JP2017211223A - Method and device for evaluating sealed inspection target - Google Patents

Abstract

PROBLEM TO BE SOLVED: To evaluate the flow rate of intrusion of an alteration causing material to an inspection target.SOLUTION: A leakage Qis measured by applying a test pressure on an inspection target 9 including a sealed package 91. The flow rate Qof intrusion by diffusion of the alteration causing material to an inspection target 9 is evaluated on the basis of the correlation between the size of a hole through which the alteration causing material for water vapor or oxygen, for example, is diffused and the flow rate of the diffusion and on the basis of the result of measurement Q.SELECTED DRAWING: Figure 1

Description

  The present invention relates to a method and an evaluation apparatus for evaluating an inspection object including a sealed package, for example, an evaluation suitable for evaluating a water absorption amount, a reaction amount with oxygen, and the like in an inspection object such as a sealed medicine or food. The present invention relates to a method and an evaluation apparatus.

For example, pharmaceutical products are usually sealed with a hermetic package such as PTP packaging or pillow packaging. However, even a sealed package may be slightly air permeable or may have fine defect holes. If it does so, it will change with air over a long period of time, especially, it may change with the water | moisture content, oxygen, etc. in air, and there exists a possibility that an effect may decline.
Conventionally, in order to assure the quality of this kind of pharmaceutical product, the amount of water absorbed was measured by placing an arbitrarily sampled sample in a predetermined test environment (for example, 40 ° C., 90% RH, etc.) for a predetermined time. The actual measurement period was, for example, about 1 month to several months.

  In Patent Document 1, the product expiration date is managed by providing a detection sensor for moisture or the like in the product and measuring the moisture absorption amount or the like of the product.

Special table 2012-529030 gazette ([0040] etc.)

  It takes a long time to evaluate the amount of water absorption by the actual measurement. Further, in the sampling inspection, when a defect determination is made, all the lots corresponding to the sample are treated as defective, which is wasteful.

In order to solve the above problems, the method of the present invention is an evaluation method of an inspection object including a sealed package,
Measuring leakage in the inspection object by applying a test pressure to the inspection object;
Characterized in that, based on the correlation between the pore size and the diffusion flow rate when the alteration-inducing substance diffuses through the pores, and the measurement result, the infiltration flow rate of the alteration-inducing substance into the test object is evaluated. To do.

The method of the present invention is an evaluation method for an inspection object including a sealed package,
Based on the correlation between the pore size and the diffusion flow rate when the alteration-inducing substance diffuses through the pores, and the measurement result of leakage obtained by applying a test pressure to the inspection object, the alteration-inducing substance The intrusion flow rate into the inspection object is evaluated.

The device of the present invention is an evaluation device for an inspection object including a sealed package,
A measurement unit that measures leakage in the inspection object by applying a test pressure to the inspection object;
An evaluation processing unit that evaluates the infiltration flow rate of the alteration-inducing substance into the test object based on the correlation between the pore size and the diffusion flow rate when the alteration-inducing substance diffuses through the pores, and the measurement result; ,
It is provided with.

If the sealed package to be inspected has a slight air permeability or has a fine defect hole, leakage occurs due to the application of the test pressure. The size of the leak depends on the degree of air permeability and the size of the defect hole in addition to the test pressure. In other words, the degree of air permeability of the sealed package and the size of the defect hole can be estimated from the test pressure and the size of the leak. By assuming that a virtual hole (leak hole) is formed in the sealed package, the degree of air permeability and the size of the defective hole can be replaced with the size of the virtual hole. It is preferable to assume that the cross-sectional shape of the virtual hole is a perfect circle. The length of the virtual hole is preferably equal to the thickness of the sealed package.
Furthermore, the diffusion flow rate when the alteration-inducing substance diffuses through the pores has a certain correlation with the pore size. As a result, the flow rate at which the alteration-inducing substance permeates into the inspection object has a certain correlation with the size (cross-sectional area and length) of the virtual hole. That is, the intrusion flow rate depends on the cross-sectional area and length of the virtual hole and the diffusion coefficient of the alteration-inducing substance, and is a theoretical formula of a correlation based on a substance diffusion principle such as Fick's law (see formula 3 described later). Can be used to estimate. Further, a correlation between the pore size and the diffusion flow rate of the alteration-inducing substance is obtained in advance by experiment, and based on the experimental data of this correlation and the size of the virtual pore estimated from the measurement result of the leak. Thus, the infiltration flow rate of the alteration-inducing substance into the test object may be estimated (evaluated). The process of estimating the size of the virtual hole from the measurement result of the leak and the process of estimating the intrusion flow rate from the size of the virtual hole and the correlation may be sequentially performed in separate steps, and the two processes are combined. Thus, the process of estimating the intrusion flow rate may be performed directly (without calculating the size of the virtual hole) from the leakage measurement result and the correlation. Even in the latter method, as long as the leakage measurement result and the intrusion flow rate are combined, it can be said that a processing portion for estimating the size of the virtual hole from the leakage measurement result is inherent.

The obtained estimated infiltration flow rate is an index for evaluating the amount of absorption of the alteration-inducing substance or the reaction amount with the alteration-inducing substance in the test object. Alternatively, the estimated intrusion flow rate can be an index for quality evaluation of an inspection target. For example, using the estimated intrusion flow rate, it is guaranteed that the quality of the inspection object is maintained until the expiration of the quality assurance period (including the expiration date, expiration date, and expiration date), or the inspection object until the expiration of the quality assurance period The quality maintenance time or quality assurance period until the amount of diffusion of the alteration-inducing substance into the test object reaches an allowable amount is determined. Can be set.
Examples of inspection targets include foods in addition to pharmaceuticals.
Examples of alteration-inducing substances include moisture (water vapor) and oxygen in the air.

  According to the present invention, it is possible to evaluate the inflow rate of the alteration-inducing substance into the test object in a very short time. For example, it is possible to evaluate the amount of water absorption and the amount of reaction with oxygen in a test object such as a pharmaceutical or food in a short time. It is also possible to inspect all inspection objects.

FIG. 1 is a circuit configuration diagram of an evaluation apparatus according to an embodiment of the present invention. FIG. 2 is a flowchart showing a method for evaluating an inspection object by the evaluation apparatus. FIG. 3 is a time chart showing the valve operation in the measurement process of the evaluation apparatus.

Hereinafter, an embodiment of the present invention will be described with reference to the drawings.
As shown in FIG. 1, the test object 9 of this embodiment is a pharmaceutical product. The inspection object 9 includes an object main body 90 that is a content and a sealed package 91. The sealed package 91 is a PTP package, but is not limited thereto, and may be another sealed package such as a pillow package. The object main body 90 is accommodated in the sealed package 91 in a sealed state. The object main body 90 is a medical main body such as a tablet. The object main body 90 has a property of causing alteration such as quality deterioration when moisture is absorbed. Air around the inspection object 9, that is, moisture (water vapor) in the atmospheric gas becomes a substance that induces alteration to the object main body 90.

  As shown in FIG. 1, the evaluation device 1 evaluates the inspection object 9. Here, the evaluation contents include calculation of the estimated intrusion flow rate of the alteration-inducing substance into the inspection object 9. Furthermore, as evaluation contents, the quality determination of the inspection object 9 using the estimated intrusion flow rate, the estimation of the quality maintenance period of the inspection object 9, the determination of the quality assurance period of the inspection object 9, the threshold for determining the quality of the inspection object 9 Settings and the like may be included.

  As shown in FIG. 1, the evaluation device 1 includes a measurement unit 2 and an evaluation processing unit 3. The measurement unit 2 includes a measurement circuit 10 and a test container 20 (a test target storage unit). The measurement circuit 10 includes a test pressure path 11, a tank 12, a differential pressure path 14, and a differential pressure gauge 15.

  A pressure source 4 is connected to the upstream end of the test pressure path 11 via a pressure supply path 17. The pressure supply path 17 is provided with a regulator 31 and a pressure supply path opening / closing valve 37. The pressure source 4 may be a positive pressure source such as a compressor or a negative pressure source such as a vacuum pump. The pressure medium of the pressure source 4 is usually dry air. Depending on the sealed package 91, it may be selected whether to use a positive pressure source or a negative pressure source. For example, in the case of PTP packaging or the like, it is preferable to select a positive pressure source when there is a possibility that the sealing portion may be peeled off due to a negative pressure.

The tank 12 and the cuvette 20 are connected by the test pressure path 11. The tank 12 is provided with a test pressure gauge 13 composed of a direct pressure gauge. A test pressure path opening / closing valve 32 is provided in the test pressure path 11. The test pressure P ₁ is set by the regulator 31.

  A differential pressure path 14 is connected to the test pressure path 11. A differential pressure gauge 15 and a differential pressure path opening / closing valve 34 are provided in the differential pressure path 14. An air release path 16 is branched from the differential pressure path 14. An atmosphere release path opening / closing valve 36 is provided in the atmosphere release path 16.

  The cuvette 20 is openable and closable and accommodates the test object 9 and can be sealed. An inspection space 19 is configured by the internal space of the inspection container 20 (excluding the space occupied by the inspection object 9) and the portion connected to the internal space when the pressure change Δp described later in the measurement circuit 10 is measured.

The evaluation processing unit 3 may be configured by a microcomputer in a controller attached to the measurement unit 2 or may be configured by a PC (personal computer). The storage unit 3m of the evaluation processing unit 3 stores arithmetic processing such as equations 1 to 3 described later, and thus a program for quality evaluation of the inspection object 9 and the like. The evaluation processing unit 3 executes arithmetic processing (evaluation processing) for the quality evaluation.
The evaluation processing unit 3 only needs to be capable of performing an evaluation process using the measurement result of the measurement unit 2, and does not necessarily have to be attached to the measurement unit 2.

A method for evaluating the quality of the inspection object 9 using the evaluation apparatus 1 will be described with reference to the flowchart of FIG.
The inspection object 9 is accommodated in the inspection container 20 of the evaluation apparatus 1 and the inspection container 20 is sealed.
Measuring the pressure leakage amount by applying a test pressure P ₁ on the test object 9 (step 101).
Specifically, as shown in the time chart of FIG. 3, the pressure is accumulated in the tank 12 through the normally open pressure supply path opening / closing valve 37.
The air release path opening / closing valve 36 is closed, the pressure supply path opening / closing valve 37 is closed, the test pressure path opening / closing valve 32 is opened, and the test pressure P ₁ is introduced into the cuvette 20.
Here, the presence or absence of a large leak is determined based on the measured pressure of the test pressure gauge 13. If the inspection object 9 has a relatively large defect hole, the measurement pressure is out of the predetermined range. Thereby, the inspection object 9 can be determined as a large leakage defective product.
Next, the test pressure path opening / closing valve 32 is closed, and then the differential pressure path opening / closing valve 34 is closed.
Then, the pressure change ΔP in the examination space 19 is measured by the differential pressure gauge 15.
Thereafter, the differential pressure path opening / closing valve 34, the atmosphere release path opening / closing valve 36, and the pressure supply path opening / closing valve 37 are sequentially opened.

ここで、Ｖ_１９は、検査空間１９の容積である。
Δｔは、圧力変化ΔＰの測定時間である。 After the measurement, the evaluation processing unit 3 calculates the leak amount Q ₉ [Pa · m ³ / s] from the pressure change measurement value ΔP using the following equation (1) (step 102).

Here, V ₁₉ is the volume of the examination space 19.
Δt is a measurement time of the pressure change ΔP.

<Estimate the size of the virtual hole>
Then, based on the amount of leakage _{Q 9} and the test pressure _{P 1,} to estimate the size of the virtual hole sealed packages 91 (step 103).
Specifically, it is assumed that a virtual hole having a perfect circular cross section with a diameter D ₉ is formed in the sealed package 91. The length of the virtual holes may be equal to the thickness t ₉ sealed packages 91. According to Hagen Poire's law, the amount of leakage Q ₉ depends on the size of the virtual hole (cross-sectional area or diameter D ₉ and length t ₉ ) and the test pressure P ₁ (absolute pressure). The relationship is expressed by the following formula, for example.

ここで、ηは、漏れ試験に用いた気体の粘性係数であり、試験環境温度に依存する。試験環境温度は、評価装置１の内部又は周辺に設けた温度センサ（図示省略）によって取得できる。
ｔ_９は、密封パッケージ９１の厚みである。
Ｐ_０は、大気圧（絶対圧）であり、試験前の密封パッケージ９１の内圧である。
式２を用いて、仮想孔径Ｄ_９を算出できる。

Here, η is the viscosity coefficient of the gas used in the leak test and depends on the test environment temperature. The test environment temperature can be acquired by a temperature sensor (not shown) provided in or around the evaluation apparatus 1.
t ₉ is the thickness of the sealed package 91.
P ₀ is atmospheric pressure (absolute pressure), and is the internal pressure of the sealed package 91 before the test.
Using Equation 2 can be calculated virtual hole diameter D _9.

Formula 1 and Formula 2 are theoretical formulas when the unit of the leakage amount Q ₉ is (Pa · m ³ / s). When the unit of the amount of leakage Q ₉ and molar flow (mol / s) of formula 1, the right side of Equation 2 may be allowed divided by the gas constant R and the absolute temperature T.
The above formula 2 is suitable when the virtual hole length t ₉ is somewhat or sufficiently larger than the diameter D ₉ , that is, when the virtual hole can be regarded as a long tube. When the virtual hole length t ₉ is not sufficiently large with respect to the diameter D ₉ , that is, when the virtual hole can be regarded as an orifice, it is preferable to use a theoretical formula corresponding to the orifice.

ここで、Ｐｅ_Ｈ２Ｏは、雰囲気ガス（空気）中の水蒸気分圧であり、好ましくは検査対象９の評価条件（温度及び湿度）に応じて決定される。例えば、評価条件が温度３１３.２Ｋ（＝４０℃）、相対湿度９０％ＲＨであれば、Ｐｅ_Ｈ２Ｏ＝６６３９．６Ｐａとする。
Ｐｉ_Ｈ２Ｏは、検査対象９内の水蒸気分圧である。例えば、検査対象９内は乾燥しているものとし、Ｐｉ_Ｈ２Ｏ＝０Ｐａとする。式３から明らかな通り、検査対象９内の水蒸気分圧Ｐｉ_Ｈ２Ｏの設定値が小さい程、評価（Ｑ_Ｈ２Ｏの大きさ）がより厳しくなり、信頼性が高まる。
Ｒは、気体定数（８．３１４［Ｊ／（ｍｏｌ・Ｋ）］）である。
Ｔは、絶対温度［Ｋ］である。
Ｄ_Ｈ２Ｏは、空気と水蒸気の相互拡散係数であり、温度Ｔに依存する。温度Ｔは、好ましくは検査対象９の評価条件に応じて決定する。例えば温度Ｔが、Ｔ＝３１３.２Ｋ（＝４０℃）であれば、Ｄ_Ｈ２Ｏ＝０．００００２５９［ｍ^２／ｓ］となる。 <Estimation of intrusion flow rate Q _H2O >
Next, based on the correlation between the pore size and the diffusion flow rate when the water vapor (the alteration-inducing substance) diffuses through the pores and the measurement result (Q _{9 and} thus D ₉ ), Estimate (evaluate) the intrusion flow rate Q _H2O due to diffusion into (step 104). That is, according to the principle of gas diffusion (Fick's law), the intrusion flow rate Q _H2O [mol / s] depends on the size of the virtual hole (diameter D ₉ and length t ₉ ). It can be assumed that the equation holds.

Here, Pe _{H 2 O} is a water vapor partial pressure in the atmospheric gas (air), and is preferably determined according to the evaluation conditions (temperature and humidity) of the inspection object 9. For example, when the evaluation conditions are a temperature of 313.2 K (= 40 ° C.) and a relative humidity of 90% RH, Pe _{H 2 O} = 6639.6 Pa.
Pi _{H 2 O} is the water vapor partial pressure in the inspection object 9. For example, the inside of the inspection object 9 is assumed to be dry, and Pi _H2O = 0 Pa. As is clear from Equation 3, the smaller the set value of the water vapor partial pressure Pi _H2O in the inspection object 9, the more severe the evaluation (the magnitude of Q _H2O ) and the higher the reliability.
R is a gas constant (8.314 [J / (mol · K)]).
T is the absolute temperature [K].
_{DH 2 O} is an interdiffusion coefficient of air and water vapor, and depends on the temperature T. The temperature T is preferably determined according to the evaluation condition of the inspection object 9. For example, when the temperature T is T = 313.2 K (= 40 ° C.), D _H2O = 0.0000259 [m ² / s].

Using Equation 3, the estimated infiltration flow rate Q _H2O [mol / year] can be calculated. Thereby, the water absorption [g or mol] of the object main body 90 per unit time (for example, one year) can be evaluated.

Furthermore, based on the estimated intrusion flow rate Q _H2O , is the diffusion amount of water vapor into the inspection object 9 before the expiration of the quality assurance period of the inspection object 9 (including the expiration date, expiry date, and expiration date) less than the allowable amount? Can be determined. Alternatively, can be set for the amount of diffusion into the test object 9 of water vapor to the expiration of the quality assurance period of the examination object 9 is within an acceptable range, a threshold amount of leakage Q ₉ or estimated penetration rate Q _{H2 O.}
Alternatively, based on the estimated intrusion flow rate Q _H2O , the quality maintenance time until the diffusion amount of the water vapor into the inspection object 9 reaches the allowable amount can be estimated.
As described above, according to the present invention, the quality of the inspection object 9 can be evaluated in a short time.

The present invention is not limited to the above embodiment, and various modifications can be made without departing from the spirit of the present invention.
For example, the estimated intrusion flow rate Q _H2O may be obtained directly from the leakage amount Q ₉ without going through the virtual hole diameter D ₉ calculation (step 103) by combining the equations 2 and 3 into one equation. Even in this case, we can be said that what is the leakage amount Q ₉ inherent long as incorporation into the theoretical equation of gas diffusion, the size of the virtual hole from leaking amount Q ₉ an operation portion for estimating a (hole diameter D ₉₎ (step 103) .
In Step 104, instead of using a theoretical formula such as Formula 3, a correlation between the pore size and the diffusion flow rate of water vapor (altering substance) is obtained in advance by experiment, and the experimental data and the measurement result are obtained. based on the (leakage amount _{Q 9} turn virtual hole diameter _{D 9),} the infiltration flow rate _{Q H2 O} by diffusion may be estimated (evaluated). The experimental data may be stored in the storage unit 3m of the evaluation processing unit 3 as a matrix or an approximate expression.
The alteration-inducing substance is not limited to water vapor (water) in the air, but may be oxygen or the like. The alteration-inducing substance may be air itself.
The inspection object 9 is not limited to a medicine, and may be food (for example, rice cracker).
The inspection object 9 may be composed of only the sealed package 91. That is, the inspection target 9 may be the sealed package 91 in which the contents are not stored. After the evaluation, the contents may be sealed in the sealed package 91. Examples of the inspection object 9 including only the sealed package 91 include a pouch container with a mouth that is sealed after the contents are accommodated, various containers at the development stage, and the like.
The circuit structure of the measurement unit 2 can be modified as appropriate. For example, a direct pressure gauge may be used in place of the differential pressure gauge 15 as a means for measuring the pressure change ΔP.

  The present invention can be applied to, for example, quality evaluation of pharmaceutical products.

P ₁ Test pressure Q ₉ Pressure leak amount Q _H2O estimated intrusion flow rate D ₉ Virtual hole diameter 9 Inspection object 90 Target body 91 Sealed package 1 Evaluation device 2 Measurement unit 3 Evaluation processing unit 3m Storage unit 4 Pressure source 10 Measurement circuit 11 Test pressure Path 12 Tank 13 Test pressure gauge 14 Differential pressure path 15 Differential pressure gauge 16 Atmospheric release path 17 Pressure supply path 19 Inspection space 20 Inspection container 31 Regulator (Test pressure setting means)
32 Test pressure path on / off valve 34 Differential pressure path on / off valve 36 Air release path on / off valve 37 Pressure supply path on / off valve

Claims (3)

An evaluation method for an inspection object including a sealed package,
Measuring leakage in the inspection object by applying a test pressure to the inspection object;
Characterized in that, based on the correlation between the pore size and the diffusion flow rate when the alteration-inducing substance diffuses through the pores, and the measurement result, the infiltration flow rate of the alteration-inducing substance into the test object is evaluated. Evaluation method to do. An evaluation method for an inspection object including a sealed package,
Based on the correlation between the pore size and the diffusion flow rate when the alteration-inducing substance diffuses through the pores, and the measurement result of leakage obtained by applying a test pressure to the inspection object, the alteration-inducing substance An evaluation method comprising evaluating an intrusion flow rate into the inspection object. An evaluation device for a test object including a sealed package,
A measurement unit that measures leakage in the inspection object by applying a test pressure to the inspection object;
An evaluation processing unit that evaluates the infiltration flow rate of the alteration-inducing substance into the test object based on the correlation between the pore size and the diffusion flow rate when the alteration-inducing substance diffuses through the pores, and the measurement result; ,
An evaluation apparatus comprising:

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