CN115031499A - Calibration method for medicinal vacuum freeze dryer - Google Patents
Calibration method for medicinal vacuum freeze dryer Download PDFInfo
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- CN115031499A CN115031499A CN202210947338.2A CN202210947338A CN115031499A CN 115031499 A CN115031499 A CN 115031499A CN 202210947338 A CN202210947338 A CN 202210947338A CN 115031499 A CN115031499 A CN 115031499A
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- 238000000034 method Methods 0.000 title claims abstract description 49
- 238000001816 cooling Methods 0.000 claims abstract description 21
- 238000007689 inspection Methods 0.000 claims abstract description 8
- 238000004108 freeze drying Methods 0.000 claims description 37
- 238000005259 measurement Methods 0.000 claims description 26
- 230000008569 process Effects 0.000 claims description 24
- 238000002955 isolation Methods 0.000 claims description 17
- 150000001875 compounds Chemical class 0.000 claims description 6
- 230000007547 defect Effects 0.000 claims description 6
- 230000009467 reduction Effects 0.000 claims description 6
- 230000000087 stabilizing effect Effects 0.000 claims description 6
- 238000012360 testing method Methods 0.000 claims description 6
- 230000008859 change Effects 0.000 claims description 5
- 238000000605 extraction Methods 0.000 claims description 5
- 238000004140 cleaning Methods 0.000 claims description 4
- 238000005070 sampling Methods 0.000 claims description 4
- 230000001954 sterilising effect Effects 0.000 claims description 4
- 238000004659 sterilization and disinfection Methods 0.000 claims description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 238000009826 distribution Methods 0.000 description 4
- 238000001035 drying Methods 0.000 description 3
- 238000007710 freezing Methods 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 238000010586 diagram Methods 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 230000007613 environmental effect Effects 0.000 description 2
- 230000008014 freezing Effects 0.000 description 2
- 238000003795 desorption Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 238000012797 qualification Methods 0.000 description 1
- 238000005057 refrigeration Methods 0.000 description 1
- 229920002545 silicone oil Polymers 0.000 description 1
- 238000000859 sublimation Methods 0.000 description 1
- 230000008022 sublimation Effects 0.000 description 1
- 238000009777 vacuum freeze-drying Methods 0.000 description 1
- 238000011179 visual inspection Methods 0.000 description 1
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- F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
- F26—DRYING
- F26B—DRYING SOLID MATERIALS OR OBJECTS BY REMOVING LIQUID THEREFROM
- F26B5/00—Drying solid materials or objects by processes not involving the application of heat
- F26B5/04—Drying solid materials or objects by processes not involving the application of heat by evaporation or sublimation of moisture under reduced pressure, e.g. in a vacuum
- F26B5/06—Drying solid materials or objects by processes not involving the application of heat by evaporation or sublimation of moisture under reduced pressure, e.g. in a vacuum the process involving freezing
-
- F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
- F26—DRYING
- F26B—DRYING SOLID MATERIALS OR OBJECTS BY REMOVING LIQUID THEREFROM
- F26B25/00—Details of general application not covered by group F26B21/00 or F26B23/00
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01D—MEASURING NOT SPECIALLY ADAPTED FOR A SPECIFIC VARIABLE; ARRANGEMENTS FOR MEASURING TWO OR MORE VARIABLES NOT COVERED IN A SINGLE OTHER SUBCLASS; TARIFF METERING APPARATUS; MEASURING OR TESTING NOT OTHERWISE PROVIDED FOR
- G01D21/00—Measuring or testing not otherwise provided for
- G01D21/02—Measuring two or more variables by means not covered by a single other subclass
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- Mechanical Engineering (AREA)
- General Engineering & Computer Science (AREA)
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- Life Sciences & Earth Sciences (AREA)
- Molecular Biology (AREA)
- Drying Of Solid Materials (AREA)
Abstract
The invention discloses a calibration method for a medicinal vacuum freeze dryer, which comprises the following steps: carrying out appearance inspection on the medical vacuum freeze dryer; calibrating the medicinal vacuum freeze dryer by acquiring the vacuum leakage rate, the cooling rate, the temperature uniformity in the shelf, the temperature uniformity among the shelves, the shelf temperature deviation, the ultimate vacuum degree and the working vacuum degree of the medicinal vacuum freeze dryer; the invention realizes the calibration work of the medicinal vacuum freeze dryer and fills the technical blank of the calibration direction of the medicinal vacuum freeze dryer.
Description
Technical Field
The invention relates to the technical field of calibration of vacuum freeze dryers, in particular to a calibration method for a medicinal vacuum freeze dryer.
Background
A medical vacuum freeze dryer (hereinafter referred to as freeze dryer) is a device which adopts a vacuum freeze drying technology and is applied to industries such as biological medicines, chemical products and the like to achieve the aim of dehydrating and drying substances and keep the original form of the substances through vacuum freezing. A freeze dryer generally consists of a freeze drying box, a condenser, a refrigeration system, a vacuum system, a silicone oil circulation system, a hydropneumatic system, an electrical control system, and an in-situ cleaning/sterilization system.
The freeze-drying process of the freeze dryer generally comprises the processes of preparation, pre-freezing, quick-freezing, vacuumizing, sublimation drying, desorption drying, post-treatment and the like. The internal temperature and vacuum parameters in the freeze-drying process are regularly changed with time, and comprise important contents such as shelf temperature, equilibrium time, vacuum degree and the like, wherein a typical freeze-drying curve is shown in figure 1, and a vacuum system is shown in figure 2.
In the prior art, a method for calibrating the medical vacuum freeze dryer is lacked, so that a calibration method for the medical vacuum freeze dryer is urgently needed to fill the blank of the prior art.
Disclosure of Invention
In order to solve the above problems, the present invention provides a calibration method for a pharmaceutical vacuum freeze dryer, comprising the steps of:
carrying out appearance inspection on the medical vacuum freeze dryer;
the medical vacuum freeze dryer is calibrated by acquiring the vacuum leakage rate, the cooling rate, the temperature uniformity in the shelf, the temperature uniformity among shelves, the shelf temperature deviation, the ultimate vacuum degree and the working vacuum degree of the medical vacuum freeze dryer.
Preferably, in the process of performing the appearance inspection of the pharmaceutical vacuum freeze dryer, the appearance requirements of the pharmaceutical vacuum freeze dryer include:
the medical vacuum freeze dryer has a complete appearance structure and clear marks, and marks the name, the model, the specification, the manufacturer, the factory number and the manufacture year and month of equipment;
the inner surface of the freeze drying box of the medicinal vacuum freeze dryer is smooth and has no defects of dent and burr, and the freeze drying box of the medicinal vacuum freeze dryer is provided with a plurality of layers of shelves;
an indicator light and an instrument display of an electrical control system of the medical vacuum freeze dryer are clear, striking and free of defects of influencing reading;
the electric, hydraulic and vacuum pipeline systems of the medical vacuum freeze dryer are compact and reasonable in arrangement and regular in arrangement, and main pipelines have medium names and flow direction marks.
Preferably, after the appearance inspection process of the medicinal vacuum freeze dryer is carried out, arranging a temperature recorder and a vacuum recorder on shelves of each layer of the freeze drying box except for a top shelf, and setting a sampling time interval to be 2min and carrying out sterilization treatment, wherein the arrangement position of the temperature recorder is that one is arranged at each of four corners of the shelf and one is arranged at the center of the shelf, and the arrangement position of the vacuum recorder is the center of the shelf;
the temperature recorder and the vacuum recorder which are arranged at the center of the shelf are positioned at the same side or different sides.
Preferably, in the process of obtaining the vacuum leakage rate, closing a door of the freeze-drying chamber and a vent valve, sequentially opening a vacuum pump, an air exhaust valve and an isolation valve, vacuumizing the freeze-drying chamber, continuously exhausting air for 20min after the vacuum degree reaches 5Pa, closing the isolation valve, and recording the change curve of the vacuum degree along with the time, wherein the recording time is not less than 30 min;
obtaining a vacuum leak rate from a linear portion of the variation curve, wherein the vacuum leak rate is expressed as:
in the formula:
the vacuum leak rate of the freeze dryer is indicated,
represents the starting time of a linear segment in the curve of the vacuum degree along with the change of the time,
the end time of the linear segment in the vacuum level versus time curve,
to represent
The degree of vacuum at the time of the operation,
represent
The degree of vacuum at the time of the operation,
the volume of the lyophilization chamber is indicated.
Preferably, in the process of obtaining the vacuum leakage rate, the vacuum leakage rate is calibrated at room temperature, whether the freeze-drying chamber is in a dry state is checked before testing, no residual water stain is left after cleaning, and if not, the freeze-drying chamber is dried and then is calibrated at room temperature.
Preferably, in the process of obtaining the cooling rate, closing the air extraction valve, opening a release valve of the freeze dryer to release air until the atmospheric pressure of the freeze drying chamber is recovered, closing the isolation valve and the release valve, and stabilizing for 10 min; the inceptive normal atmospheric temperature of recording equipment and time start freeze dryer accuse temperature procedure, set up the target temperature, start cooling procedure and begin the record, when reaching the target temperature, the cooling time of this process of record acquires cooling rate, wherein, cooling rate expresses to be:
in the formula:
which is indicative of the rate of temperature decrease,
which indicates the initial temperature of the shelf,
a target temperature of the shelf is indicated,
indicating the time difference recorded when the shelf temperature reached the target temperature from ambient.
Preferably, in the process of acquiring the temperature uniformity in the shelf, the temperature uniformity among the shelves, the temperature deviation of the shelf, the ultimate vacuum degree and the working vacuum degree, the calibration points are set to be-50 ℃, 0 ℃ and 55 ℃;
after the temperature reduction rate is calibrated, opening an isolation valve of a freeze dryer to vacuumize, after the vacuum degree tends to be balanced, recording 16 groups of temperature and vacuum degree data within 30min after the shelf temperature reaches a stable state at minus 50 ℃, and acquiring the temperature uniformity in the shelf, the temperature uniformity among shelves, the temperature deviation of the shelf and the ultimate vacuum degree;
according to the sequence of the calibration points from low to high, when the target temperature is set to be 0 ℃, starting temperature control, recording 16 groups of temperature data within 30min after reaching a stable state, and obtaining the temperature uniformity in the shelf, the temperature uniformity among the shelves and the temperature deviation of the shelf;
keeping the target temperature at 0 ℃, calibrating the working vacuum degree, closing an isolation valve of a freeze dryer, adjusting a vent valve, adjusting the equipment pressure to 10Pa, closing an air inlet adjusting valve, recording the vacuum degree value of a standard device and the vacuum degree value of the equipment after stabilizing for 2min, recording the standard vacuum degree value and the vacuum degree value of the equipment again after 2min, and obtaining the working vacuum degree; adjusting the pressure of the equipment to 100Pa, and adopting the same way to calibrate the working vacuum degree again;
setting the target temperature to 55 ℃, starting temperature control, opening an isolation valve of a freeze dryer, recording 16 groups of temperature data within 30min after reaching a stable state, and acquiring temperature uniformity in shelves, temperature uniformity among shelves and shelf temperature deviation;
and calibrating the medical vacuum freeze dryer according to the temperature uniformity in the shelf, the temperature uniformity among shelves, the temperature deviation of the shelves, the ultimate vacuum degree and the working vacuum degree which are obtained from different calibration points.
Preferably, in the process of calibrating the medicinal vacuum freeze dryer, under the stable state of the freeze drying equipment, the difference between the highest temperature and the lowest temperature of each shelf measured by each measuring point in each shelf in 30min is used as the calibration result of the temperature uniformity in each shelf;
the maximum value of the difference between the highest temperature and the lowest temperature measured in 30min by each measuring point of all shelves is used as the calibration result of the temperature uniformity among the shelves;
the shelf temperature deviation is expressed as:
in the formula (I), the compound is shown in the specification,
indicating a deviation in the temperature of the shelf,
indicating the deviation in the temperature of the shelf,
indicates the highest temperature measured within a prescribed time at each calibration point,
indicating the lowest temperature measured within the specified time at each calibration point,
indicating the set temperature of the device.
Preferably, in the process of acquiring the ultimate vacuum degree and the working vacuum degree, the ultimate vacuum degree is expressed as:
in the formula (I), the compound is shown in the specification,
the ultimate vacuum of the freeze dryer is shown,
is shown as
The number of measurements is then measured,
denotes the first layer first
The degree of vacuum of the secondary measurement,
denotes the second layer of
The degree of vacuum of the secondary measurement,
denotes the third layer
The vacuum degree of the secondary measurement;
the working vacuum is expressed as:
in the formula (I), the compound is shown in the specification,
the deviation of the working vacuum degree is shown,
the indication device indicates a degree of vacuum,
indicating the vacuum standard vacuum reference value.
Preferably, the calibration system for implementing the calibration method comprises:
the data acquisition module is used for acquiring the vacuum leakage rate, the cooling rate, the temperature uniformity in the shelf, the temperature uniformity among the shelves, the temperature deviation of the shelf, the ultimate vacuum degree and the working vacuum degree of the medical vacuum freeze dryer;
and the calibration module is used for calibrating the medical vacuum freeze dryer according to the vacuum leakage rate, the cooling rate, the temperature uniformity in the shelf, the temperature uniformity among shelves, the shelf temperature deviation, the ultimate vacuum degree and the working vacuum degree.
The invention discloses the following technical effects:
the invention realizes the calibration work of the medical vacuum freeze dryer and fills the technical blank of the medical vacuum freeze dryer in the calibration direction.
Drawings
In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings needed in the embodiments will be briefly described below, and it is obvious that the drawings in the following description are only some embodiments of the present invention, and it is obvious for those skilled in the art to obtain other drawings without creative efforts.
FIG. 1 is a schematic representation of a typical lyophilization curve according to the present invention;
FIG. 2 is a schematic view of a vacuum system according to the present invention;
fig. 3 is a schematic diagram of the layout of the recorder according to the invention.
Detailed Description
In order to make the objects, technical solutions and advantages of the embodiments of the present application clearer, the technical solutions in the embodiments of the present application will be clearly and completely described below with reference to the drawings in the embodiments of the present application, and it is obvious that the described embodiments are only a part of the embodiments of the present application, and not all the embodiments. The components of the embodiments of the present application, as generally described and illustrated in the figures herein, could be arranged and designed in a wide variety of different configurations. Thus, the following detailed description of the embodiments of the present application, presented in the accompanying drawings, is not intended to limit the scope of the claimed application, but is merely representative of selected embodiments of the application. All other embodiments, which can be derived by a person skilled in the art from the embodiments of the present application without making any creative effort, shall fall within the protection scope of the present application.
As shown in fig. 1-3, the present invention provides a calibration method for a pharmaceutical vacuum freeze dryer, which specifically comprises the following technical processes:
1. metering characteristics: the technical requirements for the temperature vacuum parameters of the freeze dryer are given in table 1.
Note: all the indexes are not used for qualification judgment and are only used for reference.
2. Calibration conditions:
2.1, environmental conditions:
temperature: 15-35 ℃;
relative humidity: not more than 85%;
air pressure: 70kPa to 106 kPa.
The periphery of the freeze dryer should not have strong vibration and corrosive gas, and other cold and heat source influences should be avoided. In actual operation, the environmental conditions should also meet the requirements for normal use of the measurement standard.
2.2, load conditions:
the calibration is performed under no-load conditions. The load may be performed under other load conditions according to the user's needs or actual conditions, but the load should be described.
2.3 measurement standards and other equipment:
2.3.1, measurement standard:
2.3.1.1, wireless temperature recorders, wireless vacuum recorders, etc. are generally used as measuring standards. The number of the temperature sensors is not less than 15, the number of the vacuum sensors is not less than 3, and the sampling frequency is not less than 1 reading/10 seconds.
Note: if the vacuum sensors are arranged on the flange, the number of the vacuum sensors is one.
2.3.1.2, technical index requirement: the measurement standard specification requirements are shown in table 2.
2.3.1.3, the measurement standard listed in Table 2 can be selected during calibration, and other measurement standards meeting the requirement can also be selected.
3. Calibration items and calibration methods:
3.1 calibration items: the items of cooling rate, shelf temperature uniformity, shelf temperature deviation, ultimate vacuum degree, working vacuum degree deviation and vacuum leakage rate are calibrated by combining the freeze-drying working process, as shown in Table 3
3.2, appearance inspection:
before calibration, visual inspection is carried out on the freeze dryer, and the appearance of the freeze dryer meets the following requirements:
(1) the freeze dryer has a complete appearance structure and clear marks, and the name, the model, the specification, the manufacturer, the factory number, the manufacture year and month and the like of equipment are marked.
(2) The freeze-drying case internal surface of freeze-drying machine should be smooth, must not have defects such as sunken and burr, and multilayer shelf should be placed to the freeze-drying case.
(3) Indicator lights and instrument displays of the freeze dryer's electrical control system should be clear, eye-catching, and free of defects that affect readings.
(4) The arrangement of the freeze dryer electrical, hydraulic, vacuum and other pipeline systems is compact and reasonable, and the arrangement is neat, and the main pipelines should be provided with medium names and flow direction marks.
3.3 calibration method
3.3.1 measuring Point positions and quantities
The distribution position of the temperature and vacuum recorders is a measurement point calibrated by a freeze dryer, the measurement is carried out on shelves except for a top shelf, the recorders are arranged on the surfaces of the shelves and are fully contacted with the shelves for heat conduction, each shelf is provided with 5 temperature test points, the distribution position is that four corners of the shelf are respectively arranged, and a vacuum measurement point is arranged in the center of each shelf. The schematic diagram of the distribution position is shown in FIG. 3, wherein the reference numerals 1-15 represent temperature test points, and P1-P3 represent vacuum measurement points.
3.3.2, the number of the equipment shelf layers is more than 7, and the number of the measuring points can be reduced according to actual needs or user requirements, as shown in figure 3.
3.3.3 setting of measurement points
Setting the sampling time interval of the temperature recorder and the vacuum recorder to be 2min, and automatically recording the temperature and the vacuum degree of each measuring point according to 3.3.1 distribution points after the recorder carries out sterilization treatment.
3.3.4 vacuum leak Rate calibration
Closing a freeze-drying chamber door and an air release valve, sequentially opening a vacuum pump, an air extraction valve and an isolation valve, vacuumizing the freeze-drying chamber, continuing to extract air for 20min after the vacuum degree reaches 5Pa, closing the isolation valve, recording the change curve of the vacuum degree along with time, recording the time not less than 30min, and calculating the vacuum leakage rate of the linear part of the curve according to 3.4.5.
Note: the vacuum leak rate was calibrated at room temperature. Before testing, whether the freeze-drying chamber is in a dry state or not is checked, no residual water stain and the like exist after cleaning, and if not, the freeze-drying chamber is dried and then is cooled to room temperature for calibration.
Note: and starting a cooling program of the water vapor condenser after the vacuum leakage rate test is finished, wherein the set temperature is-70 ℃, or the temperature is selected according to the performance of the equipment to be calibrated and the user requirement.
3.3.5 Cooling Rate calibration
And (4) closing the air extraction valve, opening a release valve of the freeze dryer to release air until the atmospheric pressure of the freeze drying chamber is recovered, closing the isolation valve and the release valve, and stabilizing for 10 min. Recording the initial normal temperature and time of the equipment, starting a temperature control program of the freeze dryer, setting the target temperature to be 50 ℃ below zero, starting a temperature reduction program, starting recording, recording the temperature reduction time of the process when the target temperature is reduced to 50 ℃ below zero, and calculating the temperature reduction rate according to 3.4.1.
3.3.6 temperature uniformity in and between shelves, shelf temperature deviation, ultimate vacuum degree and working vacuum degree calibration
1) The calibration points generally comprise at least three points, namely-50 ℃, 0 ℃ and 55 ℃, and can also be selected according to the performance of the calibrated equipment and the requirements of users.
2) After the temperature reduction rate calibration is completed, an isolation valve of a freeze dryer is opened for vacuumizing, after the vacuum degree tends to be balanced, 16 groups of temperature and vacuum degree data are recorded within 30min after the shelf temperature reaches a stable state at minus 50 ℃, and the temperature uniformity, the shelf temperature deviation and the ultimate vacuum degree between shelves are calculated.
3) According to the sequence of the calibration points from low to high, when the target temperature is set to be 0 ℃, temperature control is started, 16 groups of temperature data are recorded within 30min after the temperature data reach a stable state, and the temperature uniformity and the temperature deviation of the shelves inside and between the shelves are calculated.
4) And keeping the target temperature at 0 ℃, calibrating the working vacuum degree, closing an isolation valve of the freeze dryer, adjusting an air release valve, adjusting the equipment pressure to 10Pa, closing an air inlet adjusting valve, recording the vacuum degree value of the standard device and the vacuum degree value of the equipment after stabilizing for 2min, recording the standard vacuum degree value and the vacuum degree value of the equipment again after 2min, and calculating the working vacuum degree. The plant pressure was adjusted to 100Pa and the working vacuum was recalibrated in the same manner.
5) The target temperature is set to be 55 ℃, the temperature control is started, the isolating valve of the freeze dryer is opened, 16 groups of temperature data are recorded within 30min after the stable state is reached, and the temperature uniformity and the temperature deviation between shelves are calculated.
3.4 data processing
3.4.1, cooling rate:
in the formula:
-cooling rate, deg.c/min;
3.4.2, temperature uniformity within the shelf:
and under the stable state of the freeze-drying equipment, the difference between the highest temperature and the lowest temperature of each shelf measured by each measuring point in each shelf in 30min is used as the temperature uniformity calibration result in each shelf.
In the formula:
-shelf temperature uniformity, ° c;
3.4.3 shelf-to-shelf temperature uniformity:
and under the stable state of the freeze-drying equipment, taking the maximum value of the difference between the highest temperature and the lowest temperature measured in 30min at each measuring point of all shelves as the temperature uniformity calibration result between the shelves.
In the formula:
-shelf temperature uniformity, deg.c;
3.4.4, shelf temperature bias:
in the formula:
-deviation in shelf temperature, ° c;
3.4.5, vacuum leak rate:
in the formula:
-vacuum leak rate of freeze dryer, Pa.m. ethanol/s;
3.4.6, ultimate vacuum degree:
in the formula: pmin-ultimate vacuum degree of freeze dryer, Pa;
3.4.7, working vacuum degree deviation:
in the formula:
-working vacuum degree deviation,%;
4. Time interval of recalibration:
the interval time between rechecks is recommended to be one year, and is properly shortened when the medicine is used particularly frequently. Recalibration is generally required whenever important components are repaired, replaced, etc. during use.
Because the length of the re-calibration time interval is determined by the using condition of the freeze dryer, the user, the quality of the device and other factors, the user can determine the re-calibration time interval according to the actual using condition.
In the description of the present invention, it is to be understood that the terms "first", "second" and the like are used for descriptive purposes only and are not to be construed as indicating or implying relative importance or implying any number of technical features indicated. Thus, a feature defined as "first" or "second" may explicitly or implicitly include one or more of that feature. In the description of the present invention, "a plurality" means two or more unless specifically defined otherwise.
It will be apparent to those skilled in the art that various changes and modifications may be made in the present invention without departing from the spirit and scope of the invention. Thus, if such modifications and variations of the present invention fall within the scope of the claims of the present invention and their equivalents, the present invention is also intended to include such modifications and variations.
Claims (9)
1. A method of calibrating a vacuum freeze dryer for pharmaceutical use, comprising the steps of:
carrying out appearance inspection on the medical vacuum freeze dryer;
calibrating the medicinal vacuum freeze dryer by acquiring the vacuum leakage rate, the cooling rate, the temperature uniformity in the shelf, the temperature uniformity among the shelves, the shelf temperature deviation, the ultimate vacuum degree and the working vacuum degree of the medicinal vacuum freeze dryer;
the calibration system for implementing the calibration method comprises:
the data acquisition module is used for acquiring the vacuum leakage rate, the cooling rate, the temperature uniformity in the shelf, the temperature uniformity among the shelves, the temperature deviation of the shelf, the ultimate vacuum degree and the working vacuum degree of the medical vacuum freeze dryer;
and the calibration module is used for calibrating the medicinal vacuum freeze dryer according to the vacuum leakage rate, the cooling rate, the temperature uniformity in the shelf, the temperature uniformity among the shelves, the shelf temperature deviation, the limit vacuum degree and the working vacuum degree.
2. A method of calibrating a pharmaceutical vacuum freeze dryer according to claim 1, wherein:
in the process of performing appearance inspection on the medicinal vacuum freeze dryer, the appearance requirements of the medicinal vacuum freeze dryer include:
the medical vacuum freeze dryer is complete in appearance structure and clear in identification, and the name, the model, the specification, the manufacturer, the factory number and the manufacture year and month of equipment are marked;
the inner surface of a freeze drying box of the medicinal vacuum freeze dryer is smooth and has no defects of dent and burr, and the freeze drying box of the medicinal vacuum freeze dryer is provided with a plurality of layers of shelves;
an indicator lamp and an instrument display of an electrical control system of the medicinal vacuum freeze dryer are clear, striking and free of defects of influencing readings;
the electric, hydraulic and vacuum pipeline systems of the medical vacuum freeze dryer are compact and reasonable in arrangement and regular in arrangement, and main pipelines have medium names and flow direction marks.
3. A method of calibrating a pharmaceutical vacuum freeze dryer according to claim 2, wherein:
after the appearance inspection process of the medical vacuum freeze dryer is carried out, arranging a temperature recorder and a vacuum recorder on shelves of each layer of the freeze drying box except for a top shelf, and setting a sampling time interval to be 2min and carrying out sterilization treatment, wherein the arrangement position of the temperature recorder is that one is arranged at each of four corners of the shelf and one is arranged at the center of the shelf, and the arrangement position of the vacuum recorder is the center of the shelf;
the temperature recorder and the vacuum recorder which are arranged at the center of the shelf are positioned at the same side or different sides.
4. A method of calibrating a pharmaceutical vacuum freeze dryer according to claim 3, wherein:
in the process of obtaining the vacuum leakage rate, closing a freeze-drying chamber door and an air release valve, sequentially opening a vacuum pump, an air extraction valve and an isolation valve, vacuumizing the freeze-drying chamber, continuously extracting air for 20min after the vacuum degree reaches 5Pa, closing the isolation valve, and recording the change curve of the vacuum degree along with the time, wherein the recording time is not less than 30 min;
obtaining the vacuum leak rate from a linear portion of the variation curve, wherein the vacuum leak rate is expressed as:
in the formula:
the vacuum leak rate of the freeze dryer is indicated,
represents the starting time of a linear segment in the curve of the vacuum degree along with the change of the time,
the end time of the linear segment in the vacuum level versus time curve,
to represent
The degree of vacuum at the time of the operation,
the volume of the lyophilization chamber is indicated.
5. A calibration method for a pharmaceutical vacuum freeze dryer according to claim 4, characterized in that:
in the process of obtaining the vacuum leakage rate, the vacuum leakage rate is calibrated at room temperature, whether the freeze-drying chamber is in a dry state or not is checked before testing, no residual water stain is left after cleaning, and if not, the freeze-drying chamber is dried and then is calibrated at room temperature.
6. A method of calibrating a pharmaceutical vacuum freeze dryer according to claim 5, wherein:
in the process of obtaining the cooling rate, closing the air extraction valve, opening a release valve of the freeze dryer to release air until the atmospheric pressure of the freeze drying chamber is recovered, closing the isolation valve and the release valve, and stabilizing for 10 min; the inceptive normal atmospheric temperature of recording equipment and time start freeze dryer accuse temperature procedure, set up the target temperature, start cooling procedure and begin the record, when reaching the target temperature, the cooling time of this process of record acquires cooling rate, wherein, cooling rate expresses to be:
in the formula:
which is indicative of the rate of temperature decrease,
which is indicative of the initial temperature of the shelf,
which is indicative of a target temperature for the shelf,
indicating the time difference recorded when the shelf temperature reached the target temperature from ambient.
7. A method of calibrating a pharmaceutical vacuum freeze dryer according to claim 6, wherein:
setting calibration points to be-50 ℃, 0 ℃ and 55 ℃ in the process of obtaining the temperature uniformity in the shelf, the temperature uniformity among shelves, the temperature deviation of the shelf, the ultimate vacuum degree and the working vacuum degree;
after the temperature reduction rate is calibrated, opening an isolation valve of a freeze dryer to vacuumize, after the vacuum degree tends to be balanced, recording 16 groups of temperature and vacuum degree data within 30min after the shelf temperature reaches a stable state at minus 50 ℃, and acquiring the temperature uniformity in the shelf, the temperature uniformity among the shelves, the temperature deviation of the shelf and the limit vacuum degree;
according to the sequence of the calibration points from low to high, when the target temperature is set to be 0 ℃, starting temperature control, recording 16 groups of temperature data within 30min after reaching a stable state, and acquiring the temperature uniformity in the shelf, the temperature uniformity among the shelves and the temperature deviation of the shelf;
keeping the target temperature at 0 ℃, calibrating the working vacuum degree, closing an isolation valve of a freeze dryer, adjusting a vent valve, adjusting the equipment pressure to 10Pa, closing an air inlet adjusting valve, stabilizing for 2min, recording the vacuum degree value of a standard device and the vacuum degree value of the equipment, recording the standard vacuum degree value and the vacuum degree value of the equipment again after 2min, and obtaining the working vacuum degree; adjusting the pressure of the equipment to 100Pa, and recalibrating the working vacuum degree in the same way;
setting the target temperature to 55 ℃, starting temperature control, opening an isolation valve of a freeze dryer, recording 16 groups of temperature data within 30min after reaching a stable state, and acquiring temperature uniformity in the shelf, temperature uniformity among the shelves and temperature deviation of the shelf;
and calibrating the medical vacuum freeze dryer according to the temperature uniformity in the shelf, the temperature uniformity among the shelves, the shelf temperature deviation, the limit vacuum degree and the working vacuum degree which are obtained from different calibration points.
8. A method of calibrating a pharmaceutical vacuum freeze dryer according to claim 7, wherein:
in the process of calibrating the medicinal vacuum freeze dryer, under the stable state of freeze drying equipment, the difference between the highest temperature and the lowest temperature of the shelf of each layer, which is measured by each measuring point in each shelf in 30min, is used as the calibration result of the temperature uniformity in the shelf of each layer;
the maximum value of the difference between the highest temperature and the lowest temperature measured in 30min by each measuring point of all shelves is used as the calibration result of the temperature uniformity among the shelves;
the shelf temperature deviation is expressed as:
in the formula (I), the compound is shown in the specification,
indicating a deviation in the temperature of the shelf,
the deviation in the temperature of the shelf is indicated,
represents the highest temperature measured within a prescribed time at each calibration point,
indicating the lowest temperature measured within the specified time at each calibration point,
indicating the set temperature of the device.
9. A method of calibrating a pharmaceutical vacuum freeze dryer according to claim 8, wherein:
in the process of acquiring the ultimate vacuum degree and the working vacuum degree, the ultimate vacuum degree is expressed as:
in the formula (I), the compound is shown in the specification,
the ultimate vacuum degree of the freeze dryer is shown,
is shown as
The number of measurements is then measured,
denotes the first layer first
The degree of vacuum of the secondary measurement,
denotes the second layer of
The degree of vacuum of the secondary measurement,
denotes the third layer
The vacuum degree of the secondary measurement;
the working vacuum is expressed as:
in the formula (I), the compound is shown in the specification,
the deviation of the working vacuum degree is shown,
the indication device indicates a degree of vacuum,
indicating the vacuum standard vacuum reference value.
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