WO2013005838A1 - Appareil de purification aseptique pour des principes pharmaceutiques actifs - Google Patents

Appareil de purification aseptique pour des principes pharmaceutiques actifs Download PDF

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Publication number
WO2013005838A1
WO2013005838A1 PCT/JP2012/067350 JP2012067350W WO2013005838A1 WO 2013005838 A1 WO2013005838 A1 WO 2013005838A1 JP 2012067350 W JP2012067350 W JP 2012067350W WO 2013005838 A1 WO2013005838 A1 WO 2013005838A1
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Prior art keywords
drug substance
sterilization
filter
inert gas
crude drug
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PCT/JP2012/067350
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English (en)
Japanese (ja)
Inventor
憲幸 立道
正信 森田
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アピ 株式会社
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Priority to CN201280031665.8A priority Critical patent/CN103635175B/zh
Publication of WO2013005838A1 publication Critical patent/WO2013005838A1/fr

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    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B65—CONVEYING; PACKING; STORING; HANDLING THIN OR FILAMENTARY MATERIAL
    • B65B—MACHINES, APPARATUS OR DEVICES FOR, OR METHODS OF, PACKAGING ARTICLES OR MATERIALS; UNPACKING
    • B65B55/00—Preserving, protecting or purifying packages or package contents in association with packaging
    • B65B55/02—Sterilising, e.g. of complete packages
    • B65B55/12—Sterilising contents prior to, or during, packaging

Definitions

  • the present invention relates to an apparatus for sterilizing and purifying a drug substance for obtaining a powdery drug substance whose quality is improved by sterilizing and purifying the drug substance.
  • a drug substance used as an active ingredient of a pharmaceutical is administered directly into the body, for example, by subcutaneous, intradermal or intravenous injection, or by oral ingestion. Therefore, the drug substance is free from impurities due to its nature and is required to be highly aseptic or dust-free.
  • a drug substance for injection is manufactured through a purification process in which a target chemical substance is synthesized in a synthesis process and impurities are removed. The sterility or dustlessness of the drug substance is achieved by a post-synthesis purification process.
  • the purification process involves dissolving the synthesized crude drug substance in a solvent, sterilizing by aseptic filtration, followed by crystallization with a crystallization solvent, filtration, drying, filling into a container, etc. in order. Quality drug refinery drug substance is produced.
  • Patent Document 1 discloses a configuration in which each process is performed in an independent work room (clean room) as much as possible. Contamination can be reduced by the configuration of the manufacturing plant.
  • an object of the present invention is to provide a sterilization and purification apparatus for drug substance that can further reduce the content of impurities.
  • the first step A second step of adding aseptically filtered second solvent to the crude drug substance solution after the treatment by crystallization to crystallize the drug substance, and filtering and drying the drug substance crystallized in the second step
  • the sterilization and purification apparatus for drug substance for sterilization of crude drug substance by the third step of pulverizing and filling the obtained powdery drug substance in a container, Crude drug substance input unit for performing the process, dissolution tank, and sterilization filter, crystallization tank for performing the second process, filter dryer, pulverizer, and container filling for performing the third process
  • the first to third steps are inactivated by a series of in-line systems
  • the drug substance is filtered and dried in the third step by a pipe from the crude drug substance input unit to the container filling device.
  • the vibrating feeder After being unloaded from the filter dryer from the unloading port, the vibrating feeder is conveyed to a storage tank located below the filter dryer, and further conveyed to a pulverizer located below the storage tank by a screw conveyor.
  • the pharmaceutical active ingredient is transported from the filter dryer to the pulverizer with an air current transport for transporting the active pharmaceutical ingredient by an inert gas stream flowing in the pipe.
  • An apparatus for aseptic purification of drug substance is provided.
  • the storage tank is a hopper
  • the screw conveyor is connected to the lower end of the hopper, and stored in the hopper above the hopper.
  • a sensor for sensing the upper surface of the active pharmaceutical ingredient is preferably provided.
  • the first to third steps are preferably arranged in the vertical direction.
  • the drug substance is preferably an antibiotic that is soluble in water, a hydrophilic organic solvent, or a mixture of water and a hydrophilic organic solvent.
  • FIG. 1 is a sterilization / purification apparatus for drug substance in FIG. 1, schematically illustrating the third step of filtering and drying the crystallized drug substance and then crushing and filling the obtained powdery drug substance in a container.
  • FIG. 1 is a sterilization / purification apparatus for drug substance in FIG. 1, schematically illustrating the third step of filtering and drying the crystallized drug substance and then crushing and filling the obtained powdery drug substance in a container.
  • the sterilization purification apparatus 11 includes a crude drug substance input unit 12 for supplying a crude drug substance into the sterilization purification apparatus 11.
  • the crude drug substance charging unit 12 is connected to a dissolution tank 14 via a pipe 13.
  • the crude drug substance charging unit 12, the pipe 13, and the dissolution tank 14 are disposed in the crude drug substance charging chamber.
  • a crude drug substance input port (not shown) through which the drug substance is loaded is provided.
  • the dissolution tank 14 is located in the lower part (downstream) of the crude drug substance charging unit 12, and the inside of the dissolution tank 14 is communicated with the crude drug substance charging part 12 via the pipe 13.
  • a first solvent pipe (not shown) for introducing the first solvent into the dissolution tank 14 is connected to the dissolution tank 14. Inside the dissolution tank 14, a stirring means for dissolving the crude drug substance in the first solvent, for example, a stirring blade, may be provided. An inert gas is introduced into the dissolution tank 14 during use.
  • a crystallization tank 16 is connected to the lower part (downstream) of the dissolution tank 14 via a pipe 15. In the middle of the pipe 15, an activated carbon filter 17, a first filter 18, and a second filter 19 are sequentially arranged from the upstream side.
  • the crystallization tank 16 is connected with a second solvent pipe 20 for introducing the second solvent into the crystallization tank 16. Inside the crystallization tank 16, a stirring means for stirring the solution, for example, a stirring blade may be provided inside the crystallization tank 16.
  • a second solvent reservoir 21 is connected upstream of the second solvent pipe 20.
  • a third filter 22 and a fourth filter 23 are arranged in order from the storage unit 21 side.
  • the first filter 18 and the third filter 22 are pre-filters, and the average pore diameter of the first filter 18 and the third filter 22 is preferably 10 ⁇ m or less.
  • the second filter 19 and the fourth filter 23 are sterilization filters, and the average pore diameter of the second filter 19 and the fourth filter 23 is preferably 0.22 ⁇ m or less.
  • An inert gas is introduced into the crystallization tank 16 during use.
  • a first filter dryer 25 and a second filter dryer 26 are connected to the lower part (downstream) of the crystallization tank 16 via a branch pipe 24.
  • the branch pipe causes the crystallization tank 16 to communicate with either the first filter dryer 25 or the second filter dryer 26 by switching means (not shown).
  • An inert gas is introduced into the first filter dryer 25 and the second filter dryer 26 during use.
  • Each of the first filter dryer 25 and the second filter dryer 26 includes a filtering unit, a drying unit, and an unloading unit (not shown).
  • Commercially available filter dryers can be used as the first filter dryer 25 and the second filter dryer 26.
  • the filtering means include a filtration filter (sintered filter).
  • Examples of the drying means include a stirring blade and a gas ejection means.
  • the carry-out means includes, for example, a gas ejection means, and is configured to send the powder dried by the drying means from the carry-out port of the filter dryer together with the inert gas under the pressure of the inert gas flow.
  • Conveying means 27 extending in the horizontal direction are connected to the lower side surfaces of the first filter dryer 25 and the second filter dryer 26, respectively. Inside the transport means 27, carry-out ports extending from the inner bottom portions of the first filter dryer 25 and the second filter dryer 26 are arranged, respectively.
  • the upper end of a pipe 28 extending in the vertical direction is connected to the lower end portion of the conveying means 27.
  • a vibration feeder 29 having a piping structure extending linearly in a substantially horizontal direction is provided at the lower part (downstream) of the first filter dryer 25.
  • the vibration feeder 29 is arranged so as to be inclined slightly from the upstream side to the downstream side where the powder moves.
  • the upstream side of the vibration feeder 29 is connected to the lower end portion of the pipe 28, and the downstream side of the vibration feeder 29 is connected to the upper end portion of the pipe 30 extending in the vertical direction.
  • the lower end of the pipe 30 is connected to the upper end opening of the powder transfer hopper 31 which is a storage tank for temporarily storing powder.
  • the powder transfer hopper 31 is formed in a funnel shape, and has a predetermined capacity for storing powder.
  • a sensor 31a for sensing the upper surface of the powder (drug substance) stored in the powder transfer hopper 31 is provided above the inside of the powder transfer hopper 31, a sensor 31a for sensing the upper surface of the powder (drug substance) stored in the powder transfer hopper 31 is provided.
  • the lower end opening of the powder transfer hopper 31 is connected to the vicinity of one end of a pipe 32 for conveying the powder in the horizontal direction.
  • a screw conveyor 33 a controlled by a motor 33 is arranged inside the horizontal pipe 32.
  • the other end of the horizontal pipe 32 is disposed in a clean room 34 as a filling chamber, and is connected to a pulverizer 36 via a vertical pipe 35.
  • the interior of the clean room 34 is configured so that a sterile and dust-free environment can be created by air having a constant flow rate filtered by a HEPA filter (not shown).
  • a container filling device 39 for filling the container 38 with the refined and pulverized drug substance is connected to the lower part (downstream) of the pulverizer 36 through a vertical pipe 37.
  • an operation glove (not shown) for sealing the container 38 filled with the drug substance and sealing it, or for transporting the sealed container 38 out of the clean room 34 is attached.
  • the method for sterilizing and purifying an active pharmaceutical ingredient using the sterilization and purification apparatus 11 includes a first step, a second step, and a third step, which will be described in detail later. These steps are performed by a series of in-line systems in an inert gas atmosphere. Done under. The process until the container 38 filled with the drug substance is obtained in the third process after the drug substance is loaded into the drug substance input unit 12 in the first process is a completely closed sterilization purification apparatus. 11 is carried out without direct human intervention. Since the transfer of the drug substance between each process is performed using a pipe connecting the processes, the drug substance is not exposed to the atmosphere outside the apparatus at the time of transfer, and the human hand is not directly involved. .
  • the active pharmaceutical ingredients crystals dried by the filter dryers 25 and 26 are carried out from the outlets of the filter dryers 25 and 26 by an inert gas stream. Further, the drug substance crystal is moved in the vertical direction by conveyance by an inert gas stream and gravity through each pipe in the vertical direction. The movement of the drug substance crystal in the lateral direction is performed by an inert gas stream and conveyance by the vibration feeder 29 or the screw conveyor 33a.
  • the active pharmaceutical ingredient crystals dried by the filter dryers 25 and 26 are sent to the pulverizer 36 in the clean room 34 via the powder transfer hopper 31.
  • the drug substance crystals carried out from the filter dryers 25 and 26 descend while being leveled on the inclined surface of the vibration feeder 29 and drop into the powder transfer hopper 31 by a certain amount.
  • the crystals of the drug substance in the powder transfer hopper 31 are transferred from the lower end opening of the powder transfer hopper 31 to the pulverizer 36 located below the powder transfer hopper 31 by the screw conveyor 33a in the pipe 32.
  • a fixed amount is conveyed.
  • the powdery pharmaceutical drug substance pulverized by the pulverizer 36 is filled into the container 38 by the container filling device 39 without being exposed to the atmosphere outside the device in an inert gas atmosphere.
  • the filling operation is performed in an atmosphere in which air having a constant flow velocity filtered by the HEPA filter flows in a certain direction in the clean room 34 without direct human intervention. Since the refined drug substance is transported in the pipe into which the inert gas is introduced, it is filled in the container 38 together with the inert gas.
  • the pharmaceutical drug substance sterilization and purification method is for obtaining a powdery drug refinery drug substance by sterilizing and purifying a crude drug substance.
  • the sterilization and purification apparatus 11 is filled with an inert gas.
  • the sterilization and purification apparatus 11 is filled with the inert gas.
  • a part or all of the inside of the sterilization purification apparatus 11 is made a sealed space that is blocked from the outside air, or the part of or all of the sterilization purification apparatus 11 is filled with the inert gas.
  • the inside of the sterilization purification apparatus 11 can be kept under an inert gas atmosphere.
  • the sterilization and purification method for drug substances consists of the following first to third steps.
  • the first step is a step in which a crude drug substance is dissolved in a first solvent to prepare a crude drug solution, then decolorized using activated carbon, and subsequently sterilized by sterile filtration.
  • the crude drug substance is introduced into the crude drug substance input unit 12 from the crude drug substance inlet.
  • the crude drug substance charging unit 12 is placed under a positive pressure atmosphere of inert gas by allowing the inert gas introduced into the dissolution tank 14 to flow in through a pipe (not shown).
  • the crude drug substance is introduced into the dissolution tank 14 through the pipe 13 after the first solvent is supplied into the dissolution tank 14 from the first solvent pipe.
  • the kind and supply amount of the first solvent are appropriately set according to the kind and input amount of the crude drug substance.
  • the crude drug substance is an antibiotic that is soluble in water, a hydrophilic organic solvent, or a mixture of water and a hydrophilic organic solvent
  • water, a hydrophilic organic solvent, or a mixture of water and a hydrophilic organic solvent Is used as the first solvent.
  • the crude drug substance is dissolved under a predetermined stirring condition, for example, a predetermined stirring blade position, rotation speed, pressure, temperature and time.
  • activated carbon is added and decolorized.
  • the activated carbon-containing crude drug substance solution is first removed by the activated carbon filtration filter 17 through the pipe 15.
  • the crude drug substance solution is sterilized by aseptic filtration through which the first filter 18 and the second filter 19 are sequentially passed.
  • the second step is a step of crystallizing the drug substance by adding a second sterile filtered solvent to the crude drug substance solution sterilized in the first step.
  • the crude drug substance solution sterilized in the first step is introduced into the crystallization tank 16 through the pipe 15.
  • a second solvent that has passed through the third filter 22 and the fourth filter 23 and has been filtered aseptically is supplied into the crystallization tank 16 through the second solvent pipe 20.
  • the type and supply amount of the second solvent are appropriately set according to the type and input amount of the crude drug substance. For example, when the crude drug substance is an antibiotic that is soluble in water, a hydrophilic organic solvent, or a mixture of water and a hydrophilic organic solvent, the drug substance is insoluble and can be crystallized as the second solvent. A less polar solvent is used.
  • the drug substance is crystallized under predetermined stirring conditions, for example, a predetermined stirring blade position, rotation speed, pressure, temperature and time.
  • the third step is a step in which the active pharmaceutical ingredient crystallized in the second step is filtered and dried using a filter drier and then pulverized, and the resulting powdery active pharmaceutical ingredient is filled in the container 38. is there.
  • the drug substance crystallized in the second step is conveyed into the first filter dryer 25 or the second filter dryer 26 via the branch pipe 24 together with the solvent.
  • crystallization of an active pharmaceutical ingredient is isolate
  • the crystals separated on the sintered filter are dried under a predetermined stirring condition, for example, a predetermined stirring blade position, rotation speed, pressure, gas stream, temperature and time.
  • the gas is discharged from the filter dryers 25 and 26 through the outlet of the filter dryers 25 and 26 together with the inert gas flow by the gas jetting means that is a discharge means in the filter dryers 25 and 26. It is carried out to.
  • the active pharmaceutical ingredient crystals carried out of the filter dryers 25 and 26 are sent from the conveying means 27 to the upper end of the vertical pipe 28, and then, along with the inert gas stream, descend the pipe 28 by gravity and vibrate. It is sent into the feeder 29.
  • the drug substance crystals sent to the vibration feeder 29 are moved down the pipe 30 by gravity along with an inert gas stream by a certain amount and transferred into the powder transfer hopper 31.
  • the drug substance crystals transferred to the powder transfer hopper 31 are sent to the pipe 35 by a predetermined amount by the screw conveyor 33a in the pipe 32, and then descend the pipe 35 by gravity together with an inert gas stream, and the pulverizer 36 It is conveyed to.
  • the powdery drug refinery drug substance is sent down to the container filling device 39 through the pipe 37 by gravity together with an inert gas stream.
  • the drug refinery drug substance is filled into the container 38 together with the inert gas by the container filling device 39. Handling of the container 38 after filling is performed using an operation glove.
  • the drug refinery drug substance obtained as described above has been subjected to aseptic processing, and impurities are significantly reduced compared to the drug substance drug substance.
  • the crude drug substance is an antibiotic that is soluble in water, a hydrophilic organic solvent, or a mixture of water and a hydrophilic organic solvent, water, a hydrophilic organic solvent, or water and a hydrophilic organic solvent
  • the number of particles of 25 ⁇ m or more insoluble in the mixed solution is preferably 2 or less per gram of solid content in the pharmaceutical refinement drug substance, and the same number of particles of 10 ⁇ m or more is 1 g of solid content in the drug refinement drug substance.
  • the number is 500 or less.
  • the counting of the number of these particles can be performed based on the insoluble fine particle test of Japanese Pharmacopoeia injection.
  • the sterilization and purification apparatus 11 of this embodiment for obtaining a powdery drug refinery drug substance by sterilizing a crude drug substance is a series of steps 1 to 3 of the sterilization and purification method.
  • the in-line system is configured to be performed in an inert gas atmosphere. Therefore, the content of impurities in the pharmaceutical refinery drug substance can be further reduced.
  • the first to third steps of the present embodiment are performed in a sealed space that is blocked from outside air or in a positive pressure atmosphere of an inert gas. Therefore, these steps can be performed more reliably in an inert gas atmosphere.
  • the drug substance filtered and dried by the filter dryers 25 and 26 is conveyed to the next process by gravity, a screw conveyor 33a, an inert gas stream, and vibration. Accordingly, the powdery drug substance can be conveyed without human intervention.
  • the conveyance of the powdery drug substance from the filter dryers 25 and 26 to the pulverizer 36 disposed therebelow is accompanied by the air flow by the inert gas flow, and the vibration feeder 29
  • the powder transfer hopper 31 and the screw conveyor 33a are sequentially used. Therefore, quantitative and efficient conveyance is possible as compared with conveyance by simple gravity. In addition, clogging of the conveyance path can be prevented and proper conveyance of the drug substance can be maintained.
  • the drug substance crystal on the vibration feeder 29 falls to the powder transfer hopper 31 by a certain amount while being leveled (distributed) by the vibration.
  • the drug substance after drying with the filter dryers 25 and 26 may have uneven powder or mass. In that case, when the active pharmaceutical ingredient powder is dropped directly onto the powder transfer hopper 31 from the outlets of the filter dryers 25 and 26, the powder transfer hopper 31 suddenly overflows or the powder transfer hopper 31 There is a risk of clogging. Therefore, the function of the powder transfer hopper 31 can be maintained by moving the drug substance powder to the powder transfer hopper 31 by a certain amount.
  • the drug substance in the powder transfer hopper 31 is conveyed to the crusher 36 by the screw conveyor 33a.
  • the drug substance powder can be quantitatively supplied to the pulverizer 36.
  • the supply amount of the drug substance powder to the crusher 36 can be appropriately adjusted by the motor 33 that adjusts the rotation of the screw conveyor 33a.
  • a sensor for sensing the upper surface of the drug substance powder stored in the powder transfer hopper 31 is provided above the powder transfer hopper 31. Therefore, the amount of the drug substance powder conveyed in the third step can be easily monitored, and the amount of the powder conveyed can be adjusted by the screw conveyor 33a and the vibration feeder 29.
  • the drug substance powder is conveyed to the powder transfer hopper 31 by the vibration feeder 29. Since the vibration feeder 29 does not include a sliding portion, the powder can be conveyed while preventing foreign matter from entering.
  • the obtained powdery drug substance is filled in the container 38 together with the inert gas. Therefore, the aseptic and dust-free state of the purified drug substance can be stably maintained, and oxidative degradation and moisture absorption of the drug substance can be prevented.
  • the filling of the drug substance into the container 38 is performed in a certain direction with air having a constant flow velocity filtered by the HEPA filter in the clean room 34 that is not directly passed by human hands. It is performed in an atmosphere that has been shed. Therefore, contamination of the drug substance can be further prevented.
  • the drug substance is an antibiotic that is soluble in water, a hydrophilic organic solvent, or a mixture of water and a hydrophilic organic solvent.
  • the sterilization purification process can be performed on the antibiotic drug substance requiring strict quality control.
  • the drug substance is an antibiotic that is soluble in water, a hydrophilic organic solvent, or a mixture of water and a hydrophilic organic solvent, water, a hydrophilic organic solvent, or a mixture of water and a hydrophilic organic solvent
  • the number of particles of 25 ⁇ m or more insoluble in the liquid is preferably 2 or less per gram of solid content in the pharmaceutical refinement drug substance, and the same number of particles of 10 ⁇ m or more is preferably per 1 g of solid content in the drug refinement drug substance. 500 or less. Therefore, the drug substance that has been sterilized and purified according to this standard can be applied as a high-quality drug substance.
  • the first to third steps are arranged in the vertical direction, and more specifically, are arranged in order from top to bottom. Therefore, in manufacturing with a large scale, the efficiency of conveyance can be improved by moving the liquid raw material and the powdery raw material from the top to the bottom. In addition, it can be mass-produced in a space-saving manner. In addition, by using gravity, the liquid raw material and the powdery raw material can be easily moved in the downstream direction without direct human intervention.
  • piping is connected from the crude drug substance input unit 12 in the first step to the container filling device 39 in the third step.
  • the internal space of the sterilization purification apparatus 11 is comprised so that it may become the positive pressure atmosphere of the sealed space or inert gas which was interrupted
  • the branch pipe 24 can communicate the crystallization tank 16 with either the first filter dryer 25 or the second filter dryer 26. Therefore, the production rate can be increased by using two filter dryers in the time-consuming drying process.
  • purification apparatus 11 is not specifically limited, For example, it administers directly in the body by subcutaneous, intradermal or intravenous injection, or administers by oral ingestion. Applies to active pharmaceutical ingredients. Sterilization and purification can be performed on drug substances that require strict quality control.
  • specific examples of the inert gas introduced into the sterilization purification apparatus 11 include, for example, nitrogen and argon.
  • the particle size of the drug refinery drug substance pulverized by the pulverizer 36 is not particularly limited, and is appropriately set according to the type of drug refinery drug substance.
  • the amount of the crude drug substance used for the sterilization purification apparatus 11 is not particularly limited, but is preferably 30 to 300 kg from the viewpoint of mass production and manufacturing efficiency.
  • the active pharmaceutical ingredient crystals filtered and dried in the third step mainly flow by gravity in the vertical piping, and mainly in the horizontal piping in addition to the air flow by the inert gas.
  • Inclined vibration and the screw conveyor 33a are transported to the next process without human intervention.
  • the drug substance crystals may be transported to the next step using another transport means that does not involve human hands directly.
  • the activated carbon is directly administered into the dissolution tank 14, and then the activated carbon filter 17 removes the activated carbon, whereby the crude drug solution is decolorized.
  • the sterility confirmation test at the initial operation and the sterility confirmation test of the drug substance or system in each process are performed in-line without each purification process touching the outside air and human hands. It is preferable.
  • the cleaning and sterilization treatment in each step is performed inline so that each purification step does not come into contact with outside air.
  • the cleaning in the dissolution tank 14 and the crystallization tank 16 is preferably performed using a shower ball.
  • the inner wall of the tank can be cleaned to every corner.
  • the upstream side of the vibration feeder 29 is connected to the lower end portion of the pipe 28, and the downstream side of the vibration feeder 29 is connected to the upper end portion of the pipe 30 extending in the vertical direction.
  • These connections are preferably performed using a bellows structure or a rubber / elastomer material in order to absorb vibration.
  • the filter dryers 25 and 26 and the pulverizer 36 are connected via the vertical pipes 28, 30 and 35.
  • the vertical pipes 28, 30, and 35 may be omitted.
  • the drug substance powder is carried out of the filter dryers 25 and 26 from the filter dryers 25 and 26 by airflow conveyance using an inert gas. Is done.
  • the filter dryers 25 and 26 are further utilized by utilizing the rotational force of the rotary blades in the filter dryers 25 and 26, tilting the filter dryers 25 and 26, and applying vibration. You may comprise so that the powder in an inside may be carried out.
  • a carry-out port is provided inside the transfer means 27.
  • the carry-out port may be provided from the inside of the filter dryers 25 and 26 so that the drug substance powder is carried out of the filter dryers 25 and 26.
  • the carry-out port may be conveyed to the pipe 28.
  • Example 1 The crude drug substance was sterilized and purified using the sterilization and purification apparatus 11 shown in FIGS.
  • a crude drug substance 100 kg of cefotiam hydrochloride, which is an antibiotic, was weighed and introduced into the dissolution tank 14 from the crude drug substance inlet 12.
  • 400 L of water as the first solvent was added to the dissolution tank 14, and the mixture was stirred at a stirring speed of 90 rpm while maintaining the liquid temperature at 25 ° C.
  • the pH was adjusted with hydrochloric acid, 4.5 to 5.5 kg of activated carbon was added, decolorized for 10 minutes, and then cooled to 15 ° C.
  • the crude drug substance solution is passed through the activated carbon filtration filter 17, the first filter 18, and the second filter 19 with a specified filtration pressure, and into the crystallization tank 16. Transferred. Under a crystallization temperature of 10 ° C. and a stirring blade speed of 10 rpm, a total amount of 2200 L of acetone as a second solvent filtered aseptically while stirring was added at a flow rate of 900 L / h. After adding acetone, the crystals were aged at 5 ° C. for 1 to 5 hours.
  • Example 1 a slurry containing the crystallized drug substance was fed into the filter dryer, and after confirming that the filter cake surface was flat, pressure filtration was performed at a pressure of 0.1 to 0.18 MPa. After washing with mother liquor and acetone (300 L), the stirring blade was raised and stopped. A predetermined amount (10 to 50 L / min) of nitrogen was placed in a stirring blade (gas knife), and the stirring blade was dried at 25 ° C. under reduced pressure for 16 to 24 hours while rotating at a stirring speed of 2 rpm. After the drying, the drug refined drug substance was carried out from the inside of the filter dryer through the outlet (gate valve) by rotating the nitrogen purge 0.01 MPa and the stirring blade at 2 rpm in the filter dryer and rotating the stirring blade at 2 rpm. Thereafter, the container 38 was filled in the clean room 34 without dust and aseptically. The operation of Example 1 was performed three times.
  • Comparative Example 1 The crude drug substance was sterilized and purified using the sterilization and purification apparatus 11 shown in FIGS. However, the crystallized drug refined drug substance after filtration and drying was transported and put into a pulverizer as a next process by a person in an air atmosphere in a clean room, and the container filling process was also performed by a person in the clean room. Other than that, it processed like Example 1.
  • FIG. The operation of Comparative Example 1 was performed three times.
  • Example 2 The crude drug substance was sterilized and purified using the sterilization and purification apparatus 11 shown in FIGS. 34 kg of meropenem trihydrate which is an antibiotic as a crude drug substance was weighed and introduced into the dissolution tank 14 from the crude drug substance inlet 12. 700 L of water as the first solvent was added to the dissolution tank 14 and stirred at a stirring speed of 90 rpm while maintaining the liquid temperature at 60 ° C. After dissolution, 4 kg of activated carbon was added, decolorized for 5 minutes, and then cooled to 5 ° C.
  • the crude drug substance solution is passed through the activated carbon filtration filter 17, the first filter 18, and the second filter 19 with a specified filtration pressure, and into the crystallization tank 16. Transferred. While stirring at a crystallization temperature of 0 ° C. and a rotating speed of a stirring blade of 25 rpm, a total amount of 300 L of acetone as a second solvent aseptically filtered was added at a flow rate of 2500 L / h. After adding acetone, the crystals were aged for 4 hours. Thereafter, a further 2700 L of acetone was introduced at a flow rate of 1250 L / h, and the crystals were aged over 2 hours.
  • Comparative Example 2 The crude drug substance was sterilized and purified using the sterilization and purification apparatus 11 shown in FIGS. However, the crystallized drug refined drug substance after filtration and drying was transported and put into a pulverizer as a next process by a person in an air atmosphere in a clean room, and the container filling process was also performed by a person in the clean room. Otherwise, the same process as in Example 2 was performed. The operation of Comparative Example 2 was performed 8 times.
  • Each drug refinery drug substance obtained in each example was dissolved in water, and then an insoluble fine particle of 10 ⁇ m or more and an insoluble fine particle of 25 ⁇ m or more were counted with an automatic fine particle measuring apparatus (according to the light shielding particle counting method).
  • Tables 1 and 2 show the measurement results of insoluble fine particles in 1 g of each drug refined drug substance.
  • Comparative Examples 1 and 2 which are drug refinery drug substances filled through human hands, have a larger number of insoluble fine particles of 25 ⁇ m or more than those in Examples. Was confirmed.
  • the method for sterilizing and purifying an active pharmaceutical ingredient wherein the aseptic filtration is performed by sequentially passing a second solvent through a filter having an average pore diameter of 10 ⁇ m or less and a filter having an average pore diameter of 0.22 ⁇ m or less.

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  • Engineering & Computer Science (AREA)
  • Mechanical Engineering (AREA)
  • Medical Preparation Storing Or Oral Administration Devices (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Filling Or Emptying Of Bunkers, Hoppers, And Tanks (AREA)
  • Apparatus For Disinfection Or Sterilisation (AREA)
  • Disintegrating Or Milling (AREA)
  • Medicinal Preparation (AREA)

Abstract

Dans l'appareil de purification aseptique de la présente invention pour des principes pharmaceutiques actifs, un principe pharmaceutique actif, après avoir été transporté par un flux de gaz inerte à partir d'un séchoir par filtration (25, 26) à travers une ouverture de déchargement du séchoir par filtration (25, 26), est ensuite transporté par un distributeur vibrant (29) dans un réservoir de stockage (31) positionné au-dessous du séchoir par filtration (25, 26), et est en outre transporté par un transporteur à vis (33a) dans un broyeur (36) positionné au-dessous du réservoir de stockage (31). Le principe pharmaceutique actif est transporté du séchoir par filtration (25, 26) au broyeur (36) accompagnant l'écoulement d'air qui transporte les principes pharmaceutiques au moyen du flux de gaz inerte s'écoulant dans des tuyaux (28, 30, 32, 35).
PCT/JP2012/067350 2011-07-06 2012-07-06 Appareil de purification aseptique pour des principes pharmaceutiques actifs WO2013005838A1 (fr)

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CN110339063B (zh) * 2019-08-12 2022-01-18 浙江福瑞喜药业有限公司 一种非终端灭菌处理的无菌混悬液药剂制备工艺

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