JP2001264205A - Pinhole inspection - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a standard item efficiently measurable with excellent reproducibility and repeatedly usable as contrast when inspecting a medicine containing sealed vessel for pinholes (liquid leakage and air leakage). SOLUTION: The manufacturing method of medicine containing sealed vessel includes (1) a method of inspecting the medicine containing sealed vessel for pinholes by using as contrast the standard item which is a combination of a glass capillary having an inner diameter of 1 to 100 μm, a vessel body and a plug body, (2) the standard item which is formed by combining the glass capillary having the inner diameter of 1 to 100 μm, the vessel body and the plug body and is used as contrast when inspecting the medicine containing sealed vessel for pinholes and (3) a manufacturing method of medicine containing sealed vessel including the above pinhole inspection process.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a method for inspecting a pinhole (liquid leakage / air leakage) of a sealed container containing a medicine.

[0002]

2. Description of the Related Art According to the rules of the Japanese Pharmacopoeia, containers and sealed containers are defined as follows. The container is used to hold a medicine, and includes those used as a part of the container, such as a stopper and a lid. A sealed container is a container that is not subjected to gas or microorganisms during daily handling or in a normal storage state.

[0003] As such a sealed container, a container containing a liquid preparation (for example, an infusion preparation) and the like can be cited. However, since these must be kept hermetically sealed, they have fine holes (this is also called a pinhole). ) Caused pinholes (liquid leakage,
All products are inspected for any quality control during the manufacturing process to determine if air leaks have occurred. Methods for performing such a pinhole inspection include a vacuum differential pressure method, an applied voltage method using a high voltage, and the like. This pinhole inspection machine usually requires verification work. The test means adjusting and checking the condition (condition), measurement conditions, and the like of the inspection machine by using a container having a pinhole (referred to as a standard defective product) as a positive control. Conventionally, as this standard defective product, a defective product found in actual production or a commercially available product with a pierced metal injection needle having a minimum diameter has been used.

[0004] However, these standard defective products have the following problems. a) When a defective product found in actual production is used, a fine pinhole may expand or disappear due to an impact or the like due to a single inspection, and cannot be reused. A pinhole of any size cannot be prepared. b) When a metal injection needle is used, the inner diameter becomes relatively large.
The diameter is about 10 μm and the inner diameter is about 130 μm. In addition, since it is a metal needle, it cannot be used for an inspection device that electrically detects. In addition, reproducibility is required for the verification of the pinhole inspection machine, and the standard product is indispensable.

[0005]

SUMMARY OF THE INVENTION An object of the present invention is to provide an efficient and reproducible measurement as a control when inspecting pinholes (including liquid leaks and air leaks) in a sealed container containing a medicine. Moreover, it is to provide a standard product that can be used repeatedly.

[0006]

Means for Solving the Problems As a result of further studies in consideration of the above circumstances, the present inventors have prepared a thin glass tube having an inner diameter of 1 to 100 μm and combined it with a container body and a stopper. By creating a standard product and using it as a control, we found that the intended purpose could be achieved,
The present invention has been completed.

That is, the present invention provides 1) a method for inspecting a pinhole of a sealed container containing a medicine, comprising:
a method for testing using a standard product comprising a combination of a glass capillary having an inner diameter of μm, a container body and a stopper as a control,
2) A standard product comprising a combination of a glass capillary having an inner diameter of 1 to 100 μm, a container body and a stopper, and used as a control when inspecting a pinhole of a sealed container containing a medicine;
3) The present invention relates to a method for producing a sealed container containing a medicine, which comprises the above-described pinhole inspection step. The details will be described below.

[0008]

DESCRIPTION OF THE PREFERRED EMBODIMENTS A) Preparation of glass tubule The glass tubule of the present invention is prepared by melting a glass tube by heat and stretching the glass tube to 1 to 100 μm, preferably 10 to 70 μm.
It is prepared by making a thin tube having an inside diameter of the order and cutting it to the required length. The inside diameter is checked with a microscope.

B) Preparation of Standard Product A standard product for inspecting a pinhole of a plastic container is to insert a prepared thin glass tube into one of the gaps between the plug and the container body (bag) flange at the time of sealing the plug (cap). It is prepared by inserting and welding so that the tip is located inside the container and the other tip is located outside the container. FIG. 1 schematically shows a specific embodiment. The material and shape of the plastic are not particularly limited as long as they are acceptable as containers for pharmaceuticals. Examples of the plastic material include polyethylene, polypropylene, and polyvinyl chloride.

A standard product for inspecting a pinhole of a glass container with a rubber stopper is such that a prepared glass capillary is placed in a rubber stopper portion, one end is located inside the container, and the other end is located outside the container. Created by embedding so that it is located at Specifically, after sealing the glass container with a rubber stopper and a cap, an injection needle of an appropriate size is penetrated from the top surface of the cap to the inside of the container. Specifically, such an injection needle has a diameter of 30 G (outside diameter 310 μm,
Inner diameter of about 130 μm). It can be made by inserting the glass tube into the container and inserting the needle out of the container. FIG. 2 shows an outline of a specific embodiment. In addition, as for the medicine, a liquid preparation (content liquid) and a dry preparation may be appropriately selected according to the test object. Specifically, various infusions, for example, an electrolyte infusion, a saccharide infusion, a fat emulsion, an amino acid infusion, a dextran preparation, or various injections can be used.

C) Inspection of Inspection Machine As the pinhole inspection machine of the present invention, there are a vacuum differential pressure system, an applied voltage system and the like. The measurement principle of the vacuum differential pressure method is that the measurement part is evacuated to vacuum and the state is held for several seconds,
It detects the degree of vacuum that changes during that time and finds a pinhole. This method can be applied to both liquid leak and air leak inspection. Therefore, the medicine to be put in the container may be either a liquid preparation or a dry preparation. Specific examples of the inspection machine of this system include a package leak tester manufactured by Takachiho Seiki Co., Ltd. As the measurement conditions, a degree of vacuum of 8500 mmH ₂ O or the like is exemplified.

The measuring principle of the applied voltage method is to apply a voltage to a measuring portion, measure a passing current value, and detect a pinhole (liquid leak) according to the degree of the measurement. Since the intervention of liquid is essential, it cannot be applied to air leak inspection.
Therefore, this method can be applied to a sealed container containing a liquid preparation. More preferably, a high voltage application voltage method is used. Specific examples of the inspection machine of this system include a pinhole inspector manufactured by Nikka Denso Co., Ltd. As a measurement condition, a high voltage of 18 KV or the like is exemplified.

The measurement site of the hermetically sealed container containing a medicine is, for example, a close contact portion between a glass bottle and a rubber stopper if the container is a glass container with a rubber stopper. Further, in the case of a plastic container, a welded portion between the container body and the plug, a body portion of the container, and other places where a pinhole may be generated are exemplified.

D) Pinhole Inspection After measuring the standard product, a plurality of hermetically sealed containers containing actual pharmaceuticals are continuously measured in the same manner. In the case of the inspection by the vacuum differential pressure method, the presence or absence of a pinhole (liquid leakage / air leakage) of the container can be inspected using the degree of vacuum as an index. In the case of the inspection by the applied voltage method, the presence or absence of a pinhole (liquid leakage) of the container can be inspected by using the amount of flowing current as an index. Specifically, based on an actual measurement value of a standard product, if it is less than that value, it is evaluated as pass, and if it is more than that value, it is evaluated as reject. The pinhole inspection may be repeatedly performed on all the containers under the same conditions.

[0015]

EXAMPLES The following examples are provided to explain the present invention in more detail, but the present invention is not limited to these examples.

Example 1 Pinhole (liquid leakage) of a plastic container containing a liquid preparation
The inspection was performed as follows. The glass tubule was prepared by melting and stretching the glass tube by heat to form a tubule having an inner diameter of 50 μm and an outer diameter of 180 μm, and cutting it into a length of 10 cm. The inner diameter was confirmed with a microscope.

A standard product for inspecting a pinhole of a plastic container (made of polyethylene) is a glass tube having an inner diameter of 50 μm prepared as described above. 1) Inserted between the flanges such that one end is located inside the container and the other end is located outside the container, and was prepared by welding (FIG. 1). As a liquid preparation (content liquid), an electrolyte infusion [trade name: Physio (registered trademark) 35, manufactured by Yoshitomi Pharmaceutical Co., Ltd.] was used.

Using the prepared standard, a pinhole inspection machine was tested. The amount of current flowing under a high voltage of 18 KV was measured using an applied voltage type tester (product name: Pinhole Inspector, manufactured by Nikka Denso Co., Ltd.). The measurement points were the welded portion between the container body and the plug, and the container body. The degree of current obtained in this measurement was used as a reference value.

After the measurement of the standard product, the measurement was carried out in the same manner as in the case where 10 plastic containers containing the electrolyte infusion [Physio (registered trademark) 35] actually manufactured were continuously connected. When the flowing current was less than the reference value, the test was passed, and when the current exceeded the reference value, the test was rejected. The pinhole inspection was repeatedly performed on all the containers under the same conditions.

Example 2 A pinhole (liquid leakage) test of a glass container containing a liquid preparation was carried out as follows. A standard product for inspecting a pinhole of a glass container with a rubber stopper is such that the glass tube having an inner diameter of 50 μm prepared in Example 1 is placed in a rubber stopper portion, one end is located inside the container, and the other is. Was made by embedding so that the tip of the container was located outside the container (FIG. 2). That is, after sealing the glass container with a rubber stopper and a cap, a 30-G injection needle (outside diameter 310 μm, inside diameter 130 μm) was penetrated from the top of the cap to the inside of the container. It was created by inserting the glass tubing into this container to the inside of the container, and then extracting the needle from the inside of the container. The liquid preparation (content liquid) is ioxirane injection [nonionic X
Line contrast agent. The product name was Imaginir (registered trademark), manufactured by Japan Tobacco Inc.].

Using the prepared standard product, a pinhole inspection machine was tested. The inspection machine is a vacuum differential pressure type tester (product name is package leak tester, manufactured by Takachiho Seiki Co., Ltd.)
When the pressure was measured under a vacuum of 8500 mmH ₂ O, the degree (vacuum degree, leak value) was 25 mm.
Was H ₂ O. In addition, the measurement location was a contact portion between the rubber stopper and the cap and the container body.

After measuring the standard product, the contrast agent manufactured in actual production [top
Glass container containing 10 parts of Imaginyl (registered trademark)
The measurement was performed in the same manner as in the case of continuous measurement. Leak value 24.9
mmH _TwoPass if O or less, 25mmH_TwoO or more
Was rejected. Repeat for all containers under similar conditions.
Repeated pinhole inspection was performed.

[0023]

According to the present invention, when inspecting pinholes (liquid leakage / air leakage) of a sealed container containing a medicine, the standard product of the present invention is used as a control so that it can be efficiently used.
It is also possible to provide a standard product that can be measured and inspected with good reproducibility and that can be used repeatedly. Further, the glass thin tube of the present invention can be made with an arbitrary inner diameter. Since the pinhole is not destroyed (expanded) by the inspection machine, there is an effect that reproducibility can be obtained.

[0024]

[Brief description of the drawings]

FIG. 1 is a schematic view (cross-sectional view) of a standard product prepared when performing a pinhole (liquid leakage) test on a plastic container containing a liquid preparation according to the present invention.

FIG. 2 is a schematic diagram (cross-sectional view) of a standard product prepared when performing a pinhole (liquid leakage) test on a glass container (with a rubber stopper) containing a liquid preparation according to the present invention.

[0025]

[Explanation of symbols]

 DESCRIPTION OF SYMBOLS 1 Plug body (cap) 2 Plug body side welding part 3 Container main body (bag) 4 Container main body side welding part 5 Liquid preparation 6 Glass thin tube 7 Cap 8 Rubber stopper 9 Container main body 10 Liquid preparation 11 Glass thin tube

Claims (3)

[Claims] 1. A method for inspecting a pinhole of a sealed container containing a medicine, wherein a standard product comprising a combination of a thin glass tube having an inner diameter of 1 to 100 μm, a container body and a stopper is used as a control. 2. A standard product comprising a combination of a glass tube having an inner diameter of 1 to 100 μm, a container body and a stopper, and used as a control when inspecting a pinhole of a sealed container containing a medicine. 3. A method for producing a sealed container containing a medicine, comprising the pinhole inspection step according to claim 1.