JP4776115B2 - Manufacturing method of rubber plugs for pharmaceuticals and medical products - Google Patents

Description

【００４７】
【発明の効果】
以上の如き本発明により、各工程の雰囲気の空気の清浄度を前記レベルに管理し、洗浄工程などで使用する洗浄水の清浄度を検査工程に近づくほど高め、さらに除電処理を組み合わせることで、従来に比べて格段に清浄度の高い（異物および微粒子付着量が著減した）医薬・医療用ゴム栓を製造することができる。[0001]
BACKGROUND OF THE INVENTION
The present invention relates to a method for producing a rubber plug for pharmaceuticals / medical products, and more particularly to a method for producing a highly clean rubber plug for pharmaceuticals / medical products in which adhesion of foreign matter and fine particles to the rubber plug is significantly reduced.
[0002]
[Prior art]
(background)
In recent years, there has been a great interest in food and medical safety, such as the inclusion of foreign substances in food and medical mistakes becoming social issues. Naturally, these social phenomena are also reflected in pharmaceuticals that are indispensable for today's medical practice, and today's pharmaceuticals require not only high cleanliness but also excellent visibility and operability. It has been.
Such requests are also reflected in the medical and medical rubber stoppers that are the packaging materials, and now, not only conforms to the pharmacopoeia of each country, but also a wide variety of products with higher quality can be quickly There is a need for a manufacturing system (corresponding to HACCP).
[0003]
Conventionally, medical and medical rubber plugs with high cleanliness, that is, foreign matters such as fiber scraps and hair (diameter or length of 50 μm or more, which can be identified with the naked eye) and fine particles (diameter or length). In order to manufacture the rubber plug, there is a cleaning process in the manufacturing process, and the foreign substances and fine particles adhering in the manufacturing process are washed away. We manufactured rubber plugs with high cleanliness that satisfy product standards, Japanese Pharmacopoeia, US Pharmacopoeia standards, etc.
[0004]
In the first place, foreign matters and fine particles adhere to the rubber plug because the rubber plug is formed of a polymer material (rubber-like polymer) that has a property of being charged by friction, and the foreign matter and fine particles are in the rubber plug manufacturing process atmosphere. It exists to exist. The rubber plugs manufactured in the molding process are charged with static electricity due to contact between the rubber plugs and the rubber plugs and other articles such as containers before the final inspection process. This static electricity causes foreign matter and fine particles in the process atmosphere to adhere to the rubber plug. An antistatic agent is used as a method for preventing electrification, but an antistatic agent cannot be used for a rubber plug for the purpose of use.
Therefore, it is the best method to wash away the deposits in the washing process, but even if the washing is carried out sufficiently, there is a limit to the removal of the adhering fine particles. In some cases, the request could not be met.
[0005]
[Problems to be solved by the invention]
The present invention has been made in view of such circumstances, and an object of the present invention is to provide a medical / medical rubber that is significantly higher in cleanliness (contaminated foreign matter and fine particles are significantly less) and safer than before. It is an object of the present invention to provide a production method capable of producing a stopper reliably and efficiently.
As a result of intensive studies on a method for producing a rubber plug having a higher degree of cleanliness, the present inventors have found that it is difficult to prevent the rubber plug from being charged, and it is also difficult to remove all the fine particles once adhered. From this, it was learned that it is important how to reduce the amount of foreign matter and fine particles adhering to the rubber plug during the manufacturing process, and the present invention has been achieved.
[0006]
[Means for Solving the Problems]
According to the present invention, the air cleanliness through the blending / kneading process, the molding process, the alkali cleaning process, the acid cleaning process, the hot water cleaning process, the shower cleaning process, the drying process, and the final inspection process in this order. In a method for producing a rubber stopper for a pharmaceutical / medical product that is carried out in an atmosphere in which the level gradually increases, The blending and kneading step is carried out in an air atmosphere excluding dust through the air through a filter, Three washing treatment steps of alkaline washing treatment step, acid washing treatment step, and warm water washing treatment step are performed in one treatment tank in the above order. In the air cleanliness atmosphere of M6.5 to M4.5, the washing water in the warm water washing treatment step is washing water having a higher degree of cleanliness than the water used in the alkali washing treatment step and the acid washing treatment step. The rubber stopper is taken out from the treatment tank and transported to the shower cleaning process, and the steps after the shower cleaning process are performed. M5.5 to M3.5 In an air cleanliness atmosphere Respectively carry out (However, the air cleanliness after the shower cleaning process is higher than the air cleanliness until the cleaning process) There is provided a method for producing a clean medical / medical rubber stopper.
[0007]
DETAILED DESCRIPTION OF THE INVENTION
Next, the present invention will be described in more detail with reference to preferred embodiments of the invention.
The material used for the manufacture of the rubber plug for the pharmaceutical / medical product of the present invention (hereinafter sometimes simply referred to as a rubber plug) is a rubber material conventionally used for the manufacture of the rubber plug and the material used therefor. Any plastic material used in combination with a conventional rubber stopper can be used and is not particularly limited.
Examples of rubber materials include butyl rubber such as butyl rubber, chlorinated butyl rubber, brominated butyl rubber, divinylbenzene copolymer butyl rubber, polyisoprene rubber (high to low cis 1,4 bond), and polybutadiene rubber (high to low cis 1). , 4-bond), conjugated diene rubbers such as styrene-butadiene copolymer rubber, ethylene-propylene-diene terpolymer rubber (EPDM), thermoplastic rubber (TPE) such as SBS and SIS, and the like. Examples of the plastic material include polyethylene, polypropylene, polyamide, and polyester.
[0008]
The rubber plug in the present invention is a vulcanizable rubber composition (compound) obtained by kneading the above rubber material and a compounding agent such as a vulcanizing agent, a filler and / or a reinforcing agent, a coloring agent, and an anti-aging agent. ) And using a conventionally known molding method for rubber plugs such as compression molding and injection molding. As the compounding agent to be used, any of those conventionally used for producing rubber stoppers for pharmaceuticals and medical devices can be used, and is not particularly limited.
[0009]
Rubber plugs made entirely of a vulcanizable rubber composition, at least a surface that comes into contact with chemicals, etc. laminated with a plastic film such as fluororesin or polyethylene (plastic laminated rubber plug), infusion solution Examples include an assembly molded body of the rubber and the plastic member for joining to a plastic mouth such as a bag by fusion, but the shape and structure of the rubber plug are not particularly limited in the present invention. Specifically, for example, rubber stoppers for vials (rubber stoppers for powder preparations, rubber stoppers for liquid preparations, rubber stoppers for freeze-dried preparations, etc.), rubber stoppers for infusion preparations, pistons for syringes and container-use syringes (slip stoppers) And an assembly molded body of a rubber plug and a plastic member (for example, a pull-top type rubber plug, the above-described infusion bag mouth rubber plug, etc.) and the like. In addition, the rubber plug for medicines and medical products in the present invention refers to the rubber plug for pharmaceuticals and medical devices as described above.
[0010]
The rubber plug for a pharmaceutical / medical product of the present invention comprises: (1) a blending and kneading step for producing a vulcanizable rubber composition (compound) by kneading the weighed and weighed rubber materials and various compounding agents; (2) The obtained compound was processed into a sheet shape, molded and vulcanized into a rubber plug of a predetermined shape and structure by compression molding, injection molding, etc. using this sheet compound, and obtained after release A molding process in which the rubber plugs are separated one by one from a molded sheet connected with a large number of rubber plugs, and the visual inspection is visually inspected as necessary. (3) A cleaning process in which the rubber plugs are washed to wash off deposits and eluate. (4) The washed rubber stopper is further washed and dried, and (5) the final inspection process is sequentially performed, and the rubber stopper made into a conforming product is packaged and boxed in the packaging process.
[0011]
The manufacturing method of the highly clean rubber plug for medical / medical products according to the present invention is characterized in that the steps after the molding step are performed in a process atmosphere in which the air cleanliness is gradually increased.
The working atmosphere for manufacturing the rubber plug is ideally carried out in a clean atmosphere, that is, in a clean room, depending on the level of air cleanliness.
[0012]
However, in the rubber plug manufacturing method of the present invention, the steps after the molding step are carried out in the process atmosphere in which the air cleanliness gradually increases as described above. A preferable embodiment is an embodiment in which the drying process and the inspection process are performed in a process atmosphere having a higher level of cleanliness than the molding process and the cleaning process. A more preferred embodiment is a mode in which the quality of the washing water is gradually improved in addition to the above embodiment. The quality of the cleaning water will be described in the cleaning process and the drying process.
[0013]
In the blending / kneading step (1), which is the first step of rubber plug production, raw rubber and various compounding agents are weighed and kneaded using a mixer. Although it is not difficult to suppress or remove the floating of the compounding agent at the time of compounding or kneading, it has little effect on the cleanliness of the rubber plug of the final product, so if the working atmosphere is free of visible dust in the compounding kneading process It is enough. In the kneading step, it is preferable to use a closed mixer such as a kneader, an internal mixer or a Banbury mixer. After kneading, the compound (vulcanizable rubber composition) taken out from the mixer is allowed to cool and then conveyed to the molding step.
[0014]
In the molding process, depending on the type of rubber plug, the compound is processed into a sheet having a predetermined thickness using, for example, a feeder, a ruder or a roll, and the sheet-like compound is temporarily stored for aging and cooling. The
The primarily stored sheet-like compound is molded into a vulcanized rubber plug having a predetermined shape using a molding machine used for molding a normal rubber plug such as compression molding or injection molding. The rubber plugs are released in a state where many of them are connected to a single sheet, are individually cut off, and are put into a container made of rust-free metal such as SUS after visual inspection if necessary.
[0015]
In the molding process, the sheet-like compound and the rubber plug separated and separated are exposed to the process atmosphere. The rubber plug is cleaned in the next cleaning process, but it is preferable that the atmosphere of the molding process is as clean as possible in order to reduce deposits in the molding process, but as a result of various studies, the air cleaning described below A level 1 atmosphere is appropriate. The rubber stopper placed in the container is transported to the next cleaning process.
For rubber plugs other than plastic laminated rubber plugs, depending on the type, a cross-linked (curing) silicone composition is applied to a molded sheet connected with the above-mentioned many rubber plugs, and this is cross-linked to adhere to the rubber plug surface. In some cases, silicone treatment is performed. However, such a rubber plug is also subjected to the following washing process, whereby unreacted silicone is completely removed, and a reduction in the level of cleanliness of the final product is prevented.
[0016]
In the cleaning process, the rubber plug is washed away of foreign matters and fine particles adhering to the surface.
The cleaning process of the present invention includes the following three cleaning processes.
(1) An alkaline cleaning treatment step in which the rubber plug is immersed in cleaning water whose alkaline water is adjusted to alkaline and treated with high-pressure steam;
(2) an acid washing treatment step of neutralizing the alkali-washed rubber stopper with washing water adjusted to be acidic, and
(3) A warm water washing treatment step of washing the acid-washed rubber stopper with a higher quality washing water than the water used in the treatment steps (2) and (3).
[0017]
In the present invention, the above three processing steps can be carried out in the above order using three independent processing tanks, respectively, as in the prior art, but when sequentially transported to the next processing tank after processing. In order to prevent foreign matter and fine particles from adhering to the rubber plug and enhance the cleaning effect, three cleaning processes must be performed in one processing tank, and the rubber plug should not be transported for the next cleaning process. Is preferred. Below, the case where all the above-mentioned three washing processing steps are performed in one processing tank is explained.
[0018]
The rubber stopper transported from the molding process is manually transferred from the container to an alkali- and acid-resistant cleaning container such as a stainless steel wire mesh basket.
The first alkali cleaning treatment step (1) is a step of removing dirt, foreign matter, fine particles, eluate from the rubber plug, pyrogen (pyrogenic substance) and the like attached to the surface of the rubber plug. Since this treatment step is performed under pressure as described later, an autoclave (preferably a vertical shape) is used as a treatment tank. As the washing water, an aqueous solution (usually 0.05 to 0.15% by weight aqueous solution of NaOH) in which the water is adjusted to an alkaline agent, for example, NaOH with a pH of 8 to 12, preferably pH 8.5 to 11, is used. The The alkaline agent is not limited to NaOH, and other alkaline substances can be used.
[0019]
As water for use, in this treatment step (1) and the next neutralization treatment step (2), raw water such as well water is ion-exchanged by ion exchange resin or electric ion exchange (Electronic Deionize Ionization). Purified water obtained by ultrafiltration or reverse osmosis filtration of water and raw water can also be used. However, in order to avoid the adhering of new fine particles due to the washing water with a smaller number of washings, preferably, the sterilized raw water is subjected to ultrafiltration or reverse filtration. This is the use of high-quality water (referred to as RO water and UF water, respectively) ion-exchanged in the same manner as described above after osmotic filtration.
[0020]
A wire mesh basket containing a rubber stopper is immersed in an alkaline cleaning solution in an autoclave and is usually 100 to 150 ° C. (autoclave internal pressure is 0 to 4 kgf / cm). ² G), preferably the rubber plug is treated at 110 to 145 ° C, more preferably 130 to 140 ° C. The treatment time is usually 10 to 90 minutes although it depends on the treatment temperature. Some rubber plugs are subject to thermal degradation depending on the rubber material, so the treatment temperature and time must be determined in consideration of the treatment effect and the degradation of the rubber plug.
[0021]
Alkaline cleaning and other cleaning processes are also performed by slowly rotating or vertically moving a wire mesh basket or the like around the central axis of a vertical autoclave. However, blocking may occur where rubber plugs adhere to each other during the cleaning process. is there. When blocking occurs, the parts where the rubber plugs are self-attached are not cleaned, and depending on the part of the self-adhesion, the cleaning liquid may remain after drying. Cause a decrease in
The use form of the alkaline cleaning liquid may be either a batch type or a continuous type, and the cleaning liquid once used is preferably treated as a waste liquid in order to increase the cleanliness of the rubber stopper. In addition, the processing tank used in the cleaning process is a vertical processing tank with an open / close door at the bottom so that foreign matter and fine particles in the process atmosphere can be prevented and the wire mesh basket can be taken in and out at the lower part. preferable. The structure and shape of the treatment tank are not particularly limited.
[0022]
In the present invention, if necessary, clean water such as ion-exchanged water can also be used before the alkali cleaning treatment. Preferably, dirt, foreign matter, fine particles, etc. attached to the rubber stopper using the high-quality water are used. A preliminary (preliminary) cleaning process for preliminarily removing can also be performed. The pre-cleaning treatment can be carried out in the above autoclave, but the above-mentioned wire mesh cage is rotated or moved up and down at a temperature of room temperature to 50 ° C. in a sealed state (preferably at the bottom) in a vertical processing tank. It is preferable to carry out the movement because foreign substances and fine particles in the process atmosphere can be prevented from falling into the treatment tank during the pre-cleaning treatment. The washing water is batch type or continuous type, and is preferably treated as a waste liquid after the pre-cleaning treatment in addition to the treatment tank.
[0023]
The next acid cleaning treatment step (2) is a step of neutralizing the alkali adhering to the rubber plug by the alkali cleaning treatment. After discharging the alkali cleaning solution, an acidic neutralizing solution is added to the autoclave, In the same manner as alkali cleaning, the wire mesh basket is rotated or moved up and down. The neutralizing solution is weakly acidic and sufficient, and the acid as the neutralizing agent is not particularly limited. For example, a mineral acid such as hydrochloric acid is used, and usually a 0.05 wt% aqueous solution of hydrochloric acid (the water used is alkaline). As in the case of washing, use of high-quality water is preferable. The treatment temperature is not particularly limited, and is usually about room temperature to 50 ° C., and the treatment time is about 10 to 20 minutes. The use form of the acid cleaning liquid may be either a batch type or a continuous type, but the acid cleaning liquid once used is preferably treated as a waste liquid.
[0024]
In the final hot water washing treatment step (3), the neutralized rubber plug is used as the last treatment step of the washing step, and the cleanliness (quality) is higher than that of the water used in the treatment steps (1) and (2). This is a finishing wash that uses high washing water and removes acid and prevents particles in the washing water from newly adhering to the rubber stopper. This processing step is performed by rotating or moving up and down the wire mesh cage in a sealed state like the other processing steps. The temperature of the hot water washing is not particularly limited, but is usually about room temperature to about 50 ° C. The washing water may be used either batchwise or continuously. Although the above-mentioned high quality can be used as the washing water, it is preferable to use the highest quality water obtained by distilling the above high-quality water in order to prevent adhesion of new fine particles by the washing water with a smaller number of washings. After washing with warm water, the washing water is preferably discharged from the autoclave and treated as a waste liquid.
After completion of the hot water washing treatment process, the washing solution is discharged from the autoclave, and the rubber stopper is sufficiently drained while being put in the wire mesh basket in the autoclave, and conveyed to the next drying process.
[0025]
As described above, in the cleaning process, since the rubber plug is not exposed to the process atmosphere during the cleaning process, an air cleanliness level of 1 is appropriate for the atmosphere of the cleaning process.
In addition, the water used in the washing process prevents the fine particles contained therein from newly adhering to the rubber plug, so that the high-quality water is used in the alkali washing treatment and the acid washing treatment, and the above-mentioned highest in the hot water washing treatment. It is preferred to use quality water. Furthermore, although the washing water used in each washing treatment can be reused, it is preferable to treat it as a waste liquid as described above and not reuse it in order to increase the cleanliness of the rubber plug.
[0026]
In the drying process following the cleaning process, the rubber stopper cleaned in the last hot water cleaning process (3) of the cleaning process is further showered with the highest quality cleaning water equivalent to the cleaning water in the hot water cleaning process. It includes a step of performing a shower cleaning process for cleaning and a step of drying the cleaned rubber stopper. The washing water used here is the same as the washing water in the warm water washing treatment step, and the above-mentioned highest quality water is preferable in preventing the adhesion of new fine particles.
[0027]
In the shower cleaning process, for example, rubber plugs that are transported by a mesh conveyor belt, etc., in order to prevent new particles from adhering to the cleaning water and more thoroughly remove particles that could not be removed in the previous cleaning process This is a treatment process in which a shower of the highest quality water is taken over the entire surface, and residual particulates are washed away by the unidirectional water flow and the impact of the shower. The rubber stopper processed by the shower cleaning process in the cleaning process and the drying process is removed at a very high level even when there are residual foreign matters or fine particles in the cleaning process.
[0028]
Therefore, the drying process is performed in a process atmosphere of a cleanliness level 2 that is higher than the cleanliness level 1 up to the cleaning process, so that the adhesion of new fine particles to the rubber plug in this process is more complete. Can be prevented.
[0029]
Since the drying process is performed in the above-mentioned high-level air cleanliness atmosphere, the shower-washed rubber plug is dried with hot air, which is commonly used. In some cases, it is not preferable, and it is preferable to use a method of heating by irradiation with far infrared rays and / or irradiation with high frequency. Far-infrared irradiation is suitable for drying water on the surface of the rubber plug, but is not suitable for drying water inside the rubber plug. A particularly preferable drying method is high-frequency heating. When the rubber material of the rubber plug is a polar rubber, the rubber itself is also heated by the high frequency, and the water inside the rubber plug is removed (dried) simultaneously with the water on the surface. Even if the rubber material is non-polar, a polar substance is also added depending on the compounding agent to be used. For this reason, the rubber itself is heated, and the same effect as in the case of the polar rubber is exhibited.
The heat output of the high-frequency heating is not particularly limited, but is usually about 1 to 5 kW, and it is preferable to install at a plurality of locations along the mesh conveyor belt in order to enhance the drying effect. The dried rubber stopper is sent to the inspection process.
[0030]
In the present invention, the air cleanliness level 1 means that the SI class is M6.5 (US federal standard class 100,000) to M4.5 (same class 1,000), and the air cleanliness level 2 is M5.5 (same class 10,000) to M3.5 (same class 100). In the present invention, the cleanliness level 2 is higher than the cleanliness level 1. As much as possible, it is preferable for each process to have a higher level of air cleanliness. However, the areas (buildings or rooms) where each process is carried out have a large floor area, in order to improve the sealing performance of these areas. However, there is a limit because the cost increases and the manufacturing cost of the rubber plug increases. Preferably, at least the steps after the molding step are performed at the above air cleanliness level, and more preferably under a condition slightly pressurized from atmospheric pressure.
[0031]
In the present invention, the quality of the washing water is gradually improved, which means that the quality of the washing water in the warm water washing treatment step (3) in the washing step is the same as that in the alkali washing treatment step (1) and the acid washing treatment step. The quality of the water used in (2) should be higher, and the quality of the washing water in the washing process in the drying process should be equal to or higher than the washing water in the warm water washing process (3).
[0032]
As mentioned above, the rubber plug is made of a polymer that is easily triboelectrically charged, so if necessary, the compound processed into a sheet in the molding process, the rubber plug before being subjected to the cleaning process, and after the cleaning process is completed It is preferable that any one of the rubber plug or the rubber plug after the drying process is subjected to charge removal (charge removal) treatment in a process having a large frictional charge. Furthermore, it is also preferable to increase the cleanliness of the rubber plug by unattended automatic transfer of the rubber plug between processes without human intervention.
[0033]
As a charge removal treatment method, an electrostatic remover such as a silent corona discharge remover or a radioactive static eliminator that ionizes process atmosphere air that can be charged and removed without contact with a rubber plug is used. A preferred method is to increase the conductivity and radiate the charge of the rubber plug into the air to eliminate it. Further preferred is a blower type in which ionized air is blown directly onto a rubber stopper. Various types of static eliminators as described above are commercially available, and appropriate ones can be selected and used, and are not particularly limited. Moreover, the clean air of each said process can also be ionized and supplied.
[0034]
The final final inspection step is performed in the same level 2 air cleanliness atmosphere as the drying step. For example, the entire appearance (surface) of the rubber plug is automatically inspected by a CCD camera, inspected for the presence of molding defects, foreign matters such as burn-in foreign matter, foreign matter adhesion, etc., and nonconforming products are removed and discarded. Adherent particulates that are not known in this inspection are tested in accordance with the test method for insoluble fine particles of injectables in the 13th revision of the Japanese Pharmacopoeia. The rubber stopper packed in a plastic dust-free bag in the same atmosphere as the inspection process is boxed in the packing process. The packing process does not have to be a particularly cleaned atmosphere, but is preferably performed in an atmosphere of air cleanliness level 1 if possible. In the inspection step, it is preferable to perform a charge removal process before and / or after the inspection to remove the last adhered fine particles.
[0035]
In the production of the rubber plug of the present invention, it is preferable that unmanned automatic conveyance be used for the conveyance of the rubber plug between processes in which people are often involved.
As the unmanned automatic transfer means, for example, (i) a method of running an electrically driven vehicle on a taxiway laid under the floor, (ii) an electric drive device installed in the suspension suspended on a track provided on the ceiling Any of the conventionally known automatic conveying means such as a method of moving by the above can be used, and the automatic conveying means is not particularly limited. When all steps are performed on the same floor, the method (i) is preferable. For example, when the steps are performed on the first floor and the second floor, the combination of the above two methods is preferable. The loading and unloading of the rubber stopper (in a container or the like) may be performed manually or automatically, but automation is preferable.
In addition, the operation of unmanned automatic transfer machines and the storage management of rubber plugs in each process are controlled by a computer according to the rubber plug manufacturing plan, thereby reliably preventing troubles seen in manual transport such as lot differences and forgotten loading. be able to.
[0036]
【Example】
The present invention will be specifically described below with reference to examples and comparative examples.
[0037]
Example 1
Rubber stopper for vials using chlorinated butyl rubber (HT-1066 manufactured by ExxonMobil Chemical Co., Ltd.) (top diameter (flange) outer diameter (shade diameter) is 19 mm, shade thickness is 3.2 mm, foot diameter is 13 mm, foot height) Was 5 mm, and the total height was 8.2 mm).
The blending and kneading process is performed in an air atmosphere in which air is removed through a filter to remove dust, the molding process and the cleaning process are performed in a clean atmosphere of M6.5, and the drying process and the inspection process are cleaned of M5.5. Conducted in an air atmosphere.
[0038]
The washing step was performed using an autoclave with a lower lid. In the first alkali cleaning treatment, the well water sterilized as working water is filtered through a reverse osmosis membrane, and then ion-exchanged high-quality water is used in an electric exchange type pure water production apparatus, and caustic soda is dissolved in a concentration of 0.1%. Alkaline water was used. Insert the cylindrical stainless steel wire cage with the above rubber stopper into the autoclave, close the bottom lid, and fill with alkaline water 3 times the total volume of the rubber stopper, and fill the wire mesh cage at a rate of 5 times / minute. The internal temperature was raised to 160 ° C. while moving up and down, and the mixture was treated for 1 hour under boiling. Heating was stopped, the liquid temperature was cooled to 80 ° C., and then the alkaline washing water was discharged.
[0039]
Next, 0.05% hydrochloric acid aqueous solution (room temperature) of the above-mentioned high quality water was filled in the autoclave in the same manner as above, and acid washing was performed for 10 minutes without heating while moving the wire cage up and down. Thereafter, the acid cleaning liquid was discharged, and the wire mesh basket was continuously moved up and down to drain water.
Finally, the highest-quality water, which is the distilled water of the above-mentioned high-quality water, was filled in the autoclave in the same manner as described above, and washed by moving the wire mesh basket up and down for 10 minutes without heating. After washing water was drained and drained, the lower lid of the autoclave was opened and the wire mesh basket was taken out.
[0040]
The rubber stopper after the cleaning process was transported to the next drying process for each wire mesh cage by an unattended automatic transport machine. With a feeder that is automated so that the rubber plugs do not overlap each other on the stainless steel mesh conveyor that is manually transferred from the wire mesh to the hopper in the M5.5's clean atmosphere drying process. A rubber stopper was placed.
Here, the rubber plug is first washed in the shower cleaning zone from the top of the conveyor and then from the bottom in the shower cleaning zone for 15 seconds in total with a shower of the highest quality water in one direction, and the rubber plug is drained by natural fall. The plug reaches the drying zone, where it is heated and dried with high frequency from a high frequency heating device, and the rubber plug is carried to the inspection process. The highest quality water described above was used as the shower washing water.
[0041]
The rubber stopper is conveyed by the mesh conveyor from the drying process to the inspection process of the cleanliness atmosphere of M5.5.
In the above cleaning process, 10 rubber plugs are removed as needed before cleaning, after completion of the cleaning process, and after the completion of all processes in the inspection process, and stored in a dust-free bag. Then, the number of fine particles attached to each rubber plug was measured by the following method. The rubber stopper after the cleaning process was dried by high-frequency heating in the inspection room.
[0042]
[Method for measuring the number of fine particles]
General test method of Japanese Pharmacopoeia 13th revision (first supplement) 64. According to the insoluble fine particle test method for injections, the number of insoluble fine particles was measured using a light shielding type automatic fine particle measuring apparatus (RION KL-01: automatic fine particle measuring instrument manufactured by Rion Co., Ltd.).
Ten rubber stoppers taken out are put into a 500 ml custom hard glass vial with tweezers, 0.4 μm and then 300 ml of dust-free water passed through a 0.2 μm filter are added and sealed with a Ceylon film (Fuji Film). The rubber plug was shaken by hand for 20 seconds so that the rubber plug rotated approximately twice per second. After standing for 1 hour, 10 ml of the internal solution is taken and measured. Similarly, the measurement was performed three times in total, and the average value was obtained. The results are shown in Table 1.
[0043]
Comparative Example 1
1000 rubber plugs were produced in the same manner as in Example 1 except that the air cleanliness of the molding process and the cleaning process was the air cleanliness of the blending / kneading process, and the drying process was performed in a clean atmosphere of M6.5. The number of fine particles was measured in the same manner as in Example 1. The results are shown in Table 1.
[0044]
Comparative Example 2
1000 rubber plugs were prepared in the same manner as in Example 1 except that the molding process to the drying process were performed in an M6.5 clean atmosphere, and the inspection process was performed in an M5.5 clean atmosphere. The number of was measured. The results are shown in Table 1.
[0045]
Comparative Example 3
1000 rubber plugs were prepared in the same manner as in Example 1 except that the molding process and the cleaning process were performed in an air cleanliness atmosphere of the blending and kneading process, and the drying process and subsequent processes were performed in an M5.5 cleanliness atmosphere. The number of fine particles was measured. The results are shown in Table 1.
[0046]
Example 2
In the final inspection step, 100 rubber plugs of Example 1 were extracted, subjected to charge removal by ion blowing, 10 were extracted, and the number of fine particles was measured in the same manner as in Example 1. The results are shown in Table 1.

[0047]
【The invention's effect】
By the present invention as described above, the cleanliness of the air in the atmosphere of each process is controlled to the above level, and the cleanliness of the cleaning water used in the cleaning process and the like is increased as it approaches the inspection process, and further by combining the static elimination treatment, It is possible to manufacture a medical / medical rubber stopper that is remarkably higher in cleanliness than that of the prior art (the amount of foreign matter and fine particles attached is significantly reduced).

Claims (5)

The air cleanliness is gradually increased through the blending / kneading process, molding process, alkali cleaning process, acid cleaning process, hot water cleaning process, shower cleaning process, drying process, and final inspection process in this order. In the method for producing a rubber plug for pharmaceuticals and medical products to be carried out in an atmosphere that becomes, the compounding and kneading step is carried out in an air atmosphere excluding dust through the air filter,
The three washing treatment steps of the alkali washing treatment step, the acid washing treatment step, and the hot water washing treatment step are performed in the above order in one treatment tank, under an air cleanliness atmosphere of M6.5 to M4.5, and the hot water washing. The washing water in the treatment process is performed with washing water having a higher cleanliness than the water used in the alkali washing treatment process and the acid washing treatment process ,
Remove the rubber stopper from the treatment tank and transport it to the shower cleaning process.
The steps after the shower cleaning process are carried out in an air cleanliness atmosphere of M5.5 to M3.5 (however, the air cleanliness after the shower cleaning process is higher than the air cleanliness until the cleaning process) ) A method for producing a clean rubber stopper for pharmaceuticals and medical products. The method for producing a clean rubber plug for medical / medical products according to claim 1 , wherein the washing water in the shower washing treatment step is equivalent to the quality of the washing water in the warm water washing treatment step. The method for producing a clean rubber plug for a pharmaceutical or medical product according to claim 1 or 2 , wherein the static elimination treatment is performed in an arbitrary step after the molding step. The method for producing a clean rubber plug for medical or medical products according to any one of claims 1 to 3 , wherein the rubber plug is conveyed between the steps by an unattended automatic conveying means. Claim 1 clean pharmaceutical and medical products rubber stopper obtained by the method according to any one of 4.