chamber fluidly connected to the first and second fluid flow lines and the collection flow line. The method further includes: attaching first and second fluid-containing vessels to the first and second fluid flow lines respectively, and attaching a collection container to the collection flow line. The method further includes: activating a first centrifugal pump operatively connected to the first fluid flow line and a second centrifugal pump operatively connected to the second fluid flow line to pump fluid from the first and second fluid-containing vessels into the mixing chamber of the flow kit for mixing, and then collecting the mixed fluid flow in the collection container.

[0078] In some examples, the formulation system advantageously provides a formulation system including single-use and disposable tubes or tube arrays to ensure controlled and properly sterilized formulations. In some aspects, the formulation system may include a flow kit comprising tubes, a pump head, and a mixing chamber or cylinder for single-use and disposal to ensure formulation sterilization, and the flow kit can be easily installed each time a new formulation or batch is run.

[0079] This formulation system provides an efficient method for installing tubing, pump heads, and mixing chambers or cylinders when setting up and running different formulations. The flow kit provides disposable, arrayed tubing, pump heads, and cylinders that can be quickly validated to ensure the correct flow kit is being used for a selected formulation, and can be efficiently replaced as a self-contained unit containing the tubing, pump heads, and cylinders required to deliver new formulations.

[0080] This formulation system provides a highly efficient array of pumps for precise flow rate control when delivering formulations based on formulation specifications. The flow kit offers discardable and / or replaceable tubing, pump heads, and mixing chambers, which, once installed on the formulation system, can be used for perfusion, calibration, and batch creation without requiring additional installation for each of the perfusion, calibration, and / or batch creation processes.

[0081] II. Definition The following description will refer in detail to exemplary embodiments of the invention, examples of which are shown in the accompanying drawings. Where possible, the same reference numerals used in all figures refer to the same or similar parts.

[0082] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the methods described herein pertain. Unless otherwise stated, any reference to standard methods refers to the most recent version of the method available at the time of this disclosure.

[0083] For any method disclosed herein that includes discrete steps, these steps can be performed in any feasible order. Furthermore, appropriately, any combination of two or more steps can be performed simultaneously.

[0084] All headings are for the reader's convenience and should not limit the meaning of the text following them, unless otherwise specified.

[0085] The terms "preferred" and "ideally" refer to embodiments of the invention that provide specific benefits under particular circumstances. However, other embodiments may also be preferred under the same or different circumstances. Furthermore, listing one or more preferred embodiments does not imply that other embodiments are useless, and is not intended to exclude other embodiments from the scope of the invention.

[0086] The term "comprising" and its variations are not restrictive in the places where these terms appear in the specification and claims. Such terms are to be understood as including the stated steps, elements, or groups of steps or elements, but not excluding any other steps, elements, or groups of steps or elements.

[0087] "Comprising of..." means including and limited to anything that follows the phrase "comprising of...". Therefore, the phrase "comprising of..." indicates that the listed elements are necessary or mandatory, and no other elements may exist. "Substantially comprising..." means including any elements listed following this phrase, and is limited to other elements that do not interfere with or contribute to the activities or functions specified for the listed elements in this disclosure. Therefore, the phrase "substantially comprising..." indicates that the listed elements are necessary or mandatory, but other elements are optional and may or may not exist depending on whether they substantially affect the activities or functions of the listed elements.

[0088] The singular forms “a,” “a,” and “the” include plural references unless the context explicitly specifies otherwise. These articles refer to one or more (i.e., at least one). As used herein, unless the context explicitly specifies otherwise, the term “or” is used generally in its usual meaning, including “and / or.” The term “and / or” means any one or more items in a list linked by “and / or.” As an example, “x and / or y” means any element in the three-element set {(x),(y),(x,y)}. In other words, “x and / or y” means “one or both of x and y.” As another example, “x, y, and / or z” means any element in the seven-element set {(x),(y),(z),(x,y),(x,z),(y,z),(x,y,z)}. In other words, “x, y, and / or z” means “one or more of x, y, and z.”

[0089] When a range is given, the endpoints include all numbers covered within that range (e.g., 1 to 5 includes 1, 1.5, 2, 2.75, 3, 3.80, 4, 5, etc.). Furthermore, unless otherwise stated or otherwise apparent from the context and understanding of one of ordinary skill in the art, in the various embodiments disclosed, numerical values ​​represented as ranges may represent any specific value or subrange within the range, accurate to one-tenth of a unit of the lower limit of the range, unless the context explicitly specifies otherwise. Hereinafter, “up to” a number (e.g., up to 50) includes that number (e.g., 50). The terms “in the range” or “within the range” (and similar expressions) include the endpoints of the range.

[0090] Throughout this specification, references to "an aspect," "one aspect," "certain aspects," or "some aspects," etc., indicate that a particular feature, construction, composition, or characteristic described in connection with that aspect is included in at least one aspect of this disclosure. Therefore, such phrases appearing throughout this specification do not necessarily refer to the same embodiment of this disclosure. Furthermore, a particular feature, construction, composition, or characteristic may be combined in any suitable manner in one or more aspects.

[0091] Unless otherwise stated, all figures representing amounts of components, molecular weights, etc., used in the specification and claims should in all cases be understood to be modified by the term "about". As used herein, in relation to a measured quantity, the term "about" refers to a variation in the measured quantity as would be expected by a skilled person performing the measurement and employing a level of caution commensurate with the accuracy of the measured object and the measuring equipment used. The term "about," used throughout the specification and claims in conjunction with numerical values, indicates a range of accuracy familiar and acceptable to those skilled in the art. Generally, this range of accuracy is + / - 10%. Therefore, unless explicitly indicated otherwise, the numerical parameters set forth in the specification and claims are approximate values ​​that may vary depending on the desired characteristics sought to be obtained by the invention. At least, and without attempting to limit the doctrine of equivalence to the scope of the claims, each numerical parameter should be interpreted at least according to the number of significant figures reported and by applying conventional rounding techniques.

[0092] Although the numerical ranges and parameters illustrating the broad scope of the invention are approximations, the values ​​described in the specific examples are reported as precisely as possible. However, all values ​​inherently include the range necessarily caused by standard deviation found in their respective test measurements.

[0093] The term “exemplary” means used as a non-limiting example, instance, or illustration. As used herein, the terms “for example” and “for instance” highlight a list of one or more non-limiting aspects, examples, instances, or illustrations.

[0094] As used herein, the term "substantially" refers to a qualitative state exhibiting all or nearly all of the features or properties of interest in terms of scope or degree. Biological and chemical phenomena rarely (if ever) proceed to completion and / or continue to completion, or achieve or avoid absolute results. Therefore, the term "substantially" is used herein to encompass the potential incompleteness inherent in many biological and chemical phenomena. For example, "substantially" may mean at least about 20%, alternatively at least about 10%, or alternatively at least about 5% of the features or properties of interest.

[0095] As used herein, “fluid connection” or “fluid connectivity” means that components of a system are able to receive or transfer fluid between components. The term fluid includes gases, liquids, or combinations thereof. As used herein, “electrical communication” or “electrical connection” means that certain components are configured to communicate with each other by direct or indirect signaling via a direct or indirect electrical connection. As used herein, “operationally connected” refers to a connection, which can be direct or indirect. This connection is not necessarily a mechanical attachment.

[0096] As used herein, the term “microfluidic” refers to a system or apparatus for manipulating (e.g., flowing, mixing, etc.) a fluid sample, which includes at least one channel having a micrometer-scale size (i.e., a size less than 1 millimeter).

[0097] As used herein, the term "therapeutic material" is defined as a substance intended to provide pharmacological activity or otherwise have a direct effect in the diagnosis, cure, relief, understanding, treatment, or prevention of disease, or in the restoration, correction, or modification of physiological function. Therapeutic materials include, but are not limited to, small molecule drugs, nucleic acids, proteins, peptides, polysaccharides, inorganic ions, and radionuclides.

[0098] As used herein, the term "nanoparticle" is defined as a particle comprising more than one component material (e.g., lipids, polymers, etc.) used to encapsulate therapeutic materials and having a minimum size of less than 250 nanometers. Nanoparticles include, but are not limited to, lipid nanoparticles and polymer nanoparticles.

[0099] The invention is defined in the claims. However, the following is a non-exhaustive list of non-limiting exemplary aspects. Any one or more features of these aspects may be combined with one or more features of another example, embodiment, or aspect described herein.

[0100] III. Formulation Systems and Methods Embodiments of the present invention provide formulation systems and methods. In some aspects, the formulation systems and methods can be used to combine lipid nanoparticle compositions and nucleic acids.

[0101] Lipid nanoparticles (LNPs) are delivery systems primarily used to encapsulate and transport molecules, such as nucleic acids, drugs, or vaccines, into target cells. Composed of biocompatible lipids, LNPs are engineered to protect their cargo from degradation, improve stability, and enhance cellular uptake. LNPs are particularly prominent in mRNA-based therapies, including COVID-19 vaccines, where they play a crucial role in delivering genetic material into cells to generate the desired immune response. Their versatility, ability to evade the immune system, and capacity for controlled release make them an important tool in modern nanomedicine.

[0102] In some embodiments, the LNPs or lipid nanoparticle composition comprises a core and a shell surrounding the core, wherein the shell contains phospholipids. In one embodiment, the core comprises lipids (e.g., fatty acid triglycerides) and is solid. In another embodiment, the core is liquid (e.g., aqueous) and the particle is a vesicle, such as a liposome. In one embodiment, the shell surrounding the core is a monolayer. In one embodiment, the lipid core comprises fatty acid triglycerides. Suitable fatty acid triglycerides include C8-C20 fatty acid triglycerides. In one embodiment, the fatty acid triglyceride is oleic acid triglyceride. The lipid nanoparticle comprises a shell containing phospholipids surrounding the core. Suitable phospholipids include diacylphosphatidylcholine, diacylphosphatidylethanolamine, ceramides, sphingomyelin, dihydrosphingomyelin, cephalin, and cerebrosides. In one embodiment, the phospholipid is C8-C20 fatty acid diacylphosphatidylcholine. A representative phospholipid is 1-palmitoyl-2-oleoylphosphatidylcholine (POPC). In some embodiments, the ratio of phospholipids to fatty acid triglycerides is from 20:80 (mol:mol) to 60:40 (mol:mol). Preferably, the triglycerides are present at a ratio greater than 40% and less than 80%. In some embodiments, the nanoparticles also contain sterols. Representative sterols include cholesterol. In one embodiment, the ratio of phospholipids to cholesterol is 55:45 (mol:mol). In a representative embodiment, the nanoparticles contain 55-100% POPC and up to 10 mol% PEG-lipids.

[0103] In other embodiments, the lipid nanoparticles of this disclosure may comprise one or more other lipids (including phosphoglycerides), representative examples of which include phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, phosphatidylinositol, phosphatidic acid, palmitoyl oleoyl phosphatidylcholine, lysophosphatidylcholine, lysophosphatidylethanolamine, dipalmitoyl phosphatidylcholine, dioleoyl phosphatidylcholine, distearate phosphatidylcholine, and dilinoleoyl phosphatidylcholine. Other phosphorus-deficient compounds, such as sphingolipids and glycosphingolipids, are available. Triglycerides are also available. Representative nanoparticles of this disclosure have a diameter of about 10 to about 100 nm. The lower limit of the diameter is about 10 to about 15 nm. The limiting size lipid nanoparticles of this disclosure may comprise one or more low molecular weight compounds used as therapeutic and / or diagnostic agents. These agents are typically contained within the particle core. The nanoparticles of this disclosure may comprise a wide variety of therapeutic and / or diagnostic agents. Suitable low molecular weight compound agents include chemotherapeutic agents (i.e., antitumor agents), anesthetics, beta-adrenergic blockers, antihypertensive agents, antidepressants, anticonvulsants, antiemetics, antihistamines, antiarrhythmics, and antimalarial agents. Representative antitumor agents include doxorubicin, daunorubicin, mitomycin, bleomycin, streptozotocin, vincristine, vinblastine, nitrogen mustard, hydrochloride, melphalan, cyclophosphamide, triethylene thiophosphamide, carmustine, lomustine, semustine, fluorouracil, hydroxyurea, thioguanine, cytarabine, fluorouridine, dacarbazine, cisplatin, procarbazine, vinorelbine, ciprofloxacin, norfloxacin, paclitaxel, docetaxel, etoposide, bexarotin, teniposide, retinoic acid, isotretinoin, sirolimus, fulvestrant, penoxuridine, vindesine, leucovorin, irinotecan, capecitabine, gemcitabine, mitoxantrone hydrochloride, oxaliplatin, doxorubicin, methotrexate, carboplatin, estradiol, and pharmaceutically acceptable salts thereof. In another embodiment, the lipid nanoparticles are nucleic acid-lipid nanoparticles. The term "nucleic acid-lipid nanoparticles" refers to lipid nanoparticles containing nucleic acids. These lipid nanoparticles comprise one or more cationic lipids, one or more secondary lipids, and one or more nucleic acids.

[0104] In some embodiments, the lipid nanoparticle composition and nucleic acid are combined by mixing. In some embodiments, mixing is performed using a microfluidic mixer (such as a mixing chamber or cylinder as described below). In some embodiments, a first reagent source and a second reagent source are fed into the microfluidic mixer, and the lipid nanoparticles are collected from the outlet of the microfluidic mixer.

[0105] In some embodiments, the first source comprises a payload in a first solvent. In some embodiments, the payload may comprise nucleic acids. In some cases, the payload may comprise a therapeutic agent. The combination of payloads in the first solvent can be described as an aqueous phase. Any suitable first solvent can be used. Suitable first solvents include those in which the payload is soluble and miscible with a second solvent. In some embodiments, the first solvent comprises an aqueous buffer. In some embodiments, the aqueous buffer comprises a low-pH buffer. In some embodiments, the low-pH buffer comprises a citrate or acetate buffer.

[0106] In some embodiments, the second source comprises an example of a lipid nanoparticle composition as described herein in a second solvent. The combination of the lipid nanoparticle composition and the second solvent can be described as an organic phase. Any suitable second solvent can be used. Suitable second solvents include solvents in which the ionizable lipids according to embodiments of the invention are soluble and miscible with the first solvent. In some embodiments, the second solvent comprises one or more solvents, two or more solvents, three or more solvents, or four or more solvents. In some embodiments, the second solvent includes, but is not limited to, 1,4-dioxane, tetrahydrofuran, acetone, acetonitrile, dimethyl sulfoxide, dimethylformamide, acids, alcohols, or combinations thereof. In some embodiments, the second solvent comprises anhydrous or anhydrous alcohols. In some cases, the alcohol comprises primary, secondary, or tertiary alcohols (e.g., methanol, ethanol, n-propanol, isopropanol, n-butanol, 2-methyl-1-propanol, 2-butanol, 2-methylprop-2-ol) or combinations thereof having 1 to 12 branched or unbranched carbon atoms.

[0107] In some embodiments, a suitable device for mixing is a cylindrical body comprising one or more microchannels (i.e., channels with a maximum size of less than 1 mm). In some embodiments, the microchannels have a diameter of about 20 μm to about 300 μm. In some embodiments, at least one region of the microchannel has a main flow direction and one or more surfaces having at least one groove or protrusion defined therein, the groove or protrusion having an orientation forming an angle with the main flow direction (e.g., an interlaced herringbone mixer) or a bifurcated annular flow mixer. To obtain the maximum mixing rate, it is advantageous to avoid undue fluid resistance before the mixing region. In some embodiments, the device has non-microfluidic channels with a size greater than 1000 μm to deliver fluid to a single mixing channel.

[0108] Lipid nanoparticle compositions and nucleic acids can be combined using any suitable flow ratio. In some embodiments, the lipid nanoparticle compositions and nucleic acids are combined at a volumetric flow ratio (aqueous phase: organic phase) of about 1:1 (or 1) to about 10:1 (or 10), for example, about 1, about 2, about 3, about 4, about 5, about 6, or about 7, about 8, about 9, about 10, or a flow ratio defined by any range of two of the aforementioned values. In some cases, the flow ratio is greater than about 0.5. In some cases, the flow ratio is less than about 20, less than about 18, less than about 16, less than about 14, less than about 12, less than about 10, or less than about 8. Lipid nanoparticle compositions and nucleic acids can be combined using any suitable N / P ratio. The N / P ratio is the ratio of positively charged polymeric amine (N = nitrogen) groups to negatively charged nucleic acid phosphate (P) groups. In some embodiments, the lipid nanoparticle composition and nucleic acid are combined at an N / P ratio of about 2 to about 20, for example, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, or about 20, or at an N / P ratio defined by a range of any two of the aforementioned values. In some cases, the N / P ratio is greater than about 1, greater than about 2, greater than about 3, greater than about 4, greater than about 5, greater than about 6, greater than about 7, greater than about 8, or greater than about 9. In some cases, the N / P ratio is less than about 40, less than about 38, less than about 36, less than about 34, less than about 32, less than about 30, less than about 28, less than about 26, less than about 24, less than about 22, less than about 20, less than about 18, less than about 16, less than about 14, less than about 12, or less than about 10. Lipid nanoparticle compositions and nucleic acids can be combined using any suitable total flow rate.In some embodiments, the lipid nanoparticle composition and nucleic acid are combined at a total flow rate of about 2 to about 2000 mL / min between the organic phase and the aqueous phase, for example, about 2 mL / min, about 4 mL / min, about 6 mL / min, about 8 mL / min, about 10 mL / min, about 20 mL / min, about 40 mL / min, about 60 mL / min, about 80 mL / min, or about 100 mL / min, about 120 mL / min, about 140 mL / min, about 160 mL / min, about 180 mL / min, about 200 mL / min, about 220 mL / min, about 240 mL / min, about 260 mL / min, about 280 mL / min, about 300 mL / min, about 350 mL / min, about 400 mL / min. n, approximately 450 mL / min, or approximately 500 mL / min, approximately 550 mL / min, approximately 600 mL / min, approximately 650 mL / min, approximately 700 mL / min, approximately 750 mL / min, approximately 800 mL / min, approximately 850 mL / min, or approximately 900 mL / min, approximately 950 mL / min, approximately 1000 mL / min, approximately 1100 mL / min, approximately 1200 mL / min, approximately 1300 mL / min, approximately 1400 mL / min, approximately 1500 mL / min, approximately 1600 mL / min, approximately 1700 mL / min, approximately 1800 mL / min, approximately 1900 mL / min, approximately 2000 mL / min, or a combination of total flow rates defined by any two of the aforementioned values. In some cases, the total flow rate is greater than approximately 1 mL / min, 2 mL / min, 4 mL / min, 6 mL / min, 8 mL / min, 10 mL / min, 20 mL / min, or 40 mL / min. In other cases, the total flow rate is less than approximately 3000 mL / min, less than approximately 2800 mL / min, less than approximately 2600 mL / min, less than approximately 2400 mL / min, less than approximately 2200 mL / min, less than approximately 2100 mL / min, less than approximately 2000 mL / min, less than approximately 1800 mL / min, less than approximately 1600 mL / min, less than approximately 1500 mL / min, less than approximately 1400 mL / min, less than approximately 1200 mL / min, less than approximately 1000 mL / min, or less than approximately 800 mL / min.

[0109] The formulation system described below can be used to combine lipid nanoparticle compositions and nucleic acids, and may include a housing, a first pump for pumping a first fluid from a first source to a mixing chamber or cylinder, a second pump for pumping a second fluid from a second source to a mixing chamber or cylinder, and an array of valves for selectively controlling the flow of the first fluid to the cylinder, the flow of the second fluid to the mixing chamber, and the flow of the mixed fluid from the mixing chamber to a collection container. The formulation system may include a flow kit having: a first pump head having a first inlet and an outlet, a second pump head having a first inlet and an outlet, a mixing chamber having a first inlet fluidly connected to the outlet of the first pump head, a second inlet fluidly connected to the outlet of the second pump head, and an outlet, and an outlet fluidly connected to the cylinder and a collection tube section configured for fluidly connecting to a collection container. In one embodiment, the formulation system and flow kit are configured for the clinical and commercial production of nanoparticle drugs as described above.

[0110] Figure 1 This is a front elevation view of an exemplary formulation system according to an embodiment of the present invention, in which an exemplary flow kit is installed. Figure 2 yes Figure 1 A front perspective view of an exemplary formulation system. Figure 3 yes Figure 1 The following is a rear elevation view of an exemplary formulation system. As shown therein, the formulation system 10 includes a generally rectangular housing 12. The housing 12 may include a flow kit 200 mounted thereon.

[0111] The formulation system 10 includes various formulation units, including pumps 36, 38, and 40, a retaining clamp 42 for the pumps, valves 44, 46, 48, 50, and 52, a flowmeter housing 54, and a flowmeter cable 55. Valves may include an inlet valve 44, an outlet valve 46, a waste valve 48, a calibration valve 50, and one or more control valves 52. In some examples, the formulation unit includes containers such as fluid sources 260, 262, 264, and 268, and / or a collection container 270. The formulation system 10 is provided with a piping network that provides fluid communication between the formulation units, including one or more pumps 36, 38, 40, 60, and 64, retaining clamps 42, valves 44, 46, 48, 50, and 52, a flowmeter housing 54, etc. In some examples, the piping may be arranged in an array between one or more formulation units. The piping may extend between the formulation units as a separate entity or line, but may also be connected to one or more of the formulation units. The tubing may be disposable / replaceable and may be connected to the formulation unit via a connector that provides tool-free operation. The tubing may be of a standardized inner diameter, such that a specific length will accommodate a predictable volume. The tubing may be included as part of the formulation system 10, the flow kit 200, and / or may be supplied separately. Throughout the specification, the tubing may be referred to as, for example, a tube, a tube segment, a line, etc.

[0112] The housing 12 can be supported on a plurality of support legs 13 in an elevated position above the ground. In some examples, the support legs 13 are equipped with casters 14. In one embodiment, the support legs 13 are adjustable to allow the housing 12 to be leveled on a surface. The housing 12 has a front 16 to which operating members can be attached, as discussed in detail below; opposing side walls 18, 20; and a rear 22 having an access door (sometimes called a maintenance door) 24 allowing selective access to the interior space 34 of the housing 12. The front 16 of the housing 12 includes a drip tray 26, which may take the form of a protrusion extending forward from the front 16 of the housing 12. The housing 12 may include a plurality of handles 28, 30 to facilitate the movement and positioning of the system 10. Figure 4 As best shown in the diagram, the top wall 31 of the housing 12 may include a venting mechanism 32 that provides fluid communication between the interior space 34 of the housing 12 and the surrounding environment (in which the system 10 is positioned).

[0113] Figure 4 yes Figure 1 Another front elevation view of the exemplary formulation system is depicted without the exemplary flow kit 200. In one embodiment, system 10 includes pumps 36, 38, 40, which may be an array of pumps mounted on the lower portion of front panel 16. In some examples, the array of pumps includes three pumps: a first pump 36, a second pump 38, and a third pump 40, but more or fewer pumps may be provided depending on the amount of fluid to be mixed and the specific product formulation / application. Positioning the first, second, and third pumps 36, 38, 40 on the lower portion of front panel 16 facilitates the infusion of pumps 36, 38, 40, as discussed below. In some examples, the array of pumps 36, 38, 40 is removable. In some examples, by way of non-limiting example, pumps 36, 38, 40 are centrifugal pumps, piston pumps, gear pumps, diaphragm pumps, peristaltic pumps, vane pumps, disc pumps, positive displacement pumps (sometimes called positive displacement pumps), magnetically driven pumps, or other similar pumps, or combinations thereof. For example, pumps 36, 38, and 40 can be magnetically driven centrifugal pumps. The first pump 36, the second pump 38, and the third pump 40 are used to pump the input fluid through the flow kit 200, as described below. Figure 18 As detailed, and each is independently controlled.

[0114] The first, second, and third pumps 36, 38, and 40 each include a retaining clip 42, thereby providing a releasable engagement of the pump head of the flow kit with each pump 36, 38, and 40, as discussed in detail below. System 10 also includes a plurality of valves, which may be an array of input valves 44 (e.g., three input valves corresponding to each of the first, second, and third pumps 36, 38, and 40), output valves 46 (e.g., two output valves), a waste valve 48, and a calibration valve 50. In some examples, a control valve 52 is provided adjacent to one of the input valves, the purpose of which will be described below, and it may be a valve similar to the valves described above. In some examples, the input valves 44, 46, 48, calibration valve 50, and control valve 52 may be ball valves, diaphragm valves, needle valves, pinch valves, or similar types of throttling valves and / or control valves. In embodiments where the valve is a pinch valve, the pinch valve may be a pneumatic pinch valve, a hydraulic pinch valve, and / or a solenoid pinch valve, or any other similar type of pinch valve may be used without departing from the scope of the invention. In some examples, the system may include fewer or additional valves than those described herein.

[0115] In some examples, three input valves 44 may be provided, each of which is fluidly connected to input lines 214, 216, 218, as shown below for example. Figure 18 As disclosed. The third input line 218 may be a dilution line 218. These input valves 44 prevent unwanted forward or backward flow through system 10. Also as discussed above, two output valves 46 are used to direct fluid to waste container 272 or formulation collection container 270 (see, for example...). Figure 20 Waste valve 48 and calibration valve 50 respectively direct fluid to the waste outlet line or calibration flow meter 64 during filling and calibration.

[0116] Control valve 52 may be configured as a pinch valve and engages with a tube connected to a third pump head 206 of flow kit 200. In one embodiment, control valve 52 may include a rotatable knob that can be manually rotated to selectively allow or restrict / block fluid flow through the tube engaged with control valve 52. Control valve 52 provides additional flow resistance to a third input line 218 (e.g., a dilution line) during calibration and formulation procedures. This additional flow resistance may compensate for differences between the height and / or positioning of the inlet and outlet containers. User interface 66 may prompt the user to adjust control valve 52 during calibration unit procedures. In some examples, when turned clockwise, control valve 52 may further restrict flow through the line; when turned counterclockwise, control valve 52 may allow more fluid to flow through the line.

[0117] As further shown therein, between the first, second, and third pumps 36, 38, 40 and the inlet valve 44 are three flowmeter housings 54, corresponding to each of the first pump 36, the second pump 38, and the third pump 40. Each flowmeter housing 54 is configured to receive one or more flowmeters (e.g., 208, 210, 212) of the flow kit 200 and has an associated flowmeter cable 55 with a sensor, the purpose of which will be described below. Hooks or posts 58 may be provided near the flowmeter housings 54 so that the caps of the flowmeter housings 54 can be placed or stored during the installation or replacement of the flow kit 200. The formulation system 10 additionally includes a barrel receiver 56 having a recess for receiving the microfluidic mixing chamber or barrel 226 of the flow kit 200.

[0118] like Figure 4 As shown, the arrayed first, second, and third pumps 36, 38, and 40, flowmeter housing 54, inlet valve 44, cylinder receiver 56, and outlet valve 46 are arranged approximately linearly at an upward angle on the front side 16 of housing 12. The first, second, and third pumps 36, 38, and 40 are positioned below the inlet fluid level of system 10 and / or below the cylinder receiver 56 to support priming and allow for air bubble removal. Near waste valve 48 and calibration valve 50 are pump 60, pipe support 62, and calibration flowmeter 64. Pump 60 can be a peristaltic pump, diaphragm pump, syringe pump, gear pump, rotary vane pump, microfluidic pump, centrifugal pump, piston pump, or microfluidic pump that allows for pipe / line priming, as discussed below. In some examples, pump 60 is a peristaltic pump 60. The calibration flow meter 64 can be a Coriolis flow meter, ultrasonic flow meter, electromagnetic flow meter, thermal mass flow meter, volumetric flow meter, or turbine flow meter, but other types of pumps and / or flow meters can be used.

[0119] The formulation system 10 may include a controller (not shown), which may include memory and a processing unit (not shown). As a non-limiting example, the processing unit may be an integrated central processing unit, a standalone computer, a laptop computer, a tablet computer, etc. The processing unit may include software for controlling the user interface 66, including routines required for performing measurements or production, user guides, or software for setting up the system, maintaining the system, storing and analyzing data, perfusion, calibration, purging, etc.

[0120] The formulation system 10 may also include a user interface 66, such as a touchscreen interface, for presenting data and system information in conjunction with memory and processing units, and for controlling system operation based on various user-selectable input parameters and sets of pre-programmed instructions stored in memory and / or processing units. In one embodiment, the user interface 66 includes one or more status indicator lights 68 and an emergency stop button or switch 70. As discussed below, the user interface 66 allows for the creation of formulations and batches, provides system monitoring, and / or other operations as described above.

[0121] Now go to Figure 5 (It is) Figure 4 The exemplary formulation system (side elevation view) shows that the sidewall 18 of the housing 12 includes a pneumatic connection port 72 for connecting an external compressed air supply (not shown) to the system 10, a power cable 74 for connecting the system 10 to an electrical power supply, and a network connection port 76 (e.g., an Ethernet port) for connecting the system to the Internet or a local area network. Although Figure 5 Wired connections are shown, but other communication methods known in the art, such as Wi-Fi, cellular networks, Bluetooth, etc., can also be used to communicate with System 10. As shown, power cable 74 is electrically connected to power switch box 78 with power switch 80, enabling the user to supply or cut off power to System 10 as desired. As will be understood, internal connections and wiring are provided to transmit electrical power from external (offboard, sometimes referred to as off-board) power supply via power cable 74 to various electrical components of System 10 that require power to operate (e.g., pumps, user interfaces, etc.). Similarly, internal connections and hoses / pipes are provided to supply compressed air from external air supply via pneumatic connection port 72 to various components of System 10 that require an air source to operate (e.g., pneumatic pinch valves, purge boxes, etc.).

[0122] Figure 6 yes Figure 1 A front-view transparent perspective view of a portion of an exemplary formulation system, showing the routing of pneumatic conduits for supplying air from an air supply to a valve. As also shown therein, the inner wall of housing 12 has a programmable logic controller panel 82 mounted thereon, on which the control hardware, circuitry, power supply, etc., of system 10 are mounted.

[0123] In some embodiments, the housing 12 is made of a rigid, sterilizable material, such as stainless steel. In some embodiments, the housing 12 may be relatively impermeable to solid foreign objects and water / fluids, and may have an entry protection rating indicating this, such as an International Electrotechnical Commission (IEC) rating. In some embodiments, the housing 12 may have an entry protection rating of IP54. In some embodiments, the housing 12 may have a width of about 120 cm, a depth of about 77 cm, a height of about 170 cm, and a weight of about 300 kg, but the embodiments are not limited thereto.

[0124] refer to Figure 7 An exploded view of an exemplary valve 44 of the formulation system 10 is shown (where valves 46, 48, and 50 are identically configured). Valves 44, 46, 48, and 50 are fluidly connected to and selectively receive compressed air from a compressed air supply within the housing 12 to operate valves 44, 46, 48, and 50. As shown, the input valve 44 includes a valve housing 84 located outside the housing 12. The valve housing 84 includes a passage 86 for receiving a section of tubing for the flow kit 200, and a manually operable safety lock 88. As will be understood, valves 44, 46, 48, and 50 are used to control the path of fluid through the system 10. In some examples, seven valves are used to control the flow of liquid in the system 10. In some other examples, fewer or more valves may be used to control the flow of liquid in the system 10. Each of the input valve 44, output valve 46, waste valve 48, and calibration valve 50 has a manually or automatically operable safety lock 88. Safety lock 88 holds the tubing of flow kit 200 (described below) in place during flow kit installation and prevents valves 44, 46, 48, and 50 from being accidentally closed. Figure 8 yes Figure 1 A perspective view of the housing of an exemplary valve, depicting a safety lock in the open position. Figure 9 yes Figure 1 A perspective view of the housing of an exemplary valve, depicting a safety lock in the closed / locked position.

[0125] Figure 10 This is an exploded perspective view of an exemplary pump assembly of the formulation system 10. The exemplary pump assembly may include first, second, and third pumps 36, 38, and 40. As shown, the first, second, and third pumps 36, 38, and 40 are mounted to the front side 16 of the housing 12 via pump mount 90. Locking plate 92 allows the associated pump head of the flow kit to be releasably connected to the first, second, and third pumps 36, 38, and 40, as described below. Figure 11A yes Figure 10An enlarged perspective view of an exemplary mounting mechanism for an exemplary pump assembly, which includes a locking plate 92 and a fastening mechanism for selectively locking the pump head of the flow kit to the locking plate 92 and engaging with the first, second, and third pumps 36, 38, 40. The fastening mechanism may be a clamp, clip, or other similar fastening mechanism, such as a spring clip 94.

[0126] Figure 11B yes Figure 10 A perspective view of an exemplary locking mechanism for an exemplary pump assembly. Figure 11B As best shown, the spring clip 94 includes an annular retainer 95 with opposing elastic arms 99, and a handle or pull ring 97 that can be gripped by the user to install or remove the spring clip 94 as desired. During the installation of the flow kit 200, when the spring clip 94 snaps into place, it secures each pump head in the respective first, second, and third pumps 36, 38, and 40. The pull ring 97 on the spring clip 94 allows each pump head to be released from the respective first, second, and third pumps 36, 38, and 40 during the unloading step without rotating the pump head.

[0127] Figure 12A yes Figure 1 Enlarged perspective view of exemplary flow meters and exemplary flow sensors for exemplary formulation systems. Figure 12B yes Figure 1 Another enlarged perspective view of the exemplary flow meter and exemplary flow sensor of the exemplary formulation system. Figure 13 yes Figure 12A and 12B An enlarged perspective view of the cable-holding ports of exemplary flow meters and exemplary flow sensors. In some examples, the front side 16 of housing 12 includes flow meter housings 54 configured to receive flow meters 208, 210, 212 of flow kit 200. In some examples, the front side 16 of housing 12 includes three flow meter housings 54 to receive three flow meters 208, 210, 212; however, more or fewer flow meter housings 54 and corresponding flow meters 208, 210, 212 may be used. Each flow meter housing 54 may include a flow meter cable 55 with a sensor (not shown) that can be connected to the flow meters 208, 210, 212 on flow kit 200 and can be used to monitor the flow rate in each input line of flow kit 200 and feed the data back to the controller. Flow meters 208, 210, 212 may be Coriolis flow meters, ultrasonic flow meters, electromagnetic flow meters, thermal mass flow meters, volumetric flow meters, turbine flow meters, or any other similar type of flow meter. In some examples, flow meters 208, 210, and 212 are ultrasonic flow meters.

[0128] The front side 16 of the housing 12 may include three connector or cable holding ports 96 configured to receive Figure 12A The flow meter cable 55 is located at the distal end of the port 96. Each port 96 has an associated cap 98, which can be used to close the port 96 when the flow meter cable 55 is not connected to it. The port 96 is used to house and protect the sensor in the distal end of the cable 55, that is, when the system 10 is not in use, or when the flow kit 200 is engaged with or removed from the flow meter housing 54. When the flow kit 200 is mounted on the front 16 of the housing 12, the flow meter cable 55 is removed from the port 96 and connected to the flow meter housing 54 to monitor the flow rate in the corresponding input lines 214, 216, 218 of the flow kit 200.

[0129] Figure 14 An exploded perspective view of the venting mechanism 32 of the formulation system 10 is shown. In one embodiment, the venting mechanism 32 includes an associated air filter 102, such as a cartridge air filter. In one embodiment, the air filter 102 has a minimum efficiency of 75% for capturing all particles with a size between 0.3 μm and 1.0 μm, and a minimum efficiency of 90% for capturing all particles with a size between 1 μm and 10 μm.

[0130] refer to Figure 15 and 16 , Figure 15 yes Figure 1 A partial cross-sectional perspective view of an exemplary formulation system, including an exemplary purge chamber within the exemplary formulation system. Figure 16 yes Figure 1 A rear-view perspective view of the interior of an exemplary formulation system, including Figure 15 An exemplary purge box. Figure 17 yes Figure 1 A detailed perspective view of an exemplary purge chamber of an exemplary formulation system, including Figure 15 An exemplary purge box is provided. The interior of housing 12 contains a purge box 104. The purge box 104 is generally rectangular and defines an open interior space 106. In one embodiment, the purge box 104 contains all electrical components unsuitable for use in explosive atmospheres or hazardous locations. For example, in one embodiment, the purge box 104 contains the signal conditioners required to enable the use of disposable flow meters 208, 210, 212 of the flow kit 200. In another embodiment, the purge box 104 may be placed outside housing 12, in which case the purge box 104 is housed within an increased safety enclosure with entry protection. This allows for improved aesthetics and cleanability of the exterior surfaces of the purge box 104.

[0131] The purge box 104 is equipped with a purge system that prevents flammable gases from entering the purge box and is suitable for use in explosive atmospheres. In one embodiment, the purge box 104 is equipped with a purge unit that prevents the presence of flammable gases in the housing 12 when energized. Specifically, the purge box 104 is supplied with compressed air from a compressed air supply and includes an outlet 108. In one embodiment, the purge time is controlled by a digital pneumatic timer. During startup, the purge box 104 enters a purge mode and removes any gas from the purge box 104. Once the purge mode is complete, it enters an operating mode. In the operating mode, if a specified overpressure in the purge box 104 is not maintained: any operating operations cease, the pump stops, and the valve closes. Power to the components in the purge box 104 is interrupted, and the user is notified on the user interface 66. A red light on the status indicator may also illuminate.

[0132] As indicated, purge chamber 104 operates in two modes: purge mode and operating mode. Purge mode is automatically initiated when the system power switch on the instrument is turned on. The purge air supply must also be turned on for successful purge completion. During this procedure, a predetermined volume of air under positive pressure is flushed through purge chamber 104 to remove residual gas and minimize the risk of any flammable gas entering the purge chamber, which houses certified electrical components in non-hazardous locations. Purge mode is also activated if the pressure in the purge chamber falls below a safety threshold. Upon successful completion of purge, power to the electronics inside purge chamber 104 and pressurized housing 12 is automatically switched on, and purge chamber 104 continues to operating mode. Operating mode is used during normal operation to maintain a specific overpressure in purge chamber 104 and pressurized housing 12 to prevent the entry of flammable gases, as long as system 10 power is on. If the pressure in housing 12 drops but remains within a safe range, a warning message appears on interface 66. If the predetermined pressure above the safety threshold is not maintained in the purge chamber 104, the power supply to the electrical components inside the purge chamber 104 is automatically cut off. All activity stops, and the active formulation is paused. An alarm is automatically activated, and the purge unit enters purge mode. The system can not resume any process or formulation until the housing 12 is purged again and the alarm is confirmed.

[0133] Figure 18 Is with Figure 1 A perspective view of an exemplary flow kit 200 used in conjunction with a formulation system. Figure 19 yes Figure 18 An enlarged perspective view of a portion of an exemplary flow kit 200. Now turn to... Figure 18The formulation system 10 also includes a flow kit 200, which is releasably mounted to the front 16 of the housing 12. In one embodiment, the flow kit 200 includes three pump heads 202, 204, 206, three input lines 214, 216, 218, three flow meters 208, 210, 212, a cylinder or mixing chamber 226, and tubing connecting the components (e.g., the pump, the three pump heads 202, 204, 206, the three input lines 214, 216, 218, the three flow meters 208, 210, 212, and the mixing chamber / cylinder 226).

[0134] Three pump heads 202, 204, and 206 are configured to be connected to and driven by pumps 36, 38, and 40 of housing 12. In one embodiment, each pump head 202, 204, and 206 is a magnetic centrifugal pump and includes a magnetically driven impeller (not shown). The first pump head 202, the second pump head 204, and the third pump head 206 may include one or more inlets and one or more connectors (refer to below). Figure 19 The inlet may be attached to the inlet for fluid connection to one or more sources via a tubing section. For example, the first pump head 202 may include one or more inlets 203 for fluid connection to a first formulation fluid source 260 (aqueous input fluid) via tubing section 261 and to a first calibration fluid source 262 via tubing section 263. Similarly, the second pump head 204 may include one or more inlets 205 for fluid connection to a second formulation fluid source (organic input fluid) 264 via tubing section 265 and to a second calibration fluid source 266 via tubing section 267. The third pump head 206 may have one or more inlets 207 for fluid connection to a dilution fluid source 268 (dilution fluid) via tubing section 269.

[0135] like Figure 18 As also shown, the flow kit 200 includes three flow meters 208, 210, and 212, which are fluidly connected to the outputs of pump heads 202, 204, and 206. Flow meters 208, 210, and 212 use ultrasonic waves to measure the liquid flow rate for each line and are mounted in a flow meter housing 54 on the front of housing 12. Flow meters 208, 210, and 212 enable real-time feedback to pumps 36, 38, and 40. The flow kit 200 additionally includes a first input line 214 for conveying aqueous input fluid, a second input line 216 for conveying organic input fluid, and a third input / dilution line 218 for conveying dilution fluid. Input lines 214, 216, and 218 are configured for installation in corresponding input valves 44. The third input / dilution line 218 is also configured for installation in a control valve 52, such as... Figure 2 As best displayed in the image.

[0136] The flow kit 200 includes a fluid mixing chamber or cylinder 226 having two inlets, such as a first chamber inlet 215 and a second chamber inlet 217 configured for fluid connection to a first input line 214 and a second input line 216, and an outlet configured for selective fluid connection to a waste output line 228 and a formulation output line 230. The waste output line 228 is configured for installation in one of the output valve 46 and the waste valve 48 (see, for example...). Figure 1 The formulation output line 230 is configured to be installed in another output valve 46 and to transport the formulated product to a formulation collection container 270 for collection. In one embodiment, the cylinder 226 may be a fluid mixer of the type disclosed in U.S. Patent Nos. 10,835,878 and 10,076,730 (the entire contents of which are incorporated herein by reference), having a branched fluid flow through an annular mixing element. In one embodiment, the cylinder 226 includes a radio frequency identification (RFID) tag or other element that is read by an RFID module or similar device in the housing 12 to ensure that only compatible or approved flow kits 200 and / or cylinder 226 can be used with system 10 (and make cylinder 226 suitable for the selected formulation).

[0137] Go to Figure 19 , showed Figure 18 An enlarged perspective view of a portion of an exemplary flow kit 200. (See reference...) Figure 18 The input lines of the flow kit 200 may include one or more connectors for fluidly connecting the input lines to the pump heads. In some examples, the one or more connectors may be in-line connectors with inputs and corresponding outputs, with more than one input corresponding to one output, such as Y-connectors, T-connectors, etc. Connectors may be quick-release (Tri-Clamp(TC)) connectors, threaded connectors (e.g., DIN 11851 fittings), flange connections, cam lock connectors, compression fittings, etc., and / or combinations of one or more connectors. For example, the first pump head 202 and the second pump head 204 each have two TC connectors, and the third pump head 206 has one TC connector. For example, one or more inlets 203 of the first pump head 202 may have T-connectors 232 for connecting to two different sources 260, 262, whereby the user can load sources 260, 262 simultaneously, rather than loading each source individually to operate the formulation system 10. Similarly, one or more inlets 205 of the second pump head 204 may have T-connectors to enable connection to two different sources 264, 266. In some examples, the connector may be a T-type connector including a TC connection, which includes cap 234.

[0138] In one embodiment, the flow kit 200 is a single-use, disposable flow kit that can be discarded after batch formulation and collection. In other embodiments, the flow kit 200 is reusable. As discussed above, the flow kit 200 includes a cylinder 226 for mixing, pump heads 202, 204, 206, flow meters 208, 210, 212, and corresponding tubing. The flow kit 200 is composed of biocompatible and animal-derived materials, assembled in a cleanroom, packaged in double-layered bags, and irradiated with gamma (25.0 to 45.0 kGy) prior to delivery to reduce bioburden. The flow kit 200 is easy to install and ready for formulation in less than 60 minutes, supporting efficient transfer between production batches and products during production. Intuitive software guides users through the installation of the flow kit and the entire process workflow on a user interface 66, reducing the risk of user error. Discarding the flow kit 200 after each run minimizes the risk of cross-contamination, enabling the production of multiple mRNA products within the same facility. In one embodiment, the flow kit 200 provides a flow rate of about 6 to about 48 L / h. In another embodiment, the flow kit 200 provides a flow rate of about 6 to about 12 L / h. In yet another embodiment, the flow kit 200 provides a flow rate of about 12 to about 48 L / h. In yet another embodiment, the flow kit 200 provides a flow rate of about 24 to about 48 L / h.

[0139] Refer again Figure 1 , 2 18, the flow kit 200 is shown in its mounting position on the front 16 of the housing 12. Figure 18 The flow kit 200 is shown to be fluidly connected to a first formulation fluid source 260, a first calibration fluid source 262, a second formulation fluid source 264, a second calibration fluid source 266, a dilution fluid source 268, a formulation collection container 270, and a waste container 272. Each fluid source or container may have an independent shut-off valve or clamp on the pipeline to close the connection point with the flow kit 200. The fluid source or connected container may be a bag, vessel, receiver, or other similar container capable of containing fluid.

[0140] Figure 20This is a schematic diagram of system 10 and flow kit 200. In one embodiment, a controller (not shown) is configured to be displayed on user interface 66. As shown therein, system 10 is configured to monitor various process parameters and display the measured parameters on interface 66. For example, the speed of each pump 36, 38, 40 is monitored in real time and displayed on the interface. The flow rates through flow meters 208, 210, 212 are also measured and displayed in real time on user interface 66. In addition, the flow rate measured by calibrated flow meter 64 and the start / stop status of the peristaltic pump are displayed. Finally, interface 66 is also configured to display the air supply pressure to system 10.

[0141] In one embodiment, the formulation system 10 supports automated workflows for perfusion, calibration, formulation, and online dilution to streamline Good Manufacturing Practices (GMP) for mRNA-LNP drugs. For example, in one embodiment, a first formulation fluid source 260 may contain a payload for formulation, such as nucleic acids suspended in an aqueous buffer, and a first calibration fluid source 262 may contain only an aqueous buffer (without nucleic acids) for perfusion and calibration. A second formulation fluid source 264 may contain a lipid mixture (lipids and a solvent, such as ethanol), while a second calibration fluid source 266 may contain only a solvent (e.g., pure ethanol) for perfusion and calibration. A dilution fluid source 268 may contain a dilution buffer for dilution, depending on the chosen formulation.

[0142] Figure 21 It is used for depiction Figure 1 An exemplary graph illustrates the improved flow rate achieved by the exemplary formulation system. As a non-limiting example, using the pump of formulation system 10, a deviation percentage between + / - 6-8% can be achieved at a flow rate of 100 mL / min, and a deviation percentage between + / - 3-4% at a flow rate of 300 mL / min. At other flow rates, such as 50 mL / min, 150 mL / min, 200 mL / min, 400 mL / min, 500 mL / min, 600 mL / min, 700 mL / min, 800 mL / min, 1000 mL / min, 1500 mL / min, 2000 mL / min, 2500 mL / min, or 3000 mL / min, stringent control of the flow rate deviation percentage can be achieved.

[0143] Figure 22 It shows that it can be used Figure 1A flowchart 2200 illustrates exemplary steps for preparing a product using an exemplary formulation system. Referring to step 2202, the flow kit 200 is positioned and secured to the front 16 of the housing 12. In step 2204, the fluid source, formulation collection container, and waste container 272 are fluidly coupled to appropriate connections on the flow kit 200. A pneumatic air supply is connected to the system and then power is provided to the system 10 using a power switch 80. At this point, the user interface 66 is initialized and a purge cycle is executed according to a set of pre-programmed instructions. During purging, pressurized air is supplied to the purge chamber 104 and discharged into the internal space 34 to create positive pressure within the internal space 34, causing air to exit from the internal space through the vent mechanism 32 in the top of the housing 12 after passing through the canister air filter 102. Once purging is complete, all electrical components inside the purge chamber 104 are opened by a controller.

[0144] Next, in step 2204, the user is prompted via user interface 66 to set a batch plan and / or select from previously defined formulations stored in memory. System 10 then verifies that the installed flow kit 200 is suitable for the selected formulation. In some examples, RFID or other similar identifiers are used to verify that the correct flow kit 200 is being used.

[0145] In step 2208, after formula selection, the flow kit 200 is infused. Infusion includes setting the ultrasonic flow meters 208, 210, and 212 to the calibrated kinematic viscosity set in the formula. In some examples, the user interface 66 instructs the operator to infuse the first input line 214 and / or the second input line 216 until the corresponding tubing and connections are infused (this uses the peristaltic pump 60 and valve switching). In one embodiment, the user interface 66 instructs the operator to infuse the third input line (or dilution line) 218 ​​until the third input line 218 and the ultrasonic flow meter 212 are infused. In some other examples, the controller automatically infuses the third input line / dilution line 218 until the tubing and connections are infused, or instructs the operator to infuse the third input line 218 until the third input line 218 and the ultrasonic flow meter 212 are infused. This operation also uses the peristaltic pump 60 and valve switching. Then, system 10 performs automatic priming to purge the remainder of the lines, utilizing peristaltic pump 60, centrifugal pumps 202, 204, 206, and valve switching. For dilution line 218, a larger flush is performed to remove any remaining air up to output valve 46. During priming, system 10 also tare and zeroes ultrasonic flow meters 208, 210, 212, prompts the user to open the clamps on calibration lines 220, 222, primes calibration lines 220, 222, and prompts the user to check for air bubbles in flow kit 200.

[0146] In step 2210, once the flow kit 200 is infused, the flow meters 208, 210, 212 corresponding to each of the first input lines 214, 216, and 218 are calibrated using plain buffer (sometimes referred to as pure buffer) from the first calibration fluid source 262, plain solvent (sometimes referred to as pure solvent) from the second calibration fluid source 266, and dilution fluid from the dilution fluid source 268. In one embodiment, the system 10 is configured to instruct the operator to set the control valve on the dilution line 218 when necessary. The system 10 then independently operates each centrifugal pump 36, 38, 40 at a predetermined infusion flow rate to fill the calibration flow meter 64 with the corresponding fluid. The system 10 then operates each centrifugal pump 36, 38, 40 at a predetermined calibration flow rate to calibrate the ultrasonic flow meters 208, 210, 212 to the calibration flow meter 64. Then, all pumps 36, 38, and 40 were run together at a predetermined flow rate to verify that the mixing parameters for the selected formulation were achievable.

[0147] After flow meter calibration, the formulation process is performed in step 2212. During formulation, system 10 prompts the operator to manually close dilution line 218 and open reagent lines 214, 216, or automatically close dilution buffer line 218 and open reagent lines 214, 216, and sets the ultrasonic flow meter to the formulation flow rate set in the formulation. System 10 then runs the pumps with the aim of flushing each of the reagents from the first and second formulation fluid sources 260, 264 through each pump. In an embodiment, at least 100 ml of each corresponding reagent may be used for flushing. System 10 then switches from waste to formulation (e.g., by closing the output valve 46 along waste output line 228). Formulation is then run until the formulation volume is reached. During this step, fluid from a first formulation fluid source 260 (e.g., nucleic acid suspended in an aqueous buffer) is pumped via a first pump 36 through line 214 and into cylinder 226, while simultaneously, fluid from a second formulation fluid source 264 (e.g., lipids dissolved in a solvent such as ethanol) is pumped via a second pump 38 through line 216 and into cylinder 226. The respective fluids pass through cylinder 226 and mix to encapsulate the therapeutic material (e.g., nucleic acid) within lipid nanoparticles (e.g., as described more fully in U.S. Patent Nos. 10,835,878 and 10,076,730). In one embodiment, the fluid containing lipid nanoparticles exiting the mixing chamber can be diluted by pumping a dilution fluid / buffer via a third pump 40 through dilution line 218 and mixing the dilution fluid with the fluid exiting cylinder 226 before flowing into the formulation collection container 270. This reduces the ethanol content immediately following the formulation, resulting in a more stable product. This formulation process continues until the formulation volume is reached. In some examples, system 10 sends instructions (e.g., to an operator) to shut down and save the collected batches.

[0148] Finally, in step 2214, a flow kit removal step is performed, in which all valves are opened to allow the removal of flow kit 200. In some examples, user interface 66 provides step-by-step instructions for removing flow kit 200. In some examples, the calibration flow meter may also be purged.

[0149] Therefore, the formulation system 10 of the present invention provides an automated, single-use system for the clinical and commercial production of lipid nanoparticles (LNPs) under cGMP conditions. System 10 is designed for efficient transfer and robust manufacturing processes, enabling operational flexibility and standardized production of genomic drugs. As discussed above, formulation system 10 supports automated workflows for perfusion, calibration, formulation, and online dilution to streamline GMP manufacturing of LNP products. Its software interface 66 enables 21 CFR Part 11 compliance (sometimes referred to as compliance with Section 11 of Chapter 21 of the Federal Regulations) and electronic batch records for process monitoring of flow rates and pump speeds. The system utilizes scalable microfluidic mixing technology and low-pulsation pumps to precisely control mixing parameters, resulting in consistent flow rates from 6 to 48 L / h, producing homogeneous and reproducible nanoparticles. The single-use flow path minimizes the need for sterilization and cleaning validation, enabling efficient transfer between production runs while minimizing the risk of cross-contamination. The flow kit can be easily installed, calibrated, and ready for formulation in less than 60 minutes. System 10 is also ATEX (Explosive Atmospheres) and IECEx (International Electrotechnical Commission's standard certification system for equipment used in explosive atmospheres) certified, making it suitable for use in hazardous environments to ensure safety when handling flammable solvents during LNP formulation.

[0150] Advantageously, as described above, the system 10 of the present invention includes a purge chamber 104, which ensures that non-hazardous location certified equipment housed therein is not exposed to flammable vapors. The use of a centrifugal pump minimizes flow fluctuations, resulting in more accurate and faster formulation than has been feasible to date. Furthermore, the use of a magnetically driven centrifugal pump transmits force and provides fluid flow through the flow kit 200, while the pump, valves, etc., do not come into contact with the fluid or therapeutic material used. As will be understood, mounting the flow kit 200 externally to the housing 12 provides easy access for setup, removal, conversion, troubleshooting, and cleaning. Unlike existing systems (which typically rely on top entry), the housing 226 provides inline entry (sometimes referred to as straight-in entry) for the fluid.

[0151] As implied above, system 10 includes a centralized control unit, such as a controller, for executing the process steps disclosed herein in an automatic and / or semi-automatic manner according to an algorithm stored in memory.

[0152] This written description discloses by way of example several embodiments of the invention, including the best mode, and also enables those skilled in the art to implement embodiments of the invention, including making and using any apparatus or system and performing any incorporated methods. The patentable scope of the invention is defined by the claims, but may include other examples that would occur to those skilled in the art. Such other examples are intended to be within the scope of the claims if they have structural elements that are indistinguishable from the literal language of the claims, or if such other examples include equivalent structural elements that are not substantially different from the literal language of the claims.

[0153] All patents, patent applications, publications and descriptions mentioned above are incorporated herein by reference in their entirety.

Claims

1. A formulation system comprising: A shell with internal space and an outer surface; A first pump is used to pump a first fluid from a first fluid source to a mixing chamber configured to receive the first fluid; A second pump is used to pump a second fluid from a second fluid source to a mixing chamber configured to receive the second fluid; A mounting mechanism located on the outer surface of the housing for receiving the first pump and the second pump; as well as An array of valves is used to selectively control the flow of fluid entering the mixing chamber from the first pump and the second pump to generate a mixed fluid and to control the flow of the mixed fluid from the mixing chamber to the collection container.

2. The formulation system according to claim 1, further comprising: A third pump used to pump a third fluid from a third fluid source to a point downstream of the mixing chamber or for perfusing the formulation system.

3. The formulation system according to claim 2, further comprising: The first fluid source; The second fluid source; as well as The third fluid source, wherein the first fluid from the first fluid source comprises nucleic acid and an aqueous solution, wherein the second fluid from the second fluid source comprises a solvent and one or more lipids dissolved therein; and wherein the third fluid from the third fluid source comprises a diluent fluid.

4. The formulation system according to any one of the preceding claims, wherein, The array of valves includes pinch valves or diaphragm valves.

5. The formulation system according to any one of the preceding claims, wherein, The installation mechanism includes a first receiving seat for receiving a first pump head and a second receiving seat for receiving a second pump head.

6. The formulation system according to claim 5, wherein, The first receiver and the second receiver each include a removable retaining clip for releasably retaining the first pump head and the second pump head in the first receiver and the second receiver, respectively.

7. The formulation system according to any one of the preceding claims further includes a barrel receiving seat, wherein the barrel receiving seat includes a recess for receiving the mixing chamber.

8. The formulation system according to any one of the preceding claims further includes an outer casing located within the internal space, the outer casing being configured to receive a supply of compressed air.

9. The formulation system according to any one of the preceding claims further includes a venting mechanism comprising an outlet located on an outer surface of the housing and a filter in fluid communication with the outlet.

10. The formulation system according to any one of the preceding claims further comprises: The control panel is integrated with the housing and is accessible from the outside of the housing.

11. The formulation system according to any one of the preceding claims further comprises: At least one sensor configured to monitor one or more flow rates, wherein the at least one sensor is mounted within a cable that is movable between a sensing position and a storage position; and The housing includes a protective recess for receiving the end of the cable in the storage position.

12. The formulation system according to any one of the preceding claims, wherein, The first pump and the second pump are centrifugal pumps.

13. The formulation system according to claim 11, wherein, The at least one sensor is a flow meter.

14. The formulation system according to claim 11, wherein, The at least one sensor is a Coriolis flow meter.

15. The formulation system according to any one of the preceding claims, wherein, The third pump is a peristaltic pump.

16. The formulation system according to any one of claims 1-4 or 8-15, further comprising a flow kit, which includes: The mixing chamber; A first pump head having one or more first inlets and a first outlet, the first pump head being configured to engage with a first pump; A second pump head having one or more second inlets and a second outlet, the second pump head being configured to engage with the second pump. The mixing chamber includes a first chamber inlet fluidly connected to the first outlet of the first pump head, a second chamber inlet fluidly connected to the second outlet of the second pump head, and a chamber outlet; as well as The fluid is connected to the outlet of the mixing chamber and configured for fluid connection to the collection container.

17. The formulation system of claim 16, further comprising a tube array fluidly connected to the collection tube section, the tube array comprising: A first flow path terminating in a waste outlet, and a second flow path configured for fluid connection to at least one sensing device.

18. The formulation system according to any one of the preceding claims, wherein, The third pump is installed below the first and second pumps.

19. The formulation system according to any one of the preceding claims further includes a calibration flow meter configured to calibrate one or more ultrasonic flow meters.

20. A flow kit for a formulation system, comprising: A first pump head having one or more first inlets and first outlets; A second pump head having one or more second inlets and a second outlet; A mixing chamber having a first chamber inlet fluidly connected to the first outlet of the first pump head, a second chamber inlet fluidly connected to the first outlet of the second pump head, and a chamber outlet; as well as A tube is connected to the outlet of the mixing chamber and configured as a lead-out fluid connection from the mixing chamber to the collection container.

21. The mobile kit of claim 20, comprising: A first flow path formed by the first pump head, the second pump head, the pipe, and the lead-out fluid connector, and a second flow path including a dilution line and at least one sensing device and connected to the first flow path as an inlet fluid connector.

22. The mobile kit of claim 20, wherein, The at least one sensing device is an ultrasonic flow meter.

23. The mobile kit according to any one of claims 20-22, wherein, The second flow path includes an additional tube connected to the peristaltic pump.

24. The mobile kit according to any one of claims 20-23, wherein, The second flow path includes a third pump head having a third inlet and a third outlet, wherein the third outlet of the third pump head is fluidly connected to the dilution line.

25. The mobile kit according to any one of claims 20-24, further comprising: A first pipe section fluidly connected to one or more first inlets of the first pump head, the first pipe section being configured for fluid connection to a first fluid source; as well as A second pipe section fluidly connected to one or more second inlets of the second pump head, the second pipe section being configured for fluid connection to a second fluid source.

26. The mobile kit according to any one of claims 20-25, further comprising: A third pipe section fluidly connected to one or more first inlets of the first pump head, the third pipe section being configured for fluid connection to a third fluid source; as well as A fourth pipe section fluidly connected to one or more second inlets of the second pump head, the fourth pipe section being configured for fluid connection to a fourth fluid source.

27. The flow kit according to any one of claims 20-26, further comprising a fifth pipe section fluidly connected to the third inlet of the third pump head, the fifth pipe section being configured for fluid connection to a fifth fluid source.

28. The flow kit according to any one of claims 20-27, wherein, The fluid kit is a disposable kit.

29. The mobile kit according to any one of claims 20-28, further comprising: A first flow meter located between the first outlet of the first pump head and the inlet of the first chamber; as well as A second flow meter located between the first outlet of the second pump head and the inlet of the second chamber.

30. A formulation method, comprising: A flow kit is attached to the outside of a formulation system. The flow kit has a first input line and a second input line, a formulation output line, and a mixing chamber including a first chamber inlet, a second chamber inlet, and a chamber outlet, wherein the first chamber inlet and the second chamber inlet are fluidly connected to the first input line and the second input line, and the chamber outlet is connected to the formulation output line. The first fluid-containing source and the second fluid-containing source are respectively attached to the first input line and the second input line; Attach the collection container to the formulation output line; Start the first pump and the second pump to pump fluid from the first fluid-containing source and the second fluid-containing source into the mixing chamber respectively, so as to form a mixed fluid in the mixing chamber; as well as The flow of the mixed fluid is output from the mixing chamber to the collection container via the formulation output line.

31. The formulation method according to claim 30, further comprising: The first input line, the second input line, and / or the formulation output line of the flow kit are infused; as well as At least one flow meter is calibrated and operatively connected to the first input line, the second input line, and / or the formulation output line.

32. The formulation method according to claim 31, wherein, The infusion of the first input line, the second input line, and / or the formulation output line of the flow kit is performed using a peristaltic pump.

33. The formulation method according to claim 31 or 32, wherein, The first input line, the second input line, or the formulation output line for infusing the flow kit includes switching one or more valves.

34. The formulation method according to any one of claims 30-33, further comprising purging flammable gas from the internal space of the formulation system before activating the first pump and the second pump.

35. The formulation method according to claim 34, wherein, The purging includes supplying compressed air into an outer casing within the interior space, the outer casing isolating any components that could generate sparks.

36. The formulation method according to claim 34 or 35, wherein, Purging is initiated automatically before the first and second pumps are started, and / or after startup and when purging is initiated when the pressure in the internal space is detected to drop below a threshold pressure.

37. The formulation method according to any one of claims 30-36, wherein, The pumped fluid has a flow rate of approximately 6 to approximately 48 L / h.

38. The formulation method according to any one of claims 30-37, wherein, The formulation is entered via a user interface and is used to infuse and calibrate the formulation system.

39. The formulation method according to claim 38, wherein, The infusion includes setting one or more flow meters to the viscosity defined in the formulation.

40. The formulation method according to claim 38 or 39, wherein, The calibration includes running the first pump and the second pump at a predetermined flow rate specified in the formulation.

41. The formulation method according to any one of claims 30-40, wherein, The output continues until the predetermined formulation volume is output.

42. The formulation method according to any one of claims 41, comprising opening one or more valves once the predetermined formulation volume is output via the formulation output line.

43. The formulation method according to any one of claims 30-42, comprising using an identifier associated with the flow kit to verify the flow kit.

44. The formulation method according to any one of claims 30-43, comprising verifying whether the flow kit is compatible with the formulation.

45. The formulation method according to any one of claims 30-44, comprising pumping a buffer solution through a buffer line to dilute the mixed fluid output leaving the mixing chamber.

46. ​​The formulation method according to any one of claims 30-45, comprising flushing the first input line, the second input line, and / or the formulation output line of the flow kit after perfusing the first input line, the second input line, and / or the formulation output line of the flow kit.

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