A method for detecting the leak tightness of low-concentration plastic ampoule-filled liquid medicine

Abstract

The invention discloses a method for leak detection of a low-concentration plastic ampoule filled with liquid medicine, and belongs to the field of drug production technology. The method comprises the following steps: firstly freezing the liquid medicine in a container in liquid nitrogen, then filling the container with nitrogen in a vacuum environment, then thawing at room temperature, and finally filling the liquid medicine and adjusting the headspace volume in the plastic ampoule to ≤10%, and performing high-voltage leak detection. The invention combines the method of rapidly freezing the liquid medicine before filling, then vacuum-filling with nitrogen, and thawing and re-dissolving at room temperature with the method of adjusting the headspace volume in the bottle by 10%, thereby effectively preventing the generation of impurities during high-voltage discharge leak detection, and at the same time ensuring 100% detection of leaking samples, which complies with the requirements of the 2010 edition of China's "Good Manufacturing Practice for Pharmaceuticals" in the supplementary provisions for sterile drugs for 100% integrity testing of drugs in ampoules, and can be applied to the requirements of continuous online rapid leak detection of drugs produced in large quantities.

Description

Technical Field

[0001] The invention relates to the technical field of drug production, and in particular to a method for detecting the sealing leakage of a low-concentration plastic ampoule-filled drug solution. Background Art

[0002] In the production process of drugs, according to the requirements of the 2010 edition of China's "Good Manufacturing Practice for Pharmaceuticals" Sterile Drugs Appendix, liquid drugs in plastic ampoules need to be 100% inspected for integrity. Due to automation requirements, the three commonly used methods in the production process of conventional products include vacuum decay, headspace infrared spectroscopy and high-voltage discharge detection.

[0003] The vacuum decay method is to place the packaging container in a special test cavity, evacuate the test cavity, and the pressure difference between the inside and outside of the container causes the gas inside the container to leak into the test cavity through the leak hole. The host pressure sensor monitors the pressure change and compares the pressure change value with the reference value to determine whether the container is qualified. In actual operation, the test time of each sample is about 1 minute. For plastic ampoule drugs, the production batch is usually more than 100,000. Using this method, each leak detection takes at least 70 days. The leak detection efficiency is too low and it is not suitable for large-scale drug production and detection. At the same time, it is easy to block the leakage point for high-viscosity drugs, so this method is not applicable. Headspace infrared spectroscopy is often used to detect volatile organic compounds, and can detect methane, ethanol, gasoline, benzene, etc. It is rarely used for leak detection in the drug production process.

[0004] The high-voltage discharge equipment is constructed by setting an emitter and a receiver on both sides of the sample to be tested, and applying a preset high-voltage electric field. Under ideal conditions, that is, when the packaging is intact, due to the insulating effect of the bottle wall, a large capacitance is formed between the emitter and the receiver, and only a weak induced current is generated. However, once there is a leak in the package (such as a slight damage to the bottle mouth, bottle bottom or bottle body), the insulation barrier is broken, the capacitance effect is weakened or even disappears, and a direct loop is formed between the emitter and the receiver, resulting in a significant increase in the detected microcurrent. By accurately measuring and comparing the changes in microcurrent, the sealing status of the drug packaging can be quickly and accurately determined. The preset current limit value inside the system is used as the judgment standard. When the detected current value reaches or exceeds the limit value, it is judged as a package leak, otherwise it is qualified. The working principle diagram is shown as follows Figure 1 shown.

[0005] High-voltage discharge testing is efficient and accurate, so it has become the most commonly used method for 100% integrity testing of ampoules in the pharmaceutical industry. However, it is surprising that during the integrity test of the product, the low-concentration plastic ampoule-filled drug solution has a significant increase in impurities. This result not only occurs in formoterol fumarate inhalation solution in plastic ampoule bottles (active ingredient concentration is 0.00001), but also in another low-concentration drug studied by our company - travoprost eye drops (active ingredient concentration is 0.00004). Therefore, the quality of low-concentration drugs that are tested for integrity by high-voltage discharge testing is at great risk, especially when the degradation impurities may cause teratogenesis, carcinogenesis, and mutagenesis, the risk is even more serious.

[0006] In view of the above situation, it is urgent to find a method to solve the problem of increased impurities encountered in the high-voltage discharge leak detection production process of low-concentration drugs such as formoterol fumarate inhalation solution filled and sealed in plastic ampoules. Summary of the invention

[0007] In order to solve the above technical problems, the purpose of the present invention is to provide a method for leak detection of low-concentration plastic ampoule-filled liquid medicine, so as to solve the problem of increased impurities encountered in the existing low-concentration plastic ampoule-filled liquid medicine production process of high-voltage discharge leak detection.

[0008] The technical solution of the present invention to solve the above technical problems is as follows:

[0009] A method for leak detection of a low-concentration plastic ampoule containing liquid medicine, comprising the following steps:

[0010] First, freeze the drug solution in liquid nitrogen in a container, then fill the container with nitrogen in a vacuum environment, then thaw at room temperature, and finally fill the container with drug solution and adjust the headspace volume in the plastic ampoule to ≤10% for high-pressure leak detection.

[0011] Beneficial effects of the present invention: The present invention adjusts the headspace volume in the ampoule bottle to ≤10%, combines freezing and remelting and nitrogen filling in a vacuum environment to perform liquid medicine filling and packaging in the plastic ampoule bottle, and then performs high-pressure leak detection, thereby effectively avoiding the generation of impurities during the leak detection process.

[0012] Furthermore, the headspace volume in the bottle is adjusted by filling the bottle with a liquid medicine greater than or equal to 90% of the actual volume of the plastic ampoule bottle.

[0013] The beneficial effect of adopting the above-mentioned further technical scheme is: the present invention can quickly adjust the headspace in the low-concentration plastic ampoule bottle of liquid medicine by simply adjusting the filling amount of the liquid medicine during the filling process, thereby reducing the impurities generated by high-pressure leak detection. The processing method is simple and fast, and is suitable for large-scale use in production.

[0014] Furthermore, the liquid medicine includes fortroleum fumarate inhalation solution or travoprost eye drops.

[0015] The beneficial effects of adopting the above further technical solution are:

[0016] During the production process of fortroleum fumarate inhalation solution and travoprost eye drops, it was found that after the product underwent high-voltage discharge leak detection, the impurities increased significantly (from 0% to 2%), which did not meet the quality requirements of the product. In addition, the impurities did not belong to the known degradation impurities of fortroleum fumarate and travoprost eye drops or the process impurities in the production process. It is difficult to determine whether the impurities will cause safety hazards, and there is an urgent need for methods to effectively control the production of the impurities.

[0017] By reducing the high-voltage discharge detection voltage (to 18-20 kV), while ensuring that the leaking product can be detected, although the generation of impurities after the leak detection can be reduced to a certain extent, it still cannot meet the quality requirements of the drug, and there is a situation where the leaking product cannot be detected 100%. The present invention adjusts the filling specifications of the drug to ensure that the headspace volume in the ampoule is ≤10%, and performs vacuum nitrogen filling treatment on the quick freezing of the pre-filled drug solution, and finally performs the filling process of the drug solution by thawing and re-dissolving. After being processed by the method of the present invention, high-voltage discharge leak detection is performed under higher voltage conditions, which can still ensure that the fortrol fumarate inhalation solution and travoprost eye drops will not generate impurities after the leak detection, and at the same time ensure the leak detection voltage, avoiding the situation where the leaking product cannot be detected 100%.

[0018] Furthermore, the freezing treatment time is 10-30 min.

[0019] Furthermore, the vacuum degree of the vacuum environment is 0.01-0.1 Pa.

[0020] Furthermore, the nitrogen filling rate is 0.1-5 L / min, and the filling time is 10-30 min.

[0021] Furthermore, the voltage of the high voltage leak detection is 20~22 kV.

[0022] The present invention has the following beneficial effects:

[0023] The invention provides a method for detecting the sealing leak of a low-concentration plastic ampoule-filled liquid medicine. By adjusting the headspace volume in the plastic ampoule to ≤10% and rapidly freezing the liquid medicine, vacuum-filling with nitrogen, and finally thawing and re-dissolving the liquid medicine, the generation of impurities in the process of high-voltage discharge leak detection is effectively prevented, and at the same time, 100% detection of leaking samples is guaranteed. The method can be applicable to the requirements of continuous online rapid leak detection of drugs produced in large quantities. BRIEF DESCRIPTION OF THE DRAWINGS

[0024] Figure 1 This is a schematic diagram of the working principle of high-voltage leak detection;

[0025] Figure 2 It is the liquid chromatography detection result figure in Example 1;

[0026] Figure 3 It is a diagram of the liquid chromatography detection result in Example 2;

[0027] Figure 4 This is a graph showing the results of liquid chromatography testing before high-voltage discharge in Comparative Example 1;

[0028] Figure 5 This is a graph showing the results of liquid chromatography after high voltage discharge in Comparative Example 1;

[0029] Figure 6 It is the liquid chromatography test result figure in comparative example 2;

[0030] Figure 7 This is a diagram of the liquid chromatography test results in Comparative Example 3;

[0031] Figure 8 It is the liquid chromatography test result figure in comparative example 4;

[0032] Fig. 9 This is a diagram of the liquid chromatography test results in Comparative Example 5;

[0033] Fig.10 This is a graph showing the results of liquid chromatography testing in Comparative Example 6;

[0034] Fig.11 This is a diagram of the liquid chromatography test results in Comparative Example 7;

[0035] Fig.12 This is a diagram of the liquid chromatography test results in Comparative Example 8;

[0036] Fig.13 This is a graph showing the results of liquid chromatography testing in Comparative Example 9;

[0037] Fig.14 This is a graph showing the results of liquid chromatography testing in Comparative Example 10;

[0038] Fig.15 This is a graph showing the results of liquid chromatography testing before high-voltage discharge in Comparative Example 11;

[0039] Fig.16 This is a graph showing the results of liquid chromatography after high voltage discharge in Comparative Example 11;

[0040] Fig.17 This is a graph showing the results of liquid chromatography testing in Comparative Example 12;

[0041] Fig.18 This is a graph showing the results of liquid chromatography testing in Comparative Example 13;

[0042] Fig.19 This is a graph showing the results of liquid chromatography testing in Comparative Example 14;

[0043] Fig. 20 This is a graph showing the results of liquid chromatography testing in Comparative Example 15;

[0044] Fig.21 This is a graph showing the results of liquid chromatography testing in Comparative Example 16;

[0045] Fig. 22 This is a graph showing the results of liquid chromatography testing in Comparative Example 17;

[0046] Fig.23 This is a graph of the liquid chromatography test results in Comparative Example 18. DETAILED DESCRIPTION

[0047] The principles and features of the present invention are described below in conjunction with the accompanying drawings. The examples are only used to explain the present invention and are not used to limit the scope of the present invention. If specific conditions are not specified in the embodiments, they are carried out according to normal conditions or conditions recommended by the manufacturer. If the manufacturer is not specified for the reagents or instruments used, they are all conventional products that can be purchased commercially.

[0048] Embodiment 1:

[0049] A method for reducing impurities in high-voltage discharge leakage detection of formoterol fumarate inhalation solution in a low-concentration plastic ampoule bottled liquid medicine, comprising the following steps:

[0050] First, the formoterol fumarate inhalation solution was prepared according to the formula of the formoterol fumarate inhalation solution developed by Chengdu Push Pharmaceutical Co., Ltd. The container containing the solution was placed in liquid nitrogen for rapid freezing for 20 min, and nitrogen was filled at a rate of 4 L / min for 20 min under a vacuum environment of 0.05 Pa. Then, it was thawed at room temperature, and the solution was initially filtered (Cobetter's 1st-level 0.22 μm polyvinylidene fluoride model LHPVND0022HSF10SP filter element, the filtration pressure difference was required to be less than 0.2 MPa), sterilized and filtered (Cobetter's 2nd-level 0.22 μm polyvinylidene fluoride model LHPVND0022HSF10SP filter element, the filtration pressure difference was required to be less than 0.2 MPa), and then BFS was used to fill 2 mL (actual volume 2.4 mL) plastic ampoules (using the BFS blowing, filling and sealing integrated machine of Weiler, USA), and the filling volume of the solution was 2.16 mL; finally, light inspection and 20-22 kV high-voltage discharge leak detection (using Japan Nika HDI-14+DL high-voltage discharge leak detection machine), and the samples after leak detection were subjected to liquid chromatography detection. The test results are as follows Figure 2 shown.

[0051] Embodiment 2:

[0052] A method for reducing impurities in high-voltage discharge leakage detection of low-concentration plastic ampoule-filled travoprost eye drops, comprising the following steps:

[0053] First, travoprost eye drops were prepared according to the travoprost eye drops prescription developed by Chengdu Pushi Pharmaceutical Co., Ltd. The container containing the liquid medicine was placed in liquid nitrogen for rapid freezing for 20 min, and nitrogen was filled at a rate of 4 L / min for 20 min under a vacuum environment of 0.05 Pa. After that, it was thawed at room temperature, and then the liquid medicine was initially filtered (Cobetter's 1st-level 0.22 μm polyvinylidene fluoride model LHPVND0022HSF10SP filter element, the filtration pressure difference was required to be less than 0.2 Mpa), sterilized and filtered (Cobetter's 2nd-level 0.22 μm polyvinylidene fluoride model LHPVND0022HSF10SP filter element, the filtration pressure difference was required to be less than 0.2 Mpa), and then BFS was used to fill 0.4 mL (actual volume 0.6 mL) plastic ampoules (using the BFS blowing, filling and sealing machine of Weiler, USA), and the filling volume of the liquid medicine was 0.54 mL; finally, light inspection and 20-22 kV high-voltage discharge leak detection (using Japan Nika HDI-14+DL high-voltage discharge leak detection machine), and the samples after leak detection were subjected to liquid chromatography detection. The test results are as follows Figure 3 As shown. (RT4.2 is a known degradation impurity of API)

[0054] Comparative Example 1:

[0055] A method for detecting impurities in a low-concentration plastic ampoule bottled liquid formoterol fumarate inhalation solution by high-voltage discharge, comprising the following steps:

[0056] The liquid medicine processing method is the same as that in Example 1, except that the freezing, nitrogen filling and thawing treatments are not performed and the liquid medicine filling volume is 2 mL, the specification of the plastic ampoule is 5 mL (actual volume 7.6 mL), and a high-voltage discharge leak detection of 22-24 kV is performed. The samples before and after the leak detection are respectively subjected to liquid chromatography detection. The test results are shown as follows: Figure 4 and Figure 5 As shown. Figure 4 RT8.5 is the residual benzaldehyde in the production pipeline, and RT17.8 is the known degradation impurity of API)

[0057] Comparative Example 2-3:

[0058] A method for reducing impurities in high-voltage discharge leakage detection of formoterol fumarate inhalation solution in a low-concentration plastic ampoule bottled liquid medicine, comprising the following steps:

[0059] The treatment method is the same as that of Comparative Example 1, except that the high-voltage discharge leakage detection voltage is changed to 20~22 kV (Comparative Example 2) and 18~20 kV (Comparative Example 3). The test results are as follows: Figure 6 and Figure 7 shown.

[0060] Comparative Examples 4-5:

[0061] A method for reducing impurities in high-voltage discharge leakage detection of formoterol fumarate inhalation solution in a low-concentration plastic ampoule bottled liquid medicine, comprising the following steps:

[0062] The treatment method is the same as that of Comparative Example 1, except that the freezing and thawing are not performed, but the filled liquid is directly nitrogen-filled. The nitrogen filling time is 15 min (Comparative Example 4) and 20 min (Comparative Example 5), respectively. 18~20 kV high-voltage discharge leak detection is performed, and the samples after leak detection are subjected to liquid chromatography detection. The test results are as follows: Figure 8 and Fig. 9 shown.

[0063] Comparative Examples 6-8:

[0064] A method for reducing impurities in high-voltage discharge leakage detection of formoterol fumarate inhalation solution in a low-concentration plastic ampoule bottled liquid medicine, comprising the following steps:

[0065] The treatment method is the same as that of Comparative Example 1, except that the specification of the filled plastic ampoule is changed to 5 mL (actual volume 7.6 mL), and 2 mL (Comparative Example 6), 4 mL (Comparative Example 7) and 5 mL (Comparative Example 8) are filled respectively, and 20~22 kV high-voltage discharge leakage detection is carried out. The samples after leakage detection are subjected to liquid chromatography detection. The test results are as follows Figure 10-12 shown.

[0066] Comparative Example 9:

[0067] A method for reducing impurities in high-voltage discharge leakage detection of formoterol fumarate inhalation solution in a low-concentration plastic ampoule bottled liquid medicine, comprising the following steps:

[0068] The treatment method is the same as that of comparative example 1, except that the filling volume of the liquid medicine is changed to 2.16 mL, the specification of the plastic ampoule is changed to 2 mL (actual volume 2.4 mL), and a 20~22 kV high voltage discharge leak detection is performed. The samples after the leak detection are subjected to liquid chromatography detection. The test results are as follows Fig.13 shown.

[0069] Comparative Example 10:

[0070] A method for reducing impurities in low-voltage discharge leakage detection of formoterol fumarate inhalation solution in a low-concentration plastic ampoule bottle, comprising the following steps:

[0071] The liquid processing method is the same as that of Comparative Example 9, except that the leak detection is performed using an M-HLV low-voltage leak detector with a leak detection voltage of 8 kV. The samples after leak detection are subjected to liquid chromatography detection. The test results are as follows: Fig.14 shown.

[0072] Comparative Example 11:

[0073] A method for detecting impurities in a low-concentration plastic ampoule-filled travoprost eye drops by high-voltage discharge, comprising the following steps:

[0074] The liquid medicine processing method is the same as that in Example 2, except that the freezing, nitrogen filling and thawing treatments are not performed and the liquid medicine filling volume is 0.4 mL. A high voltage discharge leak detection of 22-24 kV is performed, and liquid chromatography is performed on the samples before and after the leak detection. The test results are shown as follows: Fig.15 and Fig.16 shown.

[0075] Comparative Example 12:

[0076] A method for reducing impurities in high-voltage discharge leakage detection of low-concentration plastic ampoule-filled travoprost eye drops, comprising the following steps:

[0077] The treatment method is the same as that of Comparative Example 11, except that the discharge leakage detection voltage is changed to 18-20 kV, and the samples after leakage detection are subjected to liquid chromatography detection. The detection results are as follows: Fig.17 shown.

[0078] Comparative Examples 13-14:

[0079] A method for reducing impurities in high-voltage discharge leakage detection of low-concentration plastic ampoule-filled travoprost eye drops, comprising the following steps:

[0080] The treatment method is the same as that of Comparative Example 11, except that the freezing and thawing are not performed, but the filled liquid is directly nitrogen-filled. The nitrogen filling time is 15 min (Comparative Example 13) and 20 min (Comparative Example 14), respectively. 18~20 kV high-voltage discharge leak detection is performed, and the samples after leak detection are subjected to liquid chromatography detection. The test results are as follows: Fig.18 and Fig.19 shown.

[0081] Comparative Examples 15-16:

[0082] A method for reducing impurities in high-voltage discharge leakage detection of low-concentration plastic ampoule-filled travoprost eye drops, comprising the following steps:

[0083] The treatment method is the same as that of Comparative Example 11. The specification of the filled plastic ampoule is changed to 0.8 mL (actual volume 1.0 mL). 0.5 mL (Comparative Example 15) and 0.7 mL (Comparative Example 16) of the drug solution are filled respectively. 20~22 kV high-voltage discharge leak detection is carried out. The samples after leak detection are tested by liquid chromatography. The test results are as follows: Fig. 20 and Fig.21 shown.

[0084] Comparative Example 17:

[0085] A method for reducing impurities in high-voltage discharge leakage detection of low-concentration plastic ampoule-filled travoprost eye drops, comprising the following steps:

[0086] The treatment method is the same as in Example 2, except that the volume of the filling liquid is changed to 0.42 mL. The test results are as follows: Fig. 22 shown.

[0087] Comparative Example 18:

[0088] A method for reducing impurities in low-voltage discharge leakage detection of low-concentration plastic ampoule bottled liquid travoprost eye drops, comprising the following steps:

[0089] The treatment method is the same as that of Comparative Example 11, except that the M-HLV low-voltage leak detector is used for leak detection, the leak detection voltage is 8kV, and the sample after leak detection is subjected to liquid chromatography detection. The test results are as follows: Fig.23 shown.

[0090] Test example:

[0091] The high-voltage discharge impurity detection results of the samples prepared in the embodiments and comparative examples and the detection conditions of the leakage samples are shown in Table 1, and the high-voltage discharge impurity content is expressed as mass fraction.

[0092] Table 1 High-voltage discharge impurity detection results and leakage sample detection

[0093]

[0094] As shown in the table above and Figure 1-Figure 22As shown in the figure, for the leak detection of formoterol fumarate inhalation solution products, after conventional 22~24 kV high-voltage discharge leak detection, impurities with a mass fraction of 2.2% will be generated, affecting the safety and quality of the drug. After the voltage reduction treatment, the impurity content can be effectively reduced to 1.1% (20~22 kV) and 0.35% (18~20 kV), but the generation of impurities cannot be completely avoided, and when the voltage is too low, the leakage sample cannot be detected 100%. By filling the drug solution with nitrogen before filling, the generation of high-voltage discharge impurities can also be effectively reduced to 0.23% (4 L / min nitrogen filling for 15 min) and 0.12% (4 L / min nitrogen filling for 20 min), but there will still be a lot of impurities remaining. By adjusting the amount of medicine and changing the headspace volume in the bottle, the generation of high-voltage discharge impurities can also be effectively reduced. When the headspace in the bottle is 10%, the impurity content is effectively reduced to 0.02%, which meets the ICH requirements. However, due to the presence of trace amounts of high-voltage discharge impurities, unpredictable risks will occur when patients use it for a long time. The present invention combines the method of rapidly freezing the drug solution before filling, vacuum nitrogen filling, and thawing and re-dissolving at room temperature with the method of adjusting the headspace volume in the bottle by 10%, and performs leak detection at a high voltage of 20~22 kV, which can effectively prevent the generation of high-voltage discharge impurities and meet the conditions for 100% detection of leaking samples, which is basically consistent with the M-HLV low-voltage discharge leak detection effect. However, since the M-HLV low-voltage discharge leak detection equipment is only suitable for laboratory single drug inspection, it is not possible to conduct continuous online rapid leak detection, and the detection efficiency is low. It cannot meet the online large-scale rapid and continuous detection of drug production and cannot be applied to the actual drug production process.

[0095] The leak detection test results of travoprost eye drops were similar to those of formoterol fumarate inhalation solution. By combining the method of rapid freezing of the drug solution before filling and then vacuum nitrogen filling and thawing and re-dissolving at room temperature with the method of adjusting the headspace volume in the bottle by 10%, and performing leak detection at a high voltage of 20~22 kV, the generation of high-voltage discharge impurities can be effectively eliminated, and the conditions for 100% detection of leaking samples can be met, which is basically consistent with the M-HLV low-voltage discharge leak detection effect.

[0096] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principle of the present invention should be included in the protection scope of the present invention.

Claims

1. A method for leak detection of low-concentration plastic ampoule-filled liquid medicine, characterized in that: The following steps are involved: First, freeze the liquid medicine in liquid nitrogen in a container, then fill the container with nitrogen in a vacuum environment, then thaw it at room temperature, and finally fill it with liquid medicine and adjust the headspace volume in the plastic ampoule to ≤10%, and perform high-pressure leak detection; The liquid medicine includes fortroleum fumarate inhalation solution or travoprost eye drops; The vacuum degree of the vacuum environment is 0.01-0.1 Pa; The nitrogen filling rate is 3-5 L / min, and the filling time is 10-30 min.

2. The method for detecting the leak tightness of a low-concentration plastic ampoule containing liquid medicine according to claim 1, characterized in that: The headspace volume in the bottle is adjusted by filling the ampoule with a volume of drug solution greater than or equal to 90% of the actual volume of the plastic ampoule.

3. The method for leak detection of low-concentration plastic ampoule-filled liquid medicine according to claim 1, characterized in that: The freezing treatment time is 10-30 min.

4. The method for leak detection of low-concentration plastic ampoule-filled liquid medicine according to claim 1, characterized in that: The voltage of the high-voltage leak detection is 20-22 kV.

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