A method for using ultrasonic flow sensors to monitor filling weight accuracy in clinical, commercial, and process development filling / finishing operations.

Abstract

The methods and systems of this disclosure generally relate to the process of filling a container with a liquid and checking compliance with the filling volume. Checking compliance with the filling volume includes measuring the flow rate during the filling time interval using a flow sensor (e.g., an ultrasonic sensor). In some exemplary implementations, multiple flow sensors may be used. Furthermore, this disclosure describes various calibration techniques for ensuring accurate filling volume measurement using numerical integration of the flow rate. Furthermore, this disclosure describes generating and displaying alerts indicating non-compliance and / or various failure modes.

Description

Technical Field

[0001] Cross - reference to related applications Priority is claimed to U.S. Provisional Patent Application No. 63 / 455,847, filed Mar. 30, 2023, the entire contents of which are incorporated herein by reference.

[0002] The present disclosure generally relates to monitoring the process of filling a container with liquid, and more specifically to using one or more flow sensors to detect the filling amount.

Background Art

[0003] Filling of pharmaceuticals is a complex unit operation, which is important to ensure that high - quality products are delivered to patients. Among several considerations, a good filling process must deliver a consistent amount of pharmaceutical product to each individual container within strict error limits so that all units can be judged to be safe and effective according to scientifically specified action limits. Such consistency must probably be 100% guaranteed in in - process control (IPC) of the filling weight. One IPC approach is to weigh each dose on a scale with sufficient accuracy to confirm that the dose is within the action limits. However, the procedure of this process (placing an empty container on a weighing instrument, taring, removing from the instrument, filling, and then returning to the instrument for re - weighing) is very time - consuming. Therefore, an alternative IPC that can guarantee accurate and consistent dosages is needed.

Summary of the Invention

Means for Solving the Problems

[0004] In one example, a system for filling a container with liquid includes a flow control device configured to transfer the liquid from a storage reservoir into the container via piping, and at least one sensor located in the piping. The system further includes one or more processors configured to cause the flow control device to transfer the liquid from the storage reservoir into the container via piping. One or more processors in the system are further configured to receive from at least one sensor a plurality of values ​​representing a plurality of respective flow rates at each of a plurality of time intervals within a filling time interval, and to calculate a fill volume instruction value based at least in part on the plurality of received values. One or more processors in the system are also configured to compare the fill volume instruction value with a target fill volume to generate a fill volume compliance instruction value.

[0005] In another example, a method for checking compliance with a container's fill volume includes one or more processors causing a flow control device to transfer liquid from a storage reservoir to a container via a tube. This method further includes one or more processors receiving multiple values ​​from at least one sensor located in the piping, each representing multiple flow rates at each of multiple time intervals within a fill time interval. The method further includes i) one or more processors calculating a fill volume indicator value based on at least some of the received values; ii) one or more processors comparing the fill volume indicator value with a target fill volume; and one or more processors generating a fill volume compliance indicator value. [Brief explanation of the drawing]

[0006] [Figure 1] An illustrative system for filling a container with liquid is schematically shown. [Figure 2] A schematic diagram illustrates another exemplary system for filling a container with liquid. [Figure 3] An illustrative system for detecting compliance with filling volume is schematically shown. [Figure 4] Other exemplary systems for detecting compliance with filling quantities are schematically shown. [Figure 5] A schematic diagram of an exemplary non-contact flow sensor placed in a section of piping is shown. [Figure 6A] The operating principle of an ultrasonic flow sensor is outlined below. [Figure 6B] The operating principle of an ultrasonic flow sensor is outlined below. [Figure 7A] An illustrative flow profile is shown schematicly. [Figure 7B] An illustrative flow profile is shown schematicly. [Figure 8] This is a block diagram illustrating an example method for checking compliance with container filling quantities. [Modes for carrying out the invention]

[0007] This disclosure relates to the operation of a system for filling dispensing containers (e.g., ampoules, vials, cartridges, syringes, etc.) with liquids (e.g., therapeutic liquids such as chemicals and biopharmaceuticals) in clinical or commercial settings. The examples described herein may supplement or replace, at least in part, gravimetric process control in the filling process with process control based on the use of flow sensors (e.g., ultrasonic, electromagnetic, etc.). Measuring dispensing volume based on flow rate offers a significant speed advantage over gravimetric systems that measure each fill. A gravimetric control system that samples only a portion of the filled container can increase throughput. This throughput improvement may come at the cost of potential product waste if the sample deviates from compliance and the entire batch must be discarded. Therefore, the flow-based process control systems of this disclosure can reduce product waste and improve efficiency compared to sampling gravimetric systems. Furthermore, the flow-based process control systems of this disclosure can be used to quickly and effectively identify problems in the filling process and thus offer diagnostic advantages over gravimetric systems. The systems and methods of this disclosure are more widely applicable to many container filling operations where filling accuracy and / or filling speed are critically important. In addition, the systems and methods described herein may include flow rate measurements during the filling operation in development, ensuring reliable process characterization, thereby allowing operators to more easily detect and address deviations in filling weight.

[0008] The systems and methods described herein overcome several challenges in converting flow rate measurements into indicated fill volumes. Some of these challenges are specific to fill processes involving the volume of therapeutic fluids. For example, the absolute accuracy required to fill volumes of fractions of a milliliter or several milliliters with high relative precision is far more difficult to achieve than the equivalent relative precision for larger volumes. Rapid fill processes with small fill volumes may rely on frequent starting and stopping of pumping or valve operation. Rapid cycling of pumping or valve operation then creates requirements for flow sampling and detection of the start and stop times of each fill time interval. Furthermore, due to the potential sensitivity of therapeutic fluids to contamination, contact with the equipment must be minimized. Therefore, the pumps, valves, and sensors used in the systems described herein may be non-contact pumps, valves, and sensors. For example, peristaltic pumps used in fill operations can introduce ripples in the flow rate. Therefore, the systems and methods of this disclosure may employ appropriate flow integration algorithms and / or other techniques to overcome fill volume errors resulting from flow rate fluctuations.

[0009] The described technology can achieve results equivalent to or better than those using weighing instruments, enabling 100% accurate, non-invasive, non-destructive, and non-product-contact in-line evaluation of filling weight without adversely impacting line speed or throughput.

[0010] Figure 1 schematically shows an exemplary system 110 for filling a container with liquid. The system 110 includes a flow control device 120, one or more sensors 130a, b, and a processing unit 140. Sensor 130b is represented by a dashed line to indicate that sensor 130b is optional, and the exemplary system 110 may consist of sensor 130a only. Sensors 130a, b are communicatively connected to the processing unit 140 and fluidly connected to the flow control device 120. The flow control device 120 may also be fluidly connected to the processing unit 140. Furthermore, the flow control device 120 may be fluidly connected to piping 150 and fluidly connected to a storage reservoir 160 and a container 170 via piping 150.

[0011] The flow control device 120 may include one or more pumps (e.g., peristaltic pumps, gear pumps, diaphragm pumps, etc.), one or more valves, and / or any other suitable flow control elements. The flow control device 120 may be distributed throughout the entire fluid portion of the system 110. For example, the pumps may be located in the reservoir 160 or at one point along the piping 150, and one or more valves may be located at different points along the piping 150.

[0012] Sensors 130a,b may be ultrasonic, electromagnetic, or any other suitable flow sensors. Additionally or alternatively, at least one of sensors 130a,b may be an image sensor, a particle velocity sensor, or any other suitable type of sensor capable of measuring the flow rate in the piping 150. The system 110 may also additionally include sensors for measuring fluid or ambient temperature, fluid or ambient pressure, fluid density, opacity, viscosity, and / or uniformity.

[0013] The processing unit 140 may include one or more processors. These one or more processors may be contained in a single computing device, or, in some examples, distributed across multiple devices. For example, the processing unit 140 may have several components incorporated into sensors 130a, b, other components incorporated into the flow control device 120, and even more components incorporated into the overall process control and / or notification system. At least one of the one or more processors included in the processing unit 140 may be implemented in the cloud. At least one of the one or more processors included in the processing unit 140 may be contained in a laptop or mobile computing device. Examples of the one or more processors in the processing unit 140 include one or more microcontrollers (μCs), single-core or multi-core central processing units (CPUs), image processing units (GPUs), field-programmable gate arrays (FPGAs), or any other suitable processor architecture.

[0014] The processing unit 140 may include memory elements that are communicatively connected to one or more processors. These memory elements may include read-only memory (ROM) components, random access memory (RAM) components, removable memory devices, and the like. The memory elements may be communicatively connected to one or more processors by a bus structure including a memory bus or memory controller, peripheral bus, or local bus, and any suitable bus architecture may be used. Examples of such architectures include, but are not limited to, the Industry Standard Architecture (ISA) bus, the Microchannel Architecture (MCA) bus, the Extended ISA (EISA) bus, and the Peripheral Device Interconnect (PCI) bus (also known as a mezzanine bus).

[0015] The processing unit 140 can be communicated to the flow control device 120 and sensors 130a and 130b by a suitable combination of wired and / or wireless connections.

[0016] The pipe 150 may be of the same type or may include a plurality of fluid connection parts. The pipe 150 may be rigid, flexible, or may include a combination of rigid and flexible parts. The pipe 150 can be made of glass, metal, plastic (e.g., silicone, Teflon, etc.), or any other suitable material. The pipe 150 may include different parts having different inner diameters and / or outer diameters. The pipe may have a nozzle configured to lead a liquid into the container 170 at its end. The diameter of the pipe 150 can be 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 15 mm or any other suitable diameter.

[0017] The reservoir 160 may be a surge container, vat, tank or any other suitable reservoir made of glass, metal, plastic, or any other suitable material or combination of materials. The reservoir 160 may include an outlet for connecting to the pipe 150. The reservoir 160 may include one or more inlets through which the reservoir 160 can receive liquid and / or gas to pressurize the reservoir 160. One or more sensors may be disposed within the reservoir 160, for example, to monitor environmental conditions within the reservoir 160. One or more pumps and / or heating elements may be disposed in the reservoir 160 to control environmental conditions within the reservoir 160. In some examples, the reservoir 160 may include a stirrer or mixing element to assist in mixing, homogenizing, or degassing the liquid within the reservoir 160.

[0018] The liquid within the reservoir 160 may be a therapeutic agent, drug, biopharmaceutical, or any other liquid for filling the container 170. In some examples, the liquid within the reservoir 160 is a suspension. The challenges of transferring the suspension from the reservoir 160 into the container 170 include maintaining a suitable composition of the suspension.

[0019] Container 170 can be a syringe, an ampoule, a cartridge, or any other suitable container for receiving liquid from reservoir 160. Container 170 can be made of glass, metal, plastic, or any other suitable material. The liquid can be an injectable therapeutic agent, and container 170 can be configured to hold a single or multiple doses of the therapeutic agent.

[0020] In some embodiments, system 110 can include a plurality of reservoirs containing different liquids and a plurality of flow control devices configured to transfer the liquids from the plurality of reservoirs into container 170 in appropriate relative ratios. One skilled in the art can apply the techniques of the present disclosure to perform measurements and / or controls for adding liquids from a plurality of reservoirs to a container in exact amounts of different liquids from the corresponding reservoirs.

[0021] During operation, flow control device 120 of system 110 can transfer at least a portion of the liquid from storage reservoir 160 to container 170. The peak flow rate in pipe 150 during the transfer of the liquid into container 170 can be 0.1, 0.2, 0.5, 1, 2, 5, 10 mL / second, or any other suitable peak flow rate. In some examples, flow control device 120 can start and / or end the transfer based on a signal from processing unit 140. That is, processing unit 140 can cause flow control device 120 to transfer a portion of the liquid from storage reservoir 160 to container 170 via pipe 150. In other examples, flow control device 120 can operate independently of processing unit 140. Further, in some implementations, flow control device 120 can be installed outside the system to identify compliance with the container filling process. In FIG. 1, the arrow symbolizing the communicable connection between processing unit 140 and flow control device 120 is shown as a dashed line to indicate that there is no need for flow control device 120 and processing unit 140 to communicate with each other.

[0022] Sensors 130a and 130b, positioned in the piping 150, are configured to directly or indirectly measure the flow rate of the liquid flowing through the piping 150, as will be described in more detail below. In some examples, sensors 130a and 130b, where the flow rate is 0.1 to 1 mL / sec, do not need to directly measure the flow rate. Instead, sensors 130a and 130b may measure, for example, the velocity of the liquid flowing through the piping 150. Even if the velocity within the piping 150 is not uniform, i.e., varies within the cross-section of the piping 150, sensors 130a and 130b can effectively measure the average velocity, or any appropriate reading of the velocity with respect to it. In some examples, the average velocity is 1 to 100 cm / sec. More generally, sensors 130a and 130b can measure any reading of the flow rate. The processing unit 140 can convert any reading of the flow rate into an accurate measurement of the flow rate using calibration data obtained, as will be described in more detail later with respect to Figures 2, 7, and 8. It should be noted that the sensor output may have different relationships to the flow depending on the flow characteristics, such as laminar flow, and / or the properties of the liquid.

[0023] In some examples, sensors 130a and 130b may convert physical characteristics of the flow, such as velocity, into analog voltages or currents. In other examples, sensors 130a and 130b may be integrated with an analog-to-digital (A / D) converter to generate a digital signal indicating flow rate. Such sensors may transfer digital data indicating flow rate measurements to the processing unit 140 using any suitable wired or wireless interface. Sensors 130a and 130b may have multiple outputs that generate multiple signals, whether analog or digital. In addition to signals indicating flow rate, sensors 130a and 130b may generate signals indicating the internal amplitude of the conversion and / or diagnostic signals, as will be explained in more detail with respect to Figures 6A and 6B.

[0024] Sensors 130a and 130b may be configured to sample values ​​indicating flow rate at a sampling frequency or at a fixed time interval indicated by sampling. In another example, sensors 130a and 130b may be configured to generate signals indicating flow rate based on a received trigger signal. For example, a processing unit 140 may generate a trigger signal to request samples from sensors 130a and 130b.

[0025] The processing unit 140 may read or receive some or all of the encoded values ​​in the signals generated by sensors 130a and 130b, whether in real time or with some delay. As described above, the values ​​may be analog or digital. The processing unit may use an A / D converter to digitize the analog values ​​received from sensors 130a and 130b. Along with the flow rate values ​​received from sensors 130a and 130b, the processing unit 140 may receive or generate values ​​indicating time associated with the flow rate values. At least some of the time values ​​associated with the flow rate values ​​may correspond to filling time intervals, i.e., the time intervals during which the liquid flowing through the piping 150 is transferred to the container 170.

[0026] In some examples, the filling time interval may correspond to a time interval or series of time intervals during which the flow control device 120 continuously transfers liquid into the container 170. That is, the flow control device 120 may interrupt the liquid flow, in which case one or more filling time intervals are interrupted with substantially zero flow. Additionally or alternatively, the filling time interval may correspond to a time interval during which a fluid connection exists between the piping 150 and the container 170. For example, during a period when the liquid flow through the piping 150 is not substantially interrupted, a robotic system (or any other appropriate method) may replace container 174 with another similar container. The processing unit 140 may receive or generate values ​​indicating the time intervals during which a fluid connection exists between the piping 150 and the container 170, and the time intervals during which the flow control device 120 transfers liquid into container 170. In some examples, the processing unit 140 may generate trigger signals that cause a change in the liquid flow through the piping 150 and / or trigger signals that replace container 170 with another similar container. In another example, the processing unit 140 may receive indicator values ​​for the time when the liquid flow started and / or stopped, and / or the time when the container 170 was fluidly connected to the piping 150.

[0027] The processing unit 140 may calculate a fill volume indicator corresponding to the amount of liquid transferred to the container 170 during a filling time interval, or equivalently, during a total filling time interval or a series of filling time intervals corresponding to the total filling time, based on a plurality of received values ​​that at least partially indicate flow rates. This calculation may also be based on time indicators corresponding to filling time intervals received and / or generated by the processing unit 140. To calculate a fill volume indicator that may be called the fill volume for simplicity, the processing unit 140 may numerically integrate the flow rate of liquid into the container 170 during the total filling time. For simplicity, the total filling time may be called a filling time interval, and it should be understood that a filling time interval may include a series of filling time intervals. That is, in the following description, we assume that the total duration during which the container 170 receives liquid is represented by a single filling time interval. The total filling time of the container 170 may be 0.1, 0.2, 0.5, 2, 5, 10 seconds, or any other appropriate time.

[0028] Once the filling amount is calculated, the processing unit 140 may compare the filling amount to a target filling amount. In some examples, the filling amount and target filling amount are 0.2 mL to 40 mL and / or 0.2 mg to 40 mg. The comparison may include calculating the absolute value of the difference between the filling amount and the target filling amount, and whether the filling amount is greater than or less than the target filling amount. In some examples, the processing unit 140 may perform analog signal comparison. To this end, the processing unit 140 may generate one or more respective binary outputs by comparing the integrated analog output of a sensor (e.g., sensor 130a or b) with a reference voltage using one or more comparators. Additionally or alternatively, the processing unit 140 may include an A / D converter after a differential amplifier for digitizing the difference between the integrated sensor voltage output and the reference voltage. In yet another example, the processing unit 140 may perform comparison in the digital domain. To this end, the processing unit 140 can receive or generate a binary value with an appropriate resolution (e.g., 8 bits, 12 bits, 16 bits, 24 bits, etc.) indicating the filling amount, and compare this binary value with a target filling amount value stored in the memory of the processing unit 140.

[0029] A compliance indicator can be generated by comparing the calculated filling amount based on sensor measurements with the target filling amount. For example, if the measured filling amount falls within the range of the target filling amount, it may be indicated as compliant. The processing unit 140 can receive the target amount and compliance range and generate a compliance indicator. The processing unit 140 can store a log of the calculated filling amount and / or the generated compliance indicator. Furthermore, the processing unit 140 can display the compliance indicator on the display unit, as will be described in more detail below with respect to Figure 2.

[0030] Figure 2 schematically shows another exemplary system 210 for filling a container with liquid. This exemplary system 210 includes a flow control device 220 (which may be a flow control device 120), one or more sensors 230a, b (which may be sensors 130a, b), and a processing unit 240 (which may be a processing unit 140). The system may further include piping 250 (which may be piping 150) and a reservoir 260 (which may be a reservoir 160) that serves as a source of liquid to be transferred to a container 270 (which may be a container 170).

[0031] The system 210 further includes a display unit 280 that is communicatively connected to the processing unit 240. The display unit 280 may include a liquid crystal display (LCD), an organic light-emitting diode display (OLED), or any other suitable matrix display. Additionally or alternatively, the display unit 280 may include one or more light indicators, such as light bulbs and / or light-emitting diodes (LEDs). Furthermore, the display unit 280 may include one or more sound generators (e.g., buzzers, speakers, etc.) configured to produce audible alerts (e.g., to indicate compliance). In some examples, the display included in the display unit 280 may be integrated into a user device (e.g., a laptop, tablet, smartphone, etc.). In any case, a graphical user interface may be rendered on the display of the display unit 280, and the processing unit 240 may display indicator values ​​for filling amount compliance via the graphical user interface, e.g., a graphical user interface including virtual buttons or a bar graph configured to change color when a bar exceeds a threshold, and / or text alerts. Furthermore, the display unit 280 can generate voice alerts as buzzer patterns, beep patterns, and / or pre-recorded or synthesized voice messages.

[0032] The processing unit 240 of system 10 may communicate with a weight measuring instrument 290 or simply a measuring instrument 290. In some examples, the measuring instrument 290 may be included in system 210. The processing unit 240 may use the measuring instrument 290 to perform one or more calibrations, as will be described in more detail below with respect to Figures 7A and 7B. Roughly speaking, the processing unit 240 may record one or more weights associated with each filling volume calculated based on measurements from sensors 230a, b, and create a lookup table and / or formula that associates the filling volumes with gravimetric leave measured weights. In other examples, system 210 may include a device (e.g., a camera, level sensor, etc.) for measuring the liquid volume or liquid level in the container 270. The processing unit 240 may use the measured liquid volume or liquid level to calibrate the filling volume calculated by the processing unit 240 based on measurements from sensors 230a, b.

[0033] In some examples, the processing unit 240 may control the flow control device 220 to perform various calibrations, such as those outlined above. For example, the processing unit 240 may cause the flow control device 220 to generate a flow of liquid in the piping for one or more periods of any suitable duration. For each period, the processing unit may calibrate the flow rate measured by sensors 230a,b using the respective weight or weight increment measured by the measuring instrument 292. Additionally or alternatively, the processing unit 240 may cause the flow control device to interrupt the flow of liquid in the piping 250 and receive baseline measurements from sensors 230a,b.

[0034] Figure 3 schematically shows an exemplary system 315 for detecting compliance with the filling volume, which may be part of a system for filling containers with liquid (e.g., system 110 or 210). System 315 includes a processing unit 340 (which may be processing unit 140 or 240) and two flow sensors 330a, b (which may be sensors 130a, b or sensors 230a, b). Note that system 315 does not have to include a flow control device. Generally, a flow control device does not need to be included in a system for detecting compliance with the filling volume, but a flow control device (e.g., flow control device 120 or 220) may be included in a larger system for filling containers with liquid, which may include system 315.

[0035] The sensors 330a and 330b of system 315 may be located in two piping sections 350a and 350b, respectively, which may be sections of piping 150 or 250. The piping sections 350a and 350b are fluid-connected to each other and connected in series to transfer liquid to container 370 (which may be container 170 or container 270). Piping section 350a may have a narrower inner diameter than piping section 350b. As a result, for liquid transfer at a constant flow rate, the flow velocity in section 350a may be faster than the flow velocity in section 350b. In some examples, the piping sections 350a and 350b may be connected via an adapter or adapter section with a gradually changing inner diameter, for example, to avoid the possibility of turbulence.

[0036] The inner diameter of section 350b may be 10%, 20%, 40%, 50%, 100%, or any other appropriate ratio larger than the inner diameter of section 350a. For example, the inner diameter of section 350b may be 2 mm, while the diameter of section 350b may be 3 mm, which is 50% larger than the diameter of section 350a.

[0037] System 315 can use two sensors 330a, b, positioned in two piping sections 350a, b, in various ways. First, similar to two sensors (e.g., sensors 130a, b or 230a, b) positioned in sections of the same diameter in the piping (e.g., pipe 150 or 250), the processing unit 340 can receive values ​​from the two sensors 350a, b and average them to reduce noise. Additionally or alternatively, the processing unit 340 can correlate time series of flow rate values ​​from the two sensors 350a, b to identify intermittent flow changes, such as forward or backward boundaries of the liquid section, as discussed with respect to Figure 5. Furthermore, also as discussed with respect to Figure 5, the processing unit 340 can identify flow anomalies (e.g., unexpected interruptions or bubbles) by correlating time series of flow rate values. By using sensors 330a, b positioned in piping sections 350a, b of different diameters, System 315 can gain a better understanding of flow characteristics or sensor performance. Since liquid flow is substantially incompressible, the average flow velocity in pipe sections 350a and 350b of different sizes is inversely proportional to the cross-sectional area of ​​each pipe. For example, if the diameter of the cross-section of pipe section 350b is 20% larger than the diameter of the cross-section of pipe section 350a, the average flow velocity in section 350a should be 44% faster than the average flow velocity in section 350b (because the area changes as the square of the diameter). The flow rate values ​​received from sensors 330a and 330b may not have the same ratio as their respective average flow velocities (depending on the precision of the flow velocity measurements), but the relationship between the two values ​​can be estimated from calibration. Deviations from the relationship estimated from calibration may indicate a change or anomaly in the flow. Furthermore, system 315 may improve the accuracy of flow velocity measurements by using velocity measurements in pipe sections 350a and 350b of different sizes, since at least one of the faster or slower velocities may be closer to the optimal range of flow sensor 330a or 330b.

[0038] Figure 4 schematically illustrates another exemplary system 415 for detecting compliance with the fill volume. System 415 includes a processing unit 440 (which may be processing units 140, 240, or 340) and three flow sensors 430a-c. Sensors 430a-c are located in piping 450 configured to transfer liquid into a container 470 (which may be containers 170, 270, or 370). Sensors 430a-c do not need to be spaced equally apart. System 415 can use the three sensors 430a-c in various ways. Firstly, the average and values ​​from multiple sensors can improve measurement accuracy. Secondly, processing unit 440 can correlate the time series of values ​​from the three sensors 430a-c to identify changes in intermittent flow, such as forward or backward boundaries of the liquid section, as discussed with respect to Figure 5. Furthermore, as also described in Figure 5, the processing unit 440 can identify flow anomalies (e.g., unexpected interruptions or bubbles) by correlating the time series of flow rate values. In addition, the system 415 may use three sensors for diagnostic purposes. For example, if a value generated by one of the sensors does not match the values ​​generated by the other two, the outlier may be ignored and the corresponding sensor may be flagged as malfunctioning.

[0039] Figure 5 schematically shows an exemplary non-contact flow sensor 530 (which may be one of flow sensors 130a, b, 230a, b, 330a, b, or 430a-c) placed in a section of piping. Having a non-contact sensor may be particularly important in medical applications. The sensor 530 may be an ultrasonic sensor, an electromagnetic sensor, an optical sensor, or other suitable non-contact sensor. The sensor may include a channel 532 configured to match the diameter of the piping. In some examples, a sleeve may be placed on top of the piping to provide better contact with the flow sensor 530. As described above, the sensor 530 can help identify breaks in intermittent flow. For example, a system (e.g., systems 110, 210, 315, or 415) may use the sensor 530 to identify a forward boundary 555a or a backward boundary 555b that separates the liquid portion 555c from the empty (i.e., gas-filled) portion of the intermittent flow. Furthermore, the system may use the sensor 530 to identify air pockets or bubbles 555e or other abnormalities within the liquid portion 555c. The system may further include vibration isolation, heat insulation, and electrical shielding to reduce measurement noise.

[0040] Figures 6A and 6B schematically illustrate the operating principle of the ultrasonic flow sensor 630 (which may be one of the flow sensors 130a, b, 230a, b, 330a, b, 430a-c, or 530). The sensor may include a channel 632 and four ultrasonic transducers 635a-d. Channel 632 is configured to constrict around a certain section of the pipe, especially when the pipe is filled with liquid, creating an ultrasonic conduction path. Of the transducers 635a-d, two, 635a and b, may be used as ultrasonic transmitters, and two, 635c and d, may be used as ultrasonic receivers. The three arrows within channel 632 schematically illustrate the flow velocity profile within channel 632. Closer to the center, the liquid may move faster than the liquid near the edges (e.g., in laminar flow). In some examples, the flow may be turbulent (e.g., at higher flow rates) or may transition between laminar and turbulent flow. In Figure 6A, the curved dashed line between transducers 635a and 635d, and in Figure 6B, the curved dashed line between transducers 635b and 635c, schematically represent the ultrasonic wavefronts. In Figures 6A and 6B, the wavefronts are equally spaced when they emerge from the ultrasonic transmitters 635a and 635b. However, in Figure 6A, the spacing of the wavefronts when they reach the ultrasonic receiver 635d is wider than that of the wavefronts when they reach the ultrasonic receiver 635c in Figure 6B. This is because the ultrasonic waves move along the flow in Figure 6A and against the flow in Figure 6B. The change in wavefront spacing can be considered an example of the Doppler effect, and the received ultrasonic frequency in Figure 6A is lower than the ultrasonic frequency in Figure 6B. Sensor 630 may include electronic components for generating an analog or digital output indicating the flow velocity based on the difference in received ultrasonic frequencies. In some examples, sensor 630 may transmit ultrasonic pulses rather than continuous ultrasonic waves. When using ultrasonic pulses, the sensor 630 may generate an output indicating the flow velocity based on the difference in transit times (propagation time difference or TTD) between ultrasonic pulses along the flow and against the flow. Additionally or alternatively, the sensor 630 may be configured to use the phase difference of the received ultrasonic signals along the flow and against the flow. The phase difference method may be particularly advantageous when the time and frequency differences of the TTD and Doppler methods are small.Furthermore, sensor 630 may output a value of the intensity of the received signal. The system (e.g., systems 110, 210, 315, or 415) may use the output value indicating signal intensity to identify liquid boundaries in intermittent flow, acoustic conversion problems, and / or changes in one or more characteristics of the liquid flowing in a pipe located within channel 632. Furthermore, the system may use the various outputs described above to generate failure mode alerts indicating poor filling quality modes (e.g., dripping, splashing, bubble formation, etc.) and / or alerts indicating system malfunctions (e.g., blockage, etc.), as will be described in more detail with respect to Figure 8. During a test or calibration process, the system may be configured to generate different sets of failures, during which sensor outputs (e.g., flow rate, signal intensity, etc.) may be sampled. Based on the generated set of failures and corresponding data, a classifier may be generated to identify the failure rate. During operation, the system may then use the classifier to estimate the probability of different types of failures and generate an alert when the probability of each exceeds its respective threshold.

[0041] Figures 7A and 7B show exemplary flow profiles of the system (e.g., system 110 or 210) during operation. The graphs in Figures 7A and 7B show flow rate samples as a function of time. The system may cause the flow control device to maintain a constant flow rate for intervals of 100 ms or more (as shown in Figure 7A) to generate a filling volume of 10 mL or more for use, for example, in flow rate calibration, which will be discussed in more detail below with respect to Figure 8. On the other hand, the flow rate during normal container filling operations may include short bursts of flow rate, with each burst generating a smaller filling volume (e.g., <2 mL). Note that during calibration, instead of using a constant flow rate in one time interval as in Figure 7A, a larger calibration volume (e.g., >10 mL) may be filled in multiple bursts. Although not visible in Figures 7A and 7B, the flow rate profile may include an initiation slope and an escaping slope. The initiation slope and escaping slope may be substantially linear with a substantially constant gradient, or any other suitable shape.

[0042] Figure 8 shows an exemplary method 800 for checking compliance with container filling amounts. Method 800 may be performed, at least in part, by one or more processors of processing units 140, 240, 340, or 440 of systems 110, 210, 315, or 415, which have already been discussed with respect to Figures 1-4. In some examples, Method 800 may be performed, at least in part, by an external processor to systems 110, 210, 315, or 415.

[0043] In block 810, method 800 includes having one or more processors cause a flow control device (e.g., flow control device 120 or 220) to transfer a liquid from a storage reservoir (e.g., storage reservoir 160 or 260) to a container (e.g., containers 170, 270, 250 or 470) via piping (e.g., piping 150, 370, 450 or piping sections 350a, b). The ends of the piping may have nozzles configured to guide the flow into the container.

[0044] In block 820, method 800 includes receiving, by one or more processors, a plurality of values ​​from at least one sensor placed in the piping, representing a plurality of respective flow rates at a plurality of different times within a filling time interval. The plurality of times at which the flow rate values ​​are received may include time intervals based on the sampling rate (equivalently, the sampling frequency or sampling period). The sampling rate may be, for example, 10 Hz to 1 kHz (10 to 1000 samples / s). The filling time interval may be 0.1 to 10 seconds. Having more sample points during the filling time interval may be advantageous. However, there is a trade-off between the sampling rate and the noise per sample. Therefore, in the case of continuous flow, increasing the sampling rate may not necessarily reduce the noise in the estimation of the average flow rate. On the other hand, a higher sampling rate may be helpful in identifying the start and stop points of the flow, especially when the increasing and decreasing flow profiles are not well known. Furthermore, in addition to random fluctuations due to thermal noise, systemic noise may affect the sample. In particular, peristaltic pumps may produce pulsatile flow. Coupling alternating current (AC) power frequencies (e.g., 50 Hz, 60 Hz, etc.) to a sensor signal can similarly induce systemic periodic fluctuations. To mitigate the problem of systemic noise, Method 800 may include receiving one or more indicators of at least one of the following by one or more processors: i) an indicator of measurement noise, ii) an indicator of periodic flow perturbation, and / or iii) an indicator of line voltage fluctuation. Method 800 may further include changing the sampling rate based on the one or more received indicators. One technique may include setting the sampling rate higher than the Nyquist rate of the signal fluctuation. Another technique may include adjusting the sampling rate to avoid aliasing effects. For example, Method 800 may include adjusting the sampling rate to match, or to a fraction of, the frequency of flow fluctuations caused by a peristaltic pump.Furthermore, to avoid the effects of inconsistent sampling with respect to the phase of fluctuations caused by the peristaltic pump, this method may include adjusting the sampling phase. Method 800 may further include generating a trigger signal by one or more processors to synchronize the operation of the flow control device with the sampling rate.

[0045] In block 830, method 800 includes calculating a fill volume indicator value based on at least a number of received values ​​using one or more processors. The fill volume indicator value may be called the fill volume, which can be converted from that indicator value using appropriate calibration and / or other multipliers. Generally, calculating the fill volume involves numerical integration of the flow sample by summing the sample values ​​or by using any other suitable numerical integration method.

[0046] Calculating the filling amount using numerical integration may involve one or more processors identifying the start and end times of a filling time interval based, at least in part, on multiple received values ​​representing multiple respective flow rates at multiple respective times within the filling time interval. For example, method 800 may include identifying the start and / or stop times by comparing the measured flow rate to a threshold. In other examples, method 800 may include identifying a gradient corresponding to a gradual increase or decrease in flow rate and finding a zero intercept to identify the start and / or stop times.

[0047] Calculating the filling amount may include calculating the filling weight. To this end, method 800 may include obtaining an estimate of the density of the liquid by one or more processors. Then, calculating the filling weight may be based on the density estimate. Obtaining the density estimate may include receiving information about the liquid (e.g., fluid composition) and measuring environmental parameters such as temperature, pressure, and / or humidity. Additionally or alternatively, obtaining the density estimate may include performing calibration. Calibration may include weighing any suitable filled container (e.g., using weighing instrument 290) and subtracting the tare weight of the container. Calibration is described in more detail below with respect to block 860.

[0048] In block 840, method 800 includes comparing an indicated filling amount with a target filling amount using one or more processors. Method 800 can perform the comparison in the analog or digital domain, as already described in more detail with respect to Figure 1.

[0049] In block 850, method 800 includes generating an instruction value for filling amount compliance by one or more processors. To this end, method 800 may include comparing the difference between the measured filling amount and the target filling amount with a threshold indicating an assigned tolerance. The tolerances for positive excursions and negative excursions with respect to the target amount do not need to be the same. The tolerances may be set for a particular filling process execution and may depend on the liquid, the target filling amount, and / or the type of container being filled.

[0050] Method 800 may further include generating alerts based on instructions for compliance with the fill volume. The alerts may be visual or audible alerts generated on a display unit (e.g., display unit 280). Additionally or alternatively, Method 800 may include generating one or more alerts indicating one or more failure modes and / or other malfunctions. The alerts may include: indicator values ​​for sensor malfunction (e.g., as described with respect to Figure 4), indicator values ​​for air pockets in the liquid (e.g., as described with respect to Figure 5), indicator values ​​for dripping, indicator values ​​for blockage (e.g., in a nozzle), and / or other appropriate indicator values. An indicator value for dripping may be generated based on the measurement or detection of a non-zero flow rate when the flow rate should nominally be zero. An indicator value for blockage may be generated based on the measurement or detection of a flow rate value in a line having an expected flow rate value. More generally, sensor data may be correlated with individually detected problems or failures to extract data features indicating each problem and failure. The system may use digital signal processing methods (e.g., correlation filters) and / or machine learning models to detect failure modes and / or other problems. The system may compare the output of a suitable digital filter and / or a suitable machine learning model to a threshold for a specific alert and issue an alert if the threshold is exceeded. Method 800 may include generating an interface to allow the user to select thresholds for different alerts.

[0051] In an optional block 860, method 800 may include, by one or more processors, receiving a calibration flow rate value from at least one sensor and calculating a fill volume instruction value based on at least some of the received calibration flow rate values. In one example, the calibration flow rate value may be a baseline or zero flow rate value generated by the sensor. To obtain a baseline value, method 800 may include, by one or more processors, causing a flow control device to prevent the transfer of liquid during a baseline calibration time interval. Calculating the fill volume instruction may be based on at least some of the received baseline values.

[0052] Additionally or alternatively, calibration may include identifying one or more conversion multipliers for converting the numerical integral of the flow indicator to the fill volume. To obtain the conversion coefficients, method 800 may include, by one or more processors, causing a flow control device to transfer liquid at a constant flow rate during the flow calibration time interval, as discussed with respect to Figures 7A, B. Method 800 may further include, by one or more processors, receiving a calibrated flow rate value or a group of calibrated flow rate values ​​from at least one sensor during the flow calibration time interval. Method 800 may further include numerically integrating the flow rate values ​​during the flow calibration time interval. Furthermore, method 800 may include an independent measurement of the amount of liquid accumulated in the container during the flow calibration time interval. The independent measurement may be, for example, a volume measurement and / or weight measurement using the measuring instrument 290 in Figure 2. As stated with respect to Figures 7A, B, the calibration amount does not need to be the same as the target amount. In some cases, the calibration amount may be greater than the target amount by a coefficient of 2, 5, 10, 20, 50, 100, or any other appropriate coefficient. Calibration can be performed for different liquids, different flow rates, different environmental conditions, etc., to compensate for changing liquid densities and the accuracy of sensor measurements.

[0053] The calibration process described above may include a series of calculations. For example, the calibration process may include accumulating liquid in a container during the calibration time interval (as shown, for example, in Figure 7A). The system may calculate estimates of the mass flow rate and volume flow rate corresponding to the sensor output during calibration as follows:

number

number

[0054] Method 800 may include performing calibration at different flow velocities, for different pipe diameters, under different environmental conditions, and so on. In some examples, calibration may include generating a calibration profile equivalent to multiple filling operation profiles (e.g., Figure 7B vs. Figure 7A). Furthermore, during the calibration process, Method 800 may include statistically analyzing a series of samples (e.g., shown in Figures 7A and B) to generate an estimate of sensor noise. In some examples, the system may change the sampling rate to find the optimal sampling rate for reducing the overall noise during integration. Additionally or alternatively, Method 800 may include generating an alert if the noise exceeds a threshold during calibration.

[0055] Herein, we address some additional considerations relating to this disclosure.

[0056] Some of the drawings described herein show exemplary block diagrams having one or more functional components. Such block diagrams are illustrative, and it should be understood that the devices described and shown may have more, fewer, or alternative components than those illustrated. In addition, in various embodiments, components (and the functions provided by each component) may be associated with any suitable component, or otherwise incorporated as part of it.

[0057] Embodiments of this disclosure relate to non-temporary computer-readable storage media having computer code for performing various computer implementation operations. The term “computer-readable storage media” is used herein to include any medium capable of storing or encoding a set of instructions or computer code for performing the operations, methods and techniques described herein. The medium and computer code may be specifically designed and configured for the purposes of embodiments of this disclosure, or may be of a type well known and available to those skilled in the art of computer software technology. Some examples of computer-readable storage media include, but are not limited to, magnetic media such as hard disks, floppy disks and magnetic tapes, optical media such as CD-ROMs and holographic devices, magneto-optical media such as optical discs, and hardware devices specifically configured to store and execute program code, such as ASICs, programmable logic devices ("PLDs"), and ROM and RAM devices.

[0058] Examples of computer code include files containing machine code, such as that generated by a compiler, and high-level code executed by a computer using an interpreter or compiler. For example, one embodiment of the present disclosure can be implemented using Java, C++, or other object-oriented programming languages ​​and development tools. Other examples of computer code include encrypted code and compressed code. Furthermore, embodiments of the present disclosure may be downloaded as a computer program product, which can be transmitted from a remote computer (e.g., a server computer) to a requesting computer (e.g., a client computer or a different server computer) via a transmission channel. Another embodiment of the present disclosure may be implemented in hardwired circuitry instead of, or in conjunction with, machine-executable software instructions.

[0059] In this specification, the singular terms “a,” “an,” and “the” may include plural forms unless the context explicitly indicates otherwise.

[0060] As used herein, the terms “approximately,” “substantially,” “effectively,” and “about” are used to describe and explain small-scale fluctuations. When used in conjunction with events or situations, these terms may refer not only to instances in which the event or situation occurs exactly, but also to instances in which it occurs approximately. For example, when used in conjunction with numerical values, these terms may mean a range of variation of that number of ±10%, such as ±5%, ±4%, ±3%, ±2%, ±1%, ±0.5%, ±0.1%, or ±0.05%. For example, two numerical values ​​can be considered “substantially” the same if the difference between them is within ±10% of the mean of those values, for example, ±5%, ±4%, ±3%, ±2%, ±1%, ±0.5%, ±0.1%, or ±0.05%.

[0061] In addition, quantities, ratios, and other numerical values ​​may be expressed in the form of ranges in this specification. It should be understood that such range forms are used for convenience and conciseness, and should be flexibly understood to include not only numerical values ​​explicitly designated as limits to a range, but also all individual numerical values ​​or subranges within that range, as if each numerical value and subrange were explicitly designated.

[0062] While this disclosure describes and illustrates specific embodiments, these descriptions and illustrations are not intended to limit the disclosure. Those skilled in the art will understand that various modifications and substitutions may be made without departing from the true intent and scope of this disclosure as defined by the appended claims. Explanatory drawings are not necessarily drawn to exact scale. Due to manufacturing processes, tolerances, and / or other reasons, the artistic depictions in this disclosure may differ from the actual devices. Other embodiments of this disclosure that are not specifically described may exist. This specification (except the claims) and drawings should be considered descriptive rather than restrictive. Modifications may be made to adapt detailed circumstances, materials, substance compositions, techniques, or methods to the purpose, intent, and scope of this disclosure. All such modifications are intended to fall within the scope of the claims appended to this specification. While the techniques disclosed herein have been described in terms of specific actions performed in a particular order, these actions may be combined, subdivided, or rearranged without departing from the teachings of this disclosure to form equivalent techniques. Therefore, unless specifically indicated herein, the order and grouping of operations are not limited to this disclosure.

Claims

1. A system for filling containers with liquid, A flow control device configured to transfer liquid from a storage reservoir into a container via piping, At least one sensor arranged in the aforementioned piping, One or more processors, The flow rate control device causes at least a portion of the liquid to be transferred from the storage reservoir to the container via the piping. From at least one of the sensors, multiple values ​​are received that indicate the respective flow rates at each of the multiple time intervals within the filling time interval. Based at least partially on the aforementioned multiple received values, the indicated value for the filling amount is calculated. The indicated value of the filling amount is compared with the target filling amount. Generate instruction values ​​to ensure compliance with the filling amount. One or more processors configured as follows, A system equipped with these features.

2. The system according to claim 1, further comprising a weighing device configured to measure the weight of one or more filled containers.

3. The system according to claim 1 or 2, wherein the one or more processors are further configured to generate a trigger signal for the flow control device.

4. The system according to any one of claims 1 to 3, wherein the target filling amount is 0.2 mL to 40 mL or 0.2 mg to 40 mg.

5. The system according to any one of claims 1 to 4, wherein the at least one sensor includes an ultrasonic sensor.

6. The system according to any one of claims 1 to 5, wherein the at least one sensor includes a first sensor and a second sensor configured to measure a first flow rate and a second flow rate in a first section of the piping and a second section of the piping, respectively.

7. The system according to claim 6, wherein the inner diameter of the first section of the piping is at least 10% larger than the inner diameter of the second section of the piping.

8. The system according to any one of claims 1 to 7, wherein the at least one sensor includes at least three sensors.

9. The system according to any one of claims 1 to 8, further comprising a display device configured to generate a visual and / or auditory representation of the indicated value that complies with the filling amount.

10. The flow rate control device includes a peristaltic pump, according to any one of claims 1 to 9.

11. A method for checking compliance with container filling amounts, One or more processors instruct the flow control device to transfer liquid from the storage reservoir to the container via piping, The one or more processors receive from at least one sensor placed in the piping a plurality of values ​​indicating the respective flow rates at each of the plurality of time intervals within the filling time interval, The one or more processors calculate an instruction value for the filling amount based at least partially on the plurality of received values, The one or more processors compare the indicated value of the filling amount with the target filling amount, The above-mentioned one or more processors generate instruction values ​​that comply with the filling amount, A method that includes this.

12. The process further includes obtaining an estimate of the density of the liquid using one or more processors. Here, Calculating the indicated value of the filling amount includes calculating the indicated value of the filling weight based at least in part on the estimated value of the density of the liquid, The aforementioned target filling amount is the target filling weight. The method according to claim 11.

13. The method according to claim 12, wherein obtaining the density estimate comprises measuring the weight of one or more filled containers.

14. The method according to claim 12 or 13, wherein obtaining an estimate of the density includes an estimate of the composition of the liquid.

15. The method according to any one of claims 11 to 14, wherein at least some of the plurality of time intervals within the filling time interval are arranged at regular intervals determined by the sampling rate, and the method further comprises controlling the sampling rate.

16. The one or more processors receive at least one of the following indicator values: i) an indicator value for measurement noise, ii) an indicator value for periodic flow perturbation, and / or iii) an indicator value for line voltage fluctuation. The sampling rate is changed based on one or more received indicator values. The method according to claim 15, further comprising:

17. The one or more processors generate a trigger signal to synchronize the operation of the flow rate control device with the sampling rate. The method according to claim 15 or 16, further comprising:

18. The method according to any one of claims 11 to 17, wherein the sampling rate is 10 Hz to 300 Hz.

19. The one or more processors cause the flow rate control device to prevent the transfer of the liquid during the baseline calibration time interval, The one or more processors receive a baseline value from at least one of the sensors, Includes, Calculating the indicated value of the filling amount is at least partially based on the received baseline value. The method according to any one of claims 11 to 18.

20. The one or more processors instruct the flow rate control device to transfer the liquid at a constant flow rate during the flow rate calibration time interval, The one or more processors receive a calibration flow rate value from at least one of the sensors, It further includes, Calculating the indicated value of the filling amount is at least partially based on the received calibration flow rate value. The method according to any one of claims 11 to 19.

21. The one or more processors determine the start and end times of the filling time interval based at least in part on the received values ​​representing the respective flow rates at each of the multiple time periods within the filling time interval. The method according to any one of claims 11 to 20, further comprising:

22. The one or more processors further include determining the indicated slope value for each of the plurality of values ​​representing the respective flow rates, Determining the start time or end time is at least partially based on the indicated value of the slope. The method according to claim 21.

23. The method according to any one of claims 11 to 22, wherein the liquid is an injectable therapeutic agent, and the container is configured to contain one or more doses of the injectable therapeutic agent.

24. The method according to any one of claims 11 to 23, wherein the target filling amount is 0.2 mL to 40 mL or 0.2 mg to 40 mg.

25. The method according to claim 11, wherein the at least one sensor includes an ultrasonic sensor.

26. The method according to any one of claims 11 to 23, further comprising measuring a first flow rate in a first section of piping using a first sensor, and measuring a second flow rate in a second section of piping using a second sensor.

27. The method according to claim 26, wherein the inner diameter of the first section of the piping is at least 10% larger than the inner diameter of the second section of the piping.

28. The aforementioned at least one sensor includes at least three sensors, The one or more processors determine that one of the at least three sensors has produced an outlier measurement, The one or more processors generate an alert based on the outlier measurement value, It further includes, The method according to any one of claims 11 to 27, wherein the calculation of the indicated value of the filling amount is at least in part based on omitting the measured value as an outlier.

29. The method according to any one of claims 11 to 28, further comprising generating an alert indicating a failure mode or other malfunction.

30. The method according to claim 29, wherein the alert indicates dripping, splashing, blockage, and / or an air pocket.

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