WO2026030217A2 - Réacteurs à fonctionnement continu, leurs réseaux et procédés d'utilisation - Google Patents

Réacteurs à fonctionnement continu, leurs réseaux et procédés d'utilisation

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Publication number
WO2026030217A2
WO2026030217A2 PCT/US2025/039482 US2025039482W WO2026030217A2 WO 2026030217 A2 WO2026030217 A2 WO 2026030217A2 US 2025039482 W US2025039482 W US 2025039482W WO 2026030217 A2 WO2026030217 A2 WO 2026030217A2
Authority
WO
WIPO (PCT)
Prior art keywords
cstr
valve
reactor
recirculation
array
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/US2025/039482
Other languages
English (en)
Other versions
WO2026030217A3 (fr
Inventor
Wei Wu
Christopher James Testa
Chuntian HU
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.)
Continuus Pharmaceuticals Inc
Original Assignee
Continuus Pharmaceuticals Inc
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Filing date
Publication date
Application filed by Continuus Pharmaceuticals Inc filed Critical Continuus Pharmaceuticals Inc
Publication of WO2026030217A2 publication Critical patent/WO2026030217A2/fr
Publication of WO2026030217A3 publication Critical patent/WO2026030217A3/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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Classifications

    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J19/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J19/18—Stationary reactors having moving elements inside
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12M—APPARATUS FOR ENZYMOLOGY OR MICROBIOLOGY; APPARATUS FOR CULTURING MICROORGANISMS FOR PRODUCING BIOMASS, FOR GROWING CELLS OR FOR OBTAINING FERMENTATION OR METABOLIC PRODUCTS, i.e. BIOREACTORS OR FERMENTERS
    • C12M23/00—Constructional details, e.g. recesses, hinges
    • C12M23/58—Reaction vessels connected in series or in parallel
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12M—APPARATUS FOR ENZYMOLOGY OR MICROBIOLOGY; APPARATUS FOR CULTURING MICROORGANISMS FOR PRODUCING BIOMASS, FOR GROWING CELLS OR FOR OBTAINING FERMENTATION OR METABOLIC PRODUCTS, i.e. BIOREACTORS OR FERMENTERS
    • C12M27/00—Means for mixing, agitating or circulating fluids in the vessel
    • C12M27/02—Stirrer or mobile mixing elements
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12M—APPARATUS FOR ENZYMOLOGY OR MICROBIOLOGY; APPARATUS FOR CULTURING MICROORGANISMS FOR PRODUCING BIOMASS, FOR GROWING CELLS OR FOR OBTAINING FERMENTATION OR METABOLIC PRODUCTS, i.e. BIOREACTORS OR FERMENTERS
    • C12M29/00—Means for introduction, extraction or recirculation of materials, e.g. pumps
    • C12M29/18—External loop; Means for reintroduction of fermented biomass or liquid percolate
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12M—APPARATUS FOR ENZYMOLOGY OR MICROBIOLOGY; APPARATUS FOR CULTURING MICROORGANISMS FOR PRODUCING BIOMASS, FOR GROWING CELLS OR FOR OBTAINING FERMENTATION OR METABOLIC PRODUCTS, i.e. BIOREACTORS OR FERMENTERS
    • C12M41/00—Means for regulation, monitoring, measurement or control, e.g. flow regulation
    • C12M41/12—Means for regulation, monitoring, measurement or control, e.g. flow regulation of temperature
    • C12M41/18—Heat exchange systems, e.g. heat jackets or outer envelopes
    • C12M41/22—Heat exchange systems, e.g. heat jackets or outer envelopes in contact with the bioreactor walls
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12M—APPARATUS FOR ENZYMOLOGY OR MICROBIOLOGY; APPARATUS FOR CULTURING MICROORGANISMS FOR PRODUCING BIOMASS, FOR GROWING CELLS OR FOR OBTAINING FERMENTATION OR METABOLIC PRODUCTS, i.e. BIOREACTORS OR FERMENTERS
    • C12M41/00—Means for regulation, monitoring, measurement or control, e.g. flow regulation
    • C12M41/44—Means for regulation, monitoring, measurement or control, e.g. flow regulation of volume or liquid level
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J19/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J19/0006—Controlling or regulating processes
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J2219/00049—Controlling or regulating processes
    • B01J2219/00051—Controlling the temperature
    • B01J2219/00074—Controlling the temperature by indirect heating or cooling employing heat exchange fluids
    • B01J2219/00087—Controlling the temperature by indirect heating or cooling employing heat exchange fluids with heat exchange elements outside the reactor
    • B01J2219/00094—Jackets
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J2219/00049—Controlling or regulating processes
    • B01J2219/00162—Controlling or regulating processes controlling the pressure
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J2219/00049—Controlling or regulating processes
    • B01J2219/00182—Controlling or regulating processes controlling the level of reactants in the reactor vessel
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J4/00—Feed or outlet devices; Feed or outlet control devices
    • B01J4/001—Feed or outlet devices as such, e.g. feeding tubes
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J4/00—Feed or outlet devices; Feed or outlet control devices
    • B01J4/001—Feed or outlet devices as such, e.g. feeding tubes
    • B01J4/002—Nozzle-type elements
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J4/00—Feed or outlet devices; Feed or outlet control devices
    • B01J4/008—Feed or outlet control devices
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12M—APPARATUS FOR ENZYMOLOGY OR MICROBIOLOGY; APPARATUS FOR CULTURING MICROORGANISMS FOR PRODUCING BIOMASS, FOR GROWING CELLS OR FOR OBTAINING FERMENTATION OR METABOLIC PRODUCTS, i.e. BIOREACTORS OR FERMENTERS
    • C12M29/00—Means for introduction, extraction or recirculation of materials, e.g. pumps
    • C12M29/06—Nozzles; Sprayers; Spargers; Diffusers

Definitions

  • ICM Integrated Continuous Manufacturing
  • CM consists of a series of unit operations that operate in flow and are integrated into a seamless end-to-end (from synthesis to final product) manufacturing process.
  • ICM represents a shift from the batch manufacturing processes used in the pharmaceutical industry.
  • ICM's unit operation integration process results in significant operational advantages. ICM significantly reduces manufacturing costs (>50% reduction) and lead times (>90% reduction) has a smaller footprint (-90% reduction) and provides higher quality drugs. Additional advantages include flexibility, decentralized and individualized manufacture, improved engineering systems, real time quality assurance, and reduced scale up costs.
  • QbD Quality by Design
  • controllers maintain quality thresholds throughout the production cycle, ensuring that the end product of the entire process meets its quality specification.
  • the unit devices may include a variety of real-time sensors and Process Analytical Technologies (PATs) that measure different process parameters and send signals to the ICM process controller. Each sensor may operate at a different sampling frequency depending on the type of sensor and the parameter to be measured.
  • PATs Process Analytical Technologies
  • a high sampling frequency enables rapid modification of the process in response to unwanted changes in process parameters.
  • the ICM process controller integrates the signals across the unit operations and adjusts the parameters to limit the variation within the product stream.
  • Current unit devices, designed to be used in batch mode are generally incompatible with ICM processes, operate at inappropriate scales, and do not provide for real time control.
  • Hu 2018 describes an automated multi-stage continuous reaction system with in-line PATs for a high viscosity reactive crystallization process.
  • the multistage system was prone to clogging and to overcome the problem of transfer line clogging, Hu 2018 provide a “forward-backward” pumping strategy to transfer a high viscosity slurry from one vessel to the next.
  • Hu 2018 provide a “forward-backward” pumping strategy to transfer a high viscosity slurry from one vessel to the next.
  • Susanne et al. incorporate ultrasound to disrupt accumulation and maintain flow.
  • Susanne et al. “Match-Making Reactors to Chemistry: A Continuous Manufacturing-Enabled Sequence to a Key Benzoxazole Pharmaceutical Intermediate,” Org. Process Res. Dev. 21:1779-1793 (2017).
  • Tom et al. describe problems with clogging even with fine well-flowing solids.
  • White et al. describe an intermittent flow approach using a combination of vacuum and inert gas pressure to prevent settling of solids.
  • White et al. “Development of a Continuous Schotten-Baumann Route to an Acyl Sulfonamide,” Org. Process Res. Dev 16:939-957 (2012); See also Polster etal, “Pilot-Scale Continuous Production of LY2886721: Amide Formation and Reactive Crystallization,” Or. Process Res. Dev. 18(11): 1295-1309 (2014).
  • the present application relates to and is directed to continuous stirred tank reactor (CSTR) arrays and methods of use.
  • CSTR continuous stirred tank reactor
  • the CSTR system is utilized to conduct chemical reaction, crystallization or reactive-crystallization activities with controlled temperature and residence time and is suitable for use in liquid, liquid-liquid, and liquid-solid phase reactions.
  • the present disclosure provides for and includes an ASME BPE compliant continuous stirred reactor (CSTR) comprising an operational range of 4 to 200 L, an aspect ratio of 1.5 to 4, an input line and dip tube (C) providing a fluid flowing at a rate of between 10 to 10000 ml per minute (mL/min), an agitator (B) comprising motorized mixing paddles comprising an impeller and propeller in combination, a recirculation and output flow system comprising a vessel output line (H) in fluid communication with a positive displacement pump PU-W41 having a variable flow rate of between 1000 ml/min to 10000 ml/min, a recirculation loop in ASME BPE standard configuration in fluid communication with said CSTR, said recirculation loop in fluid communication with a reactor exit port (H) and a recirculation return port (D) comprising a diversion control valve (CVW 51) connected to a waste line and located below the CSTR, an output line comprising an output control valve (CV-W42) line
  • the present disclosure further provides for, and includes, a method for conducting a chemical reaction in a continuous stirred tank reactor (CSTR) array, comprising introducing Reactant A and Reactant B into a first CSTR of a CSTR array, each CSTR of said CSTR array comprising a fluid jacketed CSTR reactor operably connected to a heat transfer system, inlet dip tube port (C), a temperature sensor port (I), monitoring reactor temperature in each CSTR and controlling the temperature of the reaction mixture by circulating a heat transfer and cooling fluid through the CSTR fluid jacket, maintaining a residence time across three stages of the CSTR array, with each stage providing a portion of the total residence time, setting a flow rate for the reaction mixture through the CSTR array, utilizing inline Fourier-transform infrared spectroscopy (FT-IR) connected to the recirculation loop of the third CSTR for monitoring the reaction, and controlling the reaction using equipment modules for feed flows, temperature, and level based on set parameters, wherein the CSTR array is configured to maintain the reaction
  • the present disclosure also provides for, and includes, a method for conducting a reactive crystallization process in a continuous stirred tank reactor (CSTR) array, comprising introducing a reaction mixture containing at least two reactants into a first CSTR of the CSTR array, controlling the temperature of the reaction mixture within a predetermined range suitable for reaction progression in initial stages of the CSTR array, maintaining a desired residence time across multiple stages of the CSTR array to ensure complete reaction, adjusting the temperature in a final stage of the CSTR array to a lower range suitable for crystallization of the reaction product, utilizing inline analytical tools connected to the recirculation loop of the final CSTR for monitoring the crystallization process, wherein the CSTR array is configured to maintain the reaction and crystallization under controlled conditions to optimize yield and purity of the product.
  • CSTR continuous stirred tank reactor
  • CSTR continuous stirred tank reactor
  • a method for cleaning a continuous stirred tank reactor (CSTR) array comprising flushing the reactor with aliquots of cleaning solvent to remove residual process material, directing the cleaning solvent through various reactor components including process inlet, recirculation loop, vapor riser, and reactor outlet, utilizing a series of automated valves to control the flow of cleaning solvent through the reactor components, rinsing the reactor with water following the solvent flush to remove any remaining solvent and contaminants, and drying the reactor using a nitrogen blowdown method through various reactor components to ensure removal of residual moisture and solvents.
  • CSTR continuous stirred tank reactor
  • the present specification provides for, and includes, a system for cleaning a CSTR array, comprising, a network of valves configured to direct cleaning solvent and rinse water through the reactor components in a predetermined sequence, sensors to monitor the presence of residual chemicals or moisture, providing feedback to control the duration and intensity of cleaning and drying cycles, a control system programmed with a cleaning protocol that includes solvent flush, solvent wash, optional aqueous wash, water rinse, and nitrogen blowdown steps, wherein the protocol is adjustable based on the specific chemical processes previously conducted in the CSTR array.
  • FIG. 1 is a view of a diagram of a single CSTR comprising a sight glass and a Process Analytical Technology (PAT) port (A), an agitator port (B), an inlet dip tube port (C), a recirculation return port (D), a level sensor port (E), a vapor riser port (F), a spray ball port (G), a reactor exit port and vessel output line (H), a temperature sensor port (I) and temperature sensor (TE-W01), and an additional sight glass and PAT port (J).
  • the agitator (B) consists of a top drive agitator (AG-W01) with dry running (nitrogen) double mechanical seal and four impellers comprising three axial and a bottom radial impeller.
  • An inlet dip tube (C) in fluid communication with inlet stream and liquid feeding components comprising a mass flow meter and flow controller (MFC), an isolation valve (XV-W11), and an actuating valve (XV-W12) in fluid communication with a solvent source.
  • MFC mass flow meter and flow controller
  • XV-W11 isolation valve
  • XV-W12 actuating valve
  • the recirculation return (D) is in fluid communication with reactor exit port (H) as part of a recirculation loop comprising a reactor safety valve (XV-W41), a pump bypass valve (MBV-W41), a variable flow rate recirculation and processing pump (PU-W41), a pump bypass valve (MBV-W42), a diversion control valve (CV-W51), a recirculation solvent valve (XV-W13), a set of three block valves (MBV-W43, MVB-W44, and MBV-W45) arranged for the attachment of portable equipment or instruments, a return control valve (CV-W41) and a three way recirculator diverter valve (XV-W42) located before the return line to recirculation return (D) located at the minimum CSTR level.
  • a reactor safety valve XV-W41
  • MV-W41 pump bypass valve
  • PU-W41 variable flow rate recirculation and processing pump
  • MVB-W44 pump bypass
  • Level sensor (E) comprises a level sensor (LT-WO1) with a probe submerged below the operating liquid level.
  • a Vapor riser (F) is in fluid communication with reactor pressure indicator transmitter (PIT-W61) and an exhaust isolation valve (XV-W61).
  • Spray Ball (G) is in fluid communication with the recirculation loop via diverter valve (XV-W42) and spray ball Clean in Place (CIP) isolation valve (XV-W21).
  • the reactor exit port (H) connects via the recirculation loop to the recirculation return and to a waste stream via a diversion control valve (CV-W51).
  • the product output in fluid connection with the recirculation loop through output control valve (CV-W42).
  • FIG. 1 The CSTR inlet dip tube (C) in fluid communication a low pressure nitrogen source via a low pressure nitrogen supply isolation valve (XV-W31).
  • the CSTR includes a fluid jacket for circulating a heat transfer and cooling fluid operably connected to a heat transfer system.
  • Figure 2A-O presents process flow diagrams of a single CSTR illustrating the fluid paths used in various operations. One or more flow paths are combined during CSTR operation to achieve the desired purposes (e.g., reactions, crystallizations, rinsing, cleaning, drying, etc.).
  • Figure 2 A presents the flow path la for the introduction of a process input fluid from process inlet 1, through a mass flow controller (MFC), valve XV-W11, and into the CSTR via port C (Path la).
  • MFC mass flow controller
  • Figure 2B presents the flow path lb for the introduction of a second solvent (or clean-in-place (CIP) fluid), starting from the solvent/reagent inlet 2 and controlled with an MFC, through valve XV-W12 and into the CSTER via port C (Path lb).
  • Figure 2C presents the flow Path 1c, combining Path la and Path 2b for the introduction of to solvents/reagents into the CSTR through port C.
  • Figure 2D presents the flow path from the CSTR to waste (Path 2) from reactor port exit (H) through XV-W41, pump PU-W42, valve CV-W51, and to the waste stream for proper disposal.
  • CIP clean-in-place
  • Figure 2E presents recirculation loop (Path 3) starting with the reactor port exit (H), through XV-W41, pump PU-W42, valve MBV-W43, valve CV-W41, valve XV-W42, and returned to the CSTR through the recirculation return port (D).
  • Figure 2F presents flow path 4, for transferring the output of the CSTR from reactor exit port H, through valve XV-W41, through pump PU-W42, valve MBV-W43, valve CV-W42, valve MBV-W46, to the process outlet (4).
  • Figure 2G presents flow path 5, for transferring the output of the CSTR from reactor exit port H to process outlet 4 with a diversion to a PAT monitoring loop through valve XV-W41, pump PU-W42, valve MBV- W44, valve MBV-W45, valve CV-W42, valve MBVW46, and to the process outlet (4).
  • Figure 2H presents flow path 6 for introducing a clean-in-place solvent controlled by a flow control module and flowing through valve XV-W14, valve XV-W42, valve XV-W21, and into the CSTR through spray ball port G (Path 6).
  • Figure 21 presents flow path 7, for introducing a clean-in-place solvent controlled by a flow control module and flowing through valve XV-W14, valve XV-W42, valve XV-W22, and into the CSTR through port C (Path 7).
  • Figure 2J presents flow path 8 for introducing a clean-in-place solvent controlled by a flow control module and flowing through valve XV-W14, valve XV-W42, valve XV- W23, and into the CSTR through vapor riser port F (Path 8).
  • Figure 2M presents path 11 for the introduction of high pressure nitrogen gas into the CSTR via valve PRV-W32, valve XV-W32, to inlet dip port C (Path 11).
  • Figure 2N presents path 12 for the introduction of high pressure nitrogen gas into the CSTR via valve PRV-W32, valve XV-W32, valve XV-W22, valve XV-W23, to vapor riser port F (Path 12).
  • Figure 20 presents flow path 13 for the introduction of high pressure nitrogen gas into the CSTR via valve PRV-W32, valve XV-W22, valve XV-W21, to vapor riser port F (Path 12).
  • one or more paths may be simultaneously activated depending on the process function to be achieved.
  • Figure 3A-C presents a CSTR array comprising three CSTRs arranged in series for a three stage reaction.
  • the first reactor is shown in Figure 3 A, the second in Figure 3B, and the third in Figure 3C.
  • the components of the CSTRs are described in detail in Figure 1 and the flow paths described in Figure 2A-O.
  • Reactant A is introduced into the first CSTR process inlet (C) through valve XV-111 (path 1) and Reactant B is introduced through valve XV-112 (pathlb).
  • the outlet of CSTR-1 is connected via control valve CV-142 to valve XV-211 of CSTR-2 shown in Figure 3B.
  • the outlet of the second reactor is connected to XV-311 of the third reactor shown in Figure 3C.
  • a flow cell for inline FT-IR is connected to the recirculation loop of CSTR reactor 3 through MBV-344 and MBV-345, where MBV-343 is closed and MBV-344 and MBV 345 are open.
  • Nitrogen is supplied to both high and low pressure regulating valves (PRV-131, PRV-132, PRV- 231, PRV-232, PRV-331, PRV-332), the house vacuum isolation valves (XV-162, XV-262, XV- 362) are connected to the house vacuum utility and the exhaust isolation valves (XV-161, XV-261, XV-361) are connected to the plant exhaust utility line.
  • Each CSTR includes a recirculation loop (path 3) comprising reactor exit port (H) and recirculation return (D) connected through XV-x41, PU-x41, MBV-x43, CV-x41, and XV-x42 (where x identifies the respective CSTR 1, 2, or 3).
  • Output from each CSTR is controlled by CV-x42 which directs a portion of the recirculation flow to the next CSTR via path 4.
  • path 3 and path 4 are simultaneously active.
  • Figure 4A-E presents a 5 stage CSTR array illustrative of a reactive crystallization from solution to a slurry.
  • the components of the CSTRs are described in detail in Figure 1.
  • Figure 4A to E presents CSTRs 1 to 5 respectively linked as illustrated in Figure 3 A-C where the outlet of each CSTR is connected via control valve CV-x42 to valve XV-xll of next CSTR.
  • the upstream process solution is connected to the process inlet through XV- 111.
  • the outlet of the first reactor is connected to XV-211 as an inlet for the second reactor.
  • the second to fifth reactor are connected the same way through XV-311, XV-411 and XV- 511.
  • a flow cell for inline FT-IR is connected to the recirculation loop through MBV-544 and MBV-545 on the fifth reactor.
  • Valve MBV-543 is closed, and the MBV-544 and MBV- 545 are opened to direct the flow through the flow cell.
  • the nitrogen is supplied to both high and low pressure regulating valves (PRV-131, PRV-132, PRV- 231, PRV-232, PRV-331, PRV-332, PRV-431, PRV-432, PRV-531, PRV-532), the house vacuum isolation valves (XV-162, XV-262, XV-362, XV-462, XV-562) are connected to the house vacuum utility and the exhaust isolation valves (XV-161, XV-261, XV-361, XV-461, XV-561) are connected to the plant exhaust utility line.
  • high and low pressure regulating valves PRV-131, PRV-132, PRV- 231, PRV-232, PRV-331, PRV-332, PRV-431, PRV-432, PRV-531, PRV-532
  • the house vacuum isolation valves XV-162, XV-262, XV-362, XV-462, XV-562
  • the exhaust isolation valves
  • FIG. 5 presents a schematic of a temperature control system according to an embodiment of the present application.
  • the control system includes a reactor temperature sensor TE-W01 and jacket supply temperature sensor TE-W71 to perform temperature control for the jacket temperature and process temperature.
  • Figure 6 presents a schematic of the control logic for a temperature control system according to an embodiment of the present application.
  • FIG. 7 presents a schematic of a pressure control system utilizing the pressure indicator (PIT-W61), pressure regulators (PRV-W31 and PRV-W61, and the valves within the reactor system to achieve several operations such as inerting operation, pressure check operation and nitrogen blanketing.
  • the blanketing is a passive control through the manual set-point from the nitrogen supply and exhaust pressure regulators (PRV-W31 and PRV- W61)
  • Figure 8 presents a schematic of the control logic for pressure testing according to an embodiment of the present application.
  • Figure 9 presents a schematic of the control logic for inerting a CSTR according to an embodiment of the present application.
  • FIG 10 presents a schematic of an individual mass flow controller (MFC) module according to an embodiment of the present application.
  • MFC mass flow controller
  • FIG 11 presents a schematic of the use of multiple individual mass flow controllers (MFC) for the use of three solvent/reagent addition flow control according to an embodiment of the present application.
  • MFC mass flow controllers
  • Figure 12 presents a schematic of the control logic for a ratio and flow controller according to an embodiment of the present application.
  • FIG. 13 presents a schematic of a level control system according to an embodiment of the present application.
  • the level controller comprises level sensor (LT-W01), recirculation pump (PU-W41) and three control valves (CV-W41, CV-W42 and CV-W51) to perform level or residence time control through regulating the process level.
  • level sensor LT-W01
  • PU-W41 recirculation pump
  • CV-W41, CV-W42 and CV-W51 three control valves
  • Figure 14 presents a schematic of the control logic for level control according to an embodiment of the present application.
  • Figure 15 presents a schematic of the control logic for mixer control according to an embodiment of the present application.
  • Figure 16 presents a schematic of a plant- wide operation sequence illustrating the steps for startup, operations, shut-down, and wash-in-place (CIP) according to an embodiment of the present application.
  • a Continuous Stirred-Tank Reactor (CSTR) is provided that is capable of conducting chemical reactions, crystallizations, or reactive-crystallization processes using a single flexible design with controlled flow rates, volume, temperature, and pressure.
  • the CSTRs provided herein each further provide in situ cleaning and meet American Society of Mechanical Engineers (ASME) Bioprocessing Equipment (BPE) standards (BPE-2022) (e.g., BPE compliant or BPE standard configuration).
  • ASME American Society of Mechanical Engineers
  • BPE Bioprocessing Equipment
  • BPE-2022 BPE compliant or BPE standard configuration
  • the CSTRs of the present specification are ASME BPE compliant continuous stirred reactors and all connections, transfer lines, and other components are ASME BPE compliant.
  • Each CSTR in the array includes a heat exchange loop and heat exchanger modules to provide means of regulating the input and output temperatures entering or exiting the system.
  • the stirred tanks are also equipped with their own pressure control (PRV-W31, PRV-W32, and PRV-W61), level control (LT-W01), mixing control (AG-W01), and flow control (as described in Figure 2).
  • PRV-W31, PRV-W32, and PRV-W61 level control
  • LT-W01 level control
  • mixing control AG-W01
  • flow control as described in Figure 2
  • the CSTRs described herein provide for, and include, special transfer mechanisms for the tank through a combination of recirculation loop and a control valve to handle continuous pumping of any type of fluids (e.g., solution, slurry, suspension).
  • the recirculation loop overcomes problems with pumping slurries to downstream processes.
  • the recirculation loop (path 3) allows the slurry to maintain its homogeneity with a higher recirculation rate, while the control valve at the highest point of the recirculation loop (CV-W42) trickles a stream of process liquid to the downstream process (path 4). In this way, any fluid can be continuously transferred to downstream at controllable flow rates without worrying about settling.
  • the CSTR Array system consists of an Inlet Heat Exchanger Module, two or more Stirred Tank Modules and an Outlet Heat Exchanger Module.
  • the number of CSTRs in an array is five, though not all of the CSTRs need be used for any given process step. Increasing the number of CSTRs in an array can increase the yield, though with diminishing returns. See Hu el al.. 2018 and Hu etal. 2021. As a practical matter, acceptable yields can be obtained with five reactors in series.
  • the CSTR array system provided herein is utilized to conduct chemical reaction, crystallization or reactivecrystallization activities with controlled temperature and residence time.
  • the inlet and outlet heat exchanger modules are used to provide means of regulating the input and output temperatures entering or exiting the system. The heat exchangers can be bypassed if they are not being used.
  • Each of the stirred tank module is equipped with a dynalene loop for temperature control.
  • the stirred tanks are also equipped with their own pressure control, level control, mixing control, and flow control.
  • each vessel is designed to have an aspect ratio of between 1.5 to 4 (height/diameter) with customized stirrer design to allow normal operation at a wide range of volumes (4 - 200L). Based on previous testing, low aspect ratio vessels (1-1.5) are ineffective at low volumes because the stirrer cannot reach the bottom.
  • any fluid, slurry, or suspension can be continuously transferred to downstream at controllable flow rates without worrying about settling and without having to use a reverse pumping sequence or a “forward-backward” burst pumping strategy. See Hu et al. 2018. This improvement avoids temperature spikes and other variations (introduction of low yield slurry from the previous stage) and allows a continuous flow process with decreased variability.
  • CSTR Continuous Stirred Tank Reactor
  • Table 1 The legend of Table 1 is used throughout.
  • the major equipment is identified with an equipment function identifier (WWW), the major equipment number (X), the location (U), and components (V) are sequentially numbered for the same equipment and instrument type.
  • WWW equipment function identifier
  • X major equipment number
  • U location
  • V components
  • the CSTRs are designed for flexibility, in situ cleaning (e.g., clean-in-place or “CIP”) and to accommodate a variety of products, particularly slurries having a solid concentration of up to 70% (wt/wt) and a particle size of less than 700 um, fluids having a specific gravity of between 0.6 and 1.5, and a viscosity of between 0.5 to 1000 centipoise (cP).
  • CIP centipoise
  • the CSTRs have an operational range of between 4 and 200 liters. In aspects, the operation range is between 4 and 20 liters. Smaller volumes (less than 4L) are a challenge as the impeller may not agitate effectively, and heat transfer might be less effective if the bottom of the vessel is not fully jacketed. For volumes over 200 liters, the heat transfer efficiency can drop because the surface area per volume ratio becomes too small.
  • the CSTRs of the present application comprise a sight glass and PAT port (A), an agitator (B), an input line and inlet dip tube (C) (“input line”), a recirculation return port (D), a level sensor (E), a vapor riser (F), a spray ball (G), a reactor exit port (H), a temperature sensor (I), and an additional sight glass and PAT port (J).
  • the agitator (B) consists of a top drive agitator (AG-W01) with dry running (nitrogen) double mechanical seal and four impellers comprising three axial and a bottom radial impeller.
  • An inlet dip tube (C) in fluid communication with inlet stream and liquid feeding components comprising a mass flow meter and flow controller (MFC), an isolation valve (XV-W11), and an actuating valve (XV-W12) in fluid communication with a solvent source.
  • MFC mass flow meter and flow controller
  • XV-W11 isolation valve
  • XV-W12 actuating valve
  • the recirculation return (D) is in fluid communication with reactor exit port (H) as part of a recirculation loop comprising a reactor safety valve (XV-W41), a pump bypass valve (MBV-W41), a variable flow rate recirculation and processing pump (PU-W41), a pump bypass valve (MBV-W42), a diversion control valve (CV-W51), a recirculation solvent valve (XV-W13), a set of three block valves (MBV-W43, MVB-W44, and MBV-W45) arranged for the attachment of portable equipment or instruments, a return control valve (CV-W41) and a three way diverter valve (XV-W42) located before the return line to recirculation return (D) located at the minimum CSTR level.
  • a reactor safety valve XV-W41
  • MV-W41 pump bypass valve
  • PU-W41 variable flow rate recirculation and processing pump
  • MVB-W44 pump bypass valve
  • Level sensor (E) comprises a level sensor (LT-W01) with a probe submerged below the operating liquid level.
  • a Vapor riser (F) is in fluid communication with reactor pressure indicator transmitter (PIT-W61) and an exhaust isolation valve (XV-W61).
  • Spray Ball (G) is in fluid communication with the recirculation loop via diverter valve (XV-W42) and spray ball CIP isolation valve (XV-W21).
  • the reactor exit port (H) connects via the recirculation loop to the recirculation return and to a waste stream via a diversion control valve (CV-W51).
  • Output control valve (CV-W42) and line controls the recirculation flow and diverts the product to output or back to the reactor header (G) and spray ball.
  • the CSTR inlet dip tube (C) in fluid communication a low pressure nitrogen source via a low pressure nitrogen supply isolation valve (XV-W31).
  • the CSTR is jacketed for heat transfer and connected to a heat transfer system.
  • the CSTR fluid jacket is filled with a heating or cooling fluid.
  • Suitable, non-reactive heating and cooling fluids are known to persons of skill in the art.
  • the heating or cooling fluid is a glycol based mixture.
  • the glycol based mixture is an aqueous solution of glycol.
  • the glycol based mixture is a non-aqueous solution.
  • valves CV-W41 and CV-W51 in the recirculation loop are limited to a V-notch type of self-cleaning ball valve or diaphragm valves.
  • Other valves that may have a hold up volume are unsuitable as they are unable to be cleaned to the required standards and can retain materials, particularly solid particles.
  • CV-W41 is a v-notch ball valve to control the flow at low flow rates.
  • suitable v-notch ball valves include IMI PBM’s self cleaning ball valves (IMI PBM, Irwin, PA).
  • suitable diaphragm valves include the GEMU 687 Pneumatically operated diaphragm valve (GEMU Valves Inc., Atlanta, Georgia). Suitable, equivalent valve substitutions would be known to persons of skill in the art. Further all valves are required to be sanitary valves.
  • the CSTR incorporates the following elements: a) a recirculation and process pump comprising a positive displacement pump having a controllable flow of between 10 milliliters/minute (ml/min) to 1000 ml/minute; b) two manual valves (MBV-W41, MVB-W42) for bypassing the process pump as an option to replace the process pump during cleaning activities; c) three v-notch control valves, CV-W41, CV-W42, and CV-W51 for altering flow/backpressure and pressure regulators PRV-W31 and PRV-61 located at the nitrogen line and exhaust line respectively to maintain the system pressure; d) a set of three block valves positioned for the easy attachment of portable equipment/instruments (MVB-W43/W44/W45); e) a contained sampling system within a recirculation loop via sampling block valve MBV- W43, sampling bypass valve out (MBV-W44) and sampling bypass valve in (MBV- W45) (“bypass port”);
  • Suitable block valves are diaphragm valves or self-cleaning ball valves to provide on/off control rather than flow control.
  • connection of the “in-line” PATs in the recirculation loop is accomplished by attaching hoses, flow cells, or spools, to manual valves MVB-W44 and MVB-W45. Valves MVB-W45/W45 are opened to establish flow and manual valve MVB-W44 is closed to ensure all flow is directed through the PAT.
  • the PATs are fitted with connections to a control system for data collection. In order to remove the PAT, valve MVB-W44 is then re-opened and valves MVB-W44/W45 are closed. The PAT can then be drained, disconnected, and cleaned out of place.
  • h a return line with dip pipe position at the minimum CSTR level; i) a gravity/pressured waste transfer line; j) a transfer line to a second CSTR or downstream processing equipment (filtering, drying, tableting, etc.) with level feedback from current vessel; and k) a set of hand valves (MBV-W46, MBV-W47) for routing process outputs outside of the array when bypassing.
  • the CSTRs of the present disclosure are configured as continuous stirred tank reactor arrays (CSTA) of two or more reactors in fluid communication and arranged to provide serial fluid communication.
  • CSTA continuous stirred tank reactor arrays
  • the CSTA comprises three CSTRs in serial fluid communication. In some aspects, the CSTA comprises four CSTRs in serial fluid communication.
  • each CSTR consists of the following: a) inlet stream and liquid feeding operations; b) temperature operations; c) mixing operations; d) pressure operations; e) recirculation, transfer and diversion operations; f) sampling and PAT operation; and g) waste handling and cleaning operations.
  • a CSTR, or each CSTR in a CSTR array stirred tank system is equipped with an inlet mass flow meter (MFC-W11) controller and several solvent addition points (via valves XV- Wll, XV-W12, XV-W13, and XV-W14) to adapt to various kinds of reaction scenarios.
  • Level control (via LT-W01) ensures the understanding of reactor volume and thus is used for controlling the outlet flow of the system.
  • the CSTR is equipped with sensors to measure the reactor temperature (TE-W01) and pressure (PIT-W61) and control them at desired value.
  • the CSTR, or each CSTR in a CSTA are fluid jacketed and operably linked to a heat transfer system.
  • a recirculation loop together (path 3) with three control valves provides the flexibility of transfer operations for various forms of liquids (solvent, solution, or suspension) at different flow rates.
  • the flow rates are provided by PU-W41, a variable speed pump having a flow rate between 1000 and 10000 ml per minute
  • the flow rates are provided by PU-W41, a variable speed pump having a flow rate between 10 and 1000 ml per minute.
  • the PU-W41 pump provides a flow rate between 10 and 600 ml per minute.
  • the modular design allows the selective entering, exiting, and bypassing of reactors, therefore to accommodate many steps of reactions within one array.
  • a CSTR array When configured as a CSTR array, two or more CSTRs are connected with the product output serving as the process input of the second array.
  • a CSTR array can comprise two CSTRs, three CSTRs, four CSTRs, five CSTRs, or more.
  • an array of two or more CSTRs are configured as a single “pallet” that can either be fixed within a larger overall process, or configured to connect to an existing fixed system with standard connections for process input and to a house vacuum, exhaust, solvent reservoirs/sources, and both high and low pressure nitrogen.
  • the CSTR array comprises an array of five CSTRs.
  • a CSTR array typically comprises multiple CSTR systems.
  • the five CSTR array design allows the handling of most chemical synthesis for small molecule API production and is a balance between typical reaction needs and hardware costs.
  • the solvent/reagent addition points discussed above allow the liquid to be added at different stages of the process (at input via XV-W11 and XV-W12 and during recirculation via XV- W13 or XV-W14), providing the flexibility for a chemical reaction, crystallization, or other processes.
  • the exit of the process is equipped with isolation and bypass valves (MBV-W47 and MBV-W46) to allow material to exit the array prior to entering the next reactor, improving its adaptability for complex processes.
  • Each reactor is designed to have an aspect ratio of 1.5 to 5 (height/diameter) with customized stirrer design to allow normal operation at a wide range of volumes (4 to 200L).
  • the aspect ratio is between 1.5 and four.
  • the aspect ratio of the CSTR is three (3). Testing of low aspect ratio vessels (1-1.5) demonstrates that they are ineffective at low volumes in part because the stirrer cannot reach the bottom leading to incomplete mixing or increased residence times making them unsuitable for continuous manufacturing processes. The appropriate aspect ratio is critical in continuous production systems.
  • the CSTR further provides for material to exit the reactor from the bottom (port H) so all the material can be removed prior to cleaning and with input and output lines configured with a slope to eliminate dead spaces and allow complete drainage of all liquids.
  • Each CSTR includes header pipes consisting of connections for process utilities including nitrogen gas, vacuum pump, and exhaust, to allow pressure operations of the reactor in conjunction with pressure relief valves PRV-W61, PRV-W31, and PRV-W32. Pressure control and process utilities can be used to render the void space inert, maintain the pressure within the vessel as well as support blow down drying of the vessel.
  • the CSTR arrays incorporate a special transfer mechanism for the tank through a combination of recirculation loop (path 3) and control valves (paths 4 and 5) to handle continuous pumping of any kind of fluids (e.g., solution, slurry, suspension). Slurries are particularly difficult to work with.
  • a slurry contains solids that settle when the up-flow velocity is lower than its settling velocity. This limits the minimum flow rate of continuous pumping.
  • a burst pumping strategy was adopted where the slurry is pumped at higher speed for a short period of time to achieve the same average flow rate. This traditional strategy can also cause material to stay in the process line and pump head during the pause period, which then settles and causes clogging. Once settled and clogged, the only solution is to pump from the top of the vessel and use a pump that can reverse the flow. When the pumping cycle stops, the pump flow is automatically reversed to empty the residual material. This prior approach imposes many limitations. First, the minimum volume is limited by the dip-tube level.
  • the pump needs to be reversable.
  • the bottom of the vessel cannot be emptied with the process pump.
  • using the recirculation loop configuration ensures the material is always suspended in the line and the pump is always running avoiding material settling.
  • the solids may settle if the flow rate is not high enough.
  • One solution is to maintain a high flow rate, however high flow rates may not be compatible with downstream processes and the present CSTRs address this problem.
  • the recirculation and process pumps comprise a positive displacement pump (PU-W41).
  • Suitable positive displacement pumps include progressive cavity pumps (PC Pump), gear pumps, (internal and external), vane (impeller) pumps, rotary lobe pumps, screw pumps, diaphragm pumps, and peristaltic hose pumps.
  • PC Pump progressive cavity pumps
  • gear pumps (internal and external), vane (impeller) pumps
  • rotary lobe pumps screw pumps
  • diaphragm pumps diaphragm pumps
  • peristaltic hose pumps peristaltic hose pumps.
  • Lower shear pumps provide for slurry processing and meet clean-in-place requirements. By maintaining high flow rates and recirculation, settling of slurries is prevented.
  • the lower shear pumps are progressive cavity, screw pump, and peristaltic pumps.
  • the present application provides for, and includes, a recirculation loop (path 3) that recirculates the reactor material allowing high flow rates to be obtained.
  • path 3 a recirculation loop that recirculates the reactor material allowing high flow rates to be obtained.
  • This allows the system to accommodate a wide range of viscosities and slurries having high concentrations of solids with particle sizes up to 700x1 O' 6 meters (um).
  • the slurry maintains its homogeneity with a higher recirculation rate, while the control valve at the highest point of the recirculation loop releases a stream of process liquid, including slurries, to the downstream process (path 4). In this way, any fluid can be continuously transferred downstream at controllable flow rates without worrying about settling.
  • the transfer mechanism provides for the transfer of slurries having a solid concentration of up to 70% having a particle size of less than 700xl0' 6 meters (um). Materials of this type are very difficult to work with and generally require specialized equipment that is thereby limited to certain materials. Further, handling such thick slurries with small scale equipment has previously been unattainable.
  • the present CSTR design provides a system capable of handling a wide range of materials without modification and limitation.
  • the CSTR is further designed to utilize its existing equipment to perform cleaning activities.
  • the recirculation diverter valve (XV-W42) can direct the recirculation fluid through the vapor riser headers (F) as well as the spray ball (G) to perform cleaning.
  • the process pump performs draining and recirculating of the cleaning fluid.
  • a second pump can be included for washing connected via valves MBV-W41 and MBV- W42
  • All piping is sloped with a maximum length to height ratio of 96 to ensure all the liquid drains towards the vessel and no liquid holdup.
  • Other components such as temperature control provide the capability of heating or cooling of the cleaning fluid.
  • Solvents and reagents can be charged to a CSTR or an array of CSTRs (CSTA ) comprising two or more CSTRs, depending upon process requirements.
  • Each CSTR is individually equipped with provisions for feeding various solvents and reagents into the CSTR arrays.
  • the CSTR is designed to operate with a wide variety of fluids and slurries without modification thereby providing flexibility to process and reaction needs.
  • Suitable fluids include miscible or immiscible fluids and the fluids can further comprise a suspension having a solid concentration of up to 70% (wt/wt) and a solid particle size of less than 700 um.
  • the fluids comprise a mixture of miscible or immiscible fluids and may further comprise a solid particle.
  • Solid particles can be provided as part of the input process material or generated by reacting within the CSTR.
  • the reaction is a chemical reaction that provides a precipitate.
  • the solid may be formed by physical processes such as precipitation, crystallization, or coagulation.
  • Process material enters the CSTR (or CSTR array) through XV-W11 (path la).
  • Solvents and reagents can be added to any individual reactor in the array through XV-W12 (path lb), XV-W13 (paths 3, 4, and 5), and XV-W14, with an optional “flow control module” attached.
  • a flow control module is a mass flowmeter controller (MFC) that controls the flow rate of a solvent or reagent.
  • MFC mass flowmeter controller
  • MFCs can be added as needed to any input or output flow, for example before XV-W14, XV-W13, or XV-W12.
  • an MFC is permanently installed before XV-W11. The flow rates are set up before the operation begins.
  • the solvent and reagent feeding system consists of: a) a mass flow meter with a flow controller, “MFC-W11”. b) an isolation valve XV-W11 for inlet flows c) three actuating valves (XV-W12, XV-W13, XV-W14) to accommodate “flow control modules” for additional solvent/reagent addition.
  • Solvents and reagents can be fed into the system at three locations.
  • Location one is the process inlet (C), after input isolation valve XV-W11 and before the dip tube (C) for liquids that need to be mixed with inlet stream before entering the reactor.
  • Location two provides for solvent addition during recirculation into the recirculation loop via valve XV-W13 located after the variable flow rate recirculation and process pump (PU-W41) and before the output control valve CV-W42).
  • Location three in the recirculation line between the recirculation return valve CV-W41 and the diverter valve XV-W42, normally for the introduction of CIP liquid, can be used to introduce solvents of choice as determined by the reaction process. [058] All flows coming into or out of the reactors are either measured or calculated as follows.
  • the main inlet flow rate to the array is measured by the mass flow controller “MFC”. Any additional solvent/reagent flow rates are measured by flow meters at corresponding “flow control modules”. If a CSTR Array is used for multiple steps, every step will be equipped with a flow control module for inlet flow rate.
  • the flow rate leaving a tank (flowout) can be calculated using the following method (Equation I) where the sum of inlet flow rates is measured by mass flow meter and the volume of the tank is calculated from level sensor measurement. This can either be going to a downstream reactor or bypass to another process equipment or to waste.
  • the operator selects a set point for each feed solvent to either charge the vessels or to prime the line. Once flow is established, the operator can input a setpoint in units of milliliter per minute where the “flow control modules” are automatically adjusted to achieve the setpoint. In other aspects, the operator can select a more complex ratio control through the control system programming. In ratio control, the operator inputs a desired ratio of feed streams and the ratio controller will initiate cascade control for all the flow control modules into the reactor.
  • the temperature control system on a CSTR or a CSTR array is capable of controlling the temperature of reactor contents between -45 °C and 160 °C.
  • the heat transfer system can be in any form such as a centralized heat transfer unit with local valving and plumbing to regulate the temperature, or a local heat exchanger that uses heating fluid as its source of heating and cooling.
  • the reactor temperature sensor (TE-W01) is used to measure the tank process temperature and can be connected to the control system that regulates the heat transfer fluid temperature. Therefore a cascade control strategy can be utilized to control the heat exchanger fluid output temperature.
  • the operation is manual.
  • the operator manually supplies the heat transfer fluid until there are no air pockets in the reactor jacket.
  • the operator can then manually set up the temperature of the heat transfer fluid.
  • the temperature sensor TE-W01 measures the fluid temperature, and the temperature controller can be turned on. This involves the controlling of reactor temperature, reactor temperature ramp up rates, or ramp down rates. During steady state operation, the controller is set to cascade control where the setpoint of the reactor temperature controls the heating and cooling duty of the external heat transfer system. The reactor temperature is then continuously regulated.
  • the controller will limit the rate of change and maximum differential temperature to prevent thermal shock. In practice, this temperature is specific to the material being used for the vessel. In this case, when a nickel-based corrosion-resistant alloy (for example HASTELOY) reactor is used, the rate of change is limited to 15 °C per minute and the maximum differential temperature between the jacket and the reactor material is 65 °C. Suitable limits depend on the materials and reactions and can be determined without undue experimentation by a person of skill in the art.
  • HASTELOY nickel-based corrosion-resistant alloy
  • CSTRs are fitted with an agitator comprising motor AG-W01 operably connected to mixing paddles.
  • the agitator and motorized mixing paddles are designed for facilitating heat transfer and mixing based on computational fluid dynamics (CFD) models to analyze mixing and heat transfer.
  • CFD computational fluid dynamics
  • the agitator is a top drive agitator with dry running (nitrogen) double mechanical seals and has the following attributes: MOC: Hast C-22; Design Rheology: SG 0.6 to 1.5, solid concentration 0 to 70 % (wt/wt); Viscosity 1.0 to 1000 cP; Temperature design range: -45 to 160 °; Max speed: 365 RPM; Four (4) impellers, Three (3) axial and the bottom is radial; Mixing range: 4 L to 20 L.
  • the agitator speed is controlled by the operator input of a setpoint to AG-W01 in the control system.
  • the agitator can be turned on during or before the process material is introduced, depending on the needs.
  • a CSTR is designed to accommodate a pressure range between full vacuum and 45 psig. Each reactor in an array requires pressure control over the normal operating pressure range of atm to 0.5 psig. It can also accommodate particular situations such as nitrogen blowdown for drying the system.
  • the CSTR design provides for a number pressure operations. Normal operations are maintained at ambient pressure and include heating and cooling, liquid charging and transfer as described above.
  • a CSTR provides for preparing an inert environment through evacuation (via the vacuum system and valve XV-W62) and repressurization using nitrogen (via valve XV- W31). In aspects of the present application, other gases can be included, for example, as reactants.
  • a CSTR, or a CSTR array can be pressure tested prior to a running a reaction, ensuring that valuable reactants are not wasted.
  • a CSTR provides for nitrogen blowdown at up to 32 psig, to remove residual liquids.
  • the CSTRs of the present application provide for, and include, a pressure regulation system comprising a low pressure nitrogen source, valve PRV-W31 in fluid communication with the input line and drop tube (C) and valve PRV-W61 incorporated into the vapor riser (F).
  • a pressure regulation system comprising a low pressure nitrogen source, valve PRV-W31 in fluid communication with the input line and drop tube (C) and valve PRV-W61 incorporated into the vapor riser (F).
  • the essential elements for the pressure regulation system and evacuation and repressurization system are: a) PIT-W61 Pressure Transmitter; b) PRV-W61 Exhaust Pressure Regulating Valve (set to 1 psig); c) PRV-W31 Low Pressure Nitrogen Supply Regulating Valve (set to 0.5 psig); d) PRV-W32 High Pressure Nitrogen Supply Regulating Valve (set to 32 psig); e) XV-W31 Low Pressure Nitrogen Supply (0.5 psig) Isolation Valve; f) XV-W32 High Pressure Nitrogen Supply (32 psig) Isolation Valve; g) XV-W61 Exhaust Isolation Valve; and h) XV-W62 House Vacuum Isolation Valve;
  • the reactor can be maintained as an inert environment and includes provisions to pressure test the reactor at 32 psig.
  • the system performance goal is accurate pressure control with minimal nitrogen load.
  • a deadband strategy is implemented where the nitrogen supply PRV-W31 is regulated to 0.5 psig and the vent to the exhaust PRV-W61 is regulated to 1 psig.
  • the house vacuum provides the flexibility of evacuating the reactor for inerting purposes.
  • the separate pressure regulator PRV-W32 is installed for high pressure nitrogen use in the scenario of nitrogen blowdown or pressure test of the reactor.
  • the instruments used for regulating the pressure at 0.5 psig and 32 psig are different, thus separate devices are installed (PRV-W31 and PRV-W32 respectively).
  • the pipes that are in fluid connection with the vessel are connected to the CIP header with respective CIP isolation valves for cleaning. The distance between the valves and the connection is minimized to minimize material hold up. Normal operations
  • the system is designed to maintain a pressure band of 0.5 to 1 psig during normal operation.
  • the headspace volume will change causing pressure change in the vessel.
  • the vessels undergoing heating or cooling the headspace also pressure changes.
  • the system adjusts itself to maintain a pressure slightly above atmospheric (0.5 to 1 psig).
  • the reactor can be lined up with low pressure nitrogen supply valve XV-W31 open and exhaust valve XV-W61 open. PRV-W61 will maintain pressure at 1 psig for any scenario of headspace expansion.
  • the drop in headspace volume is backfilled with nitrogen through the PRV-W32 at 0.5 psig. In this normal operation, the XV-W31 and XV-W61 are opened and XV-W32 and XV-W62 are closed.
  • the reactor evacuation and re-pressurization sequence occurs prior to start-up or cleaning if necessary. This sequence is completed automatically by actuating the valves. All regulators are calibrated and set to their desired setpoints (PRV-W31 set at 0.5 psig, PRV- W32 set at 32 psig, and PRV-W61 set at 1 psig) before the automated evacuation and repressurization can occur. In the case where the reactor requires evacuation (e.g. to facilitate nitrogen purging of the vapor space in the reactor), the operator will initiate the evacuation/re-pressurization sequence.
  • the evacuation/re-pressurization sequence is normally carried out once to get below 10% oxygen, however it is recommended to be repeated three times until below 1% oxygen is achieved.
  • the console will display the number of swings completed and once the necessary number of swings is completed, the inert operation is finished.
  • the oxygen levels can be determined using an in-line analyzer via the PAT sampling ports A or J.
  • nitrogen is introduced by opening XV-W32, with XV-W11/W12/W21/W22/W23/W31/W41/W61/W62 closed and XV-W42 in active position (the arrow on a three-way valve indicated its fail position) as not to allow pressurizing the process line or the recirculation line.
  • the pressure regulator for high pressure nitrogen supply (PRV-W32) is set to 32 psig initially. Once 32 psig is reached on PIT-W61, control signals for XV-W32 to be closed and XV-W11/W12/W21/W22/W23/W31/W41/W61/W62 are all closed. If after the allotted time, the PIT-W61 reads 32 psig, the reactor has passed the pressure test. If at the end of the test PIT-W61 drops below 32 psig, the pressure test failed and retest is needed.
  • Nitrogen is blown through the feed dip tube (path 11) to waste via the tank outlet piping (path 2).
  • Valves XV-W32/W41 and CV-W51 are open.
  • Valves XV-W11/W12/W13/W14, XV-W21/W22/W23/W31/W61/W62, CV-W41/W42 are closed.
  • Valve XV-W42 is in active position. This can be utilized to empty the bottom of the vessel.
  • Valves XV-W32/W41 and CV-W42 are open. Valves XV-W11/W12/W13/W14, XV-W21/W22/W23/W31/W61/W62, CV-W41/W51 are closed. Valve XV-W42 is in active position. This can be utilized to empty the bottom of the vessel.
  • Valves XV-W32/W41 and CV-W41/W51 are open (path 3). Valves XV-W21/W22/W23 are also open (path 12, path 13). Valves XV- W11/W12/W13/W14 and XV-W31/W61/W62, CV-W42 are closed. Valve XV-W42 is in active position. This can be utilized to empty the bottom of the vessel together with the CIP header.
  • Valves XV-W32/W41 and CV-W41/W42 are open (path 11). Valves XV-W21/W22/W23 are also open (path 12, path 13). Valves XV- W11/W12/W13/W14, XV-W31/W61/W62 and CV-W51 are closed. Valve XV-W42 is in active position. This can be utilized to empty the bottom of the vessel together with the CIP header.
  • One or more of the nitrogen blowdown methods can be repeated or combined depending on the production requirements.
  • valve XV-W 11 illustrated in Figure 1 is labeled XV-W 11 in the current CSTR, XV-N11 in the next CSTR.
  • Each CSTR is equipped with provisions for recirculating, discharging to waste, or transferring the reactor contents.
  • the recirculation and output flow system provides for flexibility in the types of fluids to include slurries. Further the recirculation system allows for the fluid or slurry contents of the reactor to be retained and the output flow controlled to accommodate downstream, continuous processes.
  • a means is required to effect inter reactor transfers with level control (control level or residence time)
  • Transfer forward allows for the inclusion of chemical processes between CSTRs such as a membrane separator, a wiped film evaporator, a filter, or a dryer.
  • Recirculation allows for establishing a representative mixture for sampling, process monitoring, and PAT measurement.
  • Recirculation allows for velocities high enough to prevent solids settling.
  • Recirculation allows for adding other pieces of portable equipment such as: i) special in-line analyzers (PAT); ii) sampling devices, and iii) combinations thereof.
  • Recirculation of cleaning solutions to effect reactor system CIP i) special in-line analyzers (PAT); ii) sampling devices, and iii) combinations thereof.
  • a positive displacement pump having a controllable flow less than or equal to 10 ml/min
  • two manual valves MV-W41, MVB-W42
  • three control valves for altering flow/backpressure.
  • CV-W41, CV-W42, and CV-W51 They are CV-W41, CV-W42, and CV-W51; d) a set of three block valves positioned for the easy attachment of portable equipment/instruments (MVB-W43/W44/W45); e) a contained sampling system; f) a level sensor (LT-W01) measuring the level of the material and controls the output rate; g) PAT Systems; h) a return line with dip pipe position at the minimum CSTR level; i) a gravity/pressured waste transfer line; j) a transfer line to the next CSTR with level feedback from current vessel; k) a set of hand valves (MBV-W46, MBV-W47) for routing process outputs outside of the array when bypassing; and l) sloped configuration of all incoming and outgoing piping to the reactor with a maximum length to height ratio of 96.
  • MV-W46, MBV-W47 a set of hand valves for routing process outputs outside of
  • the process outlet stream can be routed outside of the array by closing the block valve MBV-W46 and opening the isolation valve MBV-W47.
  • the process outlet will flow through the MBV-W47 to the processes outside of the CSTR or CSTR array.
  • a portable PAT or sampling device can be installed between MBV-W44 and MBV- W45.
  • the valve MBV-W43 can be closed to only allow the material to flow through the portable device.
  • a transfer/recirculation pump (PU-W41) is used to develop the head required to move material to the next vessel, recirculation, or waste tankage.
  • a set of manual valves (MBV-W41 and MBV-W42) can be used to install an external CIP pump if PU- W41 cannot provide enough flow rate for CIP operation.
  • MBV-W41 and MBV-W42 can be used to install an external CIP pump if PU- W41 cannot provide enough flow rate for CIP operation.
  • Pump (PU-W41) is a variable flow pump set at a designed flow rate that ensures no settling in the vertical pipe.
  • the flow velocity is adjusted to be 150% of the settling velocity of the particle in slurry system.
  • the settling velocity (terminal velocity) is calculated based on the fluid property and particle property.
  • the four inputs for calculating the required flow velocity are fluid viscosity and density, particle diameter and density. See Tilton, James N. 2019. " CHAPTER PRELIMINARIES.'' Chap. 6.0 in Perry's Chemical Engineers' Handbook. 9th ed., edited by Don W. Green and Marylee Z. Southard. New York: McGraw-Hill Education.
  • Recirculation during transfer occurs when: a) Transferring slurries from one reactor to another; b) Transferring liquids at a flow less than the minimum pump speed; or c) Transferring slurries at a flow less than the settling rate.
  • the recirculation allows pump PU-W41 to run at a high enough flow rate to prevent solids from settling out of the slurry in either the pump or recirculation lines.
  • the pump speed is determined by the settling rate of the solids (product specific) and the feed forward rate (i.e. the recirculation + forward flow must exceed the settling rate by 50%). In aspects, the settling rate is exceeded by 150%.
  • XV-W41 is open and XV-W42 is positioned towards the reactor.
  • Valve CV-W42 is set at a designed opening (usually setting at minimum Cv at approximately 0.03), and CV-W51 is closed. A portion of the material will be transferred from one reactor to the next while the remainder is recirculating.
  • the forward flow is controlled by back pressuring the system with closing a portion of CV-W41.
  • Valve CV-W42 is positioned at a high point of the loop which drops into the nozzle “C” dip-pipe of the downstream CSTR.
  • the forward flow leaving the current reactor can either be controlled to a reactor level set point or a reactor residence time set point.
  • the level transmitter on the current reactor sets the set-point of CV-W41 to maintain a constant level in that reactor. If controlling by residence time, the calculation from inlet flow rates sets a target level setpoint that LT-W01 must maintain by modulating CV-W41 to backpressure the recirculation loop, sending material to the next reactor.
  • Pump (PU-W41) is set at a designed flow rate that ensures no settling in the vertical pipe.
  • Recirculation while diverting occurs when: a) bleeding off some contents of slurry or liquid while recirculating to allow material attributes to stabilize; or b) bleeding off some contents of slurry or liquid while maintaining the level when downstream is halting or stopped.
  • the slurry needs to be directed to waste because it is out of specification (from PAT measurement) or the downstream reactor (LT-N01) cannot take the material, diversion to waste while recirculating must occur.
  • the upstream sends in material as normal, the recirculation loop keeps the material suspended.
  • CV-W41 is open and XV-W42 is positioned towards the reactor.
  • CV-W51 is open at designed opening (usually setting at minimum Cv at approximately 0.03) and CV-W42 is closed.
  • CV-W41 will backpressure the loop to control the flow rate to waste until the material is in spec or the downstream reactor can accept material. Material will be recirculating while the diversion to waste is occurring. Pump (PU-W41) is set at a designed flow rate that ensures no settling in the vertical pipe.
  • XV-W41 is open and CV-W42 is closed.
  • XV-W42 is positioned towards the reactor.
  • Valve CV-W51 is opened at a designed opening (in this case, it can be full open since the pump dictates the flow rate) and CV-W41 is closed. In this way, all liquid goes to waste with no recirculation.
  • Pump (PU-W41) is set at a designed flow rate that ensures no settling in the discharge pipe.
  • Transfer can be performed using a solution or a solvent, when no particle is present. Or a suspension running at the flow rate at, or above, the minimum settling flow rate.
  • XV-W41 is open and CV- W42 is set to fully open.
  • CV-W41 and CV-W51 are closed.
  • the liquid will be transferred from one reactor to the next without recirculation if the forward flow is at or above the minimum pump controllable flow.
  • the level transmitter on the CSTR (LT-W01) resets the speed of the pump (PU-W41) to maintain either a constant level in the current reactor or a set residence time in the current reactor.
  • Each CSTR is equipped with provisions for sampling liquids and slurries, diverting out of specification materials, or installing PATs. These provisions are required for the following reasons: a) A means is required to sample both slurry and liquid streams for in-process sampling. b) Recirculation allows for establishing a representative mixture for sampling, pH monitoring, and PAT. c) Recirculation allows for adding other pieces of portable equipment such as: i) sampling devices; ii) special in-line analyzers (PATs); or iii) combinations of either.
  • PATs special in-line analyzers
  • a positive displacement pump (PU-W41).
  • Three control valves for altering flow/backpressure They are CV-W41, CV-W42, and CV-W51 .
  • a set of three block valves (MBV- W43, MBV-W44 and MBV-W45) positioned for the easy attachment of portable equipment or instruments.
  • a contained sampling system (installed between MBV-W44 and MBV-W45 or at connection “J”).
  • a portable PAT system installed between MBV-W44 and MBV-W45).
  • Each reactor is provided with two means of sampling: a) Connection port (“J”) for the purpose of attaching sampling systems and taking liquid samples from the reactors. b) A connection in the recirculation loop via valves (MVB-W44/W45) for slurry samples and PAT connection.
  • a sample bottle is attached and secured to the sampling system and a sample valve on the system is opened, either via compressed air or manually. Once the required sample volume is extracted, the valve is once again closed and the sample bottle is removed for analysis.
  • the sample system can be purged with nitrogen prior to and after a sample is taken via connections on the system itself. The sampling system is also fully drainable for cleaning purposes.
  • a flow through/in-line type sampling system is connected, via hoses or spools, to manual valves MVB-W44 and MVB-W45. Valves MVB-W44/W45 are opened to establish flow and manual valve MVB-W43 is closed to ensure all flow is directed through the sampling system.
  • the sampling system is equipped with a separate sample valve and port for connection of a sampling bottle. Once the sampling bottle is connected to the sampling system, the sample valve is opened, either via compressed air or manually. Once the required sample volume has been extracted, the sample valve is once again closed and the sample bottle can be removed for analysis. In order to remove the sampling system, valve MVB-W43 is then re-opened and valves MVB- W44/W45 are closed. The sampling system can then be drained, disconnected, and cleaned out of place.
  • Each CSTR is equipped with a set of three block valves (MBV- W43, MBV-W44 and MBV-W45) positioned for the purpose of installing various in-line PATs, these include, but are not limited to: NIR, pH, UV, FTIR. FBRM, Raman, Density meter, Refractometer, Laser diffraction particle size measurement; and combinations thereof.
  • connection of these “in-line” PATs in the recirculation loop is accomplished by attaching hoses, flow cells, or spools, to manual valves MVB-W44 and MVB-W45. Valves MVB-W45/W45 are opened to establish flow and manual valve MVB-W43 is closed to ensure all flow is directed through the PAT. The PATs are fitted with connections to the control system for data collection. In order to remove the PAT, valve MVB-W43 is then reopened and valves MVB-W44/W45 are closed. The PAT can then be drained, disconnected, and cleaned out of place.
  • the CSTR is designed to utilize its internal equipment for the cleaning activities, for example to prevent the distribution of API substances beyond the equipment designed for their synthesis.
  • the system is designed in a way that concentrations, temperatures, and flow rates can be maintained per cleaning protocol and that surfaces are demonstrated to be wetted during operations using Riboflaven Testing.
  • Riboflavin more commonly known as vitamin B2
  • Riboflavin testing is frequently used to measure effectiveness of spray coverage. Riboflavin testing is well known, though it has no universally accepted standard, and there are variations of this test among end users.
  • the CIP procedure utilizes, as far as possible, the process piping, equipment, instruments, automated valves, and pumps.
  • the intent of the CIP approach is to flush the lines at a velocity of 5 ft/sec and to establish a turbulent falling film on the heads and straight sides of the vessels.
  • simple vessels i.e. no baffles, agitators, or dip pipes
  • this can be done by applying 2.5 GPM/ft of periphery.
  • the CIP flow rates will be in the range of 6.36 liters per minute (LPM) for a i inch (12.7 mm) pipe, 17.7 LPM for a % inch (19 mm) pipe, and 34.8 LPM for a 1 inch (25.4 mm) pipe.
  • the minimum CIP flow into an 8” vessel is 5.2 GPM (19.7 LPM).
  • Each CSTR in a CSTR array is configured in such a way that the reactor can be cleaned independent of other reactors in the array or along with a group of reactors with the associated piping systems. Provisions have also been supplied to flush vapor headers.
  • the cleaning is designed specifically for end of campaign cleaning, to prepare for the process of “crossing-over” CSTR Array, piping and associated system to a new product.
  • the control of the reactor CIP System can be either manual through the control system or by a validated “sequence”. Each intermediate or product will require a different procedure (including cleaning liquid to be used, temperature, time, etc.). This procedure is made up of common steps. CSTR cleaning can be broken down into the following possible six steps. These steps may not all be required for a particular campaign or for all systems.
  • a nitrogen blow down can be used to help drain the system. This blow down can either be directed to waste or the downstream/upstream process as discussed in the pressure operations section above. Normal Operations:
  • the CSTR jacket can be adjusted between a set point 20-40 °C. This is per the CIP protocol;
  • Transfer Control The transfer pump PU-W41 (or an alternative CIP pump through MBV-W41 and MBV-W42) is set at a determined CIP rate.
  • the purpose of the Solvent Rinse is to clear the vessel and lines of any encrusted solids to remove gross contamination from the process piping.
  • Temperature Control The CSTR jacket can be adjusted between a set point 20-40 °C. This is per the CIP protocol.
  • Transfer Control The transfer pump PU-W41 is set at a determined CIP rate.
  • Step 1 Process Inlet and Recirculation Loop Pre-Rinse
  • any lines used during the campaign need to be flushed.
  • the flushing material would be a solvent that is miscible with the material previously in that line.
  • the operator would send an aliquot of solvent through the “flow control modules” that is connected to XV-W12.
  • the XV-W12 is closed after a preset volume of solvent has been charged (measured via a totalizer).
  • valve XV-W14 to charge an aliquot of solvent while positioning the XV-W42 towards the reactor.
  • the solvent could be recirculated using PU- W41 through the recirculation loop (CV-W41, XV-W41 open, CV-W42, CV-W51 closed) to flush out any process liquid or solids in the recirculation line. This recirculation would occur for a set amount of time.
  • Step 2 Reactor Pre-rinse through Spray ball
  • the next step is a pre-rinse of the reactor with solvent for the purpose of getting solids off the top head and sides. It is important to note that from a safety standpoint, spraying solvents can potentially be dangerous. Static charges can be built up by non-conductive solvents flowing through lined pipe and then entering the vessel through a conductive spray ball.
  • the XV-W14 is opened to introduce CIP rinse solvent and the diverter valve XV-142 is positioned towards the solvent header (active position), which directs solvent to the reactor spray ball.
  • XV-W21 is open, XV-W22/W23 and CV-W41 would be closed. The operator would then initiate the Reactor Rinse where a set amount of solvent (measured by a flow control module totalizer) is charged to the reactor through the spray ball.
  • XV-W21 is closed. Valves XV-W41 and CV-W51 are open and the rinse will be sent to the waste tank via PU-W41. Once the level in the tank reaches zero (determined by LT-W01), XV-W41 and CV-W51 are closed.
  • Step 3 Vapor Riser Rinse
  • the operator would then initiate the nitrogen header rinse where a set amount of solvent (measured by a flow control module totalizer) is charged to the reactor through the nitrogen inlet. Then it is cycled to the exhaust header where XV-W23 is open, XV-W21/W22 and CV-W41 are closed. The operator would then initiate the exhaust header rinse where a set amount of solvent (measured by a flow control module totalizer) is charged to the reactor through the exhaust line.
  • the next step is to flush all of the lines which leave that reactor to their destinations.
  • a set amount of solvent will be charged and transferred to waste, to a different piece or process equipment, or when the CSTR is part of an array, to the next vessel. This will clean the transfer line in between the two reactors or other process equipment and allow the downstream vessel to be ready for their respective cleaning cycles.
  • the reactor may be connected to different pieces of process equipment depending on the campaign, the flushing of the outlet piping corresponds to the cleansing of the inlet piping in the subsequent process.
  • the XV-W14 is open to introduce the flushing solvent and the diverter valve XV-W42 is positioned towards the rector. Valve XV-W41 is closed. After the necessary volume is reached (measured by LT-101), Valves XV-W41, CV-W42 are open and valves CV- W41/W51 are closed. PU-W41 pumps from reactor to the subsequent process at the determined CIP rate.
  • the CSTR jacket can be adjusted between a set point 20-60 °C. This is per the CIP protocol.
  • Transfer Control The transfer pump PU-W41 (or an alternative CIP pump through MBV-W41 and MBV-W42) is set at a determined CIP rate.
  • Step 1 Process Transfer Line Inlet and Recirculation Loop Wash
  • the XV-W12 is open to allow a preset volume of solvent to be charged (measured via a flow control module, LT-W01).
  • the flow control module s software monitors the quantity of liquid flow through the flow control (flow rate x time). If required, the solvent can be warmed with the heat transfer fluid through the jacket. The system will then trigger recycle to wash the recirculation loop.
  • the XV-W42 remains in fail position, valves XV-W41 and CV-W41 are open and valves CV-W42/W51 are closed.
  • Pump (PU-W01) is turned on at CIP rate and the recirculation would occur for a set amount of time. If a sampling or PAT device is connected to the recirculation loop, the operator could manually switch on MBV-W44 and MBV-W45, and switch MBV-W43 to cycle through the device flow cell for cleaning.
  • Step 3 Vapor Riser Wash and Reactor Wash with Spray ball
  • the wash cycle in this step starts with the vapor riser and ends with the spray ball cleaning step.
  • XV-W41 is opened and the chosen solvent is added to the vessel to a desired level (determined by LT-W01). If required, the solvent can be warmed with the heat transfer fluid through the jacket.
  • the XV-W14 is open to introduce the wash solvent and the diverter valve XV-W42 is positioned towards the rector. Valve XV-W41 is then closed. After the necessary volume is reached (measured by LT-101), Valves XV-W41, CV-W41 are open and valves CV-W42/W51 are closed. If required, the solvent can be warmed with the heat transfer fluid through the jacket.
  • XV-W42 is positioned towards the reactor header piping.
  • XV-W22 is open, and XV- W21/W23 would be closed.
  • the wash of the nitrogen inlet header is initiated with turning on the pump (PU-W41) at CIP rate for a set amount of time. Then this will cycle to the exhaust pipe.
  • the XV-W23 is open, XV-W21/W22 are closed.
  • the exhaust pipe wash is then washed at CIP rate for a set amount of time.
  • the recirculation washing is ended with the spray ball washing.
  • the XV-W21 is open, and XV-W22/W23 would be closed.
  • the wash of the reactor internal surface is initiated by turning on the pump (PU-W41) at CIP rate for a set amount of time. Solvent flows through XV-W21 into the spray ball.
  • the spray ball is designed for a total flow that covers all the internal surfaces of the vessel. This rate will be maintained throughout the cleaning cycle for a set amount of time.
  • Step 4 Sampling During Wash Steps (optional)
  • Step 3 After a number of wash cycles, the solvent needs to be tested to ensure the contaminate level is below the acceptance criteria. This will require that after the completion of Step 3, the pump discharge is recirculated, and a sample taken at the reactor sample points (Port “J’ or between MBV-W44/W45). Then each transfer line would need to be sampled at the destination reactor and submitted for analysis as appropriate. In aspects, the analysis may be inline via MBV-W44/W45. The reactor system cannot be assumed cleaned until the results show that the concentration of the contaminants are below the required level.
  • An aqueous wash cycle can be used in place of or in addition to the solvent wash cycle. Possible fluids used could be:
  • aqueous wash fluids can be used in series and in any order.
  • a purified water/solvent rinse wash cycle can be used in addition to the wash cycle. Possible fluids used could be purified water or other solvent.
  • the steps of the cycle are the same as the solvent rinse. This is used to facilitate the drying of the reactor if water needs to be rinse out or a low vapor pressure solvent needs to be rinsed out, prior to blow dry.
  • Drying the vessel can be achieved by nitrogen blow down as described above for each of the pipes.
  • the nitrogen blow down can isolate each line and achieves a more accurate drying objective that ensures no trapped water in the pipe.
  • the term “component” is intended to be broadly construed as hardware, firmware, or a combination of hardware and software. It will be apparent that systems and/or methods described herein may be implemented in different forms of hardware, firmware, and/or a combination of hardware and software. The actual specialized control hardware or software code used to implement these systems and/or methods is not limiting of the implementations. Thus, the operation and behavior of the systems and/or methods are described herein without reference to specific software code - it being understood that software and hardware can be used to implement the systems and/or methods based on the description herein.
  • satisfying a threshold may, depending on the context, refer to a value being greater than the threshold, greater than or equal to the threshold, less than the threshold, less than or equal to the threshold, equal to the threshold, and/or the like, depending on the context.
  • the articles “a” and “an” are intended to include one or more items and may be used interchangeably with “one or more.” Further, as used herein, the article “the” is intended to include one or more items referenced in connection with the article “the” and may be used interchangeably with “the one or more.” Furthermore, as used herein, the term “set” is intended to include one or more items (e.g., related items, unrelated items, a combination of related and unrelated items, and/or the like), and may be used interchangeably with “one or more.” Where only one item is intended, the phrase “only one” or similar language is used. Also, as used herein, the terms “has,” “have,” “having,” or the like are intended to be open-ended terms.
  • a fluid can be a liquid (solvent or solution), a gas (pure or mixtures), or a slurry (solid suspension in a carrier liquid).
  • the control system consists of “unit” level and “plant-wide” logics.
  • the CSTR array is designed to be part of the integrated continuous manufacturing (ICM) line that requires the communication and interaction between the individual units for plant wide start-up, shut-down, and WIP (cleaning/wash in place). It also handles situations like plant-wide safety interlocks.
  • ICM integrated continuous manufacturing
  • the system hierarchy can be categorized into the following levels:
  • Level 2 Unit CST-101, CST-201, ...) • Level 3 Equipment Modules (Temperature Control EM, Pressure Control EM, . . .)
  • Table 4 lists each unit, the associated major equipment modules, and objectives of each for a single reactor. This is applied to all “units” within a CSTR array.
  • controllers are programmed to perform the operations which utilize a combination of various control modules (process elements such as valves, sensors, etc.) within each equipment module. Their control logic design is summarized in the sections below.
  • Temperature control relies on an external heat transfer system and two critical control modules of reactor temperature sensor TE-W01 and jacket supply temperature sensor TE-W71 to perform temperature control for the jacket temperature and process temperature.
  • the operator inputs the setpoint for the desired temperature, the controller is then controlling the heat transfer system supply to achieve the desired j acket or process temperature.
  • the control logics can be illustrated in Figure 6.
  • pressure control utilizes the pressure indicator (PIT-W61), pressure regulators (PRV-W31 and PRV-W61, and the valves within the reactor system to achieve several operations such as inerting operation, pressure check operation and nitrogen blanketing.
  • the blanketing is a passive control through the manual set-point from the nitrogen supply and exhaust pressure regulators (PRV-W31 and PRV-W61).
  • the pressure test phase is a common phase used to determine the sealed status of a vessel.
  • the automated sequence will open valves necessary to flow nitrogen into the reactor. Once a target pressure has been reached, the valves will close, and the vessel will be sealed.
  • a timer will start, and the pressure will be measured and be expected to be maintained, within a predefined tolerance, for the length of the timer.
  • a pass or fail result will be recorded and the phase will be completed if a passing result is achieved. A failure will result in the operator being prompted to retest.
  • Flow chart for the pressure test phase is shown in Figure 8.
  • the inerting phase is a common phase used to evacuate a vessel and inert with nitrogen.
  • the automated sequence will open valves necessary to vacuum the vessel and flow nitrogen into the reactor. During evacuation, once a target pressure has been reached, the valves will close, and the vessel will be sealed. Re-pressurization is then enabled to supply the reactor with nitrogen until the target pressure has been reached.
  • the control system will prompt the operator to repeat the steps as needed per recipe and prompt the operator to confirm the inerting sequence has been completed.
  • Flow chart for the inerting phase is shown in Figure 9.
  • flow control consists of a number of flow control modules (MFC-W11, MFC-W12, MFC-W13, MFC-W14) and flow controllers for adjusting both flow rate and ratios of the solvent/reagent addition.
  • Individual flow control module comprises of a flow controller that controls the flow rate in a closed loop control logic.
  • the set-point of the flow controller is achieved by regulating the control valve, confirmed by the mass flow meter.
  • Each flow controller for solvent/reagent addition can be set to normal flow control from a set-point or they can be controlled through a ratio controller at a ratio relevant to the MFC- Wll flow rate.
  • Figure 11 shows an example of all three solvent/reagent addition flow control modules (MFC-W12, MFC-W13, MFC-W14) are controlled with a ratio controller with respect to MFC-W11. System can be customized to set up the ratio controller at any combinations if needed. The control logic is illustrated in Figure 12. Level Control
  • the level controller consists of the level sensor (LT-W01), the recirculation pump (PU-W41) and three control valves (CV-W41, CV-W42 and CV-W51) to perform level or residence time control through regulating the process level.
  • the set-point for the process return control valve position (CV-W41) and the recirculation pump (PU-W41) are fixed for each system.
  • the control logic is illustrated in Figure 14.
  • mixer control of the agitator allows the AG-W01 to be operated at various speeds for mixing operations.
  • the agitator speed is controlled by the operator inputting a set-point to the agitator speed controller. There is no feedback provided nor planned to reset this set-point automatically.
  • the current draw of the motor is indicated which is helpful in determining the increase in viscosity from one CSTR to another.
  • the initial state for the system is the OFF (idle) mode where everything is turned off, and nothing is running.
  • all units In plant wide startups, all units must be in “Start-Up” (initialize) mode.
  • the recipe or equipment module will download the set points, operators have full control of all equipment module in this mode and can drive each control module to the desired position in manual mode.
  • Start-Up mode the units are organized into tiers and the tiers are completed in a certain order. Once the unit is stabilized with the critical process parameters in a state of control, the operator can drive the system to the Operation mode through a series of confirmation steps. This will close the process control loops for certain mode dependent equipment modules that may be different at various modes.
  • An American Society of Mechanical Engineers ASME
  • Bioprocessing Equipment BPE
  • CSTR continuous stirred reactor
  • ASME Bioprocessing Equipment
  • BPE Bioprocessing Equipment
  • CSTR continuous stirred reactor
  • an input line and dip tube C
  • an agitator B
  • motorized mixing paddles comprising an impeller and propeller in combination
  • a recirculation and output flow system comprising: a vessel output line (H) in fluid communication with a positive displacement pump PU-W41 having a variable flow rate of between 1000 ml/min to 10000 ml/min; a recirculation loop in BPE standard configuration in fluid communication with said CSTR, said recirculation loop in fluid communication with a reactor exit port (H) and a recirculation return port (D) comprising: a diversion control valve (CV-W51) connected to a waste line and located below the CSTR; an output line comprising an output control valve
  • CV-W51 diversion control valve
  • the CSTR of any one of embodiments 1 or 2 wherein all inflowing piping slopes towards said CSTR and all outflowing piping slopes toward a waste outlet to eliminate liquid hold up in the CSTR system.
  • the CSTR of any one of embodiments 1 to 4 further comprising a pressure regulation system comprising a low pressure nitrogen source and valve PRV-W31 in fluid communication with said input line and drop tube (C) and valve PRV-W61 incorporated into said vapor riser (F).
  • the CSTR of any one of embodiments 1 to 10 wherein said heating or cooling fluid is a glycol based mixture.
  • the CSTR of any one of embodiments 1 to 11, wherein said recirculation and output flow system further comprises a safety valve (XV-W41) below the CSTR and before said pump.
  • valve (XV-W14) connected to recirculation loop D between control valve CV-W41 and valve XV-W42, wherein said valve XV-W14 is in fluid connection to a clean-in-place fluid source and an upstream flow control module.
  • said recirculation line further comprises at least one fluid addition port and valve (XV-W14) between said recirculation return control valve (CV-W41) and recirculation diverter valve XV-W42.
  • said input line further comprises a providing a fluid flow and a mass flowmeter controller for measuring and controlling said fluid flow.
  • the CSTR of any one of embodiments 1 to 17, said CSTR further comprises a second sight glass and PAT port (J).
  • the CSTR of any one of embodiments 1 to 20 wherein said fluid is a mixture of one or more immiscible or miscible fluids.
  • the CSTR of any one of embodiments 1 to 21; wherein said heating or cooling fluid is an aqueous glycol solution.
  • a method for conducting a chemical reaction in a continuous stirred tank reactor (CSTR) array comprising: introducing Reactant A and Reactant B into a first CSTR of a CSTR array; each CSTR of said CSTR array comprising a fluid jacketed CSTR reactor operably connected to a heat transfer system, inlet dip tube port (C), a temperature sensor port (I); monitoring reactor temperature in each CSTR and controlling the temperature of the reaction mixture by circulating a heat transfer and cooling fluid through the CSTR fluid jacket; maintaining a residence time across three stages of the CSTR array, with each stage providing a portion of the total residence time; setting a flow rate for the reaction mixture through the CSTR array; utilizing inline Fourier-transform infrared spectroscopy (FT-IR) connected to the recirculation loop of the third CSTR for monitoring the reaction; and controlling the reaction using equipment modules for feed flows, temperature, and level based on set parameters; wherein the CSTR array is configured to maintain the reaction under controlled conditions to produce a product.
  • each CSTR is equipped with mass flow controllers for precise control of Reactant A and Reactant B feed rates.
  • said array includes at least three CSTRs connected in series, each equipped with temperature sensors, level sensors, and recirculation pumps, and configured to operate with inline analytical tools such as FT-IR for real-time monitoring and control of the chemical reaction.
  • CIP cleaning-in-place
  • the method of any one of embodiments 26 to 32, wherein said rinse phase is a comprises a solvent pre-rinse wherein the solvent is the same as the solvent for the reaction.
  • a method for conducting a reactive crystallization process in a continuous stirred tank reactor (CSTR) array comprising: introducing a reaction mixture containing at least two reactants into a first CSTR of the CSTR array; controlling the temperature of the reaction mixture within a predetermined range suitable for reaction progression in initial stages of the CSTR array; maintaining a desired residence time across multiple stages of the CSTR array to ensure complete reaction; adjusting the temperature in a final stage of the CSTR array to a lower range suitable for crystallization of the reaction product; utilizing inline analytical tools connected to the recirculation loop of the final CSTR for monitoring the crystallization process; and wherein the CSTR array is configured to maintain the reaction and crystallization under controlled conditions to optimize yield and purity of the product.
  • CSTR continuous stirred tank reactor
  • the method of embodiment 36 wherein the CSTR array is equipped with temperature sensors, level sensors, and recirculation pumps, each configured to operate automatically based on feedback from the process control system to maintain specified process conditions.
  • the inline analytical tools include at least one of Fourier-transform infrared spectroscopy (FT-IR), Raman spectroscopy, or ultraviolet-visible (UV-Vis) spectroscopy, configured to monitor concentration of reactants, intermediates, or products to ensure process consistency and quality.
  • FT-IR Fourier-transform infrared spectroscopy
  • Raman spectroscopy Raman spectroscopy
  • UV-Vis ultraviolet-visible
  • the method of any one of embodiments 36 to 38 further comprising a shutdown procedure that includes: ceasing the introduction of reactants; diverting the contents of the final CSTR to waste while maintaining recirculation to manage the quality of the remaining batch; sequentially shutting down upstream CSTRs in the array; initiating a cleaning-in-place (CIP) sequence post-process to prepare the CSTR array for subsequent batches.
  • a shutdown procedure that includes: ceasing the introduction of reactants; diverting the contents of the final CSTR to waste while maintaining recirculation to manage the quality of the remaining batch; sequentially shutting down upstream CSTRs in the array; initiating a cleaning-in-place (CIP) sequence post-process to prepare the CSTR array for subsequent batches.
  • CIP automated cleaning-in-place
  • a CSTR array configured to perform the method of any one of embodiments 36 to 47, wherein the array includes multiple CSTRs connected in series, each equipped with automated control systems for managing feed rates, temperature, and recirculation based on predefined process parameters.
  • a method for cleaning a continuous stirred tank reactor (CSTR) array comprising: flushing the reactor with aliquots of cleaning solvent to remove residual process material; directing the cleaning solvent through various reactor components including process inlet, recirculation loop, vapor riser, and reactor outlet; utilizing a series of automated valves to control the flow of cleaning solvent through the reactor components; rinsing the reactor with water following the solvent flush to remove any remaining solvent and contaminants; and drying the reactor using a nitrogen blowdown method through various reactor components to ensure removal of residual moisture and solvents.
  • CIP clean-in-place
  • any one of embodiments 49 or 50 wherein the reactor components are rinsed and washed sequentially, starting from the process inlet and moving towards the reactor outlet, ensuring a thorough cleaning of all internal surfaces and associated piping.
  • the method of any one of embodiments 49 to 51 wherein the nitrogen blowdown is performed through both the feed dip tube and the reactor outlet, ensuring complete drying of the reactor and associated components.
  • the method of any one of embodiments 49 to 52 further comprising the step of testing the cleanliness of the reactor post-cleaning using a sampling system to collect residues from the reactor surfaces and analyzing them to ensure compliance with cleanliness standards.
  • the method of any one of embodiments 49 to 53 wherein the cleaning process is validated using a riboflavin test to confirm the effectiveness of the spray coverage and the overall cleaning procedure.
  • a system for cleaning a CSTR array comprising: a network of valves configured to direct cleaning solvent and rinse water through the reactor components in a predetermined sequence; sensors to monitor the presence of residual chemicals or moisture, providing feedback to control the duration and intensity of cleaning and drying cycles; a control system programmed with a cleaning protocol that includes solvent flush, solvent wash, optional aqueous wash, water rinse, and nitrogen blowdown steps, wherein the protocol is adjustable based on the specific chemical processes previously conducted in the CSTR array.
  • Example 1 [171] Initially, a 5-stage CSTR array of 10L vessels was designed and installed in a pilot plant. Each vessel was designed to have a lid and a bottom drain valve. A dip tube was installed on the vessel lid and inserted below the liquid level. Then a peristaltic pump was used to transfer the material directly to the next vessel. The vessel lid was also equipped with a fin- denser that minimizes the evaporation of solvents. The vessels were jacketed to allow inlet and outlet of heat transfer fluid. There was also a level sensor and a temperature sensor installed on the lid, with the probes submerged below the liquid level to measure the level and temperature respectively. Throughout the pilot plant operation of this CSTR array, we observed a number of issues.
  • the initial system did not have the capacity of processing different fluids flow (slurry or a liquid) at a range of flow rates while maintaining their homogeneity.
  • issues were observed when the flow rate of a slurry was reduced and particle settling occurred. This required that the tube size be reduced to a smaller internal diameter to be able to pump the slurry homogeneously.
  • a burst pumping pattern (pumping at a higher rate with shorter pumping time) is implemented to achieve a lower average flow rate. This method solves the problem of pumping at a lower flow rate using the same set of equipment.
  • the vessel relied on a dip tube to transfer material, but the depth of the dip tube was limited by the agitator propeller.
  • the agitator and the dip tube both limit the minimum operation volume of the vessel.
  • Reactant A is reacting with Reactant B to form Product C in a three stage CSTR array ( Figure 3 A-C).
  • Reactant A is dissolved in Dichloromethane (DCM) at
  • Reactant B (3.0 molar equivalent) is added neat together with the Reactant A solution at 25 °C to form the product.
  • the desired residence time is 6 hours with three stages of CSTR array. With the desired flow rate at 3.82 liters/hour (63.67 mL/min), each reactor is set at 8.79 Liters and 2 hours residence time.
  • the upstream process for Reactant A solution is connected to the process inlet through XV-111.
  • Reactant B inlet stream is connected to XV-112 through the flow control module.
  • the outlet of the first reactor is connected to XV- 211 as an inlet for the second reactor.
  • the outlet of the second reactor is then connected to XV-311 as an inlet for the third reactor.
  • a flow cell for inline FT-IR is connected to the recirculation loop through MBV-344 and MBV-345 on the third reactor.
  • Valve MBV-343 is closed, and the MBV-344 and MBV-345 are opened to direct the flow through the flow cell.
  • the nitrogen is supplied to both high and low pressure regulating valves (PRV-131, PRV- 132, PRV- 231, PRV-232, PRV-331, PRV-332), the house vacuum isolation valves (XV- 162, XV-262, XV-362) are connected to the house vacuum utility and the exhaust isolation valves (XV-161, XV-261, XV-361) are connected to the plant exhaust utility line.
  • the equipment module for feed flows includes all the flow control moules and the isolation valves for solvent addition.
  • the setpoint for Reactant A and the ratio control of Reactant B stream are inputted into the equipment module.
  • Temperature control equipment modules are set with jacket temperature control at 25 °C when the reactors are empty. Once the jacket temperature is stabilized, start feeding the tank with Reactant A and Reactant B by opening both XV-111 and XV-112 ( Figure 3A).
  • the mass flow meter for Reactant A measures the Reactant A solution to be fed at a consistent rate, and the flow control module for Reactant B stabilizes the ratio of Reactant B with respect to Reactant A.
  • Both streams are mixed and fed to the reactor through port C (e.g., path 1c).
  • the recirculation ( Figure 2E, path 3) is started by opening the valve XV- 141, CV-141 and turning on the pump PU-141 at the setpoint of recirculation rate. Since both reactants are homogeneous solutions, the recirculation rate can be set at 3 turnovers per hour to ensure the recirculated material is representative of the reactor content. This requires 440 mL/min for the PU-141 setpoint.
  • the temperature controller When the temperature probe TE-101 is submerged with process material, the temperature controller is set to process temperature control to regulate the process material at 25 °C. Once the content inside the first reactor reaches 2 hours residence time, set the level control equipment module to current level LT-101 and start feeding the second reactor via path 4. The equipment module will control the level of the tank by controlling the flow rate of content leaving the first reactor through regulating the frequency and opening of the CV-142 control valve. The combination of the recirculation loop and control valve ensures material going out of the system is representative of the content inside the reactor when the average out-going flow rate is at 63.67 mL/min. The inlet valve of the second reactor XV-211 ( Figure 3B) is then opened to receive material. The recirculation control, process temperature control and the level control are turned on respectively similar to the first reactor. These operations are repeated until all three stages are set at 25 °C and the level controls are set at 2 hours each.
  • the level control equipment module is set to current level LT-301 and the recirculation and diversion operation is started.
  • the equipment module controls the level of the tank by controlling the flow rate of content leaving the third reactor through regulating the frequency and opening of the CV-351 diversion control valve.
  • the content is delivered to waste in this phase.
  • the combination of the recirculation loop and control valve ensures material going out of the system is representative of the content inside the reactor when the average outgoing flow rate is at 63.67 mL/min.
  • the FT-IR is then started to monitor the reactor content through the recirculation loop bypass ( Figure 2G, path 5) and measuring the quality attributes of the reactor contents.
  • the level control equipment module can be switched to recirculation and transfer operation where the CV-351 is closed to stop the diversion and the CV-342 is controlling the outgoing flow based on the level.
  • the system remains in the state of control through the close loop control of the equipment modules until the production is finished.
  • the shut-down procedure will “work up” the remaining process material to ensure minimum unreacted material to be discharged to waste.
  • the CSTR array immediately stops feeding the downstream process.
  • the third reactor ( Figure 3C) is switched to recirculation and diversion operation (path 4) to deplete the reactor content.
  • CV-342 is closed and CV-351 is controlled by the level controller to transfer the material to waste (path 2).
  • the CSTR array inlet feed ( Figure 3A) is stopped by closing the valve XV-111 and XV-112.
  • the level control equipment module is set to constant rate to deplete the tank volume at the rate of 63.67 mL/min. When the level drops below the minimum level for recirculation, the recirculation and transfer is stopped.
  • PU-141 is turned off and CV-141 and CV-142 are both closed to stop the recirculation and the flow into the next reactor (e.g Figure 3B).
  • the unreacted material can be either quenched with a solvent, left in the tank for extended reaction time or directly pumped to waste by opening the CV- 151.
  • the temperature control equipment module is switched off and all the valves are placed into their fail position.
  • the reactor ( Figure 3A) is then ready for cleaning.
  • the second ( Figure 3B) to the third reactor ( Figure 3C) follows the same procedure until the material is removed and ready for cleaning.
  • the PAT instrument remains attached during the shut-down process and is removed after cleaning.
  • the first four stages ensure the completion of the reaction and the last stage is reduced to 70 °C to quench the reaction and further crystallize the Product C from DMF.
  • the desired residence time is 14 hours (3.5 hours each) total for the first four stages of CSTR and 3.0 to 4.0 hours for the last stage.
  • each reactor With the desired flow rate at 1.98 liters/hour (33 mL/min), each reactor is set at 6.93 Liters.
  • the upstream process for crude reaction mixture solution is connected to the process inlet through XV-111 ( Figure 4A).
  • the outlet of the first reactor is connected to XV-211 as an inlet for the second reactor ( Figure 4B).
  • the second to fifth reactor ( Figure 4C to Figure 4E) are connected the same way through XV-311, XV-411 and XV-511.
  • a flow cell for inline FT-IR is connected to the recirculation loop through MBV- 544 and MBV-545 on the fifth reactor ( Figure 4E).
  • Valve MBV-543 is closed, and the MBV-544 and MBV-545 are opened to direct the flow through the flow cell.
  • the nitrogen is supplied to both high and low pressure regulating valves (PRV-131, PRV-132, PRV- 231, PRV-232, PRV-331, PRV-332, PRV-431, PRV-432, PRV-531, PRV-532), the house vacuum isolation valves (XV-162, XV-262, XV-362, XV-462, XV-562) are connected to the house vacuum utility and the exhaust isolation valves (XV-161, XV-261, XV-361, XV- 461, XV-561) are connected to the plant exhaust utility line.
  • high and low pressure regulating valves PRV-131, PRV-132, PRV- 231, PRV-232, PRV-331, PRV-332, PRV-431, PRV-432, PRV-531, PRV-532
  • the house vacuum isolation valves XV-162, XV-262, XV-362, XV-462, XV-562
  • the exhaust isolation valves
  • the equipment module for feed flows includes all the flow control modules and the isolation valves for solvent addition.
  • the setpoint for the crude reaction mixture is inputted into the flow control equipment module.
  • Temperature control equipment modules for the first four stages and the last stage are set with jacket temperature control at 135 °C and
  • the temperature controller When the temperature probe TE-101 is submerged with process material, the temperature controller is set to process temperature control to regulate the process material at 135 °C. Once the content inside the first reactor reaches 3.5 hours residence time, set the level control equipment module to current level LT-101 and start feeding the second reactor ( Figure 4B) via path 4. The equipment module will control the level of the tank by controlling the flow rate of content leaving the first reactor (through path 4) through regulating the frequence and opening of the CV-142 control valve. The combination of the recirculation loop (path 3) and control valve (path 4) ensures material going out of the system is representative of the content inside the reactor when the average out-going flow rate is at 33.00 mL/min.
  • the inlet valve of the second reactor XV-211 is then opened to receive material.
  • the recirculation control, process temperature control and the level control are turned on respectively similar to the first reactor. These operations are repeated until all four stages are set at 135 °C and the level controls are set at 3.5 hours each.
  • the level control equipment module will control the level of the tank by controlling the flow rate of content leaving the third reactor through regulating the frequence and opening of the CV- 551 diversion control valve.
  • the content is delivered to waste in this phase.
  • the combination of the recirculation loop and control valve ensures material going out of the system is representative of the content inside the reactor when the average out-going flow rate is at 33.00 mL/min.
  • the FT-IR is then started to monitor the reactor content through the recirculation loop bypass (path 5) and measuring the quality attributes of the reactor contents.
  • the level control equipment module can be switched to recirculation and transfer operation (path 4 or path 5 if PAT monitoring is required) where the CV-551 is closed to stop the diversion and the CV-542 is controlling the outgoing flow based on the level.
  • the system remains in the state of control through the close loop control of the equipment modules until the production is finished.
  • PU-541 is turned off and CV-541 and CV-542 are both closed to stop the recirculation and the flow into the next reactor ( Figure 4D).
  • the unreacted material can be either quenched with a solvent, left in the tank for extended reaction time or directly pumped to waste by opening the CV-551. Once the tank is empty, the temperature control equipment module is switched off and all the valves are placed into their fail position. The reactor is then ready for cleaning.
  • the second ( Figure 4B) to the third reactor ( Figure 4C) follows the same procedure until the material is removed and ready for cleaning.
  • the PAT instrument remains attached during the shut-down process and is removed after cleaning.
  • the cleaning of the CSTR array is conducted in the same order of the reaction, each tank can be cleaned individually using the equipment presented in the existing process. The cleaning is only initiated when the proper shut-down procedure has been performed.
  • the example of cleaning a single reactor is presented.
  • the sequence of single reactor cleaning operation can be incorporated into the plant wide cleaning sequence where phases of purges, rinses, and washes for all the process equipment can be performed at the same time.
  • a typical cleaning cycle consists of purge, solvent pre-rinse, solvent wash, water rinse and drying.
  • step one of a cleaning cycle the contents of the CSTR are purged.
  • the reactor is flushed with aliquots of cleaning solvent via (path lb) while pumping the inventory to waste (path 2).
  • step two of a cleaning cycle the reactor process inlet (path 1) and recirculation loop (path 3) are pre-rinsed with cleaning solvent (paths la to 1c), then pump to waste (path 2).
  • the Reactor vapor riser is pre-rinsed with cleaning solvent (path 8), then pump to waste (path 2).
  • the Reactor is rinsed through sprayball with cleaning solvent (path 6), then pump to waste (path 2).
  • Process outlet is pre-rinsed with cleaning solvent (path lb, path 4), the bypass line is rinsed by actuating the bypass valves (path 5), then the remaining prerinse solvent is pumped to waste (path 2).
  • step three of a cleaning cycle the system is washed: o Reactor process inlet and recirculation loop are washed with cleaning solvent (path lb, path 3), then pump to waste (path 2). o Reactor vapor riser is charged with cleaning solvent (path 8) and washed through the recirculation pump (path 3, path 4, path 5), then pump to waste (path 2). o Process outlet is washed with cleaning solvent (path lb, path 3), the bypass line is washed by actuating the bypass valves (path 4), then the remaining wash solvent is pumped to waste (path 2).
  • Rinse the rinse may be repeated with water if the cleaning solvent is not water: o Reactor process inlet and recirculation loop are rinsed with water (path lb, path 3), then pump to waste (path 2). o Reactor vapor riser is rinsed with water (path 8, path 5), then pump to waste (path 2). o Reactor is rinsed through sprayball with water (path 6), then pump to waste (path 2). o Process outlet is rinsed with water (path 1, path 3), the bypass line is rinsed by actuating the bypass valves (path 5), then the remaining rinse water is pumped to waste (path 2).
  • Drying o Drying is performed with nitrogen blowing through the feed tube (path 11), the vapor riser port (path 12), and sprayball port (path 13) to downstream equipment through reactor exit port H via path 3, path 4, and path 5 with the CIP header piping connected. o Drying is performed with nitrogen blowing through the feed tube (path 11) to waste (path 2) with the CIP header piping connected.

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Abstract

La présente demande concerne un réseau de réacteurs à fonctionnement continu (CSTR) conforme à un équipement de biotraitement (BPE) de l'American Society of Mechanical Engineers (ASME) conçu pour des applications chimiques, pharmaceutiques et biotechnologiques continues. Chaque réseau comprend deux à cinq CSTR incorporant un système d'écoulement de recirculation et de sortie complet comportant une pompe volumétrique, une vanne de dérivation de recirculation à trois voies, et des vannes de commande pour une gestion précise de sortie et de déchets permettant la manipulation de solutions, de suspensions et de mélanges de fluides, de solides et de gaz. Des caractéristiques supplémentaires prennent en charge une maintenance facile et une surveillance de processus en temps réel, améliorant la flexibilité et la commande opérationnelles. Ce système CSTR est adapté pour satisfaire aux normes industrielles rigoureuses et pour améliorer l'efficacité du traitement.
PCT/US2025/039482 2024-07-29 2025-07-28 Réacteurs à fonctionnement continu, leurs réseaux et procédés d'utilisation Pending WO2026030217A2 (fr)

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