JP2017127283A - Device for processing cultured product, method for processing cultured product, and apparatus for purifying cultured product - Google Patents

Device for processing cultured product, method for processing cultured product, and apparatus for purifying cultured product Download PDF

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JP2017127283A
JP2017127283A JP2016010592A JP2016010592A JP2017127283A JP 2017127283 A JP2017127283 A JP 2017127283A JP 2016010592 A JP2016010592 A JP 2016010592A JP 2016010592 A JP2016010592 A JP 2016010592A JP 2017127283 A JP2017127283 A JP 2017127283A
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culture solution
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勝 難波
Masaru Nanba
勝 難波
近藤　健之
Takeyuki Kondo
健之 近藤
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Hitachi Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2/00—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor
    • A61L2/02—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor using physical phenomena
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2/00—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor
    • A61L2/02—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor using physical phenomena
    • A61L2/08—Radiation
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    • C12M1/00—Apparatus for enzymology or microbiology
    • C12M1/12—Apparatus for enzymology or microbiology with sterilisation, filtration or dialysis means
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N1/00—Microorganisms, e.g. protozoa; Compositions thereof; Processes of propagating, maintaining or preserving microorganisms or compositions thereof; Processes of preparing or isolating a composition containing a microorganism; Culture media therefor

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Abstract

PROBLEM TO BE SOLVED: To provide a device for processing a cultured product and a method for processing the cultured product, which can efficiently perform a virus inactivation treatment instead of a conventional low pH treatment; and also provide an apparatus for purifying the cultured product, the apparatus comprising the device for processing the culture product.SOLUTION: According to the present invention, a device 3 for processing a cultured product comprises a flat flow channel 5 having an inflow port 5b and an outflow port 5c, which allows a culture solution to pass therethrough, the culture solution being free of cells and comprising a cultured product; a heating unit 6 for heating the culture solution, which is disposed in contact with or close to one surface of the flow channel 5; and an ultraviolet-irradiating unit 8 for irradiating ultraviolet rays on the culture solution, which is disposed in contact with or close to the other surface of the flow channel 5 at a position opposite to the heating unit 6.SELECTED DRAWING: Figure 1

Description

本発明は、培養生産物の処理装置、培養生産物の処理方法、及び培養生産物の精製装置に関する。   The present invention relates to a culture product processing apparatus, a culture product processing method, and a culture product purification apparatus.

例えば、バイオ医薬品や飲料品、食料品の製造工程において、微生物、細胞、菌類等の生体細胞を培養する培養法が用いられている。バイオ医薬品の場合、培養に用いた生体細胞に内在するウイルスや製造工程における偶然の混入によるウイルスのほか、生体細胞の培養に使用する培地成分に由来するウイルスの混入等のリスクがある。細胞を培養した培養液から抗体タンパク質等の培養生産物を回収する精製工程においては、培養生産物の安全性を確保するために、培養液に混入する可能性のある細菌を確実に低減する滅菌処理及びウイルスを確実に低減する不活化処理が必要とされる。ここで、ウイルスの不活化処理とは、ウイルスの感染力を失わせる処理を意味する。   For example, in the manufacturing process of biopharmaceuticals, beverages, and foodstuffs, a culture method for culturing living cells such as microorganisms, cells, and fungi is used. In the case of biopharmaceuticals, there is a risk of contamination of viruses derived from the medium components used for culturing living cells in addition to viruses inherent in living cells used for culturing and viruses due to accidental contamination in the manufacturing process. In the purification process of recovering culture products such as antibody proteins from the culture medium in which cells are cultured, sterilization that reliably reduces bacteria that may be mixed in the culture liquid in order to ensure the safety of the culture product There is a need for inactivation treatments that reliably reduce processing and viruses. Here, the virus inactivation process means a process for losing the infectivity of the virus.

従来、抗体精製には、一般的にアフィニティリガンドとして微生物由来のＦｃリセプターであるプロテインＡを固定化したアフィニティクロマトグラフが用いられている。抗体精製の際は、中性条件下でプロテインＡに抗体を吸着させて、非吸着成分を洗浄、除去した後、ｐＨ３以下の酸性条件下で吸着抗体をリガンドから溶離させて回収する。このような低ｐＨ条件は、ウイルスの不活化処理も兼用できるため、一般的には、酸性の溶離液を低ｐＨ条件で保持することによってウイルスの不活化処理（本明細書において「低ｐＨ処理」という。）を行っている。   Conventionally, an affinity chromatograph in which protein A, which is an Fc receptor derived from a microorganism, is immobilized as an affinity ligand is generally used for antibody purification. In antibody purification, the antibody is adsorbed to protein A under neutral conditions, and non-adsorbed components are washed and removed, and then the adsorbed antibody is eluted from the ligand and collected under acidic conditions of pH 3 or lower. Such low pH conditions can also be used for virus inactivation treatment. Therefore, in general, by maintaining an acidic eluent at low pH conditions, virus inactivation treatment (referred to herein as “low pH treatment”). ").

しかし、低ｐＨ処理を行うと、抗体の高次構造が変化し、抗体が失活したり、凝集体を生成したりして、抗体の品質が低下するおそれがあることが知られている。近年では、低ｐＨ処理による抗体の失活や凝集体の生成を回避するため、温度によって吸脱着特性が異なる温度応答性のアフィニティクロマトグラフなどの機能性担体の開発も進められているが、このような機能性担体を用いる場合、低ｐＨ処理に代わるウイルス不活化処理が必要となる。   However, it is known that when a low pH treatment is performed, the higher-order structure of the antibody changes, the antibody is deactivated, or an aggregate is formed, which may reduce the quality of the antibody. In recent years, in order to avoid antibody inactivation and aggregate formation due to low pH treatment, the development of functional carriers such as temperature-responsive affinity chromatographs with different adsorption / desorption characteristics depending on temperature has been promoted. When such a functional carrier is used, a virus inactivation treatment is required in place of the low pH treatment.

そのようなウイルス不活化処理として、例えば、特許文献１に記載の発明が提案されている。この特許文献１には、熱処理とＵＶ照射処理を組み合わせて適用することで、流体媒体を滅菌し、場合によりウイルスを不活性化する連続方法が記載されている。また、この特許文献１には、連続方法において流体媒体の熱処理を４０〜１３５℃の滅菌温度で行い、照射処理を５〜３００Ｗ／ｍ２の照射密度で行う旨記載されている。 As such virus inactivation treatment, for example, the invention described in Patent Document 1 has been proposed. This Patent Document 1 describes a continuous method of sterilizing a fluid medium and optionally inactivating viruses by applying a combination of heat treatment and UV irradiation treatment. Moreover, this patent document 1 describes that the heat treatment of the fluid medium is performed at a sterilization temperature of 40 to 135 ° C. and the irradiation treatment is performed at an irradiation density of 5 to 300 W / m 2 in a continuous method.

また、この特許文献１には、熱処理反応器とＵＶ照射反応器の各々が、硬質で、まっすぐな円筒形の支持体の壁に対して、緊密に引き入れられる、変形可能な、らせん状の輪郭を有する中空円筒から作られている旨記載されている。そして、特許文献１には、熱処理反応器とＵＶ照射反応器の各々が、流体媒体が通過する滅菌及び／又は不活性化チャンバーを含んで成る旨、及び熱処理反応器の円筒形の支持体は熱伝導性材料から作られ、ＵＶ照射反応器の円筒形の支持体はＵＶ照射に対し透明である旨記載されている。   Further, this Patent Document 1 discloses a deformable, helical profile in which each of the heat treatment reactor and the UV irradiation reactor is tightly drawn into the wall of a hard, straight cylindrical support. It is described that it is made from a hollow cylinder having Patent Document 1 discloses that each of the heat treatment reactor and the UV irradiation reactor includes a sterilization and / or inactivation chamber through which a fluid medium passes, and a cylindrical support of the heat treatment reactor Made from a thermally conductive material, the cylindrical support of the UV irradiation reactor is stated to be transparent to UV irradiation.

特開２００４−３２１７８４号公報JP 2004-321784 A

しかしながら、特許文献１に記載の発明（例えば装置）においては、熱処理反応器とＵＶ照射反応器を各々設けているので、これらの処理を同時に行うことができず、ウイルス不活性化処理を効率良く行うことができないおそれがあった。   However, in the invention (for example, the apparatus) described in Patent Document 1, since each of the heat treatment reactor and the UV irradiation reactor is provided, these treatments cannot be performed simultaneously, and the virus inactivation treatment is efficiently performed. There was a risk that it could not be done.

本発明は前記状況に鑑みてなされたものであり、従来の低ｐＨ処理に代わるウイルス不活性化処理を効率良く行うことのできる培養生産物の処理装置及び培養生産物の処理方法を提供することを課題とする。また、本発明は、培養生産物の処理装置を備えた培養生産物の精製装置を提供することを課題とする。   The present invention has been made in view of the above circumstances, and provides a culture product treatment apparatus and a culture product treatment method capable of efficiently performing virus inactivation treatment in place of conventional low pH treatment. Is an issue. Moreover, this invention makes it a subject to provide the refinement | purification apparatus of the culture product provided with the processing apparatus of the culture product.

前記課題を解決した本発明に係る培養生産物の処理装置は、細胞が除去されており、且つ培養生産物を含んでいる培養液を通流する流入口及び流出口を備えた扁平な流路部と、前記流路部の一方の面に接触又は近接させて設けられており、前記培養液を加熱する加熱部と、前記流路部の他方の面において、前記加熱部と対向する位置に接触又は近接させて設けられており、前記培養液に紫外線を照射する紫外線照射部と、を備える。   An apparatus for treating a cultured product according to the present invention that has solved the above problems is a flat flow path having an inlet and an outlet through which a culture solution containing the cultured product is passed, from which cells have been removed. And a heating part that heats the culture solution and a position facing the heating part on the other surface of the flow path part. An ultraviolet irradiation unit that is provided in contact with or close to the medium and that irradiates the culture solution with ultraviolet rays.

また、本発明に係る培養生産物の処理方法は、細胞が除去されており、且つ培養生産物を含んでいる培養液を通流する流入口及び流出口を備えた扁平な流路部と、前記流路部の一方の面に接触又は近接させて設けられており、前記培養液を加熱する加熱部と、前記流路部の他方の面において、前記加熱部と対向する位置に接触又は近接させて設けられており、前記培養液に紫外線を照射する紫外線照射部と、を備える培養生産物の処理装置を用いて前記培養生産物を処理する方法であり、前記流路部内の培養液を前記加熱部で加熱しつつ、前記紫外線照射部から前記流路部内の培養液に前記紫外線を照射する。   Further, the culture product processing method according to the present invention includes a flat flow path portion provided with an inlet and an outlet through which a culture solution containing the culture product is passed, and from which cells have been removed. It is provided in contact with or in proximity to one surface of the flow channel, and in contact with or in proximity to the heating unit that heats the culture medium and the other surface of the flow channel that faces the heating unit An ultraviolet irradiation unit that irradiates the culture solution with ultraviolet rays, and the culture product processing apparatus using the culture product processing apparatus comprising: While being heated by the heating section, the ultraviolet light is irradiated from the ultraviolet irradiation section to the culture solution in the flow path section.

さらに、本発明に係る培養生産物の精製装置は、細胞を培養して生産した培養生産物を精製する装置であり、前記細胞が除去されており、且つ培養生産物を含む培養液を通流する流入口及び流出口を備えた扁平な流路部と、前記流路部の一方の面に接触又は近接させて設けられており、前記培養液を加熱する加熱部と、前記流路部の他方の面において、前記加熱部と対向する位置に接触又は近接させて設けられており、前記加熱部による前記培養液の加熱と共に紫外線を照射する紫外線照射部と、を備える培養生産物の処理装置と、前記培養液の流れ方向を基準として、前記培養生産物の処理装置の前及び後の少なくとも一方にクロマトグラフと、を有する。   Furthermore, the culture product purification apparatus according to the present invention is an apparatus for purifying a culture product produced by culturing cells, wherein the cells are removed and a culture solution containing the culture product is passed through. A flat flow path portion having an inlet and an outlet, and a heating section that is provided in contact with or close to one surface of the flow path section, heating the culture solution, and An apparatus for treating a cultured product, comprising: an ultraviolet irradiation unit that irradiates ultraviolet rays together with heating of the culture solution by the heating unit, provided on the other surface in contact with or close to a position facing the heating unit And a chromatograph at least one before and after the culture product treatment apparatus with reference to the flow direction of the culture solution.

本発明に係る培養生産物の処理装置、培養生産物の処理方法、及び培養生産物の精製装置は、従来の低ｐＨ処理に代わるウイルス不活性化処理を効率良く行うことができる。   The culture product treatment apparatus, culture product treatment method, and culture product purification apparatus according to the present invention can efficiently perform virus inactivation treatment in place of conventional low pH treatment.

本発明に係る精製装置１０の全体構成を説明する概略図である。It is the schematic explaining the whole structure of the refiner | purifier 10 which concerns on this invention. 流路ガイドの形成例を示す概略図である。It is the schematic which shows the example of formation of a flow-path guide. 流路ガイドの形成例を示す概略図である。It is the schematic which shows the example of formation of a flow-path guide. 本発明に係る処理装置の一変形例を示す概略図である。It is the schematic which shows the modification of the processing apparatus which concerns on this invention. 本発明に係る処理装置の一変形例を示す概略図である。It is the schematic which shows the modification of the processing apparatus which concerns on this invention. 本発明に係る処理装置の他の変形例を示す概略図である。It is the schematic which shows the other modification of the processing apparatus which concerns on this invention.

以下、適宜図面を参照して、本発明に係る培養生産物の処理装置、培養生産物の処理方法、及び培養生産物の精製装置を実施するための形態について詳細に説明する。   DESCRIPTION OF EXEMPLARY EMBODIMENTS Hereinafter, a culture product processing apparatus, a culture product processing method, and a culture product purification apparatus according to the present invention will be described in detail with reference to the drawings as appropriate.

［培養生産物の精製装置］
説明の便宜上、はじめに、本発明に係る培養生産物の精製装置（単に「精製装置」と呼称することもある）について説明する。図１は、本発明に係る精製装置１０の全体構成を説明する概略図である。 [Purification equipment for cultured products]
For the convenience of explanation, first, the culture product purification apparatus (sometimes simply referred to as “purification apparatus”) according to the present invention will be described. FIG. 1 is a schematic diagram illustrating the overall configuration of a purification apparatus 10 according to the present invention.

図１に示す精製装置１０は、細胞を培養して生産した培養生産物を精製する装置である。この精製装置１０は、医薬品や健康食品（飲料品や食料品）等の主原料となる物質を生産する微生物や動植物の細胞を培養することによって得られた培養生産物を精製する際に適用することができる。   A purification apparatus 10 shown in FIG. 1 is an apparatus for purifying a culture product produced by culturing cells. This purification apparatus 10 is applied when purifying a culture product obtained by culturing microorganisms or animal and plant cells that produce substances used as main raw materials such as pharmaceuticals and health foods (beverages and foods). be able to.

培養対象となる細胞としては、動物細胞、植物細胞、光合成細菌、微細藻類、ラン藻類、昆虫細胞、細菌、酵母、真菌及び藻類等を挙げることができる。特に、抗体や酵素等のタンパク質を生産する動物細胞を培養対象とすることが好ましい。細胞を培養する培地は特に限定されることなく培養対象となる細胞に応じて適宜のものを用いることができるが、液体培地であることが好ましい。   Examples of cells to be cultured include animal cells, plant cells, photosynthetic bacteria, microalgae, cyanobacteria, insect cells, bacteria, yeasts, fungi, and algae. In particular, animal cells that produce proteins such as antibodies and enzymes are preferably cultured. The medium for culturing the cells is not particularly limited, and an appropriate one can be used according to the cells to be cultured, but a liquid medium is preferable.

生産対象の物質となる培養生産物としては、例えば、抗体や酵素等のタンパク質、低分子化合物、高分子化合物等の生理活性物質等を挙げることができるが、これらに限定されるものではない。また、β−カロテンやアスタキサンチン等のカロチノイド、クロロフィルやバクテリオクロロフィル等の色素、食品や化粧品などの着色等に使用されるフィコシアニン等のフィコビリン蛋白質、脂肪酸等の生理活性物質も生産対象の物質となる培養生産物として挙げることができる。   Examples of the culture product to be produced include, but are not limited to, proteins such as antibodies and enzymes, physiologically active substances such as low molecular compounds and high molecular compounds, and the like. In addition, carotenoids such as β-carotene and astaxanthin, pigments such as chlorophyll and bacteriochlorophyll, phycobilin proteins such as phycocyanin used for coloring foods and cosmetics, and other physiologically active substances such as fatty acids are cultures to be produced. It can be mentioned as a product.

図１に示すように、本発明に係る精製装置１０は、後に説明する本発明に係る培養生産物の処理装置（単に「処理装置」と呼称することもある）３と、クロマトグラフ９と、を有している。具体的には、精製装置１０は、図１に示すように、培養槽１と、第１の貯留槽２ａと、処理装置３と、クロマトグラフ９と、第２の貯留槽２ｂと、を有している。これらの構成要素はそれぞれこの順で配置されており、各構成要素は移送配管チューブＴ１、Ｔ２、Ｔ３、Ｔ４でそれぞれ接続されている。すなわち、培養槽１と第１の貯留槽２ａは、移送配管チューブＴ１で接続されており、第１の貯留槽２ａと処理装置３は、移送配管チューブＴ２で接続されている。また、処理装置３とクロマトグラフ９は、移送配管チューブＴ３で接続されており、クロマトグラフ９と第２の貯留槽２ｂは、移送配管チューブＴ４で接続されている。移送配管チューブＴ１、Ｔ２、Ｔ３、Ｔ４は、培養液を汚染することなく無菌的に送液することができるものであればどのようなものも用いることができる。また、本発明で用いるクロマトグラフ９としては、例えば、温度応答性のアフィニティクロマトグラフ、高速液体クロマトグラフ（High Performance Liquid Chromatograph；ＨＰＬＣ）、イオン交換クロマトグラフ等を挙げることができる。   As shown in FIG. 1, the purification apparatus 10 according to the present invention includes a culture product processing apparatus 3 (sometimes simply referred to as “processing apparatus”) 3, which will be described later, a chromatograph 9, have. Specifically, as shown in FIG. 1, the purification apparatus 10 has a culture tank 1, a first storage tank 2a, a processing apparatus 3, a chromatograph 9, and a second storage tank 2b. doing. These components are arranged in this order, and each component is connected by transfer piping tubes T1, T2, T3, and T4. That is, the culture tank 1 and the 1st storage tank 2a are connected by the transfer piping tube T1, and the 1st storage tank 2a and the processing apparatus 3 are connected by the transfer piping tube T2. Moreover, the processing apparatus 3 and the chromatograph 9 are connected by the transfer piping tube T3, and the chromatograph 9 and the 2nd storage tank 2b are connected by the transfer piping tube T4. Any transfer piping tubes T1, T2, T3, and T4 can be used as long as they can be sent aseptically without contaminating the culture solution. Examples of the chromatograph 9 used in the present invention include a temperature-responsive affinity chromatograph, a high performance liquid chromatograph (HPLC), and an ion exchange chromatograph.

なお、図１では、培養液の洗浄を行うクロマトグラフ９が、処理装置３の後（処理装置３と第２の貯留槽２ｂとの間）に設けられている様子を図示しているが、クロマトグラフ９の配置位置はこれに限定されない。クロマトグラフ９は、精製装置１０内を通流する培養液の流れ方向を基準として、精製装置１０内における当該処理装置３の前及び後の少なくとも一方に設けることができる。例えば、培養槽１と第１の貯留槽２ａの間、すなわち、移送配管チューブＴ１上に配置することができるし、第１の貯留槽２ａと処理装置３の間、すなわち、移送配管チューブＴ２上に配置することができる。クロマトグラフ９は、必要に応じて処理装置３の前及び後の両方に設けることができることは言うまでもない。つまり、図１に示すように、処理装置３と第２の貯留槽２ｂとの間にクロマトグラフ９を配置すると共に、移送配管チューブＴ１上及び／又は移送配管チューブＴ２上にクロマトグラフ９を配置することができる。生産対象の物質となる培養生産物が抗体であって、クロマトグラフ９として温度応答性のアフィニティクロマトグラフ９を採用する場合は、処理装置３の前に設けるのが好ましい。このようにすると、当該温度応答性のアフィニティクロマトグラフ９によって処理装置３の前で培養液の洗浄を行うことができる。そのため、一部のウイルスや培養液に含まれるタンパク質、アミノ酸といった紫外線を吸収する物質を培養液から予め除去することが可能であり、紫外線照射部８による照射効率を向上することができる（紫外線及び紫外線照射部８については後述する）。   In addition, in FIG. 1, although the chromatograph 9 which wash | cleans a culture solution has illustrated a mode that it is provided after the processing apparatus 3 (between the processing apparatus 3 and the 2nd storage tank 2b), The arrangement position of the chromatograph 9 is not limited to this. The chromatograph 9 can be provided at least before or after the treatment apparatus 3 in the purification apparatus 10 with reference to the flow direction of the culture solution flowing through the purification apparatus 10. For example, it can be arranged between the culture tank 1 and the first storage tank 2a, that is, on the transfer pipe tube T1, and between the first storage tank 2a and the processing apparatus 3, that is, on the transfer pipe tube T2. Can be arranged. It goes without saying that the chromatograph 9 can be provided both before and after the processing apparatus 3 as required. That is, as shown in FIG. 1, the chromatograph 9 is disposed between the processing device 3 and the second storage tank 2b, and the chromatograph 9 is disposed on the transfer piping tube T1 and / or the transfer piping tube T2. can do. When the culture product to be produced is an antibody and the temperature-responsive affinity chromatograph 9 is employed as the chromatograph 9, it is preferably provided in front of the processing apparatus 3. In this way, the culture solution can be washed in front of the treatment apparatus 3 by the temperature-responsive affinity chromatograph 9. Therefore, it is possible to remove in advance from the culture medium substances that absorb ultraviolet rays, such as proteins and amino acids contained in some viruses, culture solutions, and the irradiation efficiency of the ultraviolet irradiation unit 8 can be improved (ultraviolet and The ultraviolet irradiation unit 8 will be described later).

培養槽１は、前記した培養対象となる細胞を培養し、培養生産物を生産させる容器である。培養槽１は、目的の細胞を培養するために予め組成を調製した培地を用いて、最適な温度と撹拌を維持した状態で培養する。図１中には図示していないが、培養槽１には不可欠であるところの、空気、酸素、窒素及び炭酸ガス等のガス供給設備、温水冷水供給設備及び給排水設備、さらに、流加培養に際しては培養中に添加する添加培地の供給設備等を具備している。   The culture tank 1 is a container for culturing cells to be cultured as described above and producing a culture product. The culture tank 1 is cultured in a state where optimal temperature and agitation are maintained using a medium whose composition is prepared in advance for culturing target cells. Although not shown in FIG. 1, gas supply equipment such as air, oxygen, nitrogen and carbon dioxide, hot water / cold water supply equipment and water supply / drainage equipment, which are indispensable for the culture tank 1, and in addition to the fed-batch culture Is equipped with a supply facility for an additional medium to be added during culture.

第１の貯留槽２ａは、培養槽１で培養した培養液を一時的に貯留する容器である。第２の貯留槽２ｂは、処理装置３で処理した培養液を一時的に貯留する容器である。第１の貯留槽２ａ及び第２の貯留槽２ｂは、ステンレス製やガラス製等とすることができるが、予めガンマ線、紫外線、エチレンオキシドガス等によって滅菌されて無菌状態を維持し、気体や液体等の内容物がほぼ抜かれて清浄な状態で提供されている市販のシングルユースのバッグを用いることもできる。
処理装置３は後に詳述するように、ウイルスの不活性化処理を行う装置である。 The 1st storage tank 2a is a container which stores temporarily the culture solution cultured by the culture tank 1. FIG. The 2nd storage tank 2b is a container which stores temporarily the culture solution processed with the processing apparatus 3. FIG. The first storage tank 2a and the second storage tank 2b can be made of stainless steel, glass, or the like, but are sterilized in advance by gamma rays, ultraviolet rays, ethylene oxide gas, etc., and maintained in a sterile state, such as gas or liquid. It is also possible to use a commercially available single-use bag that is provided in a clean state with its contents almost removed.
As will be described later in detail, the processing device 3 is a device that performs virus inactivation processing.

また、本発明に係る精製装置１０は、必要に応じて細胞を破砕する細胞破砕部、細胞や破砕した細胞の細胞壁、細胞膜、タンパク質等の不要物を取り除くろ過フィルタや連続遠心分離機等を備えることができる（いずれも図示せず）。これらの構成要素はこの設置順で処理装置３の前に設けるのが好ましい。このようにすると、培養液を清澄化することができるため、後記するように、処理装置３において効率良く紫外線を照射することが可能となる。つまり、培養液の濁りによって紫外線が十分に照射されなくなるという事態を回避することが可能となる。なお、これらの構成要素は移送配管チューブＴ１上に設けるのがより好ましい。このようにすると、第１の貯留槽２ａ内を清浄に保つことができる。   The purification apparatus 10 according to the present invention includes a cell crushing unit that crushes cells as necessary, a filtration filter that removes unnecessary substances such as cells, cell walls of the crushed cells, cell membranes, proteins, and a continuous centrifuge. (Both not shown). These components are preferably provided in front of the processing apparatus 3 in the order of installation. In this way, since the culture solution can be clarified, as described later, it becomes possible to efficiently irradiate the treatment apparatus 3 with ultraviolet rays. That is, it is possible to avoid a situation in which ultraviolet rays are not sufficiently irradiated due to the turbidity of the culture solution. In addition, it is more preferable to provide these components on the transfer piping tube T1. If it does in this way, the inside of the 1st storage tank 2a can be kept clean.

［培養生産物の処理装置］
次に、本発明に係る処理装置３の一態様について説明する。既に説明しているように、この処理装置３は前記した精製装置１０内に設けられる。
図１に示すように、この処理装置３は、流路部５と、加熱部６と、紫外線照射部８と、を備えている。流路部５を通流する培養液は、細胞が除去されており、且つ培養生産物を含んだものである。 [Processing equipment for cultured products]
Next, an aspect of the processing apparatus 3 according to the present invention will be described. As already described, the processing apparatus 3 is provided in the purification apparatus 10 described above.
As shown in FIG. 1, the processing apparatus 3 includes a flow path unit 5, a heating unit 6, and an ultraviolet irradiation unit 8. The culture solution flowing through the flow path portion 5 is a cell from which cells have been removed and contains a culture product.

流路部５は、ハウジング部４ａとハウジング部４ｂに覆われるようにして形成されている。また、流路部５は、培養液を通流する流入口５ｂ及び流出口５ｃを備えた扁平な形状を成している。ここで、本明細書において扁平な形状とは、平面方向の寸法（縦方向の寸法及び横方向の寸法）が長く、高さ方向（ハウジング部４ａとハウジング部４ｂの間の厚み方向の寸法）が短い形状をいう。流路部５の平面方向の寸法は問わないが、厚み方向の寸法は、後記する加熱部６による流路部５内の培養液の加熱、及び紫外線照射部８による流路部５内の培養液への紫外線の照射が適切に行われるように設定するのが好ましい。流路部５の厚み方向の寸法は、例えば、０．５〜１０ｃｍとするのが好ましく、１〜５ｃｍに設定するのがより好ましい。   The flow path part 5 is formed so as to be covered by the housing part 4a and the housing part 4b. Moreover, the flow path part 5 has comprised the flat shape provided with the inflow port 5b and the outflow port 5c which flow a culture solution. Here, in this specification, the flat shape means that the dimension in the plane direction (longitudinal dimension and lateral dimension) is long, and the height direction (dimension in the thickness direction between the housing part 4a and the housing part 4b). Is a short shape. Although the dimension of the flow path part 5 in the planar direction is not limited, the dimension in the thickness direction depends on the heating of the culture solution in the flow path part 5 by the heating part 6 described later and the culture in the flow path part 5 by the ultraviolet irradiation part 8. It is preferable to set so that the liquid is appropriately irradiated with ultraviolet rays. The dimension in the thickness direction of the flow path portion 5 is preferably set to, for example, 0.5 to 10 cm, and more preferably set to 1 to 5 cm.

加熱部６は、流路部５の一方の面に接触又は近接させて設けられており、流路部５内の培養液を加熱する。加熱部６は、電気ヒータ等で構成することができる。加熱部６による培養液の加熱温度は、培養生産物の熱変性を生じさせない温度以下とするのが好ましい。培養生産物の熱変性を生じさせない温度は培養生産物によって異なり、培養生産物に合わせて適宜に設定可能であり、例えば、８０℃などとすることができるが、７５℃や６５℃などとすることもできる。加熱部６による培養液の加熱温度の上限をこれらのように設定すると、例えば、培養生産物が抗体タンパク質である場合であっても、培養液中のウイルスの不活化処理を行いつつ、熱変性によって活性を損なってしまうといった事態を回避することができる。なお、加熱部６による培養液の加熱温度の下限は、例えば、６０℃とするのが好ましい。   The heating unit 6 is provided in contact with or close to one surface of the flow path unit 5 and heats the culture solution in the flow path unit 5. The heating unit 6 can be composed of an electric heater or the like. The heating temperature of the culture solution by the heating unit 6 is preferably set to a temperature that does not cause thermal denaturation of the culture product. The temperature that does not cause the heat denaturation of the cultured product varies depending on the cultured product, and can be appropriately set according to the cultured product. For example, it can be set to 80 ° C. or the like, but may be set to 75 ° C. or 65 ° C. or the like. You can also. When the upper limit of the heating temperature of the culture solution by the heating unit 6 is set as described above, for example, even when the culture product is an antibody protein, heat denaturation is performed while inactivating the virus in the culture solution. It is possible to avoid such a situation that the activity is impaired by. In addition, it is preferable that the minimum of the heating temperature of the culture solution by the heating part 6 shall be 60 degreeC, for example.

ここで、不活化処理の対象となるウイルスに関して、加熱等の滅菌処理に対して比較的抵抗性が高いとされる非エンベロープ・ウイルスに属するウイルス１２種について熱失活特性を調べた文献（Nims, RW and Plavsic, M.：Intra-family and inter-family comparisons for viral susceptibility to hest inactivation：J. Microb.Biochem.Technol.,5,136-141 (2013)）がある。当該文献では、加熱７０℃、加熱処理時間１分間でＬＲＶ（対数減少指数）が４以上の不活化効果を示すウイルスとして、Caliciviridae科（Feline calicivirus、Murine norovirus）、Picornaviridae科（Foot and mouth disease virus (strain OPN)、Hepatitis A virus、Coxsackie B-5 (Faulker strain)）、Birnaviridae科（Infectious pancreatic necrosis virus、Infectious bursal disease virus）が報告されている。一方、当該文献には、Parvoviridae科（Mouse minute virus、Bovine parvovirus、Canine parvovirus）のウイルスは、ＬＲＶ＝４以上のウイルス不活化効果を得るために、加熱７０℃では加熱時間が４０分以上を要すると報告されている。加熱時間が１分以下で、ＬＲＶ＝４以上のウイルス不活化効果を得るためには、加熱温度は約１１０℃が必要とされる。そのため、本発明に係る処理装置３は、ウイルスの不活性化処理にあたって、このような情報を勘案して加熱温度及び加熱時間を設定することができる。ここで、本発明に係る処理装置３によれば、培養液中のウイルスの不活化処理と同時に殺菌・滅菌処理を行うことができることは言うまでもない。   Here, with regard to viruses to be subjected to inactivation treatment, a literature (Nims) that investigated heat inactivation characteristics of 12 viruses belonging to non-enveloped viruses that are considered to be relatively resistant to sterilization treatment such as heating. , RW and Plavsic, M .: Intra-family and inter-family comparisons for viral susceptibility to hest inactivation: J. Microb. Biochem. Technol., 5, 136-141 (2013)). In this document, viruses exhibiting an inactivation effect with an LRV (logarithmic decrease index) of 4 or more after heating at 70 ° C. for 1 minute are included in the family Caliciviridae (Feline calicivirus, Murine norovirus) and Picornaviridae (Foot and mouth disease virus). (Strain OPN), Hepatitis A virus, Coxsackie B-5 (Faulker strain)), Birnaviridae (Infectious pancreatic necrosis virus, Infectious bursal disease virus) have been reported. On the other hand, in this document, viruses of the family Parvoviridae (Mouse minute virus, Bovine parvovirus, Canine parvovirus) require a heating time of 40 minutes or more at 70 ° C. in order to obtain a virus inactivation effect of LRV = 4 or more. It has been reported. In order to obtain a virus inactivation effect with a heating time of 1 minute or less and LRV = 4 or more, the heating temperature is required to be about 110 ° C. Therefore, the processing apparatus 3 according to the present invention can set the heating temperature and the heating time in consideration of such information in the virus inactivation process. Here, it cannot be overemphasized that according to the processing apparatus 3 which concerns on this invention, disinfection and a sterilization process can be performed simultaneously with the inactivation process of the virus in a culture solution.

なお、培養液の流れ方向を基準として、加熱部６の下流には培養液を冷却するための冷却部７を備えているのが好ましい。当該冷却部７による培養液の冷却温度は、培養生産物の熱安定性、及び後工程での処理に応じて任意に設定することができる。冷却部７は適宜の手段によって成すことができる。例えば、冷却部７は、流路部５に接触させて培養液の熱を吸収する冷却ブロックと、この冷却ブロックと接続され、水等の冷却媒体を流通させるチューブと、このチューブと接続され、冷却媒体を循環させるポンプと、前記したチューブと接続され、冷却媒体を冷却するラジエータと、ラジエータに空気を送るファンと、で構成することができる。また、例えば、冷却部７は、気流を発生させるファンを設けただけの構成とすることもできる。このようにすると、簡易な構成であるため、低コスト化を図ることができる。   In addition, it is preferable to provide the cooling part 7 for cooling a culture solution downstream from the heating part 6 on the basis of the flow direction of a culture solution. The cooling temperature of the culture solution by the cooling unit 7 can be arbitrarily set according to the thermal stability of the culture product and the processing in the subsequent process. The cooling unit 7 can be formed by appropriate means. For example, the cooling section 7 is connected to the cooling block that contacts the flow path section 5 and absorbs the heat of the culture solution, a tube that is connected to the cooling block and distributes a cooling medium such as water, and the tube. A pump that circulates the cooling medium, a radiator that is connected to the tube and cools the cooling medium, and a fan that sends air to the radiator can be used. In addition, for example, the cooling unit 7 may be configured by simply providing a fan that generates an airflow. In this case, since the configuration is simple, the cost can be reduced.

紫外線照射部８は、流路部５の他方の面において、加熱部６と対向する位置に接触又は近接させて設けられており、流路部５内の培養液に紫外線を照射する。本発明では、このような構成とすることにより、ウイルス不活化処理を効果的に行うことを可能としている。紫外線照射部８は、図１に示すように、紫外線（紫外光）を発する紫外線源８ａと、紫外線源８ａから発した紫外線を反射させて培養液に効率的に照射する紫外線反射部８ｂと、で構成するのが好ましいが、紫外線反射部８ｂは設けなくてもよい。紫外線の波長は、ウイルスの不活性化に最も効果的とされている２５４ｎｍとするのが好ましいが、いわゆる紫外線に分類される範囲であればこれよりも波長の短い紫外線及び波長の長い紫外線を用いることができる。紫外線源８ａとしては、例えば、低圧水銀ランプや紫外線ＬＥＤ（Light Emitting Diode）等を用いることができる。不活化に必要となる紫外線照射量はウイルス種によって異なり、概ね５０〜１０００Ｊ／ｍ２の範囲であるが、抗体等のタンパク質に有害な影響を与えない照射量として、１００〜５００Ｊ／ｍ２となるように光源の照射光強度と照射時間を設定することが好ましい。例えば、紫外線照射光強度が１０Ｗ／ｍ２の紫外線照射光源を用いる場合、照射時間が１０〜５０秒となるように培養液の流速を設定するのが好ましい。紫外線照射強度をこの範囲で設定するとより確実にウイルスの不活性化処理を行うことができる。 The ultraviolet irradiation unit 8 is provided on the other surface of the flow channel unit 5 so as to be in contact with or close to a position facing the heating unit 6 and irradiates the culture solution in the flow channel unit 5 with ultraviolet light. In this invention, it becomes possible to perform a virus inactivation process effectively by setting it as such a structure. As shown in FIG. 1, the ultraviolet irradiation unit 8 includes an ultraviolet ray source 8a that emits ultraviolet rays (ultraviolet light), an ultraviolet ray reflection unit 8b that reflects the ultraviolet ray emitted from the ultraviolet ray source 8a and efficiently irradiates the culture solution, However, the ultraviolet reflecting portion 8b may not be provided. The wavelength of ultraviolet rays is preferably 254 nm, which is most effective for inactivating viruses, but ultraviolet rays having shorter wavelengths and longer wavelengths are used as long as they are classified as so-called ultraviolet rays. be able to. As the ultraviolet source 8a, for example, a low-pressure mercury lamp, an ultraviolet LED (Light Emitting Diode), or the like can be used. The amount of UV irradiation required for inactivation varies depending on the virus type, and is generally in the range of 50 to 1000 J / m 2 , but the dose that does not adversely affect proteins such as antibodies is 100 to 500 J / m 2 . It is preferable to set the irradiation light intensity and irradiation time of the light source. For example, when an ultraviolet irradiation light source having an ultraviolet irradiation light intensity of 10 W / m 2 is used, it is preferable to set the flow rate of the culture solution so that the irradiation time is 10 to 50 seconds. If the ultraviolet irradiation intensity is set within this range, the virus inactivation treatment can be performed more reliably.

そして、前記構成の処理装置３は、紫外線照射部８による培養液への紫外線の照射を、加熱部６による培養液の加熱と同時に行う。そのため、処理装置３は、流路部５内を流通する培養液中のウイルスの不活性化処理を効率良く行うことができる。つまり、この処理装置３によれば、従来の低ｐＨ処理に代わるウイルス不活性化処理を効率良く行うことができる。   And the processing apparatus 3 of the said structure performs irradiation of the ultraviolet-ray to the culture solution by the ultraviolet irradiation part 8 simultaneously with the heating of the culture solution by the heating part 6. FIG. Therefore, the processing apparatus 3 can efficiently inactivate the virus in the culture solution flowing through the flow path section 5. That is, according to this processing apparatus 3, the virus inactivation process can be efficiently performed in place of the conventional low pH process.

本発明においては、加熱部６で培養液を加熱するため、加熱部６と接触又は近接するハウジング部４ｂは、熱伝導性の良い金属や石英ガラス等を用いて形成するのが好ましい。また、紫外線照射部８で培養液に紫外線を照射するため、紫外線照射部８と接触又は近接するハウジング部４ａは、紫外線に対して透過性を有する石英ガラスや樹脂等を用いて形成するのが好ましい。   In the present invention, since the culture solution is heated by the heating part 6, the housing part 4b in contact with or close to the heating part 6 is preferably formed using a metal having good thermal conductivity, quartz glass, or the like. In addition, since the ultraviolet irradiating unit 8 irradiates the culture solution with ultraviolet rays, the housing part 4a that is in contact with or close to the ultraviolet irradiating unit 8 is formed using quartz glass, resin, or the like that is permeable to ultraviolet rays. preferable.

また、処理装置３による処理時間は、ウイルスを不活性化することができる範囲で任意に設定することができる。つまり、処理装置３による処理時間は、加熱温度、紫外線の照射時間、照射強度等の条件に応じて適宜設定することができる。特に、加熱温度と紫外線照射強度、及び処理時間の設定は、細胞の培養環境において混入が予想されるウイルス種について、ウイルス不活化の特性を評価したうえで設定することが好ましい。特に限定されるものではないが、処理装置３による処理時間の目安として、例えば、流路部５の流入口５ｂから流出口５ｃまでの培養液の滞留時間を３０秒以上３０分以下とすることが挙げられる。このようにすると、確実なウイルスの不活性化処理を行うことができる。なお、より確実なウイルスの不活性化処理と、効率的な処理の観点から、当該滞留時間は１分以上２０分以下とするのが好ましい。   Moreover, the processing time by the processing apparatus 3 can be arbitrarily set within a range in which the virus can be inactivated. That is, the processing time by the processing apparatus 3 can be appropriately set according to conditions such as the heating temperature, the ultraviolet irradiation time, and the irradiation intensity. In particular, it is preferable to set the heating temperature, the ultraviolet irradiation intensity, and the treatment time after evaluating the characteristics of virus inactivation for virus species that are expected to be mixed in the cell culture environment. Although not particularly limited, for example, the retention time of the culture solution from the inflow port 5b to the outflow port 5c of the flow path unit 5 is set to 30 seconds or more and 30 minutes or less as a guide for the processing time by the processing apparatus 3. Is mentioned. In this way, reliable virus inactivation processing can be performed. In addition, from the viewpoint of more reliable virus inactivation treatment and efficient treatment, the residence time is preferably 1 minute or more and 20 minutes or less.

ここで、図２Ａ及び図２Ｂは、流路ガイド５ａの形成例を示す概略図である。流路ガイド５ａは、図２Ａに示すように、培養液の流れ方向に準じるように、流れ方向に対して平行な方向となるように１つ以上設けることができる。また、流路ガイド５ａは、図２Ｂに示すように、培養液の流れが蛇行するように、流れ方向に対して直角な方向となるように１つ以上設けることができる。このように、流路部５に培養液の流れ方向をガイドする流路ガイド５ａを設けることによって、処理装置３による処理時間を調整することができる。なお、流路ガイド５ａの取り付け長さ及び方向、取り付け本数等は、処理する培養液の量と、加熱温度及び処理時間、紫外線照射時間等を考慮して設定することが好ましい。   Here, FIG. 2A and FIG. 2B are schematic views showing an example of forming the flow path guide 5a. As shown in FIG. 2A, one or more flow path guides 5a can be provided so as to be parallel to the flow direction so as to conform to the flow direction of the culture solution. In addition, as shown in FIG. 2B, one or more flow path guides 5a can be provided so as to be in a direction perpendicular to the flow direction so that the flow of the culture solution meanders. Thus, by providing the flow path guide 5 with the flow path guide 5a that guides the flow direction of the culture solution, the processing time by the processing apparatus 3 can be adjusted. Note that the attachment length and direction of the flow path guide 5a, the number of attachments, and the like are preferably set in consideration of the amount of the culture solution to be treated, the heating temperature, the treatment time, the ultraviolet irradiation time, and the like.

また、処理装置３による処理時間は、精製装置１０及び処理装置３において培養液を送液させるポンプの圧力を制御することによって調整することもできる。流路ガイド５ａは、ハウジング部４ａ及び／又はハウジング部４ｂから流路部５内に向けて設けられた板材等で形成することができる。培養液を送液させるポンプとしては、例えば、チューブポンプ、ローラーポンプ、ペリスタルティックポンプ等が用いられる。   Moreover, the processing time by the processing apparatus 3 can also be adjusted by controlling the pressure of the pump for feeding the culture solution in the purification apparatus 10 and the processing apparatus 3. The flow path guide 5a can be formed of a plate material or the like provided from the housing part 4a and / or the housing part 4b toward the flow path part 5. As a pump for feeding the culture solution, for example, a tube pump, a roller pump, a peristaltic pump or the like is used.

次に、図３Ａ及び図３Ｂを参照して、本発明に係る処理装置３の一変形例について説明する。図３Ａ及び図３Ｂに示す処理装置３は、前記した加熱部６、流路部５及び紫外線照射部８を１つのユニットＵとして、当該ユニットＵを２以上並列に設けた（積層化した）ものである。
例えば、図３Ａに示すように、前記ユニットを単に３つ並列に設けた処理装置３とすることができる。この処理装置３によれば、複数のユニットで同時に処理を行うことができるので、ウイルス不活性化処理の処理能力を向上させることができる（例えば、ユニット数を２つにすれば処理能力を２倍にすることができ、ユニット数を３つにすれば処理能力を３倍にすることができる）。 Next, a modification of the processing apparatus 3 according to the present invention will be described with reference to FIGS. 3A and 3B. The processing apparatus 3 shown in FIGS. 3A and 3B has the heating unit 6, the flow path unit 5, and the ultraviolet irradiation unit 8 as one unit U, and two or more such units U are provided in parallel (stacked). It is.
For example, as shown in FIG. 3A, a processing apparatus 3 in which only three units are provided in parallel can be used. According to this processing apparatus 3, since processing can be performed simultaneously with a plurality of units, it is possible to improve the processing capacity of virus inactivation processing (for example, if the number of units is two, the processing capacity is 2). Can be doubled, and if the number of units is three, the processing capacity can be tripled).

また、図３Ｂに示す処理装置３では、前記ユニットＵを４つ設けた例を図示している。当該変形例について具体的に説明すると、図３Ｂ中の上側２つのユニットＵが、紫外線照射部８を中心としてその外側に流路部５、５を配置し、さらにその外側に加熱部６、６を配置した構成となっている。つまり、この２つのユニットＵは、ユニット間において紫外線照射部８を共用する形式で構成されている。そして、図３Ｂ中の下側２つのユニットＵもこれと同様の構成となっている。なお、図３Ｂ中の中央２つのユニットＵにおいては、上側の流路部５と下側の流路部５の間に配置された加熱部６を共用する形式で構成されている。このように、図３Ｂに示す処理装置３とすれば、加熱部６及び紫外線照射部８を複数のユニットＵ（２つのユニットＵ）で共用する構成となっているので、装置のコンパクト化を図ることができる。また、この処理装置３によれば、加熱部６及び紫外線照射部８を複数のユニットＵで共用するので加熱及び紫外線の照射を同時に行うことができる。そのため、この処理装置３によれば、ウイルス不活性化処理を効率的に行うことができるだけでなく、省エネルギー化を図ることができる。   3B shows an example in which four units U are provided. The modification will be described in detail. The upper two units U in FIG. 3B have flow paths 5 and 5 arranged on the outer side with the ultraviolet irradiation unit 8 at the center, and further heating units 6 and 6 on the outer side. It is the composition which arranged. That is, the two units U are configured in such a manner that the ultraviolet irradiation unit 8 is shared between the units. And the lower two units U in FIG. 3B have the same configuration. In addition, in the center two unit U in FIG. 3B, it is comprised in the format which shares the heating part 6 arrange | positioned between the upper flow path part 5 and the lower flow path part 5. FIG. Thus, if it is the processing apparatus 3 shown to FIG. 3B, since it becomes the structure which shares the heating part 6 and the ultraviolet irradiation part 8 by several units U (two units U), size reduction of an apparatus is aimed at. be able to. Moreover, according to this processing apparatus 3, since the heating part 6 and the ultraviolet irradiation part 8 are shared by the some unit U, a heating and ultraviolet irradiation can be performed simultaneously. Therefore, according to this processing apparatus 3, not only can virus inactivation processing be performed efficiently, but also energy saving can be achieved.

次に、図４を参照して、本発明に係る処理装置３の他の変形例について説明する。図４に示す処理装置３は、流路部５が可撓性を有するバッグ１１と、このバッグ１１を覆うハウジング部４ａ、４ｂと、を有して構成されている。そして、このハウジング部４ａの内側には、前記したバッグ１１の一部を閉じて培養液の流れ方向をガイドする流路ガイド５ａが設けられている。なお、図４では、ハウジング部４ａの内側に設ける流路ガイド５ａの一例として、図２Ｂに示した形式で、つまり、培養液の流れが蛇行するように設けられているが、図２Ａに示した形式で設けることができることは言うまでもない。また、この変形例においては、ハウジング部４ａ、４ｂ内へのバッグ１１の出し入れを可能とするため、ヒンジ等により開閉可能に構成されている。このような構成とすると、ハウジング部４ａ、４ｂ内にバッグ１１を入れ、ハウジング部４ａ、４ｂを閉じてバッグ１１を挟み込んだときに、前記した流路ガイド５ａによって流路を形成することができる。   Next, another modification of the processing apparatus 3 according to the present invention will be described with reference to FIG. The processing apparatus 3 shown in FIG. 4 is configured so that the flow path portion 5 includes a flexible bag 11 and housing portions 4 a and 4 b that cover the bag 11. A flow path guide 5a for closing the part of the bag 11 and guiding the flow direction of the culture solution is provided inside the housing part 4a. In FIG. 4, as an example of the flow path guide 5a provided inside the housing portion 4a, the flow guide 5a is provided in the form shown in FIG. 2B, that is, the flow of the culture solution is meandering. Needless to say, it can be provided in different forms. Moreover, in this modification, in order to enable the bag 11 to be taken in and out of the housing portions 4a and 4b, the bag 11 can be opened and closed by a hinge or the like. With such a configuration, when the bag 11 is put in the housing parts 4a and 4b, the housing parts 4a and 4b are closed and the bag 11 is sandwiched, the flow path guide 5a can form a flow path. .

可撓性を有するバッグ１１は、例えば、エチレン・ビニル・アセテートやエチル・ビニル・アルコール等の多層フィルムで構成された各社市販の医薬品包装用途のシングルユースのバッグ１１を用いることができる。このようなシングルユースのバッグ１１は、予めガンマ線、紫外線、エチレンオキシドガス等によって滅菌されて無菌状態を維持し、気体や液体等の内容物がほぼ抜かれて清浄な状態で提供されているので、本発明に好適に用いることができる。また、このようなシングルユースのバッグ１１を用いると、ステンレス製やガラス製の流路部５を採用する場合と比較して、滅菌、洗浄の工程が不要であり、無菌スチーム発生装置や無菌洗浄水等の付帯設備を不要とすることができる。そのため、操作性の簡便化、装置の簡略化を図ることができ、また、これにより運転コストの低減を図ることができる。   As the flexible bag 11, for example, a single-use bag 11 for use in pharmaceutical packaging that is made of a multilayer film of ethylene / vinyl / acetate or ethyl / vinyl / alcohol can be used. Such a single-use bag 11 is sterilized in advance by gamma rays, ultraviolet rays, ethylene oxide gas or the like and maintained in a sterile state, and the contents such as gas and liquid are almost removed and provided in a clean state. It can use suitably for invention. In addition, when such a single-use bag 11 is used, a sterilization and washing process is not necessary as compared with the case where the stainless steel or glass flow path section 5 is adopted. Ancillary facilities such as water can be dispensed with. Therefore, the operability can be simplified and the apparatus can be simplified, and the operation cost can be reduced.

以上に説明した本発明に係る処理装置３及び当該処理装置３を有する精製装置１０は、培養液を加熱する加熱部６と、培養液に紫外線を照射する紫外線照射部８と、を有しており、加熱処理と紫外線照射処理を同時に行うので、従来の低ｐＨ処理に代わるウイルス不活性化処理を効率良く行うことができる。   The processing apparatus 3 according to the present invention described above and the purification apparatus 10 having the processing apparatus 3 include the heating unit 6 that heats the culture solution and the ultraviolet irradiation unit 8 that irradiates the culture solution with ultraviolet rays. In addition, since the heat treatment and the ultraviolet irradiation treatment are simultaneously performed, the virus inactivation treatment can be efficiently performed instead of the conventional low pH treatment.

［培養生産物の処理方法］
次に、本発明に係る培養生産物の処理方法（単に「処理方法」と呼称することもある）について説明する。本発明に係る処理方法は、前記した処理装置３を用いて培養生産物を処理する。処理装置３の備える構成要素である流路部５、加熱部６、及び紫外線照射部８などについては前記したとおりであるので説明を省略する。また、処理方法の説明において、処理装置３で説明したものと同一の構成要素については同一の符号を付し、その説明を省略する。 [Treatment method for cultured products]
Next, a method for treating a cultured product according to the present invention (sometimes simply referred to as “treatment method”) will be described. The treatment method according to the present invention treats the cultured product using the treatment apparatus 3 described above. Since the flow path section 5, the heating section 6, the ultraviolet irradiation section 8, and the like, which are constituent elements of the processing apparatus 3, are as described above, description thereof will be omitted. In the description of the processing method, the same components as those described in the processing device 3 are denoted by the same reference numerals, and the description thereof is omitted.

本発明に係る処理方法は、はじめに、培養槽１で細胞を培養し、培養生産物を含む培養液を得る。次いで、細胞破砕部やろ過フィルタ、連続遠心分離機等を用いて培養液から少なくとも細胞を除去する。そして、細胞が除去され、且つ培養生産物を含んでいる培養液を第１の貯留槽２ａに貯留する。次いで、第１の貯留槽２ａから処理装置３に培養液を移送し、加熱部６による加熱と、紫外線照射部８による紫外線の照射と、を同時に行い、ウイルス不活性化処理を行う。ウイルス不活性化処理が行われた培養液は、クロマトグラフ９で洗浄され、第２の貯留槽２ｂに貯留される。   In the treatment method according to the present invention, cells are first cultured in the culture tank 1 to obtain a culture solution containing a culture product. Next, at least cells are removed from the culture solution using a cell disruption unit, a filtration filter, a continuous centrifuge, or the like. And the culture solution from which the cell was removed and containing the culture product is stored in the 1st storage tank 2a. Next, the culture solution is transferred from the first storage tank 2a to the processing apparatus 3, and the virus inactivation process is performed by simultaneously performing the heating by the heating unit 6 and the ultraviolet irradiation by the ultraviolet irradiation unit 8. The culture solution on which the virus inactivation process has been performed is washed by the chromatograph 9 and stored in the second storage tank 2b.

ここで、本発明に係る処理方法においては、加熱部６による培養液の加熱温度は、培養生産物の熱変性を生じさせない温度以下とするのが好ましい。培養生産物の熱変性を生じさせない温度は培養生産物によって異なり、培養生産物に合わせて適宜に設定可能であり、例えば、８０℃などとすることができるが、７５℃や６５℃などとすることもできる。加熱部６による培養液の加熱温度の上限をこれらのように設定すると、例えば、培養生産物が抗体タンパク質である場合であっても、培養液中のウイルスの不活化処理を行いつつ、熱変性によって活性を損なってしまうといった事態を回避することができる。なお、加熱部６による培養液の加熱温度の下限は、例えば、６０℃とするのが好ましい。   Here, in the treatment method according to the present invention, the heating temperature of the culture solution by the heating unit 6 is preferably set to a temperature that does not cause thermal denaturation of the cultured product. The temperature that does not cause the heat denaturation of the cultured product varies depending on the cultured product, and can be appropriately set according to the cultured product. For example, it can be set to 80 ° C. or the like, but may be set to 75 ° C. or 65 ° C. or the like. You can also. When the upper limit of the heating temperature of the culture solution by the heating unit 6 is set as described above, for example, even when the culture product is an antibody protein, heat denaturation is performed while inactivating the virus in the culture solution. It is possible to avoid such a situation that the activity is impaired by. In addition, it is preferable that the minimum of the heating temperature of the culture solution by the heating part 6 shall be 60 degreeC, for example.

また、本発明に係る処理方法においては、流路部５の流入口５ｂから流出口５ｃまでの培養液の滞留時間を３０秒以上３０分以下とすることが好ましい。このようにすると、確実なウイルスの不活性化処理を行うことができる。なお、より確実なウイルスの不活性化処理と、効率的な処理の観点から、当該滞留時間は１分以上２０分以下とするのが好ましい。   Further, in the treatment method according to the present invention, it is preferable that the residence time of the culture solution from the inlet 5b to the outlet 5c of the flow path portion 5 is 30 seconds or longer and 30 minutes or shorter. In this way, reliable virus inactivation processing can be performed. In addition, from the viewpoint of more reliable virus inactivation treatment and efficient treatment, the residence time is preferably 1 minute or more and 20 minutes or less.

さらに、本発明に係る処理方法においては、紫外線の波長を２５４ｎｍとするのが好ましい。このようにすると、ウイルスの不活性化を効果的に行うことができる。なお、紫外線の波長はこれに限定されるものではなく、いわゆる紫外線に分類される範囲であればこれよりも波長の短い紫外線及び波長の長い紫外線を用いることができる。   Furthermore, in the processing method according to the present invention, it is preferable that the wavelength of ultraviolet light is 254 nm. If it does in this way, inactivation of a virus can be performed effectively. Note that the wavelength of the ultraviolet light is not limited to this, and ultraviolet light having a shorter wavelength and ultraviolet light having a longer wavelength can be used as long as they fall within the so-called ultraviolet light.

このように、本発明に係る処理方法は、前記した処理装置３を用いて培養液に対して加熱処理と紫外線照射処理を同時に行うので、従来の低ｐＨ処理に代わるウイルス不活性化処理を効率良く行うことができる。   As described above, the treatment method according to the present invention performs the heat treatment and the ultraviolet irradiation treatment on the culture solution at the same time using the treatment apparatus 3 described above, and thus efficiently performs the virus inactivation treatment instead of the conventional low pH treatment. Can be done well.

以上、本発明の一実施形態に係る培養生産物の処理装置、培養生産物の処理方法、及び培養生産物の精製装置について詳細に説明したが本発明の主旨はこれに限定されるものではなく、様々な変形例が含まれる。例えば、バッグ１１には、予め溶着等により流路ガイド５ａを形成しておいてもよい。   Although the culture product processing apparatus, the culture product processing method, and the culture product purification apparatus according to an embodiment of the present invention have been described in detail above, the gist of the present invention is not limited thereto. Various modifications are included. For example, the channel guide 5a may be formed in the bag 11 in advance by welding or the like.

なお、前記した実施形態は本発明を分かり易く説明するために詳細に説明したものであり、必ずしも説明した全ての構成を備えるものに限定されるものではない。また、ある実施形態の構成の一部を他の実施形態の構成に置き換えることが可能であり、また、ある実施形態の構成に他の実施形態の構成を加えることも可能である。また、各実施形態の構成の一部について、他の構成の追加・削除・置換をすることが可能である。   The above-described embodiment has been described in detail for easy understanding of the present invention, and is not necessarily limited to the one having all the configurations described. Further, a part of the configuration of an embodiment can be replaced with the configuration of another embodiment, and the configuration of another embodiment can be added to the configuration of an embodiment. In addition, it is possible to add, delete, and replace other configurations for a part of the configuration of each embodiment.

１０ 精製装置（培養生産物の精製装置）
１ 培養槽
２ａ 第１の貯留槽
２ｂ 第２の貯留槽
３ 処理装置（培養生産物の処理装置）
４ａ ハウジング部
４ｂ ハウジング部
５ 流路部
５ａ 流路ガイド
５ｂ 流入口
５ｃ 流出口
６ 加熱部
７ 冷却部
８ 紫外線照射部
８ａ 紫外線源
８ｂ 紫外線反射部
９ クロマトグラフ 10 Purification equipment (culture product purification equipment)
DESCRIPTION OF SYMBOLS 1 Culture tank 2a 1st storage tank 2b 2nd storage tank 3 Processing apparatus (processing apparatus of culture product)
4a Housing part 4b Housing part 5 Flow path part 5a Flow path guide 5b Inlet 5c Outlet 6 Heating part 7 Cooling part 8 Ultraviolet irradiation part 8a Ultraviolet source 8b Ultraviolet reflection part 9 Chromatograph

Claims (15)

細胞が除去されており、且つ培養生産物を含んでいる培養液を通流する流入口及び流出口を備えた扁平な流路部と、
前記流路部の一方の面に接触又は近接させて設けられており、前記培養液を加熱する加熱部と、
前記流路部の他方の面において、前記加熱部と対向する位置に接触又は近接させて設けられており、前記培養液に紫外線を照射する紫外線照射部と、を備えることを特徴とする培養生産物の処理装置。 A flat channel section having an inlet and an outlet through which a culture solution containing a culture product is removed and from which cells have been removed;
A heating section that is provided in contact with or close to one surface of the flow path section, and heats the culture solution;
A culture production comprising: an ultraviolet irradiation unit that irradiates the culture solution with ultraviolet rays, provided on the other surface of the flow path part in contact with or in proximity to a position facing the heating unit Material processing equipment. 前記加熱部による前記培養液の加熱温度が、前記培養生産物の熱変性を生じさせない温度以下であることを特徴とする請求項１に記載の培養生産物の処理装置。   The apparatus for treating a cultured product according to claim 1, wherein the heating temperature of the culture solution by the heating unit is equal to or lower than a temperature that does not cause thermal denaturation of the cultured product. 前記培養生産物の熱変性を生じさせない温度が８０℃であることを特徴とする請求項２に記載の培養生産物の処理装置。   The apparatus for treating a cultured product according to claim 2, wherein a temperature at which the cultured product does not cause thermal denaturation is 80 ° C. 前記流入口から前記流出口までの前記培養液の滞留時間が３０秒以上３０分以下であることを特徴とする請求項１に記載の培養生産物の処理装置。   The culture product processing apparatus according to claim 1, wherein a residence time of the culture solution from the inlet to the outlet is 30 seconds to 30 minutes. 前記紫外線の波長が２５４ｎｍであることを特徴とする請求項１に記載の培養生産物の処理装置。   The apparatus for treating a cultured product according to claim 1, wherein the wavelength of the ultraviolet light is 254 nm. 前記流路部に前記培養液の流れ方向をガイドする流路ガイドが設けられていることを特徴とする請求項１に記載の培養生産物の処理装置。   The culture product processing apparatus according to claim 1, wherein a flow path guide for guiding a flow direction of the culture solution is provided in the flow path section. 前記加熱部、前記流路部及び前記紫外線照射部を１つのユニットとして、当該ユニットを２以上並列に設けたことを特徴とする請求項１に記載の培養生産物の処理装置。   The culture product processing apparatus according to claim 1, wherein the heating unit, the flow path unit, and the ultraviolet irradiation unit are provided as one unit, and two or more of the units are provided in parallel. 前記流路部が、可撓性を有するバッグと、前記バッグを覆うハウジング部と、を有しており、
前記ハウジング部の内側には、前記バッグの一部を閉じて前記培養液の流れ方向をガイドする流路ガイドが設けられていることを特徴とする請求項１に記載の培養生産物の処理装置。 The flow path portion has a flexible bag, and a housing portion that covers the bag,
The culture product processing apparatus according to claim 1, wherein a flow path guide that closes a part of the bag and guides a flow direction of the culture solution is provided inside the housing portion. . 前記培養生産物が抗体タンパク質であることを特徴とする請求項１に記載の培養生産物の処理装置。   The culture product processing apparatus according to claim 1, wherein the culture product is an antibody protein. 細胞が除去されており、且つ培養生産物を含んでいる培養液を通流する流入口及び流出口を備えた扁平な流路部と、
前記流路部の一方の面に接触又は近接させて設けられており、前記培養液を加熱する加熱部と、
前記流路部の他方の面において、前記加熱部と対向する位置に接触又は近接させて設けられており、前記培養液に紫外線を照射する紫外線照射部と、
を備える培養生産物の処理装置を用いて前記培養生産物を処理する方法であり、
前記流路部内の培養液を前記加熱部で加熱しつつ、前記紫外線照射部から前記流路部内の培養液に前記紫外線を照射することを特徴とする培養生産物の処理方法。 A flat channel section having an inlet and an outlet through which a culture solution containing a culture product is removed and from which cells have been removed;
A heating section that is provided in contact with or close to one surface of the flow path section, and heats the culture solution;
On the other surface of the flow path part, provided in contact with or close to the position facing the heating part, an ultraviolet irradiation part for irradiating the culture solution with ultraviolet light,
A method for treating the culture product using a culture product processing apparatus comprising:
A method for treating a cultured product, comprising: irradiating the culture solution in the flow channel from the ultraviolet irradiation unit while heating the culture solution in the flow channel by the heating unit. 前記加熱部による前記培養液の加熱温度が、前記培養生産物の熱変性を生じさせない温度以下であることを特徴とする請求項１０に記載の培養生産物の処理方法。   The method for treating a cultured product according to claim 10, wherein the heating temperature of the culture solution by the heating unit is equal to or lower than a temperature that does not cause thermal denaturation of the cultured product. 前記培養生産物の熱変性を生じさせない温度が８０℃であることを特徴とする請求項１１に記載の培養生産物の処理方法。   The method for treating a cultured product according to claim 11, wherein a temperature at which the cultured product is not denatured is 80 ° C. 前記流入口から前記流出口までの前記培養液の滞留時間が３０秒以上３０分以下であることを特徴とする請求項１０に記載の培養生産物の処理方法。   The culture product treatment method according to claim 10, wherein a residence time of the culture solution from the inlet to the outlet is 30 seconds to 30 minutes. 前記紫外線の波長が２５４ｎｍであることを特徴とする請求項１０に記載の培養生産物の処理方法。   The method for treating a cultured product according to claim 10, wherein the wavelength of the ultraviolet light is 254 nm. 細胞を培養して生産した培養生産物を精製する装置であり、
前記細胞が除去されており、且つ培養生産物を含む培養液を通流する流入口及び流出口を備えた扁平な流路部と、前記流路部の一方の面に接触又は近接させて設けられており、前記培養液を加熱する加熱部と、前記流路部の他方の面において、前記加熱部と対向する位置に接触又は近接させて設けられており、前記加熱部による前記培養液の加熱と共に紫外線を照射する紫外線照射部と、を備える培養生産物の処理装置と、
前記培養液の流れ方向を基準として、前記培養生産物の処理装置の前及び後の少なくとも一方にクロマトグラフと、を有することを特徴とする培養生産物の精製装置。 An apparatus for purifying a culture product produced by culturing cells.
A flat channel portion having an inlet and an outlet through which the culture solution containing the culture product is passed, from which the cells have been removed, and one surface of the channel portion are provided in contact with or close to each other. A heating unit that heats the culture solution, and is provided in contact with or in proximity to a position facing the heating unit on the other surface of the flow path unit. An apparatus for treating a cultured product, comprising: an ultraviolet irradiation unit that irradiates ultraviolet rays together with heating;
An apparatus for purifying a culture product, comprising: a chromatograph at least one before and after the treatment apparatus for the culture product with reference to the flow direction of the culture solution.
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