Background
In the production process of medicines, 100% of integrity detection is required for liquid medicines bottled by plastic ampoule bottles according to requirements in the asepsis medicine rule of Chinese 2010 edition 'medicine production quality management Specification', and due to the requirement of automation, three methods commonly used in the conventional product production process comprise vacuum attenuation, headspace infrared spectrum and high-voltage discharge detection.
The vacuum attenuation method is to put the packaging container in a special testing cavity, vacuumize the testing cavity, the pressure difference between the inside and outside of the container causes the gas in the container to leak into the testing cavity through the leak hole, the pressure change value is compared with the reference value to judge whether the container is qualified or not, the testing time of each sample is about 1 min in practical operation, for the plastic ampoule medicines, the production batch is usually more than 10 ten thousand, at least 70 days are needed for each leak detection by adopting the method, the leak detection efficiency is too low to be suitable for mass medicine production detection, and meanwhile, the leak point is easy to be blocked for the high-viscosity medicines, so the method is not applicable. The headspace infrared spectrum is often used for detecting volatile organic compounds, can detect methane, ethanol, gasoline, benzene and the like, and has less leak detection application in the drug production process.
The high-voltage discharge equipment is characterized in that an emitter electrode and a receiving electrode are respectively arranged on two sides of a tested sample, and a preset high-voltage electric field is applied. In the ideal situation, i.e. when the package is intact, a large capacitance is formed between the emitter and the receiver due to the insulating action of the bottle wall, and only a weak induced current is generated. However, once there is a leak in the package (e.g., a minor breakage of the neck, bottom or body), the insulating barrier is broken, the capacitive effect weakens or even disappears, and a direct circuit is formed between the emitter and the receiver, resulting in a significant increase in the detected microcurrent. The sealing state of the medicine package is rapidly and accurately judged by accurately measuring and comparing the change of the micro current. And when the detected current value reaches or exceeds the limit value, the packaging leakage is judged, otherwise, the packaging leakage is qualified, and the working principle is shown in the figure 1.
The high-voltage discharge is efficient and accurate in detection, so that the method is the most common method for 100% integrity test of ampoule bottles in the pharmaceutical industry. It is surprising that the low concentration plastic ampoule bottles have significant impurity build up during the integrity test of the product. This result was similar not only in the plastic ampoule bottle of formoterol fumarate inhalation solution (active ingredient concentration of 0.00001) but also in the travoprost eye drops (active ingredient concentration of 0.00004), another low concentration drug studied by me. Therefore, the quality of low concentration drugs tested for integrity by high voltage discharge detection is at greater risk, especially when degraded impurities may cause teratogenic mutations.
In view of the above, there is a need to find a method to solve the problem that the impurity is increased in the high-voltage discharge leakage detection production process of the medicine filled and sealed in the plastic ampoule bottle due to the low concentration of formoterol fumarate inhalation solution.
Disclosure of Invention
In order to solve the technical problems, the invention aims to provide a leak detection method for sealing liquid medicine in low-concentration plastic ampoule bottles, so as to solve the problem that impurities are increased in the high-voltage discharge leak detection production process of the existing liquid medicine in low-concentration plastic ampoule bottles.
The technical scheme for solving the technical problems is as follows:
A leak detection method for sealing liquid medicine in a low-concentration plastic ampoule bottle comprises the following steps:
The liquid medicine is frozen in liquid nitrogen in a container, then nitrogen is filled into the container in a vacuum environment, the container is thawed at room temperature, and finally the liquid medicine is filled, the headspace volume in a plastic ampoule bottle is adjusted to be less than or equal to 10%, and high-pressure leak detection is carried out.
The invention has the beneficial effects that the liquid medicine filling and packaging of the plastic ampoule bottle are carried out by adjusting the volume of the head space in the ampoule bottle to be less than or equal to 10 percent and combining the modes of freezing and re-dissolving and nitrogen filling in a vacuum environment, and then the high-pressure leak detection is carried out, so that the generation of impurities in the leak detection process is effectively avoided.
Further, the headspace volume in the bottle is adjusted by filling a liquid medicine which is more than or equal to 90% of the actual volume of the plastic ampoule bottle.
The technical scheme has the advantages that the method can finish the quick adjustment of the headspace in the liquid medicine bottle of the low-concentration plastic ampoule bottle by simply adjusting the filling and sealing amount of the liquid medicine in the filling and sealing process of the liquid medicine, reduces impurities generated by high-pressure leakage detection, has a simple and quick treatment method, and is suitable for large-scale use in production.
Further, the medicinal liquid comprises a ford fumarate inhalation solution or travoprost eye drops.
The beneficial effects of adopting the further technical scheme are as follows:
In the production process of the futrole fumarate inhalation solution and the travoprost eye drops, the impurity is found to be obviously increased (0 percent is increased to 2 percent) after the product is subjected to high-voltage discharge leakage detection, the quality requirement of the product is not met, the impurity does not belong to known degradation impurities of the futrole fumarate and the travoprost eye drops or process impurities in the production process, whether the impurity can generate potential safety hazards or not is difficult to judge, and a method for effectively controlling the generation of the impurity is needed.
Through the mode that reduces high-pressure discharge detection voltage (reduce to 18~20 kV), under the circumstances that guarantees can detect out the weeping product, though can reduce the impurity production after the leak hunting to a certain extent, still can not satisfy the quality requirement of medicine, and there is the condition that can not 100% detect out the weeping product. According to the invention, the filling specification of the medicine is adjusted to ensure that the volume of the head space in the ampoule bottle is less than or equal to 10%, the vacuum nitrogen filling treatment is carried out after quick freezing of the medicine liquid before filling, and finally the medicine liquid filling processing is carried out in a thawing and re-dissolving mode.
Further, the time of the freezing treatment is 10-30 min.
Further, the vacuum degree of the vacuum environment is 0.01-0.1 Pa.
Further, the filling speed of the nitrogen is 0.1-5L/min, and the filling time is 10-30 min.
Further, the voltage of the high-voltage leakage detection is 20-22 kV.
The invention has the following beneficial effects:
The invention provides a leak detection method for sealing liquid medicine in a low-concentration plastic ampoule bottle, which effectively eliminates the generation of impurities in the high-voltage discharge leak detection process by adjusting the headspace volume in the plastic ampoule bottle to be less than or equal to 10 percent and performing quick freezing, vacuum nitrogen filling and final thawing and re-dissolving on the liquid medicine, ensures 100 percent detection of a leak sample, and can meet the continuous online quick leak detection requirement of medicines in mass production.
Drawings
FIG. 1 is a schematic diagram of the high pressure leak detection principle;
FIG. 2 is a graph showing the results of the liquid chromatography test in example 1;
FIG. 3 is a graph showing the results of the liquid chromatography test in example 2;
FIG. 4 is a graph showing the results of the liquid chromatography test prior to high-voltage discharge in comparative example 1;
FIG. 5 is a graph showing the results of liquid chromatography after high-voltage discharge in comparative example 1;
FIG. 6 is a graph showing the results of liquid chromatography in comparative example 2;
FIG. 7 is a graph showing the results of liquid chromatography in comparative example 3;
FIG. 8 is a graph showing the results of liquid chromatography in comparative example 4;
FIG. 9 is a graph showing the results of liquid chromatography in comparative example 5;
FIG. 10 is a graph showing the results of liquid chromatography in comparative example 6;
FIG. 11 is a graph showing the results of liquid chromatography in comparative example 7;
FIG. 12 is a graph showing the results of liquid chromatography in comparative example 8;
FIG. 13 is a graph showing the results of liquid chromatography in comparative example 9;
FIG. 14 is a graph showing the results of liquid chromatography test in comparative example 10;
FIG. 15 is a graph showing the results of liquid chromatography detection before high-voltage discharge in comparative example 11;
FIG. 16 is a graph showing the results of liquid chromatography after high-voltage discharge in comparative example 11;
FIG. 17 is a graph showing the results of liquid chromatography in comparative example 12;
FIG. 18 is a graph showing the results of liquid chromatography in comparative example 13;
FIG. 19 is a graph showing the results of liquid chromatography test in comparative example 14;
FIG. 20 is a graph showing the results of liquid chromatography test in comparative example 15;
FIG. 21 is a graph showing the results of liquid chromatography in comparative example 16;
FIG. 22 is a graph showing the results of liquid chromatography in comparative example 17;
FIG. 23 is a graph showing the results of liquid chromatography in comparative example 18.
Detailed Description
The principles and features of the present invention are described below with reference to the drawings, the examples are illustrated for the purpose of illustrating the invention and are not to be construed as limiting the scope of the invention. The specific conditions are not noted in the examples and are carried out according to conventional conditions or conditions recommended by the manufacturer. The reagents or apparatus used were conventional products commercially available without the manufacturer's attention.
Example 1:
a method for reducing high-voltage discharge leakage detection impurities of formoterol fumarate inhalation solution of low-concentration plastic ampoule bottled liquid medicine comprises the following steps:
The method comprises the steps of preparing formoterol fumarate inhalation solution liquid medicine according to a formoterol fumarate inhalation solution prescription developed by Dou Pushen pharmaceutical company, placing a container filled with the liquid medicine in liquid nitrogen for quick freezing treatment of 20 min, filling nitrogen at a speed of 4L/min under a vacuum environment of 0.05 Pa for 20 min, thawing at room temperature, carrying out liquid medicine primary filtration (polyvinylidene fluoride model LHPVND0022HSF10SP filter core of class 1 0.22 mu m of Kebaite, requiring filtration pressure difference <0.2 Mpa), degerming filtration (polyvinylidene fluoride model LHPVND HSF10SP filter core of class 2.22 mu m of Kebaite, requiring filtration pressure difference <0.2 Mpa), then carrying out BFS filling of 2mL (BFS blowing filling and sealing integrated machine of American color filter), filling volume of 2.16 mL, finally carrying out lamp inspection and 20-22 kV high-voltage discharge (adopting Japan Nicard HDI-14+Gastroma), and carrying out leak detection on liquid medicine detection samples, as shown in a leak detection result of a liquid chromatography detection chart.
Example 2:
A method for reducing high-voltage discharge leakage detection impurities of a low-concentration plastic ampoule bottled liquid medicine travoprost eye drops comprises the following steps:
The method comprises the steps of preparing travoprost eye drops according to a travoprost eye drop prescription developed by Dou Pushen pharmaceutical limited company, placing a container filled with liquid medicine in liquid nitrogen for quick freezing treatment of 20min, filling nitrogen at a speed of 4L/min under a vacuum environment of 0.05 Pa for 20min, thawing at room temperature, performing liquid medicine primary filtration (polyvinylidene fluoride model LHPVND0022HSF10SP filter core of class 1 0.22 mu m of Kebaite, requiring filtration pressure difference <0.2 Mpa), degerming filtration (polyvinylidene fluoride model LHPVND HSF10SP filter core of class 2.22 mu m of Kebaite, requiring filtration pressure difference <0.2 Mpa), filling liquid medicine into a plastic ampoule of 0.4 mL specification (BFS blowing filling and sealing machine of American Weiler), filling liquid medicine volume of 0.54 mL, performing lamp inspection and 20-22 high voltage leakage detection (using Nicard HDI-14 high voltage detection), and performing liquid chromatography detection results as shown in a liquid chromatography detection result. (RT 4.2 known degradation impurities for API)
Comparative example 1:
A method for detecting impurities by high-voltage discharge of formoterol fumarate inhalation solution of low-concentration plastic ampoule bottled liquid medicine comprises the following steps:
The liquid medicine processing method is the same as in example 1, except that the freezing, nitrogen charging and thawing treatment are not performed, the liquid medicine filling volume is 2 mL, the specification of the plastic ampoule is 5mL (actual volume is 7.6 mL), the high-voltage discharge leakage detection is performed at 22-24 kV, the liquid chromatography detection is performed on samples before and after the leakage detection, and the detection results are shown in fig. 4 and 5. (in FIG. 4, RT8.5 is benzaldehyde remaining in the production line, RT17.8 is an API-known degradation impurity)
Comparative examples 2 to 3:
a method for reducing high-voltage discharge leakage detection impurities of formoterol fumarate inhalation solution of low-concentration plastic ampoule bottled liquid medicine comprises the following steps:
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), respectively, and the detection results are shown in fig. 6 and 7.
Comparative examples 4 to 5:
a method for reducing high-voltage discharge leakage detection impurities of formoterol fumarate inhalation solution of low-concentration plastic ampoule bottled liquid medicine comprises the following steps:
The treatment method is the same as in comparative example 1, except that the liquid medicine after filling is directly subjected to nitrogen charging treatment without freezing and thawing, the nitrogen charging time is 15 min (comparative example 4) and 20 min (comparative example 5), the leakage detection is carried out by 18-20 kV high-voltage discharge, the liquid chromatography detection is carried out on the sample after the leakage detection, and the detection results are shown in fig. 8 and 9.
Comparative examples 6 to 8:
a method for reducing high-voltage discharge leakage detection impurities of formoterol fumarate inhalation solution of low-concentration plastic ampoule bottled liquid medicine comprises the following steps:
The treatment method is the same as in comparative example 1, except that the specification of the plastic ampoule is changed to 5mL (actual volume 7.6 mL), 2 mL (comparative example 6), 4 mL (comparative example 7) and 5mL (comparative example 8) are respectively filled, 20-22 kV high-voltage discharge leakage detection is carried out, and liquid chromatography detection is carried out on the samples after the leakage detection, wherein the detection results are shown in fig. 10-12.
Comparative example 9:
a method for reducing high-voltage discharge leakage detection impurities of formoterol fumarate inhalation solution of low-concentration plastic ampoule bottled liquid medicine comprises the following steps:
the treatment method is the same as in 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 is 2.4 mL), the leakage detection is carried out by 20-22 kV high-voltage discharge, the liquid chromatography detection is carried out on the sample after the leakage detection, and the detection result is shown in figure 13.
Comparative example 10:
A method for reducing low-voltage discharge leakage detection impurities of formoterol fumarate inhalation solution of low-concentration plastic ampoule bottled liquid medicine comprises the following steps:
the liquid medicine processing method is the same as comparative example 9, except that the leakage detection is carried out by using an M-HLV low-pressure leakage detector, the leakage detection voltage is 8 kV, the liquid chromatography detection is carried out on the sample after the leakage detection, and the detection result is shown in figure 14.
Comparative example 11:
A method for detecting impurities by high-voltage discharge of a low-concentration plastic ampoule bottled liquor travoprost eye drops comprises the following steps:
the liquid medicine processing method is the same as in example 2, except that the freezing, nitrogen charging and thawing treatment are not performed, the liquid medicine filling volume is 0.4 mL, the high-voltage discharge leakage detection is performed at 22-24 kV, the liquid chromatography detection is performed on samples before and after the leakage detection, and the detection results are shown in fig. 15 and 16.
Comparative example 12:
A method for reducing high-voltage discharge leakage detection impurities of a low-concentration plastic ampoule bottled liquid medicine travoprost eye drops comprises the following steps:
the treatment method is similar to that of comparative example 11, the difference is that the discharge leakage detection voltage is changed to 18-20 kV, and the liquid chromatography detection is carried out on the sample after leakage detection, and the detection result is shown in figure 17.
Comparative examples 13 to 14:
A method for reducing high-voltage discharge leakage detection impurities of a low-concentration plastic ampoule bottled liquid medicine travoprost eye drops comprises the following steps:
The treatment method is the same as in comparative example 11, except that the liquid medicine after filling is directly subjected to nitrogen charging treatment without freezing and thawing, the nitrogen charging time is 15min (comparative example 13) and 20min (comparative example 14), the leakage detection is carried out by 18-20 kV high-voltage discharge, the liquid chromatography detection is carried out on the sample after the leakage detection, and the detection results are shown in fig. 18 and 19.
Comparative examples 15 to 16:
A method for reducing high-voltage discharge leakage detection impurities of a low-concentration plastic ampoule bottled liquid medicine travoprost eye drops comprises the following steps:
the treatment method is the same as that of comparative example 11, the specification of the filled plastic ampoule is modified to 0.8 mL (actual volume 1.0 mL), the liquid medicines of 0.5 mL (comparative example 15) and 0.7 mL (comparative example 16) are respectively filled, 20-22 kV high-voltage discharge leakage detection is carried out, liquid chromatography detection is carried out on the samples after leakage detection, and the detection results are shown in fig. 20 and 21.
Comparative example 17:
A method for reducing high-voltage discharge leakage detection impurities of a low-concentration plastic ampoule bottled liquid medicine travoprost eye drops comprises the following steps:
the treatment method was the same as in example 2 except that the filling liquid volume was changed to 0.42 mL, and the detection result was shown in fig. 22.
Comparative example 18:
a method for reducing leakage detection impurities of low-pressure discharge of travoprost eye drops of liquid medicine filled in low-concentration plastic ampoule bottles comprises the following steps:
The treatment method is the same as in comparative example 11, except that the leakage detection is performed by using an M-HLV low-pressure leakage detector, the leakage detection voltage is 8 kV, and the liquid chromatography detection is performed on the sample after the leakage detection, and the detection result is shown in FIG. 23.
Test example:
The results of high-voltage discharge impurity detection and the leakage sample detection of the samples prepared in examples and comparative examples are shown in table 1, and the high-voltage discharge impurity content is mass fraction.
TABLE 1 detection results of high voltage discharge impurities and detection conditions of leakage samples
As shown in the table and figures 1-22, for the leakage detection of formoterol fumarate inhalation solution products, after conventional 22-24 kV high-voltage discharge leakage detection, impurities with mass fraction of 2.2% are generated, the safety and quality of the medicine are affected, after depressurization 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 can not be completely avoided, and the condition that a leakage sample can not be detected by 100% can be generated when the voltage is too low. The method for filling nitrogen into the liquid medicine before filling can also effectively reduce the generation of high-voltage discharge impurities to 0.23 percent (4L/min for filling nitrogen 15 min) and 0.12 percent (4L/min for filling nitrogen 20 min), but still has more impurity residues. The mode of changing the volume of the head space in the bottle can also effectively reduce the generation of high-voltage discharge impurities by adjusting the medicine loading amount, when the head space in the bottle is 10%, the impurity content is effectively reduced to 0.02%, and the ICH requirement is met, but because trace high-voltage discharge impurities still exist, the risk which cannot be predicted is generated when a patient uses the bottle for a long time. According to the invention, the mode of quickly freezing the liquid medicine before filling and then carrying out vacuum nitrogen filling and room temperature thawing and redissolving is combined with the mode of adjusting the volume of the head space in the bottle by 10%, and the leak detection is carried out at a high voltage of 20-22 kV, so that the generation of high-voltage discharge impurities can be effectively stopped, the 100% detection condition of a liquid leakage sample can be met, and the leakage detection effect is basically consistent with that of M-HLV low-voltage discharge, but because the M-HLV low-voltage discharge leak detection equipment is only suitable for laboratory single medicine inspection, the continuous online quick leak detection cannot be realized, the detection efficiency is low, the online large-batch quick continuous detection of medicine production cannot be met, and the leakage detection equipment cannot be applied to the actual medicine production process.
The leak detection experimental result of the travoprost eye drop is similar to the result of formoterol fumarate inhalation solution, the mode of vacuum nitrogen charging and room temperature thawing re-dissolution after quick freezing of the liquid medicine before filling is combined with the mode of adjusting the volume of the head space in the bottle by 10%, and leak detection is carried out at a high voltage of 20-22 kV, so that the generation of high-voltage discharge impurities can be effectively stopped, the condition of 100% detection of a liquid leakage sample can be met, and the leak detection effect is basically consistent with that of M-HLV low-voltage discharge leak detection.
The foregoing description of the preferred embodiments of the invention is not intended to limit the invention to the precise form disclosed, and any such modifications, equivalents, and alternatives falling within the spirit and scope of the invention are intended to be included within the scope of the invention.