JP-2026514434-A - A method for using ultrasonic flow sensors to monitor filling weight accuracy in clinical, commercial, and process development filling/finishing operations.

JP2026514434AJP 2026514434 AJP2026514434 AJP 2026514434AJP-2026514434-A

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.

Inventors

マトゥール，イアン
パルデシ，ネハ・エヌ
クルチョーイー，エバン
パドマクマール，ビカシュニ
ウェットストーン，サラ
ベレンファン，タイラー
ゴンザレス，イノホサ・オスカー

Assignees

アムジエン・インコーポレーテツド

Dates

Publication Date: 20260511
Application Date: 20240329
Priority Date: 20230330

Claims (20)

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. One or more processors configured to generate instruction values for compliance with filling amounts, A system equipped with these features.
The system according to claim 1, further comprising a weighing device configured to measure the weight of one or more filled containers.
The system according to claim 1 or 2, wherein one or more processors are further configured to generate trigger signals for the flow control device.
The system according to any one of claims 1 to 3, wherein the target filling volume is 0.2 mL to 40 mL or 0.2 mg to 40 mg.
The system according to any one of claims 1 to 4, wherein the at least one sensor includes an ultrasonic sensor.
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.
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.
The system according to any one of claims 1 to 7, wherein the at least one sensor includes at least three sensors.
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 in accordance with the filling amount.
The flow rate control device includes a peristaltic pump, as described in any one of claims 1 to 9.
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.
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.
The method according to claim 12, wherein obtaining the density estimate includes measuring the weight of one or more filled containers.
The method according to claim 12 or 13, wherein obtaining the estimated density includes obtaining the estimated composition of the liquid.
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.
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:
The method according to claim 15 or 16, further comprising using one or more processors to generate a trigger signal for synchronizing the operation of the flow control device with the sampling rate.
The method according to any one of claims 11 to 17, wherein the sampling rate is 10 Hz to 300 Hz.
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.
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.

Description

Cross-reference to related applications: Priority is claimed to be to U.S. Provisional Patent Application No. 63/455,847, filed on March 30, 2023, and its entire contents are incorporated herein by reference. This 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 amount of liquid being filled. The filling of pharmaceutical formulations is a complex unit operation, crucial for ensuring that high-quality products are delivered to patients. Among numerous considerations, a good filling process must consistently deliver a consistent amount of drug product into each container within tight margins, ensuring that all units are deemed safe and effective according to scientifically specified action limits. Such consistency should ideally be 100% guaranteed through in-process control (IPC) of filling weight. One IPC approach involves weighing each dose on a sufficiently accurate scale to verify that the dose is within the action limit. However, this process (placing an empty container on a weighing scale, tare, removing it, filling, and then returning it to the scale for re-weighing) is often very time-consuming. Therefore, an alternative IPC approach is needed that can guarantee accurate and consistent dosage. An illustrative system for filling a container with liquid is schematically shown.A schematic diagram illustrates another exemplary system for filling a container with liquid.An illustrative system for detecting compliance with filling volume is schematically shown.Other exemplary systems for detecting compliance with filling quantities are schematically shown.A schematic diagram of an exemplary non-contact flow sensor placed in a section of piping is shown.The operating principle of an ultrasonic flow sensor is outlined below.The operating principle of an ultrasonic flow sensor is outlined below.An illustrative flow profile is shown schematicly.An illustrative flow profile is shown schematicly.This is a block diagram illustrating an example method for checking compliance with container filling quantities. 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, biopharmaceuticals, etc.) 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 described herein are 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 during development, ensuring reliable process characterization and thereby allowing operators to more easily detect and address deviations in filling weight. 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 for 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