JP2014083272A - Chemical manufacturing system - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a chemical manufacturing system which solves the problem that a chemical holding sterility has been difficult heretofore when a chemical factory is not provided with equipment special for enabling a person to safely conduct the work in the interior while the cleanness of an operation room is maintained.SOLUTION: A chemical manufacturing system for manufacturing a chemical and treating a waste liquid in a plurality of compartments formed by dividing a space enclosed with an outer wall by inner walls and doors includes: a transport apparatus for transporting a chemical, a material for the chemical, a container or machinery and materials used for manufacturing the chemical between a first manufacturing compartment and a second manufacturing compartment on the basis of a signal received from a control device provided outside of the outer wall; a measuring device for measuring the amount of particles in the air in the first manufacturing compartment on the basis of a signal received from the control device; and a compartment management device for determining whether or not the door between the first manufacturing compartment and the second manufacturing compartment is opened according to the comparison result between a measurement value and a first threshold of amount of particles in a predetermined air in transporting from the first manufacturing compartment to the second manufacturing compartment on the basis of the signal received from the control device.

Description

The present invention relates to a chemical manufacturing system. In particular, the present invention relates to a technique for producing a chemical that ensures sterility.

  In recent years, pharmaceuticals such as PET drugs used in the fields of cancer screening and cancer screening have attracted attention. For such a PET drug, it is necessary to ensure high sterility in order to make it safe and reliable in consideration of a decrease in immunity of a patient to be administered. For example, in Patent Document 1, an airtight wall is provided between a high cleanliness area and a medium cleanliness area, and an air lock and necessary cleaning equipment (such as an air shower) are provided at the opening of the airtight wall. A configuration for preventing microbial contamination via a person from a medium cleanliness zone to a high cleanliness zone is disclosed. Patent Document 2 discloses a configuration that provides a radiopharmaceutical manufacturing system that does not require a heavy shield (cabinet) that is indispensable for a radiopharmaceutical manufacturing apparatus and is heavy.

JP 2004-353875 A JP 2006-288523 A

  When installing a shield for a radiopharmaceutical manufacturing apparatus as disclosed in Patent Document 1 or Patent Document 2, a special water supply / drainage facility or air supply / exhaust facility is provided in the facility to be installed while providing the shield. There is a need. For example, clean room equipment for maintaining the cleanliness of the working room.

  In other words, in the past, it was possible to manufacture chemicals that ensure sterility, unless a chemical factory equipped with dedicated equipment for the safe operation of people inside was maintained while maintaining the cleanliness of the work room. It was difficult.

  Therefore, the present invention has an object to provide a chemical manufacturing system capable of manufacturing chemicals in an environment in which cleanliness is ensured without requiring the introduction or expansion of clean room facilities or the like for a person to work inside. To do.

  As one aspect of the present invention for solving at least one of the above-described problems, a chemical manufacturing system that performs chemical manufacturing and waste liquid processing in a plurality of sections in which a space surrounded by an outer wall is divided by an inner wall and a door, A first manufacturing section that performs the first chemical manufacturing process by the first chemical manufacturing mechanism and a cleanliness higher than the cleanliness of the first manufacturing section, and the second chemical manufacturing mechanism The second manufacturing section for carrying out the chemical manufacturing process, a control device provided outside the outer wall, the transport apparatus for transporting between the first manufacturing section and the second manufacturing section Measuring the amount of particles in the air in the first manufacturing section, and transmitting the result of the measurement to the control device, and the second manufacturing from the first manufacturing section by the transport device Carrying the compartment through the door A compartment for opening a door between the first production compartment and the second production compartment based on the measured value and a first threshold value of the amount of particles in the air. And a management device.

  ADVANTAGE OF THE INVENTION According to this invention, the production | generation of the pharmaceutical which ensured sterility is realizable, without providing the dedicated equipment for a person to work inside.

  Problems, configurations, and effects other than those described above will be clarified by the following description of embodiments.

1 is a schematic diagram showing a configuration example of a radiopharmaceutical production system 100. FIG. It is the schematic which shows the structural example of the outer case 101. FIG. It is a functional block diagram which shows each functional block of the external control apparatus 124, and the connection relation between each apparatus. It is an example of a structure of the database of the recording part. It is a flowchart which shows an example of the processing flow of carrying in / out of the material in an outer box, and a pharmaceutical. It is a flowchart which shows an example of the processing flow of carrying in / out of the material in an outer box, and a pharmaceutical. It is a flowchart which shows an example of the processing flow of carrying in / out of the material in an outer box, and a pharmaceutical. It is a flowchart which shows an example of the processing flow of radioactive waste processing. It is a flowchart which shows an example of manufacture of a radiopharmaceutical, and the processing flow of the said manufacture. It is a flowchart which shows an example of manufacture of a radiopharmaceutical, and the processing flow of the said manufacture. It is a flowchart which shows an example of manufacture of a radiopharmaceutical, and the processing flow of the said manufacture. It is an example of a structure of a dilution filling plan table. It is a structural example of a non-radioactive material storage rack. It is an example of a block diagram of an outer box and a conveyance manipulator. It is an example of the block diagram of a conveyance manipulator.

Hereinafter, examples will be described with reference to the drawings.
Example 1
In this embodiment, an example of a radiopharmaceutical production system that can be installed in a general clean area will be described. FIG. 1 is an example of a configuration diagram of the radiopharmaceutical production system of the present embodiment.
The radiopharmaceutical production system 100 includes an outer box 101, an air conditioner 102, a drug substance synthesis apparatus 103, a dilution filling apparatus 104, a quality analysis apparatus 105, a radioactivity measurement apparatus 106, a weight measurement section 107, a radiopharmaceutical raw material storage section 108, Radiopharmaceutical material storage rack 109, transport manipulator 110, unpacking device 111, material information reader 112, transport device 113, radiopharmaceutical primary container information providing device 114 for subject, secondary container storage rack 115 before filling, secondary after filling Container storage rack 116, secondary container information giving device 117, utility gas supply unit 118, waste liquid recovery unit 119, air compressor 120, waste gas recovery unit 121, suspended particulate measurement device 122, suspended microorganism measurement device 123, external control device 124, radioactive waste recovery device 125, internal partition wall operation device 126, monitoring Mela 128, having an air sample tube 129. The external control device 124 includes a communication processing unit 301, a control unit 302, an arithmetic processing unit 303, and a recording unit 304, as will be described later with reference to FIG.

  FIG. 2 is an example of a structural diagram of the outer box 101. The outer box 101 is surrounded by an outer wall having a shielding structure that prevents leakage of radioactivity to the outside, and has an inner partition wall 208 that can partition the inside according to the required level of a dust-free and sterile environment. The internal partition has an internal compartment door 205 for transporting materials and radiopharmaceuticals between compartments with different dust and aseptic environment. In addition, an outer box door 206 is provided on a part of the outer wall so that materials and parts can be carried in and out from the outside of the outer box 101. In addition, the outer box 101 has a shielding structure including an external partition wall and a filter that do not leak a substance to be handled to the outside in preparation for the scattering of radioactive gas from the internal drug substance synthesis apparatus 103, dilution filling apparatus 104, and quality analysis apparatus 105. doing.

  With this configuration, the inside of the outer box 101 can be partitioned according to the required level of dust-free and sterile environment. Furthermore, by opening and closing the internal compartment door 205 only when the dust-free and sterile environment between adjacent compartments meets the required level, the non-radioactive pharmaceutical raw materials and subjects can be used without impairing the dust-free and sterile environment of each compartment. Radiopharmaceutical primary containers can be carried in and out. Here, the radiopharmaceutical container for a subject is a container that contains a radiopharmaceutical and has no risk of gas or microorganisms entering during normal handling, transportation, or storage.

Hereinafter, each configuration shown in FIG. 1 will be described in detail. The air conditioner 102 maintains the cleanliness of the space partitioned by the internal partition wall 208 shown in FIG. 2 at a high cleanness. For example, the important section 201 is maintained in the ISO 146441-1 standard class 5, the direct support section 202 is maintained in the ISO 146441-1 standard class 7, the support section 203 is maintained in the ISO 146441-1 standard class 8, and the cleanliness is maintained in the important section 201. The height is increased in the order of the direct support section 202 and the support section 203. Here, the important section refers to a limited area in which a sterilized product or material and a material and a surface in direct contact with these are subjected to a manufacturing operation in which the environment is exposed to the environment. The direct support section is an area that is the background of the important section.
The support section is a section that performs a manufacturing operation in which products and materials before sterilization are exposed to the environment.

  The drug substance synthesizing device 103 stores the radiopharmaceuticals stored in the manufacturing plan database 402, which will be described later with reference to FIG. From the raw material storage unit 108, the radiopharmaceutical raw material is sucked through the tubes, and the radiopharmaceutical raw material is collected. By adopting such a configuration, it is possible to introduce an optimal amount of a radiopharmaceutical material according to the planned production amount of radiopharmaceuticals, production start time, and the like into the drug substance synthesizer 103.

  The recovered radiopharmaceutical raw material is injected into the nonradioactive pharmaceutical material stored in the nonradioactive pharmaceutical material storage rack 109, and operations such as labeling, hydrolysis, separation generation, and formulation are automatically performed. Furthermore, information such as the amount of radioactivity, temperature, and flow rate in the synthesis process is output to the external control device 124. Non-radioactive pharmaceutical materials for drug substance synthesis include reagents, tubes, and syringes. For example, small chips are used. The non-radiopharmaceutical material is sealed in a sterilized double packaging bag. The non-radiopharmaceutical material is taken out from the outer sterilized packaging bag and then introduced into the outer box in a state of being sealed in the inner sterilized packaging bag as shown in FIG.

The drug substance synthesizer 103 collects the manufactured bulk preparation and stores it in the bulk preparation container. The bulk drug refers to a drug substance synthesized and recovered at a time in the drug substance synthesizer 103. As the container, for example, a sterilized glass vial or a sterilized syringe is used.
The dilution filling device 104 fills the preliminary quality analysis container with the sample for preliminary quality analysis from the bulk preparation container based on the production plan database 402. The preliminary quality analysis sample is used for quality analysis to determine the amount of bulk formulation and diluent added to the subject radiopharmaceutical primary container. The quality analysis described above includes, for example, measurement of drug substance concentration and impurity concentration using a high performance liquid chromatograph apparatus.
Furthermore, the dilution filling apparatus 104 performs dilution filling of the subject-provided pharmaceutical and the quality analysis sample according to the conditions of the dilution filling plan table 601. The dilution filling plan table 601 is stored in the manufacturing plan database 402. An example of the dilution filling plan table is shown in FIG.
The quality analysis apparatus 105 adds the preparatory quality analysis sample or the quality analysis sample filled in the dilution filling apparatus 104 to the quality analysis material. The change of the added quality analysis material is photographed by the monitoring camera 128, and the photographed data is output to the external control device 124. Further, the quality analysis of the sample is performed using a measuring instrument stored in the quality analysis apparatus, and the measurement value is output to the external control apparatus 124. For example, the object of analysis includes pH, chemical impurity content, radiochemical purity, endotoxin content, and the like.

  The radioactivity measuring device 106 measures the amount of radioactivity and the measurement time in the bulk preparation container, the preliminary quality analysis sample container, the quality analysis sample container, the subject radiopharmaceutical primary container, and outputs the measurement data to the external control device 124. To do. Here, the sample container for quality analysis refers to a container for storing a specimen for quality analysis diluted and filled under the same conditions as the radiopharmaceutical container for test subject. The weight measuring device 107 measures the weight of the bulk preparation container, the preliminary quality analysis sample container, the quality analysis sample container, and the subject radiopharmaceutical primary container, and outputs the measurement value and the measurement time to the external control device 124. The tare weight of the container is registered in the material database 401 of the recording unit 304 provided in the external control device 124. The bulk preparation container, the preliminary quality analysis sample container, the quality analysis sample container, and the subject radiopharmaceutical primary By subtracting the tare weight from the weight of the container, the external control device 124 calculates the weight of the net filling liquid.

  With this configuration, the net filling amount is accurately measured without manually weighing the tare weight of the bulk preparation container, preliminary quality analysis sample container, and quality analysis sample container at the system installation facility. It becomes possible. Here, the sample container for preliminary quality analysis refers to a container in which a specimen for determining the amount of the bulk preparation and diluent added to the primary container for subject provision is placed.

  The radiopharmaceutical material storage unit 108 stores the radiopharmaceutical material sealed with a vial or the like. In addition, in accordance with a command signal received from the external control device 124, it has a drive unit and a slit through which a tube, a needle, and a vent needle can be punctured to feed a radiopharmaceutical raw material to the drug substance synthesizer. For example, a radiopharmaceutical raw material includes a fluorine 18 liquid.

  As shown in FIG. 9, the non-radiopharmaceutical material storage rack 109 fixes and stores non-radiopharmaceutical material sealed with sterilized packaging or the like. For example, by fixing the ring portion provided at the distal end portion of the sterilized package with the sterilized package fixing pin 907, the fishing manipulator 110, which will be described later with reference to FIG. .

  For example, for non-radioactive pharmaceutical materials, as shown in FIG. 9, a drug substance synthesis chip 901, drug substance synthesis reagent 902, quality analysis chip 903, quality analysis reagent 904, bulk drug product container / dilution solution 905, There is a radiopharmaceutical primary container 906 for subjects. Moreover, the non-radiopharmaceutical material storage rack can store the non-radiopharmaceutical material necessary for the production of a plurality of radiopharmaceuticals separately. Here, the configuration and operation of the transport manipulator 110 will be described with reference to FIGS. 10 and 11. FIG. 10 is a configuration diagram of the transport manipulator 110, the X-axis direction guide rail 1001, the Y-axis direction guide rail 1003, the X-axis direction drive unit 1002, and the Y-axis direction 1004 inside the outer box 101. The transfer manipulator 110 moves the transfer manipulator to the XY coordinate position according to the storage position coordinate information of the necessary material input from the external control device 124.

  FIG. 11 is a configuration diagram of the transport manipulator 110. The transfer manipulator 110 operates the gripping claw rotation driving unit 1104 according to the shape information of the drug substance synthesis chip 901 input from the external control device 124 and switches the gripping claw. Furthermore, the drug substance synthesizing chip 901 is fixed by expanding and contracting in the Z-axis direction according to the shape information of the drug substance synthesizing chip 901 and adjusting the XY coordinate position of the gripping claws. Further, the drug substance synthesis chip 901 is conveyed to the material information reader 112. Further, the drug substance synthesis chip is installed in the drug substance synthesis apparatus 103. Further, the drug substance synthesis reagent 902 is installed in the drug substance synthesizer 103 by the above-described operation method. Further, the quality analysis chip 903 and the quality analysis reagent 904 are installed in the quality analysis apparatus 105 by the above-described operation method. Furthermore, the bulk preparation vial / dilution solution 905 and the subject radiopharmaceutical primary container 906 are installed in the dilution filling apparatus 104 by the above-described operation method.

  Further, the transfer manipulator 110 completes the drug synthesis and collects the bulk preparation in the bulk preparation container, and then, according to the flowchart of FIG. 7 described later, the bulk preparation container, the preliminary quality analysis sample container, the quality analysis sample container, After grabbing the radiopharmaceutical primary container for the subject and installing it on the radioactivity measuring device 106 and the weight measuring device 107, the radiopharmaceutical primary container is installed at a predetermined position of the dilution filling device and the quality analysis device. In addition, the subject radiopharmaceutical primary container is grasped and installed in the secondary container through the internal compartment door 205. In addition, install the upper lid of the secondary container. Here, the secondary container refers to a shielding container for storing a radiopharmaceutical container provided for a subject and protecting the radiation to a transportable level. Further, the used non-radioactive pharmaceutical material is grabbed by the drug substance synthesizer 103, the dilution filling device 104, and the quality analyzer 105 and dropped into the waste pass box 207.

  By the configuration and operation of the transfer manipulator 110, it is possible to remotely carry out the dust-free introduction of reagents and consumables into the sterile area and the removal of the radiopharmaceutical primary container for subjects from the dust-free and sterile area. It is possible to prevent dust and bacteria from being brought into the dust-free and sterile area.

Returning to the description of FIG.
The unpacking device 111 opens the sterilization bag of the non-radioactive pharmaceutical material conveyed by the conveyance manipulator 110 according to the command signal of the external control device 124. The material information reader 112 reads information such as the lot number and expiration date of the non-radiopharmaceutical material conveyed by the conveyance manipulator 110 by means of barcode, electronic tag reading, etc., and inputs the information to the external controller 124. .
In accordance with the signal input from the external control device 124, the transport device 113 moves the radiopharmaceutical material storage rack 109, the unpacking device 111, the secondary container storage rack 115, and the secondary container storage rack 116 into the horizontal X axis and Y axis. Move in the direction.

  The subject radiopharmaceutical primary container information providing device 114 assigns a signal input from the external control device 124 to the subject radiopharmaceutical primary container by an electronic method or the like. For example, as a method of giving information, there are a method of inputting information to an electronic tag wirelessly, or a method of printing necessary information on a label and affixing it to a primary radiopharmaceutical container for a subject. With this configuration, since the radiopharmaceutical production record can be given to the subject radiopharmaceutical primary container without directly touching the subject radiopharmaceutical container, the radiation exposure of the operator can be reduced. Furthermore, it is possible to avoid the adhesion of bacteria from a person to the primary radiopharmaceutical container for a subject.

  The secondary container storage rack 115 stores the secondary container carried in through the front outer box door 206. The secondary container is made of a material such as lead and has a thickness that can sufficiently shield the radiation generated from the primary radiopharmaceutical container for subjects. The secondary container storage rack 116 stores the secondary container after the filled radiopharmaceutical primary container for the subject is installed by the transport manipulator 110.

  The secondary container information giving device 117 gives the signal input from the external control device 124 to the secondary container by an electronic method or the like. For example, as a method of giving information, there are a method of inputting information to an electronic tag through radio, or a method of printing necessary information on a label and sticking it to a secondary container. With this configuration, the radiopharmaceutical production record can be given to the secondary container without directly touching the secondary container, so that the radiation exposure of the operator can be reduced. Furthermore, it is possible to avoid the adhesion of bacteria from a person to the primary radiopharmaceutical container for a subject.

  The utility gas supply unit 118 includes a gas cylinder, a pressure regulator, and a filter, and supplies necessary gas to the drug substance synthesis apparatus 103, the dilution filling apparatus 104, and the quality analysis apparatus 105. The waste liquid collection unit 119 sorts the collection containers according to the generation date or lot according to the input signal from the external control device 124, and stores the radioactive waste liquid generated in the drug substance synthesis apparatus 103, the dilution filling apparatus 104, and the quality analysis apparatus 105. To do. The air compressor 120 collects the radioactive gas generated from the drug substance synthesizer 104 through the exhaust gas line and compresses it to the waste gas recovery unit 121. The waste gas recovery unit 121 divides the recovery container for each generation date or lot according to the input signal from the external control device 124 and stores the radioactive gas sent from the air compressor 120. With this configuration, radioactive waste gas generated in the system can be stored with a small capacity.

  The suspended particulate measuring device 122 collects air in each section in the outer box via the air sample tube 129 shown in FIG. 1 and measures suspended particulates in the air. Further, the measurement result is output to the external control device 124. The floating microorganism measuring device 123 collects the air in each compartment in the outer box via the air sample tube and measures the floating microorganisms in the air. Further, the measurement result is output to the external control device 124.

  Below, an example of the information processing of the radiopharmaceutical production system 100 is demonstrated using FIG. 3, FIG. As shown in FIG. 3, the external control device 124 includes a communication processing unit 301, a control unit 302, an arithmetic processing unit 303, and a recording unit 304. As illustrated in FIG. 4, the recording unit 304 includes a material database 401, a manufacturing plan database 402, a manufacturing performance database 403, and a waste management database 404. Note that the material database 401, the manufacturing plan database 402, the manufacturing performance database 403, and the waste management database 404 are not provided in the recording unit 304 of the external control device 124, and are externally readable / writable by connecting the external control device 124. The recording medium may be configured to be constructed.

  In the material database 401, the material name, lot number, expiration date, analysis certificate image data, warehousing person, warehousing person, storage temperature range, storage humidity range, necessity of shading, vial tare weight, Information indicating an applied drug and a drug synthesis sequence program is stored.

  Here, the test report is a document provided by a material maker and certifies the quality analysis result for the material of the lot. The vial tare weight means the weight of an empty vial. Moreover, the said applicable chemical | medical agent means the name of the chemical | medical agent which can provide the said material. The drug synthesis sequence refers to a series of instruction programs for sequentially executing drug synthesis in the drug substance synthesizing apparatus according to predetermined conditions such as reaction time, temperature, and addition of a drug solution amount.

  On the other hand, in the production plan database 402, bulk production order ID, drug name, production start time, input radioactivity amount, bulk radioactivity plan value, provision vial use time, provision vial liquid amount, provision vial for radiopharmaceutical production Radioactivity, number of quality test samples, quality test sample volume, quality test item, usable material lot, suspended particulate upper limit value, suspended microorganism upper limit value, quality test standard value, dilution / filling standard value, production control standard value, preliminary quality Information indicating sample amount, necessary material, and bulk preparation standard value is stored.

  Here, the production order ID refers to a unique number assigned to each production request for a bulk preparation. Moreover, the said bulk radioactivity plan value means the amount of radioactivity in the bulk drug product container at the time of the drug substance synthetic yield expected in the production of one bulk drug product. The provided vial use time refers to a time when the radiopharmaceutical filled in the subject unit is used mainly for the purpose of administration. Further, the provided vial liquid amount refers to the amount of radiopharmaceutical filled in the subject. The provided vial radioactivity refers to the radioactivity of the radiopharmaceutical filled in the subject unit. The number of quality test samples refers to the required number of quality test samples planned for each production order ID. The quality test sample volume refers to the amount of liquid required for each quality test sample. The usable material lot refers to a lot number that can be used for manufacturing the drug. For example, information on usable material lots is provided from the material department and registered in the manufacturing plan database 402.

  The upper limit value of suspended fine particles and the upper limit value of suspended microorganisms refer to the number of fine particles and microorganisms in a unit air volume that can be allowed in the compartment set for each inner compartment of the outer box. For example, “Fifteenth revised Japanese Pharmacopoeia” reference information There is the maximum allowable number of fine particles in the microbial evaluation test method in the aseptic drug manufacturing area. The quality test reference value refers to a determination reference value in a quality test for a radiopharmaceutical defined for each drug name. For example, the criterion value is provided for each test item such as pH, radiochemical purity, endotoxin content and the like. The dilution / filling reference value is a value that defines the minimum and maximum values of the bulk preparation amount and the diluted solution amount that can be charged into the bulk preparation collection container and the radiopharmaceutical primary container for subjects. The manufacturing control reference value is a reference value for outputting an alarm and an interlock signal when an abnormal value is recognized in the manufacturing process. For example, there are an upper limit value and a lower limit value of the amount of radioactivity in the synthesis unit. The preliminary quality sample amount refers to the amount of a sample collected for preliminary quality analysis from a filled bulk preparation collection container. Moreover, the said required material means the kind of radiopharmaceutical material and non-radiopharmaceutical material which are used for every medicine name. Moreover, the said bulk formulation reference value means the reference value which the bulk formulation provided for every chemical | medical agent name should satisfy. For example, there is a chemical content concentration and a radioactivity concentration in the bulk drug product collection container.

  On the other hand, the production performance database 403 includes a bulk production lot, a raw material name, a raw material lot, a suspended particulate measurement value, a suspended microorganism measurement value, a synthesis radioactivity log, a synthesis temperature log, and a synthesis radiopharmaceutical product. Pressure log, synthesis flow log, quality test data (pH, radioactivity concentration, etc), synthesis start time, synthesis end time, input radioactivity, provided vial serial number, provided vial volume, provided vial radioactivity, provided vial Stores information indicating the expiration date, production order approval record, quality manager approval record, QA manager approval record, shipping manager approval record, takeover approval record, drug name, and lot number of materials used.

  Here, the said bulk formulation lot means the unique number provided for every manufactured bulk manufacture. The raw material lot refers to the lot number of the material used for manufacturing the radiopharmaceutical. The measured value of suspended particulates refers to the measured value of suspended particulates measured before the opening operation of the internal compartment door and at the time of manufacturing the radiopharmaceutical. Moreover, the said floating microorganisms measured value means the measured value of the floating microorganisms measured before the opening operation of the internal compartment door and at the time of manufacturing the radiopharmaceutical. The radioactivity log at the time of synthesis refers to a measured value of radioactivity measured in the process of synthesizing the radiopharmaceutical in the drug substance synthesizer 103. The synthesis flow rate log is a measured value of the flow rate of the utility gas measured in the process of synthesizing the radiopharmaceutical in the drug substance synthesizer 103. The quality test data refers to image data and numerical data such as vial properties, pH, radiochemical purity, endotoxin content, chemical impurity amount, and the like measured by a quality analyzer. The amount of input radioactivity refers to the amount of radioactivity input from the radiopharmaceutical raw material storage unit 108 to the drug substance synthesizer 103 for each bulk production. In addition, the provided vial production number refers to a unique number assigned every time the subject radiopharmaceutical primary container is produced. The provided vial radioactivity amount refers to the radioactivity amount at the time of measurement filled in each subject radiopharmaceutical primary container.

  In addition, the production order approval record refers to a record in which the production order for the bulk preparation and the provided vial is approved by electronic means. For example, the manufacturing instruction approval record includes the name of the instructor, the instruction time, the instruction content, the person verification means, the person verification result, and the like. The quality test approval record is a record in which the quality test results of the preliminary quality analysis sample and the quality test sample are approved by electronic means. For example, the quality test approval record includes the name of the quality tester, the approval time, the approval content, the personal verification means, the personal verification result, and the like. In addition, the QA manager approval record refers to a record in which the QA manager confirms and approves the contents of the production records and quality test records of the bulk preparation and the provided vial by electronic means. For example, the QA manager approval record includes the name of the QA manager, approval time, approval details, identity verification means, identity verification results, and the like. The shipping manager approval record refers to a record in which the shipping manager approves the shipment of the provided vial by electronic means. For example, the shipping approval record includes the name of the person in charge of shipping, the approval time, the details of the approval, the identity verification means, the identity verification result, and the like. In addition, the receipt manager approval record refers to a record approved by the receipt manager of the provided vial by electronic means. For example, the receipt approval record includes the name of the person in charge of receipt, the approval time, the details of the approval, the identity verification means, the identity verification result, and the like.

  On the other hand, the waste management database 404 includes the name of collection material, collection time, collection container ID, waste generation batch ID, waste generation time, radioactivity at the time of waste generation, shielding container storage period, external Stores information indicating the storage period in the box.

  Here, the recovery container ID refers to a unique number assigned to each container installed in each of the waste liquid recovery unit 112, the waste gas recovery unit 121, and the waste recovery unit 125. When reusing a container, the old ID is erased and a new number is given when the container is installed. Further, the waste generation batch ID is an ID unique to the radioactive waste given to each used raw material and collection container after completion of the production of the bulk preparation. The waste generation time refers to the time when the attachment and recovery of radioactive waste to each used raw material and collection container are completed. Moreover, the said radioactivity at the time of waste generation means the result of evaluating the adhesion and recovery amount of the radioactive waste in each raw material and recovery container at the time of generation of the waste. For example, the waste generation radioactivity is calculated from the input radioactivity amount, the input time, and the radioactive substance distribution rate to each recovered material. The shielding container storage period refers to a period during which the collection container needs to be stored in the shielding container in order to keep the radiation dose rate on the surface of the outer box 101 at a sufficiently low level in terms of radiation management. The storage period in the outer box refers to a period until the amount of radioactivity in the collection container becomes equivalent to the background level and the amount of radioactivity becomes an amount that can be carried out to the outside in terms of half-life.

  As described above, the external control device 124 includes the recording unit 304 including the material database 401, the manufacturing plan database 402, the manufacturing performance database 403, and the waste management database 404. In addition, the external control device 124 processes input information from the material information reading device 112, the suspended particulate measurement device 122, and the suspended microorganism measurement device 123 in the arithmetic processing unit 303 and stores it in the recording unit 304.

  Further, as shown in FIG. 3, the external control device 124 includes a material information reading device 112, a suspended particulate measuring device 120, a suspended microorganism measuring device 121, a drug substance synthesizing device 103, a dilution filling device 104, a quality analyzing device 105, Radioactivity measuring device 106, weight measuring device 107, monitoring camera 128, radiopharmaceutical raw material storage unit 108, transfer manipulator 110, unpacking device 111, transfer device 113, internal partition wall operating device 126, waste liquid recovery unit 117, air compressor 118 The waste gas recovery unit 119, the radioactive waste recovery device 125, the radiopharmaceutical primary container information providing device 114 for the subject, and the secondary container information providing device 117 are connected to each other, and processing as described below is performed. In addition, although the example of a wired connection is shown in FIG. 3, it is also possible to use a wireless connection.

  The external control device 124 transmits a command signal from the control unit 302 to the drug substance synthesis device 103, the dilution filling device 104, the quality analysis device 105, the radioactivity measurement device 106, and the weight measurement device 107. Further, the external control device 124 processes the data measured by the drug substance synthesis device 103, the dilution filling device 104, the quality analysis device 105, the radioactivity measurement device 106, and the weight measurement device 107 by the arithmetic processing unit 303 and records them. Stored in the unit 304. The arithmetic processing unit 303 includes a radiopharmaceutical raw material storage unit 108, a transport manipulator 110, an unpacking device 111, a transport device 113, a waste liquid recovery unit 119, an air compression device 120, a waste gas recovery unit 121, and a radioactive waste recovery device 125. A command signal is transmitted to the internal partition wall operating device 126. Further, the external control device 124 processes the incidental information of the subject radiopharmaceutical primary container by the arithmetic processing unit 303 and inputs the processed information to the subject radiopharmaceutical primary container information giving device 114 and the secondary container information giving device 117. Further, the arithmetic processing unit 303 inputs the processed information to the external control device 124 via the communication processing unit 301. Thus, by realizing remote control from the outside of the outer box 101 by the external control device 124, it is possible to prevent the exposure of the manufacturing worker and to safely produce a radiopharmaceutical that ensures sterility.

  On the other hand, according to the input signal from the external control device 124, the radioactive waste recovery device 125 sorts containers for the radioactive waste recovered through the waste pass box 207 for each generation date or lot, and is dropped from the transport manipulator 110. Stores used non-radioactive pharmaceutical materials. Further, the internal partition wall operating device 126 opens and closes the internal partition door 205 in accordance with an input signal from the external control device 124. Further, the external control device 124 inputs manufacturing records and quality records, and outputs information as images or print information.

  Next, using the flowcharts shown in FIGS. 5 a, 5 b, and 5 c, subjects who have transported the radiopharmaceutical material and the non-radiopharmaceutical material to the important section 201 under the control of the external control device 124 and produced in the important section 201. An operation flow when the radiopharmaceutical for medical use is carried out of the outer box 101 will be described.

  First, as shown in FIG. 5a, the outer box door 206 is opened, and in the direct support section 202 and the support section 203, the radiopharmaceutical raw material storage unit 108, the non-radioactive pharmaceutical raw material storage rack 109, and the secondary container before filling. A radiopharmaceutical raw material, a non-radiopharmaceutical material, and a secondary container are attached to the storage rack 115 (501). The radiopharmaceutical raw material, the non-radiopharmaceutical material, and the secondary container are processed so as not to bring dust and microorganisms into the outer box 101, for example, after being cleaned and sterilized and sealed. Next, the number of suspended fine particles and the number of suspended microorganisms in the direct support section 202 are measured (502). Next, it is determined whether or not the number of suspended particles or the number of suspended microorganisms in the direct support section 202 is less than the management reference value (503). Here, if the number of suspended particulates or suspended microorganisms in the direct support section 202 is less than the management reference value, the sterilization bag of the non-radioactive pharmaceutical material is cut by the unpacking device 111 (504). On the other hand, if the number of suspended particulates or the number of suspended microorganisms in the direct support section 202 is equal to or greater than the management reference value, a warning signal is output to the external control device (505). When the sterilization bag is cut in step 504, the aspiration needle of the radiopharmaceutical raw material part 108 is punctured into the radiopharmaceutical storage container (506), and the internal compartment door 205 between the important compartment 201 and the direct support compartment 202 is opened (step 504). 507).

  Next, as shown in FIG. 5b, after opening the internal compartment door 205 in step 507, according to the manufacturing instruction information of the external control device 124, the types and quantities of the radiopharmaceutical raw materials and non-radiopharmaceuticals required for radiopharmaceutical production are used. Material is transported to the critical compartment 201 by the transport manipulator 110 and transport device 113 (508), and the internal compartment door 205 between the critical compartment 201 and the direct support compartment 202 is closed (509). Next, when the internal partition door 205 of the direct support section 202 and the important section 201 is opened or when the unpacking operation of the sterilization bag is performed in the direct support section, the number of suspended particles and the number of suspended microorganisms in the direct support section 202 are measured. (510), it is determined whether or not the measured values of suspended fine particles and suspended microorganisms are less than the suspended particulate upper limit value and less than the suspended microorganism upper limit value in the production plan database 402 (511). If the measured values of suspended particulates and suspended microorganisms are less than the suspended particulates upper limit value and less than the suspended microorganisms upper limit value in the production plan database 402, the internal partition door 205 is opened, and the subject is provided with diluted filling in the important compartment 201 The vial is transported directly to the support compartment 202 by the transport manipulator 110 (512), and the internal compartment door between the critical compartment 201 and the direct support compartment 202 is closed (514). On the other hand, if the number of suspended particulates or suspended microorganisms in the direct support section 202 is greater than or equal to the management reference value, a warning signal is output to the external control device (513).

Next, as shown in FIG. 5c, the number of suspended particulates and suspended microorganisms in the support section 203 are measured (515), and the measured values of suspended particulates and suspended microorganisms are less than the upper limit of suspended particulates in the production plan database 402 and suspended microorganisms. It is determined whether it is less than the upper limit (516). If the measured values of suspended particulates and suspended microorganisms are less than the suspended particulate upper limit value and less than the suspended microorganism upper limit value in the production plan database 402, the internal partition door 205 is opened (517), and the subject-provided vial is directly supported in the support section 202. Is stored in the secondary storage container of the support section 203 (519), and the internal partition door between the direct support section 202 and the support section 203 is closed (520). On the other hand, if the number of suspended particulates or suspended microorganisms in the direct support section 202 is equal to or greater than the management reference value, a warning signal is output to the external control device (518). Next, the radiopharmaceutical vial for providing the subject is transported to the secondary container information providing device 117 by the transport device 113 (521), and necessary information for shipping examination and approval of the provided vial is output to the external control device 124, and external control is performed. A shipping approval signal is input from the device 124 to release the lock of the outer box door 206, and the secondary storage container storing the filled radiopharmaceutical primary container for the subject can be taken out (522). For example, the necessary information includes a measurement result of a quality test, pass / fail judgment, raw data, manufacturing record, expiration date of the provided vial, and the like.
With the above operation, the radiopharmaceutical for the subject is produced in the important section 201, and the radiopharmaceutical for the subject is carried out of the outer box 101.

  Next, referring to the flowchart shown in FIG. 6, a flow of processing until the radioactive drainage, the radioactive waste gas, and the radioactive waste are collected, stored, and transported to the outer box 101 under the control of the external control device 124. Will be described.

  First, at the production start time of the batch, the amount of radioactivity contained in the radiopharmaceutical raw material storage unit 108 and the drug substance synthesizing device 103 is measured and registered in the waste management database 404 of the recording unit 304 of the external control device 124 (601). ). For example, the radioactivity amount of the radiopharmaceutical raw material is input to the waste management database by the value input from the external control device 124, and the radioactivity in the drug substance synthesizer 103 is the measured value of the radioactivity concentration during the manufacturing process of the drug substance synthesizer Is registered in the waste management database.

  In the arithmetic processing unit 303 of the external control device 124, based on the information in the manufacturing performance database 402, the radioactive waste liquid, radioactive exhaust gas, and radioactive waste generated in each batch are calculated (602), and the calculated radiation is calculated. From the capacity and capacity, the radioactive waste liquid, radioactive waste gas, and radioactive waste in the shielding container are stored in the shielding container and in the outer box (603).

  Next, radioactive liquid waste, radioactive waste gas, and radioactive waste generated in the production process of radiopharmaceuticals are collected in different collection containers for each production date or batch, and each collection container contains the above-mentioned storage period in the shielding container and Information on the storage period in the outer box is given (604). For example, as a method of giving information, there are a method of inputting information to an electronic tag wirelessly, or a method of printing necessary information on a label and affixing it to a primary radiopharmaceutical container for a subject. Further, after the batch is manufactured, the used non-radiopharmaceutical material is stored in a shielding container dedicated to the batch in an important area by the transfer manipulator 110 (605).

  Then, after the storage period in the shielding container has elapsed, the waste liquid collecting unit 119, the waste gas collecting unit 121, and the radioactive waste collecting device 125 are used to store the radioactive waste liquid, radioactive waste gas, and radioactive waste of the batch without shielding. (606), and stores the used non-radioactive pharmaceutical material of the batch through the waste pass box 207 in a radioactive waste recovery device dedicated to the batch (607).

After the storage period in the outer box elapses, the external control device 124 displays a message indicating that the batch of radioactive waste water, radioactive waste gas, and radioactive waste can be taken out (608).
A carry-out operation signal is input from the external control device 124, and the carry-out interlock of the storage container of the batch of the waste liquid collecting unit 118, the waste gas collecting unit 121, and the radioactive waste collecting device 125 is released (609).

  Here, the storage period in the outer box is the specified radioactivity defined by laws and regulations when multiplying the input activity at the synthesis start time in the manufacturing results database by the attenuation coefficient calculated based on the half-life according to the type of radioactive material. The period until concentration is reached.

With the above configuration, it is possible to safely produce a radiopharmaceutical that ensures sterility without providing a dedicated radiopharmaceutical manufacturing facility in a facility such as a hospital.
Furthermore, since the radioactive waste generated in the manufacturing process is stored in the system until it decays to the amount of radioactivity that can be discarded, the facility does not have a dedicated radioactive waste treatment facility. Can produce radiopharmaceuticals.
Furthermore, a radiopharmaceutical supply vial for a subject can be produced based on the optimal dilution / filling conditions calculated according to the result of manufacturing the radiopharmaceutical and the result of preliminary quality analysis.
Furthermore, the radiation exposure of the manufacturing worker can be reduced by remotely providing the radiopharmaceutical manufacturing and quality test results to the radiopharmaceutical supply vial.
Example 2
In the present embodiment, an example of a radiopharmaceutical production system that can change the capacity, filling liquid amount, and filling radioactivity of a primary radiopharmaceutical container for a subject according to the results of radiopharmaceutical production and quality analysis using FIG. explain.

  FIG. 7 shows that based on the measurement information of the drug substance synthesis apparatus 103, the radioactivity measurement apparatus 106, the weight measurement apparatus 107, and the quality analysis apparatus 105, the subject radiopharmaceutical primary container is filled with a bulk preparation and a diluent, and necessary information is obtained. It is an example of the flowchart provided to the radiopharmaceutical primary container for test subjects, and a secondary container.

  First, as shown in FIG. 7a, based on the manufacturing plan database 402 of the recording unit 304 of the external control device 124, the transport manipulator 110 collects the non-radiopharmaceutical material and transports it to the material information reader 112 (701). Next, the information on the non-radiopharmaceutical material input from the material information reader 112 is collated with the available material lot information in the manufacturing plan database 402 (702). (704). On the other hand, when the non-radiopharmaceutical material matches the usable material lot information in the production plan database 402, the information on the non-radiopharmaceutical material is registered in the production performance database 403 (703), and the registered non-radiopharmaceutical material is stored. The transport manipulator 110 is attached to the drug substance synthesizer 104, the dilution filling device 104, and the quality analyzer 105 (705). Next, the time and radiopharmaceutical raw material registered in advance in the manufacturing plan database 402 are put into the drug substance synthesizer 103 (706). Then, the drug substance synthesizer 103 synthesizes the bulk preparation and collects it in the bulk collection vial (707).

  Next, as shown in FIG. 7b, the delivery manipulator 110 installs the bulk preparation vial in the radioactivity measuring device 106, and then installs it in the weight measuring unit 107 (708). Then, the radioactivity measuring device 106 and the weight measuring unit 107 input the radioactivity and weight of the bulk preparation vial into the manufacturing performance database of the external control device 124 (709).

  The dilution and filling device 104 collects a preliminary analysis sample of a volume registered in the production plan database 402 from the bulk preparation vial and injects it into the quality analysis device 105 (710).

  Next, the quality analyzer 105 measures the chemical substance-containing concentration in the preliminary analysis sample and determines whether it is less than the standard upper limit value in the production plan database 402 (711). Here, if the upper limit value of the specification is exceeded, a diluent is added to the bulk drug product vial, or if it is necessary to fill with a diluent exceeding the allowable amount of diluent addition, a production failure signal is sent to the external control device. It is displayed on 124 (713). On the other hand, if it is less than the upper limit of the standard, the drug name, provided vial use time, provided vial radioactivity information in the production plan database 402, and the radioactivity, liquid volume, and chemical substance content of the bulk preparation vial in the production performance database The information is checked against whether or not the pharmaceutical standard is satisfied, and the diluted filling amount that provides the minimum provided vial volume is calculated and registered in the diluted filling plan table 601 (712).

  Based on the dilution filling plan table, the transfer manipulator 110 carries the subject-provided vial from the important support section 202 to the important section 201 according to the procedure described in the flow of 502 to 509 in FIGS. 5a and 5b (714). Then, based on the dilution filling plan table, the bulk preparation and the diluent are filled into the subject-providing vial (715). Then, the subject providing vial is carried out according to the same flow as in Example 1 (716).

  Next, the dilution filling plan table will be described with reference to FIG. A table 801 is a table showing the amount of radioactivity, the amount of liquid, and the radioactivity concentration of the bulk preparation vial based on the measurement result in step 709 of FIG. 7b. In addition, it is set as the liquid amount of a formulation vial by multiplying the specific gravity data and the weight for every medicine registered in the manufacturing plan database 402. The table 802 is a table showing the measurement values of the preliminary quality analysis sample based on the measurement results in the step 709 of FIG. 7b. The table 803 is a table that compares the measurement results of the tables 801 and 802 with the conditions of the allowable value of the concentration of the bulk preparation, and outputs the liquid amount when the necessity of dilution of the bulk preparation is necessary and when dilution is necessary. . A table 804 is a table showing the measured values of the radioactive amount and the liquid amount of the diluted bulk preparation vial. The table in 805 compares the evaluation results of the radioactive concentration, liquid volume, drug substance concentration, impurity concentration of the diluted bulk product vial with the permissible values per provided vial, and the conditions for the bulk filling liquid volume in the provided vial Is a table that outputs In addition, the table of 806 is less than the upper limit of the bulk preparation filling liquid amount of the table of 805, contains administration radioactivity at the time of administration to each subject, and satisfies the provided vial radioactivity concentration standard, And it is a table | surface which outputs the filling conditions used as the minimum amount of filling liquids.

  In addition, this invention is not limited to an above-described Example, Various modifications are included. For example, the above-described embodiments have been described in detail for easy understanding of the present invention, and are not necessarily limited to those having all the configurations described. Further, it is possible to add, delete, and replace other configurations for a part of the configuration of a certain embodiment.

  Note that the above functional blocks and the like can be realized by software by interpreting and executing a program stored in a memory that realizes each function by the processor. Each of the above-described configurations, functions, processing units, processing means, and the like may be realized by hardware by designing a part or all of them with, for example, an integrated circuit. Information such as programs, tables, and files for realizing each function can be stored in a memory, a hard disk, a recording device such as an SSD (Solid State Drive), or a recording medium such as an IC card, an SD card, or a DVD.

  Further, the control lines and information lines indicate what is considered necessary for the explanation, and not all the control lines and information lines on the product are necessarily shown. Actually, it may be considered that almost all the components are connected to each other.

101 ... Outer box, 109 ... Non-radioactive pharmaceutical material storage rack, 110 ... Transport manipulator, 122 ... Airborne particulate measurement device, 123 ... Airborne microbe measurement device, 124 ... External control device, 201 ... Critical compartment, 202 ... Direct support compartment, 203 ... Support section 204 ... Utility section 205 ... Internal section door 301 ... Communication processing section 302 ... Control section 303 ... Calculation processing section 304 ... Recording section 401 ... Material database 402 Production plan database 403 ... Manufacturing results database, 404… Waste management database

Claims (9)

A chemical manufacturing system that performs chemical manufacturing and waste liquid treatment in a plurality of compartments in which a space surrounded by an outer wall is divided by an inner wall and a door,
A first manufacturing section for performing a first chemical manufacturing process by a first chemical manufacturing mechanism;
A second manufacturing section having a higher cleanliness than the cleanliness of the first manufacturing section and performing a second chemical manufacturing process by a second chemical manufacturing mechanism;
A control device provided outside the outer wall;
Based on a signal received from the control device, the medicine or the medicine material, the medicine container, or the medicine is produced between the first manufacturing section and the second manufacturing section. A transport device for transporting the equipment;
A measuring device for measuring the amount of particles in the air in the first production section based on a signal received from the control device, and transmitting the result of the measurement to the control device;
Based on a signal received from the control device, when the transfer device performs the transfer from the first manufacturing section to the second manufacturing section through the door, the measured value and a predetermined air Comparing with a first threshold of the amount of particles in the compartment management device that opens the door between the first production compartment and the second production compartment when the measured value is less than the threshold And comprising
A pharmaceutical manufacturing system characterized by that. The chemical manufacturing system according to claim 1,
The chemical to be manufactured is a radioactive chemical,
The chemical manufacturing system according to claim 1, wherein the outer wall has a shielding structure that prevents leakage of radioactivity to the outside. The chemical manufacturing system according to claim 1,
The chemical to be manufactured is a radioactive chemical,
Based on a signal received from the control device, a radioactivity measuring device that measures the radioactivity at the time of manufacturing the medicine in the first or second manufacturing section;
A waste liquid management section having a shielding structure capable of carrying out the transportation by the transportation device between the first manufacturing section and preventing leakage of radioactivity to the outside,
Based on a signal received from the control device, a waste liquid management device that manages waste liquid generated by the manufacture of the chemical in the waste liquid management section;
In the waste liquid management section, further comprising a waste liquid recovery unit for holding the waste liquid inside,
The waste liquid management device manages the manufacturing time of the chemical and the amount of radioactivity at the time of manufacturing, and the waste liquid is disposed inside the waste liquid recovery unit based on the manufacturing time and the amount of radioactivity at the time of manufacturing. A chemical manufacturing system, characterized in that a period of time for holding is calculated. The chemical manufacturing system according to claim 1,
The chemical to be manufactured is a radioactive chemical,
A chemical manufacturing system, further comprising a chemical radioactivity management device that manages the radioactivity amount of the chemical filled in a container unit in a container unit based on a signal received from the control device. The chemical manufacturing system according to claim 4,
The second medicine manufacturing mechanism fills the container with the medicine according to a subject. The chemical manufacturing system according to claim 1,
A drug manufacturing system, further comprising a manufacturing information adding device that electronically applies information indicating a manufacturing process of the drug to a container for storing the drug based on a signal received from the control device. The chemical manufacturing system according to claim 6,
The chemical to be manufactured is a radioactive chemical,
The said manufacturing information provision apparatus provides the said radioactive amount of the said chemical | medical agent to the said container, The chemical | medical agent manufacturing system characterized by the above-mentioned. The chemical manufacturing system according to claim 6,
Further comprising a shipment approval device that approves shipment for each container based on the manufacturing information based on a signal received from the control device and electronically gives the approval information to the container. A chemical manufacturing system. The chemical manufacturing system according to claim 1,
The particles to be measured by the measuring device include bacteria,
The medicine manufacturing system according to claim 1, wherein the particles to be compared by the section management device include bacteria.