A high-voltage discharge leak detection method for an injection solution packaging system

Abstract

The application provides a high-voltage discharge leak detection method of an injection package system, and relates to the field of drug detection. Specifically, the application provides a high-voltage discharge leak detection method suitable for ampoules, plastic bottles and westlin bottles. When the method is used to detect a sample, the current threshold is confirmed by the current values of positive samples and the current values of negative samples screened out. On the basis of the traditional leak detection method, the current parameter of the positive sample is introduced to correct the current threshold, the determination mode of the current threshold is optimized, the accuracy and reliability of the leak detection result are greatly improved, the quality risk during product storage is reduced, and the quality of the product and the safety of clinical medication are effectively ensured.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of drug detection, in particular to a high-voltage discharge leak detection method for injection solution packaging system. BACKGROUND

[0002] Article 77 in Annex 1 of the 2010 edition of the Good Manufacturing Practice for Drugs: the sealing detection method of the sterile drug packaging container should be verified to avoid the pollution of the sterile product; the 100% leak detection test should be conducted for the fusion sealed product (such as glass ampoule or plastic ampoule); the sealing system of the container of the sterile product should prevent the invasion of microorganisms, so that the sealing property of the drug packaging material is an important physical monitoring index related to the quality of the drug. The high-voltage discharge method is a commonly used leak detection technology in the actual production process, and is especially suitable for the sealing property inspection of the micro-pore leakage of the ampoule bottle, plastic bottle and the like. The sealing property of the sample to be detected is checked and confirmed according to the difference between the electrical parameters and the characteristics when there is no defect and when there is a defect by applying high-voltage electricity to the sample to be detected. The high-voltage electricity leak detection can also be divided into manual high-voltage electricity leak detection and automatic online high-voltage electricity leak detection according to the actual production requirements. Both methods require that the liquid filled in the container has a certain electrical conductivity.

[0003] At present, there are mature high-voltage discharge leak detection machines on the market for checking and confirming the sealing property of the packaging material. The traditional high-voltage discharge method sets a fixed current value for leak detection of different injection solutions, and the current value is usually set to 1.5 times the average value of the maximum current value of 20 groups of negative samples (i.e. samples with perfect sealing property). When the sample current is greater than the value, it is determined to be positive (i.e. a sample with sealing defects). The inventors found during the research that the leak detection by the method is prone to miss the positive sample, thereby leading to inaccurate or even unreliable detection results, increasing the quality risk during product storage, and thus it is necessary to develop a high-voltage discharge leak detection method for injection solution packaging system with more reliable results, to improve the accuracy or reliability of the detection results, thereby ensuring the safety of clinical medication. SUMMARY

[0004] The purpose of the present application is to provide a high-voltage discharge leak detection method for injection solution packaging system, which has high accuracy and reliable results compared with the traditional method, and effectively ensures the product quality and the safety of clinical medication.

[0005] The technical solution adopted by the present application is as follows:

[0006] A high-voltage discharge leak detection method for injection solution packaging system, comprising the following steps:

[0007] (1) Prepare positive sample vials with a diameter of 3-5 μm by laser drilling. The drilling positions are located at the bottle head, neck, body, and bottom. Prepare at least 2 vials at each position. After filling with injection solution, seal the vials to obtain positive samples. Place the positive samples into a high-voltage discharge leak detector and measure the current value at each station. Run each positive sample continuously at least 5 times, record the minimum current value at each station, and calculate the average current value of the total number of runs at each station. Use the average current value of each station as the I-value of each station.

[0008] (2) Screen multiple negative samples, group them into groups of at least 10 samples each, and run each group of samples at least 10 times to detect their current values ​​and calculate the maximum average current Imax of each group between each running sequence.

[0009] (3) The current threshold I threshold is jointly confirmed by Imax and Iyang. The calculated I threshold is then input into the high-voltage discharge leak detector to perform leak detection on the sample to be tested.

[0010] In a preferred embodiment of the present invention, in step (3), I threshold = (Imax average + Iyang average) / 2, and is less than the minimum current value of the positive sample.

[0011] In a preferred embodiment of the present invention, when the calculated threshold I is not an integer, it is rounded to the nearest integer.

[0012] In a preferred embodiment of the present invention, the perforation diameter of the positive sample vial is 3 μm; each positive sample is run 10 to 20 times continuously.

[0013] In a preferred embodiment of the present invention, in step (2), the sample is detected with a current value lower than the minimum current value of the positive sample at each station as a provisional threshold for each station, and the sample with a current value lower than the provisional threshold for each station is used as a negative sample.

[0014] In a preferred embodiment of the present invention, 15 to 50 negative samples are used as a group, and each group is run continuously for 15 to 30 times. The maximum current value of each group of samples at each station is recorded, and the average maximum current value Imax of each group between each running sequence is calculated as the average Imax of each station.

[0015] In a preferred embodiment of the present invention, the provisional threshold of each station is 30-80 (0.25 μA) lower than the minimum current value of the positive sample.

[0016] The high-voltage discharge leak detection method of the injection packaging system of the present invention is applicable to injection products with different active ingredients and different formulations. In some embodiments, the injection solution in the high-voltage discharge leak detection method of the present invention is selected from dopamine hydrochloride injection, asarone injection, and ambroxol hydrochloride injection.

[0017] This invention provides a high-voltage discharge leak detection method applicable to ampoules, plastic bottles, and vials. When using this method to detect leaks in samples, the current threshold is determined by combining the current values ​​of selected positive and negative samples. Based on traditional leak detection methods, the current parameters of positive samples are introduced to correct the current threshold, optimizing the determination of the current threshold and greatly improving the accuracy and reliability of leak detection results. This reduces quality risks during product storage and effectively ensures product quality and clinical medication safety. Detailed Implementation

[0018] The following detailed embodiments further illustrate the above-described content of the present invention. However, this should not be construed as limiting the scope of the present invention to the following examples. All technologies implemented based on the above-described content of the present invention fall within the scope of the present invention.

[0019] The high-voltage discharge leak detector used in this invention is an AJL44 automatic leak detector, purchased from Chutian Technology Co., Ltd. (model AJL44). It has four stations (stations 1-4), each with a voltage threshold of 14000V, used to measure the current values ​​at the bottle head, neck, body, and bottom. The dopamine hydrochloride injection, asarone injection, and ambroxol hydrochloride injection are all from Hainan Better Pharmaceutical Co., Ltd.

[0020] Example 1

[0021] This embodiment provides a high-voltage discharge leak detection method for an injection packaging system, and verifies the preparedness and reliability of this leak detection method. The sample used in this embodiment is dopamine hydrochloride injection solution packaged in borosilicate glass ampoules. The specific operation is as follows:

[0022] (1) Prepare positive samples and measure the average current value Ipositive of the positive samples.

[0023] Positive sample vials with a diameter of 3–5 μm were prepared using a laser drilling device. 5 mL glass ampoules were drilled at the head, neck, body, and bottom of the vial, with at least two ampoules at each location. Then, 5.20–5.40 mL of dopamine hydrochloride injection solution (5 mL: 0.2 g) was filled, sealed, and marked to obtain the positive sample. The prepared positive samples were placed in a high-voltage discharge leak detector and run through different stations. The current value at each station was measured, with each ampoule running continuously at least 5 times. The minimum current value at each station was recorded, and the average current value for the total number of runs at each station was calculated as the Ipositive average for each station. In this embodiment, 3 μm positive sample vials were used, with two vials at each location (head, neck, body, and bottom). Each ampoule was run continuously 10 times. The average current value (Ipositive average) for 20 runs at different stations is shown in Table 1.

[0024] Table 1. Current detection results of positive samples

[0025]

[0026]

[0027] (2) Screen negative samples and measure the maximum current value Imax of the negative samples.

[0028] Provisional thresholds were set for each station of the high-voltage discharge leak detector. Dopamine hydrochloride injection solution from normal production (to be leak-tested) was used as the sample, and samples were grouped and placed into the leak detector. Each group was run multiple times, and the current value was measured. Samples with current values ​​not exceeding the provisional threshold were selected as qualified samples (i.e., negative samples). The provisional threshold for each station was lower than the minimum current value of its positive sample, typically 30–80 (0.25 μA) lower. In this embodiment, the provisional threshold for each station was 50 (0.25 μA) lower than the minimum current value of its positive sample (as shown in Table 1). Specifically, the provisional threshold for station one was set to 598 (0.25 μA), for station two to 765 (0.25 μA), for station three to 560 (0.25 μA), and for station four to 680 (0.25 μA).

[0029] Each group should contain 15-50 negative samples, and each group should be run continuously for 15-30 times. Record the maximum current value of the negative samples at each station, and calculate the average maximum current (Imax) of the negative samples in each group between each running sequence. In this embodiment, each group contains 20 negative samples, and each group is run continuously for 20 times. The calculation results of the average maximum current (Imax) of the negative samples in each group between each station and each running sequence are shown in Table 2.

[0030] Table 2. Detection and calculation results of negative sample current.

[0031]

[0032] (3) Calculate the current threshold for each workstation.

[0033] The I threshold is calculated as (Imax_average + I_positive_average) / 2, and is less than the minimum current value of the positive sample. If the calculated I threshold is not an integer, it is rounded to the nearest integer. The current threshold calculation results for each station are shown in Table 3.

[0034] Table 3. Calculation results of current threshold for each station in Example 1

[0035]

[0036]

[0037] (4) Verify the accuracy and reliability of the leak detection method provided by the present invention.

[0038] Input the calculated current threshold I values ​​for each station from Table 3 into the high-voltage discharge leak detector. Prepare a batch of dopamine hydrochloride injection solutions to be leak-tested. Run the leak detection program and screen samples that do not exceed the threshold values ​​for each station as negative samples. Select 10,000 negative samples and randomly insert pre-prepared positive samples numbered with a marker. The holes of the positive samples are located at the bottle head, neck, body, and bottom, with hole diameters of 3 μm and 5 μm, respectively. Two positive samples of each specification are used, for a total of 16 samples. Run the leak detection program three times to verify the positive sample detection rate of the method of this invention (record the insertion position of the positive bottle, check the detection results at the corresponding positions, and only if the number and position of the finally detected positive samples correspond to the number and position of the insertions can it be considered a detection). The verification results are shown in Table 4.

[0039] Table 4 Verification results of Example 1

[0040]

[0041]

[0042] Example 2

[0043] This embodiment provides a high-voltage discharge leak detection method for an injection packaging system, and verifies the preparedness and reliability of this leak detection method. The sample used in this embodiment is a borosilicate glass ampoule packaged with asarum injection solution. The specific operation is as follows:

[0044] The current threshold for each station was determined according to the method in steps (1)-(3) of Example 1. The current thresholds determined for each station are shown in Table 5.

[0045] Table 5 Current threshold values ​​for each workstation in Example 2

[0046]

[0047] Input the calculated current threshold I values ​​for each workstation from Table 5 into the high-voltage discharge leak detector, prepare a batch of Asarum injection solution to be leaked, and run the leak detection program. Verify the detection rate of mixed positive samples using the same method as in step (4) of Example 1. The verification results are shown in Figure 6.

[0048] Table 6 Verification Results of Example 2

[0049]

[0050]

[0051] Example 3

[0052] This embodiment provides a high-voltage discharge leak detection method for an injection packaging system, and verifies the preparedness and reliability of this leak detection method. The sample used in this embodiment is ambroxol hydrochloride injection packaged in borosilicate glass ampoules. The specific operation is as follows:

[0053] The current threshold for detecting ambroxol hydrochloride (2 ml: 15 mg) at each station was determined according to the method in steps (1)-(3) of Example 1. The current threshold determined for each station is shown in Table 7.

[0054] Table 7 Current threshold values ​​for each workstation in Example 3

[0055]

[0056] Input the calculated current threshold I values ​​for each workstation from Table 5 into the high-voltage discharge leak detector, prepare a batch of ambroxol hydrochloride injection solution to be leaked, and run the leak detection program. Verify the detection rate of mixed positive samples using the same method as in step (4) of Example 1. The verification results are shown in Figure 8.

[0057] Table 8 Verification Results of Example 3

[0058]

[0059]

[0060] Comparative Example

[0061] This comparative example provides a prior art high-voltage discharge leak detection method, in which the current threshold is set to 1.5 times the average of the maximum current values ​​of 20 negative samples. The specific operation method is as follows:

[0062] The dopamine hydrochloride injection solution to be leak-tested (i.e., the sample) was completely immersed in a 0.02% methylene blue aqueous solution. The pressure was evacuated to -50 kPa and maintained for 30 minutes. The pressure was then restored to normal and maintained for another 30 minutes. The sample was removed, its outer surface cleaned, and the presence of methylene blue aqueous solution was observed to seep into the bottle. Samples without methylene blue seepage were considered negative samples. Negative samples were grouped into sets of 15–50, and each set was run continuously for 15–30 cycles. The maximum current value at each station was recorded, and the average maximum current value (Imax) of these sets was calculated. In this comparative example, each set contained 20 negative samples, and each set was run continuously for 20 cycles. The maximum current detection results at each station are shown in Table 9. Based on the average Imax obtained in Table 9, the current threshold was calculated, and the results are shown in Table 10. When the calculated Imax threshold in Table 10 is not an integer, it was rounded to the nearest integer.

[0063] Table 9 shows the calculation results of Imax in the comparative examples.

[0064]

[0065]

[0066] Table 10. Current threshold I threshold results in the comparative examples

[0067]

[0068] The current threshold I obtained from Table 10 for each workstation was input into the high-voltage discharge leak detector. A batch of dopamine hydrochloride injection solution to be leaked was prepared. A batch of negative samples were screened using the aforementioned methylene blue aqueous solution immersion method. 10,000 negative samples were selected, and 3μm or 5μm positive samples that had been prepared in advance and numbered with a marker were randomly inserted. The leak detection program was run 3 times. The specifications and quantity of positive samples were the same as in Example 1, "(4) Verify the accuracy and reliability of the leak detection method provided by the present invention". The positive sample detection rate of the method in this comparative example was verified (the detection standard was the same as in Example 1). The verification results are shown in Table 7.

[0069] Table 7 Comparative Verification Test Results

[0070]

[0071]

[0072] Leak testing was performed on Asarum Injection in Example 2 and Ambroxol Hydrochloride Injection in Example 3 using the same method as in this comparative example, and pre-prepared positive samples were inserted to verify the detection rate of mixed positive samples. The results showed that the detection rates of mixed positive samples in Asarum Injection and Ambroxol Hydrochloride Injection were 87.5% and 75%, respectively.

[0073] Therefore, existing leak detection methods have a low detection rate for contaminated positive samples, resulting in missed detections and increasing quality risks during product storage. The high-voltage discharge leak detection method provided by this invention achieves a 100% detection rate for contaminated positive samples, with high accuracy and reliable results, effectively ensuring product quality and clinical drug safety.

Claims

1. A high pressure discharge leak detection method for an injection liquid packaging system, characterized in that, It includes the following steps: (1) Prepare positive sample vials with a diameter of 3-5 μm by laser drilling. The drilling positions are located at the bottle head, neck, body, and bottom. Prepare at least 2 vials at each position. After filling with injection solution, seal the vials to obtain positive samples. Place the positive samples into a high-voltage discharge leak detector and measure the current value at each station. Run each positive sample continuously at least 5 times, record the minimum current value at each station, and calculate the average current value of the total number of runs at each station. Use the average current value of each station as the I-value of each station. (2) The provisional threshold for each station is 30-80 (0.25 μA) lower than the minimum current value of the positive samples at each station. The negative samples are grouped into groups of at least 10 samples each. Each group of samples is run at least 10 times. The maximum current value of each group of samples at each station is recorded. The average maximum current value Imax of each group between each running sequence is calculated and used as the average Imax of each station. (3) The current threshold I threshold is confirmed by Imax and Iyangjun. The calculated I threshold is input into the high-voltage discharge leak detector to detect the leak of the sample to be tested. I threshold = (Imaxjun + Iyangjun) / 2, and is less than the minimum current value of the positive sample.

2. The leak detection method of claim 1, wherein, If the calculated I threshold is not an integer, it is rounded to the nearest integer.

3. The leak detection method according to claim 1 or 2, characterized in that, The perforation diameter of the positive sample vial is 3μm; each positive sample is run 10 to 20 times continuously.

4. The leak detection method according to claim 1 or 2, characterized in that, In step (2), 15 to 50 negative samples are used as a group, and each group is run 15 to 30 times consecutively.

5. A high voltage discharge leak detection method for a dopamine hydrochloride injection packaging system, characterized by, Leak detection is performed using any one of claims 1-4.

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