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WO2025119933A2 - Kit de formulation, système et procédé - Google Patents

Kit de formulation, système et procédé Download PDF

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Publication number
WO2025119933A2
WO2025119933A2 PCT/EP2024/084574 EP2024084574W WO2025119933A2 WO 2025119933 A2 WO2025119933 A2 WO 2025119933A2 EP 2024084574 W EP2024084574 W EP 2024084574W WO 2025119933 A2 WO2025119933 A2 WO 2025119933A2
Authority
WO
WIPO (PCT)
Prior art keywords
formulation
flow
fluid
pump
kit
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/EP2024/084574
Other languages
English (en)
Other versions
WO2025119933A3 (fr
Inventor
Benjamin Albert VERSTEEG
Curtis M ROBIN
Robert Young
Maria KERIN
Kenneth Victor DYCK
Janice Lee
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Global Life Sciences Solutions Canada ULC
Global Life Sciences Solutions Uk Ltd
Original Assignee
Global Life Sciences Solutions Canada ULC
Global Life Sciences Solutions Uk Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Global Life Sciences Solutions Canada ULC, Global Life Sciences Solutions Uk Ltd filed Critical Global Life Sciences Solutions Canada ULC
Publication of WO2025119933A2 publication Critical patent/WO2025119933A2/fr
Publication of WO2025119933A3 publication Critical patent/WO2025119933A3/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
    • B01F35/00—Accessories for mixers; Auxiliary operations or auxiliary devices; Parts or details of general application
    • B01F35/71—Feed mechanisms
    • B01F35/717—Feed mechanisms characterised by the means for feeding the components to the mixer
    • B01F35/7176—Feed mechanisms characterised by the means for feeding the components to the mixer using pumps
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
    • B01F23/00—Mixing according to the phases to be mixed, e.g. dispersing or emulsifying
    • B01F23/40—Mixing liquids with liquids; Emulsifying
    • B01F23/48—Mixing liquids with liquids; Emulsifying characterised by the nature of the liquids
    • B01F23/483—Mixing liquids with liquids; Emulsifying characterised by the nature of the liquids using water for diluting a liquid ingredient, obtaining a predetermined concentration or making an aqueous solution of a concentrate
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
    • B01F23/00—Mixing according to the phases to be mixed, e.g. dispersing or emulsifying
    • B01F23/40—Mixing liquids with liquids; Emulsifying
    • B01F23/49—Mixing systems, i.e. flow charts or diagrams
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
    • B01F25/00—Flow mixers; Mixers for falling materials, e.g. solid particles
    • B01F25/40—Static mixers
    • B01F25/42—Static mixers in which the mixing is affected by moving the components jointly in changing directions, e.g. in tubes provided with baffles or obstructions
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
    • B01F33/00—Other mixers; Mixing plants; Combinations of mixers
    • B01F33/30—Micromixers
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
    • B01F33/00—Other mixers; Mixing plants; Combinations of mixers
    • B01F33/50—Movable or transportable mixing devices or plants
    • B01F33/502—Vehicle-mounted mixing devices
    • B01F33/5024—Vehicle-mounted mixing devices the vehicle being moved by human force
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
    • B01F35/00—Accessories for mixers; Auxiliary operations or auxiliary devices; Parts or details of general application
    • B01F35/71—Feed mechanisms
    • B01F35/712—Feed mechanisms for feeding fluids
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
    • B01F2101/00—Mixing characterised by the nature of the mixed materials or by the application field
    • B01F2101/22—Mixing of ingredients for pharmaceutical or medical compositions

Definitions

  • Embodiments of the invention relate generally to pharmaceutical formulation systems and, more particularly, to a formulation kit, system, and method for the clinical and commercial manufacturing of nanoparticle medicines.
  • a formulation system includes a housing having an interior space and an exterior 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 the mixing chamber configured to receive the second fluid; a mounting mechanism on the exterior surface of the housing for receiving the first pump and the second pump; and an array of valves for selectively controlling a flow of the fluid from the first pump and the second pump into the mixing chamber to produce a mixed fluid and for controlling a flow of the mixed fluid from the mixing chamber to a collection container.
  • the formulation system further includes a third pump for pumping a third fluid from a third fluid source to a point downstream from the mixing chamber or for priming the formulation system.
  • the formulation system further includes the first fluid source; the second fluid source; and the third fluid source, wherein the first fluid from the first fluid source includes a nucleic acid and an aqueous solution, wherein the second fluid from the second fluid source includes a solvent and one or more lipids dissolved therein; and wherein the third fluid from the third fluid source includes a dilution fluid.
  • the array of valves includes pinch valves or diaphragm valves.
  • the mounting mechanism includes a first receptacle for receiving a first pump head and a second receptacle for receiving a second pump head.
  • the first receptacle and the second receptacle each include a removable retention clip for releasably retaining the first pump head and the second pump head in the first receptacle and the second receptacle, respectively.
  • the formulation system further includes a cartridge receptacle, wherein the cartridge receptacle includes a recess for receiving the mixing chamber.
  • the formulation system further includes an enclosure within the interior space, the enclosure being configured to receive a supply of compressed air.
  • the formulation system further includes a venting mechanism including an outlet on an exterior surface of the housing and a filter in fluid communication with the outlet.
  • the formulation system further includes a control panel integrated with the housing and accessible from an exterior of the housing.
  • the formulation system further includes at least one sensor configured to monitor one or more flow rates, wherein the at least one sensor is mounted within a cable, the cable being moveable between a sensing position and a stowed position; and wherein the housing includes a protective recess for receiving an end of the cable in the stowed position.
  • the first pump and the second pump are centrifugal pumps.
  • the at least one sensor is a flow meter.
  • the at least one sensor is a Coriolis flow meter.
  • the third pump is a peristaltic pump.
  • the formulation system further includes a flow kit including the mixing chamber; a first pump head having one or more first inlets and a first outlet, the first pump head configured to be engaged with the first pump; a second pump head having one or more second inlets and a second outlet, the second pump head configured to be engaged with the 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 tubing fluidly connected to the chamber outlet of the mixing chamber and configured for fluid connection to the collection container.
  • the formulation system further includes a tubing array fluidly connected to the collection tubing segment, the tubing 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.
  • third pump is mounted lower than the first and second pumps.
  • the formulation system further includes a calibration flow meter configured to calibrate one or more ultrasonic flow meters.
  • One aspect of the 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 tubing fluidly connected to the chamber outlet of the mixing chamber and configured as an outgoing fluid connection from the mixing chamber to a collection container.
  • the flow kit includes a first flow path formed by the first pump head, the second pump head, the tubing, and the outgoing fluid connection, and a second flow path including a dilution line and at least one sensing device and connected to the first flow path as an incoming fluid connection.
  • the at least one sensing device is an ultrasonic flow meter.
  • the second flow path includes additional tubing connected to a peristaltic pump.
  • 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.
  • the flow kit further includes a first tubing segment fluidly connected to the one or more first inlets of the first pump head, the first tubing segment being configured for fluid connection to a first fluid source; and a second tubing segment fluidly connected to the one or more second inlets of the second pump head, the second tubing segment being configured for fluid connection to a second fluid source.
  • the flow kit further includes a third tubing segment fluidly connected to the one or more first inlets of the first pump head, the third tubing segment being configured for fluid connection to a third fluid source; and a fourth tubing segment fluidly connected to the one or more second inlets of the second pump head, the fourth tubing segment being configured for fluid connection to a fourth fluid source.
  • the flow kit further includes a fifth tubing segment fluidly connected to the third inlet of the third pump head, the fifth tubing segment being configured for fluid connection to a fifth fluid source.
  • the flow kit is a single-use, disposable kit.
  • the flow kit further includes a first flow meter intermediate the first outlet of the first pump head and the first chamber inlet; and a second flow meter intermediate the first outlet of the second pump head and the second chamber inlet.
  • One aspect of the disclosure includes a formulation method including securing a flow kit to an exterior of a formulation system, the flow kit having first input line and a second input line, a formulation output line, and a mixing chamber comprising a first chamber inlet, a second chamber inlet, and a chamber outlet, wherein the first chamber inlet and 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 first and second fluid-containing sources to the first and second input lines respectively; attaching a collection container to the formulation output line; activating a first pump and a second pump to pump fluids from the first and second fluid-containing sources, respectively, into the mixing chamber for forming a mixed fluid in the mixing chamber; and outputting a flow of the mixed fluid from the mixing chamber via the formulation output line into the collection container.
  • the formulation method further includes priming the first input line, the second input line, and/or the formulation output line of the flow kit; and calibrating at least one flow meter operatively connected to the first input line, the second input line, and/or the formulation output line.
  • the priming the first input line, the second input line, and/or the formulation output line of the flow kit is carried out utilizing a peristaltic pump.
  • the priming the first input line, the second input line, or the formulation output line of the flow kit comprises toggling one or more valves.
  • the formulation method further includes purging flammable gases from an interior space of the formulation system prior to activating the first and second pumps.
  • the purging comprises supplying compressed air to an enclosure within the interior space, the enclosure isolating any spark-producing components.
  • the purging is automatically initiated prior to activating the first and second pumps, and/or initiated after activation and upon detection of a pressure within the interior space dropping below a threshold pressure.
  • a formulation recipe is input via a user interface, and the formulation recipe is used for priming and calibrating the formulation system.
  • the priming includes setting one or more flow meters to a viscosity defined in the formulation recipe.
  • the calibrating includes running the first pump and the second pump at a predetermined flow rate designated in the formulation recipe.
  • the outputting continues until a predetermined formulation recipe volume is output.
  • the formulation method includes opening one or more valves once the predetermined formulation recipe volume is output via the formulation output line.
  • the formulation method includes verifying the flow kit using an identifier associated with the flow kit.
  • the formulation method includes verifying that the flow kit is compatible with the formulation recipe. [00049] In an aspect, the formulation method includes pumping a buffer fluid through a buffer line to dilute the mixed fluid output exiting the mixing chamber.
  • the formulation method includes flushing the first input line, the second input line, and/or the formulation output line of the flow kit after the priming the first input line, the second input line, and/or the formulation output line of the flow kit.
  • FIG. 1 is a first front elevational view of an exemplary formulation system with an exemplary flow kit installed.
  • FIG. 2 is a front, perspective view of the exemplary formulation system of FIG. 1
  • FIG. 3 is a rear elevational view of exemplary the formulation system of FIG. 1.
  • FIG. 4 is second elevational view of the exemplary formulation system of FIG. 1, depicted without the exemplary flow kit installed.
  • FIG. 5 is a side elevational view of the exemplary formulation system of FIG. 4.
  • FIG. 6 is a front, transparent perspective view of a portion of the exemplary formulation system of FIG. 1.
  • FIG. 7 is an exploded view of an exemplary valve of the exemplary formulation system of FIG. 1.
  • FIG. 8 is a perspective view of a housing of the exemplary valve of FIG. 7, depicting a safety lock in an open position.
  • FIG. 9 is a perspective view of a housing of the exemplary valve of FIG. 7, depicting the safety lock in a closed/locked position.
  • FIG. 10 is an exploded view of an exemplary pump assembly of the exemplary formulation system of FIG. 1.
  • FIG. 11A is an enlarged, perspective view of an exemplary mounting mechanism of the exemplary pump assembly.
  • FIG. 11B is a perspective view of an exemplary locking mechanism of the exemplary pump assembly of FIG. 10.
  • FIG. 12A is an enlarged, perspective view of an exemplary flow meter and exemplary flow sensor of the exemplary formulation system of FIG. 1.
  • FIG. 12B is a second enlarged, perspective view of the exemplary flow meter and exemplary flow sensor of the exemplary formulation system of FIG. 1.
  • FIG. 13 is an enlarged, perspective view of a cable retention/stowing port of the exemplary flow meter and exemplary flow sensor of FIGs. 12A and 12B.
  • FIG. 14 is an enlarged, perspective view of an exemplary venting mechanism of the formulation system of FIG. 1.
  • FIG. 15 is a perspective, partial cutaway view of the exemplary formulation system of FIG. 1, including an exemplary purge box within the exemplary formulation system.
  • FIG. 16 is a rear, perspective view of an interior of the exemplary formulation system of FIG. 1, including the exemplary purge box of FIG. 15.
  • FIG. 17 is a perspective detailed view of the exemplary purge box of the exemplary formulation system of FIG. 1, including the exemplary purge box of FIG. 15.
  • FIG. 18 is a perspective view of an exemplary flow kit for use with the formulation system of FIG. 1.
  • FIG. 19 is an enlarged, perspective view of portions of the exemplary flow kit of FIG. 18.
  • FIG. 20 is a schematic diagram of the exemplary formulation system of FIG. 1.
  • FIG. 21 is an exemplary graph depicting improved flow rates achieved using the exemplary formulation system of FIG. 1.
  • FIG. 22 is a flow chart illustrating exemplary steps that may be utilized for formulating a product using the exemplary formulation system of FIG. 1.
  • a formulation system in an embodiment, includes a housing having an interior space containing electrical, electro-mechanical, mechanical components, and a purged and pressurized enclosure to house non-Hazloc rated electrical components, an interface on an exterior 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 the mixing chamber, and an array of pinch valves for selectively controlling a flow of the first fluid to the mixing chamber, the second fluid to the mixing chamber, and a flow of mixed fluid from the mixing chamber to a collection container.
  • a flow kit for a formulation system 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 tubing segment fluidly connected to the outlet of the mixing chamber and configured for fluid connection to a collection container.
  • a formulation method includes securing a flow kit to an exterior of a housing of a formulation system, 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 to 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 a collection flow line.
  • the method also 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 fluids from the first and second fluid containing vessels into a mixing chamber of the flow kit for mixing, and then collecting a flow of mixed fluids in the collection container.
  • the formulation system advantageously provides a formulation system including tubing or a tubing array that may be used once and disposed of to ensure that formulations are controlled and properly sanitized.
  • the formulation system may include a flow kit that includes tubing, pump heads, and a mixing chamber or cartridge for onetime use and disposal to ensure that the formulation is sanitized and the flow kit is easily installed each time a new recipe or batch is run.
  • the formulation system provides an efficient method for installing tubing, pump heads, and a mixing chamber or cartridge when setting up and running different formulation recipes.
  • the flow kit provides a disposable array of tubing, pump heads, and cartridge that can quickly be verified to ensure that the correct flow kit is being used for a selected formulation recipe and which can be efficiently replaced as a self-contained unit including the tubing, pump heads, and cartridge needed to provide a new formulation.
  • the formulation system provides an efficient array of pumps for providing an precist flow rate control when providing formulations based on a formulation recipe.
  • the flow kit provides disposable and/or replaceable tubing, pump heads, and a mixing chamber which can be used to prime, calibrate, and create a batch once installed on a formulation system, without requiring additional installation for each of the priming, calibrating, and/or creating the batch.
  • the steps may be conducted in any feasible order. And, as appropriate, any combination of two or more steps may be conducted simultaneously.
  • x, y, and/or z means any element of the seven-element set ⁇ (x), (y), (z), (x, y), (x, z), (y, z), (x, y, z) ⁇ .
  • x, y and/or z means "one or more of x, y and z”.
  • endpoints include all numbers subsumed within that range (e.g., 1 to 5 includes 1, 1.5, 2, 2.75, 3, 3.80, 4, 5, etc.).
  • values that are expressed as ranges can assume any specific value or subrange within the stated ranges in different embodiments of the disclosure, to the tenth of the unit of the lower limit of the range, unless the context clearly dictates otherwise.
  • “up to” a number includes the number (for example, 50).
  • the term “in the range” or “within a range” includes the endpoints of the stated range.
  • exemplary means serving as a non-limiting example, instance, or illustration.
  • terms "e.g.,” and “for example” set off lists of one or more nonlimiting aspects, examples, instances, or illustrations.
  • the term “substantially” refers to the qualitative condition of exhibiting total or near-total extent or degree of a characteristic or property of interest. Biological and chemical phenomena rarely, if ever, go to completion and/or proceed to completeness or achieve or avoid an absolute result. The term “substantially” is therefore used herein to capture the potential lack of completeness inherent in many biological and chemical phenomena. For example, “substantially” may refer to being within at least about 20%, alternatively at least about 10%, alternatively at least about 5% of a characteristic or property of interest.
  • fluidly coupled or “fluid communication” means that the components of the system are capable of receiving or transferring fluid between the components.
  • the term fluid includes gases, liquids, or combinations thereof.
  • electrical communication or “electrically coupled” means that certain components are configured to communicate with one another through direct or indirect signaling by way of direct or indirect electrical connections.
  • operatively coupled refers to a connection, which may be direct or indirect. The connection is not necessarily a mechanical attachment.
  • microfluidic refers to a system or device for manipulating (e.g., flowing, mixing, etc.) a fluid sample including at least one channel having micron-scale dimensions (i.e., a dimension less than 1 mm).
  • therapeutic material is defined as a substance intended to furnish pharmacological activity or to otherwise have direct effect in the diagnosis, cure, mitigation, understanding, treatment or prevention of disease, or to have direct effect in restoring, correcting or modifying physiological functions.
  • Therapeutic material includes but is not limited to small molecule drugs, nucleic acids, proteins, peptides, polysaccharides, inorganic ions and radionuclides.
  • Nanoparticles is defined as a particle comprising more than one component material (for instance lipid, polymer etc.) that is used to encapsulate a therapeutic material and possesses a smallest dimension that is less than 250 nanometers. Nanoparticles include, but are not limited to, lipid nanoparticles and polymer nanoparticles.
  • Embodiments of the invention provide formulation systems and methods.
  • the formulation systems and methods may be used combine lipid nanoparticle compositions and nucleic acids.
  • Lipid nanoparticles are delivery systems used primarily 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 to cells to produce a desired immune response. Their versatility, ability to evade the immune system, and controlled release capabilities make them essential tools in modern nanomedicine.
  • the LNPs or lipid nanoparticle compositions comprise a core and a shell surrounding the core, wherein the shell comprises a phospholipid.
  • the core comprises a lipid (e.g., a fatty acid triglyceride) and is solid.
  • the core is liquid (e.g., aqueous) and the particle is a vesicle, such as a liposomes.
  • the shell surrounding the core is a monolayer.
  • the lipid core comprises a fatty acid triglyceride. Suitable fatty acid triglycerides include C8-C20 fatty acid triglycerides.
  • the fatty acid triglyceride is an oleic acid triglyceride.
  • the lipid nanoparticle includes a shell comprising a phospholipid that surrounds the core. Suitable phospholipids include diacylphosphatidylcholines, diacylphosphatidylethanolamines, ceramides, sphingomyelins, dihydrosphingomyelins, cephalins, and cerebrosides.
  • the phospholipid is a C8-C20 fatty acid diacylphosphatidylcholine.
  • a representative phospholipid is l-palmitoyl-2-oleoyl phosphatidylcholine (POPC).
  • the ratio of phospholipid to fatty acid triglyceride is from 20:80 (mol:mol) to 60:40 (mol:mol).
  • the triglyceride is present in a ratio greater than 40% and less than 80%.
  • the nanoparticle further comprises a sterol.
  • Representative sterols include cholesterol.
  • the ratio of phospholipid to cholesterol is 55:45 (mol:mol).
  • the nanoparticle includes from 55-100% POPC and up to 10 mol % PEG-lipid.
  • the lipid nanoparticles of the disclosure may include one or more other lipids including phosphoglycerides, representative examples of which include phosphatidylcholine, phosphatidylethanolamine, phosphatidyl serine, phosphatidylinositol, phosphatidic acid, palmitoyloleoylphosphatidylcholine, lyosphosphatidylcholine, lysophosphatidylethanolamine, dipalmitoylphosphatidylcholine, di oleoylphosphatidylcholine, distearoylphosphatidylcholine, and dilinoleoylphosphatidylcholine.
  • phosphoglycerides representative examples of which include phosphatidylcholine, phosphatidylethanolamine, phosphatidyl serine, phosphatidylinositol, phosphatidic acid, palmitoyloleoylphosphatidylcholine
  • Representative nanoparticles of the disclosure have a diameter from about 10 to about 100 nm. The lower diameter limit is from about 10 to about 15 nm.
  • the limit size lipid nanoparticles of the disclosure can include one or more low molecular weight compounds that are used as therapeutic and/or diagnostic agents. These agents are typically contained within the particle core.
  • the nanoparticles of the disclosure can include a wide variety of therapeutic and/or diagnostic agents.
  • Suitable low molecular weight compounds agents include chemotherapeutic agents (i.e., anti -neoplastic agents), anesthetic agents, beta-adrenaergic blockers, anti-hypertensive agents, anti-depressant agents, anti-convulsant agents, anti-emetic agents, antihistamine agents, anti-arrhythmic agents, and anti-malarial agents.
  • chemotherapeutic agents i.e., anti -neoplastic agents
  • anesthetic agents i.e., beta-adrenaergic blockers, anti-hypertensive agents, anti-depressant agents, anti-convulsant agents, anti-emetic agents, antihistamine agents, anti-arrhythmic agents, and anti-malarial agents.
  • antineoplastic agents include doxorubicin, daunorubicin, mitomycin, bleomycin, streptozocin, vinblastine, vincristine, mechlorethamine, hydrochloride, melphalan, cyclophosphamide, triethylenethiophosphoramide, carmaustine, lomustine, semustine, fluorouracil, hydroxyurea, thioguanine, cytarabine, floxuridine, decarbazine, cisplatin, procarbazine, vinorelbine, ciprofloxacion, norfloxacin, paclitaxel, docetaxel, etoposide, bexarotene, teniposide, tretinoin, isotretinoin, sirolimus, fulvestrant, valrubicin, vindesine, leucovorin, irinotecan, capecitabine, gemcitabine, mitoxantrone hydrochloride
  • lipid nanoparticles are nucleic-acid lipid nanoparticles.
  • nucleic acid-lipid nanoparticles refers to lipid nanoparticles containing a nucleic acid.
  • the lipid nanoparticles include one or more cationic lipids, one or more second lipids, and one or more nucleic acids.
  • the lipid nanoparticle composition and the nucleic acid are combined by mixing.
  • the mixing is done using a microfluidic mixer such as a mixing chamber or cartridge as described below.
  • a first source and second source of reagents are input into the microfluidic mixer, and lipid nanoparticles are collected from an outlet of the microfluidic mixer.
  • the first source includes a payload in a first solvent.
  • the payload may include a nucleic acid.
  • the payload may include a therapeutic agent.
  • the combination of the payload in the first solvent may be described as the aqueous phase. Any suitable first solvent may be used. Suitable first solvents include solvents in which the payload is soluble and that are miscible with the second solvent.
  • the first solvent comprises aqueous buffers.
  • the aqueous buffer includes a low pH buffer.
  • the low pH buffer includes a citrate or acetate buffer.
  • the second source includes embodiments of the lipid nanoparticle composition as described herein in a second solvent.
  • the combination of the lipid nanoparticle composition and the second solvent may be described as the organic phase.
  • Any suitable second solvent may be used.
  • Suitable second solvents include solvents in which the ionizable lipids according to embodiments of the invention are soluble, and that are miscible with the first solvent.
  • the second solvent comprises one or more solvents, two or more solvents, three or more solvents, or four or more solvents.
  • the second solvent includes, but is not limited to, 1,4-di oxane, tetrahydrofuran, acetone, acetonitrile, dimethyl sulfoxide, dimethylformamide, acids, alcohols, or a combination thereof.
  • the second solvent comprises aqueous or anhydrous alcohols.
  • the alcohol includes a primary, secondary, or tertiary alcohol having from 1 to 12 branched or unbranched carbons (e.g., methanol, ethanol, n-propanol, isopropanol, n-butanol, 2-methyl 1- propanol, 2-butanol, 2-methylpropan-2-ol), or a combination thereof.
  • a suitable device for mixing is a cartridge which includes one or more microchannels (i.e., a channel having its greatest dimension less than 1 millimeter).
  • the microchannel has a diameter from about 20 pm to about 300 pm.
  • at least one region of the microchannel has a principal flow direction and one or more surfaces having at least one groove or protrusion defined therein, the groove or protrusion having an orientation that forms an angle with the principal direction e.g., a staggered herringbone mixer) or a bifurcating toroidal flow mixer.
  • a device has non-microfluidic channels having dimensions greater than 1000 pm, to deliver the fluids to a single mixing channel.
  • any suitable flow ratio may be used to combine the lipid nanoparticle composition and the nucleic acid.
  • the lipid nanoparticle composition and the nucleic acid are combined using a flow ratio of about 1 : 1 (or 1) to about 10: 1 (or 10) (aqueous phase: organic phase) by volume, e.g., 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 a range of any two of the aforementioned values.
  • the flow ratio is more than about 0.5.
  • 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.
  • any suitable N/P ratio may be used to combine the lipid nanoparticle composition and the nucleic acid.
  • the lipid nanoparticle composition and the nucleic acid are combined at a N/P ratio from about 2 to about 20, e.g., 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 NZP ratio defined by a range of any two of the aforementioned values.
  • the N/P ratio is more than about 1, more than about 2, more than about 3, more than about 4, more than about 5, more than about 6, more than about 7, more than about 8, or more than about 9. In some case, 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. Any suitable total flow rate can be used to combine the lipid nanoparticle composition and the nucleic acid.
  • the lipid nanoparticle composition and the nucleic acid are combined with a total flow rate of the organic phase and aqueous phase from about 2 to about 2000 mL/min, e.g., 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, about 450 mL/min, or about 500 mL/min, about a total flow rate
  • the total flow rate is more than about 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.
  • the total flow rate is less than about 3000 mL/min, less than about 2800 mL/min, less than about 2600 mL/min, less than about 2400 mL/min, less than about 2200 mL/min, less than about 2100 mL/min, less than about 2000 mL/min, less than about 1800 mL/min, less than about 1600 mL/min, less than about 1500 mL/min, less than about 1400 mL/min, less than about 1200 mL/min, less than about 1000 mL/min, or less than about 800 mL/min.
  • the formulation system described below may be used to combine the lipid nanoparticle composition and the nucleic acid and may include a housing, a first pump for pumping a first fluid from a first source to a mixing chamber or cartridge, a second pump for pumping a second fluid from a second source to the mixing chamber or cartridge, and an array of valves for selectively controlling a flow of the first fluid to the cartridge, the second fluid to the mixing chamber, and a flow of 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, the 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 tubing segment fluidly connected to the outlet of the cartridge and configured for fluid connection to the collection container.
  • the formulation system and flow kit are configured for the clinical and commercial manufacturing of nanoparticle medicines as described above.
  • FIG. 1 is a front elevational view of an exemplary formulation system according to an embodiment of the invention, with an exemplary flow kit installed.
  • FIG. 2 is a front, perspective view of the exemplary formulation system of FIG. 1.
  • FIG. 3 is a rear elevational view of exemplary the formulation system of FIG. 1.
  • the formulation system 10 includes a generally rectangular housing 12.
  • the housing 12 may include a flow kit 200 mounted thereon.
  • the formulation system 10 includes a variety of formulation units, including pumps 36, 38, 40, retention clips 42 for the pumps, valves 44, 46, 48, 50, 52, flow meter housings 54, flow meter cables 55.
  • the valves may include input valves 44, output valves 46, waste valve 48, calibration valve 50, and one or more control valves 52.
  • the formulation units include containers, such as fluid sources 260, 262, 264, 268, and/or collection containers 270.
  • the formulation system 10 is provided with a network of tubing, providing fluid communication between the formulation units, including the one or more pumps 36, 38, 40, 60, 64, the retention clips 42, the valves 44, 46, 48, 50, 52, the flow meter housings 54, etc.
  • the tubing may form an array between one or more of the formulation units.
  • the tubing may run between the formulation units as separate entities or lines, but may also be joined to one or more of the formulation units.
  • the tubing may be disposable/replaceable and may be connected to the formulation units via connectors, which may provide a tool-less operation.
  • the tubing may be tubing of standardized inner dimensions so that a certain length will hold a predictable volume.
  • the tubing may be included as part of the formulation system 10, the flow kit 200, and/or may be provided separately.
  • the tubing may be referred to as, for example, tubing, tubing segments, lines, etc. throughout the specification.
  • the housing 12 may be supported in an elevated position above the ground on a plurality of support legs 13.
  • the support legs 13 are outfitted with casters 14.
  • the support legs 13 are adjustable to enable leveling of the housing 12 on a surface.
  • the housing 12 has a front face 16 on which operational components may be connected, as discussed in detail below, opposing sidewalls 18, 20, and a rear face 22 having an access door 24 allowing selective access to the interior space 34 of the housing 12.
  • the front face 16 of the housing 12 includes a drip tray 26, which may take the form of a ledge extending forward from the front face 16 of the housing 12.
  • the housing 12 may include a plurality of handles 28, 30 for facilitating movement and positioning of the system 10.
  • a top wall 31 of the housing may include a venting mechanism 32 providing fluid communication between the interior space 34 within the housing 12 and the ambient environment within which the system 10 is positioned.
  • FIG. 4 is another front elevational view of the exemplary formulation system of FIG. 1, depicted without the exemplary flow kit 200.
  • the system 10 includes pumps 36, 38, 40, which may be an array of pumps mounted to a lower portion of the front face 16.
  • the array of pumps includes three pumps: a first pump 36, a second pump 38, and a third pump 40, although additional or fewer pumps may also be provided depending on the number of fluids to be mixed and particular product formulation/application.
  • the positioning of the first, second, and third pumps 36, 38, 40 to the lower portion of the front face 16 may facilitate priming of the pumps 36, 38, 40, as discussed below.
  • the array of pumps 36, 38, 40 is removable.
  • the pumps 36, 38, 40 are centrifugal pumps, piston pumps, gear pumps, diaphragm pumps, peristaltic pumps, vane pumps, disk pumps, positive displacement pumps, magnetic drive pumps, or other similar pumps, or a combination thereof, as non-limiting examples.
  • the pumps 36. 38, 40 may be magnetic drive, centrifugal pumps.
  • the first pump 36, second pump 38, and third pump 40 are used to pump input fluids through a flow kit 200, as detailed hereinafter with regards to FIG. 18, for example, and are each controlled independently.
  • Each of the first, second, and third pumps 36, 38, 40 includes a retention clip 42 providing for releasable engagement of a pump head of a flow kit with each of the pumps 36, 38, 40, as discussed in detail hereinafter.
  • the 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, 40), output valves 46 (e.g., two output valves), a waste valve 48, and a calibration valve 50.
  • a control valve 52 is provided, which may be adjacent to one of the input valves, the purpose of which will be described hereinafter, and which may be a similar valve to the valves described above.
  • the input valves 44, output valves 46, waste valve 48, calibration valve 50, and control valve 52 may be globe valves, diaphragm valves, needle valves, pinch valves, or similar-type of throttling and/or control valves.
  • the vales are pinch valves
  • the pinch valves may be pneumatic pinch valves, hydraulic pinch valves, and/or solenoid pinch valves, or any other similar types of pinch valves may also be utilized without departing from the scope of the invention.
  • the system may include fewer or additional valves than the valves described herein.
  • three input valves 44 may be provided, with each input valve 44 fluidly connected to an input line 214, 216, 218 as disclosed below with respect to FIG. 18, for example.
  • the third input line 218 may be a dilution line 218.
  • These input valves 44 prevent undesired forward or backward flow through the system 10.
  • two output valves 46 are used to direct fluid to a waste container 272 or formulation collection container 270 (see, e.g., FIG. 20).
  • the waste valve 48 and the calibration valve 50 direct fluid to either a waste outlet line or to the calibration flow meter 64, respectively, during priming and calibration.
  • the control valve 52 may be formed as a pinch valve and interfaces with tubing connected to a third pump head 206 of the flow kit 200.
  • the control valve 52 may include a rotatable knob that can be manually rotated to selectively allow or restrict/prevent a flow of fluid through the tubing engaged with the control valve 52.
  • the control valve 52 provides additional flow resistance on the third input line 218 (e.g., dilution line) during calibration and formulation procedures. This additional flow resistance may compensate for variations between inlet and outlet container heights and/or positioning.
  • the user interface 66 may prompts the user to adjust the control valve 52 during the calibration unit procedure.
  • control valve 52 when turned clockwise, the control valve 52 may further restrict flow through the line; when turned counter-clockwise, the control valve 52 may allow more fluid to flow through the line. In some examples, when turned counter-clockwise, the control valve 52 may further restrict flow through the line; when turned clockwise, the control valve 52 may allow more fluid to flow through the line.
  • each of the flow meter housings 54 is configured to receive one or more flow meters (e.g., 208, 210, 212) of the flow kit 200, and has an associated flow meter cable 55 having a sensor, the purpose of which will be described hereinafter.
  • a hanger or post 58 may be provided adjacent to the flow meter housings 54 so that covers of the flow meter housing 54 may be placed during installation or changeover of a flow kit 200 or stored.
  • the formulation system 10 additionally includes a cartridge receptacle 56 with a recess for receiving a microfluidic mixing chamber or cartridge 226 of the flow kit 200.
  • the array of first, second, and third pumps 36, 38, 40, flow meter housings 54, input valves 44, cartridge receptacle 56, and output valves 46 are generally linearly aligned along a generally upward angle on the front face 16 of the housing 12.
  • the first, second, and third pumps 36, 38, and 40 are positioned below the input fluid levels of the system 10 and/or the cartridge receptacle 56 to support priming and enable bubble clearing.
  • Adjacent to the waste valve 48 and calibration valve 50 is a pump 60, a tube support 62, and a calibration flow meter 64.
  • the pump 60 may be a peristaltic, diaphragm, syringe, gear, rotary lobe, microfluidic, centrifugal, piston, or microfluidic pump, which allows priming of the tubing/lines, as discussed hereinafter.
  • the pump 60 is a peristaltic pump 60.
  • the calibration flow meter 64 may be a Coriolis, ultrasonic, electromagnetic, thermal mass, positive displacement, or turbine flow meter, although other similar types of pumps and/or flow meters may be utilized.
  • the formulation system 10 may include a controller (not shown) which may include a memory, processing unit (not shown), which may be an integrated central processing unit, a stand-alone computer, a laptop, a tablet, etc., as non-limiting examples.
  • the processing unit may comprise software to control the user interface 66, including routines needed to perform measurements or production, user guides or software for setting up the system, maintaining the system, storing and analyzing data, priming, calibrating, purging, etc.
  • the formulation system 10 may also include a user interface 66 such as, for example, a touchscreen interface for presenting data and system information in connection with the memory and processing unit and for controlling operation of the system according to a variety of user-selectable input parameters and a set of pre-programmed instructions stored in the memory and/or processing unit.
  • the user interface 66 includes one or more status indicator lights 68 and an emergency stop button or switch 70.
  • the user interface 66 allows for recipe and batch creation, provides for system monitoring, and/or other operations as described above.
  • FIG. 5 is a side elevational view of the exemplary formulation system of FIG. 4, the sidewall 18 of the housing 12 includes a pneumatic connection port 72 for connecting an external supply of compressed air (not shown) to the system 10, a power cable 74 for connecting the system 10 to a supply of electrical power, and a network connection port 76 (e.g., an Ethernet port) for connecting the system to the Internet or local area network. While a wired connection is illustrated in FIG. 5, other communication means known in the art such as Wi-Fi, Cellular, Bluetooth and the like may also be utilized for communicating with the system 10.
  • a wired connection is illustrated in FIG. 5, other communication means known in the art such as Wi-Fi, Cellular, Bluetooth and the like may also be utilized for communicating with the system 10.
  • the power cable 74 is electrically connected to a power switch box 78 having a power switch 80 enabling a user to provide or cut power to the system 10, as desired.
  • internal connections and cabling are provided so as to transmit electrical power from the offboard power supply, through the power cable 74 to the various electrical components of the system 10 requiring power for operation (e.g., the pumps, user interface, etc.).
  • internal connections and hoses/tubing are provided so as to provide compressed air from the offboard air supply, through the pneumatic connection port 72 to the various components of the system 10 requiring a source of air for operation (e.g., pneumatic pinch valves, purge box, etc.).
  • FIG. 6 is a front, transparent perspective view of a portion of the exemplary formulation system of FIG. 1 in which routing of the pneumatic tubing for suppling air from the air supply to the valves is shown.
  • the interior sidewall of the housing 12 has a programmable logic controller panel 82 mounted thereto, to which the control hardware, circuitry, power supplies, etc. of the system 10 are mounted.
  • the housing 12 is manufactured from a rigid, sterilizable material such as stainless steel.
  • the housing 12 may be relatively impervious to solid foreign objects and water/fluids, and may have an ingress protection rating, e.g., an International Electrotechnical Commission (IEC) rating, indicative of such.
  • the housing 12 may have an ingress protection (IP) rating of IP 54.
  • 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, though embodiments are not limited in this regard.
  • valves 46, 48, 50 are fluidly connected to the supply of compressed air interior to the housing 12 and selectively receive compressed air therefrom for operation of the valves 44, 46, 48, 50.
  • the input valves 44 include a valve housing 84 exterior to the housing 12.
  • the valve housing 84 includes a channel 86 for receiving a section of tubing of the flow kit 200, and a manually operable safety lock 88.
  • the valves 44, 46, 48, 50 are used to control the path of the fluid through the system 10. In some examples, seven valves are utilized to control the flow of liquid in the system 10.
  • FIG. 8 is a perspective view of a housing of the exemplary valve of FIG. 1, depicting a safety lock in an open position.
  • FIG. 9 is a perspective view of a housing of the exemplary valve of FIG. 1, depicting the safety lock in a closed/locked position.
  • FIG. 10 is an exploded, perspective view of an exemplary pump assembly of the formulation system 10.
  • the exemplary pump assembly may include the first, second, and third pumps 36, 38, 40. As shown therein, the first, second, and third pumps 36, 38, 40 are mounted to the front face 16 of the housing 12 via a pump mount 90.
  • a locking plate 92 allows for releasable connection of associated pump heads of the flow kit to the first, second, and third pumps 36, 38, 40, as described below.
  • FIG. 11A is an enlarged, perspective view of an exemplary mounting mechanism of the exemplary pump assembly of FIG.
  • the fastening mechanism may be a clamp, clip, or other similar fastening mechanism, such as a spring clips 94.
  • FIG. 11B is a perspective view of an exemplary locking mechanism of the exemplary pump assembly of FIG. 10.
  • the spring clips 94 include an annular retention member 95 having opposed, resilient arms 99, and a handle or pull tab 97 that can be grasped by a user to install or remove the spring clips 94, as desired.
  • the spring clips 94 secure the each of the pump heads in the respective first, second, and third pumps 36, 38, 40 when the spring clip 94 is clicked into place during the installation of the flow kit 200.
  • the pull tab 97 on the spring clip 94 allows each of the pump heads to be released from the respective first, second, and third pumps 36, 38, 40 during the uninstall step without the need to rotate the pump heads.
  • FIG. 12A is an enlarged, perspective view of an exemplary flow meter and exemplary flow sensor of the exemplary formulation system of FIG. 1.
  • FIG. 12B is another enlarged, perspective view of an exemplary flow meter and exemplary flow sensor of the exemplary formulation system of FIG. 1.
  • FIG. 13 is an enlarged, perspective view of a cable retention port of the exemplary flow meter and exemplary flow sensor of FIGs. 12A and 12B.
  • the front face 16 of the housing 12 includes flow meter housings 54 configured to receive flow meters 208, 210, 212 of the flow kit 200.
  • the front face 16 of the 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 of the flow meter housings 54 may include a flow meter cable 55 with a sensor (not shown) that may be connected to the flow meters 208, 210, 212 on the flow kit 200 and may be used to monitor the flow rates in each input line of the flow kit 200, and feed the data back to the controller.
  • the flow meters 208, 210, 212 may be Coriolis, ultrasonic, electromagnetic, thermal mass, positive displacement, turbine, or any other similar-type flow meter. In some examples, flow meters 208, 210, 212 are ultrasonic flow meters.
  • the front face 16 of the housing 12 may include three connectors or cable retention ports 96 configured to receive a distal end of the flow meter cables 55 of FIG. 12A, therein.
  • Each port 96 has an associated cap 98 that can be utilized to close off the port 96 when a flow meter cable 55 is not connected to the port 96.
  • the ports 96 are utilized to house and protect a sensor in the distal end of the cables 55 that is when the system 10 is not being used, or when installing or removing the flow kit 200 from engagement with the flow meter housings 54.
  • the flow meter cables 55 are removed from the ports 96 and connected to the flow meter housings 54 in order to monitor the flow rates in corresponding input lines 214, 216, 218 of the flow kit 200.
  • FIG. 14 illustrates an exploded, perspective view of the venting mechanism 32 of the formulation system 10.
  • the venting mechanism 32 includes an associated air filter 102, such as a cartridge air filter.
  • the air filter 102 has a minimum efficiency of capturing 75% of all particles between 0.3pm - 1.0pm in size, and a minimum efficiency of capturing 90% of all particles between 1pm - 10pm in size.
  • FIG. 15 is a perspective, partial cutaway view of the exemplary formulation system of FIG. 1, including an exemplary purge box within the exemplary formulation system.
  • FIG. 16 is a rear, perspective view of an interior of the exemplary formulation system of FIG. 1, including the exemplary purge box of FIG. 15.
  • FIG. 17 is a perspective detailed view of the exemplary purge box of the exemplary formulation system of FIG. 1, including the exemplary purge box of FIG. 15.
  • An interior of the housing 12 contains a purge box 104.
  • the purge box 104 is generally rectangular in shape and defines an open interior space 106.
  • the purge box 104 contains all electrical components that are not rated for use in explosive atmospheres or hazardous locations.
  • the purge box 104 contains signal conditioners that are required to be able to use the single use flow meters 208, 210, 212 of the flow kit 200.
  • the purge box 104 may be placed outside the housing 12, in which case, the purge box 104 is contained within an increased-safety enclosure having ingress protection. This allows for improved aesthetics and cleanability of surfaces external to the purge box 104.
  • the purge box 104 is equipped with a purging system that prevents flammable gases from entering the purge box, and is rated for use in an explosive atmosphere.
  • the purge box 104 is equipped with a purging unit which prevents flammable gases from being present in the housing 12 when energized.
  • the purge box 104 is provided with compressed air from the compressed air supply, and includes an outlet 108.
  • the purge time is controlled by a digital, pneumatic timer. During start-up, the purge box 104 goes into purging mode and removes any gases from the purge box 104. Once purging mode is complete it goes into operation mode.
  • the purge box 104 operates in two modes, a purging mode and an operation mode.
  • the purging mode is automatically started when the system power switch on the instrument is turned on.
  • the purge air supply must also be turned on for the purge to be successfully completed.
  • a predetermined volume of air under positive pressure is flushed through the purge box 104 to remove gases remaining in the purge box 104 and to minimize the risk of any flammable gases entering the purge box which houses the non-Hazloc rated electrical components.
  • Purging mode is also activated if the pressure in the purge box falls below the safe threshold.
  • Operation mode is used during normal operation to maintain a certain overpressure in the purge box 104 and pressurized housing 12 to prevent flammable gases from entering as long as the system 10 power is turned on. If the pressure in the housing 12 drops but stays within the safe range, a warning message appears on the interface 66. If a predetermined pressure is not maintained in the purge box 104 above the safe threshold, the power supply to the electrical components inside the purge box 104 is automatically turned off. Any active processes are stopped, and the active formulation is paused. An alarm is automatically activated and the purging unit goes into purging mode. The system cannot start any processes or formulations until the housing 12 is purged again, and the alarm is acknowledged.
  • FIG. 18 is a perspective view of an exemplary flow kit 200 for use with the formulation system of FIG. 1.
  • FIG. 19 is an enlarged, perspective view of portions of the exemplary flow kit 200 of FIG. 18.
  • the formulation system 10 further includes a llow kit 200 that is releasably mountable to the front face 16 of the housing 12.
  • the flow kit 200 includes three pump heads 202, 204, 206, three input lines 214, 216, 218, three flow meters 208, 210, 212, a cartridge or mixing chamber 226, and tubing connecting the various components (e.g., pump three pump heads 202, 204, 206, three input lines 214, 216, 218, three flow meters 208, 210, 212, a mixing chamber/cartridge 226).
  • the three pump heads 202, 204, 206 are configured to connect to, and be driven by, the pumps 36, 38, 40 of the housing 12.
  • each of the pump heads 202, 204, 206 is a magnetic centrifugal pump and includes a magnetically-driven impeller (not shown).
  • the first pump head 202, second pump head 204, and third pump head 206 may include one or more inlets where one or more connectors (as described below with reference to FIG. 19) may be attached for fluid connection via a tubing segment to one or more sources.
  • the first pump head 202 may include one or more inlets 203 for fluid connection via tubing segment 261 to a first formulation fluid source 260 (aqueous input fluid) and via tubing segment 263 a first calibration fluid source 262.
  • the second pump head 204 may include one or more inlets 205 for fluid connection via tubing segment 265 to a second formulation fluid source (organic input fluid) 264 and via tubing segment 267 to a second calibration fluid source 266.
  • the third pump head 206 may have one or more inlets 207 for fluid connection via tubing segment 269 to a dilution fluid source 268 (dilution fluid).
  • the flow kit 200 also includes three flow meters 208, 210, 210 fluidly connected to the output of the pump heads 202, 204, 206.
  • the flow meters 208, 210, 212 measure the liquid flow rate for each line, using ultrasound, and are installed in the flow meter housings 54 on the front of the housing 12.
  • the flow meters 208, 210, 212 enable real-time feedback to the pumps 36, 38, 40.
  • the flow kit 200 additionally includes a first input line 214 that carries the aqueous input fluid through the flow kit 200, a second input line 216 that carries the organic input fluid through the flow kit 200, and a third input line/dilution line 218 that carries the dilution fluid through the flow kit 200.
  • the input lines 214, 216 and 218 are configured for installation in the corresponding input valves 44.
  • the third input line/dilution line 218 is also configured for installation in control valve 52, as best shown in FIG. 2.
  • the flow kit 200 includes a fluidic mixing chamber or cartridge 226 having two inputs, such as a first chamber inlet 215 and a second chamber inlet 217 configured for fluid connection with the first input line 214 and second input line 216, and an outlet configured for selective fluid connection with the waste output line 228 and formulation output line 230.
  • the waste output line 228 is configured for installation in one of the output valves 46, and waste valve 48 (see, e.g., FIG. 1), and carries waste from a process/procedure to the waste output.
  • the formulation output line 230 is configured for installation in the other output valve 46 and carries the formulated product to a formulation collection container 270 for collection.
  • the cartridge 226 may be a fluidic mixer having bifurcated fluidic flow through toroidal mixing elements of the type disclosed in U.S. Patent Nos. 10,835,878 and 10,076,730, which are incorporated by reference herein in their entireties.
  • the cartridge 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 cartridges 226 can be utilized with the system 10 (and so that the cartridge 226 is suitable for the recipe selected).
  • RFID Radio Frequency Identification
  • the input lines of the flow kit 200 may include one or more connectors for fluid connection of the input lines to the pump heads.
  • the one or more connectors may be in-line connectors with an input and corresponding output, more than one input corresponding to an output, such as Y-connectors, T- connectors, etc.
  • the connectors may be Tri-Clamp (TC) connectors, threaded connectors (e g., DIN 11851 fittings), flange connections, camlock couplings, compression fittings, etc., and/or a combination of one or more connectors.
  • TC Tri-Clamp
  • 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.
  • the one or more inlets 203 of the first pump head 202 may have a T-connector 232 to enable connection to two different sources 260 262, wherein a user is able to load the sources 260262 at the same time instead of loading each source separately for operation of the formulation system 10.
  • the one or more inlets 205 of the second pump head 204 may have a T- connector to enable connection to two different sources 264266.
  • the connectors may be T-connectors including TC connections including a cap 234.
  • the flow kit 200 is a single-use, disposable flow kit that can be discarded after a batch is formulated and collected. In other embodiments, the flow kit 200 may be reused. As discussed above, the flow kit 200 includes the cartridge 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 ingredient free materials, assembled in a cleanroom, packed in double bags, and gamma-irradiated (25.0 to 45.0 kGy) for bioburden reduction before delivery.
  • the flow kit 200 can be easily installed and ready for formulation in less than 60 minutes, supporting efficient changeover between production batches and products during manufacturing.
  • the flow kit 200 provides for flow rates between about 6 to about 48 L/hour. In an embodiment the flow kit 200 provides for flow rates between about 6 to about 12 L/hour. In another embodiment the flow kit 200 provides for flow rates between about 12 to about 48 L/hour. In another embodiment the flow kit 200 provides for flow rates between about 24 to about 48 L/hour.
  • FIG. 18 shows the flow kit 200 fluidly connected to the first formulation fluid source 260, first calibration fluid source 262, second formulation fluid source 264, second calibration fluid source 266, dilution fluid source 268, formulation collection container 270, and waste container 272.
  • Each fluid source or container may have an independent shut off valve or pinch clamp on the tubing line to close the point of connection with the flow kit 200.
  • the fluid sources or connected containers may be bags, vessels, receptacles, or other similar containers that are able to hold fluids.
  • FIG. 20 is a schematic illustration of the system 10 and flow kit 200.
  • the controller (not shown) is configured to be displayed on the user interface 66.
  • the system 10 is configured to monitor a variety of process parameters and to display the measured parameters on the interface 66.
  • the speed of each pump 36, 38, 40 is monitored in real-time and displayed on the interface.
  • the flow rate through flow meters 208, 210, 212 is also measured and displayed on the user interface 66 in real-time.
  • the flow rate measured by the calibration flow meter 64 is displayed, as is the start/stopped state of the peristaltic pump.
  • the interface 66 is also configured to display the air supply pressure to the system 10.
  • the formulation system 10 supports an automated workflow of priming, calibration, formulation, and in-line dilution to simplify the Good Manufacturing Practices (GMP) of mRNA-LNP drug products.
  • the first formulation fluid source 260 may contain a payload for formulation, such as a nucleic acid suspended in an aqueous buffer
  • the first calibration fluid source 262 contains just aqueous buffer for priming and calibrating (no nucleic acid).
  • the second formulation fluid source 264 may contain a lipid mix (lipid and solvent such as ethanol), while the second calibration fluid source 266 contains just solvent for priming and calibrating (e.g., pure ethanol).
  • the dilution fluid source 268 contains a dilution buffer for diluting, if applicable for a chosen recipe.
  • FIG. 21 is an exemplary graph depicting improved flow rates achieved using the exemplary formulation system of FIG. 1.
  • a pump using the formulation system 10 may achieve a deviation percentage between +/- 6-8% for flow rates of 100 mL/min and a deviation percentage between +/- 3-4% with flow rates of 300 mL/min.
  • Tight control of deviation percentage of flow rates can be achieved with other flow rates, for example, flow rates of 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.
  • FIG. 22 is a flow chart 2200 illustrating exemplary steps that may be utilized for formulating a product using the exemplary formulation system of FIG. 1.
  • the flow kit 200 is positioned and secured to the front face 16 of the housing 12.
  • the fluid sources, formulation collection container, and waste container 272 may be fluidly coupled to appropriate connections on the flow kit 200.
  • the pneumatic air supply is connected to the system and power is then provided to the system 10 by using power switch 80.
  • the user interface 66 initializes and a purge cycle is carried out according to a set of preprogrammed instructions.
  • pressurized air is provided to the purge box 104 and exhausted into the interior space 34 to create positive pressure within the interior space 34, which pushes air from the interior space out of the venting mechanism 32 in the top of the housing 12 after passing through the cartridge air filter 102.
  • all electrical components inside the purge box 104 are turned on by the controller.
  • a user via the user interface 66, is prompted to set up a batch plan and/or select from a previously defined formulation recipe stored in memory.
  • the system 10 then verifies that the flow kit 200 installed is appropriate for the selected formulation recipe.
  • an RFID or other similar identification is used to verify that the correct flow kit 200 is being utilized.
  • the flow kit 200 priming is carried out. Priming involves setting the ultrasonic flow meters 208, 210, 212 to the calibration kinematic viscosities set in the recipe.
  • the user interface 66 directs the operator to prime the first input line 214 and/or second input line 216 until the respective tubing and connections are primed (which uses the peristaltic pump 60 and valve toggling).
  • the user interface 66 directs the operator to prime the third input line (or dilution line) 218 until the third input line 218 and ultrasonic flow meter 212 are primed.
  • the controller automatically primes the third input line/dilution line 218 until the tubing and connections are primed or directs the operator to prime the third input line 218 until the third input line 218 and ultrasonic flow meter 212 are primed.
  • This operation uses the peristaltic pump 60 and valve toggling as well.
  • the system 10 then runs an auto prime to clear the rest of the line, which utilizes the peristaltic pump 60, the centrifugal pumps 202, 204, 206, and valve toggling. For the dilution line 218, a larger flush is carried out to clear the remaining air up to the output valves 46.
  • the system 10 also tares the ultrasonic flow meters 208, 210, 212, prompts the user to open the clamps on the calibration lines 220, 222, primes the calibration lines 220, 222, and prompts the user to check for bubbles in the flow kit 200.
  • step 2210 once priming of the flow kit 200 is complete, using the plain buffer from first calibration fluid source 262, plain solvent from second calibration fluid source 266, and dilution fluid from dilution fluid source 268, the flow meters 208, 210, 212 corresponding to each of the first input line 214, second input line 216, and dilution line 218 are calibrated.
  • the system 10 is configured to guide the operator in setting the control valve on the dilution line 218, if required.
  • the system 10 then runs each centrifugal pump 36, 38, 40 independently at a predetermined fill flow rate to fill the calibration flow meter 64 with the respective fluid.
  • a formulation process is carried out at step 2212.
  • the system 10 prompts the operator to manually close the dilution line 218 and open the reagent lines 214, 216 or automatically closes the dilution buffer line 218 and opens the reagent lines 214, 216, and sets the ultrasonic flow meters to the formulation kinematic velocities set in the recipes.
  • the system 10 then runs the pumps with the goal of flushing each of the reagents from first and second formulation fluid sources 260, 264 through each pump. In embodiments, at least 100 mb of each respective reagent may be used for flushing.
  • the respective fluids pass through the cartridge 226 and are mixed so as to encapsulate a therapeutic material (e.g., the nucleic acid) inside a lipid nanoparticle (e.g., as described more fully in U.S. Patent Nos. 10,835,878 and 10,076,730).
  • the fluid exiting the mixing chamber comprising lipid nanoparticles, may be diluted by pumping the dilution fluid/buffer through the dilution line 218 via the third pump 40 and mixing the dilution fluid with the fluid exiting the cartridge 226 before flowing to the formulation collection container 270. This lowers the ethanol content immediately following formulation, resulting in a more stable product. This formulation process is run until the recipe volume is reached.
  • the system 10 sends an instruction (e.g., to the operator) to close and save the collected batch.
  • a flow kit removal step is carried out where all the valves are opened to allow for removal of the flow kit 200.
  • the user interface 66 provides step-by-step instructions for removing the flow kit 200.
  • the calibration flow meter may also be drained.
  • the formulation system 10 of the invention thus provides an automated, single-use system for the clinical and commercial production of lipid nanoparticles (LNPs) under cGMP conditions.
  • the system 10 is designed for efficient changeover and robust manufacturing processes, and enables operational flexibility and standardized manufacturing of genomic medicines.
  • the formulation system 10 supports an automated workflow of priming, calibration, formulation, and in-line dilution to simplify GMP manufacturing of LNP products.
  • Its software interface 66 enables 21 CFR Part 11 compliance and electronic batch records that capture in-process monitoring of flow rate and pump speed.
  • the system uses scalable microfluidic mixing technology and low-pulsation pumps for precise control of mixing parameters, resulting in consistent flow rates from 6 to 48 L/h that produce homogenous and reproducible nanoparticles.
  • the single-use flow path minimizes the need for sanitizing and performing cleaning validation, enabling efficient changeover 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.
  • the system 10 is also ATEX (ATmospheres EXplosibles) and lECEx (International Electrotechnical Commission System for Certification to Standards Relating to Equipment for Use in Explosive Atmospheres) rated for use in hazardous locations to ensure safety when handling flammable solvents during LNP formulation.
  • the system 10 of the invention includes a purge box 104 which ensures non-Hazloc rated equipment contained within is not exposed to flammable vapors.
  • the use of centrifugal pumps minimizes flow fluctuations, resulting in more accurate and quicker formulation than has heretofore been possible.
  • the use of the magnetic drive, centrifugal pumps transfer force and provide for fluid flow through the flow kit 200 without the pumps, valves, etc., interfacing with the fluids or therapeutic material used.
  • mounting of the flow kit 200 on the exterior of the housing 12 provides for easy access for set up, removal, changeover, troubleshooting and cleaning.
  • the cartridge 226 provides for the inline entry of fluids as opposed to existing systems, which often relied on overhead entry.
  • the system 10 includes a centralized control unit, e.g., a controller, for carrying out the process steps disclosed herein according to algorithm(s) stored in memory in an automated and/or semi -automated manner.

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  • Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Dispersion Chemistry (AREA)
  • Infusion, Injection, And Reservoir Apparatuses (AREA)
  • Catching Or Destruction (AREA)
  • Accessories For Mixers (AREA)

Abstract

L'invention concerne un système de formulation qui comprend un boîtier présentant un espace intérieur, une interface sur une surface extérieure du boîtier pour recevoir un kit d'écoulement, une première pompe pour pomper un premier fluide d'une première source à une chambre de mélange, une seconde pompe pour pomper un second fluide d'une seconde source à la chambre de mélange, et une ou plusieurs vannes pour réguler de manière sélective un écoulement du premier fluide vers la chambre de mélange, du second fluide vers la chambre de mélange, et un écoulement de fluide mélangé de la chambre de mélange à un récipient de collecte.
PCT/EP2024/084574 2023-12-04 2024-12-03 Kit de formulation, système et procédé Pending WO2025119933A2 (fr)

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US202363605862P 2023-12-04 2023-12-04
US63/605,862 2023-12-04

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WO2025119933A3 WO2025119933A3 (fr) 2025-10-16

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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10076730B2 (en) 2016-01-06 2018-09-18 The University Of British Columbia Bifurcating mixers and methods of their use and manufacture

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US5372421A (en) * 1986-06-05 1994-12-13 Pardikes; Dennis Method of inverting, mixing, and activating polymers
US6203183B1 (en) * 1999-04-23 2001-03-20 The Boeing Company Multiple component in-line paint mixing system
US7632080B2 (en) * 2003-10-30 2009-12-15 Deka Products Limited Partnership Bezel assembly for pneumatic control
JP2017535412A (ja) * 2014-10-07 2017-11-30 アクセス ビジネス グループ インターナショナル リミテッド ライアビリティ カンパニー 個人用製剤装置
CA2883052A1 (fr) * 2015-02-24 2016-08-24 Euan Ramsay Systeme microfluidique a ecoulement continu
US20240100492A1 (en) * 2020-11-30 2024-03-28 Andre Wild Non aggregating microfluidic mixer and methods therefor

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Publication number Priority date Publication date Assignee Title
US10076730B2 (en) 2016-01-06 2018-09-18 The University Of British Columbia Bifurcating mixers and methods of their use and manufacture
US10835878B2 (en) 2016-01-06 2020-11-17 The University Of British Columbia Bifurcating mixers and methods of their use and manufacture

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