Preparation method of microporous positive bottle

Abstract

The invention discloses a preparation method of a microporous positive bottle. The preparation method comprises the following steps: S1, selecting a proper microporous preparation method to prepare the microporous positive bottle; s2, after the microporous positive bottle is prepared, a leak detector is adopted to detect the profiling solid body, the standard leakage holes with different hole diameters and the microporous positive bottle with the same parameters, and then detection data between the microporous positive bottle and the profiling solid body and detection data between the microporous positive bottle and the standard leakage holes are compared; determining the final actual leakage aperture of the microporous positive bottle and judging whether the final actual leakage aperture meets the requirement or not; and S3, labeling detection data of the microporous positive bottles meeting the requirements, and packaging and storing the detection data. The preparation method of the microporous positive bottle effectively ensures that the final leakage aperture of each positive bottle for verification of leakage detection equipment can be quantified and traced, eliminates the risk of misjudgment of the performance of the leakage detection equipment caused by fuzzy aperture, and provides an accurate and reliable standard sample support for a container sealing integrity test.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of container sealing integrity testing, in particular to a micro-hole positive bottle preparation method. BACKGROUND

[0002] With the development of new technologies, various countries have introduced some regulations and guidelines on the sealing requirements of pharmaceuticals. For example, USP1207, State Food and Drug Administration-Good Supply Practice, and other guidelines. They all point out that sterile drugs should have perfect integrity throughout the effective period of the drug to prevent the invasion of microorganisms. The recognized deterministic detection methods include vacuum decay method, pressure decay method, laser headspace analysis method, helium mass spectrometry leak detector, etc.

[0003] Vacuum decay method, high-voltage discharge method, laser analysis method, etc. are required to prepare micro-hole positive bottles with certain pore size for performance verification. The current industry regulations and the industry generally accepted micro-hole positive bottle preparation methods include laser drilling method, micropipette implantation method, capillary implantation method, etc.

[0004] The above methods all have a fatal flaw. All of them can be proved before preparation, but after preparation, the pore size cannot be accurately proved. Laser drilling method is an open preparation method, and the drilling accuracy is verified, but whether the pore size (leakage rate) changes after the ampoule is fused or the vial is capped is unknown. The equivalent leakage rate of micropipette and capillary before implantation is proved, but the leakage rate of micro-hole positive bottle after implantation is unknown.

[0005] Therefore, the present application provides a micro-hole positive bottle preparation method to solve the above problems. SUMMARY

[0006] The present application aims to provide a micro-hole positive bottle preparation method, which can determine the final leakage pore size of the prepared micro-hole positive bottle.

[0007] To solve the above technical problems, the present application provides a micro-hole positive bottle preparation method, comprising the following steps: S1, selecting a suitable micro-hole preparation method to prepare a micro-hole positive bottle; S2, after the micro-hole positive bottle is prepared, a leak detector is used to detect the profiled solid body, a plurality of standard leakage holes with different pore sizes, and the micro-hole positive bottle with the same parameters, and then the detection data between the micro-hole positive bottle and the profiled solid body and a plurality of standard leakage holes are compared to determine the final actual leakage pore size of the micro-hole positive bottle and determine whether it meets the requirements; S3, labeling and packaging the micro-hole positive bottle that meets the requirements.

[0008] Furthermore, in step S1, the micropore preparation method is selected according to the leak detection method of the packaging container, and the specific logic includes: If the packaging container is to be verified using a high-voltage discharge device, laser drilling should be the preferred method. If the packaging container is to be verified using a vacuum decay leak detector, the laser drilling method, microdroplet implantation method, or capillary implantation method should be selected.

[0009] Furthermore, the microporous positive bottle prepared by the laser drilling method is in an open state. The flow rate of the processed micropores is verified by mass flow rate method and an equivalent pore diameter certificate is issued before the sealing process is carried out.

[0010] Furthermore, the sealing process employs either a capping or a fusion sealing operation.

[0011] Furthermore, in step S2, the detection accuracy of the leak detector is ≥1μm.

[0012] Furthermore, in step S2, the leak detector has both an absolute pressure sensor and a differential pressure sensor.

[0013] Furthermore, in step S2, the multiple standard leakage holes include a first standard leakage hole with a leakage rate consistent with the target hole diameter, a second standard leakage hole with a leakage rate greater than the target hole diameter by a preset accuracy value Y, and a third standard leakage hole with a leakage rate less than the target hole diameter by a preset accuracy value Y. When comparing data, if the relative deviation of the same test data between the microporous positive bottle and the first standard leak hole is within a preset range, and the absolute value of the difference between the same test data between the microporous positive bottle and the second and third standard leak holes is greater than the absolute value of the difference between the same test data between the microporous positive bottle and the first standard leak hole, then the final actual leak hole diameter of the microporous positive bottle is determined to be the target hole diameter, the hole diameter accuracy level is ±Y, and it is a product that meets the requirements.

[0014] Furthermore, the value of Y ranges from 0.2 to 0.25 μm.

[0015] Furthermore, in step S2, the detection of the conformal solid body, multiple standard leakage holes, and microporous positive bottles is repeated multiple times. When the data of each group are close, the average value is used as the basis for comparison.

[0016] Furthermore, in step S3, the packaging is preserved by placing the product in a sealed bag or a vacuum-sealed bag.

[0017] Compared with the prior art, the present invention has at least the following beneficial effects: The microporous positive bottle preparation method provided by this invention overcomes the technical limitations of traditional methods where "the pore size is verifiable before preparation but unknown after preparation." Through a design that incorporates a conformal solid body, multiple standard leak holes, and the same parameters for the microporous positive bottle, a complete pore size verification closed loop is constructed: the conformal solid body detection eliminates environmental interference and equipment errors, providing a leak-free blank control; the multiple standard leak holes form a multi-pore size gradient reference, and combined with data comparison, accurately anchor the final actual leak pore size of the microporous positive bottle, avoiding the neglect of pore size changes caused by sealing, transportation, and other processes. This effectively ensures that the final leak pore size of each positive bottle used for leak detection equipment verification is quantifiable and traceable, eliminating the risk of misjudgment of leak detection equipment performance due to pore size ambiguity, and providing accurate and reliable standard sample support for container seal integrity testing. Attached Figure Description

[0018] Figure 1 This is a flowchart of the microporous positive bottle preparation method in an embodiment of the present invention; Figure 2 This is a flowchart illustrating the operation of the leak detector in an embodiment of the present invention. Detailed Implementation

[0019] The method for preparing the microporous positive bottle of the present invention will now be described in more detail with reference to the schematic diagrams, which illustrate preferred embodiments of the invention. It should be understood that those skilled in the art can modify the invention described herein while still achieving its advantageous effects. Therefore, the following description should be understood as being of general knowledge to those skilled in the art and is not intended to limit the invention.

[0020] Furthermore, based on the teachings of this specification, those skilled in the art can form new technical solutions through cross-combination of different implementation methods without creating technical contradictions. Such variations should all be considered to fall within the protection scope of this patent.

[0021] The invention is described more specifically by way of example in the following paragraphs with reference to the accompanying drawings. The advantages and features of the invention will become clearer from the following description. It should be noted that the drawings are in a very simplified form and use non-precise proportions, and are only used to facilitate and clarify the illustration of the embodiments of the invention.

[0022] like Figure 1 As shown in the figure, an embodiment of the present invention proposes a method for preparing a microporous positive bottle, comprising the following steps: S1. Select a suitable microporous preparation method to prepare microporous positive bottles.

[0023] Specifically, the micropore preparation method is selected based on the leak detection method of the packaging container, and the specific logic includes: If packaging containers (such as ampoules, vials, pre-filled syringes, and other microporous positive vials) are to be verified using high-voltage discharge equipment, laser drilling should be the preferred method. If the packaging container is to be verified using a vacuum decay leak detector, the laser drilling method, microdroplet implantation method, or capillary implantation method can be selected.

[0024] Positive bottles prepared using the microdroplet implantation method typically have microdroplet tubes with their own aperture certificates. Positive bottles prepared using this method are sealed bottles.

[0025] Positive bottles prepared by the capillary implantation method have different combinations of inner diameter and length to calculate the equivalent leakage rate. Positive bottles prepared by this method are sealed positive bottles.

[0026] For open positive bottles made by laser drilling, after preparation, the flow rate of the processed micropores needs to be verified by mass flow method and an equivalent aperture certificate needs to be issued before the sealing process (crimping or fusion sealing) is carried out. It should be noted that the sealing process should take care to minimize the impact on the micropores. The transportation and sealing processes should minimize the interference of environmental and human factors. At the same time, depending on the verification requirements, you can choose to fill with liquid medicine or empty bottles.

[0027] S2. After the microporous positive bottle is prepared, a leak detector is used to test the conformal solid body, multiple standard leak holes with different diameters and the microporous positive bottle with the same parameters. Then, the test data between the microporous positive bottle and the multiple standard leak holes are compared to determine the final actual leak hole diameter of the microporous positive bottle and whether it meets the requirements.

[0028] Specifically, the leak detector used has a detection accuracy of ≥1μm and is equipped with both absolute pressure and differential pressure sensors. The absolute pressure sensor measures the absolute pressure of the test chamber, ensuring that the preset vacuum level is reached during the vacuuming phase and the pressure remains stable during the pressure holding phase, providing benchmark data for leak detection. The differential pressure sensor measures the pressure difference between the test chamber and the reference chamber, capturing minute pressure changes caused by micropore leaks. The two sensors work together to achieve accurate leak detection, ensuring more reliable test results.

[0029] Before the leak detector is used for testing, prepare the solid body required for verifying the microporous positive bottle and several standard leak holes with different diameters. Among them, the multiple standard leak holes include a first standard leak hole X1 with the same leakage rate as the target diameter, a second standard leak hole X1+Y with a leakage rate greater than the target diameter by a preset accuracy value Y, and a third standard leak hole X1-Y with a leakage rate less than the target diameter by a preset accuracy value Y.

[0030] Preferably, the value of Y is in the range of 0.2~0.25μm to ensure the rationality of the aperture gradient setting. This avoids both insufficient accuracy due to an excessively wide range and failure of judgment due to an excessively narrow range.

[0031] It should be noted that the range of values ​​for Y is not the only limitation mentioned above, and can be adjusted appropriately according to the detection accuracy requirements or the type of packaging container.

[0032] After preparing the solid protective body required for verifying the microporous positive bottle and several standard leak holes of different diameters, adjust the equipment parameters of the leak detector, such as... Figure 2 As shown, parameters such as vacuuming time T1, pressure holding time T2, detection time T3, differential pressure detection time T4, maximum threshold N1, C1 threshold N2, and differential pressure detection threshold N3 are set. Then, the leak detector is run to test multiple sets of data. The detection targets include a conformal solid body, the first standard leak hole X1, the actually prepared microporous positive bottle, the second standard leak hole X1+Y, and the third standard leak hole X1-Y.

[0033] This embodiment provides an example, and the relevant test data for this example are shown in Tables 1 and 2. It should be noted that in the test of this example, the value of X1 is set to 5.07μm and the value of Y is set to 0.23μm.

[0034] Table 1: Table 1 shows the test data for the conformal solid body, the first standard leakage hole X1, and the actually prepared microporous leak-positive bottle. In the table, number 1 represents the data from the conformal solid body placed in the test chamber of the leak detector, indicating a leak-free product; number 2 represents the test data from the conformal solid body placed in the test chamber and connected to the first standard leakage hole X1, representing a leak equivalent to a pore size of X1 micrometers; number 3 represents the test data from the actually prepared microporous leak-positive bottle obtained through the leak detector. The data shows that the test data for numbers 2 and 3 are approximately equal, indicating that they belong to the same micropore leakage rate, thus demonstrating the reliability of the microporous leak-positive bottle preparation method of this invention.

[0035] Table 2: Table 2 shows the relevant test data for the first standard leak hole X1, the second standard leak hole X1+Y, and the third standard leak hole X1-Y. As can be seen from Table 2, as the diameter of the standard leak hole increases, the C1 difference of the leak detector increases synchronously, reflecting the linear correlation that "the larger the diameter, the higher the leakage-related detection data", which verifies the leak detector's ability to distinguish leakage states of different diameters.

[0036] Preferably, the above data are tested repeatedly for multiple groups, and when the data in each group are close, the average value is used as the basis for comparison to ensure that the data is more convincing.

[0037] After the leak detector test is completed, the test data can be compared. When comparing the data, if the relative deviation of the same test data (such as the C1 difference) between the microporous positive bottle and the first standard leak hole is within the preset range, and the absolute value of the difference between the same test data of the microporous positive bottle and the second and third standard leak holes is greater than the absolute value of the difference between the same test data of the microporous positive bottle and the first standard leak hole, then the final actual leak hole diameter of the microporous positive bottle is determined to be the target hole diameter, the hole diameter accuracy level is ±Y, and it is a product that meets the requirements. If the test data of the microporous positive bottle is similar to that of the conformal solid body, then the microporous positive bottle is considered to be blocked.

[0038] In the above implementation process, relative deviation refers to the proportion of the absolute difference between the test data and the standard data to the standard data, usually expressed as a percentage. Taking the comparison of the C1 value of the positive test bottle and the C1 value of the first standard leak hole as an example: the C1 value (standard data) of the first standard leak hole is 1.031; the C1 value (test data) of the positive test bottle is 1.061, then the absolute difference between the two is 2.9%. =0.029.

[0039] By introducing relative deviation, the degree to which the test data deviates from the standard can be intuitively shown, which is an effective basis for judging that the pore size of the microporous positive bottle is "approximately equal" to the first standard leakage pore (i.e., the target pore size).

[0040] At the same time, the judgment condition of "the absolute value of the difference between the detection data of the microporous positive bottle and the second standard leakage hole and the third standard leakage hole is greater than the absolute value of the difference between the detection data of the microporous positive bottle and the first standard leakage hole" is introduced, forming a dual guarantee of "close to the target + not exceeding the boundary", avoiding misjudgment caused by equipment error, environmental interference, and slight deformation of micropores, and ensuring that the pore size of each qualified microporous positive bottle is strictly controlled within a precise range.

[0041] S3. Label the test data of the qualified microporous positive bottles and package and store them.

[0042] Specifically, the labeled test data includes the final actual leakage pore diameter, test date, relative deviation value, and batch number. The packaging and storage method uses clean, impurity-free sealed bags or high-barrier vacuum packaging bags, which reduces micropore blockage caused by environmental factors and extends the shelf life of the micropore positive bottles to a certain extent.

[0043] In summary, the microporous positive bottle preparation method provided by this invention has at least the following advantages over the prior art: The microporous positive bottle preparation method provided by this invention overcomes the technical limitations of traditional methods where "the pore size is verifiable before preparation but unknown after preparation." Through a design that incorporates a conformal solid body, multiple standard leak holes, and the same parameters for the microporous positive bottle, a complete pore size verification closed loop is constructed: the conformal solid body detection eliminates environmental interference and equipment errors, providing a leak-free blank control; the multiple standard leak holes form a multi-pore size gradient reference, and combined with data comparison, accurately anchor the final actual leak pore size of the microporous positive bottle, avoiding the neglect of pore size changes caused by sealing, transportation, and other processes. This effectively ensures that the final leak pore size of each positive bottle used for leak detection equipment verification is quantifiable and traceable, eliminating the risk of misjudgment of leak detection equipment performance due to pore size ambiguity, and providing accurate and reliable standard sample support for container seal integrity testing.

[0044] Furthermore, improved storage methods reduced micropore clogging caused by environmental factors and extended the shelf life of micropore positive bottles to some extent.

[0045] Obviously, those skilled in the art can make various modifications and variations to this invention without departing from its spirit and scope. Therefore, if these modifications and variations fall within the scope of the claims of this invention and their equivalents, this invention also intends to include these modifications and variations.

Claims

1. A method for preparing a microporous positive bottle, characterized by, It comprises the following steps: S1, selecting a suitable micropore preparation method to prepare a micropore positive bottle; S2, after the micropore positive bottle is prepared, a leak detector is used to detect the profiled solid body, a plurality of standard leakage holes with different aperture and the micropore positive bottle with the same parameters, and then the detection data between the micropore positive bottle and the profiled solid body and the plurality of standard leakage holes are compared to determine the final actual leakage aperture of the micropore positive bottle and determine whether it meets the requirements; S3, labeling the detection data of the micropore positive bottle meeting the requirements and packaging and storing.

2. The microporous positive bottle preparation method according to claim 1, wherein, In step S1, the micropore preparation method is selected according to the leak detection method of the packaging container, and the specific logic includes: If the packaging container is verified by a high-voltage discharge device, the laser drilling method is preferred; If the packaging container is verified by a vacuum decay leak detector, the laser drilling method, micropipette implantation method or capillary implantation method is selected.

3. The microporous positive bottle preparation method according to claim 2, wherein The micropore positive bottle prepared by the laser drilling method is in an open state, and the flow rate of the micropore is verified by mass flow method and an equivalent aperture certificate is issued, and then a sealing process is performed.

4. The microporous positive bottle preparation method according to claim 3, wherein The sealing process adopts rolling or fusion sealing operation.

5. The microporous positive bottle preparation method according to claim 1, wherein In step S2, the detection accuracy of the leak detector is ≥1 μm.

6. The microporous positive bottle preparation method according to claim 1, wherein In step S2, the leak detector has an absolute pressure sensor and a differential pressure sensor.

7. The microporous positive bottle preparation method according to claim 1, wherein In step S2, the plurality of standard leakage holes include a first standard leakage hole with a target aperture leakage rate, a second standard leakage hole with a target aperture leakage rate plus a preset precision value Y, and a third standard leakage hole with a target aperture leakage rate minus a preset precision value Y. When comparing data, if the relative deviation of the micropore positive bottle and the first standard leakage hole with the same detection data is within the preset range, and the absolute value of the difference between the micropore positive bottle and the second standard leakage hole and the third standard leakage hole with the same detection data is greater than the absolute value of the difference between the micropore positive bottle and the first standard leakage hole with the same detection data, it is determined that the final actual leakage aperture of the micropore positive bottle is the target aperture, the aperture precision level is ±Y, and it is a product meeting the requirements.

8. The microporous positive bottle preparation method according to claim 1, wherein The value range of Y is 0.2-0.25 μm.

9. The microporous positive bottle preparation method according to claim 1, wherein In step S2, the detection of the profiled solid body, the plurality of standard leakage holes and the micropore positive bottle is repeated for multiple groups, and when each group of data is close, the average value is taken as the comparison basis.

10. The microporous positive bottle preparation method according to claim 1, wherein In step S3, the packaging and storage are performed by loading into a sealed bag or a vacuum packaging bag.

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