CN-121981598-A - Hepatitis B vaccine production overall process quality monitoring and early warning system

CN121981598ACN 121981598 ACN121981598 ACN 121981598ACN-121981598-A

Abstract

The invention relates to the technical field of hepatitis B vaccine production and discloses a hepatitis B vaccine production whole-process quality monitoring and early warning system which comprises a system initialization and basic construction module, a production whole-link quality monitoring module and a system dynamic optimization and upgrading module, wherein the system initialization and basic construction module comprises a supplier qualification auditing terminal, a sensor cluster, RFID (radio frequency identification) read-write equipment, an early warning terminal, a raw material quality standard database, a supplier basic archive, a supplier rating subsystem, an LSTM (least squares) process prediction model training platform, a parameter threshold setting terminal and an early warning grade setting unit, and the production whole-link quality monitoring module comprises a raw material purchasing accurate management and control sub-module, an engineering bacteria fermentation real-time monitoring sub-module, a purification inactivation accurate management and control sub-module, a raw liquid and semi-finished product quality comprehensive evaluation early warning sub-module.

Inventors

YOU JIANSONG
Qu Fanxian
LI GUIXING
WANG SHIGUANG
ZHANG LI
Gao Shanwen
ZHANG PING
ZHANG HAICHUN
XU GUIQIU
Yang Tengpiao

Assignees

艾美诚信生物制药有限公司

Dates

Publication Date: 20260505
Application Date: 20260108

Claims (8)

1. The hepatitis B vaccine production whole process quality monitoring and early warning system is characterized by comprising the following modules and components: A system initialization and foundation construction module, a production full-link quality monitoring module and a system dynamic optimization and upgrading module; The system initialization and foundation construction module comprises a supplier qualification auditing terminal, a sensor cluster, RFID read-write equipment, an early warning terminal, a raw material quality standard database, a supplier foundation archive, a supplier rating subsystem, an LSTM process prediction model training platform, a parameter threshold setting terminal and an early warning grade setting unit; the production full-link quality monitoring module comprises a raw material purchasing admission control sub-module, an engineering bacteria fermentation real-time monitoring sub-module, a purification and inactivation accurate control sub-module, and a stock solution and semi-finished product quality comprehensive evaluation and early warning sub-module; The system dynamic optimization and upgrading module comprises a production data archiving server, a model parameter iteration tool, a process standard updating terminal, an optimization effect verification subunit and a supplier grading updating terminal.
2. The hepatitis B vaccine production whole process quality monitoring and early warning system according to claim 1 is characterized in that a supplier qualification auditing terminal inputs and verifies supplier qualification files, a sensor cluster covers cell culture and purification inactivation equipment to collect parameters such as temperature, pH value and the like, an RFID read-write equipment generates and reads raw material RFID labels, the early warning terminal comprises an audible and visual alarm, a mobile phone APP and a system popup window, the raw material quality standard database stores key quality indexes and qualification thresholds of antigen production and inspection raw materials, auxiliary materials and packaging materials, and a supplier base archive inputs information such as supplier qualification and historical quality inspection data.
3. The hepatitis B vaccine production overall process quality monitoring and early warning system according to claim 1, wherein the provider rating subsystem selects 4 indexes of qualification integrity, historical quality stability, delivery timeliness and after-sale response efficiency by adopting an entropy weight TOPSIS method, and weights are respectively 0.3, 0.4, 0.2 and 0.1, and the information entropy formula is adopted: Weight formula: The comprehensive score formula: The method comprises the steps of calculating scores, dividing A, B, C levels according to the steps of not less than 0.8, 0.6-0.8 and <0.6, initializing learning rate of 0.001, hidden layer node number of 128, iteration number of 500, batch size of 32 by an LSTM process prediction model training platform, introducing historical 5 years of associated data training by an activation function of ReLU, inputting key parameters of links such as cell culture, purification inactivation and the like by a parameter threshold setting terminal, and making three-level early warning thresholds of not less than 10%, 5% -10%, and <5% and corresponding response mechanisms by an early warning level setting unit.
4. The hepatitis B vaccine production whole process quality monitoring and early warning system according to claim 3 is characterized in that the raw material purchasing admission control submodule comprises a multi-dimensional quality inspection data acquisition unit, a supplier grading subsystem, an RFID traceability label printer, a data synchronization interface and an abnormal early warning trigger unit, wherein the multi-dimensional quality inspection data acquisition unit acquires detection data such as raw material purity and activity and supplier qualification files, the supplier grading subsystem calculates a comprehensive score of a supplier in the current period by multiplexing an entropy weight TOPSIS method to complete admission judgment, the RFID traceability label printer generates a unique RFID label containing information such as supplier number and batch number, the data synchronization interface conforms to HL7FHIR standard to achieve data real-time synchronization and format unification, and the abnormal early warning trigger unit compares the quality inspection data with a qualification threshold to trigger corresponding grades.
5. The hepatitis B vaccine production whole process quality monitoring and early warning system according to claim 1, wherein the engineering bacteria fermentation real-time monitoring submodule comprises an equipment parameter acquisition terminal, a data preprocessing unit, an LSTM process prediction model, a parameter deviation early warning unit and a production data recording unit, wherein the equipment parameter acquisition terminal acquires parameters such as temperature, pH value, dissolved oxygen concentration and the like of a cell culture equipment, and the data preprocessing unit adopts a 3 sigma principle Outliers were culled and normalized by the Z-score formula: the LSTM process prediction model is used for predicting a future 2-hour parameter trend based on real-time parameters and outputting quality standard probability, the parameter deviation early-warning unit is used for calculating parameter deviation degree and generating an optimization scheme and synchronizing the optimization scheme to an operation terminal, and the production data recording unit is used for recording parameter curves, early-warning conditions, adjustment measures and the like and storing associated batch numbers.
6. The hepatitis B vaccine production whole process quality monitoring and early warning system according to claim 1, wherein the purification and inactivation accurate management and control submodule comprises a key index monitoring unit, a multi-dimensional index fusion analysis terminal, a risk prejudging subsystem and an inactivation process parameter recorder, wherein the key index monitoring unit is used for collecting indexes such as pH/conductivity of a chromatographic buffer solution, flow rate of a chromatographic column, column pressure, eluent components and inactivation temperature, the multi-dimensional index fusion analysis terminal is used for selecting 4 indexes, and weights are respectively 0.25, 0.3 and 0.2, and the indexes are obtained by the steps of The risk pre-judging subsystem pushes the checking direction of the process stability score of <85 time sharing, the inactivation process parameter recorder records a temperature and time curve, triggers process compensation and marks key recheck batches.
7. The hepatitis B vaccine production overall process quality monitoring and early warning system according to claim 1, wherein the stock solution and semi-finished product quality comprehensive evaluation and early warning submodule comprises a stock solution and semi-finished product quality comprehensive evaluation unit, a grading treatment unit, a grading early warning terminal, a quality report automatic generation unit and a reject interception triggering subsystem, wherein the stock solution and semi-finished product quality comprehensive evaluation unit is used for monitoring and early warning of the whole hepatitis B vaccine production overall process quality The grading treatment unit is used for grading batches according to the MQI of more than or equal to 90, 80-89 and <80, the grading early warning terminal is used for triggering corresponding early warning modes according to the batches, the quality report automatic generation unit is used for integrating data to generate reports containing raw material information, process curves and the like, and the unqualified product interception triggering subsystem is used for intercepting batches with the MQI of < 80.
8. The hepatitis B vaccine production whole process quality monitoring and early warning system according to claim 1, wherein the production data archiving server files whole link data such as raw material quality inspection, process parameters and the like in a month, and the model parameter iteration tool adopts a gradient descent method to pass The LSTM model parameters are updated, the learning rate dynamic adjustment range is 0.0001-0.001, the process standard updating terminal updates the raw material quality standard and the process parameter threshold, the optimization effect verification subunit verifies the optimization effect through early warning accuracy, unqualified rate and early warning response time, and the supplier grading updating terminal updates the supplier grading result every quarter so as to eliminate the C-level suppliers.

Description

Hepatitis B vaccine production overall process quality monitoring and early warning system Technical Field The invention relates to the technical field of hepatitis B vaccine production, in particular to a quality monitoring and early warning system for the whole process of hepatitis B vaccine production. Background The quality monitoring and early warning of the hepatitis B vaccine production is a systematic management means which penetrates through the whole production process of the vaccine and covers key links of raw material purchase, strain culture, engineering bacteria fermentation, purification, preparation, split charging, finished product inspection and the like, scientific qualification threshold and grading early warning rules are set through real-time acquisition of technological parameters and quality indexes, abnormal fluctuation and potential quality risk in the production process are timely identified, basis is provided for production adjustment and risk disposal, and finally vaccine products are ensured to meet the national medicine standard and a core management system with safety and effectiveness requirements. The existing monitoring mode of hepatitis B vaccine production is mostly dependent on off-line sampling detection and manual recording analysis, the real-time performance and the comprehensiveness are seriously insufficient, in the production process, the process parameters of key links such as fermentation culture, purification, quality inspection and the like are mostly intermittently collected, instantaneous fluctuation cannot be captured in real time, so that the source is difficult to trace after abnormality occurs, meanwhile, the monitoring center of gravity is mostly concentrated on the final quality inspection of a finished product, the process quality of the intermediate link is weak, and the problem of batch quality caused by process deviation is difficult to avoid at the source. Disclosure of Invention The invention aims to provide a quality monitoring and early warning system for the whole process of hepatitis B vaccine production, which aims to solve the problems that in the prior art, the monitoring mode of the existing hepatitis B vaccine production is mostly dependent on offline sampling detection and manual recording analysis, the real-time performance and the comprehensiveness are seriously insufficient, the process parameters of key links such as fermentation culture, purification and the like are mostly intermittently collected in the production process, instantaneous fluctuation cannot be captured in real time, so that the source is difficult to trace in time after abnormality occurs, and meanwhile, the monitoring center of gravity is mostly concentrated on the final quality inspection of a finished product, the process quality of the intermediate link is weak, and the batch quality problem caused by process deviation is difficult to avoid at the source. In order to achieve the above purpose, the present invention adopts the following technical scheme: the hepatitis B vaccine production whole process quality monitoring and early warning system comprises the following modules and components: A system initialization and foundation construction module, a production full-link quality monitoring module and a system dynamic optimization and upgrading module; The system initialization and foundation construction module comprises a supplier qualification auditing terminal, a sensor cluster, RFID read-write equipment, an early warning terminal, a raw material quality standard database, a supplier foundation archive, a supplier rating subsystem, an LSTM process prediction model training platform, a parameter threshold setting terminal and an early warning grade setting unit; the production full-link quality monitoring module comprises a raw material purchasing admission control sub-module, an engineering bacteria fermentation real-time monitoring sub-module, a purification and inactivation accurate control sub-module, and a stock solution and semi-finished product quality comprehensive evaluation and early warning sub-module; The system dynamic optimization and upgrading module comprises a production data archiving server, a model parameter iteration tool, a process standard updating terminal, an optimization effect verification subunit and a supplier grading updating terminal. The technical scheme is further improved in that the supplier qualification audit terminal records and verifies supplier qualification files, the sensor cluster covers cell culture and purification inactivation equipment, temperature, pH value and other parameters are collected, the RFID read-write equipment generates and reads raw material RFID labels, the early warning terminal comprises an audible and visual alarm, a mobile phone APP and a system popup window, the raw material quality standard database stores key quality indexes and qualified thresholds of antigen production and inspection raw