Continuous stirred tank reactors, arrays thereof, and methods of use

Abstract

The present application relates to an American Society of Mechanical Engineers (ASME) Bioprocessing Equipment (BPE) compliant continuous stirred tank reactor (CSTR) array designed for continuous chemical, pharmaceutical, and biotechnological applications. Each array features two to five CSTRs incorporating a comprehensive recirculation and output flow system with a positive displacement pump, a three-way recirculation diverter valve, and control valves for precise management of output and waste allowing handling of solutions, suspensions, and mixtures of fluids, solids, and gases. Additional features support easy maintenance and real-time process monitoring, enhancing operational flexibility and control. This CSTR system is tailored to meet stringent industry standards and improve process efficiency.

Description

[0001] CONTINUOUS STIRRED TANK REACTORS, ARRAYS THEREOF, AND

[0002] METHODS OF USE

[0003] CROSS-REFERENCE TO RELATED APPLICATION

[0004]

[0001] This Patent Application claims priority to U.S. Provisional Patent Application No. 63 / 676,586, filed on July 29, 2024, and entitled “Continuous Stirred Tank Reactors, Arrays Thereof, and Methods of Use.” The disclosure of the prior Application is considered part of and is incorporated by reference into this Patent Application.

[0005] BACKGROUND

[0006]

[0002] Current pharmaceutical manufacturing consists of unconnected individual steps in large batch units including chemical reactions, filtering, precipitating, drying, milling, and tableting. Quality is evaluated by testing at each step (e.g., quality by testing, QbT). This batch process is plagued by long lead times, geographical dispersion of unit operations, and large manufacturing footprints. It is estimated that more than $50 billion a year is wasted due to inefficient manufacturing. Meanwhile, attempts to improve quality have resulted in increasing numbers of product recalls.

[0007]

[0003] Integrated Continuous Manufacturing (ICM), 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. In contrast to batch manufacturing, 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. These advantages were demonstrated in the first-of-its kind ICM pilot plant ( capacity of 1.5 tons of Active Pharmaceutical Ingredient ((API) / year) at MIT, which was able to produce finished coated tablets from raw ingredients through a single, seamless end-to-end process. See Mascia, etal., "End-to-end continuous manufacturing of pharmaceuticals: integrated synthesis, purification, and final dosage formation," Angewandte Chemie International Edition, 52( 47): 12,359-12,363 (2013).

[0008]

[0004] In contrast to the quality by testing approach of the batch manufacturing process, for ICM processes, quality is designed into the system (Quality by Design, QbD). In QbD processes, controllers maintain quality thresholds throughout the production cycle, ensuring that the end product of the entire process meets its quality specification. To create ICM systems, devices and methods for each of the various unit operations need to be developed that can process streams of materials. Further, the unit devices require the ability to adjust to variations in the process stream and to provide feedback to the ICM process controller. 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. 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.

[0009]

[0005] There exists a number of U.S. patents directed to stirred tank apparatus including United States Patent Number 4,064, 111 issued to Masuda et al. on December 20, 1977; United States Patent Number 10,927,054 issued to Kreischer on February 23, 2021; United States Patent Publication Number US 2002 / 0180099 issued to Keillor on December 5, 2002; see also Hu et al., “Development of an automated multi-stage continuous reactive crystallization system with inline PATs for high viscosity process,” React. Chem. Eng. 3:658-667 (2018) (“Hu 2018"), Hu etal., “Reactor design and selection for effective continuous manufacturing of pharmaceuticals,” Journal of Flow Chemistry 11 :243-263 (2021) (“Hu 2021”). 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. To overcome the problem of solids, 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.

[0010] 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).

[0011]

[0006] There is a need for the development of unit operation processes and devices that can be incorporated into ICM methods. The present application relates to and is directed to continuous stirred tank reactor (CSTR) arrays and methods of use. 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.

[0012] SUMMARY OF THE INVENTION

[0013]

[0007] 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 located above the top of the CSTR, recirculation return control valve (XV-W41) located above the top of the CSTR, a three way recirculation diverter valve (XV-W42) located between said recirculation return valve (CV-W42) and the CSTR for diverting the recirculation flow to a reactor header comprising a spray ball SB-W01 at port (G) and vapor riser (F) located at or near the top of the CSTR, and at least one bypass port comprising valves J\1BVW43, J\l BV-W44, JVI BV-W45, for sampling and PAT, wherein each component is configured to comply with BPE requirements.

[0014]

[0008] 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 under controlled conditions to produce a product.

[0015]

[0009] 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.

[0016]

[0010] Also included and provide for by the present application is 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.

[0017] [OH] 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.

[0018] BRIEF DESCRIPTION OF THE DRAWINGS

[0019]

[0012] The present invention is disclosed with reference to the accompanying drawings

[0020]

[0013] Figure 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. 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. 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). 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.

[0014] 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). 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. 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 2K presents path 9 for recirculating a CIP fluid through the CSTR from exit port H, through valve XV-W41, pump PU-W41, valve MBV-W43, valve CV-W41, valve XV-W42, XV-W23, and into the CSTR via vapor riser port F (Path 9). Figure 2L presents path 10 for recirculating a CIP fluid through the CSTR from exit port H, through valve XV-W41, pump PU-W41, valve MBV- W43, valve CV-W41, valve XV-W42, XV-W22, and into the CSTR via inlet dip port C (Path 10). 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). As will be discussed, one or more paths may be simultaneously activated depending on the process function to be achieved.

[0021]

[0015] 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. As shown in Figure 3A, 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. During continuous processing, both path 3 and path 4 are simultaneously active.

[0022]

[0016] 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.

[0023]

[0017] Figure 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.

[0024]

[0018] Figure 6 presents a schematic of the control logic for a temperature control system according to an embodiment of the present application.

[0025]

[0019] Figure 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)

[0026]

[0020] Figure 8 presents a schematic of the control logic for pressure testing according to an embodiment of the present application.

[0027]

[0021] Figure 9 presents a schematic of the control logic for inerting a CSTR according to an embodiment of the present application.

[0028]

[0022] Figure 10 presents a schematic of an individual mass flow controller (MFC) module according to an embodiment of the present application.

[0029]

[0023] Figure 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. The system provides for flexible customization of the ratio controller with combinations of individual controller modules.

[0030]

[0024] Figure 12 presents a schematic of the control logic for a ratio and flow controller according to an embodiment of the present application.

[0031]

[0025] Figure 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.

[0032]

[0026] Figure 14 presents a schematic of the control logic for level control according to an embodiment of the present application.

[0033]

[0027] Figure 15 presents a schematic of the control logic for mixer control according to an embodiment of the present application.

[0034]

[0028] 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.

[0035]

[0029] Corresponding reference characters indicate corresponding parts throughout the several views. The examples set out herein illustrate several embodiments of the invention but should not be construed as limiting the scope of the invention in any manner.

[0036] DETAILED DESCRIPTION

[0037]

[0030] Referring to Figure 1, 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). 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.

[0038]

[0031] 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). 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. When a slurry is pumped to the downstream process, the solids may settle if the flow rate is not high enough. 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.

[0039]

[0032] The CSTR Array system consists of an Inlet Heat Exchanger Module, two or more Stirred Tank Modules and an Outlet Heat Exchanger Module. In aspects, 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.

[0040]

[0033] The five tanks design allows the handling of most chemical synthesis for small molecule API production, 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.

[0041]

[0034] To ensure transfer between reactors or to downstream processes, we developed a special transfer mechanism for the tank through a combination of recirculation loop (path 3) and a control valve to handle continuous pumping of any kinds of fluids (e.g., solution, slurry, suspension). When a slurry is pumped to the downstream process, the solids may settle if the flow rate is not high enough. The recirculation loop allows the slurry to maintain its homogeneity with a higher recirculation rate, while the control valve at the highest point of the recirculation loop trickles a stream of process liquid to the downstream process via path 4. That is, the solids are maintained in suspension by a high flow rate through path 3 and a smaller portion of the slurry or suspension is directed to the downstream process via path 5. In this way, 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.

[0042]

[0035] Continuous Stirred Tank Reactor (CSTR) Arrays: Frequently the process calls for multiple streams to be combined and maintained at a specific temperature profile for a specific time so that a chemical reaction can take place. The number of stirred tank reactors may vary but the typical number seems to be five (5).

[0043]

[0036] 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.

[0044] Table l:Equipment codes (WWW-XUV) and locations

[0045]

[0037] The equipment list and reactor port information is provided in Table 2.

[0046] Table 2: Equipment list

[0047]

[0038] The vessel ports are provided in Table 3: Table 3: Vessel Ports

[0048]

[0039] 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). 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.

[0049]

[0040] 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. 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. 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. During operation, 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. In aspects, the heating or cooling fluid is a glycol based mixture. In aspects, the glycol based mixture is an aqueous solution of glycol. In other aspect, the glycol based mixture is a non-aqueous solution.

[0050]

[0041] Second, 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. In aspects, CV-W41 is a v-notch ball valve to control the flow at low flow rates. Examples of suitable v-notch ball valves include IMI PBM’s self cleaning ball valves (IMI PBM, Irwin, PA). Examples of 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.

[0051]

[0042] 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”); f) a level sensor (LT-W01) measuring the level of the material and controls the output rate; g) a PAT system comprising one or more in-line analyzers comprising NIR, pH, UV, FTIR, FBRM, Raman, Density, Refractometer, and laser diffraction particle size measurement connected to the contained sampling system via block valves MBV-W44 and MBV- W45. Suitable block valves are diaphragm valves or self-cleaning ball valves to provide on / off control rather than flow control. In operation, 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.

[0052]

[0043] Importantly, all the liquid piping is sloped with a maximum length to height ratio of 96 (e.g., a minimum slope of 3.175 mm per 304.8 mm of length (1 / 8 inch per foot)) (inflowing piping) towards the reactors and all the waste line piping is sloped towards a waste outlet with a maximum length to height ratio of 96 (e.g., a minimum slope of 3.175 mm per 304.8 mm of length (1 / 8 inch per foot)) (outflowing piping) so that there will be no liquid hold up in the system.

[0044] In aspects, 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. In aspects, the CSTA comprises three CSTRs in serial fluid communication. In some aspects, the CSTA comprises four CSTRs in serial fluid communication. In practice, CSTAs having five CSTRs in serial fluid communication provides a balance between system flexibility and utility and costs. The operational descriptions below are based on one vessel, other arrays and individual reactors are identical, with equipment and instrument numbers changed appropriately. The major equipment number (X) is denoted with the letter “W”, W=l,2,3,4,5 as an example for total of five vessels. Additional CSTRs can be added if desired without changing the overall operation of the array. Additional CSTRs can increase conversion efficiency however the efficiency is generally balanced by the additional costs.

[0053]

[0045] The operation of 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.

[0054]

[0046] 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. In aspects, 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. In aspects, the PU-W41 pump provides a flow rate between 10 and 600 ml per minute. In a CSTR array, the modular design allows the selective entering, exiting, and bypassing of reactors, therefore to accommodate many steps of reactions within one array.

[0055]

[0047] 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. In aspects, a CSTR array can comprise two CSTRs, three CSTRs, four CSTRs, five CSTRs, or more. In typical practice, 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. In an aspect, the CSTR array comprises an array of five CSTRs.

[0056]

[0048] In practice, 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.

[0057]

[0049] 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). In some aspects, the aspect ratio is between 1.5 and four. In aspects, 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.

[0058]

[0050] 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.

[0051] 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. In order to address this issue in the art, 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. Second, the pump needs to be reversable. Third, the bottom of the vessel cannot be emptied with the process pump. As provided herein, using the recirculation loop configuration ensures the material is always suspended in the line and the pump is always running avoiding material settling. In traditional approaches, when a slurry is pumped to a downstream process, 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.

[0059]

[0052] 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. 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. In aspects, the lower shear pumps are progressive cavity, screw pump, and peristaltic pumps.

[0060]

[0053] The present application provides for, and includes, a recirculation loop (path 3) 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'6meters (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. In aspects, the transfer mechanism provides for the transfer of slurries having a solid concentration of up to 70% having a particle size of less than 700xl0'6meters (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.

[0061]

[0054] 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. In an aspect, a second pump can be included for washing connected via valves MBV-W41 and MBV- W42

[0062]

[0055] 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.

[0063] Inlet stream and liquid feeding operations

[0064]

[0056] 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. In aspects, 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. In aspects, the reaction is a chemical reaction that provides a precipitate. In aspects, 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. MFCs can be added as needed to any input or output flow, for example before XV-W14, XV-W13, or XV-W12. In aspects, an MFC is permanently installed before XV-W11. The flow rates are set up before the operation begins.

[0065]

[0057] 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.

[0066] 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.

[0058] All flows coming into or out of the reactors are either measured or calculated as follows.

[0067] 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.

[0068] Equation I:

[0069]

[0059] During normal operations, prior to start up, the operation is fully manual. One, two or more, reagents or solvents are selected and the appropriate connections are made in the CSTR or CSTR array. The operator sets up the connection of flow control modules to the appropriate locations (XV-W12, XV-W13 or XV-W14). Most of the time, the CIP fluid and the process solvent are the same. When this is not the case, the CIP fluid must always be connected to one of these ports as well before starting up, preferably the XV-W14 position. This allows a direct flow path to the spray ball for initial rinse of the vessel. Details are described in the cleaning section below.

[0070]

[0060] During the process start up, 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.

[0071]

[0061] In a normal continuous operation under steady state, the set point (flow rate) for the mass flowmeter, the solvent or reagent to be charged, and the controller that sets up the ratio control are chosen. Reagent or solvent enters the reactor through the dip tube or in the recirculation loop continuously.

[0072]

[0062] To prepare for cleaning (e.g., cleaning in place (CIP)) after the production, all the liquid piping is sloped towards the reactors, all the waste line piping is sloped towards the waste outlet so that there will be no liquid hold up in the pipe.

[0073] Temperature operations

[0074]

[0063] 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.

[0075] Normal Operations:

[0076]

[0064] During the start-up of the system, 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.

[0077]

[0065] Once the process material is introduced, 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.

[0078]

[0066] 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.

[0079] Mixing operations

[0080]

[0067] 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. The analysis assumed an open bottom outlet, a net outflow and recirculation. The only baffling is the dip tube at the inlet process flow and recirculation below the 4 L level. 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.

[0081]

[0068] 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.

[0082] Pressure operations

[0083]

[0069] 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.

[0070] 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. Finally, following the CIP methods described below, a CSTR provides for nitrogen blowdown at up to 32 psig, to remove residual liquids.

[0084]

[0071] 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). 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;

[0085] Thus the reactor can be maintained as an inert environment and includes provisions to pressure test the reactor at 32 psig.

[0086]

[0072] The system performance goal is accurate pressure control with minimal nitrogen load. To minimize 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

[0087]

[0073] The system is designed to maintain a pressure band of 0.5 to 1 psig during normal operation. In the case of charging an initially inerted atmospheric reactor or depleting the reactor (either pumped or gravity), the headspace volume will change causing pressure change in the vessel. When the vessels undergoing heating or cooling, the headspace also pressure changes. In both cases, 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.

[0088] Reactor Evacuation and Re-pressurization

[0089]

[0074] 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.

[0090]

[0075] The automated sequence will begin with XV-W62 open and XV- W11 / W12 / W21 / W22 / W23 / W31 / W32 / W41 / W61 closed and XV-W42 in active position (the arrow on a three-way valve indicates its fail position) as not to allow vacuum from being pulled on the process line or the recirculation line.

[0091]

[0076] When the set pressure (100 torr) is reached on PIT-W61, the control signals for XV- W61 to be closed, the vacuum pump to be turned off, and the re-pressurization step begins. For the automated sequence of re-pressurization from vacuum, nitrogen will be introduced by opening XV-W31 (W62 closed). PRV-W32 controls the pressure in the reactor to reach 0.5 psig. Once 0.5 psig is reached on PIT-W61, valves XV-W21 / W22 / W23 / W41 are opened and XV-W42 is set to fail position to allow air exchange between the tank, recirculation line and the trapped air in the header. Then the XV-W11 / W12 and W61 valves are opened to bring the system back to initial state.

[0092]

[0077] 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. In aspects, the oxygen levels (or other parameters) can be determined using an in-line analyzer via the PAT sampling ports A or J.

[0093]

[0078] The inerting method of pulling vacuum and backfill with nitrogen produces a reactor atmosphere with 2.7 v% after one cycle. After two swings, the oxygen concentration in the reactor can be reduced to below 1%. The calculations are shown below:

[0094] Vessel starts out atmospheric conditions (21 v% O2 and 79% N2)

[0095] Pressure Swing 1 :

[0096] Vessel depressurized to 100 torr (1.93 psia) P02 = 1.93 psia (0.21) = 0.41 psia Vessel pressurized to 0.5 psig (15.2 psia) %O2= 0.41 / 15.2 = 2.7% Pressure Swing 2

[0097] Vessel depressurized to 100 torr (1.93 psia) P02 = 1.93 psia (0.027) = 0.052 psia Vessel pressurized to 0.5 psig (15.2 psia) %O2 = 0.052 / 15.2 = 0.34%

[0098] Pressure Test

[0099]

[0079] For the automated sequence of performing a pressure test, 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.

[0100]

[0080] 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.

[0101]

[0081] After pressure test, the reactor pressure is released by opening XV-W61, PRV-W61 will control the pressure in the reactor to reach 1 psig. Once 1 psig is reached on PIT-W61, valves XV-W21 / W22 / W23 / W41 are opened and XV-W42 is set to fail position. Then the XV-W11 / W12 / W31 / W61 are opened to bring the system back to initial state. Nitrogen Blowdown

[0102]

[0082] During cleaning, nitrogen blowdown can be utilized to dry out lines. There are four blowdown paths that can be utilized.

[0103]

[0083] 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.

[0104]

[0084] Alternatively, nitrogen is blown through the feed dip tube (path 11) to downstream equipment via the outlet piping (path 4). 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.

[0105]

[0085] In a third aspect, nitrogen is blown through the feed tube (path 11) to waste with the CIP header piping connected. 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.

[0106]

[0086] In a fourth aspect, nitrogen is blown through the feed tube to downstream equipment with the CIP header piping connected. 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.

[0107]

[0087] One or more of the nitrogen blowdown methods can be repeated or combined depending on the production requirements.

[0108] Recirculation, Transfer, and Diversion Operation

[0109]

[0088] When used as an array, most typically as an array of five CSTRs, the major equipment numbers are denoted with the letter “W” The next equipment in the array (W+l) is denoted with the letter “N”. Thus, 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. These provisions are required for the following reasons: a) A means is required to effect inter reactor transfers with level control (control level or residence time) b) 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. c) Recirculation allows for establishing a representative mixture for sampling, process monitoring, and PAT measurement. d) Recirculation allows for velocities high enough to prevent solids settling. e) Recirculation allows for adding other pieces of portable equipment such as: i) special in-line analyzers (PAT); ii) sampling devices, and iii) combinations thereof. f) Recirculation of cleaning solutions to effect reactor system CIP. g) Shutdown, Waste Handling, and Cleaning such as i) discharging to waste due to a controlled shut down; ii) discharging to waste due to a diversion operation; iii) discharging to waste due to purging the system; and iv) combinations thereof

[0110]

[0089] The important elements of this system are: a) a positive displacement pump having a controllable flow less than or equal to 10 ml / min; b) two manual valves (MBV-W41, MVB-W42) for bypassing the process pump as an option; c) three control valves for altering flow / backpressure. 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.

[0111] Normal Operations:

[0112]

[0090] Prior to normal operation, 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. During normal operation, depending on if the material being transferred is a slurry or a liquid, different methods are used.

[0113] Recirculation Only

[0114]

[0091] Recirculation only occurs for slurries and liquids during: a) CIP operations when the agitator needs to be flooded and all circuits need to be flushed. b) Initial start-up when CSTRs are being brought up to operational temperature. c) Initial start-up when products are being built up to a sufficient level before transferring to the next reactor. d) Operation when a reaction mass must be held for a short period of time without settling to fix a mechanical problem or replenish some reaction.

[0115]

[0092] During recirculation only, XV-W41 is open, CV-W41 is open, CV W42 / W51 are closed, XV-W42 is diverted toward the reactor (fail position). XV-W62 / W32 are open to allow nitrogen blanketing. Pump (PU-W41) is a variable flow pump set at a designed flow rate that ensures no settling in the vertical pipe. In aspects, 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.

[0116] Recirculation / Transfer

[0117]

[0093] 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.

[0118]

[0094] 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%.

[0119]

[0095] During a transfer with recirculation, 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. In level set point, the level transmitter on the current reactor (LT-W01) 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.

[0120] Recirculation / Diversion

[0121]

[0096] 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.

[0097] If 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.

[0122] Diversion Only

[0123]

[0098] Diversion only occurs when: a) eliminating or purging prior to CIP; or b) PAT determines that the material is off specification for a slurry or liquid requiring that the entire tank material be evacuated.

[0124]

[0099] If the liquid or slurry needs to be transferred from one reactor to waste at a rate that does not require recirculation, 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.

[0125] Transfer Only

[0126]

[0100] 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.

[0127]

[0101] If a liquid is being transferred from one reactor to another, 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.

[0128] Sampling and PAT

[0102] 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.

[0129]

[0103] The important elements of this system are: a) A positive displacement pump (PU-W41). b) Three control valves for altering flow / backpressure. They are CV-W41, CV-W42, and CV-W51 c) A set of three block valves (MBV- W43, MBV-W44 and MBV-W45) positioned for the easy attachment of portable equipment or instruments. d) A contained sampling system (installed between MBV-W44 and MBV-W45 or at connection “J”). e) A portable PAT system (installed between MBV-W44 and MBV-W45). f) Return line with dip pipe positioned at the minimum CSTR level. g) Connections (“A” and “J”) on the vessel wall for easy attachment of PAT systems.

[0130] Sampling Operations

[0131]

[0104] 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.

[0132]

[0105] During liquid sampling operations, 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.

[0106] During slurry sampling operations, 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.

[0133] PAT Operation

[0134]

[0107] 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.

[0135]

[0108] 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.

[0136] Waste handling and cleaning

[0137]

[0109] 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, is an orange-yellow needlelike solid that fluoresces with a greenish-yellow glow when illuminated with ultraviolet light in the range of 100 to 400 nm. 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. Riboflavin testing methods are described in greater detail in Seiberling, D.A. (Ed.). (2008). Clean-In-Place for Biopharmaceutical Processes (1st ed.). CRC Press. doi.org / 10.3109 / 9781420014051.

[0138] [HO] 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. In simple vessels (i.e. no baffles, agitators, or dip pipes) this can be done by applying 2.5 GPM / ft of periphery. To achieve 5 ft / sec, 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.

[0139]

[0111] 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.

[0140]

[0112] 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.

[0141]

[0113] 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.

[0142] • Purge;

[0143] • Solvent Rinse;

[0144] • Solvent Wash;

[0145] • Aqueous Wash (if required);

[0146] • Purified Water / Solvent Rinse; and

[0147] • Drying

[0148]

[0114] Throughout any of these steps, 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:

[0149]

[0115] The normal operation that is carried out during End of Campaign Cleaning is the most encompassing. It can be applied to other scenarios such as mid-campaign shutdown cleaning or start-up cleaning.

[0150] Purge:

[0151]

[0116] At the end of a campaign, it is assumed that the array is inerted at its appropriate temperature, the CIP solvent is connected to XV-W14, and the reactor is filled with reaction mixture that is considered waste. While it may be possible to “work off’ CSTR liquid inventory in a controlled depletion, it is also possible that when the required quantity of API is produced, the CSTRs are filled with inventory. Several things should occur in the various control modules:

[0152] • Temperature Control: The CSTR jacket can be adjusted between a set point 20-40 °C. This is per the CIP protocol;

[0153] • Pressure Control: The CSTR will remain under nitrogen blanket (XV- W31 / W61 open);

[0154] • Mixer Control: the agitator (AG-W01) will run at the pre-programmed CIP speed; and

[0155] • 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.

[0156]

[0117] All upstream operations are assumed to have been cleaned and the inlet pipe including the MCF is washed with aliquots of cleaning solvent from upstream. The inventory is pumped to waste with XV-W41 and CV-W51 open and the pump PU-W41 is on. While the inventory in the CSTR is pumped to waste, the transfer line into the system can be flushed with clean process (CIP) fluid from XV-W12 to facilitate the purging. While the inlet line flushing is taking place, the transfer pump will be directing liquid through CV-W51 to waste. This process will run for a set volume calculated by the “flow control module” connected to the XV-W12 until the purge step is considered complete.

[0157] Solvent Rinse:

[0158]

[0118] 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. During Solvent Rinse, several things should occur in the various control modules: • Temperature Control: The CSTR jacket can be adjusted between a set point 20-40 °C. This is per the CIP protocol.

[0159] • Pressure Control: The CSTR will remain under nitrogen blanket (XV- W31 / W61 open). Before solvent directed to the spray balls, the pressure operation will undergo “Reactor Evacuation and Repressurization” to inert the reactor again. Then, the control module will resume nitrogen blanketing. If nitrogen blowdown is required in between any steps, the operator can prompt one of the several nitrogen blowdown flow paths.

[0160] • Mixer Control: the agitator (AG-W01) will run at the CIP speed.

[0161] • Transfer Control: The transfer pump PU-W41 is set at a determined CIP rate.

[0162] Step 1 : Process Inlet and Recirculation Loop Pre-Rinse

[0163]

[0119] Any lines used during the campaign need to be flushed. In most cases, 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).

[0164]

[0120] Then the operator would open 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.

[0165]

[0121] After a set amount of time, the operator will open XV-W41 and CV-W51 and the rinse will be sent to the waste tank via PU-W41 under control of the transfer operations. Once the level in the tank reaches zero (determined by LT-W01), XV-W41 and CV-W51 are closed.

[0166] Step 2: Reactor Pre-rinse through Spray ball

[0167]

[0122] 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.

[0168]

[0123] It should be noted that the reactor vessel piping and auxiliary equipment are grounded. To prevent the ignition of a flammable mixture by a spark, the vessel must be inerted. At this point, the CIP sequence will prompt the operator to carry out the “Reactor Evacuation and Re-pressurization” under the control of pressure operations.

[0169]

[0124] 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.

[0170]

[0125] Then 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.

[0171] Step 3 : Vapor Riser Rinse

[0172]

[0126] After steps 1 and 2, it is possible that some splashing could occur up into the vapor riser (Port “F”). For this reason, a pre-rinse of the vapor riser line is needed. The nitrogen inlet that connects to the dip tube, due to its open connection with the process inlet, is also rinsed. In this step, the XV-W14 is opened to introduce CIP rinse solvent and the diverter valve XV-142 is positioned towards the reactor header (active position), which directs solvent to the pipes that connects the vapor riser. XV-W22 is open, XV-W21 / W23 and CV-W41 would be closed. 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.

[0173]

[0127] Then the XV-W23 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.

[0174] Step 4: Reactor Outlet Pre-Rinse

[0175]

[0128] The next step is to flush all of the lines which leave that reactor to their destinations. In this step, 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.

[0176]

[0129] 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.

[0177]

[0130] Once the level (LT-W01) reads zero, the pump (PU-W41) will shut off. Once the pump is shut off, CV-W41 / W51 will open and CV-W42 is closed. This will allow the vertical process outlet line to drain for a set amount of time.

[0178] Solvent Wash

[0179]

[0131] During Solvent Wash, several things occur in the various control modules:

[0180] • Temperature Control: The CSTR jacket can be adjusted between a set point 20-60 °C. This is per the CIP protocol.

[0181] • Pressure Control: The CSTR remains under nitrogen blanket (XV-W31 / W61 open) throughout the wash. If nitrogen blowdown is required in between any steps, the operator can prompt one of the nitrogen blowdown flow paths.

[0182] • Mixer Control: The agitator (AG-W01) will run at the CIP speed.

[0183] • 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.

[0184]

[0132] All upstream operations are assumed to have been cleaned and the inlet pipe including the MCF has been washed with aliquots of cleaning solvent from upstream. At the beginning of Solvent Wash and at the completion of each step in the Solvent Wash, the valves will return to the positions below:

[0185] • XV-W42 FAIL POSITION

[0186] • CV-W41 / W42 / W51 CLOSED

[0187] • XV-W14 / W21 / W22 / W23 / W41 CLOSED

[0188] Step 1 : Process Transfer Line Inlet and Recirculation Loop Wash

[0189]

[0133] 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.

[0190]

[0134] 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.

[0191]

[0135] After a set amount of time, the operator will open CV-W51 and the wash solvent will be sent to the waste tank via PU-W41 under control of the transfer operations. Once the level in the tank reaches zero (determined by LT-W01), XV-W41, CV-W41 and CV-W51 are closed.

[0192] Step 2: Transfer Out Wash

[0193]

[0136] All of the lines that leave that reactor to their destinations is washed at this step. 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-W42 are open and valves CV-W41 / W51 are closed. If required, the solvent can be warmed with the heat transfer fluid through the jacket. PU-W41 pumps from reactor to the subsequent process at the determined CIP rate. Sufficient solvent volume must be added to the vessel into account for washing at least 1 minute.

[0194]

[0137] Once the level (LT-W01) reads zero, the pump (PU-W41) will shut off. Once the pump is shut off, CV-W41 / W51 will open and CV-W42 is closed. This will allow the vertical process outlet line to drain for a set amount of time.

[0195] Step 3: Vapor Riser Wash and Reactor Wash with Spray ball

[0196]

[0138] 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.

[0197]

[0139] In this step, 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.

[0198]

[0140] 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.

[0199]

[0141] Once both nitrogen and exhaust header are washed, 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.

[0200]

[0142] Then the XV-W21 is closed. Valve CV-W51 is open and the wash liquid 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.

[0201] Step 4: Sampling During Wash Steps (optional)

[0202]

[0143] 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.

[0203] Aqueous Wash (optional)

[0204]

[0144] An aqueous wash cycle can be used in place of or in addition to the solvent wash cycle. Possible fluids used could be:

[0205] • Purified water

[0206] • Purified water with a surfactant

[0207] • Purified water with caustic cleaning chemical wash

[0208] • Purified water with acid cleaning chemical wash The steps of the cycle are the same as the solvent wash, including the sampling procedures. In aspects, different aqueous wash fluids can be used in series and in any order.

[0209] Purified Water / Solvent Rinse

[0210]

[0145] 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.

[0211] Drying

[0212]

[0146] 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.

[0213] Definitions:

[0214]

[0147] As used herein, 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.

[0215] As used 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. Although particular combinations of features are recited in the claims and / or disclosed in the specification, these combinations are not intended to limit the disclosure of various implementations. In fact, many of these features may be combined in ways not specifically recited in the claims and / or disclosed in the specification.

[0216]

[0148] Although each dependent claim listed below may directly depend on only one claim, the disclosure of various implementations includes each dependent claim in combination with every other claim in the claim set. No element, act, or instruction used herein should be construed as critical or essential unless explicitly described as such.

[0149] As used herein, 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. Further, the phrase “based on” is intended to mean “based, at least in part, on” unless explicitly stated otherwise. Also, as used herein, the term “or” is intended to be inclusive when used in a series and may be used interchangeably with “and / or,” unless explicitly stated otherwise (e.g., if used in combination with “either” or “only one of’).

[0217]

[0150] As used herein, a fluid can be a liquid (solvent or solution), a gas (pure or mixtures), or a slurry (solid suspension in a carrier liquid).

[0218]

[0151] The foregoing disclosure provides illustration and description but is not intended to be exhaustive or to limit the implementations to the precise form disclosed. Modifications may be made in light of the above disclosure or may be acquired from practice of the implementations.

[0219] Control Systems

[0220]

[0152] 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.

[0221] Unit Control Logics

[0222]

[0153] Each “unit” level control determines the main control objectives for each unit. It handles the control system for each unit to achieve the state of control. It is also equipped with various modes and specific logics that can allow for “plant- wide” control.

[0223]

[0154] The system hierarchy can be categorized into the following levels:

[0224] • Level 0 Production Lines (Product 1, Product 2, . . .)

[0225] • Level 1 Systems (Reactor System 1, Filtration System 1, . . .)

[0226] • Level 2 Unit (CST-101, CST-201, ...) • Level 3 Equipment Modules (Temperature Control EM, Pressure Control EM, . . .)

[0227] • Level 4 Various Operations (Inert Operation, Pressure Test Operation, . . .))

[0228]

[0155] Table 4 below 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.

[0229] Table 4: CST Array Equipment Modules

[0230]

[0156] The 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.

[0231] Temperature Control

[0232]

[0157] A schematic of the temperature control system is presented in Figure 5. 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.

[0233] 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.

[0234] Pressure Control

[0235]

[0158] As illustrated in the schematic of Figure 7, 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).

[0236]

[0159] The operations for inerting and pressure check experienced sequences of “phases” that are programmed to achieve their operation. The control modules involved are the pressure indicator (PIT-W61) and the valves within the reactor system.

[0237]

[0160] 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.

[0238]

[0161] 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.

[0239] Flow Control

[0240]

[0162] As shown in Figure 10, 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.

[0241]

[0163] 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.

[0242]

[0164] 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

[0243]

[0165] As shown in Figure 13, 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.

[0244] Mixer Control

[0245]

[0166] As shown in Figure 15, 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.

[0246] Plant-Wide Control Logics

[0247]

[0167] The desired plant-wide operation sequence consists of the following steps listed below.

[0248] • OFF

[0249] • Start-Up

[0250] • Operation

[0251] • Shut-Down

[0252] • WIP (CIP)

[0253]

[0168] The initial state for the system is the OFF (idle) mode where everything is turned off, and nothing is running. 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. In 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. The plant wide start-up is complete when the last unit is switched to Operation mode. System under Operation mode will be fully automatic, and the process is driven by the set-point and various close loop process control algorithms. It’s important to note that start-up may be interrupted due to unexpected events. In the case of these events, the system may be switched to Shut-Down mode to abort the unit operation.

[0169] Halt (hold) mode, and its subsequent Restart mode are introduced as transition modes for process interruptions. Figure 16 shows illustrative sequences of operation that may occur during production.

[0254] Embodiments

[0255] 1. An American Society of Mechanical Engineers (ASME) Bioprocessing Equipment (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 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-W42) line located above the top of the CSTR, recirculation return control valve (XV-W41) located above the top of the CSTR; a three way recirculation diverter valve (XV-W42) located between said recirculation return valve (CV-W42) and the CSTR for diverting the recirculation flow to a reactor header comprising a spray ball (G) and vapor riser (F) located at or near the top of the CSTR; and at least one bypass port comprising valves MBV-W43, MBV-W44, MBV-W45, for sampling and PAT; wherein each component is configured to comply with BPE requirements.

[0256] 2. The CSTR of embodiment 1, wherein said CSTR is part of an array (CSTA) comprising at least two CSTRs arranged in series. 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 3, wherein the vapor riser (F) comprises a nitrogen line and an exhaust line. 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 6, further comprising a sight glass and PAT port (A). The CSTR of any one of embodiments 1 to 6, further comprising temperature sensor port (I) and a temperature sensor (TE-W01). The CSTR of any one of embodiments 1 to 7, further comprising a spray ball SB-W01 at port (G) located at the top of the reactor and in fluid communication with process utilities comprising a vapor riser header and valve XV-W23, a nitrogen supply line and valve XV- W22, and a clean-in-place (CIP) fluid addition line and valve XV-W14, wherein said CIP fluid addition line is in fluid communication with said recirculation loop before valve XV- W42 The CSTR of any one of embodiments 1 to 8, further comprising a level sensor port (E) and a level sensor LT-W01. The CSTR of any one of embodiments 1 to 9, wherein said CSTR is fluid jacketed wherein said fluid jacket comprises a heating or cooling fluid in fluid communication with a heating and cooling system. 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. The CSTR of any one of embodiments 1 to 12, wherein said recirculation and output flow system further comprises at least one fluid addition port and valve (XV-W13) located downstream of said PU-W41 pump. 13 The CSTR of any one of embodiments 1 to 13, further comprising 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. The CSTR of any one of embodiments 1 to 15, wherein 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. The CSTR of any one of embodiments 1 to 16, wherein 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 18, wherein said fluid is a solution, a mixture of solutions, a suspension, or a mixture of a fluid and a gas. The CSTR of any one of embodiments 1 to 19, wherein said fluid is a suspension having a solid concentration of up to 70% (wt / wt) and said solid has a particle size of less than 700 um. 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. The CSTR of any one of embodiments 1 to 22, wherein said CSTR is part of an array (CSTA) comprising at least three CSTRs arranged in series. The CSTR of any one of embodiments 1 to 22, wherein said CSTR is part of an array (CSTA) comprising at least four CSTRs arranged in series. The CSTR of any one of embodiments 1 to 22, wherein said CSTR is part of an array (CSTA) comprising at least five CSTRs arranged in series. 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. The method of embodiment 26, wherein each CSTR is equipped with mass flow controllers for precise control of Reactant A and Reactant B feed rates. The method of any one of embodiments 26 or 27, wherein each CSTR is configured to automatically adjust the flow rate of the reaction mixture based on real-time measurements from the inline FT-IR to ensure product quality and reaction efficiency. The method of any one of embodiments 26 to 28, further comprising a shutdown procedure that comprises: stopping the feed of Reactant A and Reactant B; depleting the content of the third CSTR by diverting to waste while maintaining recirculation; sequentially shutting down upstream CSTRs in the array; and cleaning the CSTR array post-reaction using a controlled sequence of solvent and water rinses. The method of any one of embodiments 26 to 29, wherein 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. The method of any one of embodiments 26 to 30, wherein the control of the reaction mixture flow rate and the residence time in each CSTR is achieved by a combination automated control valves that are responsive to the process control system of the CSTR array. The method of any one of embodiments 26 to 31, wherein the CSTR array is further configured to perform cleaning-in-place (CIP) operations automatically following the completion of the reaction process or upon initiation of a shutdown procedure, wherein the CIP operations comprise a purge phase, a rinse phase, a wash phase, and drying phase. 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. The method of any one of embodiments 26 to 33, wherein the wash phase comprises a solvent wash followed by a water rinse. The method of any one of embodiments 26 to 34, wherein said drying phase comprises blowing nitrogen through the feed tube (C) to downstream equipment and blowing nitrogen through the feed tube (C) to waste. 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. 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 method of any one of embodiments 36 or 37, wherein 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. 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. The method of any one of embodiments 36 to 39, wherein the control of the reaction mixture flow rate and the residence time in each CSTR is achieved by a combination of automated control valves and manual adjustments based on real-time data from the process control system. The method of any one of embodiments 36 to 40, wherein the CSTR array is further configured to perform automated cleaning-in-place (CIP) operations following the completion of the crystallization process or upon initiation of a shutdown procedure, using a sequence of cleaning agents and techniques specified in a reactor cleaning protocol. The method of any one of embodiments 36 to 41, wherein the temperature control for both reaction and crystallization stages is achieved using a heat transfer system integrated with each CSTR, capable of rapid adjustment to meet process demands. The method of any one of embodiments 36 to 42, wherein the CSTR array is adaptable to various solvent systems and reactant types by configuring material compatibility and operational parameters of the CSTRs to prevent chemical degradation or contamination. The method of any one of embodiments 36 to 43, wherein said CSTR array comprises two CSTRs in series. The method of any one of embodiments 36 to 43, wherein said CSTR array comprises three CSTRs in series. The method of any one of embodiments 36 to 43, wherein said CSTR array comprises four CSTRs in series. The method of any one of embodiments 36 to 43, wherein said CSTR array comprises five CSTRs in series. 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. The method of any one of embodiment 49, wherein the cleaning solvent is introduced through a dedicated clean-in-place (CIP) fluid inlet and controlled by a flow control module to regulate the volume and rate of solvent introduced. The method of 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. The method of any one of embodiments 49 to 54, wherein the cleaning process includes the use of a heat transfer system to control the temperature of the cleaning solvents and rinse water, enhancing the effectiveness of the cleaning process by optimizing solvent and water temperatures. The method of any one of embodiments 49 to 55, wherein the drying step includes isolating each line within the reactor system during nitrogen blowdown to achieve targeted drying, minimizing the risk of cross-contamination and ensuring readiness for subsequent processing operations. The method of any one of embodiments 49 to 56, wherein the cleaning process is initiated automatically following a shutdown procedure or manually by an operator through a user interface that allows customization of the cleaning parameters based on the specific needs of the reactor system. 58. The method of any one of embodiments 49 to 57, wherein said CSTR array comprises two CSTRs in series.

[0257] 59. The method of any one of embodiments 49 to 57, wherein said CSTR array comprises three CSTRs in series.

[0258] 60. The method of any one of embodiments 49 to 57, wherein said CSTR array comprises four CSTRs in series.

[0259] 61. The method of any one of embodiments 49 to 57, wherein said CSTR array comprises five CSTRs in series.

[0260] 62. 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.

[0261] 63. The system of embodiment 62, wherein said CSTR array comprises two CSTRs in series.

[0262] 64. The system of embodiment 62, wherein said CSTR array comprises three CSTRs in series.

[0263] 65. The system of embodiment 62, wherein said CSTR array comprises four CSTRs in series.

[0264] 66. The system of embodiment 62, wherein said CSTR array comprises five CSTRs in series.

[0265] 67. The methods of any one of embodiments 26 to 35, of any one of embodiments 36 to 48, of any one of embodiments 49 to 61, and the system of any one of embodiments 62 to 66, wherein the CSTR and CSTA comprises any one of embodiments 1 to 25.

[0266] Examples

[0267]

[0170] As used throughout the examples, groups of control modules form an equipment module that has additional operations to those illustrated in the specifications, the actual operation requires each of the equipment modules to be individually operated in their respective operations only the certain inter-CSTR operations are mentioned.

[0268] Example 1:

[0171] 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.

[0269]

[0172] First, 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. In particular, 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. In some aspects, 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.

[0270]

[0173] Second, the vessel, connected to atmosphere through the fin-denser with no pressure control or means of inerting the head space precluded CIP processes.

[0271]

[0174] Third, 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.

[0272]

[0175] Fourth, cleaning of the vessel required significant effort, the only equipment that could be utilized was the agitator, requiring that the lid be cleaned separately. Emptying the vessel required manual operation with only assistance from gravity. The system required that ability to be cleaned-in-place with its existing equipment to protect the operator from chemical exposure prior to opening the system.

[0273]

[0176] The initial system limited flexibility in the process (a primary design goal) so the system was redesigned to incorporate additional capabilities. The system needed to be flexible to different chemistry conditions, such as various residence time, temperature, pH and chemical compatibility. The system required flexibility to integrate into a continuous manufacturing train with all the process utilities ports in place. The original system lacked the utility lines of the present CSTR, such as nitrogen, exhaust, or waste. Example 2: Reaction Processing (solution only)

[0274]

[0177] In this reaction, 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

[0275] 25 °C. 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.

[0276] Startup

[0277]

[0178] 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 (path la for Reactant A and path lb for Reactant B) are mixed and fed to the reactor through port C (e.g., path 1c). Once reactor content reaches the minimum level for recirculation (about 4 Liters), 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. 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.

[0278]

[0179] Once the content inside the third reactor (Figure 3C) reaches 2 hours residence time, 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. Once the PAT result stabilized (indicating the 3 stages reactor array has established the state of control (e.g., steady state), 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. When the start-up is finished, the system remains in the state of control through the close loop control of the equipment modules until the production is finished.

[0279] Shut down

[0280]

[0180] The shut-down procedure will “work up” the remaining process material to ensure minimum unreacted material to be discharged to waste. When the shut-down is initiated, 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. 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 (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.

[0281] Example 3: Reactive Crystallization (from solution to a slurry)

[0282]

[0181] A reactive crystallization process is conducted in five stages of CSTR array (Figure 4A- E). Reactant A and reactant B (1.11 molar equivalent of reactant A) are both dissolved in dimethylformamide (DMF) at 70 °C, and the solution is fed to the reactor at 135 °C to form Product C. The reaction takes 4 stages of CSTR array at 135 °C and the crystallization takes the last stage of the CSTR at 70 °C for crystallization. As the reaction progresses in stages one to four, the product C is formed and started to crystallize out due to its low solubility in DMF. 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. 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.

[0283] Startup

[0284]

[0182] 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

[0285] 75 °C, respectively, when the reactors are empty. Once the jacket temperature is stabilized, feeding the tank is started with the crude reaction mixture by opening the valve XV-111 (Figure 4A). The mass flow meter for the crude reaction mixture ensures the solution to be fed at a consistent rate towards the reactor through port C. Once reactor content reaches the minimum level for recirculation (about 4 Liters), start the recirculation by opening the valve XV-141, CV-141 and turning on the pump PU-141 at the setpoint of recirculation rate (e.g., path 3). Calculations demonstrate that minimum 600 mL / min is required to suspend the solid in DMF, thus the PU-141 is set at 600 mL / min for recirculation. 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.

[0286]

[0183] The last stage of the CSTR (Figure 4E) then starts to receive material at 33 mL / min. The reaction material is quenched at 70 °C and more product C is crystallized from the reaction mixture. Once the crystallization mixture reaches the minimum level for recirculation (about 4 Liters), start the recirculation (path 3) by opening the valve XV-541, CV-541 and turning on the pump PU-541 at the setpoint of recirculation rate. When the temperature probe TE- 501 is submerged with process material, the temperature controller is set to process temperature control to regulate the process material at 70 °C. Once the content inside the fifth reactor reaches 3.5 hours residence time, set the level control equipment module to current level LT-501 and start the recirculation (path 3) and diversion operation (path 2). The 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. In this case, a mathematical model reflecting the reactant A concentration is designed and the FT-IR is able to measure the concentration of residual reactant A to understand the impurity profile. Once the PAT result stabilized, indicating the 5 stages reactive crystallization has established the state of control, 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. When the start-up is finished, the system remains in the state of control through the close loop control of the equipment modules until the production is finished.

[0287] Shutdown

[0288]

[0184] Template: The shut-down procedure will “work up” the remaining process material to ensure minimum unreacted material to be discharged to waste. When the shut-down is initiated, the CSTR array immediately stops feeding the downstream process. The fifth reactor (Figure 4E) is switched to recirculation (path 3) and diversion operation (path 2) to deplete the reactor content. CV-542 is closed and CV-551 is controlled by the level controller to transfer the material to waste. The CSTR array inlet feed is stopped by closing the valve XV-111. The level control equipment module is set to constant rate to deplete the tank volume at the rate of 33.00 mL / min. When the level drops below the minimum level for recirculation, the recirculation and transfer is stopped. 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.

[0289] Cleaning

[0290]

[0185] 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.

[0291] • In 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).

[0292] • In 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). o The Reactor vapor riser is pre-rinsed with cleaning solvent (path 8), then pump to waste (path 2). o The Reactor is rinsed through sprayball with cleaning solvent (path 6), then pump to waste (path 2). o 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).

[0293] • In 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).

[0294] • 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).

[0295] • 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.

Claims

WHAT IS CLAIMED IS:

1. An American Society of Mechanical Engineers (ASME) Bioprocessing Equipment (BPE) compliant continuous stirred reactor (CSTR) comprising at least two CSTRs arranged in series (CSTA), said CSTR comprising: an operational range of 4 to 200 L; an aspect ratio of 1.5 to 4; an input line comprising at least one fluid addition port and valve (XV-W12) located upstream of said CSTR and a 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 fluid jacket comprising a heating or cooling fluid in fluid communication with a heating and cooling system; and a fluid 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 reactor exit port (H) and 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-W42) line located above the top of the CSTR, at least one fluid addition port and valve (XV-W14) connected between 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; a recirculation return control valve (XV-W41) located above the top of the CSTR; at least one fluid addition port and valve (XV-W14) between said recirculation return control valve (CV-W41) and recirculation diverter valve XV-W42;a three way recirculation diverter valve (XV-W42) located between said recirculation return valve (CV-W42) and the CSTR for diverting the recirculation flow to a reactor header comprising a spray ball (G) and vapor riser (F) located at or near the top of the CSTR; at least one bypass port comprising valves MBV-W43, MBV-W44, MBV-W45, for sampling and PAT; and at least one fluid addition port and valve (XV-W13) located downstream of said PU-W41 pump; wherein said fluid is a solution, a mixture of solutions, a suspension, or a mixture of a fluid and a gas; a temperature sensor port (I) and a temperature sensor (TE-W01); and a level sensor port (E) and a level sensor LT-W01; wherein each component is configured to comply with ASME BPE requirements.

2. The CSTR of claim 1, wherein the vapor riser (F) comprises a nitrogen line and an exhaust line.

3. The CSTR of claim 2, 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).

4. The CSTR of claim 1, further comprising a sight glass and PAT port (A).

5. The CSTR of claim 1, further comprising a spray ball SB-W01 at port (G) located at the top of the reactor and in fluid communication with process utilities comprising a vapor riser header and valve XV-W23, a nitrogen supply line and valve XV-W22, and a clean-in-place (CIP) fluid addition line and valve XV-W14, wherein said CIP fluid addition line is in fluid communication with said recirculation loop before valve XV-W426. The CSTR of claim 1, wherein said input line further comprises a providing a fluid flow and a mass flowmeter controller for measuring and controlling said fluid flow.

7. The CSTR of claim 1, said CSTR further comprises a second sight glass and PAT port (J).

8. The CSTR of claim 1; wherein said heating or cooling fluid is an aqueous glycol solution.

9. 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 having at least three CSTRs to form a reaction mixture; 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 the at least three CSTRs of the CSTR array, with each stage providing a portion of a 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 a recirculation loop of the last of said at least three CSTRs for monitoring the reaction; and controlling the reaction using a process control system comprising equipment modules for feed flows, temperature, and level based on set parameters; wherein the CSTR array process control system is configured to maintain the reaction under controlled conditions to produce a product.

10. The method of claim 9, wherein each CSTR is equipped with mass flow controllers for precise control of Reactant A and Reactant B feed rates by said process control system.

11. The method of claim 9, wherein the process control system is configured to automatically adjust the flow rate of the reaction mixture for each CSTR based on real-time measurements from the inline FT-IR to ensure product quality and reaction efficiency.

12. The method of claim 9, further comprising a shutdown procedure that comprises: stopping the feed of Reactant A and Reactant B; depleting the contents of the last of the at least three CSTRs by diverting to waste while maintaining recirculation; sequentially shutting down upstream CSTRs in the array; and cleaning the CSTR array post-reaction using a controlled sequence of solvent and water rinses.

13. The method of claim 9, wherein 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 realtime monitoring and control of the chemical reaction.

14. The method of claim 9, wherein the control of the reaction mixture flow rate and the residence time in each CSTR is achieved by a combination automated control valves that are responsive to the process control system of the CSTR array.

15. The method of claim 9, wherein the CSTR array is further configured to perform cleaning-in-place (CIP) operations automatically following completion of a reaction process or upon initiation of a shutdown procedure, wherein the CIP operations comprise a purge phase, a rinse phase, a wash phase, and drying phase.

16. The method of claim 15, wherein said rinse phase comprises a solvent pre-rinse wherein the solvent is the same as the solvent for the reaction.

17. The method of claim 15, wherein the wash phase comprises a solvent wash followed by a water rinse.

18. The method of claim 15, wherein said drying phase comprises blowing nitrogen through the feed tube (C) to downstream equipment and blowing nitrogen through the feed tube (C) to waste.

19. A system for cleaning a CSTR array, comprising: at least two CSTRs in series; a network of valves configured to direct cleaning solvent and rinse water through the CSTR array in a predetermined sequence; sensors to monitor residual chemicals or moisture, providing feedback to control the duration and intensity of cleaning and drying cycles; and 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 specific chemical processes previously conducted in the CSTR array.

20. The system of claim 19, wherein said CSTR array comprises three, four, or five, CSTRs in series.

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