JP7848817B2 - Method for manufacturing powder-filled containers - Google Patents

Description

This invention relates to a method for inspecting for foreign matter in powder contained in a transparent container, and to a method for manufacturing a powder-containing container.

Conventionally, powdered pharmaceuticals such as injectables, powders, granules, and fine powders are packaged in transparent containers such as vials. Methods for inspecting for foreign matter in the powder within these transparent containers include visual inspection and analysis of optically obtained image data (Patent Document 1). The foreign matter detection method described in Patent Document 1 involves applying a combined vertical and horizontal vibration to a transparent container filled with powder to optically detect foreign matter in the powder.

Patent No. 5307459

However, powders with poor fluidity do not disperse and flow due to synthetic vibrations, but rather flow as clumps. This means that foreign matter contained within the flowing powder does not appear on the surface of the clumps, resulting in a poor detection rate of foreign matter. Consequently, there is a risk that a product containing foreign matter may be mistakenly identified as a good product, even if such foreign matter is present.

This invention has been made in view of the above circumstances, and its objective is to provide a method for manufacturing a powder-containing container that can accurately determine the presence of foreign matter in the powder inside a transparent container and has a low defect rate.

(1) The method for manufacturing a powder-containing container according to the present invention includes a sealing step of sealing powder in a transparent container, an inspection step of inspecting for foreign matter in the powder, and a defective product sorting step of determining that transparent containers containing foreign matter are defective. The inspection step involves applying vibration to the transparent container via a support portion, while simultaneously applying reciprocating vibration in a first direction and reciprocating vibration in a second direction intersecting the first direction to the support portion, thereby causing the powder inside the transparent container to flow. The flowing powder is then optically photographed through the transparent container, and a determination is made based on the captured image whether foreign matter is present in the powder.

During the inspection process, vibrations applied via the support structure cause clumps of powder inside the transparent container to break down, making the powder more likely to scatter. Reciprocating vibrations in the first and second directions cause the powder to circulate and flow within the transparent container. As a result, the powder flows and scatters within the transparent container, making it easier for foreign matter to be exposed during the inspection process and appear in the captured images. Furthermore, in the defective product sorting process, transparent containers found to contain foreign matter are considered defective, resulting in a low foreign matter contamination rate among the manufactured powder-containing containers.

(2) Preferably, the transparent container has a container body having a mouth, a side wall continuous with the mouth, and a bottom continuous with the side wall, and a lid that is sealed at the mouth. In the sealing process, the lid is sealed at the container body that stores the powder.

By accurately inspecting the powder sealed in transparent containers for foreign matter contamination, powder-containing containers with a low foreign matter contamination rate are manufactured.

(3) Preferably, in the inspection process described above, the first direction and the second direction are perpendicular to each other, and the support portion supports the third direction in which the opening and the bottom face each other, perpendicular to the first and second directions, and photographs the flowing powder through the side wall.

Because the powder accumulating at the bottom of the transparent container flows along the side walls, foreign matter within the powder is easily exposed, making it more likely to appear in the captured images.

(4) Preferably, the third direction is inclined with respect to the horizontal direction such that the opening is above the bottom.

Because the powder flowing along the side wall of the transparent container is located towards the bottom, the area in which the image is captured is easily limited.

(5) Preferably, in the inspection process described above, the flowing powder is photographed from below the transparent container.

Since the image captures the collision between powder flowing through the transparent container and the reciprocating vibration of the container, foreign objects are likely to appear in the captured image.

(6) Preferably, the angle of repose of the powder is within the range of 30 to 60 degrees.

According to the present invention, the presence of foreign matter in the powder inside the transparent container can be accurately determined, thus enabling the creation of a powder packaging container with a low rate of foreign matter contamination.

Figure 1 is a perspective view of vial 20. Figure 2 is a schematic diagram of the foreign object inspection device 10. Figure 3 shows the inclination of the vial 20 held by the clamp 12. Figure 4 shows the powder 21 undergoing elliptical motion within the vial 20.

The embodiments of the present invention will be described below with reference to the drawings as appropriate. It should be noted that the embodiments described below are merely examples of the present invention, and the embodiments can be modified as appropriate without altering the essence of the invention. In the following description, the vertical direction 5 is defined with respect to the top and bottom, the front-to-back direction 6 (the direction perpendicular to the plane of the paper in Figure 2) is defined perpendicular to the vertical direction 5, and the left-to-right direction 7 is defined perpendicular to both the vertical direction 5 and the front-to-back direction 6.

[Vial 20 and powder 21]
As shown in Figure 1, the object to be inspected by the foreign matter inspection device 10 described later is a vial 20 (an example of a transparent container and a powder-containing container) containing the powder 21. Although not shown, the vial 20 is sealed by a known method, for example, by wrapping the lid 22 and the container body 23 with an aluminum cap. The powder 21 is a drug such as an injectable drug, powder, fine granules, or granules. The drug is not particularly limited, but for example, cell wall synthesis inhibitory antibiotics, cell membrane inhibitory antibiotics, nucleic acid synthesis inhibitory antibiotics, protein synthesis inhibitory antibiotics, folic acid metabolic pathway inhibitory antibiotics, β-lactamase inhibitors, sulfonamides, and anti-infective drugs are preferred. In addition, the drugs include ampicillin, bacampicillin, amoxicillin, pibmecillinam, amoxicillin, sultamicillin, piperacillin, aspoxylin, benzylpenicillin, cloxacillin, oxacillin, carbenicillin, cephalocul, cefuroxazine, cefadroxyl, cefixime, cefteram pivoxil, cefuroxime axetil, cefpodoxime proxetil, cefotiam hexetil, cefdinir, ceftibuten, cefditoren pivoxil, cefcapene pivoxil, cefazolin, cefozopran, cefmetazole, cefotiam, cefsulodine, cefoperazone, cefotaxime, and cefmenoxy. Ceftriaxone, ceftazisim, cefodisim, cefpirom, cefepime, faropenem, imipenem, panipenem, meropenem, biapenem, doripenem, aztreonam, vancomycin, teicoplanin, fosfomycin, polymyxin sulfate B, colistin sulfate, gramicidin S, amphotericin B, levofloxacin, ofloxacin, norfloxacin, enoxacin, ciprofloxacin, lomefloxacin, tosufloxacin, sparfloxacin, gatifloxacin, prulifloxacin, moxifloxacin, pazufloxan, rifampicin, dibekacin, tobramycin, amikacin, isepamycin Micronomycin, streptomycin, kanamycin, gentamicin, erythromycin, rokitamycin, josamycin, loxromycin, clarithromycin, azithromycin, telithromycin, doxycycline, minocycline, chloramphenicol, lincomycin, clindamycin, trimethoprim, clavulanic acid, sulbactam, tazobactam, sulfamethoxazole, salazopyrin, isoniazid, rifampicin, pyrazinamide, ethambutol, griseofulvin, amphotericin B, 5-fluorocytosine, fluconazole, miconazole, itraconazole, acyclovir, Examples include ganciclovir, foscavir, doxuridine, amantadine, interferon-gamma, ribapirin, lamipudine, metronidazole, tinidazole, fluconazole, mebendazole, pyrantel pamoate, diethylcarbamazine, praziquantel, albendazole, ivermectin, quinupristin, dalfopristin, linezolid, spectinomycin, netylmycin, sisomycin, lincosamin, ramoplanin, telithromycin, nystatin, fusidic acid, chlorhexidine, and polyhexanide.

The characteristics of the powder 21 include, for example, the angle of repose, particle size, packing amount, and bulk density. Specifically, the angle of repose of the powder 21 is in the range of 30 to 60 degrees, preferably in the range of 33 to 60 degrees. Specifically, the particle size of the powder 21 is in the range of 20 μm to 70 μm for the average particle diameter (median diameter: d50), preferably in the range of 21.1 μm to 55.7 μm. The packing amount of powder 21 contained in the vial 20 is at least 0.25 g, and even if the packing amount is large, it can be inspected by the foreign matter inspection device 10. Specifically, the bulk density of the powder 21 is in the range of 0.300 g/mL to 0.700 g/mL, preferably in the range of 0.340 g/mL to 0.670 g/mL.

As shown in Figure 1, the vial 20 (an example of a transparent container) has a lid 22 and a container body 23. The lid 22 is molded from a resin such as rubber or elastomer. The container body 23 is made of, for example, transparent glass. The container body 23 only needs to have enough light transmission so that the powder 21 inside the container can be optically photographed by the imaging device 15 (see Figure 2).

The container body 23 has a mouth portion 24 that forms an opening to the internal space, side walls 25, and a bottom portion 26. The container body 23 is generally cylindrical in shape, and is a so-called narrow-mouthed container, where the outer diameter of the mouth portion 24 is smaller than the outer diameter of the side walls 25. The mouth portion 24 and the bottom portion 26 face each other. The bottom portion 26 is disc-shaped, and the container body 23 stands upright with the bottom portion 26 resting on a table or the like, with the opening formed by the mouth portion 24 facing upwards. The side walls 25 are cylindrical. The mouth portion 24 is continuous with the side walls 25. The mouth portion 24 has a shape where its outer diameter gradually widens towards the side walls 25. The side walls 25 and the bottom portion 26 are continuous. The outer diameters of the side walls 25 and the bottom portion 26 are equivalent.

The lid 22 has a shape in which a protrusion extends from a disc that is in close contact with the mouth portion 24, and enters and fits into the opening formed by the mouth portion 24. For example, powder 21 is filled into the container body 23 by a filling machine, the lid 22 is pressed onto the mouth portion 24, and an aluminum cap is rolled up to seal the container body 23.

[Foreign object inspection device 10]
The foreign matter inspection device 10 inspects whether foreign matter is present in the powder 21 sealed in the vial 20. As shown in Figure 2, the foreign matter inspection device 10 comprises a frame 11, a clamp 12 (an example of a support), a vibration generator 13, a composite vibration generator 14, an imaging device 15, an analysis device 16, and an illumination device 17. The support 12, vibration generator 13, composite vibration generator 14, and imaging device 15 are supported by the frame 11. The frame 11 is capable of changing its orientation so that its front-to-back direction 6 is tilted from the horizontal direction while supporting the support 12, vibration generator 13, composite vibration generator 14, and imaging device 15. The analysis device 16 is connected to the imaging device 15 for data communication.

The clamps 12 are divided into pairs, one on the left and one on the right, and by moving each of them in the left and right directions 7, they change between a state where they grip the vial 20 and a state where they do not grip the vial 20. The clamps 12 grip the side walls 25 of the vial 20 from the left and right directions 7. When the clamps 12 are gripping the vial 20, the direction in which the mouth 24 and the bottom 26 face each other (an example of a third direction), that is, the axial direction of the container body 23, is parallel to the front and back direction 6.
Furthermore, when the clamp 12 is holding the vial 20, a portion of the side wall 25 of the vial 20 is exposed in the vertical direction 5.

The vibration generator 13 is fixed to each of the pair of clamps 12 in a position that does not come into contact with the vial 20. The vibration generator 14 generates vibrations, for example, by the rotation of an eccentric motor. The vibrations generated by the vibration generator 13 are transmitted to the vial 20 via the clamps 12.

The combined vibration generator 14 applies reciprocating vibrations to the clamp 12 in the vertical direction 5 (an example of a first direction) and in the horizontal direction 7 (an example of a second direction). The combined vibration generator 14 includes a motor 40, a vertical vibration generating mechanism 41, and a horizontal vibration generating mechanism 42. The motor 40 generates the driving force transmitted to the vertical vibration generating mechanism 41 and the horizontal vibration generating mechanism 42.

The vertical vibration generating mechanism 41 includes an eccentric disc cam 43, a camshaft 44, a link arm 45, and a slider 46. The eccentric disc cam 43 is rotatably supported on a camshaft 44 that is supported by the frame 11 and extends along the longitudinal direction 6. The eccentric disc cam 43 is mounted on the camshaft 44. The eccentric disc cam 43 protrudes radially from the camshaft 44. The length of the eccentric disc cam 43 protruding from the camshaft 44 changes continuously in the circumferential direction of the camshaft 44.

The link arm 45 is slidably fitted to the eccentric disc cam 43. The rotation of the eccentric disc cam 43 is transmitted to the link arm 45, causing the link arm 45 to rotate while being displaced vertically 5. The link arm 45 is connected to the slider 46 via a shaft 47. The slider 46 is movable along the vertical direction 5 by fitting into a slide rail 54 provided on the slider 51 of the left-right vibration generating mechanism 42. Therefore, the slider 46 reciprocates vertically 5 by the amount of vertical movement 5 of the rotation of the link arm 45.

The link arm 45 has a support arm 55 that extends along the left-right direction 7. The support arm 55 supports the clamp 12 and the vibration generator 14.

The left-right vibration generating mechanism 42 includes an eccentric disc cam 48, a camshaft 49, a link arm 50, and a slider 51. The eccentric disc cam 48 is rotatably supported on a camshaft 49 that is supported by the frame 11 and extends along the front-rear direction 6. The eccentric disc cam 48 is mounted on the camshaft 49. The eccentric disc cam 48 protrudes radially from the camshaft 49. The length of the eccentric disc cam 48 protruding from the camshaft 49 changes continuously in the circumferential direction of the camshaft 49.

The link arm 50 is slidably fitted to the eccentric disc cam 48. The rotation of the eccentric disc cam 48 is transmitted to the link arm 50, causing the link arm 50 to rotate while displacing in the left-right direction 7. The link arm 50 is connected to the slider 51 via a shaft 52. The slider 51 is movable along the left-right direction 7 by fitting into a slide rail 53 provided on the frame 11. Therefore, the slider 51 reciprocates in the left-right direction 7 by the amount of movement in the left-right direction 7 of the rotation of the link arm 50.

A slide rail 54 extending vertically 5 is formed at the left end of the slider 51. The slide rail 54 is engaged with the slider 46 of the vertical vibration generating mechanism 41. The reciprocating movement of the slider 51 in the left-right direction 7 is transmitted to the slider 46 via the slide rail 54. As a result, the slider 46 reciprocates both horizontally 7 and vertically 5. In other words, the combined vibration of the horizontal and vertical reciprocating movement is transmitted to the support arm 55.

Assuming that the amplitude of the vertical reciprocating movement 5 by the vertical vibration generation mechanism 41 is the same as the amplitude of the horizontal reciprocating movement 7 by the horizontal vibration generation mechanism 42, the resulting vibration can be circular, linear, or elliptical by adjusting the phase difference between the eccentric disk cams 43 and 48. For example, the phase difference between the eccentric disk cams 43 and 48 can be set so that the resulting vibration becomes elliptical.

The imaging device 15 is installed below the clamp 12. The imaging device 15 is a camera that optically photographs the powder 21 inside the vial 20, while the vial 20 is held by the clamp 12, through a portion of the side wall 25 exposed in the vertical direction 5. The imaging device 15 captures multiple images of the vibrating vial 20 over a predetermined period of time, for example, at a frame rate of 30 or 60 frames per second.

The analysis device 16 is a computer with software installed that analyzes images captured by the imaging device 15 to determine whether foreign matter is present in the powder 21. The analysis device 16 is connected to the imaging device 15 for data transmission and reception. The analysis device 16 includes, for example, input devices such as a keyboard and mouse, and a display device such as a monitor. Images received from the imaging device 15 may be displayed on the analysis device 16's monitor.

The judgment software determines whether foreign matter is present in the powder 21 of the vial 20 based on the image of the vial 20 captured by the imaging device 15, i.e., image data. Specifically, the software divides the obtained image data into a predetermined number of vertically and horizontally subdivided regions, and identifies the color intensity of each region in multiple stages. If the powder 21 is white, the foreign matter is recognized as black. Then, the software determines whether foreign matter is present based on the peak value (color intensity of the foreign matter) and the intensity area value (vertical × horizontal of the foreign matter) in the image data. For example, if both the peak value and the intensity area value are within predetermined conditions, for example, if each value is above a threshold and a continuous predetermined range exists, the software determines that foreign matter is present in the powder 21 of the vial 20. Note that there are no particular limitations on detectable foreign matter; any object that appears in the image with a different brightness than the powder 21 is acceptable.

The illumination devices 17 are installed above and below the clamp 12. The two illumination devices 17 illuminate the vial 20, which is held and vibrated by the clamp 12, from both the upper and lower directions 5. The illumination device 17 located below the clamp 12 does not overlap with the area where the imaging device 15 and the clamp 12 face each other, and is positioned offset 6 in the front-to-back direction relative to that area.

[Method for manufacturing vial 20 containing powder 21]
The method for manufacturing a vial 20 containing powder 21 is described below. The method for manufacturing the vial 20 includes the following steps.
(1) A sealing step in which the powder 21 is sealed into the vial 20.
(2) An inspection process for inspecting foreign matter in the powder 21 (an example of an inspection method).
(3) A defective product sorting process in which vials 20 in which foreign matter is determined to be present in the powder 21 are deemed to be defective products.

In the sealing process, the powder 21 is filled into the container body 23 using an auger-type filling machine. Then, a lid 22 is fitted onto the container body 23 that stores the powder 21, and an aluminum cap is wrapped around it to seal the boundary between the lid 22 and the container body 23. This results in a vial 20 with the powder 21 sealed inside.

The inspection process is performed using the foreign object inspection device 10. The vial 20, in which the powder 21 is sealed within its internal space, is held by the clamp 12 of the foreign object inspection device 10. The axial direction C (see Figure 3) of the vial 20 held by the clamp 12 is parallel to the front-to-back direction 6.

When the foreign object inspection device 10 is activated, the frame 11 tilts. As shown in Figure 3, the tilting of the frame 11 causes the axial direction C of the vial 20 to tilt with respect to the front-to-back direction 6 (horizontal direction), with the mouth 24 of the container body 23 being above the bottom 26. The tilt angle is within the range of 0 to 15 degrees, preferably within the range of 1 to 10 degrees. When the foreign object inspection device 10 is activated, the illumination device 17 is turned on.

After the frame 11 is tilted, the vibration generator 13 and motor 40 are activated. The activation of the vibration generator 13 applies vibration to the vial 20 held by the clamp 12. This vibration causes the powder 21 to separate from the side wall 25, even if powder 21 is adhering to the side wall 25. Furthermore, clumps of powder 21 break apart. This makes it easier for any foreign matter mixed in the powder 21 to be exposed on the inner surface of the side wall 25 of the vial 20.

When the motor 40 is activated, the composite vibration generator 14 imparts a composite vibration to the vial 20 that, when viewed from the front-rear direction 6, results in elliptical motion. This composite vibration causes the powder 21 to circulate and flow in an elliptical pattern within the internal space of the vial 20, as shown in Figure 4. In this flow of powder 21, foreign matter with different size and weight from the individual particles of powder 21 flows separately from the powder 21. For example, foreign matter heavier than the individual particles of powder 21 tends to move to the outside of the circulating powder 21, and is therefore more likely to appear on the inner surface of the side wall 25 of the vial 20.

Furthermore, the axial direction C of the vial 20 is inclined with respect to the front-to-back direction 6, with the mouth portion 24 of the container body 23 being above the bottom portion 26. Therefore, the powder 21 tends to accumulate towards the bottom portion 26. Also, foreign matter heavier than the individual particles of the powder 21 tends to move towards the bottom portion 26, and thus is more likely to appear on the inner surface of the side wall 25 near the bottom portion 26 of the vial 20.

The analysis device 16 determines whether or not there is foreign matter in the powder 21 inside the vial 20 based on the image of the vial 20 taken by the imaging device 15 when vibration and combined vibration are applied to the vial 20.

In the defective product sorting process, vials 20 that are determined to contain foreign matter in the powder 21 are excluded from shipment as defective products.

[Effects of the Embodiment]
According to the embodiment described above, in the inspection process, the vibrations applied via the clamp 12 cause clumps of powder 21 inside the vial 20 to break apart or the powder 21 to separate from the side wall 25, making the powder 21 more likely to scatter. In addition, the combined vibrations in the vertical direction 5 and the horizontal direction 7 cause the powder 21 to circulate and flow inside the vial 20. As a result, the powder 21 flows while scattering inside the vial 20, making it easier for foreign matter in the powder 21 to be exposed during the inspection process and appearing in the captured images. In the defective product sorting process, vials 20 that are determined to contain foreign matter are considered defective, resulting in a low foreign matter contamination rate among the manufactured vials 20.

Furthermore, during the inspection process, since the axial direction C of the vial 20 is supported parallel to the front-to-back direction 6, the flowing powder 21 is captured through the side wall 25 of the vial 20.

Furthermore, during the inspection process, because the axial direction C of the vial 20 is inclined from the front-to-back direction 6, the powder 21 accumulated at the bottom 26 of the vial 20 flows along the side wall 25. This makes it easier for foreign matter in the powder 21 to be exposed, and therefore more likely to appear in the captured image. Also, because foreign matter tends to appear near the bottom 26 of the side wall 25 of the vial 20, the range in which images are captured for foreign matter detection is limited.

Furthermore, during the inspection process, the flowing powder 21 is photographed from below the vial 20. Therefore, the image captures the moment when the powder 21, flowing within the vial 20 and falling due to gravity, collides with the vibrating side wall 25 of the container body 23. This makes it easier for foreign objects to appear in the captured image.

10... Foreign object inspection device 11... Frame 12... Clamp (support part)
13...Vibration generator 14...Synthetic vibration generator 15...Photography device 16...Analysis device 20...Vial 21...Powder 22...Lid 23...Container body 24...Mouth 25...Side wall 26...Bottom

Claims (1)

The sealing process involves sealing the powder into a transparent container,
An inspection process for inspecting for foreign matter in the above powder,
A method for manufacturing a powder-filled container, comprising a defective product sorting step in which the transparent container in which foreign matter is determined to be present is deemed a defective product,
The transparent container described above has a container body having a mouth, a side wall continuous with the mouth, and a bottom continuous with the side wall, and a lid that is fitted onto the mouth.
The angle of repose of the above powder is in the range of 30 to 60 degrees.
The average particle size of the above powder is in the range of 20 μm to 70 μm.
In the above sealing process, the lid is sealed onto the container body for storing the powder.
The above inspection process is:
The support portion that supports the transparent container is positioned such that the third direction in which the opening and the bottom face each other is perpendicular to the first direction and the second direction perpendicular to the first direction, and intersects with respect to the vertical direction. A combined vibration of the reciprocating vibration in the first direction and the reciprocating vibration in the second direction is applied to the support portion to cause the powder inside the transparent container to flow, while a vibration different from the combined vibration is applied to the transparent container via the support portion.
The flowing powder is photographed optically from below through the side wall of the transparent container while illuminating the transparent container from above and below.
A method for manufacturing a powder-containing container, comprising dividing a captured image into a predetermined number of vertically and horizontally subdivided regions, identifying multiple levels of grayscale intensity in each region, and determining whether foreign matter is present in the powder based on whether there is a predetermined range where each region whose identified grayscale intensity is above a threshold for being recognized as black is continuous vertically or horizontally.