WO2018147176A1

WO2018147176A1 - Containment-performance inspection system

Info

Publication number: WO2018147176A1
Application number: PCT/JP2018/003558
Authority: WO
Inventors: 川崎　康司; はるか二村; 至洋矢崎; 志強郭; 司北野
Original assignee: 株式会社エアレックス
Priority date: 2017-02-13
Filing date: 2018-02-02
Publication date: 2018-08-16
Also published as: JP2018132305A; JP6779524B2

Abstract

Provided is a containment-performance inspection system that: uses a mock contaminant that, without the need for complicated production work, can be easily removed from a device after inspections; and can determine the scattering/leakage state of the mock contaminant in real time as a quantitative value. The present invention has: a mist generation means that generates a mist of a mock contaminant inside a work chamber; a collection means that collects inspection air in an external environment at a location for confirming leakage of the mock contaminant; and a detection means that detects mock contaminant included in the inspection air collected by the collection means. The present invention detects leakage of the mock contaminant from the inside of the work chamber to the outside environment and thereby inspects the containment-performance of the work chamber.

Description

Containment performance inspection system

The present invention relates to a containment performance inspection system for confirming the containment performance of a manufacturing facility or the like so that substances such as highly pharmacologically active pharmaceutical agents that affect the human body and the environment do not leak to the external environment. This system can also be used to monitor the scattering status of suspended solids in a clean environment.

In production and handling facilities for highly pharmacologically active pharmaceuticals such as anticancer drugs and immunosuppressive drugs, for example, devices such as containment isolators should be used so that the chemicals do not contaminate workers or the external environment. is required. Usually, in a containment isolator that handles non-sterile preparations, the inside of the isolator is managed under a negative pressure from the external environment. However, in negative pressure management, there is a concern that the inside of the isolator may be contaminated with attractants from the external environment. Therefore, it is difficult to employ negative pressure management in an isolator for aseptic preparations. In the Ministry of Health, Labor and Welfare's “Guidelines for the production of aseptic medicines by aseptic operation method (2011 revised edition)”, the differential pressure in the isolator requires a positive pressure control of at least about 17.5 Pa for the installation room. .

For example, in an operation in which an injection solution or the like is used as a lyophilized preparation, when an injection solution is filled in a freeze-drying vial, a highly sterile environment is required, and positive pressure management in an isolator is effective. However, when injection solution spills in such an operation and the vial is broken, the injected injection solution spreads in the isolator as a mist and leaks from the positive pressure isolator to the external environment. There is a risk of doing. On the other hand, there is a risk that the powder drug after lyophilization leaks from the inside of the positive pressure isolator to the external environment due to the breakage of the vial.

Thus, in manufacturing and handling facilities such as highly pharmacologically active pharmaceuticals, it is required to manage the positive pressure inside the device such as an isolator and to thoroughly control containment. From these backgrounds, it is important to evaluate in advance the containment performance of an apparatus such as an isolator. For example, in the case of a containment isolator, leakage can be confirmed and repaired in advance by inspecting its containment performance in advance. In addition, it is possible to grasp where leakage is likely to occur, and it is possible to take precautions such as installing a sampler at that position.

When evaluating the containment performance of a device such as an isolator in advance, if a pharmaceutical product with high pharmacological activity is used, there is a risk that the operator may be adversely affected by adhesion to the skin or suction. For this reason, usually, a safe alternative substance is used as a simulated contaminant, and the containment performance is inspected by using this simulated contaminant.

For example, Non-Patent Document 1 below relates to leak risk management of an isolator using a particle visualization technology. According to this, lactose powder that is harmless to the human body, easily soluble in water, and has good stability is used as a simulated contaminant. Then, lactose is scattered and the scattered light of the particles in the light film (laser sheet) in the space is captured by a camera to observe the scattering and leakage of the simulated contaminants. However, in Non-Patent Document 1 below, the scattering state at a specific position can be visualized, but this requires a large-scale device such as a laser light source system, an imaging system, or an image processing system.

It should be noted that visualization is possible only by using each of the above systems, but the simulated contaminant cannot be quantified. Non-patent document 1 below also describes a method of quantification. For this purpose, the amount of lactose supplemented by the sampler at the inspection position is analyzed by a high-performance liquid chromatograph, and the relationship between the position and the amount of scattering. Is evaluated quantitatively. However, when lactose is used as a simulated pollutant, an expensive and large-scale apparatus is required for quantitative analysis, and there is a disadvantage that evaluation cannot be performed in a short time.

On the other hand, Patent Document 1 below proposes a method for evaluating the scattering state of a pharmaceutical powder and a simulated powder for evaluating the scattering state used in the method. According to this evaluation method, a simulated powder in which hollow or porous particles, metal oxide fine particles, or the like are used as core particles and a fluorescent material is provided on the surface thereof is used. The simulated powder is scattered, supplemented by a sampler at the inspection position, and the fluorescence emission amount is directly measured by a fluorescence detection device. This fluorescence emission amount is compared with a calibration curve prepared in advance to determine the concentration of the simulated powder in the air.

Japanese Patent No. 5618863

By the way, in the evaluation method of the above-mentioned Patent Document 1, it is possible to obtain in real time a quantitative value of the state of scattering and leakage of simulated contaminants. However, in the evaluation method described in Patent Document 1, a special simulated powder in which a fluorescent material is provided on the surface of the core particles must be prepared, and a complicated manufacturing operation is required. In addition, there has been a problem that the simulated powder adhering to the inner wall of an apparatus such as an isolator has to be completely removed after the inspection, and labor is required for the cleaning work.

Therefore, the present invention addresses the above-mentioned problems, uses simulated contaminants that do not require complicated manufacturing operations and can be easily removed from the apparatus after inspection, and the simulated contaminants are scattered or leaked. It is an object of the present invention to provide a containment performance inspection system that can obtain a quantitative value in real time.

In solving the above-mentioned problems, the present inventors, as a result of diligent research, adopted a liquid mist instead of powder as a simulated contaminant, and previously dissolved a fluorescent light-emitting substance having a predetermined concentration in the mist. Thus, the present inventors have found that the mist can be detected as simulated contaminant particles using the fluorescent light emitting particle detection means, and the present invention has been completed.

That is, the containment performance inspection system according to the present invention, according to claim 1,
An inspection system (20) for detecting leakage of simulated contaminants from the inside of a work room (12) to the outside environment and inspecting the containment performance of the work room,
A mist generating means (23) for generating a mist (22) of the simulated pollutant inside the working chamber;
In the external environment, a collecting means (24) for collecting inspection air at a position where the leakage of the simulated contaminant is confirmed.
And detecting means (25) for detecting the simulated contaminant contained in the inspection air collected by the collecting means.

Moreover, according to the description of Claim 2, this invention is the containment performance test | inspection system of Claim 1, Comprising:
The detection means includes a fine particle detection unit and a fluorescence detection unit,
In the fine particle detection unit, while detecting the total particle concentration of the simulated contaminant in the inspection air,
In the fluorescence detection unit, by detecting the positive particle concentration in the test air,
A positive particle ratio is calculated from the total particle concentration and the positive particle concentration, and leakage of the simulated contaminant is confirmed.

Moreover, according to the description of Claim 3, this invention is the containment performance test | inspection system of Claim 2, Comprising:
The fluorescence detection unit detects the simulated contaminant in the inspection air by a laser excitation fluorescence method.

According to the description of claim 4, the present invention is the containment performance inspection system according to any one of claims 1 to 3,
The mist generating means is an ultrasonic atomizer.

According to the description of claim 5, the present invention is the containment performance inspection system according to any one of claims 1 to 4,
The simulated contaminant is an aqueous solution of a fluorescent material.

Moreover, according to the description of Claim 6, this invention is the containment performance test | inspection system of Claim 5, Comprising:
The aqueous solution of the fluorescent substance is an aqueous solution in which riboflavin or a derivative thereof is dissolved.

Moreover, according to the description of Claim 7, this invention is the containment performance test | inspection system of Claim 6, Comprising:
The aqueous solution of the fluorescent light-emitting substance is a 0.1% by mass to 5.0% by mass aqueous solution of sodium riboflavin phosphate.

According to the configuration of the first aspect, the containment performance inspection system according to the present invention includes the mist generating means, the collecting means, and the detecting means. The mist generating means generates mist of simulated contaminants inside the work chamber. The collecting means collects the inspection air at a position where the leakage of the simulated contaminant is confirmed in the external environment. The detection means detects the simulated contaminant contained in the inspection air collected by the collection means.

By these things, it is possible to obtain in real time a quantitative value of the state of scattering / leakage of simulated contaminants. In addition, the use of liquid mist as a simulated contaminant eliminates the need for complicated manufacturing operations. Further, the simulated contaminant can be easily removed from the apparatus after the inspection, and the labor of the inspection work can be reduced.

Further, according to the configuration of claim 2, the detection means includes the fine particle detection unit and the fluorescence detection unit. The fine particle detection unit instantaneously detects the total particle concentration of the simulated contaminants in the inspection air. Further, the fluorescence detection unit instantaneously detects the positive particle concentration in the test air. Further, the positive particle ratio is calculated from the total particle concentration and the positive particle concentration. Therefore, according to the structure of the said Claim 2, the effect similar to Claim 1 can be exhibited more concretely.

Further, according to the configuration of claim 3, the fluorescence detection unit detects the simulated contaminant in the inspection air by a laser excitation fluorescence method. Therefore, according to the structure of the said Claim 3, the effect similar to Claim 2 can be exhibited more concretely.

Further, according to the configuration of claim 4, the mist generating means is an ultrasonic atomizer. Therefore, according to the configuration of the fourth aspect, the same effect as any one of the first to third aspects can be more specifically exhibited.

Further, according to the configuration of claim 5, the simulated contaminant is an aqueous solution of a fluorescent luminescent material. Therefore, according to the configuration of the fifth aspect, the same effect as that of any one of the first to fourth aspects can be more specifically exhibited.

Further, according to the configuration of claim 6, the aqueous solution of the fluorescent light-emitting substance is an aqueous solution in which riboflavin or a derivative thereof is dissolved. Therefore, according to the structure of the said Claim 6, the effect similar to Claim 5 can be exhibited more concretely.

Further, according to the configuration of claim 7, the aqueous solution of the fluorescent light-emitting substance is a 0.1% by mass to 5.0% by mass aqueous solution of sodium riboflavin phosphate. Therefore, according to the structure of the said Claim 7, the effect similar to Claim 6 can be exhibited more concretely.

It is the front view and left view of the isolator which test | inspects the containment performance by one Embodiment of this invention. FIG. 2 is a front view and a left side view illustrating a sampling point in the isolator of FIG. 1. It is the schematic which shows a mode that a simulated contaminant is scattered inside the chamber of the isolator of FIG. 1, and the containment performance is test | inspected.

Hereinafter, the present invention will be described in detail. The present embodiment relates to a test of the containment performance of a containment isolator used in a manufacturing facility or a research and development facility of a highly pharmacologically active pharmaceutical agent that has a strong medicinal effect on the human body in a small amount such as an anticancer agent. The present invention is not limited to containment of highly pharmacologically active pharmaceuticals, but can be applied to evaluate the scattering and leakage of all contaminants.

FIG. 1 is a front view A and a left side view B of an isolator 10 for inspecting containment performance according to this embodiment. In FIG. 1, an isolator 10 is joined to a gantry 11 placed on a floor surface, a working chamber (chamber) 12 placed on the gantry 11, and a wall portion on the upper surface of the chamber 12. It is comprised by the control part 13. FIG.

The chamber 12 is made of a stainless steel box that is airtightly shielded from the outside environment, and the

filter units

14a, 14b, and 14c for intake and exhaust and the air inside the chamber 12 are filtered by the filter unit. After that, a blower 15 for exhausting to the outside is provided. Further, a pass box 16 disposed on the left side wall portion of the chamber 12 and a bag-out port 17 disposed on the right side wall portion are provided.

An opening / closing door 12 a is provided on the front wall of the chamber 12. The open / close door 12 a has three circular glove ports 12 b that communicate the outside with the inside of the chamber 12. A work glove is airtightly attached to each of these glove ports 12b.

In this embodiment, the containment performance of the chamber 12 is inspected. The chamber 12 has a risk in its containment performance at a plurality of locations such as the opening / closing door 12a, the pass box 16, and the bag-out port 17. Therefore, before using the isolator 10 as a containment isolator, it is important to inspect the containment performance centering on these locations. FIG. 2 is a front view A and a left side view B illustrating the sampling point P in the isolator 10. Note that the sampling points in FIG. 2 are merely examples, and it is necessary to inspect many points having a leakage risk without being limited thereto.

Here, an outline of the inspection of the containment performance of the chamber 12 of the isolator 10 will be described. FIG. 3 is a schematic view showing a state in which a simulated contaminant is scattered inside the chamber 12 and its containment performance is inspected. In FIG. 3, the containment performance inspection system 20 includes an aqueous solution of a fluorescent luminescent material (described later), a container 21 that accommodates the solution, an ultrasonic atomizer 23 that generates mist by applying ultrasonic vibration thereto, A collector 24 that collects the generated mist, a detection device 25 that detects the collected mist, and a suction pipe 25 a that communicates between the collector 24 and the detection device 25 are provided.

In the present embodiment, a mist 22 of a simulated pollutant is generated in place of the spray (mist) or powder of the highly pharmacologically active drug in the chamber 12. Specifically, the simulated contaminant is an aqueous solution of a fluorescent luminescent material, and the mist 22 is generated by applying ultrasonic vibration by the ultrasonic atomizer 23 to the aqueous solution contained in the container 21 (see FIG. 3).

Here, an aqueous solution of the fluorescent light-emitting substance employed in this embodiment will be described. When the special simulated powder or phosphor powder used in Patent Document 1 is directly scattered as simulated contaminants, not only does the amount of scattered powder increase and the chemical cost increases, but also the isolator as described above. The cleaning work to completely remove the powder adhering to the inner wall of the steel requires excessive labor.

Therefore, in the present embodiment, a water-soluble fluorescent substance is used, and an aqueous mist 22 diluted with water is used as a simulated contaminant. In addition, the mist 22 of the aqueous solution of the fluorescent substance is similar in scattering behavior to the mist 22 when the actual highly pharmacologically active pharmaceutical agent (liquid agent before lyophilization) is scattered. The inventors of the present invention have confirmed that mist 22 exhibits a scattering behavior similar to that of an actual highly pharmacologically active pharmaceutical product (powder after lyophilization).

Here, the fluorescent substance used in the present embodiment will be described. The fluorescent substance used in the present invention is not particularly limited as long as it is a substance that emits fluorescence. In the present embodiment, it is preferable that the substance is safe for the human body and has no environmental pollution, and is water-soluble. Since the fluorescent light-emitting substance is water-soluble, an aqueous solution can be easily prepared without using any other solvent to make a mist. As a result, the actual amount of scattered fluorescent light-emitting substance is very small compared to the amount of scattered mist, which not only reduces the chemical cost, but also facilitates a cleaning operation for removing the fluorescent light-emitting substance attached to the inner wall of the isolator.

It should be noted that various fluorescent light-emitting substances that are safe for the human body, have no environmental pollution, and are water-soluble can be used. In this embodiment, riboflavin (vitamin B2) or a derivative thereof that has a proven record in this technical field is employed. Specifically, riboflavin phosphate sodium was employed. The solubility of this riboflavin phosphate sodium in water is 50 g / L, and it has sufficient water solubility.

The concentration of the aqueous solution of the fluorescent luminescent substance to be used must be less than the solubility of the fluorescent luminescent substance. Moreover, in the combination of the ultrasonic atomization apparatus and detection apparatus which are actually used, if it is the density | concentration beyond which the presence of the fluorescent luminescent substance can be detected clearly, it will not specifically limit. When sodium riboflavin phosphate is used as the fluorescent substance, it is preferably used in the range of 0.1% by mass to 5.0% by mass aqueous solution (described later). This is because the detection sensitivity is good when the concentration of sodium riboflavin phosphate is 0.1% by mass or more, and the dissolution of sodium riboflavin phosphate is easy when the concentration is 5.0% by mass or less. In this embodiment, a 0.2% aqueous solution of sodium riboflavin phosphate is used.

Next, mist generating means using an aqueous solution of a fluorescent light-emitting substance as mist will be described. In FIG. 3, a container 21 containing an aqueous solution of a fluorescent luminescent substance (0.2% aqueous solution of riboflavin phosphate sodium) is placed on the vibration surface of an ultrasonic atomizer 23 serving as a mist generating means to fluoresce. A mist 22 of material is generated. In addition, about the structure and performance of the ultrasonic atomizer 23, it does not specifically limit. However, it is preferable to use an aqueous solution of a fluorescent light-emitting substance as a simulated contaminant and a mist having an appropriate droplet diameter. An appropriate droplet size as a simulated contaminant means that it exhibits a scattering behavior similar to that of an actual highly pharmacologically active pharmaceutical mist (liquid agent before freeze-drying) or powder (powder after freeze-drying). For this purpose, the frequency and output of the ultrasonic atomizer 23 are adjusted in consideration of the specific gravity of the mist 22 of simulated contaminants and the droplet diameter.

When the aqueous solution of the fluorescent light-emitting substance becomes the mist 22, the simulated contaminant is scattered as mist in the air throughout the interior of the chamber 12. The inside of the chamber 12 is managed at a positive pressure in the same manner as when actually used as a containment isolator. In FIG. 3, the containment performance is confirmed for the bug out port 17 among the sampling points shown in FIG. In FIG. 3, the bag-out port 17 disposed on the right side wall of the chamber 12 is covered with a collector 24 as a collecting means from the outside environment side. The collector 24 is in communication with the detection device 25 and the suction pipe 25a.

In this state, when the mist 22 of the simulated pollutant leaks from the vicinity of the bag-out port 17, the mist 22 is collected by the collector 24 as the inspection air together with the ambient air. The inspection air collected by the collector 24 is sent to the detection device 25 as detection means via the suction pipe 25a. The detection device 25 has a built-in pump (not shown) that sucks the inspection air.

Here, the detection device 25 will be described. In the present embodiment, a rapid microorganism testing apparatus used in the rapid microorganism testing method (RMM) can be used as the detection device 25. This rapid microorganism testing apparatus generally includes a particle counter and a floating bacteria counter. These counters draw a certain amount of test air sent from the suction pipe as a sample from the collection port, and detect particles (microparticles) and airborne microbes (microorganism microparticles) in the sample using an optical instrument. Is. Particularly in recent years, it has been said that a rapid microorganism testing apparatus using an optical measuring instrument can greatly improve the working efficiency as compared with a conventional culture method as a method capable of instantaneously distinguishing microorganism-derived microparticles. In this embodiment, airborne bacteria (microorganism microparticles) are not measured, but a microorganism rapid inspection apparatus is used to detect mist that emits fluorescence.

In the present embodiment, a particle counter using particle size sorting by a light scattering method is employed as the particle detection unit of the detection device 25. This particle counter instantaneously detects the total number of fine particles in the inspection air. In the present embodiment, the total number of fine particles detected by the particle counter is defined as “total particle concentration (number / L)” in the inspection air.

On the other hand, as a fluorescence detection part of the detection device 25, a floating bacteria counter using fluorescence identification by a laser excitation fluorescence method was adopted. The laser-excited fluorescence method utilizes the fact that among microparticles floating in test air, microparticles related to microorganisms and cell viability emit fluorescence when excited by ultraviolet rays. This airborne microbe counter instantaneously detects the total number of fluorescent luminescent particles in the test air. In the present embodiment, the total number of fluorescent light-emitting fine particles detected by the airborne microbe counter is defined as “positive particle concentration (number / L)” in the test air.

Next, in the present embodiment, the positive particle ratio (%) is calculated from the total particle concentration (number / L) detected by the particle counter and the positive particle concentration (number / L) detected by the floating bacteria counter. When this positive particle ratio (%) is clearly distinguishable from the positive particle ratio (%) of the background (water mist that does not contain fluorescent substances), it is determined that simulated contaminants are present in the test air. can do.

Here, the detection of the mist 22 by the detection device 25 and the criteria for judging the presence of the simulated contaminant leaked into the inspection air will be described. Here, mist of sodium riboflavin phosphate aqueous solution will be described as a simulated contaminant.

First, the present inventors prepared several types of sodium riboflavin phosphate aqueous solutions (samples) with different concentrations and water not containing a fluorescent substance (comparative sample). Next, with respect to these samples, the mist 22 of each sample was generated using the container 21 and the ultrasonic atomizer 23 described in FIG. Next, the air containing the generated mist 22 was collected by the collector 24 as inspection air. The inspection air collected by the collector 24 was supplied to the detection device 25 via the suction pipe 25a, and the fluorescent light emitting material was detected. As a result, the total particle concentration (number / L), the positive particle concentration (number / L), and the calculated positive particle ratio (%) for each sample were obtained.

As a result, it was confirmed that the positive particle ratio (%) for each sample having a different concentration of the fluorescent substance changed depending on the concentration. In addition, when the concentration of the fluorescent light-emitting substance was high, a clear difference was confirmed as compared with water not containing the fluorescent light-emitting substance (comparative sample). As a result, it was confirmed that leakage of simulated contaminants could be detected from the positive particle ratio (%) in the test air.

From these facts, the present inventors have determined that when sodium riboflavin phosphate is used as a simulated contaminant, it is preferably used in the range of 0.1% by mass to 5.0% by mass aqueous solution. . In the present embodiment, the concentration of the fluorescent light-emitting substance to be used is determined by conducting the preliminary test as described above for the type of the fluorescent light-emitting substance actually used and the combination of the ultrasonic atomizer and the detection device. It is preferable to confirm.

From the above, in the present invention, a simulated contaminant that does not require a complicated manufacturing operation and can be easily removed from the apparatus after the inspection is used, and the state of scattering and leakage of the simulated contaminant is a quantitative value. It is possible to provide a containment performance inspection system that can be obtained in real time.

In carrying out the present invention, not only the above-described embodiment but also the following various modifications can be mentioned.
(1) In the above embodiment, sodium riboflavin phosphate is adopted as the fluorescent light-emitting substance, but the present invention is not limited to this, and riboflavin itself or other water-soluble fluorescent light-emitting substances may be used. .
(2) In the above-described embodiment, the containment performance of the containment isolator chamber is inspected. However, the present invention is not limited to this. Contaminants at various positions inside a clean room, RABS (access restriction barrier system), etc. You may make it use this system for grasping (monitoring) of the scattering situation of a.

10 ... Isolator, 11 ... Stand,
12 ... Chamber, 12a ... Open / close door, 12b ... Globe port,
13 ... Control unit, 14a, 14b, 14c ... Filter unit, 15 ... Blower,
16 ... pass box, 17 ... bug out port,
20 ... containment performance inspection system, 21 ... container, 22 ... mist, 23 ... ultrasonic atomizer, 24 ... collector
25 ... Detection device, 25a ... Suction piping,
P: Sampling point.

Claims

An inspection system for detecting leakage of simulated pollutants from the inside of a work room to the outside environment and checking the containment performance of the work room,
Mist generating means for generating a mist of the simulated contaminant inside the working chamber;
In the external environment, collecting means for collecting inspection air at a position for confirming leakage of the simulated contaminants;
A containment performance inspection system comprising: detection means for detecting the simulated contaminant contained in the inspection air collected by the collection means.
The detection means includes a fine particle detection unit and a fluorescence detection unit,
In the fine particle detection unit, while detecting the total particle concentration of the simulated contaminant in the inspection air,
In the fluorescence detection unit, by detecting the positive particle concentration in the test air,
The containment performance inspection system according to claim 1, wherein a leakage ratio of the simulated contaminant is confirmed by calculating a positive particle ratio from the total particle concentration and the positive particle concentration.
3. The containment performance inspection system according to claim 2, wherein the fluorescence detection unit detects the simulated contaminant in the inspection air by a laser excitation fluorescence method.
The containment performance inspection system according to any one of claims 1 to 3, wherein the mist generating means is an ultrasonic atomizer.
The containment performance inspection system according to any one of claims 1 to 4, wherein the simulated contaminant is an aqueous solution of a fluorescent luminescent material.
6. The containment performance inspection system according to claim 5, wherein the aqueous solution of the fluorescent light-emitting substance is an aqueous solution in which riboflavin or a derivative thereof is dissolved.
The containment performance inspection system according to claim 6, wherein the aqueous solution of the fluorescent light-emitting substance is a 0.1% by mass to 5.0% by mass aqueous solution of sodium riboflavin phosphate.