CN111175391A - Method for measuring residual amount of methanol in recombinant hand-foot-and-mouth disease vaccine stock solution and application of method in preparation of recombinant hand-foot-and-mouth disease vaccine - Google Patents
Method for measuring residual amount of methanol in recombinant hand-foot-and-mouth disease vaccine stock solution and application of method in preparation of recombinant hand-foot-and-mouth disease vaccine Download PDFInfo
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- CN111175391A CN111175391A CN201911390090.9A CN201911390090A CN111175391A CN 111175391 A CN111175391 A CN 111175391A CN 201911390090 A CN201911390090 A CN 201911390090A CN 111175391 A CN111175391 A CN 111175391A
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- G—PHYSICS
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- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
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- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
- G01N30/26—Conditioning of the fluid carrier; Flow patterns
- G01N30/28—Control of physical parameters of the fluid carrier
- G01N30/30—Control of physical parameters of the fluid carrier of temperature
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
- G01N30/62—Detectors specially adapted therefor
- G01N30/64—Electrical detectors
- G01N30/68—Flame ionisation detectors
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Abstract
The embodiment of the invention discloses a method for measuring residual quantity of methanol in recombinant hand-foot-and-mouth disease vaccine stock solution and application of the method in preparation of recombinant hand-foot-and-mouth disease vaccine. The determination method comprises the following steps: preparing a sample solution; and (4) introducing the sample solution into a gas chromatograph through a headspace sample injector, and determining the content of methanol in the sample solution. By implementing the method, the methanol residual quantity of the recombinant hand-foot-and-mouth disease vaccine stock solution can be accurately measured, a basis is provided for the safety of the recombinant hand-foot-and-mouth disease vaccine, and real, reliable and effective data is provided for the stability of the process.
Description
Technical Field
The invention relates to a preparation technology of a recombinant hand-foot-and-mouth disease vaccine in genetic engineering, in particular to a method for measuring residual quantity of methanol in a recombinant hand-foot-and-mouth disease vaccine stock solution and application thereof in preparation of the recombinant hand-foot-and-mouth disease vaccine.
Background
Methanol is used as an energy source and an inducer and is indispensable in the preparation process of the hand-foot-and-mouth disease vaccine expressed by recombinant hansenula polymorpha and the like, but trace residue of the methanol brings great hidden danger to the safety of vaccine products. Methanol is added into yeast in the fermentation process as an energy source and an inducer, and the recombinant hand-foot-and-mouth disease vaccine inoculation object is mainly a young child which is not full of the whole year of age, has lower tolerance to methanol residue, and causes discomfort such as skin reddish halo even if trace amount of the residue is left. Therefore, the method is particularly important for detecting the residual quantity of the methanol in the recombinant hand-foot-and-mouth disease vaccine stock solution.
In the prior art, a scheme for accurately measuring the residual quantity of methanol in a recombinant hand-foot-and-mouth disease vaccine stock solution is lacked.
Disclosure of Invention
The technical problem solved by the invention is to provide a method for measuring the residual amount of methanol in the recombinant hand-foot-and-mouth disease vaccine stock solution, which can accurately measure the residual amount of methanol in the recombinant hand-foot-and-mouth disease vaccine stock solution, provide a basis for the safety of the recombinant hand-foot-and-mouth disease vaccine, and provide real, reliable and effective data for the stability of the process.
The invention further solves the technical problem of providing the application of the method for measuring the residual quantity of the methanol in the recombinant hand-foot-and-mouth disease vaccine stock solution in the preparation process of the recombinant hand-foot-and-mouth disease vaccine, wherein the application can accurately measure the residual quantity of the methanol in the recombinant hand-foot-and-mouth disease vaccine stock solution, provide a basis for the safety of the recombinant hand-foot-and-mouth disease vaccine and provide real, reliable and effective data for the stability of the process.
In order to solve the technical problem, the invention discloses a method for measuring the residual amount of methanol in a recombinant hand-foot-and-mouth disease vaccine stock solution, which comprises the following steps:
preparing a sample solution;
and (4) introducing the sample solution into a gas chromatograph through a headspace sample injector, and determining the content of methanol in the sample solution.
In some possible embodiments, the sample solution comprises: solvent control sample, system applicability sample, standard curve solution, and test sample.
In some possible embodiments, the methanol content is determined by:
detecting a sample signal;
and fitting a linear regression equation by using the concentration of the methanol standard curve solution as a horizontal coordinate and the corresponding methanol peak area as a vertical coordinate according to an external standard method, substituting the average value of the methanol peak areas of the samples into the equation, and calculating the measured value of the methanol content of the sample solution.
In some possible embodiments, the solvent control sample is 0.01mol/L phosphate buffer containing 100 μ g/mL polysorbate 80.
In some possible embodiments, the system-adapted sample is prepared by:
preparing a methanol reference substance storage solution from a methanol reference substance, and adding a phosphate buffer solution containing polysorbate 80 to a constant volume to obtain a methanol reference substance solution;
several portions of methanol reference solution were taken to obtain several portions of system adaptability samples.
In some possible embodiments, the standard curve solution is prepared by:
taking a plurality of methanol reference substance stock solutions with different volumes, adding phosphate buffer solution containing polysorbate 80 into each methanol reference substance stock solution to the same volume, and preparing a plurality of methanol standard curve solutions with different concentrations.
In some possible embodiments, the methanol standard curve solution has a solubility of 2.0, 5.0, 10.0, 25.0, 50.0 μ g/mL, respectively.
In some possible embodiments, a flame ionization detector is used to detect the sample signal.
In some possible embodiments, the hand-foot-and-mouth disease vaccine is a recombinant enterovirus type 71 vaccine.
Correspondingly, the invention also discloses an application of the method for determining the residual amount of methanol in the recombinant hand-foot-and-mouth disease vaccine stock solution in preparation of the hand-foot-and-mouth disease vaccine.
The invention has the beneficial effects that:
embodiments of the present invention determine the methanol content of a sample solution by preparing the sample solution and passing the sample solution through a headspace sampler into a gas chromatograph. Thereby accurately measuring the content of the methanol in the recombinant hand-foot-and-mouth disease vaccine stock solution. The method is simple and convenient to operate, has high detection accuracy on trace methanol residues, provides reliable data for the safety of the recombinant hand-foot-and-mouth disease vaccine, and simultaneously provides reference for the detection of the methanol residues of other recombinant protein vaccines.
Detailed Description
The following describes in detail an embodiment of the method for determining the residual amount of methanol in the recombinant hand-foot-and-mouth disease vaccine stock solution provided by the present invention; the embodiment mainly comprises the following steps:
preparing a sample solution;
and (4) introducing the sample solution into a gas chromatograph through a headspace sample injector, and determining the content of methanol in the sample solution.
In some possible embodiments, the sample solution comprises: solvent control sample, system applicability sample, standard curve solution, and test sample.
In some possible embodiments, the methanol content is determined by:
detecting a sample signal;
and fitting a linear regression equation by using the concentration of the methanol standard curve solution as a horizontal coordinate and the corresponding methanol peak area as a vertical coordinate according to an external standard method, substituting the average value of the methanol peak areas of the samples into the equation, and calculating the measured value of the methanol content of the sample solution.
In some possible embodiments, the solvent control sample is 0.01mol/L phosphate buffer containing 100 μ g/mL polysorbate 80.
In some possible embodiments, the system-adapted sample is prepared by:
preparing a methanol reference substance storage solution from a methanol reference substance, and adding a phosphate buffer solution containing polysorbate 80 to a constant volume to obtain a methanol reference substance solution;
several portions of methanol reference solution were taken to obtain several portions of system adaptability samples.
In some possible embodiments, the standard curve solution is prepared by:
taking a plurality of methanol reference substance stock solutions with different volumes, adding phosphate buffer solution containing polysorbate 80 into each methanol reference substance stock solution to the same volume, and preparing a plurality of methanol standard curve solutions with different concentrations.
In some possible embodiments, the methanol standard curve solution has a solubility of 2.0, 5.0, 10.0, 25.0, 50.0 μ g/mL, respectively.
In some possible embodiments, a flame ionization detector is used to detect the sample signal.
In some possible embodiments, the hand-foot-and-mouth disease vaccine is a recombinant enterovirus type 71 vaccine.
The application of the method for measuring the residual amount of methanol in the recombinant hand-foot-and-mouth disease type vaccine stock solution disclosed by the embodiment of the invention in the preparation of the hand-foot-and-mouth disease vaccine comprises the method for measuring the residual amount of methanol described in the embodiment, and the rest is the same as the prior art and is not repeated.
In order to further explain the technical means and effects adopted by the embodiment to achieve the predetermined invention, the specific steps of the method for measuring the residual amount of methanol in the stock solution of the recombinant hand-foot-and-mouth disease vaccine of the embodiment are described in detail by the example data as follows.
Example 1:
the instrument equipment comprises:
(1) gas chromatograph: agilent 7890B
(2) Headspace sampler: agilent 7697A type
(3) Analytical balance: sartoriusAC-210S, division value 0.1mg
(4) Hydrogen generator manufacturers and models: beijing east essence garden science and technology SGH-300 high-purity hydrogen generator
(5) Analyzing a chromatographic column: an Agilent Technios DB-624 capillary chromatographic column with a length of 30m, an inner diameter of 0.32mm, a film thickness of 1.80 μm and a temperature range of-20 ℃ to 260 ℃.
(6) A headspace bottle: agilent, 20mL
(7) Nitrogen gas: high-purity nitrogen with the purity more than or equal to 99.999 percent.
Reagent:
methanol control: chemical reagent of national drug group, product number SCRC40030561, chromatography pure (GC)
A detection step:
(1) preparing a 1000 mu g/mL methanol reference substance stock solution, precisely measuring 100mg of the methanol reference substance into a 100mL volumetric flask filled with a small amount of purified water, fixing the volume to a scale mark by using the purified water, and uniformly mixing to obtain the 1000 mu g/mL methanol reference substance stock solution.
(2) 0.01mol/L phosphate buffer solution containing 100 mu g/mL polysorbate 80 is prepared by precisely weighing 0.696g of disodium hydrogen phosphate, 0.734g of monobasic sodium phosphate monohydrate, 8.766g of sodium chloride and 80100mg of polysorbate, and adding purified water to a constant volume of 1000 mL.
(3) Solvent control preparation, 1mL of 0.01mol/L phosphate buffer containing 100 μ g/mL polysorbate 80 was weighed into a 20mL headspace bottle, and 1 sample was prepared.
(4) Preparing a system applicability sample, namely taking 0.1mL of a 1000 mu g/mL methanol reference substance stock solution, adding 0.01mol/L phosphate buffer solution containing 100 mu g/mL polysorbate 80, and fixing the volume to 10mL, namely obtaining a 10.0 mu g/mL methanol reference substance solution. 1mL of 10.0. mu.g/mL methanol control solution was precisely measured and placed in a 20mL headspace bottle to prepare 5 samples.
(5) And (3) preparing a methanol standard curve solution, namely respectively taking the methanol reference substance stock solutions of 1000 mu g/mL to 10mL in volumetric flasks of 20, 50, 100, 250, 500 mu L and adding 0.01mol/L phosphate buffer solution containing 100 mu g/mL polysorbate 80 to scale marks to prepare the methanol standard curve solutions of 2.0, 5.0, 10.0, 25.0 and 50.0 mu g/mL. 2 samples were prepared by placing 1mL of each standard curve solution in a 20mL headspace bottle.
(6) Sample solution preparation, using purified water to dilute 1000 mug/mL of methanol reference stock solution into 100 mug/mL of methanol reference solution, preparing a sample according to the following table, measuring 1mL of sample solution, placing the sample solution into a 20mL headspace bottle, and preparing 2 samples.
Watch I,
| Sample (I) | 100 μ g/mL methanol control solution (mL) | Stock solution (mL) | Theoretical additive amount (mu g/mL) |
| Sample 1 | 0 | 10 | 0 |
| Sample 2 | 0.2 | 9.8 | 2 |
| Sample 3 | 0.1 | 9.9 | 1 |
(7) Installing chromatographic column, opening carrier gas (nitrogen), head space injector power supply and gas chromatograph host in turn. And after the self-checking of the headspace sample injector and the gas chromatograph host is passed, setting the nitrogen flow rate of the capillary chromatographic column to be 1.0mL/min, turning on the power supply of the high-purity hydrogen generator, and when the pressure is increased to 0.4 MPa.
(8) Setting a column incubator temperature-raising program on a GC host panel, wherein the initial column temperature is 40 ℃, raising the temperature to 230 ℃ (30 ℃ lower than the highest use temperature) at a speed of 10 ℃/min, keeping the temperature for at least 30min, then lowering the temperature to the initial column temperature at a speed of 10 ℃/min, setting the injection port temperature to be 200 ℃, the detector temperature to be 250 ℃, and clicking START to age the chromatographic column according to the set program.
(9) And (3) opening an air source, setting the oxygen flow rate to be 400mL/min and the hydrogen flow rate to be 40mL/min, and clicking 'On/Yes' On the control panel to ignite after the flow rates are stable.
(10) Setting the peak area, retention time and theoretical plate number of the collected sample, sending the established collection method to the instrument, starting the gas chromatograph to balance the instrument (chromatographic column and detector) under the method until the baseline drift does not exceed 1pA within 20 minutes, and operating all modules of the instrument in a green ready state.
(11) Placing the prepared sample into a headspace sample injector in the following sequence: solvent control, system applicability sample, standard curve solution, test sample.
(12) Chromatographic conditions
(13) And (3) adopting top air sample injection, wherein the top air condition is that the temperature of the constant temperature furnace is 80 ℃, the temperature of a sample flow path is 150 ℃, the temperature of a transmission line is 170 ℃, the balance time is 30min, and the sample injection amount is 1mL, storing a sample sequence, starting to operate the sample by clicking operation, and recording the retention time and the peak area of a main peak.
(14) Data processing
A standard curve and a sample data processing method are established by using the system applicability sample chromatogram, and the integral parameters of the standard curve and the sample data processing method are set as follows:
A second meter,
| Event(s) | Value of |
| Slope sensitivity | 1.00 |
| Peak width | 0.02 |
| Minimum peak area | 1.00 |
| Minimum peak height | 0.01 |
All samples were processed using established sample processing methods.
(15) And fitting a linear regression equation by taking the concentration of the methanol standard curve solution as a horizontal coordinate and the corresponding methanol peak area as a vertical coordinate, and substituting the average value of the methanol peak area of the sample into the equation to calculate the measured value of the methanol content of the sample solution.
Table three, detection results:
| sample name | Scalar quantity (mu g/mL) | Methanol content (μ g/mL) | Recovery (%) |
| Sample 1 | 0 | Not detected out | N/A |
| Sample 2 | 1.0 | 1.06 | 106 |
| Sample 3 | 2.0 | 2.10 | 105 |
The standard recovery rate of the methanol meets the requirement of 80.0-120.0% in pharmacopoeia of the people's republic of China, and the method is proved to be capable of accurately measuring the content of the methanol in the recombinant hand-foot-and-mouth disease vaccine stock solution.
As can be seen from the data of the residual amount of methanol determined in the above examples, the embodiment of the invention can realize accurate determination of the residual amount of methanol in the recombinant hand-foot-and-mouth disease vaccine stock solution.
The foregoing is a more detailed description of the invention that is presented in conjunction with specific embodiments, and the practice of the invention is not to be considered limited to those descriptions. For those skilled in the art to which the invention pertains, several simple deductions or substitutions can be made without departing from the spirit of the invention, and all shall be considered as belonging to the protection scope of the invention.
Claims (10)
1. A method for measuring the residual amount of methanol in a hansenula polymorpha expressed recombinant hand-foot-and-mouth disease vaccine stock solution is characterized by comprising the following steps:
preparing a sample solution;
and (4) introducing the sample solution into a gas chromatograph through a headspace sample injector, and determining the content of methanol in the sample solution.
2. The method of claim 1, wherein the sample solution comprises: solvent control sample, system applicability sample, standard curve solution, and test sample.
3. The method of claim 2, wherein the methanol content is determined by:
detecting a sample signal;
and fitting a linear regression equation by using the concentration of the methanol standard curve solution as a horizontal coordinate and the corresponding methanol peak area as a vertical coordinate according to an external standard method, substituting the average value of the methanol peak areas of the samples into the equation, and calculating the measured value of the methanol content of the sample solution.
4. The method of any one of claims 1-3, wherein the solvent control sample is 0.01mol/L phosphate buffer containing 100 μ g/mL polysorbate 80.
5. The method of any one of claims 1-3, wherein the system-adapted sample is prepared by:
preparing a methanol reference substance storage solution from a methanol reference substance, and adding a phosphate buffer solution containing polysorbate 80 to a constant volume to obtain a methanol reference substance solution;
several portions of methanol reference solution were taken to obtain several portions of system adaptability samples.
6. The method of claim 1, wherein the standard curve solution is prepared by:
taking a plurality of methanol reference substance stock solutions with different volumes, adding phosphate buffer solution containing polysorbate 80 into each methanol reference substance stock solution to the same volume, and preparing a plurality of methanol standard curve solutions with different concentrations.
7. The method of claim 3, wherein the methanol standard curve solution has a solubility of 2.0, 5.0, 10.0, 25.0, 50.0 μ g/mL, respectively.
8. The method of claim 3, wherein the sample signal is detected using a flame ionization detector.
9. The method of any one of claims 1-8, wherein said hand-foot-and-mouth disease vaccine is a recombinant enterovirus type 71 vaccine.
10. Use of the method for determining residual amount of methanol in the recombinant hand-foot-and-mouth disease vaccine stock solution according to any one of claims 1-9 in the preparation of a recombinant hand-foot-and-mouth disease vaccine.
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| CN201911390090.9A CN111175391A (en) | 2019-12-27 | 2019-12-27 | Method for measuring residual amount of methanol in recombinant hand-foot-and-mouth disease vaccine stock solution and application of method in preparation of recombinant hand-foot-and-mouth disease vaccine |
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| CN201911390090.9A CN111175391A (en) | 2019-12-27 | 2019-12-27 | Method for measuring residual amount of methanol in recombinant hand-foot-and-mouth disease vaccine stock solution and application of method in preparation of recombinant hand-foot-and-mouth disease vaccine |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2114918A1 (en) * | 2007-01-18 | 2009-11-11 | LEK Pharmaceuticals D.D. | Process for solvent removal from omeprazole salts |
| CN104330505A (en) * | 2014-10-29 | 2015-02-04 | 锦州奥鸿药业有限责任公司 | Method for determining residual solvent in deproteinised calf serum injection |
| US20150216969A1 (en) * | 2013-09-25 | 2015-08-06 | Sequoia Sciences, Inc. | Compositions of vaccines and adjuvants and methods for the treatment of urinary tract infections |
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2019
- 2019-12-27 CN CN201911390090.9A patent/CN111175391A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2114918A1 (en) * | 2007-01-18 | 2009-11-11 | LEK Pharmaceuticals D.D. | Process for solvent removal from omeprazole salts |
| US20150216969A1 (en) * | 2013-09-25 | 2015-08-06 | Sequoia Sciences, Inc. | Compositions of vaccines and adjuvants and methods for the treatment of urinary tract infections |
| CN104330505A (en) * | 2014-10-29 | 2015-02-04 | 锦州奥鸿药业有限责任公司 | Method for determining residual solvent in deproteinised calf serum injection |
Non-Patent Citations (3)
| Title |
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| CHUN-YUNZHANG 等: "Rapid determination of methanol content in paper materials by alkaline extraction, coupled with headspace analysis", 《JOURNAL OF CHROMATOGRAPHY A》 * |
| 刘胜春 等: "顶空毛细管气相色谱法测定福尔可定原料药中5种有机溶剂的残留量", 《中国药房》 * |
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