CN110793730A - Method for analyzing package integrity of injection by color water method - Google Patents
Method for analyzing package integrity of injection by color water method Download PDFInfo
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- CN110793730A CN110793730A CN201911148053.7A CN201911148053A CN110793730A CN 110793730 A CN110793730 A CN 110793730A CN 201911148053 A CN201911148053 A CN 201911148053A CN 110793730 A CN110793730 A CN 110793730A
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- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 title claims abstract description 62
- 238000002347 injection Methods 0.000 title claims abstract description 47
- 239000007924 injection Substances 0.000 title claims abstract description 47
- 238000000034 method Methods 0.000 title claims abstract description 34
- 239000000243 solution Substances 0.000 claims abstract description 56
- 238000002835 absorbance Methods 0.000 claims abstract description 39
- 239000003814 drug Substances 0.000 claims abstract description 27
- 239000007864 aqueous solution Substances 0.000 claims abstract description 24
- 229930182555 Penicillin Natural products 0.000 claims abstract description 20
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 claims abstract description 20
- 229940049954 penicillin Drugs 0.000 claims abstract description 20
- 238000001514 detection method Methods 0.000 claims abstract description 18
- 239000007788 liquid Substances 0.000 claims abstract description 18
- 238000004458 analytical method Methods 0.000 claims abstract description 16
- 238000012360 testing method Methods 0.000 claims abstract description 8
- 238000002360 preparation method Methods 0.000 claims abstract description 5
- 239000000523 sample Substances 0.000 claims description 93
- 239000010453 quartz Substances 0.000 claims description 37
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicon dioxide Inorganic materials O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 37
- 239000008213 purified water Substances 0.000 claims description 27
- 239000013641 positive control Substances 0.000 claims description 21
- 238000007789 sealing Methods 0.000 claims description 16
- 229960000907 methylthioninium chloride Drugs 0.000 claims description 15
- 238000001291 vacuum drying Methods 0.000 claims description 15
- 238000004140 cleaning Methods 0.000 claims description 11
- 230000000149 penetrating effect Effects 0.000 claims description 11
- 239000004033 plastic Substances 0.000 claims description 11
- 238000005520 cutting process Methods 0.000 claims description 9
- 239000003292 glue Substances 0.000 claims description 9
- 238000005406 washing Methods 0.000 claims description 9
- 239000012528 membrane Substances 0.000 claims description 4
- 239000013642 negative control Substances 0.000 claims description 4
- 239000011148 porous material Substances 0.000 claims description 4
- 239000012088 reference solution Substances 0.000 claims description 4
- 238000010521 absorption reaction Methods 0.000 claims description 3
- 238000005086 pumping Methods 0.000 claims description 3
- 239000012488 sample solution Substances 0.000 claims description 3
- 238000012216 screening Methods 0.000 claims description 3
- 238000003556 assay Methods 0.000 claims description 2
- 238000007865 diluting Methods 0.000 claims description 2
- 238000010790 dilution Methods 0.000 claims description 2
- 239000012895 dilution Substances 0.000 claims description 2
- 238000001914 filtration Methods 0.000 claims description 2
- 238000005303 weighing Methods 0.000 claims description 2
- RBTBFTRPCNLSDE-UHFFFAOYSA-N 3,7-bis(dimethylamino)phenothiazin-5-ium Chemical compound C1=CC(N(C)C)=CC2=[S+]C3=CC(N(C)C)=CC=C3N=C21 RBTBFTRPCNLSDE-UHFFFAOYSA-N 0.000 claims 5
- 230000035945 sensitivity Effects 0.000 abstract description 4
- XQAXGZLFSSPBMK-UHFFFAOYSA-M [7-(dimethylamino)phenothiazin-3-ylidene]-dimethylazanium;chloride;trihydrate Chemical compound O.O.O.[Cl-].C1=CC(=[N+](C)C)C=C2SC3=CC(N(C)C)=CC=C3N=C21 XQAXGZLFSSPBMK-UHFFFAOYSA-M 0.000 description 11
- 238000004806 packaging method and process Methods 0.000 description 9
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 7
- 229940079593 drug Drugs 0.000 description 6
- 239000000843 powder Substances 0.000 description 4
- 230000000052 comparative effect Effects 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 239000005022 packaging material Substances 0.000 description 3
- 230000009286 beneficial effect Effects 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 230000036512 infertility Effects 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 238000005457 optimization Methods 0.000 description 2
- 239000000825 pharmaceutical preparation Substances 0.000 description 2
- 229940127557 pharmaceutical product Drugs 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 239000004094 surface-active agent Substances 0.000 description 2
- AFCARXCZXQIEQB-UHFFFAOYSA-N N-[3-oxo-3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propyl]-2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carboxamide Chemical compound O=C(CCNC(=O)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)N1CC2=C(CC1)NN=N2 AFCARXCZXQIEQB-UHFFFAOYSA-N 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 238000004737 colorimetric analysis Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000000813 microbial effect Effects 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000004904 shortening Methods 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
Classifications
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01M—TESTING STATIC OR DYNAMIC BALANCE OF MACHINES OR STRUCTURES; TESTING OF STRUCTURES OR APPARATUS, NOT OTHERWISE PROVIDED FOR
- G01M3/00—Investigating fluid-tightness of structures
- G01M3/02—Investigating fluid-tightness of structures by using fluid or vacuum
- G01M3/04—Investigating fluid-tightness of structures by using fluid or vacuum by detecting the presence of fluid at the leakage point
- G01M3/20—Investigating fluid-tightness of structures by using fluid or vacuum by detecting the presence of fluid at the leakage point using special tracer materials, e.g. dye, fluorescent material, radioactive material
- G01M3/22—Investigating fluid-tightness of structures by using fluid or vacuum by detecting the presence of fluid at the leakage point using special tracer materials, e.g. dye, fluorescent material, radioactive material for pipes, cables or tubes; for pipe joints or seals; for valves; for welds; for containers, e.g. radiators
- G01M3/226—Investigating fluid-tightness of structures by using fluid or vacuum by detecting the presence of fluid at the leakage point using special tracer materials, e.g. dye, fluorescent material, radioactive material for pipes, cables or tubes; for pipe joints or seals; for valves; for welds; for containers, e.g. radiators for containers, e.g. radiators
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
- G01N21/17—Systems in which incident light is modified in accordance with the properties of the material investigated
- G01N21/25—Colour; Spectral properties, i.e. comparison of effect of material on the light at two or more different wavelengths or wavelength bands
- G01N21/31—Investigating relative effect of material at wavelengths characteristic of specific elements or molecules, e.g. atomic absorption spectrometry
- G01N21/33—Investigating relative effect of material at wavelengths characteristic of specific elements or molecules, e.g. atomic absorption spectrometry using ultraviolet light
Abstract
The invention discloses an analysis method for the package integrity of an injection by a color water method, which comprises the following steps: placing the injection packaged in a penicillin bottle in a colored aqueous solution with a certain concentration, placing for a certain time under a proper vacuum condition, taking out the injection and placing at normal pressure, comparing the absorbance values of the liquid medicine and the limiting solution, and judging the result. Compared with the existing color water method, the preparation method of the test sample provided by the invention effectively solves the limit problem of the detection of the package integrity of the injection sample, is simple and convenient to operate and high in sensitivity, and has very important significance for ensuring that the product keeps the integrity of a container in the shelf life.
Description
Technical Field
The invention relates to the field of penicillin bottle package integrity detection, in particular to an analysis method for detecting the penicillin bottle package integrity by a color water method.
Technical Field
The sterile medicine refers to preparations and raw material medicines listed in the legal medicine standard with sterility test items, and comprises sterile preparations and sterile raw material medicines. To demonstrate the sterility of parenteral products, it is important to maintain container integrity over the shelf life of the product.
The container of the sterile pharmaceutical product should have a perfect seal against microbial ingress throughout the pharmaceutical product's useful life. The seal integrity test is used for detecting cracks or seal leakage and evaluating the product package tightness, and has important significance for fully protecting the aseptic state of the product in the storage period. The color water method is an economic, simple, reliable and high-sensitivity leak detection method for package integrity, but the color water method is used for detecting the package integrity, particularly the integrity of penicillin bottles, and related patents and literature reports are few, and the method is lack of optimization of detection parameters of the color water method, determination of detection limit and other reports.
Disclosure of Invention
In order to overcome the defect of detecting the integrity of the packaging of the penicillin bottle by the conventional color water method, the invention provides a novel detection method, and the method is ensured to be suitable for the stability monitoring of the penicillin bottle by verifying the specificity (selectivity and interference), linearity, LOD, LOQ and limit.
The invention provides a method for analyzing the package integrity of an injection by a color water method, which comprises the following steps:
and (3) placing the injection packaged in a penicillin bottle into a colored aqueous solution with a certain concentration, placing for a certain time under a proper vacuum condition, taking out, further placing at normal pressure, comparing the absorbance values of the liquid medicine and the limiting solution, and judging the result.
The invention relates to an analysis method for package integrity of an injection by a color water method, wherein a color water solution is a methylene blue solution, and the concentration of the methylene blue solution is 1 mg/mL. The control solution was 2. mu.g/mL methylene blue in water. Both of them should be prepared immediately before use.
The invention relates to a method for analyzing the integrity of an injection color water method package, wherein a limiting solution is obtained by diluting a color water solution with a liquid medicine, and the concentration of the limiting solution is not less than the LOQ concentration; the absorbance value of the limiting solution is that when sample detection and result judgment are carried out, the ultraviolet absorption of the reference solution and the ultraviolet absorption of the limiting solution are respectively scanned within the wavelength range of 664 +/-2 nm by taking the liquid medicine as a blank.
According to the method for analyzing the package integrity of the injection by the color water method, the proper vacuum condition is that the vacuum degree is pumped to below 50mb, preferably 35mb +/-5 mb; the vacuum condition is kept for more than 15 hours, preferably 15 to 18 hours; the standing at normal pressure needs 4 to 24 hours, preferably 6 to 8 hours, and most preferably 6 hours.
The invention relates to a method for analyzing the integrity of an injection by a color water method, wherein a limiting solution is prepared by the following steps:
randomly taking 20 injection samples, standing for 15h under the vacuum condition of 35mb +/-5 mb, and standing for 6h under normal pressure; removing the label and the plastic cover of the injection sample, repeatedly cleaning the sample for 5 times by using purified water, penetrating a rubber plug by using a 21G needle, penetrating a 10-micron quartz capillary tube through the hole of the needle, pulling out the 21G needle, keeping the quartz capillary tube in the rubber plug, cutting off the quartz capillary tube remained outside the injection bottle at a position about 0.5cm away from the rubber plug, and sealing the gap between the quartz capillary tube and the rubber plug by using 101 glue; putting the sample in a clean beaker, and adding a proper amount of 1mg/mL color water solution to completely immerse the sample; placing the beaker in a vacuum drying box, vacuumizing to the vacuum degree of 35mb +/-5 mb, maintaining the vacuum degree of 35mb +/-5 mb for 15 hours, recovering for 6 hours under normal pressure, washing the sample with purified water for 3 times to ensure that the outer wall of the sample is washed cleanly without obvious color residue, sucking a proper amount of liquid medicine by a new injector, and measuring the absorbance value;
the sample is placed for 15 hours under the vacuum condition of 35mb +/-5 mb, is placed for 6 hours under normal pressure, contains 5mL of liquid medicine, and the minimum absorbance value of a positive control sample of 15 penicillin bottles with the specification of 5mL is further reduced to be below 1/5 of the minimum absorbance value, meanwhile, the absorbance value of the limit solution is ensured to be larger than the LOQ of an instrument, and finally, the limit solution concentration with proper dilution times is selected.
The invention also provides a preferable technical scheme, and the method for analyzing the package integrity of the injection by the color water method comprises the following steps:
preparing a color water solution: weighing a proper amount of methylene blue, dissolving the methylene blue by using purified water, and filtering the methylene blue by using a filter membrane of 0.22 mu m to obtain a 1mg/mL colored aqueous solution a;
group a negative control samples: taking 3 injection samples which are not destroyed in penicillin bottles and are not immersed in the color water solution to prepare a negative control solution;
① pricking holes, removing a label and a plastic cover, repeatedly cleaning the sample for at least 5 times by using purified water, penetrating a 10-micron quartz capillary tube through a rubber plug, cutting off the quartz capillary tube remained outside an injection bottle at a position about 0.5cm away from the rubber plug, sealing a gap between the quartz capillary tube and the rubber plug by using 101 glue, ② screening, namely placing the sample in a clean beaker, adding a proper amount of purified water to completely immerse the sample, placing the beaker in a vacuum drying box, vacuumizing to below 50mb, maintaining for 5min, observing the bubble emergence speed, immediately recovering normal pressure, removing the sample without bubble emergence, and quickly emerging the residual bubbles from the pore of the capillary tube to obtain a qualified positive control sample, ③ detecting, namely placing the qualified positive control sample in the clean beaker, treating the positive control sample according to a preparation method of a sample solution, adding a proper amount of 1mg/mL of a water solution in a to completely immerse the sample, sealing the beaker, placing the beaker in a plurality of small vacuum drying boxes, vacuumizing to a vacuum drying box, continuously extracting the sample for 5 hours, preferably 35-5 hours, continuously extracting the sample with a proper amount of a pure water solution, preferably 35-5 hours, and continuously washing the sample with a syringe with a proper amount of a clean water solution with a vacuum of less than 35 hours and a vacuum degree of less than 35 hours, and a clean syringe, and a proper amount of less than 5 hours, and a clean syringe, wherein the sample is preferably less than 35 hours;
group C test samples: randomly taking 30 injection samples, and dividing the samples into three groups, namely A1 positive placement, A2 reverse placement and A3 flat placement, wherein each group comprises 10 samples; removing the label and the plastic cover, repeatedly cleaning the sample for at least 5 times by using purified water, placing the sample in a clean beaker, adding a proper amount of 1mg/mL colored aqueous solution a in the solution a to completely immerse the sample, sealing the beaker by using a sealing film and pricking a plurality of small holes; placing the beaker in a vacuum drying box, vacuumizing to below 50mb, preferably 35mb +/-5 mb, maintaining the vacuum degree of below 50mb, preferably below 35mb +/-5 mb for at least 15 hours, quickly recovering to normal pressure, continuously placing for 4-24 hours, preferably 6 hours, taking out, washing the sample with purified water for 3 times to ensure that the outer wall is washed clean without obvious color residues, and sucking a proper amount of liquid medicine as a test sample solution by using a new syringe;
sample detection and result judgment: and under the wavelength of 664nm +/-2 nm, using the liquid medicine as a blank, establishing system applicability by using a reference solution, respectively measuring the absorbance values of A, B, C groups of samples, and judging that the sample is qualified if the absorbance value of the C group of samples is less than the average absorbance value of the limit solution read for 3 times.
The invention has the beneficial technical effects that:
1. a10 μm pore was made on the vial packaging material as a positive control sample. And (3) immersing the positive control sample in the colored aqueous solution, optimizing the vacuum degree, the vacuum standing time and the normal-pressure standing time, ensuring that the analysis method can detect the leakage hole with the diameter of 10 mu m on the packaging material, overcoming the defect of detecting the packaging integrity of the penicillin bottle by the conventional colored aqueous solution method, and having simple and convenient operation and reliable result.
2. The analysis method provided by the invention ensures that the absorbance value of the color aqueous solution permeating into the positive control sample bottle is more than 5 times of LOQ by optimizing the vacuum degree, the vacuum standing time and the normal pressure standing time, further reduces the limit value to be not less than LOQ, and further determines the concentration of the limit solution so as to better ensure the detection capability of the method on the package integrity.
3. According to the analysis method provided by the invention, when the packaging specifications and the loading amount of the medicines are different, the minimum absorbance values of the positive control samples placed under the same condition are different. Therefore, the vacuum degree, the vacuum standing time and the normal pressure standing time of the medicines with different packaging specifications and loading quantities need to be optimized through a positive control experiment respectively, and the absorbance value of the color aqueous solution permeating into the positive control sample bottle is ensured to be more than 5 times of LOQ.
4. The analysis method has important significance for detecting the integrity of the injection package. The method can simply and accurately determine the integrity of the packaging of the penicillin bottle, ensure the quality of the medicine, reduce potential risks and be widely applied to product detection.
Detailed Description
The following specific examples are given for a more complete understanding of the present invention, but the present invention is not limited to the following examples.
Experimental materials and instruments experimental materials:
reagent: methylene blue trihydrate, indicator, Shanghai-derived leaf Biotech, Inc.; sodium Dodecyl Sulfate (SDS), surfactant, alatin reagent (shanghai) ltd;
the instrument comprises the following steps: a vacuum drying oven; a UV1800 ultraviolet spectrophotometer; quartz capillary, 10 μm, Polymicro.
All positive controls in the comparative examples and examples were screened for eligibility.
Comparative example 1:
the operation steps are as follows:
preparing a color water solution: a proper amount of methylene blue powder is precisely weighed, dissolved by purified water and filtered by a filter membrane of 0.22 mu m to prepare a 1mg/mL colored aqueous solution.
Taking 5 injection samples, removing labels and plastic covers, repeatedly cleaning the samples with purified water for 5 times, allowing a 10-micron quartz capillary tube to penetrate through a rubber plug, cutting off the quartz capillary tube remained outside the injection bottle at a position about 0.5cm away from the rubber plug, and sealing a gap between the quartz capillary tube and the rubber plug by using 101 glue. The sample was then placed in a clean beaker and the appropriate amount of 1mg/mL of colored aqueous solution was added to completely immerse the sample. With reference to the specification under the < USP >1207 package tightness test technique, the beaker is placed in a vacuum drying oven and evacuated to 270mb for 30 min. Immediately returning to normal pressure, continuously standing for 30min, taking out, washing the outer wall with purified water for at least 5 times, and ensuring that the outer wall and the rubber plug are washed clean. And (5) extracting the solution in the penicillin bottle by using a new syringe, and measuring the absorbance.
The experimental results show that: the quartz capillary tube with the diameter of 10 mu m is placed for 30min under the condition of 270mb vacuum degree, the quartz capillary tube is placed for 30min under normal pressure, and the absorbance values of 5 injection samples are all lower than the detection limit, which indicates that the vacuum condition and time can not effectively detect the pores with the diameter of about 10 mu m on the packaging material of the penicillin bottle, and indicates that the method has insufficient sensitivity.
Comparative example 2:
the operation steps are as follows:
preparing an SDS color aqueous solution: a proper amount of methylene blue powder and SDS powder were precisely weighed, dissolved in purified water, and filtered through a 0.22 μm filter to prepare a chromous aqueous solution containing 2.5mg/mL SDS and 1mg/mL methylene blue.
Taking 5 injection samples, removing labels and plastic covers, repeatedly cleaning the samples with purified water for 5 times, allowing a 10-micron quartz capillary tube to penetrate through a rubber plug, cutting off the quartz capillary tube remained outside the injection bottle at a position about 0.5cm away from the rubber plug, and sealing a gap between the quartz capillary tube and the rubber plug by using 101 glue. The sample was then placed in a clean beaker and an appropriate amount of 2.5mg/mL SDS-colored aqueous solution was added to completely immerse the sample. Placing the beaker in a vacuum drying oven, vacuumizing to 270mb, and maintaining for 30 min. Immediately returning to normal pressure, continuously standing for 30min, taking out, washing the outer wall with purified water for at least 5 times, and ensuring that the outer wall and the rubber plug are washed clean. And extracting the solution in the penicillin bottle by using a new syringe, and measuring the absorbance value.
The experimental results are as follows: placing 10 μm quartz capillary tube under 270mb vacuum degree for 30min, and placing at normal pressure for 30min, wherein the absorbance values of 5 injection samples are all below the detection limit. SDS is used as a surfactant, has the function of reducing the surface tension of the aqueous solution, and further promotes the aqueous solution to enter the penicillin bottle through the capillary. This result indicates that the addition of SDS does not promote the entry of the aqueous color solution, and the sensitivity of the method is still insufficient.
Example 1:
the operation steps are as follows:
preparing a color water solution: a proper amount of methylene blue powder is precisely weighed, dissolved by purified water and filtered by a filter membrane of 0.22 mu m to prepare a 1mg/mL colored aqueous solution.
20 injection samples of 5mL size and loading were randomly taken and divided into 4 groups of 5 samples each. Removing the label and plastic cover of the injection sample, repeatedly cleaning the sample with purified water for 5 times, penetrating the rubber plug with a 21G needle, penetrating a 10-micron quartz capillary tube through the hole of the needle, pulling out the 21G needle, keeping the quartz capillary tube in the rubber plug, cutting off the quartz capillary tube remained outside the injection bottle at a position about 0.5cm away from the rubber plug, and sealing the gap between the quartz capillary tube and the rubber plug with 101 glue. The sample was placed in a clean beaker and the appropriate amount of 1mg/mL of colored aqueous solution was added to completely immerse the sample. The beaker was placed in a vacuum drying oven and evacuated to a vacuum of 35 mb. + -. 5mb, and the time for maintaining the vacuum degree and the recovery time under normal pressure for 4 groups of injection samples are shown in Table 1. After the end, the sample is washed by purified water for 3 times to ensure that the outer wall of the sample is washed cleanly without obvious color residue, a proper amount of liquid medicine is absorbed by a new injector, and the absorbance value is measured, and the result is shown in table 1.
TABLE 1 vacuum time screening
The results in table 1 above illustrate that: the longer the vacuum degree maintaining time is, the higher the absorbance value of the sample is, by adopting a 10-micron quartz capillary tube under the condition of 35mb +/-5 mb vacuum degree. The selected vacuumizing time is 15 hours, and the light absorbance value and the operation are both considered. The high vacuum degree is selected to be beneficial to shortening the vacuum-pumping time, but the vacuum degree is lower than 30mb to cause boiling of the color water solution, so the vacuum degree of 35mb +/-5 mb is selected to carry out experiments.
Example 2:
the operation steps are as follows: 20 injection samples of 5mL size and loading were randomly taken and divided into 4 groups of 5 samples each. Removing the label and plastic cover of the injection sample, repeatedly cleaning the sample with purified water for 5 times, penetrating the rubber plug with a 21G needle, penetrating a 10-micron quartz capillary tube through the hole of the needle, pulling out the 21G needle, keeping the quartz capillary tube in the rubber plug, cutting off the quartz capillary tube remained outside the injection bottle at a position about 0.5cm away from the rubber plug, and sealing the gap between the quartz capillary tube and the rubber plug with 101 glue. The sample was placed in a clean beaker and the appropriate amount of 1mg/mL of colored aqueous solution was added to completely immerse the sample. The beaker is placed in a vacuum drying oven, and is vacuumized until the vacuum degree is 35mb +/-5 mb, and the vacuum degree is maintained for 15 hours at 35mb +/-5 mb. Immediately thereafter, the 4 groups of injection samples were placed under normal pressure for 2h, 4h, 6h and 8h, respectively. The sample was washed with purified water 3 times to ensure the outer wall of the sample was washed clean without significant color residue, a new syringe was used to aspirate an appropriate amount of the drug solution, and the absorbance values were determined with the results shown in table 2.
TABLE 2 atmospheric standing time optimization
The results of table 2 above illustrate that: different normal pressure placing time is adopted, the absorbance value of the sample is increased along with the extension of the normal pressure placing time, the absorbance value reaches the maximum and is not obviously changed after the placing time is more than or equal to 4 hours, therefore, the requirement can be met when the normal pressure placing time is more than 4 hours, the optimal normal pressure placing time is more than 6 hours, and meanwhile, the sufficient placing time and the convenient operation are ensured.
Example 3:
the operation steps are as follows: 20 samples of the injection are randomly selected, and the conditions screened in the example 1-2 are used as experimental parameters, namely the samples are placed for 15 hours under the vacuum condition of 35mb +/-5 mb and are placed for 6 hours under normal pressure. Removing the label and plastic cover of the injection sample, repeatedly cleaning the sample with purified water for 5 times, penetrating the rubber plug with a 21G needle, penetrating a 10-micron quartz capillary tube through the hole of the needle, pulling out the 21G needle, keeping the quartz capillary tube in the rubber plug, cutting off the quartz capillary tube remained outside the injection bottle at a position about 0.5cm away from the rubber plug, and sealing the gap between the quartz capillary tube and the rubber plug with 101 glue. The sample was placed in a clean beaker and the appropriate amount of 1mg/mL of colored aqueous solution was added to completely immerse the sample. Placing the beaker in a vacuum drying box, vacuumizing to the vacuum degree of 35mb +/-5 mb, maintaining the vacuum degree of 35mb +/-5 mb for 15 hours, continuing to place for 6 hours after recovering the normal pressure, washing the sample with purified water for 3 times to ensure that the outer wall of the sample is washed clean and has no obvious color residue, sucking a proper amount of liquid medicine by using a new injector, and measuring the absorbance value, wherein the result is shown in table 3.
Table 3-determination of the limiting solution,
the results in table 3 above illustrate that: the sample is placed for 15 hours under the vacuum condition of 35mb +/-5 mb, the sample is placed for 6 hours under normal pressure, the minimum absorbance value of a positive control sample of 15 penicillin bottles with the specification of 5mL (containing 5mL of liquid medicine) is 0.1464, in order to ensure the detection capability of the method for the package integrity, the limit value is further reduced to be below 1/5 of the minimum absorbance value, meanwhile, the absorbance value of the limit solution is ensured to be larger than the LOQ of an instrument, and finally, the concentration of the limit solution is selected to be set to be 0.05 mu g/mL, so that the requirements can be met.
When the penicillin bottle packaged medicines with different packaging specifications and loading quantities are detected, the packaging specifications and the loading quantities are different, the minimum absorbance values of the positive control samples are different, and the concentrations of the limiting solutions are different. Therefore, in the actual sample detection, proper vacuum degree, vacuum standing time and normal pressure standing time are optimized through a positive control experiment aiming at each injection with different packaging and loading amount, and sufficient colored water is ensured to enter the bottle. The concentration of the limiting solution of the colorimetric method is further calculated by the minimum absorbance value of the positive control group. Generally speaking, it is recommended that the absorbance value of the positive control group is not less than 5 times of LOQ, and the limiting solution concentration is further tightened to be slightly more than the LOQ concentration so as to improve the sensitivity of the method and simultaneously take account of the detection capability of products with different specifications.
Finally, this example shows that the assay of the invention is suitable for use in the detection of the integrity of the packaging of injectables.
Claims (10)
1. An analysis method for package integrity of injection by a color water method comprises the following steps:
and (3) placing the injection packaged in a penicillin bottle into a colored aqueous solution with a certain concentration, placing for a certain time under a proper vacuum condition, taking out, further placing at normal pressure, comparing the absorbance values of the liquid medicine and the limiting solution, and judging the result.
2. The analytical method of claim 1, wherein: the color water solution is methylene blue solution.
3. The analytical method of claim 2, wherein: the concentration of the methylene blue aqueous solution is 1 mg/mL.
4. The analytical method of claim 1, wherein: the limiting solution is obtained by diluting a colored aqueous solution with a liquid medicine, and the concentration of the limiting solution is not less than the LOQ concentration.
5. The analytical method of claim 1, wherein: the absorbance value of the limiting solution is to take the liquid medicine as a blank when carrying out sample detection and result judgment, respectively scan the reference solution and the limiting solution within the wavelength range of 664 +/-2 nm and measure the ultraviolet absorption.
6. The analytical method of claim 1, wherein: the suitable vacuum condition is vacuum pumping to below 50mb, and preferably 35mb +/-5 mb vacuum degree.
7. The analytical method of claim 1, wherein: the standing under vacuum condition is maintained for 15 hours or more, preferably 15 to 18 hours.
8. The analytical method of claim 1, wherein: the standing at normal pressure needs 4 to 24 hours, preferably 6 to 8 hours, and most preferably 6 hours.
9. The assay of any one of claims 1 to 8, wherein the limiting solution is prepared by:
randomly taking 20 injection samples, standing for 15h under the vacuum condition of 35mb +/-5 mb, and standing for 6h under normal pressure; removing the label and the plastic cover of the injection sample, repeatedly cleaning the sample for 5 times by using purified water, penetrating a rubber plug by using a 21G needle, penetrating a 10-micron quartz capillary tube through the hole of the needle, pulling out the 21G needle, keeping the quartz capillary tube in the rubber plug, cutting off the quartz capillary tube remained outside the injection bottle at a position about 0.5cm away from the rubber plug, and sealing the gap between the quartz capillary tube and the rubber plug by using 101 glue; putting the sample in a clean beaker, and adding a proper amount of 1mg/mL color water solution to completely immerse the sample; placing the beaker in a vacuum drying box, vacuumizing to the vacuum degree of 35mb +/-5 mb, maintaining the vacuum degree of 35mb +/-5 mb for 15 hours, recovering for 6 hours under normal pressure, washing the sample with purified water for 3 times to ensure that the outer wall of the sample is washed cleanly without obvious color residue, sucking a proper amount of liquid medicine by a new injector, and measuring the absorbance value;
the sample is placed for 15 hours under the vacuum condition of 35mb +/-5 mb, is placed for 6 hours under normal pressure, contains 5mL of liquid medicine, and the minimum absorbance value of a positive control sample of 15 penicillin bottles with the specification of 5mL is further reduced to be below 1/5 of the minimum absorbance value, meanwhile, the absorbance value of the limit solution is ensured to be larger than the LOQ of an instrument, and finally, the limit solution concentration with proper dilution times is selected.
10. An analysis method for package integrity of injection by a color water method comprises the following steps:
preparing a color water solution: weighing a proper amount of methylene blue, dissolving the methylene blue by using purified water, and filtering the methylene blue by using a filter membrane of 0.22 mu m to obtain a 1mg/mL colored aqueous solution a;
group a negative control samples: taking 3 injection samples which are not destroyed in penicillin bottles and are not immersed in the color water solution to prepare a negative control solution;
① pricking holes of positive control sample, removing label and plastic cover, repeatedly cleaning sample with purified water for at least 5 times, passing 10 μm quartz capillary through the rubber plug, cutting off the quartz capillary left outside the injection bottle at a position about 0.5cm away from the rubber plug, sealing the gap between the quartz capillary and the rubber plug with 101 glue, ② screening, placing the sample in a clean beaker, adding appropriate amount of purified water to completely immerse the sample, placing the beaker in a vacuum drying box, vacuumizing to below 50mb, maintaining for 5min, observing bubble emergence speed, immediately recovering normal pressure, removing the sample without bubble emergence, rapidly emerging residual bubbles from the capillary pore to obtain qualified positive control sample, ③ detecting, placing the qualified positive control sample in a clean beaker, treating the positive control sample according to the preparation method of the solution, adding appropriate amount of 1mg/mL of water solution in a to completely immerse the sample, sealing the beaker with sealing film, pricking several small vacuum drying boxes, pumping the beaker to a vacuum, continuously extracting the sample with a vacuum for 5 + -5 hours, preferably 35-5 hours, and preferably washing the sample with a syringe with a vacuum degree of less than 5 hours, and preferably less than 5 hours, and continuously extracting the sample with a new color solution after the sample is cleaned and the sample is carried out, and the sample is carried out after the sample is carried out, and the sample is carried out for 5 hours, preferably carried out, after the sample is carried out for 5 hours, and the time, after the time, the sample is carried out, after;
group C test samples: randomly taking 30 injection samples, and dividing the samples into three groups, namely A1 positive placement, A2 reverse placement and A3 flat placement, wherein each group comprises 10 samples; removing the label and the plastic cover, repeatedly cleaning the sample for at least 5 times by using purified water, placing the sample in a clean beaker, adding a proper amount of 1mg/mL colored aqueous solution a in the solution a to completely immerse the sample, sealing the beaker by using a sealing film and pricking a plurality of small holes; placing the beaker in a vacuum drying box, vacuumizing to below 50mb, preferably 35mb +/-5 mb, maintaining the vacuum degree of below 50mb, preferably below 35mb +/-5 mb for at least 15 hours, quickly recovering to normal pressure, continuously placing for 4-24 hours, preferably 6 hours, taking out, washing the sample with purified water for 3 times to ensure that the outer wall is washed clean without obvious color residues, and sucking a proper amount of liquid medicine as a test sample solution by using a new syringe;
sample detection and result judgment: and under the wavelength of 664nm +/-2 nm, using the liquid medicine as a blank, establishing system applicability by using a reference solution, respectively measuring the absorbance values of A, B, C groups of samples, and judging that the sample is qualified if the absorbance value of the C group of samples is less than the average absorbance value of the limit solution read for 3 times.
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111896192A (en) * | 2020-08-12 | 2020-11-06 | 重庆华邦制药有限公司 | Test method for measuring packaging tightness by color water method |
| CN112525875A (en) * | 2020-12-11 | 2021-03-19 | 南京明捷生物医药检测有限公司 | Method for testing sealing integrity of medicine packaging container by improved color water intrusion method |
| CN113418660A (en) * | 2021-06-22 | 2021-09-21 | 江苏吉泰肽业科技有限公司 | Method for detecting tightness of penicillin bottle |
| CN113588812A (en) * | 2021-07-05 | 2021-11-02 | 贵州景峰注射剂有限公司 | Detection method of methylene blue in Tirofiban hydrochloride injection package tightness experiment |
| CN114518201A (en) * | 2020-11-19 | 2022-05-20 | 西华大学 | Method for verifying container tightness by fluorescent agent tracing method |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN111896192A (en) * | 2020-08-12 | 2020-11-06 | 重庆华邦制药有限公司 | Test method for measuring packaging tightness by color water method |
| CN114518201A (en) * | 2020-11-19 | 2022-05-20 | 西华大学 | Method for verifying container tightness by fluorescent agent tracing method |
| CN112525875A (en) * | 2020-12-11 | 2021-03-19 | 南京明捷生物医药检测有限公司 | Method for testing sealing integrity of medicine packaging container by improved color water intrusion method |
| CN113418660A (en) * | 2021-06-22 | 2021-09-21 | 江苏吉泰肽业科技有限公司 | Method for detecting tightness of penicillin bottle |
| CN113588812A (en) * | 2021-07-05 | 2021-11-02 | 贵州景峰注射剂有限公司 | Detection method of methylene blue in Tirofiban hydrochloride injection package tightness experiment |
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