Integrated forming method of medical sterile blister box

Abstract

This invention provides an integrated molding method for a sterile medical blister pack, relating to the field of blister molding technology, comprising the following steps: S1: Calculating the chemical migration potential index of the raw materials before the coating material is joined to the pre-formed plastic box body; S2: Calculating the process activation risk index during the heat sealing connection between the coating and the box body; S3: Obtaining the signal intensity of an online chemical probe, and coupling it with the raw material chemical migration potential index and the process activation risk index to calculate the batch migration release index; S4: Obtaining the batch migration release index, clinical adverse event correlation score, increase in migratings from retained sentinel samples, and supply chain reverse verification confirmation rate of the batch, generating a market feedback closed-loop correction coefficient. This invention can assess risks in real time, automatically adjust processes, classify products according to test results, and continuously optimize production standards using feedback from clinical use, thereby achieving intelligent closed-loop control from source to finished product.

Description

Technical Field

[0001] This invention relates to the field of thermoforming technology, specifically to an integrated molding method for a sterile medical thermoforming box. Background Technology

[0002] Medical sterile blister packs are typically manufactured using thermoforming of medical-grade plastic sheets to form the box body. Then, coating materials such as Tyvek lid material and sterilization indicator inks are bonded to the box body via heat sealing or coating to create a complete sterile barrier system. However, after the box base material and coating materials are heat-sealed, there is a long-term risk of migration of leachable substances such as coating monomers and ink photoinitiators. Therefore, a method should be developed to continuously assess the safety of the coating materials, automatically adjust the production process, classify products based on test results, and continuously optimize production standards based on feedback from hospitals.

[0003] Existing technology, disclosed in CN117863520A, provides a method for forming a thermoformed product with a back structure, the thermoformed product itself, and a mold. This technology includes: placing an internal support within a mold and adsorbing the internal support onto the mold; placing a thermoforming sheet on the mold and covering the internal support, so that the thermoformed outer skin adheres to the internal support; and welding the edges where the outer skin adheres to the internal support to form the thermoformed product with a back structure. This solution solves the problems of existing thermoformed products having complex internal structures that are difficult to form in one piece, and the cumbersome steps, long production cycle, and high costs.

[0004] However, in the aforementioned existing technologies, after the substrate and coating material are heat-sealed, there is a long-term risk of migration of leachable substances such as coating monomers and ink photoinitiators. Current methods only monitor physical parameters such as temperature and pressure to ensure sealing, lacking online quantitative assessment and proactive control of chemical migration risks. Migration problems often only surface after market launch. Furthermore, production lines use fixed processes and release standards for different combinations of risky materials, failing to dynamically adjust based on actual material risks. Market feedback on compatibility defects cannot be automatically relayed to the front end to prevent the re-production of the same combination, resulting in a gap in risk management.

[0005] The information disclosed in the background section is only intended to enhance the understanding of the background of this disclosure, and therefore may include information that does not constitute prior art known to those skilled in the art. Summary of the Invention

[0006] The purpose of this invention is to provide an integrated molding method for medical sterile blister packs to solve the problems mentioned in the background art. This invention moves chemical compatibility risks forward to pre-coating bonding and real-time control during processing, achieving preventative measures; dynamic weighting enables release decisions to adaptively match the risk level of raw materials, avoiding misjudgments based on fixed thresholds; market feedback closed-loop correction transforms actual compatibility performance into a permanent self-evolving access standard; all parameters can be measured online, and the index directly drives physical actions such as sorting and process adjustment, achieving integrated risk assessment and manufacturing execution.

[0007] To achieve the above objectives, the present invention provides the following technical solution:

[0008] A method for integral molding of a sterile medical blister pack includes the following steps:

[0009] S1: Before the coating material is bonded to the pre-formed plastic box, the total amount of low molecular weight substances precipitated from the substrate, the concentration of specific leachable markers, and the crosslinking density of the coating are collected and combined with the raw material safety benchmark coefficient to calculate the raw material chemical migration potential index; the raw material chemical migration potential index is used to determine whether the coating material is allowed to enter the subsequent bonding process.

[0010] S2: During the heat-sealing connection between the cladding and the box, the peak temperature of the heat-sealing zone, the cooling rate of the sealing flange zone, and the maximum local strain of the sealing flange zone are collected in real time. The process activation risk index is calculated by combining it with the process activation reference coefficient. The temperature, cooling rate, and closing pressure of the heat-sealing connection are dynamically adjusted according to the process activation risk index in order to actively reduce the activation intensity of chemical migration caused by the process.

[0011] S3: Obtain the signal intensity of the online chemical probe, and couple it with the chemical migration potential index of the raw material and the process excitation risk index to calculate the batch migration release index; according to the range of the batch migration release index, perform differentiated post-processing diversion on the formed and connected products, and classify them into the regular release, tightened sample retention and scrap isolation paths respectively;

[0012] S4: Obtain the batch migration release index, clinical adverse event correlation score, increase of migratings from retained sentinel samples, and supply chain reverse verification confirmation rate of the batch's historical records, and generate a market feedback closed-loop correction coefficient; multiply the market feedback closed-loop correction coefficient back to the weighting coefficient of the corresponding coating material in S1, so that when subsequent batches are subject to coating insertion admission again, the tightened risk baseline will be automatically adopted.

[0013] Furthermore, the safety benchmark coefficient for the raw materials includes the detection limit of low molecular weight substances, the toxicological concern threshold for specific markers, and the ideal crosslinking density; the chemical migration potential index of the raw materials is calculated using the following formula:

[0014]

[0015] in: The chemical migration potential index of the raw materials;

[0016] The total amount of low molecular weight substances precipitated from the substrate; The detection limit of the analytical method;

[0017] For specific leachable material marker concentrations; For toxicological studies, the upper limit of the threshold safety is important.

[0018] This refers to the crosslinking density of the coating. Ideal crosslinking density;

[0019] The multiple of the total amount precipitated relative to the detection limit; It is the ratio of the concentration of the biomarker to the upper limit of safety. This refers to cross-linking defects. These are the multiples of the total precipitate relative to the detection limit, the ratio of the marker concentration to the safety upper limit, and the weighting coefficients for the crosslinking defect term, respectively, satisfying the following conditions: .

[0020] Furthermore, the raw material chemical migration potential index is used to quantify the baseline of the inherent chemical migration risk of the coating material before bonding the coating material to the molded plastic box. When the calculated value of the raw material chemical migration potential index is lower than a preset threshold, the coating material is allowed to enter the bonding process. When the calculated value of the raw material chemical migration potential index exceeds the limit, the coating bonding is stopped, thereby intercepting high-risk material groups at the physical starting point of the molding connection.

[0021] Furthermore, the process activation reference coefficient includes the optimal peak temperature of the target, the half-width of the temperature process window, and the ideal cooling rate that does not introduce internal stress; the process activation risk index is calculated using the following formula:

[0022]

[0023] in: To stimulate the risk index of the process;

[0024] This represents the actual peak temperature of the heat-sealed zone. The optimal peak temperature for the target; The temperature process window is half its width;

[0025] This represents the actual cooling rate of the sealed flange area. The ideal cooling rate that does not introduce internal stress;

[0026] This represents the local maximum strain in the sealing flange area;

[0027] This is a penalty for temperature deviation. This is the cooling rate ratio term; This is a mechanical strain term; These are the weighting coefficients for the temperature offset penalty term, the cooling rate ratio term, and the mechanical strain term, respectively, satisfying... .

[0028] Furthermore, in this method, the process activation risk index is used to quantify in real time the activation intensity of the chemical migration potential of the material under processing conditions during the heat-sealing connection between the coating material and the pre-formed plastic box. The process activation risk index participates in feedback control in real time during the forming and connection process. When the calculated value of the process activation risk index exceeds the preset adjustment threshold, it triggers dynamic adjustment of the heat-sealing temperature, cooling rate and closing pressure to actively pull the activation intensity back to a safe range.

[0029] Furthermore, the batch migration release index is calculated using the following formula:

[0030]

[0031] in: Batch migration release index

[0032] The signal intensity of the online chemical probe;

[0033] The threshold for the warning signal;

[0034] This is the ratio of online chemical probe signals; This is a weighting factor for the raw material chemical migration potential index, the process activation risk index, and the online chemical probe signal ratio term. .

[0035] Furthermore, the batch migration release index is used to comprehensively assess the absolute chemical migration risk of a batch of products after the coating material and the molded plastic box have been heat-sealed, and directly drives the differentiated post-processing diversion of the molded products; wherein The release decision is dynamically adjusted based on the chemical migration potential index of the raw materials, so that the release decision is adaptively matched with the actual risk level of the raw materials. When the batch migration release index is lower than the first threshold, the product enters the regular release channel. When the batch migration release index is between the first threshold and the second threshold, the product enters the tightened sample retention channel and the sentinel monitoring is activated. When the batch migration release index reaches or exceeds the second threshold, the product enters the scrap isolation channel.

[0036] Furthermore, the market feedback closed-loop correction coefficient is calculated using the following formula:

[0037]

[0038] in: This is the market feedback closed-loop correction coefficient;

[0039] Scoring the correlation between clinical adverse events;

[0040] Increase in the amount of migrating material from the sampled sentinel;

[0041] To verify the confirmation rate of the supply chain;

[0042] m is the learning rate; This is the MRPI impact factor.

[0043] Furthermore, the market feedback closed-loop correction coefficient in this method is used to convert the real-world compatibility performance into a permanent correction to the front-end coating access standard of the production line after a batch of products that has been released has encountered compatibility issues with auxiliary materials at the market terminal. When the market feedback closed-loop correction coefficient is greater than 1, the corresponding grade of coating material involved in the problematic batch is located through the batch traceability code. The weighting coefficient in the raw material chemical migration potential index is multiplied by the market feedback closed-loop correction coefficient and normalized, so that when any subsequent batch uses the corresponding grade of coating material again, the raw material chemical migration potential index will automatically output a higher value under the same measured parameters, and the access standard will be tightened accordingly.

[0044] Furthermore, when the market feedback closed-loop correction coefficient is greater than 1, the composition of the coating material is analyzed by parsing the material traceability code of the problematic batch, and the corresponding grade weighting coefficient in the raw material database is located. The market feedback closed-loop correction coefficient is combined with Multiply each term individually to obtain the amplified intermediate coefficients; then normalize by dividing each intermediate coefficient by the sum of the intermediate coefficients to obtain the new weighted coefficients. The sum of the new weighting coefficients is always 1, and the weighting coefficients in the corresponding grade raw material database are overwritten with the new weighting coefficients. After that, when any new batch calls the corresponding grade coating material to perform coating insertion admission calculation again, the system automatically reads the new weighting coefficients and substitutes them into the raw material chemical migration potential index formula, so that the output value of the raw material chemical migration potential index under the same measured parameters is higher than that before the correction, and the admission standard is automatically tightened accordingly.

[0045] Compared with existing technologies, the advantages of this invention are: it shifts chemical compatibility risk control from passive end-point detection to pre-entry interception before coating bonding and real-time control during the bonding process, achieving proactive risk prevention on the molding and joining production line; through a dynamic weighting mechanism, it adaptively matches release decisions with the actual risk level of raw materials, avoiding the misjudgment defects of fixed thresholds; and through a market feedback closed-loop correction coefficient, it transforms real-world compatibility performance into a permanent correction of the raw material risk baseline, enabling the production line to continuously self-evolve from historical failures. All parameters involved in the index calculation can be measured online without offline sampling, meeting the requirements of continuous production cycle time. The index calculation results directly drive the feeding mechanism, process controller, and sorting device to perform corresponding physical actions, seamlessly integrating risk assessment with manufacturing execution. Attached Figure Description

[0046] Figure 1 This is a schematic diagram of the overall process flow of an integrated molding method for a sterile medical blister pack according to the present invention. Detailed Implementation

[0047] To make the objectives, technical solutions, and advantages of this invention clearer, the invention will be further described in detail below with reference to specific embodiments.

[0048] It should be noted that, unless otherwise defined, the technical or scientific terms used in this invention should have the ordinary meaning understood by one of ordinary skill in the art to which this invention pertains. The terms "first," "second," and similar terms used in this invention do not indicate any order, quantity, or importance, but are merely used to distinguish different components. Terms such as "comprising" or "including" mean that the element or object preceding the word encompasses the elements or objects listed following the word and their equivalents, without excluding other elements or objects. Terms such as "connected" or "linked" are not limited to physical or mechanical connections, but can include electrical connections, whether direct or indirect. Terms such as "upper," "lower," "left," and "right" are used only to indicate relative positional relationships; when the absolute position of the described object changes, the relative positional relationship may also change accordingly.

[0049] Example:

[0050] Please see Figure 1 The present invention provides a technical solution:

[0051] A method for integral molding of a sterile medical blister pack includes the following steps:

[0052] S1: Before bonding the coating material to the pre-formed plastic box, chemical migration risk parameters of the coating material are collected. The collected parameters include: the total amount of low molecular weight substances leached from the substrate, which is determined by headspace gas chromatography and reflects the total content of volatile or easily migratable small molecules in the coating material; the concentration of specific leachable markers, which is determined by liquid chromatography-mass spectrometry, and the markers are representative migratory substances known to have toxicological risks; and the coating crosslinking density, which is determined by dynamic mechanical analysis and characterizes the density of the polymer network of the heat-sealing coating or adhesive layer in the coating material. The above parameters are combined with the raw material safety benchmark coefficient to calculate the raw material chemical migration potential index.

[0053] The raw material safety baseline factors include: the analytical method detection limit, a constant representing the lowest reliable detection concentration of low molecular weight substances in the substrate by headspace gas chromatography, used to normalize the total amount of low molecular weight substances precipitated from the substrate to a multiple of the relative detection limit; the toxicological concern threshold safety upper limit, a constant representing the maximum permissible concentration of a specific leachable marker determined based on toxicological data and device contact properties, used to directly compare the measured concentration of the marker with its safety upper limit; and the ideal crosslinking density, a constant representing the optimal theoretical crosslinking density that balances thermal strength and barrier performance, used to compare the measured crosslinking density of the coating with the ideal state to quantify the degree of network defects.

[0054] The chemical migration potential index of raw materials is calculated using the following formula:

[0055]

[0056] in: The chemical migration potential index of the raw materials;

[0057] The total amount of low molecular weight substances precipitated from the substrate; The detection limit of the analytical method;

[0058] For specific leachable material marker concentrations; For toxicological studies, the upper limit of the threshold safety is important.

[0059] This refers to the crosslinking density of the coating. Ideal crosslinking density;

[0060] The multiple of the total amount precipitated relative to the detection limit, if When the value is below the detection limit, this item approaches 0; the higher the value, the more precipitate is released, and the higher the risk. This is the ratio of the concentration of the marker to the upper limit of safety. When it equals 1, the risk is unacceptable; when it exceeds 1, this item is greater than 1, directly raising the index value. For crosslinking defects, the closer the coating crosslinking density is to the ideal crosslinking density, the closer this term is to 0; the worse the crosslinking, the closer the value is to 1. These are the multiples of the total precipitate relative to the detection limit, the ratio of the marker concentration to the safety upper limit, and the weighting coefficients for the crosslinking defect term, respectively, satisfying the following conditions: .

[0061] The raw material chemical migration potential index is an access control indicator used to quantify the baseline of inherent chemical migration risk of the coating material before bonding it to the pre-molded plastic box. This index is calculated by weighting the total amount of low molecular weight substances leached from the substrate, the concentration of specific leachable markers, and the coating crosslinking density with a raw material safety benchmark coefficient. The value ranges from 0 to 1; a higher value indicates a stronger inherent tendency for leachable migration during subsequent processing and long-term contact. When the calculated index value is below a preset threshold, the chemical migration risk of the coating material is considered acceptable, and the coating material is allowed to proceed to the bonding process. When the calculated index value reaches or exceeds the preset threshold, the coating material is considered to have an unacceptable chemical migration risk, and the bonding process is terminated, intercepting high-risk coating material at the physical starting point of the molding and joining process.

[0062] S2: During the heat-sealing connection between the cladding and the housing, real-time acquisition of process parameters is performed on the sealing flange area. The acquired parameters include: peak temperature of the heat-sealing zone, acquired by a temperature sensor integrated into the heat-sealing station at the instantaneous highest temperature of the sealing flange area during heat-sealing pressurization; cooling rate of the sealing flange area, acquired by a temperature sensor after heat-sealing, using the maximum slope of the cooling curve near the material's glass transition temperature as the cooling rate value; and maximum local strain in the sealing flange area, acquired by an image correlation measurement system, using the displacement field of the sealing flange surface during heat-sealing pressurization and cooling contraction, and extracting the maximum local plastic strain value after strain calculation. The peak temperature of the heat-sealing zone, the cooling rate of the sealing flange area, and the maximum local strain in the sealing flange area are combined with the process activation reference coefficient to calculate the process activation risk index.

[0063] The process activation reference coefficients include: the optimal peak temperature of the target, which is determined by orthogonal experiments to jointly optimize the sealing strength and the amount of leachable material generated at different heat sealing temperatures, and is defined as the optimal heat sealing peak temperature that simultaneously satisfies reliable sealing and the minimum migration activation amount; the half-width of the temperature process window, which is defined as the half-width of the acceptable fluctuation range around the optimal peak temperature of the target, and its value is determined by the intersection boundary of the acceptable sealing range and the acceptable migration range; and the ideal cooling rate that does not introduce internal stress, which is determined by material thermomechanical analysis and is defined as the slow cooling rate at which the material molecular chains can fully relax and reach the minimum residual internal stress during the cooling process.

[0064] The process-induced risk index is calculated using the following formula:

[0065]

[0066] in: To stimulate the risk index of the process;

[0067] This represents the actual peak temperature of the heat-sealed zone. The optimal peak temperature for the target; The temperature process window is half its width;

[0068] This represents the actual cooling rate of the sealed flange area. The ideal cooling rate that does not introduce internal stress;

[0069] This represents the local maximum strain in the sealing flange area;

[0070] As a temperature offset penalty term, when the offset of the actual peak temperature of the heat-sealed zone from the optimal peak temperature of the target increases, the Gaussian function term increases exponentially, and the process activation risk index increases accordingly. As the cooling rate ratio term increases, the ratio of the actual cooling rate to the ideal cooling rate increases when the actual cooling rate in the sealing flange area increases. This term increases linearly, and the process activation risk index increases accordingly. As the mechanical strain term increases, the logarithmic function term increases nonlinearly with a slowing growth rate when the local maximum strain in the sealing flange area increases, and the process activation risk index increases accordingly; when the local maximum strain decreases and approaches zero, the logarithmic function term approaches zero, and the process activation risk index decreases accordingly. These are the weighting coefficients for the temperature offset penalty term, the cooling rate ratio term, and the compressive strain term, respectively, satisfying... .

[0071] In this method, the process activation risk index is used to quantify in real time the intensity of the activation of the chemical migration potential of the coating material by the processing conditions during the heat sealing connection between the coating material and the pre-formed plastic box. During the molding and connection process, this index participates in feedback control in real time: when the calculated value of the process activation risk index does not exceed the preset adjustment threshold, the current heat sealing process parameters remain unchanged; when the calculated value of the process activation risk index exceeds the preset adjustment threshold, dynamic adjustment of the heat sealing process parameters is triggered. The adjustment actions include at least one of the following: reducing the heating power of the heat sealing mold to make the actual peak temperature return to the target optimal peak temperature, extending the pressure holding and cooling time to reduce the actual cooling rate of the sealing flange area, and reducing the closing pressure of the heat sealing mold to reduce the local maximum strain in the sealing flange area. This actively suppresses the activation effect of the processing process on chemical migration and pulls the activation intensity back to a safe range.

[0072] S3: After the heat sealing connection is completed, the total ion flow intensity of the gaseous volatiles is collected in real time above the sealing flange area in a non-contact manner as the online chemical probe signal intensity. The signal intensity is expressed in arbitrary units and is used to reflect the release flux of leachable substances instantaneously activated during the heat sealing process. The collection time is within a fixed time window after the heat sealing mold is opened and before the product enters the cooling and conveying section.

[0073] The batch migration release index is calculated by coupling the online chemical probe signal intensity with the raw material chemical migration potential index and the process excitation risk index; the batch migration release index is calculated using the following formula:

[0074]

[0075] in: Batch migration release index

[0076] The signal intensity of the online chemical probe is the total ion current intensity of gaseous volatiles collected in a non-contact manner in the sealed flange area after heat sealing, which is used to reflect the release flux of leachable substances excited at the moment of heat sealing.

[0077] The warning signal threshold is a critical value set by statistical analysis of historical D1 signals from qualified batches that have been verified to have no compatibility issues over a long period of time. It is used to normalize the measured signal to a multiple of the relative normal level.

[0078] This is an online chemical probe signal ratio term used to provide real-time physical evidence for the batch migration release index, independent of the raw material chemical migration potential index and the process excitation risk index, in order to capture the additional contribution of the sudden release of volatiles during heat sealing to the final migration risk. This is a weighting factor for the raw material chemical migration potential index, the process activation risk index, and the online chemical probe signal ratio term. .

[0079] In this method, the batch migration release index is used to comprehensively assess the absolute chemical migration risk of a batch of products after the coating material and the molded plastic box have been heat-sealed, and directly drives the differentiated post-processing diversion of the molded products; among which, the weighting factors It is not a fixed constant, but dynamically adjusted according to the risk range of the raw material chemical migration potential index: when the raw material chemical migration potential index is in the high-risk range... The maximum value is used to strengthen the weight of material items, strictly preventing high-risk raw material batches from slipping through; when the chemical migration potential index of raw materials is in the low-risk range... Take the maximum value to strengthen the weight of process items and ensure that process anomalies are fully identified; The risk level remains constant across all risk ranges to independently capture the sudden release of volatiles during heat treatment;

[0080] After the batch migration release index is calculated, the system performs corresponding post-processing diversion actions based on the threshold range in which the value falls. When the calculated batch migration release index is lower than the first threshold, the product enters the regular release channel. When it is between the first and second thresholds, the product enters the tightened sample retention channel and the sentinel long-term monitoring is activated. When the second threshold is reached or exceeded, the product enters the scrap isolation channel.

[0081] S4: Obtain the set of input parameters required for market feedback closed-loop correction, including the batch migration release index of the batch history; clinical adverse event correlation score, which is obtained by extracting key features from the description text of suspected events reported by the terminal through natural language processing, and toxicology experts assign structured values ​​of 0 to 5 integers to the causal correlation strength between the event and the excipient migration according to the preset correlation judgment criteria; incremental migration of sentinel samples, which is the result of periodic sampling of sentinel samples that enter the tightened sampling channel when the batch migration release index is in the yellow light range, retesting the marker concentration by liquid chromatography-mass spectrometry, and calculating the ratio of the difference between the sample concentration and the factory concentration to the factory concentration; supply chain reverse verification confirmation rate, which is obtained by parsing the bill of materials through batch traceability code and comparing it with the digital passport records of raw material suppliers. If unreported changes are confirmed, the value is 1; otherwise, the value is 0.

[0082] The market feedback closed-loop correction coefficient is calculated using the following formula:

[0083]

[0084] in: This is the market feedback closed-loop correction coefficient;

[0085] Scoring the correlation between clinical adverse events;

[0086] Increase in the amount of migrating material from the sampled sentinel;

[0087] To verify the confirmation rate of the supply chain;

[0088] m is the learning rate, a preset constant between 0 and 1, used to control the maximum correction magnitude of a single market feedback event to the raw material risk baseline; The MRPI impact factor is a preset constant used to adjust the contribution of the historical batch migration release index to the correction magnitude; the hyperbolic tangent function maps inputs of arbitrary size to the (0,1) interval, so that when there is no feedback evidence, FBCF=1, no correction is triggered; when multiple pieces of irrefutable evidence are superimposed and the input becomes increasingly large, Approaching 1, FBCF approaches The correction range is strictly locked within the upper limit set by the learning rate; this mechanism ensures that a single correction will not be over-adjusted due to extreme events, thus ensuring the stability of the raw material risk baseline update.

[0089] When the market feedback closed-loop correction coefficient is greater than 1, it indicates that a confirmed or highly suspected excipient compatibility migration event has occurred at the market terminal after the batch of products has been released from the factory. The system then initiates a closed-loop correction procedure for the front-end coating access standards of the production line. Specifically, the system first analyzes the composition of the coating material of the problematic batch through the material traceability code. The material traceability code is recorded during batch production and permanently stored with the batch file. Its associated information includes all or part of the following combinations: the base material sheet grade, the heat-sealing coating grade of the capping material, the sterilization indicator ink grade, and the hot melt adhesive grade used in the batch. Based on the analysis results, the system locates the weighted coefficient records of each grade of coating material in the raw material database. The weighted coefficients include k1, k2, and k3, the sum of which is always 1. These correspond to the contribution weights of the coating material in the raw material chemical migration potential index formula for the total amount of low molecular weight substances precipitated, the concentration of specific leachable markers, and the coating crosslinking density.

[0090] After completing the positioning, the system multiplies the calculated market feedback closed-loop correction coefficient by k1, k2, and k3 respectively to obtain the first, second, and third intermediate coefficients. Since the market feedback closed-loop correction coefficient is greater than 1, the three intermediate coefficients are proportionally amplified compared to the original weighted coefficients. Subsequently, the system normalizes the three intermediate coefficients: the first intermediate coefficient is divided by the sum of the three intermediate coefficients to obtain the first new weighted coefficient. Divide the second intermediate coefficient by the sum of the three intermediate coefficients to obtain the second new weighted coefficient. Divide the third intermediate coefficient by the sum of the three intermediate coefficients to obtain the third new weighted coefficient. After this normalization process, the sum of the three new weighting coefficients is always 1, maintaining the mathematical consistency of the raw material chemical migration potential index formula.

[0091] After normalization, the system uses three new weighting coefficients. The original weighted coefficient record of the corresponding grade of coating material in the raw material database is overwritten, and the timestamp of this correction, the batch number that triggered the correction, the specific value of the market feedback closed-loop correction coefficient, and the source of each input parameter are recorded to form a complete correction audit log.

[0092] Subsequently, whenever any new batch of production calls upon the corresponding grade of coating material again and performs the raw material chemical migration potential index calculation during the coating insertion admission stage, the system automatically reads the newly overwritten weighting coefficients from the raw material database. The new weighting coefficients are then substituted into the raw material chemical migration potential index formula for calculation. Since the new weighting coefficients have been multiplied and normalized using market feedback closed-loop correction coefficients, under the condition that the three measured parameters—total low molecular weight substances precipitated from the substrate, concentration of specific leachable markers, and coating crosslinking density—are exactly the same as before the correction, the output value of the raw material chemical migration potential index will be higher than the output value before the correction. This means that under the same measured parameter conditions, this grade of coating material is more likely to meet the preset admission threshold requirements, and the coating insertion admission criteria are automatically tightened.

[0093] The above formulas are all dimensionless calculations. The formulas are derived from software simulations based on a large amount of collected data to obtain the most recent real-world results. The preset parameters in the formulas are set by those skilled in the art according to the actual situation.

[0094] The above embodiments can be implemented, in whole or in part, by software, hardware, firmware, or any other combination thereof. When implemented in software, the above embodiments can be implemented, in whole or in part, as a computer program product. Those skilled in the art will recognize that the units and algorithm steps of the various examples described in conjunction with the embodiments disclosed herein can be implemented by electronic hardware, or a combination of computer software and electronic hardware. Whether these functions are implemented in hardware or software depends on the specific application and design constraints of the technical solution.

[0095] The units described as separate components may or may not be physically separate. The components shown as units may or may not be physical units; they may be located in one place or distributed across multiple network units. Some or all of the units can be selected to achieve the purpose of this embodiment, depending on actual needs.

[0096] The above description is merely a specific embodiment of this application, but the scope of protection of this application is not limited thereto. Any changes or substitutions that can be easily conceived by those skilled in the art within the scope of the technology disclosed in this application should be included within the scope of protection of this application.

Claims

1. A method for integral molding of a medical sterile blister pack, characterized in that, Includes the following steps: S1: Before the coating material is bonded to the pre-formed plastic box, the total amount of low molecular weight substances precipitated from the substrate, the concentration of specific leachable markers, and the crosslinking density of the coating are collected and combined with the raw material safety benchmark coefficient to calculate the raw material chemical migration potential index; the raw material chemical migration potential index is used to determine whether the coating material is allowed to enter the subsequent bonding process. S2: During the heat-sealing connection between the cladding and the box, the peak temperature of the heat-sealing zone, the cooling rate of the sealing flange zone, and the maximum local strain of the sealing flange zone are collected in real time and combined with the process activation reference coefficient to calculate the process activation risk index. The temperature, cooling rate, and closing pressure of the heat-sealed connection are dynamically adjusted according to the process activation risk index in order to proactively reduce the activation intensity of chemical migration during processing. S3: Obtain the online chemical probe signal intensity and couple it with the raw material chemical migration potential index and process excitation risk index to calculate the batch migration release index; Based on the range of the batch migration release index, differentiated post-processing and diversion are performed on the finished connected products, which are respectively classified into regular release, stricter sample retention and scrap isolation paths; S4: Obtain the batch migration release index, clinical adverse event correlation score, increase of migrants in the retained sentinel product, and supply chain reverse verification confirmation rate for this batch, and generate market feedback closed-loop correction coefficient. Multiply the market feedback closed-loop correction coefficient back to the weighting coefficient of the corresponding coating material in S1, so that when subsequent batches perform coating insertion admission again, the tightened risk baseline will be automatically adopted.

2. The integrated molding method for a sterile medical blister pack according to claim 1, characterized in that: The safety benchmark coefficients for raw materials include the detection limit of low molecular weight substances by analytical methods, the toxicological concern threshold for specific markers, and the ideal cross-linking density. The chemical migration potential index of the raw materials is calculated using the following formula: in: The chemical migration potential index of the raw materials; The total amount of low molecular weight substances precipitated from the substrate; The detection limit of the analytical method; For specific leachable material marker concentrations; For toxicological studies, the upper limit of the safety threshold is important. This refers to the crosslinking density of the coating. Ideal crosslinking density; The multiple of the total amount precipitated relative to the detection limit; It is the ratio of the concentration of the biomarker to the upper limit of safety. This refers to cross-linking defects. These are the multiples of the total precipitate relative to the detection limit, the ratio of the marker concentration to the safety upper limit, and the weighting coefficients for the crosslinking defect term, respectively, satisfying the following conditions: .

3. The integrated molding method for a sterile medical blister pack according to claim 2, characterized in that: The raw material chemical migration potential index is used to quantify the baseline of inherent chemical migration risk of the coating material before the coating material is bonded to the pre-formed plastic box. When the calculated value of the chemical migration potential index of the raw material is lower than the preset threshold, the coating material is allowed to enter the bonding process; When the calculated value of the chemical migration potential index of the raw materials exceeds the limit, the coating bonding is stopped, thereby intercepting high-risk material groups at the physical starting point of the forming connection.

4. The integrated molding method for a sterile medical blister pack according to claim 1, characterized in that: The process activation reference coefficients include the optimal peak temperature of the target, the half-width of the temperature process window, and the ideal cooling rate without introducing internal stress; the process activation risk index is calculated using the following formula: in: To stimulate the risk index of the process; This represents the actual peak temperature of the heat-sealed zone. The optimal peak temperature for the target; The temperature process window is half the width; This represents the actual cooling rate of the sealed flange area. The ideal cooling rate that does not introduce internal stress; This represents the local maximum strain in the sealing flange area; This is a penalty for temperature deviation. This is the cooling rate ratio term; This is a mechanical strain term; These are the weighting coefficients for the temperature offset penalty term, the cooling rate ratio term, and the mechanical strain term, respectively, satisfying... .

5. The integrated molding method for a sterile medical blister pack according to claim 4, characterized in that: The process-induced risk index is used in this method to quantify in real time the intensity of the induced chemical migration potential of the material by the processing conditions during the heat-sealing connection between the coating material and the pre-formed plastic box. The process activation risk index participates in feedback control in real time during the molding and connection process. When the calculated value of the process activation risk index exceeds the preset adjustment threshold, it triggers dynamic adjustment of heat sealing temperature, cooling rate and closing pressure to actively pull the activation intensity back to a safe range.

6. The integrated molding method for a sterile medical blister pack according to claim 1, characterized in that: The batch migration release index is calculated using the following formula: in: Batch migration release index The signal intensity of the online chemical probe; The threshold for the warning signal; This is the ratio of online chemical probe signals; This is a weighting factor for the raw material chemical migration potential index, the process activation risk index, and the online chemical probe signal ratio term. .

7. The integrated molding method for a sterile medical blister pack according to claim 6, characterized in that: The batch migration release index is used to comprehensively assess the absolute chemical migration risk of a batch of products after the coating material and the molded plastic box have been heat-sealed, and directly drives the differentiated post-processing diversion of the molded products; wherein The release decision is dynamically adjusted based on the chemical migration potential index of the raw materials, so that the release decision is adaptively matched with the actual risk level of the raw materials; when the batch migration release index is lower than the first threshold, the product enters the regular release channel. When the batch migration release index is between the first and second thresholds, the product enters the tightened sample retention channel and sentinel monitoring is activated. When the batch migration release index reaches or exceeds the second threshold, the product enters the scrap isolation channel.

8. The integrated molding method for a sterile medical blister pack according to claim 1, characterized in that: The market feedback closed-loop correction coefficient is calculated using the following formula: in: This is the market feedback closed-loop correction coefficient; Scoring the correlation between clinical adverse events; Increase in the amount of migrating material from the sampled sentinel; To verify the confirmation rate of the supply chain; m is the learning rate; This is the MRPI impact factor.

9. The integrated molding method for a sterile medical blister pack according to claim 8, characterized in that: In this method, the market feedback closed-loop correction coefficient is used to convert real-world compatibility issues into permanent corrections to the front-end coating access standards of the production line when a batch of products that has already been released experiences material compatibility problems at the market terminal. When the market feedback closed-loop correction coefficient is greater than 1, the corresponding grade of coating material involved in the problematic batch is located through the batch traceability code. The weighting coefficient in the raw material chemical migration potential index is multiplied by the market feedback closed-loop correction coefficient and normalized. This ensures that when any subsequent batch uses the corresponding grade of coating material again, the raw material chemical migration potential index will automatically output a higher value under the same measured parameters, and the access standards will be tightened accordingly.

10. The integrated molding method for a sterile medical blister pack according to claim 9, characterized in that: When the market feedback closed-loop correction coefficient is greater than 1, the composition of the coating material is analyzed by parsing the material traceability code of the problematic batch, and the corresponding grade weighting coefficient in the raw material database is located. The market feedback closed-loop correction coefficient is combined with Multiply each term individually to obtain the amplified intermediate coefficients; then normalize by dividing each intermediate coefficient by the sum of the intermediate coefficients to obtain the new weighted coefficients. The sum of the new weighting coefficients is always 1, and the weighting coefficients in the corresponding grade raw material database are overwritten with the new weighting coefficients. After that, when any new batch calls the corresponding grade coating material to perform coating insertion admission calculation again, the system automatically reads the new weighting coefficients and substitutes them into the raw material chemical migration potential index formula, so that the output value of the raw material chemical migration potential index under the same measured parameters is higher than that before the correction, and the admission standard is automatically tightened accordingly.

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