Antibody-drug conjugate production method including purification step using activated carbon material

Abstract

The purpose of the present inventio is to provide an antibody-drug conjugate production method including a purification method for efficiently removing a by-product derived from an exatecan compound.　Provided is a method for producing an antibody-drug conjugate in which a drug linker represented by the formula shown below (wherein A represents a position at which an antibody is bound) and the antibody is bound to each other through a thioether bond, the method being characterized by including (i) a step for removing a by-product derived from an exatecan compound from a solution containing the antibody-drug conjugate using an activated carbon material.

Description

Method for producing antibody-drug conjugates, including a purification step using activated carbon material The present invention relates to a method for producing an antibody-drug conjugate, comprising a purification step using an activated carbon material. In particular, the present invention relates to a method for producing an antibody-drug conjugate, comprising a purification step using an activated carbon material to remove by-products derived from the exatecan compound. Antibody-drug conjugates (ADCs), which are antibodies that bind to antigens expressed on the surface of cancer cells and can be internalized into the cells and are bound to cytotoxic drugs, are expected to selectively deliver drugs to cancer cells, accumulating the drugs in the cancer cells and killing the cancer cells (Non-Patent Documents 1 to 5). One example of an antibody-drug conjugate is an antibody-drug conjugate (hereinafter referred to as "DXd-ADC") that is composed of an antibody and a derivative of exatecan, a topoisomerase I inhibitor (Patent Documents 1 to 6 and Non-Patent Documents 6 to 9). These antibody-drug conjugates have excellent antitumor effects and safety, and for example, trastuzumab deruxtecan has already been approved as a drug in various countries around the world, and many clinical trials are currently underway. In general, in an antibody-drug conjugate, a drug with high cytotoxic activity is bound to an antibody, and it is preferable to remove highly active impurities derived from the drug that is not bound to the antibody from the antibody-drug conjugate drug substance as much as possible, which is an extremely important requirement for the quality of the drug substance. Examples of Patent Documents 7 to 15 describe methods for producing antibody-drug conjugates other than DXd-ADC, which include a purification step by chromatography such as hydrophobic chromatography or gel filtration chromatography. Patent documents 1 to 6 describe a method for producing an antibody-drug conjugate, DXd-ADC, by conjugating an antibody with a drug linker intermediate and purifying the resulting crude antibody-drug conjugate. Examples in patent documents 2 to 4 describe that the crude antibody-drug conjugate was purified by ultrafiltration using a sorbitol-containing acetate buffer. Patent document 5 describes that the crude antibody-drug conjugate can be purified by ultrafiltration using an acetate buffer, a histidine buffer, or a phosphate buffer. Patent document 6 describes that the crude antibody-drug conjugate can be effectively purified by ultrafiltration using a buffer containing a salt. The Examples of Patent Document 16 describe a method for removing pyrrolobenzodiazepine-related impurities from a product mixture of a pyrrolobenzodiazepine-antibody conjugate (hereinafter also referred to as "PBD-ADC") by activated carbon filtration. As mentioned above, several techniques related to purification methods for antibody-drug conjugates are known, but with regard to DXd-ADC, there was a need to develop an improved method for purifying impurities derived from highly active drugs. International Publication No. 2014 / 057687 International Publication No. 2015 / 098099 International Publication No. 2015 / 115091 International Publication No. 2015 / 155998 International Publication No. 2017 / 002776 International Publication No. 2020 / 022363 International Publication No. 2002 / 098883 International Publication No. 2005 / 037992 International Publication No. 2005 / 084390 International Publication No. 2006 / 086733 International Publication No. 2007 / 024536 International Publication No. 2010 / 141566 International Publication No. 2011 / 039724 International Publication No. 2012 / 135517 International Publication No. 2015 / 104359 International Publication No. 2014 / 143622 Ducry L., et al.,Bioconjudate Chem.(2010),21(1),5-13.Alley SC,et al.,Current Opinion in Chemical Biology(2010),14(4),529-537.Damle NK,Expert Opin.Ther.(2004),4(9),1445-1452.Senter PD,et al.,Nature Biotechnology(2012),30(7),631-637.Howard A.,et al.,J. Clin. Oncol.(2011),29(4),398-405.Ogitani Y.,et al.,Clinical Cancer Research(2016),22(20),5097-5108.Ogitani Y.,et al.,Canser Science(2016),107(7),1039-1046.Doi T.,et al.,Lancet Oncol.(2017),18(11),1512-1522.Takegawa N.,et al.,Int. J. Cancer(2017),141(8),1682-1689. An object of the present invention is to provide a method for producing an antibody-drug conjugate, which includes a purification step for efficiently removing by-products derived from the exatecan compound. Another object of the present invention is to provide a production method that reduces waste liquid containing highly active impurities that may be generated in the production of an antibody-drug conjugate. The inventors conducted intensive research to solve the above problems and discovered that by using activated carbon materials in the purification process of antibody-drug conjugates, it is possible to efficiently remove by-products derived from the highly active exatecan compound derived from the exatecan derivative of DXd-ADC, and thus completed the present invention. That is, the present invention includes the following inventions. [1] Formula (1) (wherein A represents the binding site to the antibody) and an antibody via a thioether bond, (i) removing by-products derived from the exatecan compound from a solution containing the antibody-drug conjugate using an activated carbon material; A manufacturing method comprising the steps of: [2] The method of [1], wherein the step (i) is a step of filtering a solution containing the antibody-drug conjugate through an activated carbon filter. [3] The manufacturing method according to [1] or [2], wherein the step (i) is a step of filtering a solution containing an antibody-drug conjugate using an activated carbon filter, and the solution is passed through the activated carbon filter only once. [4] The activated carbon contained in the activated carbon material has a melting point of 1000 to 2000 m 2 The method according to any one of [1] to [3], wherein the surface area of ​​the resulting product is 1 / g. [5] The manufacturing method according to any one of [1] to [4], wherein the activated carbon contained in the activated carbon material has an average particle size of 5 to 40 μm. [6] The method according to any one of [1] to [5], wherein the activated carbon contained in the activated carbon material has an average particle size of 5 to 40 μm at least 98% by weight. [7] The manufacturing method of any one of [1] to [6], wherein the temperature of the solution containing the antibody-drug conjugate used in step (i) is 0°C to 30°C. [8] (ii) reducing the antibody with a reducing agent; (iii) Formula (2) reacting the compound represented by the formula: with the antibody reduced in step (ii); (iv) adding a reagent having a thiol group to react with the compound represented by formula (2) remaining from step (iii); The manufacturing method of any one of [1] to [7], [9] Any one of the manufacturing methods [1] to [8], comprising the step (i) after the step (iv).

[0010] Any one of the manufacturing methods [1] to [9], wherein the by-product derived from the exatecan compound includes a compound in which the reducing agent used in step (ii) is added to the maleimidyl group of the compound represented by formula (2), and / or a compound in which the reagent having a thiol group used in step (iv) is added to the maleimidyl group of the compound represented by formula (2).

[0011] The by-product derived from the exatecan compound is represented by the formula (3): and / or a compound represented by formula (4) A method for producing any one of [1] to

[0010] , comprising the compound represented by the formula:

[0012] The method according to any one of [1] to

[0011] , wherein the reducing agent used in step (ii) is tris(2-carboxyethyl)phosphine or a salt thereof.

[0013] The method according to any one of [1] to

[0012] , wherein the reducing agent used in step (ii) is tris(2-carboxyethyl)phosphine hydrochloride.

[0014] The method for producing any one of [1] to

[0013] , wherein step (ii) is carried out in a buffer solution.

[0015] A manufacturing method according to

[0014] , wherein the buffer solution is a histidine buffer solution.

[0016] A manufacturing method according to

[0014] or

[0015] , wherein the buffer solution is an aqueous L-histidine solution.

[0017] The manufacturing method of

[0014] , wherein the buffer solution is an aqueous solution of disodium hydrogen phosphate.

[0018] The manufacturing method of

[0014] , wherein the buffer solution is an acetate buffer solution.

[0019] A manufacturing method according to

[0014] or

[0018] , wherein the buffer solution is an aqueous sodium acetate solution.

[0020] The method for producing any one of [1] to

[0019] , wherein the step (i) is carried out in the presence of a chelating agent.

[0021] The manufacturing method of

[0020] , wherein the chelating agent is ethylenediaminetetraacetic acid.

[0022] The manufacturing method according to any one of

[0014] to

[0021] , wherein the buffer solution used in step (ii) contains a surfactant.

[0023] The manufacturing method of

[0022] , wherein the surfactant is polysorbate 20.

[0024] The manufacturing method of

[0022] , wherein the surfactant is polysorbate 80.

[0025] The manufacturing method according to any one of

[0014] to

[0021] , wherein the buffer solution used in step (ii) does not contain a surfactant.

[0026] The method for producing any one of [1] to

[0025] , wherein the compound represented by formula (2) used in step (ii) is 2.0 to 10.0 equivalents.

[0027] The method according to any one of [1] to

[0026] , wherein the compound represented by formula (2) used in step (ii) is 8.0 to 10.0 equivalents.

[0028] The method according to any one of [1] to

[0027] , wherein the compound represented by formula (2) used in step (ii) is 8.9 to 10.0 equivalents.

[0029] The method according to any one of [1] to

[0026] , wherein the compound represented by formula (2) used in step (ii) is 4.0 to 6.0 equivalents.

[0030] The method according to any one of [1] to

[0029] , wherein the reagent having a thiol group used in step (iii) is N-acetylcysteine.

[0031] (v) The method for producing any one of [1] to

[0030] , which includes a step of adjusting the pH of the reaction solution.

[0032] The method for producing any one of [1] to

[0031] , comprising step (v) following step (iv).

[0033] The method for producing according to

[0031] or

[0032] , wherein the step (v) is a step of adjusting the pH of the reaction solution to a range of 4 to 6.

[0034] The method for producing any one of

[0031] to

[0033] , wherein the step (v) is a step of adjusting the pH of the reaction solution using an aqueous acetic acid solution.

[0035] (vi) The method for producing any one of [1] to

[0034] , further comprising a step of washing an activated carbon filter.

[0036] A method for producing the compound represented by formula (0035), comprising the step (i) followed by the step (vi).

[0037] A manufacturing method according to

[0035] or

[0036] , wherein a histidine buffer is used in step (vi).

[0038] Any one of the production methods according to

[0035] to

[0037] , wherein in step (vi), an 8.5 mmol / L L-histidine buffer is used.

[0039] A manufacturing method according to any one of [1] to

[0028] and

[0030] to

[0038] , wherein the average number of drug linkers bound per antibody in the antibody-drug conjugate is in the range of 7 to 8.

[0040] A manufacturing method according to any one of [1] to

[0028] and

[0030] to

[0039] , wherein the average number of drug linkers bound per antibody in the antibody-drug conjugate is in the range of 7.5 to 8.

[0041] A method for producing any one of [1] to

[0028] and

[0030] to

[0040] , wherein the antibody is an anti-GPR20 antibody.

[0042] A method for producing an anti-GPR20 antibody according to

[0041] , which is an antibody comprising a heavy chain consisting of the amino acid sequence set forth in amino acid numbers 20 to 472 in SEQ ID NO: 1 and a light chain consisting of the amino acid sequence set forth in amino acid numbers 21 to 234 in SEQ ID NO: 2.

[0043] A method for producing an anti-GPR20 antibody according to

[0041] or

[0042] , in which the lysine residue at the carboxyl terminus of the heavy chain is deleted.

[0044] A manufacturing method according to any one of [1] to

[0028] and

[0030] to

[0040] , wherein the antibody is an anti-CD37 antibody.

[0045] A method for producing an anti-CD37 antibody according to

[0044] , which is an antibody comprising a heavy chain consisting of the amino acid sequence set forth in amino acid numbers 20 to 468 of SEQ ID NO: 3 and a light chain consisting of the amino acid sequence set forth in amino acid numbers 21 to 234 of SEQ ID NO: 4.

[0046] A method for producing an anti-CD37 antibody according to

[0044] or

[0045] , in which the lysine residue at the carboxyl terminus of the heavy chain is deleted.

[0047] A method for producing any one of [1] to

[0028] and

[0030] to

[0040] , wherein the antibody is an anti-MUC1 antibody.

[0048] A method for producing an anti-MUC1 antibody according to

[0047] , wherein the anti-MUC1 antibody is an antibody comprising a heavy chain consisting of the amino acid sequence set forth in amino acid numbers 1 to 447 in SEQ ID NO:5 or the amino acid sequence set forth in amino acid numbers 1 to 447 in SEQ ID NO:6, and a light chain consisting of the amino acid sequence set forth in amino acid numbers 1 to 219 in SEQ ID NO:7.

[0049] A method for producing an anti-MUC1 antibody according to

[0047] or

[0048] , in which the lysine residue at the carboxyl terminus of the heavy chain is deleted.

[0050] A manufacturing method according to any one of [1] to

[0028] and

[0030] to

[0040] , wherein the antibody is an anti-HER2 antibody.

[0051] A method for producing an anti-HER2 antibody according to

[0050] , which is an antibody comprising a heavy chain consisting of the amino acid sequence set forth in amino acid numbers 1 to 449 in SEQ ID NO: 8 and a light chain consisting of the amino acid sequence set forth in amino acid numbers 1 to 214 in SEQ ID NO: 9.

[0052] A method for producing an anti-HER2 antibody according to

[0050] or

[0051] , wherein the anti-HER2 antibody is an antibody comprising a heavy chain consisting of the amino acid sequence set forth in SEQ ID NO: 8 and a light chain consisting of the amino acid sequence set forth in SEQ ID NO: 9.

[0053] A manufacturing method according to any one of [1] to

[0028] and

[0030] to

[0040] , wherein the antibody is an anti-HER3 antibody.

[0054] A method for producing an anti-HER3 antibody according to

[0053] , which is an antibody comprising a heavy chain consisting of the amino acid sequence set forth in SEQ ID NO: 12 and a light chain consisting of the amino acid sequence set forth in SEQ ID NO: 13.

[0055] A method for producing an anti-HER3 antibody according to

[0053] or

[0054] , in which the lysine residue at the carboxyl terminus of the heavy chain is deleted.

[0056] A manufacturing method according to any one of [1] to

[0028] and

[0030] to

[0040] , wherein the antibody is an anti-CDH6 antibody.

[0057] A method for producing an anti-CDH6 antibody according to

[0056] , which is an antibody comprising a heavy chain consisting of the amino acid sequence set forth in amino acid numbers 20 to 471 of SEQ ID NO: 16 and a light chain consisting of the amino acid sequence set forth in amino acid numbers 21 to 233 of SEQ ID NO: 17.

[0058] A method for producing an anti-CDH6 antibody according to

[0056] or

[0057] , in which the lysine residue at the carboxyl terminus of the heavy chain is deleted.

[0059] A manufacturing method according to any one of [1] to

[0026] and

[0029] to

[0038] , wherein the average number of drug linkers bound per antibody in the antibody-drug conjugate is in the range of 3 to 4.

[0060] A manufacturing method according to any one of [1] to

[0026] ,

[0029] to

[0038] , and

[0059] , wherein the average number of drug linkers bound per antibody in the antibody-drug conjugate is in the range of 3.5 to 4.

[0061] A method for producing any one of [1] to

[0026] ,

[0029] to

[0038] ,

[0059] and

[0060] , wherein the antibody is an anti-TROP2 antibody.

[0062] A method for producing an anti-TROP2 antibody according to

[0061] , which is an antibody comprising a heavy chain consisting of the amino acid sequence set forth in amino acid numbers 20 to 470 of SEQ ID NO: 10 and a light chain consisting of the amino acid sequence set forth in amino acid numbers 21 to 234 of SEQ ID NO: 11.

[0063] A method for producing an anti-TROP2 antibody according to

[0061] or

[0062] , in which the lysine residue at the carboxyl terminus of the heavy chain is deleted.

[0064] A manufacturing method according to any one of [1] to

[0026] ,

[0029] to

[0038] ,

[0059] and

[0060] , wherein the antibody is an anti-B7-H3 antibody.

[0065] A method for producing an anti-B7-H3 antibody according to

[0064] , which is an antibody comprising a heavy chain consisting of the amino acid sequence set forth in amino acid numbers 20 to 471 of SEQ ID NO: 14 and a light chain consisting of the amino acid sequence set forth in amino acid numbers 21 to 233 of SEQ ID NO: 15.

[0066] A method for producing an anti-B7-H3 antibody according to

[0064] or

[0065] , in which the lysine residue at the carboxyl terminus of the heavy chain is deleted.

[0067] Any one of the production methods [1] to

[0066] , characterized in that it does not include a purification step by chromatography.

[0068] A manufacturing method according to

[0067] , wherein the chromatography is at least one selected from the group consisting of gel filtration chromatography, ion exchange chromatography, hydrophobic interaction chromatography, and affinity chromatography.

[0069] An antibody-drug conjugate is produced by any one of the production methods of [1] to

[0068] , and further (vii) adding a buffer solution to the solution containing the antibody-drug conjugate; (viii) concentrating the solution containing the antibody-drug conjugate; and (ix) adjusting the solution containing the antibody-drug conjugate to a predetermined pH; At least one step selected from the group consisting of: and, (x) adding an excipient to the solution containing the antibody-drug conjugate; By carrying out a process including A method for making a pharmaceutical composition comprising an antibody-drug conjugate, a buffer, and an excipient.

[0070] A manufacturing method according to

[0069] , wherein the buffer solution is a histidine buffer solution.

[0071] A manufacturing method according to

[0069] or

[0070] , wherein the excipient is sucrose.

[0072] A manufacturing method according to

[0069] or

[0070] , wherein the excipient is trehalose.

[0073]

[0069] -

[0072] A pharmaceutical composition comprising an antibody-drug conjugate, a buffer, and an excipient is produced by any one of the production methods, (xi) adding a surfactant to the pharmaceutical composition; By carrying out a process including A method for making a pharmaceutical composition comprising an antibody-drug conjugate, a buffer, an excipient, and a surfactant.

[0074] A manufacturing method according to

[0073] , wherein the surfactant is polysorbate 80.

[0075] A manufacturing method of

[0073] , wherein the surfactant is polysorbate 20.

[0076] 1000-2000m to remove by-products derived from the exatecan compound 2 3. An activated carbon material comprising an activated carbon having a surface area of ​​1 / g.

[0077] The activated carbon material of

[0076] , wherein the activated carbon contained therein has an average particle size of 5 to 40 μm.

[0078] An activated carbon material according to

[0076] or

[0077] , in which at least 98% by weight of the activated carbon contained therein has an average particle size of 5 to 40 μm. Furthermore, the present invention also includes the following inventions. [A1] A method for producing an antibody-drug conjugate, comprising the steps of: (i) removing by-products derived from the exatecan compound from a solution containing the antibody-drug conjugate using an activated carbon material; A manufacturing method comprising the steps of: [A2] The method for producing [A1], wherein the drug of the antibody-drug conjugate is a topoisomerase I inhibitor. [A3] The antibody-drug conjugate comprises a drug represented by the following formula: A method for producing [A2], which exerts antitumor activity by releasing [A4] The antibody-drug conjugate is an antitumor compound represented by the following formula: The method for producing [A2], in which the nitrogen atom of the amino group at position 1 is used as the binding site to an antibody via a linker. [A5] The method for producing the antibody-drug conjugate according to [A4], wherein the antitumor compound is bound to the antibody via a linker through a thioether bond formed at a disulfide bond present in the antibody. [A6] The production method of [A4] or [A5], wherein the linker of the antibody-drug conjugate contains a tetrapeptide residue of -Gly-Gly-Phe-Gly-. [A7] Formula (1) (wherein A represents the binding site to the antibody) and an antibody via a thioether bond, (i) removing by-products derived from the exatecan compound from a solution containing the antibody-drug conjugate using an activated carbon material; The method for producing any one of [A1] to [A6], comprising: [A8] The manufacturing method of [A7], wherein the step (i) is a step of filtering a solution containing the antibody-drug conjugate using an activated carbon filter. [A9] The manufacturing method according to [A7] or [A8], wherein the step (i) is a step of filtering a solution containing an antibody-drug conjugate using an activated carbon filter, and the solution is passed through the activated carbon filter only once. [A10] A method for producing [A8] or [A9], comprising, prior to step (i), a step of washing an activated carbon filter before use. [A11] The manufacturing method of [A10], wherein an aqueous solution containing a surfactant is used in the step of washing before use. [A12] The production method of [A10] or [A11], wherein an aqueous solution of polysorbate 20 or an aqueous solution of polysorbate 80 is used in the step of washing before use. [A13] The production method of [A10] or [A11], wherein an aqueous solution of polysorbate 20 is used in the step of washing before use. [A14] The manufacturing method of [A10] or [A11], wherein an aqueous solution of polysorbate 80 is used in the step of washing before use. [A15] The activated carbon contained in the activated carbon material has a viscosity of 10 to 10,000 m 2 The method for producing any one of [A7] to [A14], wherein the surface area of ​​the method is 1 / g. [A16] The method for producing any one of [A7] to [A15], wherein the activated carbon contained in the activated carbon material has an average particle diameter of 2 μm or more. [A17] The method for producing any one of [A7] to [A16], wherein the activated carbon contained in the activated carbon material has an average particle size of 5 to 40 μm at least 90% by weight. [A18] The manufacturing method of any one of [A7] to [A17], wherein the temperature of the solution containing the antibody-drug conjugate used in step (i) is 0°C to 30°C. [A19] The manufacturing method of any one of [A7] to [A18], wherein the temperature of the solution containing the antibody-drug conjugate used in step (i) is 10°C to 20°C. [A20] The manufacturing method of any one of [A7] to [A19], wherein the temperature of the solution containing the antibody-drug conjugate used in step (i) is about 15°C. [A21] The manufacturing method of any one of [A7] to [A20], wherein the pH of the solution containing the antibody-drug conjugate used in step (i) is 4.0 to 6.0. [A22] The manufacturing method of any one of [A7] to [A21], wherein the pH of the solution containing the antibody-drug conjugate used in step (i) is about 5. [A23] The manufacturing method of any one of [A7] to [A21], wherein the pH of the solution containing the antibody-drug conjugate used in step (i) is about 4.5. [A24] (ii) reducing the antibody with a reducing agent; (iii) Formula (2) reacting the compound represented by the formula: with the antibody reduced in step (ii); (iv) adding a reagent having a thiol group to react with the compound represented by formula (2) remaining from step (iii); The manufacturing method of any one of [A7] to [A23], [A25] The manufacturing method of any one of [A7] to [A24], comprising step (i) after step (iv). [A26] A manufacturing method according to any one of [A7] to [A25], wherein the by-product derived from the exatecan compound includes a compound in which the reducing agent used in step (ii) is added to the maleimidyl group of the compound represented by formula (2), and / or a compound in which the reagent having a thiol group used in step (iv) is added to the maleimidyl group of the compound represented by formula (2). [A27] A by-product derived from the exatecan compound is represented by the formula (3) and / or a compound represented by formula (4) A method for producing any one of [A7] to [A26], which comprises a compound represented by the following formula: [A28] The production method of [A27], wherein the content of the compound represented by formula (3) in the solution containing the antibody-drug conjugate used in step (i) is 300 μM or less. [A29] The production method of [A27] or [A28], wherein the content of the compound represented by formula (3) in the solution containing the antibody-drug conjugate used in step (i) is 0 to 150 μM. [A30] The manufacturing method of any one of [A27] to [A29], wherein the content of the compound represented by formula (4) in the solution containing the antibody-drug conjugate used in step (i) is 160 μM or less. [A31] Any one of the manufacturing methods of [A27] to [A30], wherein the content of the compound represented by formula (4) in the solution containing the antibody-drug conjugate used in step (i) is 0 to 80 μM. [A32] The manufacturing method of any one of [A7] to [A31], wherein the solution containing the antibody-drug conjugate obtained by step (i) contains 0.3% or less of a by-product derived from compound (2). [A33] The production method of any one of [A7] to [A32], wherein the reducing agent used in step (ii) is tris(2-carboxyethyl)phosphine or a salt thereof. [A34] The method for producing any one of [A7] to [A33], wherein the reducing agent used in step (ii) is tris(2-carboxyethyl)phosphine hydrochloride. [A35] The method for producing any one of [A7] to [A34], wherein step (ii) is carried out in a buffer solution. [A36] The method for producing [A35], wherein the buffer solution is a histidine buffer solution. [A37] The method according to [A35] or [A36], wherein the buffer solution is an aqueous L-histidine solution. [A38] The method for producing [A35], wherein the buffer solution is an aqueous solution of disodium hydrogen phosphate. [A39] The method for producing [A35], wherein the buffer solution is an acetate buffer solution. [A40] The method for producing [A35] or [A39], wherein the buffer solution is an aqueous sodium acetate solution. [A41] The method for producing any one of [A7] to [A40], wherein the step (ii) is carried out in the presence of a chelating agent. [A42] The method for producing [A41], wherein the chelating agent is ethylenediaminetetraacetic acid. [A43] The method for producing any one of [A35] to [A42], wherein the buffer solution used in step (ii) contains a surfactant. [A44] The method for producing [A43], wherein the surfactant is polysorbate 20. [A45] The method for producing [A43], wherein the surfactant is polysorbate 80. [A46] The manufacturing method of any one of [A35] to [A42], wherein the buffer solution used in the step (ii) does not contain a surfactant. [A47] The method for producing any one of [A7] to [A46], wherein the compound represented by formula (2) used in the step (iii) is 2.0 to 10.0 equivalents. [A48] The method for producing any one of [A7] to [A47], wherein the compound represented by formula (2) used in the step (iii) is 8.0 to 10.0 equivalents. [A49] The method for producing any one of [A7] to [A48], wherein the compound represented by formula (2) used in the step (iii) is 8.9 to 10.0 equivalents. [A50] The method for producing any one of [A7] to [A47], wherein the compound represented by formula (2) used in the step (iii) is 4.0 to 6.0 equivalents. [A51] The method for producing any one of [A7] to [A50], wherein the reagent having a thiol group used in step (iv) is N-acetylcysteine. [A52] (v) The method for producing any one of [A7] to [A51], which comprises a step of adjusting the pH of the reaction solution. [A53] A method for producing any one of [A7] to [A52], comprising step (v) following step (iv). [A54] The method for producing [A52] or [A53], wherein the step (v) is a step of adjusting the pH of the reaction solution to a range of 4 to 6. [A55] The production method of any one of [A52] to [A54], wherein the step (v) is a step of adjusting the pH of the reaction solution to about 5. [A56] The production method of any one of [A52] to [A54], wherein the step (v) is a step of adjusting the pH of the reaction solution to about 4.5. [A57] The method for producing any one of [A52] to [A56], wherein the step (v) is a step of adjusting the pH of the reaction solution using an aqueous acetic acid solution. [A58] (vi) The manufacturing method of any one of [A7] to [A57], comprising a step of rinsing the activated carbon filter. [A59] A method for producing [A58], comprising step (i) and then step (vi). [A60] The production method of [A58] or [A59], wherein a histidine buffer is used in step (vi). [A61] The production method of any one of [A58] to [A60], wherein 8.5 mmol / L L-histidine buffer is used in step (vi). [A62] The method for producing any one of [A7] to [A61], wherein the average number of drug linkers bound per antibody in the antibody-drug conjugate is in the range of 7 to 8. [A63] The method for producing any one of [A7] to [A62], wherein the average number of drug linkers bound per antibody in the antibody-drug conjugate is in the range of 7.5 to 8. [A64] The method for producing any one of [A7] to [A63], wherein the antibody is an anti-GPR20 antibody. [A65] A method for producing [A64], wherein the anti-GPR20 antibody is an antibody comprising a heavy chain consisting of the amino acid sequence set forth in amino acid numbers 20 to 472 of SEQ ID NO: 1 and a light chain consisting of the amino acid sequence set forth in amino acid numbers 21 to 234 of SEQ ID NO: 2. [A66] The method for producing either one of [A64] or [A65], wherein the lysine residue at the carboxyl terminus of the heavy chain of the anti-GPR20 antibody is deleted. [A67] The method for producing any one of [A7] to [A63], wherein the antibody is an anti-CD37 antibody. [A68] A method for producing [A67], wherein the anti-CD37 antibody is an antibody comprising a heavy chain consisting of the amino acid sequence set forth in amino acid numbers 20 to 468 of SEQ ID NO: 3 and a light chain consisting of the amino acid sequence set forth in amino acid numbers 21 to 234 of SEQ ID NO: 4. [A69] A method for producing [A67] or [A68], in which the lysine residue at the carboxyl terminus of the heavy chain of the anti-CD37 antibody is deleted. [A70] The method for producing any one of [A7] to [A63], wherein the antibody is an anti-MUC1 antibody. [A71] A method for producing [A70], wherein the anti-MUC1 antibody is an antibody comprising a heavy chain consisting of the amino acid sequence set forth in amino acid numbers 1 to 447 of SEQ ID NO:5 or the amino acid sequence set forth in amino acid numbers 1 to 447 of SEQ ID NO:6, and a light chain consisting of the amino acid sequence set forth in amino acid numbers 1 to 219 of SEQ ID NO:7. [A72] A method for producing [A70] or [A71], wherein the lysine residue at the carboxyl terminus of the heavy chain of the anti-MUC1 antibody is deleted. [A73] The method for producing any one of [A7] to [A63], wherein the antibody is an anti-HER2 antibody. [A74] A method for producing [A73], wherein the anti-HER2 antibody is an antibody comprising a heavy chain consisting of the amino acid sequence set forth in amino acid numbers 1 to 449 of SEQ ID NO: 8 and a light chain consisting of the amino acid sequence set forth in amino acid numbers 1 to 214 of SEQ ID NO: 9. [A75] The method for producing [A73] or [A74], wherein the anti-HER2 antibody is an antibody comprising a heavy chain consisting of the amino acid sequence set forth in SEQ ID NO: 8 and a light chain consisting of the amino acid sequence set forth in SEQ ID NO: 9. [A76] The method for producing any one of [A7] to [A63], wherein the antibody is an anti-HER3 antibody. [A77] The method for producing [A76], wherein the anti-HER3 antibody is an antibody comprising a heavy chain consisting of the amino acid sequence set forth in SEQ ID NO: 12 and a light chain consisting of the amino acid sequence set forth in SEQ ID NO: 13. [A78] A method for producing either one of [A76] or [A77], wherein the lysine residue at the carboxyl terminus of the heavy chain of the anti-HER3 antibody is deleted. [A79] The method for producing any one of [A7] to [A63], wherein the antibody is an anti-CDH6 antibody. [A80] A method for producing [A79], wherein the anti-CDH6 antibody is an antibody comprising a heavy chain consisting of the amino acid sequence set forth in amino acid numbers 20 to 471 of SEQ ID NO: 16 and a light chain consisting of the amino acid sequence set forth in amino acid numbers 21 to 233 of SEQ ID NO: 17. [A81] A method for producing [A79] or [A80], in which the lysine residue at the carboxyl terminus of the heavy chain of the anti-CDH6 antibody is deleted. [A82] The method of any one of [A7] to [A61], wherein the average number of drug linkers bound per antibody in the antibody-drug conjugate is in the range of 3 to 4. [A83] The method for producing any one of [A7] to [A61] and [A82], wherein the average number of drug linkers bound per antibody in the antibody-drug conjugate is in the range of 3.5 to 4. [A84] The method for producing any one of [A7] to [A61], [A82] and [A83], wherein the antibody is an anti-TROP2 antibody. [A85] A method for producing [A84], wherein the anti-TROP2 antibody is an antibody comprising a heavy chain consisting of the amino acid sequence set forth in amino acid numbers 20 to 470 of SEQ ID NO: 10 and a light chain consisting of the amino acid sequence set forth in amino acid numbers 21 to 234 of SEQ ID NO: 11. [A86] A method for producing [A84] or [A85], in which the lysine residue at the carboxyl terminus of the heavy chain of the anti-TROP2 antibody is deleted. [A87] The method for producing any one of [A7] to [A61], [A82] and [A83], wherein the antibody is an anti-B7-H3 antibody. [A88] A method for producing [A87], wherein the anti-B7-H3 antibody is an antibody comprising a heavy chain consisting of the amino acid sequence set forth in amino acid numbers 20 to 471 of SEQ ID NO: 14 and a light chain consisting of the amino acid sequence set forth in amino acid numbers 21 to 233 of SEQ ID NO: 15. [A89] A method for producing [A87] or [A88], in which the lysine residue at the carboxyl terminus of the heavy chain of the anti-B7-H3 antibody is deleted. [A90] A method for producing any one of [A7] to [A89], characterized in that it does not include a purification step by chromatography. [A91] The production method of [A90], wherein the chromatography is at least one selected from the group consisting of gel filtration chromatography, ion exchange chromatography, hydrophobic interaction chromatography, and affinity chromatography. [A92] Formula (1) (wherein A represents the binding site to the antibody) and an antibody via a thioether bond, (ii) reducing the antibody with tris(2-carboxyethyl)phosphine hydrochloride in the presence of ethylenediaminetetraacetic acid in an aqueous solution of L-histidine with or without polysorbate 20 or polysorbate 80; (iii) Formula (2) reacting 8.9 to 10.0 equivalents or 4.0 to 6.0 equivalents of a compound represented by the formula: (iv) adding N-acetylcysteine ​​to react with the compound of formula (2) remaining from step (iii); (v) adjusting the pH of the reaction solution to about 5 or about 4.5 using an aqueous solution of acetic acid; (i) A solution containing an antibody-drug conjugate is filtered at about 15° C. by passing it through an activated charcoal filter only once to obtain a compound represented by formula (3). and a compound represented by formula (4) removing the compound represented by (vi) rinsing the activated carbon filter with 8.5 mmol / L L-histidine buffer; The manufacturing method includes, in the above order. [A93] An antibody-drug conjugate is produced by any one of the production methods [A7] to [A92], and further (vii) adding a buffer solution to the solution containing the antibody-drug conjugate; (viii) concentrating the solution containing the antibody-drug conjugate; and (ix) adjusting the solution containing the antibody-drug conjugate to a predetermined pH; At least one step selected from the group consisting of: and, (x) adding an excipient to the solution containing the antibody-drug conjugate; By carrying out a process including A method for making a pharmaceutical composition comprising an antibody-drug conjugate, a buffer, and an excipient. [A94] The method for producing [A93], wherein the buffer solution is a histidine buffer solution. [A95] The method for producing [A93] or [A94], wherein the excipient is sucrose. [A96] The method for producing [A93] or [A94], wherein the excipient is trehalose. [A97] A pharmaceutical composition comprising an antibody-drug conjugate, a buffer solution, and an excipient is produced by any one of the production methods of [A93] to [A96], and further comprising: (xi) adding a surfactant to the pharmaceutical composition; By carrying out a process including A method for making a pharmaceutical composition comprising an antibody-drug conjugate, a buffer, an excipient, and a surfactant. [A98] The method for producing [A97], wherein the surfactant is polysorbate 80. [A99] The method for producing [A97], wherein the surfactant is polysorbate 20. [A100] The method for producing any one of [A93] to [A99], wherein the pharmaceutical composition contains 0.3% or less of a by-product derived from compound (2). [A101] 10-10000 m for removing by-products derived from exatecan compound 2 3. An activated carbon material comprising an activated carbon having a surface area of ​​1 / g. [A102] An activated carbon material according to [A101], wherein the activated carbon contained therein has an average particle size of 2 μm or more. [A103] An activated carbon material according to [A101] or [A102], in which at least 90% by weight of the activated carbon contained therein has an average particle size of 5 to 40 μm. The purification step using an activated carbon material included in the production method of the present invention can efficiently remove by-products derived from the highly active exatecan compound derived from the exatecan derivative of DXd-ADC. According to the purification step included in the production method of the present invention, a part of the antibody-drug conjugate of interest may be adsorbed on the activated carbon, but it is possible to recover the antibody-drug conjugate without elution of by-products derived from the exatecan compound from the activated carbon by rinsing with a buffer solution. In addition, the purification step included in the production method of the present invention can reduce the amount of waste liquid containing highly active impurities compared to existing purification methods. Furthermore, the present invention can provide an efficient production method for antibody-drug conjugates and pharmaceutical compositions containing antibody-drug conjugates. According to the purification step included in the production method of the present invention, low molecular weight impurities can be removed. FIG. 1 shows the concentration of by-products derived from compound (2) and the protein recovery rate when an activated carbon filter is used and when an activated carbon filter is not used in the filtration process of a reaction solution containing an anti-GPR20 antibody-drug conjugate. FIG. 1 shows the concentration of by-products derived from compound (2) and the protein recovery rate when the reaction solution containing an anti-GPR20 antibody-drug conjugate is passed through an activated carbon filter at liquid temperatures of 0° C. and 30° C. in the filtration process of a reaction solution containing an anti-GPR20 antibody-drug conjugate. FIG. 1 shows the concentration of by-products derived from compound (2) and the protein recovery rate when the reaction solution containing an anti-GPR20 antibody-drug conjugate is passed through an activated carbon filter at pH 4.0 and 6.0 in the filtration process of a reaction solution containing an anti-GPR20 antibody-drug conjugate. FIG. 1 shows the concentration of by-products derived from compound (2) and the protein recovery rate when the reaction solution containing an anti-GPR20 antibody-drug conjugate is passed through an activated carbon filter at a high concentration. FIG. 1 shows the concentration of by-products derived from compound (2) and the protein recovery rate when an activated carbon filter is passed through an acetate buffer solution and a phosphate buffer solution in the filtration process of a reaction solution containing an anti-GPR20 antibody-drug conjugate. FIG. 2 shows the concentration of by-products derived from compound (2) and the protein recovery rate in the presence or absence of an additive (polysorbate 20) in the filtration process of a reaction solution containing an anti-GPR20 antibody-drug conjugate. FIG. 3 shows the concentration of by-products derived from compound (2) and the protein recovery rate when an activated carbon filter is rinsed with a buffer solution in the filtration process of a reaction solution containing an anti-GPR20 antibody-drug conjugate. FIG. 4 shows the amino acid sequence (SEQ ID NO: 1) of an anti-GPR20 antibody heavy chain (h046-H4e). FIG. 5 shows the amino acid sequence (SEQ ID NO: 2) of an anti-GPR20 antibody light chain (h046-L7). FIG. 6 shows the amino acid sequence (SEQ ID NO: 3) of an anti-CD37 antibody heavy chain (hmAb-H541). FIG. 1 shows the amino acid sequence (SEQ ID NO: 4) of an anti-CD37 antibody light chain (hmAb-L11). FIG. 2 shows the amino acid sequence (SEQ ID NO: 5) of an anti-MUC1 antibody heavy chain (N54Q). FIG. 3 shows the amino acid sequence (SEQ ID NO: 6) of an anti-MUC1 antibody heavy chain (PankoMab). FIG. 4 shows the amino acid sequence (SEQ ID NO: 7) of an anti-MUC1 antibody light chain (N54Q and PankoMab). FIG. 5 shows the amino acid sequence (SEQ ID NO: 8) of an anti-HER2 antibody heavy chain.FIG. 1 shows the amino acid sequence of an anti-HER2 antibody light chain (SEQ ID NO: 9). FIG. 2 shows the amino acid sequence of an anti-TROP2 antibody heavy chain (hTINA1-H1) (SEQ ID NO: 10). FIG. 3 shows the amino acid sequence of an anti-TROP2 antibody light chain (hTINA1-L1) (SEQ ID NO: 11). FIG. 4 shows the amino acid sequence of an anti-HER3 antibody heavy chain (SEQ ID NO: 12). FIG. 5 shows the amino acid sequence of an anti-HER3 antibody light chain (SEQ ID NO: 13). FIG. 6 shows the amino acid sequence of an anti-B7-H3 antibody heavy chain (M30-H1) (SEQ ID NO: 14). FIG. 7 shows the amino acid sequence of an anti-B7-H3 antibody light chain (M30-L4) (SEQ ID NO: 15). FIG. 8 shows the amino acid sequence of an anti-CDH6 antibody heavy chain (hH01) (SEQ ID NO: 16). FIG. 9 shows the amino acid sequence of an anti-CDH6 antibody light chain (hL02) (SEQ ID NO: 17). This figure shows the by-product concentration and protein recovery rate derived from compound (2) when the activated carbon filter was rinsed with a buffer solution in the filtration process of a reaction solution containing an anti-CD37 antibody-drug conjugate. This figure shows the by-product concentration and protein recovery rate derived from compound (2) when the activated carbon filter was rinsed with a buffer solution in the filtration process of a reaction solution containing an anti-MUC1 antibody-drug conjugate. This figure shows the by-product concentration and protein recovery rate derived from compound (2) when the activated carbon filter was washed with 15 mL of an aqueous polysorbate 80 solution before use in the filtration process of a reaction solution containing an anti-CD37 antibody-drug conjugate. This figure shows the by-product concentration and protein recovery rate derived from compound (2) when the activated carbon filter was washed with 40 mL of an aqueous polysorbate 80 solution before use in the filtration process of a reaction solution containing an anti-CD37 antibody-drug conjugate. 1. Definition Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by a person of ordinary skill in the art to which the present invention belongs. In this specification, the terms and phrases defined below are to be interpreted as defined. As used herein, the term "antibody" refers to a monoclonal antibody, a polyclonal antibody, a chimeric antibody, a humanized antibody, a human antibody, a multispecific antibody (including a bispecific antibody) formed from at least two intact antibodies, an Fc fusion protein, and a functional fragment of an antibody exhibiting biological activity. As used herein, the term "monoclonal antibody" refers to an antibody that is derived from a single clone, including any eukaryotic, prokaryotic, or phage clone, and is not limited to antibodies produced through hybridoma technology. As used herein, the term "functional antibody fragment" refers to an antibody fragment that exhibits at least a part of the function exhibited by the original antibody. Examples of "functional antibody fragments" include, but are not limited to, Fab, F(ab')2, scFv, Fab', single-chain immunoglobulin, and the like. Such antibody functional fragments may be those obtained by treating a full-length antibody protein molecule with an enzyme such as papain or pepsin, as well as recombinant proteins produced in suitable host cells using recombinant genes. Among "functional antibody fragments", those that have binding activity to antigens are referred to as "antigen-binding antibody fragments". As used herein, the term "antibody-drug conjugate" refers to a complex of an antibody and a drug, typically a complex in which a drug is linked to an antibody via a linker. The drug is not particularly limited, but a drug having cytotoxic activity (e.g., exatecan, described below, etc.) is typically used. The linker may contain a cleavable unit, and examples of the cleavable unit include a disulfide-containing linker that can be cleaved by disulfide exchange, an acid-labile linker that can be cleaved at acidic pH, and a linker that can be cleaved by hydrolase, esterase, peptidase, or glucoronidase (e.g., a peptide linker, a glucoronide linker), etc. In the present specification, "exatecan" refers to a topoisomerase I inhibitor represented by the IUPAC name: (1S,9S)-1-amino-9-ethyl-5-fluoro-1,2,3,9,12,15-hexahydro-9-hydroxy-4-methyl-10H,13H-benzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinoline-10,13-dione, and the chemical name: (1S,9S)-1-amino-9-ethyl-5-fluoro-2,3-dihydro-9-hydroxy-4-methyl-1H,12H-benzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinoline-10,13(9H,15H)-dione. Exatecan is represented by the following formula (5): It is a camptothecin derivative having an antitumor effect, represented by the following formula: As used herein, a "by-product derived from an exatecan compound" refers to a by-product containing at least the exatecan structure that is generated during the process of producing an antibody-drug conjugate having an antibody and an exatecan derivative as components. In the present specification, the term "by-product derived from compound (2)" refers to a by-product represented by the following formula (2): (hereinafter also referred to as "compound (2)"), for example, a by-product derived from a compound represented by the following formula (3): and a compound represented by the following formula (4): Examples of the by-products derived from compound (2) include, but are not limited to, dimers, trimers, and multimers of trimers or more in which compound (2) is bound intermolecularly, adducts of other molecules (e.g., N-hydroxysuccinimide) to the maleimide moiety of compound (2), oxidized forms of compound (2), reduced forms of compound (2), and linkers in which the exatecan moiety is cleaved at the hemiaminal moiety. The by-products derived from compound (2) contain highly active exatecan derivatives in their structures, and are therefore one of the important control items in the production of antibody-drug conjugates. The purification step included in the production method of the present invention can remove host cell-derived impurities (host cell proteins; HCPs) such as proteins and DNA, target substance-derived impurities (aggregates, related substances, etc.), and virus-like particles present in the culture supernatant of an antibody produced by a production system using cells as hosts, in the same manner as the by-products derived from compound (2). In addition, in this specification, "by-products derived from compound (2)" are included in "by-products derived from the exatecan compound." As used herein, "small molecule impurities" include tris(2-carboxyethyl)phosphine (hereinafter also referred to as "TCEP") and N-acetylcysteine ​​(hereinafter also referred to as "NAC"). As used herein, "activated carbon material" refers to any substance composed of or containing carbon, including activated carbon. As used herein, "activated carbon" or "activated charcoal" refers to a carbonaceous material that has been treated to enhance its pore structure. Activated carbons are porous solids with very high surface areas. They can be obtained from a variety of sources, including coal, wood, coconut shells, nut shells, and peat. Activated carbons can be produced from these materials using physical activation involving heating in a controlled environment or chemical activation using strong acids, bases, or oxidizing agents. The activation method creates a porous structure with a high surface area that gives the activated carbon a high impurity clearance capacity. In contrast to most other adsorbent materials, activated carbon is believed to interact with molecules using relatively weak van der Waals forces. The activated carbons used in the purification process of the present invention may be one type of activated carbon alone or two or more types of activated carbons alone or in mixtures. In this specification, the term "activated carbon filter" refers to a filter containing an activated carbon material. In the narrow sense, it refers to a depth filter that is filled with an activated carbon material in advance and formed as an integral part. In the broad sense, it also includes a case where the activated carbon is not integrated with a filter, such as when the activated carbon is suspended in a mixed liquid (hereinafter also referred to as a "process liquid") containing a substance to be removed, and then the activated carbon material is removed using a filter. The filter used in this case is not particularly limited, and examples thereof include a depth filter, a Celite filtration filter, a centrifugal filtration filter, and the like. In this specification, the term "activated carbon filter" is used in both the narrow sense and the broad sense. As used herein, "depth filter" refers to a series of serially arranged filters with decreasing pore size used to remove particles from a solution containing antibody-drug conjugates. The three-dimensional matrix of a depth filter forms a labyrinth-like path through which a solution containing antibody-drug conjugates passes, adsorbing and mechanically trapping particles randomly throughout the depth of the matrix. Various depth filters are constructed from activated charcoal, rolled cotton, polypropylene, rayon cellulose, glass fiber, sintered metal, porcelain, diatomaceous earth, or other known components. In this specification, the term "buffer" refers to a solution in which the change in pH caused by the addition or release of an acidic or basic substance is leveled by the dissolved buffer substance. Any buffer substance having such properties can be used. In general, a pharma- ceutical acceptable buffer substance is used. The buffer used in the present invention is not particularly limited, and examples thereof include a phosphate buffer consisting of phosphoric acid and / or its salts, an acetate buffer consisting of acetic acid and its salts, a histidine buffer consisting of histidine and / or its salts, a citric acid buffer consisting of citric acid and / or its salts, a morpholine buffer, a 2-(N-morpholino)ethanesulfonic acid buffer, a glycine buffer, a tris(hydroxymethyl)aminomethane (TRIS) buffer, a piperazine-1,4-bis(2-ethanesulfonic acid) (hereinafter also referred to as "PIPES") buffer, a 4-(2-hydroxyethyl)-1-piperazine ethanesulfonic acid (hereinafter also referred to as "HEPES") buffer, and the like. Buffers used in the present invention may optionally contain additional salts, such as sodium chloride, sodium sulfate, potassium chloride, potassium sulfate, sodium citrate, potassium citrate, and the like. In the present specification, the term "chelating agent" refers to a bidentate or multidentate ligand having at least two groups that can bind to a metal ion (preferably a divalent or polyvalent metal ion). Examples of groups that can bind to a metal ion include a carboxy group, a hydroxy group, and an amino group. The chelating agent used in the present invention is not particularly limited and can be appropriately selected from chelating agents commonly used by those skilled in the art. Examples of the chelating agent include EDTA (ethylenediaminetetraacetic acid), DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid), HEDTA (N-(2-hydroxyethyl)ethylenediamine-N,N',N'-triacetic acid), DHEDDA (dihydroxyethylethylenediaminediacetic acid), 1,3-PDTA (1,3-propanediaminetetraacetic acid), DTPA (diethylenediaminetetraacetic acid), and the like. Examples of such iminodisulfonate include nitrilotriacetic acid (TTHA), triethylenetetramine-N,N,N',N'',N-hydroxy'''-hexaacetic acid (TTHA), nitrilotriacetic acid (NTA), gluconic acid, HIMDA (hydroxyethyliminodiacetic acid), ASDA (L-aspartic acid diacetic acid), NTMP (nitrilotrismethylenephosphonic acid), HEDP (1-hydroxyethylidene-1,1-diphosphonic acid), 3-hydroxy-2,2'-iminodisuccinic acid tetrasodium, phenanthroline, porphyrin, and crown ether. In this specification, the term "surfactant" refers to a substance that has a hydrophilic group and a hydrophobic group and is used as one of the components of a pharmaceutical preparation. The surfactant used in the present invention is not particularly limited, but examples thereof include polysorbates (including polysorbate 80 (Tween 80 (registered trademark)), polysorbate 20 (Tween 20 (registered trademark)), and polysorbate 60 (Tween 60 (registered trademark))), polyoxyethylene (160) polyoxypropylene (30) glycol, polyoxyethylene hydrogenated castor oil 60, polyoxyethylene castor oil, sodium lauryl sulfate, polyoxyethylene-sorbitan fatty acid ester, polyethylene-polypropylene glycol, polyoxyethylene-stearic acid, polyoxyethylene alkyl ethers (e.g., polyoxyethylene monolauryl ether, alkylphenyl polyoxy-ethylene ether (Triton-X), polyoxyethylene-polyoxypropylene copolymers (poloxamer, Pluronic (registered trademark)), and sodium dodecyl sulfate (SDS)). In this specification, "gel filtration chromatography" refers to a liquid chromatography technique in which a column is filled with a porous gel, and components contained therein are separated by the molecular weight difference of the molecules due to the molecular sieve effect. Gel filtration chromatography is not only used for precise separation of biological components such as proteins, peptides, nucleic acids, and polysaccharides, but is also widely used for molecular weight measurement. Gel filtration chromatography is also used for desalting and buffer exchange of samples for ion exchange chromatography, and in some manufacturing applications, for preparing components of final purified products. In principle, separation is possible if the sample is in a solution state and there is a difference in the molecular size of the components to be separated, and a major feature of this technique is that it has a wider range of sample application than other liquid chromatography techniques. As used herein, "ion exchange chromatography" refers to a method of separating components that utilizes the difference in charge state (electrostatic interaction) in the mobile phase / sample relative to the stationary phase in a column, and is primarily used for the analysis of ionic compounds. There are two types of ion exchange chromatography: anion exchange chromatography and cation exchange chromatography, and the stationary phase used varies depending on the ionic strength of the ion exchange group. As used herein, the terms "cation exchange material" or "CEX (;Cation EXchange) material" are used interchangeably to refer to a solid phase that is negatively charged and thus has free cations for exchange with cations in an aqueous solution that has passed over or through the solid phase. As used herein, the terms "anion exchange material" or "AEX (;Anion EXchange) material" are used interchangeably to refer to a positively charged solid phase that has one or more positively charged ligands, such as primary, secondary, tertiary, or quaternary amino groups, bound to the solid phase. Strong ion exchange functional groups are always ionized, while weak ion exchange functional groups change the dissociation state of ions depending on the pH of the mobile phase. The type of stationary phase can be selected according to the charge and characteristics of the target components to be analyzed. Examples of stationary phases for cation exchange chromatography include sulfonic acid as a strong ion exchange functional group and carboxylic acid as a weak ion exchange functional group. Examples of stationary phases for anion exchange chromatography include quaternary ammonium as a strong ion exchange functional group and tertiary amine as a weak ion exchange functional group. As used herein, "hydrophobic interaction chromatography" or "HIC" refers to a process for separating molecules based on their hydrophobicity, i.e., their ability to adsorb to hydrophobic surfaces from an aqueous solution. Hydrophobic interaction chromatography typically relies on differences in hydrophobic groups on the surface of solute molecules. These hydrophobic groups have a tendency to bind to hydrophobic groups on the surface of an insoluble matrix. HIC uses a more polar, less denaturing environment than reversed-phase liquid chromatography and is therefore commonly used in antibody purification, often in combination with ion exchange or gel filtration chromatography. As used herein, "affinity chromatography" refers to a protein separation technique in which a target protein (e.g., an antibody or a protein containing an Fc region of interest) is specifically bound to a ligand specific for the target protein. In the case of purifying antibodies, such a ligand is Protein A or Protein G, or a functional variant thereof, which is covalently attached to a chromatographic solid phase material and binds to antibodies in solution when the antibody solution contacts the chromatographic solid phase material. In this specification, the term "excipient" refers to a substance added to make a pharmaceutical product have a certain size or concentration in order to improve the convenience of molding, handling, and administration, etc. Such excipients are not particularly limited as long as they exhibit the effects of the present invention, and examples thereof include sucrose, trehalose, sorbitol, etc. As used herein, "removal," "reduction," and "clearance" are used interchangeably and refer to lowering the amount of one or more impurities in a sample containing the antibody-drug conjugate to be purified. As used herein, "purify" or "remove impurities" are used interchangeably and refer to reducing by removing one or more impurities from a sample, for example, reducing the impurities contained in a sample to 1 μM or less, 0.5 μM or less, 0.25 μM or less, or 0.1 μM or less. As used herein, the term "purification step" refers to a step of purifying a sample or a step of removing impurities from a sample. That is, the term "purification step" refers to a step of reducing one or more impurities by removing them from a sample, for example, a step of reducing the impurities contained in a sample to 1 μM or less, 0.5 μM or less, 0.25 μM or less, or 0.1 μM or less. In this specification, "irreversible adsorption" means that a solute is irreversibly adsorbed to activated carbon. "Irreversibly" means that a solute once adsorbed cannot be easily dissociated from activated carbon. In this specification, "reversible adsorption" means that a solute is reversibly adsorbed to activated carbon. "Reversibly" means that a solute once adsorbed can be dissociated and adsorbed from activated carbon. "Irreversible adsorption" and "reversible adsorption" are not absolute phenomena between activated carbon and solute, but are relative phenomena that depend on the affinity (solvation power) between the eluent and the solute for the adsorption of the activated carbon and the solute. That is, when rinsing activated carbon with a certain eluent, the solute may be irreversibly adsorbed without being eluted, and even if the same activated carbon and solute are used, when rinsing activated carbon with a different eluent, the solute may be eluted and reversibly adsorbed. As used herein, a method of manufacture, pharmaceutical composition, etc., that "comprises" one or more recited elements may include other unrecited elements. As used herein, numerical ranges (eg, "X to Y") include the beginning and end points defining the range, as well as all values ​​subsumed within the range. As used herein, "about" refers to values ​​that vary by plus or minus 10%, 8%, 6%, 5%, 4%, 3%, 2%, or 1%, respectively, from the reference value. Preferably, "about" refers to a range of plus or minus 10%, 5%, or 1%, respectively, from the reference value. 2. Antibody-drug conjugates The antibody-drug conjugate produced by the present invention is not particularly limited. For example, the antibody-drug conjugate in which the drug is a topoisomerase I inhibitor, the drug represented by the following formula: an antibody-drug conjugate that exerts antitumor activity by releasing an antitumor compound represented by the following formula: and antibody-drug conjugates in which an antitumor compound is bound to an antibody via a linker at the nitrogen atom of the amino group at position 1 of the antibody as the binding site; antibody-drug conjugates in which an antitumor compound is bound to an antibody via a linker via a thioether bond formed at a disulfide bond present in the antibody; and antibody-drug conjugates in which the linker comprises a tetrapeptide residue of -Gly-Gly-Phe-Gly-. Preferred antibody-drug conjugates produced according to the present invention include The following formula (1) (wherein A represents the binding site to the antibody) The antibody-drug conjugate is an antibody-drug conjugate in which a drug linker represented by the formula: In the present invention, a partial structure of an antibody-drug conjugate consisting of a linker and a drug is referred to as a “drug linker.” This drug linker is bonded to a thiol group (in other words, a sulfur atom of a cysteine ​​residue) generated at the interchain disulfide bond site (two sites between heavy chains and two sites between heavy chains and light chains) of the antibody. The drug linker of the antibody-drug conjugates produced by the present invention is comprised of the topoisomerase I inhibitor exatecan. The following formula (5) It is a camptothecin derivative having an antitumor effect, represented by the following formula: The antibody-drug conjugate produced by the present invention comprises: The following formula (6) It can also be expressed as: Here, the drug linker is bound to the antibody via a thioether bond, and n is synonymous with the so-called average drug binding number (DAR; Drug-to-Antibody Ratio), and indicates the average number of drug linkers bound per antibody. In one embodiment, the number of drugs or attached drug linkers per antibody molecule in the antibody-drug conjugate produced in the present invention is preferably an integer in the range of 2 to 8, more preferably 2, 4, 6 or 8, and even more preferably 4 or 8. The antibody-drug conjugate produced by the present invention is transported into cancer cells and then reacts with the antibody-drug conjugate represented by the following formula (7): This liberates a compound represented by the formula: The compound represented by formula (7) is considered to be the main component of the antitumor activity of the antibody-drug conjugate produced by the present invention, and has been confirmed to have a topoisomerase I inhibitory effect (Ogitani Y. et al., Clinical Cancer Research, 2016, Oct. 15; 22(20): 5097-5108, Epub. 2016 Mar. 29). The compound represented by formula (7) is, for example, a compound represented by the following formula (8), which is believed to be generated by cleavage of the linker portion of the antibody-drug conjugate produced by the present invention. This is believed to occur due to decomposition of the aminal structure of the compound represented by the following formula: The antibody-drug conjugate produced by the present invention is also known to have a bystander effect (Ogitani Y. et al., Cancer Science (2016) 107, 1039-1046). This bystander effect is exerted when the antibody-drug conjugate produced by the present invention is internalized into a target-expressing cancer cell, and the compound represented by formula (7) is released, exerting an antitumor effect on nearby cancer cells that do not express the target. In certain embodiments of the present invention, the antibody-drug conjugates produced by the present invention include, for example, the antibody-pyrrolobenzodiazepine derivative conjugates described in WO 2019 / 065964, U.S. Patent Publication No. 2020 / 0261594, WO 2020 / 196474 or U.S. Patent Publication No. 2022 / 0168440 (the disclosures of which are incorporated by reference herein) or the antibody-cyclic dinucleotide derivative conjugates described in WO 2020 / 050406, U.S. Patent Publication No. 2022 / 0008549, WO 2021 / 177438 or U.S. Patent Publication No. 2023 / 0330248 (the disclosures of which are incorporated by reference herein). In certain embodiments of the present invention, the antibody-drug conjugates produced by the present invention include, for example, the antibody-drug conjugates described in WO 2014 / 057687 or U.S. Patent Publication No. 2015 / 0297748 (the disclosures of which are incorporated herein by reference), and preferably have the following structure as the drug-linker structural moiety attached to the antibody: -(Succinimid-3-yl-N)-CH2CH2CH2CH2CH2-C(=O)-GGFG-NH-CH2-O-CH2-C(=O)-(NH-DX), -(Succinimid-3-yl-N)-CH2CH2CH2CH2CH2-C(=O)-GGFG-NH-CH2CH2-O-CH2-C(=O)-(NH-DX), -(Succinimid-3-yl-N)-CH2CH2-C(=O)-NH-CH2CH2O-CH2CH2O-CH2CH2-C(=O)-GGFG-NH-CH2CH2CH2-C(=O)-(NH-DX). Here, -(Succinimid-3-yl-N)- is represented by the following formula: The structure is represented by the formula: GGFG represents an amino acid sequence linked by peptide bonds consisting of glycine-glycine-phenylalanine-glycine; -(NH-DX) is a compound of the formula: In this case, the nitrogen atom of the amino group at position 1 serves as the bonding site. 3. Antibodies used in the preparation of antibody-drug conjugates The antibody used in the production of the antibody-drug conjugate of the present invention may be derived from any species, but is preferably derived from human, rat, mouse, or rabbit. When the antibody is derived from a species other than human, it is preferably chimerized or humanized using well-known techniques. The antibody of the present invention may be a polyclonal or monoclonal antibody, but is preferably a monoclonal antibody. The antibody used for producing the antibody-drug conjugate of the present invention preferably has the property of targeting cancer cells, and preferably has the property of recognizing cancer cells, the property of binding to cancer cells, the property of being taken up and internalized within cancer cells, and / or cytocidal activity against cancer cells. The binding of the antibody to the cancer cells can be confirmed by flow cytometry. The uptake of the antibody into the cancer cells can be confirmed by (1) an assay in which the antibody taken up into the cells is visualized by a fluorescence microscope using a secondary antibody (fluorescently labeled) that binds to the therapeutic antibody (Cell Death and Differentiation (2008) 15, 751-761), (2) an assay in which the amount of fluorescence taken up into the cells is measured using a secondary antibody (fluorescently labeled) that binds to the therapeutic antibody (Molecular Biology of the Cell Vol. 15, 5268-5282, December 2004), or (3) a Mab-ZAP assay in which an immunotoxin that binds to the therapeutic antibody is released when the antibody is taken up into the cells, thereby suppressing cell proliferation (Bio Techniques 28: 162-165, January 2000). A recombinant complex protein of the catalytic domain of diphtheria toxin and protein G can also be used as the immunotoxin. The antitumor activity of an antibody can be confirmed in vitro by measuring the inhibitory activity against cell proliferation. For example, a cancer cell line that overexpresses the antibody's target protein is cultured, and the antibody is added to the culture system at various concentrations to measure the inhibitory activity against focus formation, colony formation, and spheroid proliferation. In vivo, the antitumor activity can be confirmed, for example, by administering the antibody to nude mice transplanted with a cancer cell line that highly expresses the target protein, and measuring the changes in the cancer cells. Although it is preferable that the antibody itself has an antitumor effect, since the antibody-drug conjugate is bound to a compound that exerts an antitumor effect, the antibody itself does not necessarily have an antitumor effect. For the purpose of exerting the cytotoxicity of the antitumor compound specifically and selectively in cancer cells, it is important and preferable that the antibody has the property of being internalized and transferred into the cancer cells. The antibody used for producing the antibody-drug conjugate of the present invention can be obtained by known means. For example, it can be obtained by immunizing an animal with an antigenic polypeptide, and collecting and purifying the antibody produced in the body, using a method commonly used in this field. The origin of the antigen is not limited to humans, and an animal can also be immunized with an antigen derived from an animal other than a human, such as a mouse or a rat. In this case, an antibody applicable to a human disease can be selected by testing the cross-reactivity of the obtained antibody that binds to a heterologous antigen with a human antigen. Alternatively, a hybridoma can be established by fusing an antibody-producing cell that produces an antibody against an antigen with a myeloma cell according to known methods (e.g., Kohler and Milstein, Nature (1975) 256, p. 495-497; Kennet, R. ed., Monoclonal Antibodies, p. 365-367, Plenum Press, NY (1980)), thereby obtaining a monoclonal antibody. The antigen can be obtained by genetically engineering a gene encoding an antigen protein in a host cell to produce it. Specifically, a vector capable of expressing an antigen gene is prepared, introduced into a host cell to express the gene, and the expressed antigen is purified. Antibodies can also be obtained by immunizing an animal with the above genetically engineered antigen-expressing cells or a cell line expressing the antigen. The antibody used in the production of the antibody-drug conjugate of the present invention is preferably a genetically engineered antibody that has been artificially modified for the purpose of reducing heterologous antigenicity to humans, such as a chimeric antibody or a humanized antibody, or is preferably an antibody having only the genetic sequence of an antibody derived from humans, i.e., a human antibody. These antibodies can be produced using known methods. Chimeric antibodies include antibodies whose variable and constant regions are heterologous, for example, chimeric antibodies in which the variable region of a mouse or rat-derived antibody is joined to a constant region of human origin (Proc. Natl. Acad. Sci. USA, 81, 6851-6855, (1984)). Examples of humanized antibodies include antibodies in which only the complementarity determining region (CDR) of a heterologous antibody has been incorporated into an antibody of human origin (Nature (1986) 321, p. 522-525), antibodies in which not only the CDR sequence of a heterologous antibody but also some framework amino acid residues of the heterologous antibody have been grafted onto a human antibody by CDR grafting (WO 90 / 07861), and antibodies humanized using a gene conversion mutagenesis strategy (U.S. Pat. No. 5,821,337). Examples of human antibodies include antibodies produced using human antibody-producing mice having a human chromosome fragment containing the heavy and light chain genes of a human antibody (see, for example, Tomizuka, K. et al., Nature Genetics (1997) 16, p. 133-143; Kuroiwa, Y. et al., Nucl. Acids Res. (1998) 26, p. 3447-3448; Yoshida, H. et al., Animal Cell Technology: Basic and Applied Aspects vol. 10, p. 69-73 (Kitagawa, Y., Matsuda, T. and Iijima, S. eds.), Kluwer Academic Publishers, 1999; Tomizuka, K. et al., Proc. Natl. Acad. Sci. USA (2000) 97, p. 722-727). Alternatively, antibodies obtained by phage display selected from a human antibody library can also be used (see Wormstone, IM et al., Investigative Ophthalmology & Visual Science. (2002) 43 (7), p. 2301-2308; Carmen, S. et al., Briefings in Functional Genomics and Proteomics (2002), 1(2), p. 189-203; Siriwardena, D. et al., Ophthalmology (2002) 109(3), p. 427-431, etc.). The antibody used in the production of the antibody-drug conjugate of the present invention also includes modified antibodies. The modified antibody means an antibody according to the present invention that has been chemically or biologically modified. Chemical modifications include those having a chemical moiety bonded to the amino acid backbone, or a chemical moiety bonded to an N- or O-linked carbohydrate chain. Biological modifications include those that have been post-translationally modified (e.g., addition of an N- or O-linked sugar chain, processing of the N-terminus or C-terminus, deamidation, isomerization of aspartic acid, oxidation of methionine, etc.), and those that have been expressed using a prokaryotic host cell to add a methionine residue to the N-terminus. In addition, those labeled to enable detection or isolation of the antibody or antigen according to the present invention, such as enzyme-labeled, fluorescent-labeled, and affinity-labeled, are also included in the meaning of such modified antibodies. Such modified antibodies according to the present invention are useful for improving the stability and blood retention of the antibody, reducing antigenicity, and detecting or isolating the antibody or antigen, etc. Furthermore, antibody-dependent cellular cytotoxicity can be enhanced by regulating the sugar chain modification bound to the antibody of the present invention (glycosylation, defucosylation, etc.). Techniques for regulating the sugar chain modification of antibodies are known, including, but not limited to, those disclosed in International Publication Nos. 99 / 54342, 00 / 61739, and 02 / 31140. The antibody of the present invention also includes an antibody in which the sugar chain modification has been regulated. It is known that antibodies produced in cultured mammalian cells have a deletion of the lysine residue at the carboxyl terminus of their heavy chains (Journal of Chromatography A, 705: 129-134 (1995)), and also have two amino acid residues, glycine and lysine, deleted from the carboxyl terminus of the heavy chain, and amidated proline residues located at the carboxyl terminus (Analytical Biochemistry, 360: 75-83 (2007)). However, these deletions and modifications of the heavy chain sequence do not affect the antigen-binding ability and effector functions (complement activation, antibody-dependent cellular cytotoxicity, etc.) of the antibody. Thus, the antibody according to the present invention also includes modified antibodies and functional fragments of the antibodies, including deletions in which one or two amino acids are deleted from the carboxyl terminus of the heavy chain, and amidated deletions (for example, heavy chains in which the proline residue at the carboxyl terminus is amidated). However, as long as the antigen-binding ability and effector function are maintained, the deletion of the carboxyl terminus of the heavy chain of the antibody according to the present invention is not limited to the above types. The two heavy chains constituting the antibody according to the present invention may be any one type of heavy chain selected from the group consisting of full-length and the above deletions, or may be a combination of any two types. The quantitative ratio of each deletion may be influenced by the type and culture conditions of the cultured mammalian cells producing the antibody according to the present invention, but the antibody according to the present invention is preferably one in which one amino acid residue is deleted at the carboxyl terminus of both of the two heavy chains. Examples of the isotype of the antibody according to the present invention include IgG (IgG1, IgG2, IgG3, IgG4), and preferably IgG1 or IgG2. When IgG1 is used as the isotype of the antibody according to the present invention, the IgG1 antibody may have a mutation, and the effector function can be adjusted by substituting a part of the amino acid residues in the constant region (see WO88 / 007089, WO94 / 28027, WO94 / 29351). Examples of IgG1 mutants with reduced effector function include IgG1 LALA mutation (IgG1-L234A, L235A), IgG1 LALA-PA mutation (IgG1-L234A, L235A, P329A), and the like. The L234A, L235A, and P329A indicate substitutions of leucine at positions 234 and 235 with alanine, and substitution of proline at position 329 with alanine, respectively, as specified by the EU index (Proceedings of the National Academy of Sciences of the United States of America, Vol. 63, No. 1 (May 15, 1969), pp. 78-85). The antibody in the antibody-drug conjugate used in the present invention is not particularly limited, and examples thereof include an anti-HER2 antibody, an anti-TROP2 antibody, an anti-HER3 antibody, an anti-B7-H3 antibody, an anti-GPR20 antibody, an anti-CDH6 antibody, an anti-MUC1 antibody, an anti-CD37 antibody, an anti-CD3 antibody, an anti-CD30 antibody, an anti-CD33 antibody, an anti-CD56 antibody, an anti-CD98 antibody, an anti-DR5 antibody, an anti-EGFR antibody, an anti-EPHA2 antibody, an anti-FGFR2 antibody, an anti-FGFR4 antibody, an anti-FOLR1 antibody, an anti-VEGF antibody, an anti-CD20 antibody, an anti-C Examples of antibodies include D22 antibody, anti-CD70 antibody, anti-PSMA antibody, anti-CEA antibody, anti-Mesothelin antibody, anti-A33 antibody, anti-CanAg antibody, anti-Cripto antibody, anti-G250 antibody, anti-GPNMB antibody, anti-Integrin antibody, anti-Tenascin-C antibody, and anti-SLC44A4 antibody, and preferred examples include anti-HER2 antibody, anti-TROP2 antibody, anti-HER3 antibody, anti-B7-H3 antibody, anti-GPR20 antibody, anti-CDH6 antibody, anti-MUC1 antibody, and anti-CD37 antibody. In the present invention, the term "anti-HER2 antibody" refers to an antibody that specifically binds to HER2 (Human Epidermal Growth Factor Receptor Type 2; ErbB-2), and preferably has the activity of being internalized into HER2-expressing cells upon binding to HER2. Examples of anti-HER2 antibodies include trastuzumab (US Pat. No. 5,821,337) and pertuzumab (International Publication No. WO 01 / 00245), with trastuzumab being preferred. In the present invention, the term "anti-TROP2 antibody" refers to an antibody that specifically binds to TROP2 (TACSTD2: Tumor-associated calcium signal transducer 2; EGP-1), and preferably has the activity of being internalized into TROP2-expressing cells by binding to TROP2. An example of an anti-TROP2 antibody is hTINA1-H1L1 (WO 2015 / 098099). In the present invention, the term "anti-HER3 antibody" refers to an antibody that specifically binds to HER3 (Human Epidermal Growth Factor Receptor Type 3; ErbB-3), and preferably has the activity of being internalized into HER3-expressing cells upon binding to HER3. Examples of anti-HER3 antibodies include Patritumab (U3-1287), U1-59 (WO 2007 / 077028), MM-121 (Seribantumab), the anti-ERBB3 antibodies described in WO 2008 / 100624, RG-7116 (Lumretuzumab), and LJM-716 (Elgemtumab), and preferably Patritumab and U1-59. In the present invention, the term "anti-B7-H3 antibody" refers to an antibody that specifically binds to B7-H3 (B cell antigen #7 homolog 3; PD-L3; CD276), and preferably has the activity of being internalized into B7-H3-expressing cells through binding to B7-H3. An example of an anti-B7-H3 antibody is M30-H1-L4 (WO 2014 / 057687). In the present invention, the term "anti-GPR20 antibody" refers to an antibody that specifically binds to GPR20 (G protein-coupled receptor 20), and preferably has the activity of being internalized into GPR20-expressing cells through binding to GPR20. An example of an anti-GPR20 antibody is h046-H4e / L7 (International Publication No. 2018 / 135501). In the present invention, the term "anti-CDH6 antibody" refers to an antibody that specifically binds to CDH6 (Cadherin-6), and preferably has the activity of being internalized into CDH6-expressing cells through binding to CDH6. An example of an anti-CDH6 antibody is H01L02 (International Publication No. 2018 / 212136). In the present invention, the term "anti-MUC1 antibody" refers to an antibody that specifically binds to MUC1, and preferably has the activity of being internalized into MUC1-expressing cells through binding to MUC1. Examples of anti-MUC1 antibodies include PankoMab and PankoMab variant (PM-N54Q) (International Publication No. 2019 / 219891). In the present invention, the term "anti-CD37 antibody" refers to an antibody that specifically binds to CD37, and preferably has the activity of being internalized into CD37-expressing cells through its binding to CD37. An example of an anti-CD37 antibody is hmAb-H541L11 (WO 2023 / 068226). In certain embodiments of the present invention, the antibodies used in the manufacture of the antibody-drug conjugates of the present invention include, for example, those described in WO 2014 / 057687 or U.S. Patent Publication No. 2015 / 0297748 (the disclosures of which are incorporated herein by reference), WO 2019 / 065964, U.S. Patent Publication No. 2020 / 0261594, WO 2020 / 196474 or U.S. Patent Publication No. 2022 / 0168440 (the disclosures of which are incorporated herein by reference), or those described in WO 2020 / 050406, U.S. Patent Publication No. 2022 / 0008549, WO 2021 / 177438 or U.S. Patent Publication No. 2023 / 0330248 (the disclosures of which are incorporated herein by reference). 4. Drug-Linker Intermediates Used in the Preparation of Antibody-Drug Conjugates The drug linker intermediate used in the production of the antibody-drug conjugate of the present invention is not particularly limited, and examples thereof include the drug linker intermediates used in the production of antibody-drug conjugates described in "2. Antibody-drug conjugates", and are preferably compounds represented by the following formula (2): The compound represented by formula (2) can be produced with reference to the descriptions in WO 2014 / 057687, WO 2015 / 098099, WO 2015 / 115091, WO 2015 / 155998, WO 2019 / 044947, and the like. In one embodiment of the present invention, when the antibody-drug conjugate produced by the present invention is an antibody-pyrrolobenzodiazepine derivative conjugate, the drug linker intermediate used in the production of the antibody-drug conjugate of the present invention may be a drug linker described in WO 2019 / 065964, U.S. Patent Publication No. 2020 / 0261594, WO 2020 / 196474 or U.S. Patent Publication No. 2022 / 0168440. These drug linkers can be produced with reference to the descriptions in the publications and the like. In one embodiment of the present invention, when the antibody-drug conjugate produced by the present invention is an antibody-cyclic dinucleotide derivative conjugate, the drug linker intermediate used in the production of the antibody-drug conjugate of the present invention may be a drug linker described in WO 2020 / 050406, U.S. Patent Publication No. 2022 / 0008549, WO 2021 / 177438, or U.S. Patent Publication No. 2023 / 0330248. These drug linkers can be produced with reference to the descriptions in the publications and the like. In one embodiment of the present invention, the drug linker intermediate used in the preparation of the antibody-drug conjugate of the present invention includes the drug linkers described in WO 2014 / 057687 or U.S. Patent Publication No. 2015 / 0297748 (the disclosures of which are incorporated by reference herein), and is preferably a drug-linker having the following structure: (maleimide-N-yl)-CH2CH2CH2CH2CH2-C(=O)-GGFG-NH-CH2-O-CH2-C(=O)-(NH-DX), (maleimide-N-yl)-CH2CH2CH2CH2CH2-C(=O)-GGFG-NH-CH2CH2-O-CH2-C(=O)-(NH-DX), (maleimide-N-yl)-CH2CH2-C(=O)-NH-CH2CH2O-CH2CH2O-CH2CH2-C(=O)-GGFG-NH-CH2CH2CH2-C(=O)-(NH-DX). These drug linkers can be produced by referring to the descriptions in the publication and the like. Here, (maleimide-N-yl)- is represented by the following formula: wherein the nitrogen atom is the bonding site. 5. Conjugation of the antibody and drug-linker intermediate In the production of the antibody-drug conjugate of the present invention, the conjugation of the antibody with the drug linker intermediate is carried out by: (ii) reducing the antibody with a reducing agent; (iii) reacting the compound represented by formula (2) with the antibody reduced in step (ii); (iv) adding a reagent having a thiol group to react with the compound represented by formula (2) remaining from step (iii); Includes. The reducing agent used in step (ii) is not particularly limited as long as it can reduce the interchain disulfide of the antibody. For example, tris(2-carboxyethyl)phosphine or a salt thereof, dithiothreitol, or 2-mercaptoethanol can be used. Preferably, tris(2-carboxyethyl)phosphine or a salt thereof can be used. More preferably, tris(2-carboxyethyl)phosphine hydrochloride can be used. The equivalent amount of the reducing agent used in step (ii) per antibody molecule (hereinafter, in the present invention, "equivalent amount" means molar equivalent amount) can be appropriately selected depending on the average number of drug linkers bound per antibody in the antibody-drug conjugate to be produced and the type of antibody. The optimal amount of the reducing agent for each antibody used will be described below, but the optimal amount is a parameter that can vary depending on the cell line from which the antibody is derived, the production method, etc. For example, when the average number of drug linkers bound per antibody in the antibody-drug conjugate to be produced is in the range of 7 to 8, and the antibody is an anti-HER2 antibody (preferably an antibody comprising a heavy chain consisting of the amino acid sequence set forth in amino acid numbers 1 to 449 in SEQ ID NO: 8 and a light chain consisting of the amino acid sequence set forth in amino acid numbers 1 to 214 in SEQ ID NO: 9, or an antibody comprising a heavy chain consisting of the amino acid sequence set forth in SEQ ID NO: 8 and a light chain consisting of the amino acid sequence set forth in SEQ ID NO: 9), the reducing agent can be preferably used in an amount of 4.1 to 5.1 equivalents, more preferably 4.4 to 4.8 equivalents, and even more preferably about 4.6 equivalents per antibody molecule. Here, "about 4.6 equivalents" preferably means 4.5 to 4.7 equivalents, and more preferably 4.6 equivalents. Furthermore, when the average number of drug linkers bound per antibody in the antibody-drug conjugate to be produced is in the range of 3.5 to 4.5, and the antibody is an anti-TROP2 antibody (preferably an antibody comprising a heavy chain consisting of the amino acid sequence set forth in amino acid numbers 20 to 470 in SEQ ID NO: 10 and a light chain consisting of the amino acid sequence set forth in amino acid numbers 21 to 234 in SEQ ID NO: 11, or an antibody in which a lysine residue is deleted at the carboxyl terminus of the heavy chain), the reducing agent is preferably 1.9 to 2.5 equivalents, more preferably 2.1 to 2.3 equivalents, per antibody molecule. Furthermore, when the average number of drug linkers bound per antibody in the antibody-drug conjugate to be produced is in the range of 7 to 8, and the antibody is an anti-HER3 antibody (preferably an antibody comprising a heavy chain consisting of the amino acid sequence set forth in SEQ ID NO: 12 and a light chain consisting of the amino acid sequence set forth in SEQ ID NO: 13, or an antibody in which a lysine residue at the carboxyl terminus of the heavy chain is deleted), the reducing agent can be preferably used in an amount of 5.5 to 6.5 equivalents, more preferably 5.8 to 6.2 equivalents, and even more preferably about 6 equivalents, per antibody molecule. Here, "about 6 equivalents" preferably means 5.9 to 6.1 equivalents, and more preferably 6.0 equivalents. Furthermore, when the average number of drug linkers bound per antibody in the antibody-drug conjugate to be produced is in the range of 3.5 to 4.5, and the antibody is an anti-B7-H3 antibody (preferably an antibody comprising a heavy chain consisting of the amino acid sequence set forth in amino acid numbers 20 to 471 in SEQ ID NO: 14 and a light chain consisting of the amino acid sequence set forth in amino acid numbers 21 to 233 in SEQ ID NO: 15, or an antibody in which a lysine residue is deleted at the carboxyl terminus of the heavy chain), the reducing agent is preferably 1.9 to 2.5 equivalents, more preferably 2.1 to 2.3 equivalents, per antibody molecule. Furthermore, when the average number of drug linkers bound per antibody in the antibody-drug conjugate to be produced is in the range of 7 to 8, and the antibody is an anti-GPR20 antibody (preferably an antibody comprising a heavy chain consisting of the amino acid sequence set forth in amino acid numbers 20 to 472 in SEQ ID NO: 1 and a light chain consisting of the amino acid sequence set forth in amino acid numbers 21 to 234 in SEQ ID NO: 2, or an antibody in which a lysine residue at the carboxyl terminus of the heavy chain is deleted), the reducing agent can be preferably used in an amount of 4.3 to 5.3 equivalents, more preferably 4.6 to 5 equivalents, and even more preferably about 4.75 equivalents per antibody molecule. Here, "about 4.75 equivalents" preferably means 4.65 to 4.85 equivalents, and more preferably 4.75 equivalents. Furthermore, when the average number of drug linkers bound per antibody in the antibody-drug conjugate to be produced is in the range of 7 to 8, and the antibody is an anti-CDH6 antibody (preferably an antibody comprising a heavy chain consisting of the amino acid sequence set forth in amino acid numbers 20 to 471 in SEQ ID NO: 16 and a light chain consisting of the amino acid sequence set forth in amino acid numbers 21 to 233 in SEQ ID NO: 17, or an antibody in which a lysine residue at the carboxyl terminus of the heavy chain is deleted), the reducing agent can be preferably used in an amount of 4.3 to 5.3 equivalents, more preferably 4.6 to 5 equivalents, and even more preferably about 4.8 equivalents per antibody molecule. Here, "about 4.8 equivalents" preferably means 4.7 to 4.9 equivalents, and more preferably 4.8 equivalents. Furthermore, when the average number of drug linkers bound per antibody in the antibody-drug conjugate to be produced is in the range of 7 to 8, and the antibody is an anti-MUC1 antibody (preferably an antibody comprising a heavy chain consisting of the amino acid sequence set forth in amino acid numbers 1 to 447 in SEQ ID NO:5 or the amino acid sequence set forth in amino acid numbers 1 to 447 in SEQ ID NO:6 and a light chain consisting of the amino acid sequence set forth in amino acid numbers 1 to 219 in SEQ ID NO:7, or an antibody in which a lysine residue at the carboxyl terminus of the heavy chain of the antibody is deleted), the reducing agent can be preferably used in an amount of 4.3 to 5.3 equivalents, more preferably 4.6 to 5.0 equivalents, and even more preferably about 4.75 equivalents, per antibody molecule. Here, "about 4.75 equivalents" preferably means 4.65 to 4.85 equivalents, and more preferably 4.75 equivalents. Furthermore, when the average number of drug linkers bound per antibody in the antibody-drug conjugate to be produced is in the range of 7 to 8, and the antibody is an anti-CD37 antibody (preferably an antibody comprising a heavy chain consisting of the amino acid sequence set forth in amino acid numbers 20 to 468 in SEQ ID NO: 3 and a light chain consisting of the amino acid sequence set forth in amino acid numbers 21 to 234 in SEQ ID NO: 4, or an antibody in which a lysine residue at the carboxyl terminus of the heavy chain is deleted), the reducing agent can be preferably used in an amount of 4.3 to 5.3 equivalents, more preferably 4.6 to 5.0 equivalents, and even more preferably about 4.75 equivalents per antibody molecule. Here, "about 4.75 equivalents" preferably means 4.65 to 4.85 equivalents, and more preferably 4.75 equivalents. Step (ii) may be preferably carried out in a buffer solution. The pH of the buffer used in step (ii) is preferably 6 to 8, more preferably 6.5 to 7.5, even more preferably 6.9 to 7.4, and even more preferably 7.0 to 7.3. The buffer used in step (ii) is not particularly limited as long as it can be used during reduction of interchain disulfides in an antibody. For example, acetate buffer, histidine buffer, phosphate buffer, PIPES buffer, HEPES buffer, etc. can be used, and preferably acetate buffer, histidine buffer, or phosphate buffer. For example, when the average number of drug linkers bound per antibody in the antibody-drug conjugate to be produced is in the range of 7 to 8, and the antibody is an anti-HER2 antibody (preferably an antibody comprising a heavy chain consisting of the amino acid sequence set forth in amino acid numbers 1 to 449 in SEQ ID NO: 1 and a light chain consisting of the amino acid sequence set forth in amino acid numbers 1 to 214 in SEQ ID NO: 2, or an antibody comprising a heavy chain consisting of the amino acid sequence set forth in SEQ ID NO: 1 and a light chain consisting of the amino acid sequence set forth in SEQ ID NO: 2), preferably, an acetate buffer adjusted to pH 6 to 8 can be used, more preferably, an acetate buffer adjusted to pH 6 to 8 with an aqueous solution of disodium hydrogen phosphate can be used, even more preferably, an acetate buffer adjusted to pH 6.8 to 7.8 with an aqueous solution of disodium hydrogen phosphate can be used, and even more preferably, an acetate buffer adjusted to pH about 7.3 with an aqueous solution of disodium hydrogen phosphate can be used. Here, "about 7.3" preferably means a range of 7.1 to 7.5, more preferably a range of 7.2 to 7.4, and even more preferably, 7.3. Furthermore, when the average number of drug linkers bound per antibody in the antibody-drug conjugate to be produced is in the range of 3.5 to 4.5, and the antibody is an anti-TROP2 antibody (preferably an antibody comprising a heavy chain consisting of the amino acid sequence set forth in amino acid numbers 20 to 470 of SEQ ID NO: 10 and a light chain consisting of the amino acid sequence set forth in amino acid numbers 21 to 234 of SEQ ID NO: 11, or an antibody lacking a lysine residue at the carboxyl terminus of the heavy chain), preferably, an aqueous L-histidine solution adjusted to pH 6.4 to 7.4 with an aqueous disodium hydrogen phosphate solution can be used, more preferably, an aqueous L-histidine solution adjusted to pH 6.7 to 7.1 with an aqueous disodium hydrogen phosphate solution can be used, and even more preferably, an aqueous L-histidine solution adjusted to pH 6.9 with an aqueous disodium hydrogen phosphate solution can be used. Furthermore, when the average number of drug linkers bound per antibody in the antibody-drug conjugate to be produced is in the range of 7 to 8, and the antibody is an anti-HER3 antibody (preferably an antibody comprising a heavy chain consisting of the amino acid sequence set forth in SEQ ID NO: 3 and a light chain consisting of the amino acid sequence set forth in SEQ ID NO: 4, or an antibody in which a lysine residue at the carboxyl terminus of the heavy chain of the antibody is deleted), preferably, an acetate buffer adjusted to pH 6 to 8 can be used, more preferably, an acetate buffer adjusted to pH 6 to 8 with an aqueous solution of disodium hydrogen phosphate can be used, even more preferably, an acetate buffer adjusted to pH 6.5 to 7.5 with an aqueous solution of disodium hydrogen phosphate can be used, and even more preferably, an acetate buffer adjusted to pH about 7 with an aqueous solution of disodium hydrogen phosphate can be used. Here, "about 7" preferably means a range of 6.8 to 7.2, more preferably a range of 6.9 to 7.1, and even more preferably, 7.0. Furthermore, when the average number of drug linkers bound per antibody in the antibody-drug conjugate to be produced is in the range of 3.5 to 4.5, and the antibody is an anti-B7-H3 antibody (preferably an antibody comprising a heavy chain consisting of the amino acid sequence set forth in amino acid numbers 20 to 471 in SEQ ID NO: 14 and a light chain consisting of the amino acid sequence set forth in amino acid numbers 21 to 233 in SEQ ID NO: 15, or an antibody lacking a lysine residue at the carboxyl terminus of the heavy chain), preferably, an aqueous L-histidine solution of 0.005 mol / L to 0.3 mol / L can be used, more preferably, an aqueous L-histidine solution of 0.025 mol / L to 0.1 mol / L can be used, and even more preferably, an aqueous L-histidine solution of 0.05 mol / L can be used. In addition, when the average number of drug linkers bound per antibody in the antibody-drug conjugate to be produced is in the range of 7 to 8, and the antibody is an anti-GPR20 antibody (preferably an antibody comprising a heavy chain consisting of the amino acid sequence set forth in amino acid numbers 20 to 472 in SEQ ID NO: 1 and a light chain consisting of the amino acid sequence set forth in amino acid numbers 21 to 234 in SEQ ID NO: 2, or an antibody lacking a lysine residue at the carboxyl terminus of the heavy chain), the buffer used in step (ii) is preferably a buffer adjusted to pH 6 to 8. More preferably, a buffer solution adjusted to a pH of 6.5 to 7.5 can be used, even more preferably, a buffer solution adjusted to a pH of 6.8 to 7.2 can be used, even more preferably, a buffer solution adjusted to a pH of 7.0 to 7.1 can be used, even more preferably, an acetate buffer solution, a histidine buffer solution, or a phosphate buffer solution adjusted to a pH of 7.0 to 7.1 can be used, and even more preferably, a sodium acetate buffer solution, an L-histidine buffer solution, or an aqueous disodium hydrogen phosphate solution adjusted to a pH of 7.0 to 7.1 can be used. In addition, when the average number of drug linkers bound per antibody in the antibody-drug conjugate to be produced is in the range of 7 to 8, and the antibody is an anti-MUC1 antibody (preferably an antibody comprising a heavy chain consisting of the amino acid sequence set forth in amino acid numbers 1 to 447 in SEQ ID NO:5 or the amino acid sequence set forth in amino acid numbers 1 to 447 in SEQ ID NO:6 and a light chain consisting of the amino acid sequence set forth in amino acid numbers 1 to 219 in SEQ ID NO:7, or an antibody in which a lysine residue at the carboxyl terminus of the heavy chain of the antibody is deleted), the buffer used in step (ii) is preferably a buffer having a pH of 6 to 8. A buffer solution adjusted to pH 6.8 can be used, more preferably a buffer solution adjusted to pH 6.5 to 7.5, even more preferably a buffer solution adjusted to pH 6.8 to 7.2, even more preferably a buffer solution adjusted to pH 7.0 to 7.1, even more preferably an acetate buffer, a histidine buffer, or a phosphate buffer adjusted to pH 7.0 to 7.1, and even more preferably a sodium acetate buffer, an L-histidine buffer, or an aqueous disodium hydrogen phosphate solution adjusted to pH 7.0 to 7.1 can be used. In addition, when the average number of drug linkers bound per antibody in the antibody-drug conjugate to be produced is in the range of 7 to 8, and the antibody is an anti-CD37 antibody (preferably an antibody comprising a heavy chain consisting of the amino acid sequence set forth in amino acid numbers 20 to 468 in SEQ ID NO: 3 and a light chain consisting of the amino acid sequence set forth in amino acid numbers 21 to 234 in SEQ ID NO: 4, or an antibody lacking a lysine residue at the carboxyl terminus of the heavy chain), the buffer used in step (ii) is preferably a buffer adjusted to pH 6 to 8. More preferably, a buffer solution adjusted to a pH of 6.5 to 7.5 can be used, even more preferably, a buffer solution adjusted to a pH of 6.8 to 7.2 can be used, even more preferably, a buffer solution adjusted to a pH of 7.0 to 7.1 can be used, even more preferably, an acetate buffer, a histidine buffer, or a phosphate buffer adjusted to a pH of 7.0 to 7.1 can be used, and even more preferably, a sodium acetate buffer, an L-histidine buffer, or an aqueous disodium hydrogen phosphate solution adjusted to a pH of 7.0 to 7.1 can be used. The use of such a buffer can minimize the formation of aggregates. The buffer used in step (ii) may contain a buffer derived from the antibody production. Step (ii) is preferably carried out in the presence of a chelating agent. The chelating agent is not particularly limited as long as it can be used in reducing interchain disulfides of an antibody, and examples of the chelating agent that can be used include ethylenediaminetetraacetic acid (hereinafter also referred to as "EDTA"), diethylenetriaminepentaacetic acid, and glycoletherdiaminetetraacetic acid, and preferably ethylenediaminetetraacetic acid. The chelating agent can be used preferably in an amount of 1 to 20 equivalents per antibody molecule, more preferably in an amount of 3 to 8 equivalents per antibody molecule, even more preferably in an amount of 4 to 6 equivalents per antibody molecule, and even more preferably in an amount of 5 equivalents per antibody molecule. The buffer used in step (ii) may contain a surfactant. In the present invention, the term "surfactant" refers to a substance that has a hydrophilic group and a hydrophobic group and can be used as one of the components of a pharmaceutical preparation. The surfactant contained in the buffer used in step (ii) is not particularly limited, but examples thereof include polysorbates (including polysorbate 80 (Tween 80), polysorbate 20 (Tween 20) and polysorbate 60 (Tween 60)), polyoxyethylene (160) polyoxypropylene (30) glycol, polyoxyethylene hydrogenated castor oil 60, polyoxyethylene castor oil, sodium lauryl sulfate, etc., and preferably includes polysorbate 20 or polysorbate 80. Whether the buffer used in step (ii) contains a surfactant and the type of surfactant can be appropriately selected depending on the average number of drug linkers bound per antibody in the antibody-drug conjugate to be produced and the type of antibody. For example, when the average number of drug linkers bound per antibody in the antibody-drug conjugate to be produced is in the range of 7 to 8, and the antibody is an anti-HER2 antibody (preferably an antibody comprising a heavy chain consisting of the amino acid sequence set forth in amino acid numbers 1 to 449 of SEQ ID NO: 8 and a light chain consisting of the amino acid sequence set forth in amino acid numbers 1 to 214 of SEQ ID NO: 9, or an antibody comprising a heavy chain consisting of the amino acid sequence set forth in SEQ ID NO: 8 and a light chain consisting of the amino acid sequence set forth in SEQ ID NO: 9), the buffer used in step (ii) preferably does not contain a surfactant. Furthermore, when the average number of drug linkers bound per antibody in the antibody-drug conjugate to be produced is in the range of 3.5 to 4.5, and the antibody is an anti-TROP2 antibody (preferably an antibody comprising a heavy chain consisting of the amino acid sequence set forth in amino acid numbers 20 to 470 of SEQ ID NO: 10 and a light chain consisting of the amino acid sequence set forth in amino acid numbers 21 to 234 of SEQ ID NO: 11, or an antibody lacking a lysine residue at the carboxyl terminus of the heavy chain), the buffer used in step (ii) contains polysorbate 80 and can be preferably used. Furthermore, when the average number of drug linkers bound per antibody in the antibody-drug conjugate to be produced is in the range of 7 to 8, and the antibody is an anti-HER3 antibody (preferably an antibody comprising a heavy chain consisting of the amino acid sequence set forth in SEQ ID NO: 12 and a light chain consisting of the amino acid sequence set forth in SEQ ID NO: 13, or an antibody lacking a lysine residue at the carboxyl terminus of the heavy chain), the buffer used in step (ii) contains polysorbate 20 and can be preferably used. Furthermore, when the average number of drug linkers bound per antibody in the antibody-drug conjugate to be produced is in the range of 3.5 to 4.5, and the antibody is an anti-B7-H3 antibody (preferably an antibody comprising a heavy chain consisting of the amino acid sequence set forth in amino acid numbers 20 to 471 in SEQ ID NO: 14 and a light chain consisting of the amino acid sequence set forth in amino acid numbers 21 to 233 in SEQ ID NO: 15, or an antibody lacking a lysine residue at the carboxyl terminus of the heavy chain), the buffer used in step (ii) contains polysorbate 20 and can be preferably used. Furthermore, when the average number of drug linkers bound per antibody in the antibody-drug conjugate to be produced is in the range of 7 to 8, and the antibody is an anti-GPR20 antibody (preferably an antibody comprising a heavy chain consisting of the amino acid sequence set forth in amino acid numbers 20 to 472 in SEQ ID NO: 1 and a light chain consisting of the amino acid sequence set forth in amino acid numbers 21 to 234 in SEQ ID NO: 2, or an antibody lacking a lysine residue at the carboxyl terminus of the heavy chain), the buffer used in step (ii) contains polysorbate 80 and can be preferably used. Furthermore, when the average number of drug linkers bound per antibody in the antibody-drug conjugate to be produced is in the range of 7 to 8, and the antibody is an anti-CDH6 antibody (preferably an antibody comprising a heavy chain consisting of the amino acid sequence set forth in amino acid numbers 20 to 471 in SEQ ID NO: 16 and a light chain consisting of the amino acid sequence set forth in amino acid numbers 21 to 233 in SEQ ID NO: 17, or an antibody lacking a lysine residue at the carboxyl terminus of the heavy chain), the buffer used in step (ii) contains polysorbate 80 and can be preferably used. Furthermore, when the average number of drug linkers bound per antibody in the antibody-drug conjugate to be produced is in the range of 7 to 8, and the antibody is an anti-MUC1 antibody (preferably an antibody comprising a heavy chain consisting of the amino acid sequence set forth in amino acid numbers 1 to 447 of SEQ ID NO:5 or the amino acid sequence set forth in amino acid numbers 1 to 447 of SEQ ID NO:6 and a light chain consisting of the amino acid sequence set forth in amino acid numbers 1 to 219 of SEQ ID NO:7, or an antibody lacking a lysine residue at the carboxyl terminus of the heavy chain), the buffer used in step (ii) contains polysorbate 80 and can be preferably used. Furthermore, when the average number of drug linkers bound per antibody in the antibody-drug conjugate to be produced is in the range of 7 to 8, and the antibody is an anti-CD37 antibody (preferably an antibody comprising a heavy chain consisting of the amino acid sequence set forth in amino acid numbers 20 to 468 of SEQ ID NO: 3 and a light chain consisting of the amino acid sequence set forth in amino acid numbers 21 to 234 of SEQ ID NO: 4, or an antibody lacking a lysine residue at the carboxyl terminus of the heavy chain), the buffer used in step (ii) contains polysorbate 80 and can be preferably used. The reaction temperature in step (ii) can be appropriately selected depending on the type of antibody in the antibody-drug conjugate composition to be produced. When the average number of drug linkers bound per antibody in the antibody-drug conjugate to be produced is in the range of 7 to 8, step (ii) can be preferably carried out at an internal temperature of 25 to 50°C, and when the average number of drug linkers bound per antibody in the antibody-drug conjugate to be produced is in the range of 3.5 to 4.5, step (ii) can be preferably carried out at -5°C to 35°C, more preferably at 0 to 20°C, even more preferably at 5 to 20°C, and even more preferably at 5 to 10°C or about 10°C. In the present invention, "about 10°C" is preferably 8°C to 12°C, more preferably 9°C to 11°C, and even more preferably 10°C to 11°C, or 10°C. The reaction time in step (ii) can be appropriately selected depending on the type of antibody in the antibody-drug conjugate composition to be produced. When the average number of drug linkers bound per antibody in the antibody-drug conjugate to be produced is in the range of 7 to 8, the reaction time in step (ii) is preferably 1 to 4 hours. When the average number of drug linkers bound per antibody in the antibody-drug conjugate to be produced is in the range of 3.5 to 4.5, the reaction time in step (ii) is preferably 6 to 50 hours, 12 to 48 hours, 20 to 51 hours, 24 to 48 hours (or 36 to 48 hours), or 48 to 50 hours. For example, when the average number of drug linkers bound per antibody in the antibody-drug conjugate to be produced is in the range of 7 to 8, and the antibody is an anti-HER2 antibody (preferably an antibody comprising a heavy chain consisting of the amino acid sequence set forth in amino acid numbers 1 to 449 in SEQ ID NO: 8 and a light chain consisting of the amino acid sequence set forth in amino acid numbers 1 to 214 in SEQ ID NO: 9, or an antibody comprising a heavy chain consisting of the amino acid sequence set forth in SEQ ID NO: 8 and a light chain consisting of the amino acid sequence set forth in SEQ ID NO: 9), step (ii) can be preferably carried out at an internal temperature of 30 to 40°C, more preferably at an internal temperature of about 35°C. Here, "about 35°C" preferably means 33°C to 37°C, more preferably 34°C to 36°C, and even more preferably 35°C. Furthermore, when the average number of drug linkers bound per antibody in the antibody-drug conjugate to be produced is in the range of 3.5 to 4.5, and the antibody is an anti-TROP2 antibody (preferably an antibody comprising a heavy chain consisting of the amino acid sequence set forth in amino acid numbers 20 to 470 in SEQ ID NO: 10 and a light chain consisting of the amino acid sequence set forth in amino acid numbers 21 to 234 in SEQ ID NO: 11, or an antibody lacking a lysine residue at the carboxyl terminus of the heavy chain), step (ii) can be preferably carried out at about 10°C for 20 hours or more, and, inclusive of the upper limit, can be preferably carried out at about 10°C for 20 to 51 hours. Furthermore, when the average number of drug linkers bound per antibody in the antibody-drug conjugate to be produced is in the range of 7 to 8, and the antibody is an anti-HER3 antibody (preferably an antibody comprising a heavy chain consisting of the amino acid sequence set forth in SEQ ID NO: 12 and a light chain consisting of the amino acid sequence set forth in SEQ ID NO: 13, or an antibody lacking a lysine residue at the carboxyl terminus of the heavy chain), step (ii) can be preferably carried out at an internal temperature of 30 to 40° C., more preferably at about 35° C. Here, "about 35° C." preferably means 33 to 37° C., more preferably 34 to 36° C., and even more preferably 35° C. Furthermore, when the average number of drug linkers bound per antibody in the antibody-drug conjugate to be produced is in the range of 3.5 to 4.5, and the antibody is an anti-B7-H3 antibody (preferably an antibody comprising a heavy chain consisting of the amino acid sequence set forth in amino acid numbers 20 to 471 in SEQ ID NO: 14 and a light chain consisting of the amino acid sequence set forth in amino acid numbers 21 to 233 in SEQ ID NO: 15, or an antibody in which a lysine residue at the carboxyl terminus of the heavy chain of the antibody is deleted), the step (ii) can be preferably carried out at 5 to 10°C (more preferably, 6°C, 7°C, 8°C, 9°C, or 10°C) for 12 hours or more, or at 5°C for 20 hours or more, and, inclusive of the upper limit, can be preferably carried out at 5 to 10°C (more preferably, 6°C, 7°C, 8°C, 9°C, or 10°C) for 12 hours to 48 hours, or at 5°C for 20 hours to 48 hours. Furthermore, when the average number of drug linkers bound per antibody in the antibody-drug conjugate to be produced is in the range of 7 to 8, and the antibody is an anti-GPR20 antibody (preferably an antibody comprising a heavy chain consisting of the amino acid sequence set forth in amino acid numbers 20 to 472 in SEQ ID NO: 1 and a light chain consisting of the amino acid sequence set forth in amino acid numbers 21 to 234 in SEQ ID NO: 2, or an antibody lacking a lysine residue at the carboxyl terminus of the heavy chain), step (ii) can be preferably carried out at an internal temperature of 25 to 35°C, more preferably at about 30°C. Here, "about 30°C" preferably means 28°C to 32°C, more preferably 29°C to 31°C, and even more preferably 30°C. Furthermore, when the average number of drug linkers bound per antibody in the antibody-drug conjugate to be produced is in the range of 7 to 8, and the antibody is an anti-CDH6 antibody (preferably an antibody comprising a heavy chain consisting of the amino acid sequence set forth in amino acid numbers 20 to 471 in SEQ ID NO: 16 and a light chain consisting of the amino acid sequence set forth in amino acid numbers 21 to 233 in SEQ ID NO: 17, or an antibody in which a lysine residue at the carboxyl terminus of the heavy chain is deleted), step (ii) can be preferably performed at an internal temperature of 25 to 35° C., more preferably at about 30° C. Here, "about 30° C." preferably means 28° C. to 32° C., more preferably 29° C. to 31° C., and even more preferably 30° C. Furthermore, when the average number of drug linkers bound per antibody in the antibody-drug conjugate to be produced is in the range of 7 to 8, and the antibody is an anti-MUC1 antibody (preferably an antibody comprising a heavy chain consisting of the amino acid sequence set forth in amino acid numbers 1 to 447 in SEQ ID NO:5 or the amino acid sequence set forth in amino acid numbers 1 to 447 in SEQ ID NO:6 and a light chain consisting of the amino acid sequence set forth in amino acid numbers 1 to 219 in SEQ ID NO:7, or an antibody in which a lysine residue at the carboxyl terminus of the heavy chain of the antibody is deleted), step (ii) can be preferably performed at an internal temperature of 25 to 35°C, more preferably at about 30°C. Here, "about 30°C" preferably means 28°C to 32°C, more preferably 29°C to 31°C, and even more preferably 30°C. Furthermore, when the average number of drug linkers bound per antibody in the antibody-drug conjugate to be produced is in the range of 7 to 8, and the antibody is an anti-CD37 antibody (preferably an antibody comprising a heavy chain consisting of the amino acid sequence set forth in amino acid numbers 20 to 468 of SEQ ID NO: 3 and a light chain consisting of the amino acid sequence set forth in amino acid numbers 21 to 234 of SEQ ID NO: 4, or an antibody lacking a lysine residue at the carboxyl terminus of the heavy chain), step (ii) can be preferably carried out at an internal temperature of 25 to 35°C, more preferably at about 30°C. Here, "about 30°C" preferably means 28°C to 32°C, more preferably 29°C to 31°C, and even more preferably 30°C. The equivalent amount of the compound represented by formula (2) used in step (iii) per antibody molecule can be appropriately selected depending on the average number of drug linkers bound per antibody in the antibody-drug conjugate to be produced and the type of antibody. The optimal amount of drug linker for each antibody used is described below, but the optimal amount is a parameter that can vary depending on the cell line from which the antibody is derived, the production method, etc. For example, when the average number of drug linkers bound per antibody in the antibody-drug conjugate to be produced is in the range of 7 to 8, and the antibody is an anti-HER2 antibody (preferably an antibody comprising a heavy chain consisting of the amino acid sequence set forth in amino acid numbers 1 to 449 in SEQ ID NO: 8 and a light chain consisting of the amino acid sequence set forth in amino acid numbers 1 to 214 in SEQ ID NO: 9, or an antibody comprising a heavy chain consisting of the amino acid sequence set forth in SEQ ID NO: 8 and a light chain consisting of the amino acid sequence set forth in SEQ ID NO: 9), the compound represented by formula (2) can be preferably used in an amount of 8 to 10 equivalents, more preferably 8.2 to 9.2 equivalents, and even more preferably about 8.7 equivalents per antibody molecule. Here, "about 8.7 equivalents" preferably means 8.5 to 8.9 equivalents, more preferably 8.6 to 8.8 equivalents, and even more preferably 8.7 equivalents. Furthermore, when the average number of drug linkers bound per antibody in the antibody-drug conjugate to be produced is in the range of 3.5 to 4.5, and the antibody is an anti-TROP2 antibody (preferably an antibody comprising a heavy chain consisting of the amino acid sequence set forth in amino acid numbers 20 to 470 in SEQ ID NO: 10 and a light chain consisting of the amino acid sequence set forth in amino acid numbers 21 to 234 in SEQ ID NO: 11, or an antibody in which a lysine residue is deleted at the carboxyl terminus of the heavy chain), the compound represented by formula (2) is preferably 4 to 5 equivalents, more preferably 4.2 to 4.6 equivalents, and even more preferably 4.4 equivalents, per antibody molecule. Furthermore, when the average number of drug linkers bound per antibody in the antibody-drug conjugate to be produced is in the range of 7 to 8, and the antibody is an anti-HER3 antibody (preferably an antibody comprising a heavy chain consisting of the amino acid sequence set forth in SEQ ID NO: 12 and a light chain consisting of the amino acid sequence set forth in SEQ ID NO: 13, or an antibody lacking a lysine residue at the carboxyl terminus of the heavy chain), the compound represented by formula (2) can be used preferably in an amount of 8 to 10 equivalents, more preferably 9 to 10 equivalents, and even more preferably about 9.5 equivalents per antibody molecule. Here, "about 9.5 equivalents" preferably means 9.3 to 9.7 equivalents, more preferably 9.4 to 9.6 equivalents, and even more preferably 9.5 equivalents. Furthermore, when the average number of drug linkers bound per antibody in the antibody-drug conjugate to be produced is in the range of 3.5 to 4.5, and the antibody is an anti-B7-H3 antibody (preferably an antibody comprising a heavy chain consisting of the amino acid sequence set forth in amino acid numbers 20 to 471 in SEQ ID NO: 14 and a light chain consisting of the amino acid sequence set forth in amino acid numbers 21 to 233 in SEQ ID NO: 15, or an antibody in which a lysine residue is deleted at the carboxyl terminus of the heavy chain), the compound represented by formula (2) is preferably 4 to 5 equivalents, more preferably 4.2 to 4.6 equivalents, and even more preferably 4.4 equivalents per antibody molecule. Furthermore, when the average number of drug linkers bound per antibody in the antibody-drug conjugate to be produced is in the range of 7 to 8, and the antibody is an anti-GPR20 antibody (preferably an antibody comprising a heavy chain consisting of the amino acid sequence set forth in amino acid numbers 20 to 472 in SEQ ID NO: 1 and a light chain consisting of the amino acid sequence set forth in amino acid numbers 21 to 234 in SEQ ID NO: 2, or an antibody lacking a lysine residue at the carboxyl terminus of the heavy chain), the compound represented by formula (2) can be used preferably in an amount of 8 to 10 equivalents, more preferably 8.3 to 9.3 equivalents, and even more preferably about 8.9 equivalents, per antibody molecule. Here, "about 8.9 equivalents" preferably means 8.7 to 9.1 equivalents, more preferably 8.8 to 9.0 equivalents, and even more preferably 8.9 equivalents. Furthermore, when the average number of drug linkers bound per antibody in the antibody-drug conjugate to be produced is in the range of 7 to 8, and the antibody is an anti-CDH6 antibody (preferably an antibody comprising a heavy chain consisting of the amino acid sequence set forth in amino acid numbers 20 to 471 in SEQ ID NO: 16 and a light chain consisting of the amino acid sequence set forth in amino acid numbers 21 to 233 in SEQ ID NO: 17, or an antibody lacking a lysine residue at the carboxyl terminus of the heavy chain), the compound represented by formula (2) can be used preferably in an amount of 8 to 10 equivalents, more preferably 8.6 to 9.6 equivalents, and even more preferably about 9.1 equivalents per antibody molecule. Here, "about 9.1 equivalents" preferably means 8.9 to 9.3 equivalents, more preferably 9.0 to 9.2 equivalents, and even more preferably 9.1 equivalents. Furthermore, when the average number of drug linkers bound per antibody in the antibody-drug conjugate to be produced is in the range of 7 to 8, and the antibody is an anti-MUC1 antibody (preferably an antibody comprising a heavy chain consisting of the amino acid sequence set forth in amino acid numbers 1 to 447 in SEQ ID NO:5 or the amino acid sequence set forth in amino acid numbers 1 to 447 in SEQ ID NO:6 and a light chain consisting of the amino acid sequence set forth in amino acid numbers 1 to 219 in SEQ ID NO:7, or an antibody in which a lysine residue at the carboxyl terminus of the heavy chain of the antibody is deleted), the compound represented by formula (2) can be used preferably in an amount of 8 to 10 equivalents, more preferably 8.3 to 9.3 equivalents, and even more preferably about 8.9 equivalents, per antibody molecule. Here, "about 8.9 equivalents" preferably means 8.7 to 9.1 equivalents, more preferably 8.8 to 9.0 equivalents, and even more preferably 8.9 equivalents. Furthermore, when the average number of drug linkers bound per antibody in the antibody-drug conjugate to be produced is in the range of 7 to 8, and the antibody is an anti-CD37 antibody (preferably an antibody comprising a heavy chain consisting of the amino acid sequence set forth in amino acid numbers 20 to 468 in SEQ ID NO: 3 and a light chain consisting of the amino acid sequence set forth in amino acid numbers 21 to 234 in SEQ ID NO: 4, or an antibody lacking a lysine residue at the carboxyl terminus of the heavy chain), the compound represented by formula (2) can be used preferably in an amount of 8 to 10 equivalents, more preferably 8.3 to 9.3 equivalents, and even more preferably about 8.9 equivalents, per antibody molecule. Here, "about 8.9 equivalents" preferably means 8.7 to 9.1 equivalents, more preferably 8.8 to 9.0 equivalents, and even more preferably 8.9 equivalents. The compound represented by formula (2) can be preferably added to the reaction solution obtained in step (ii) in a state dissolved in a solvent. The solvent is not particularly limited as long as it can be used in a binding reaction with an antibody, but preferably, dimethyl sulfoxide, an aqueous dimethyl sulfoxide solution, acetone, or an aqueous acetone solution can be used, and more preferably, an aqueous dimethyl sulfoxide solution can be used. Furthermore, these solvents can be preferably used in a state containing acetic acid. When the average number of drug linkers bound per antibody in the antibody-drug conjugate to be produced is in the range of 7 to 8, step (iii) can be preferably carried out at an internal temperature of 5 to 25° C., more preferably at an internal temperature of 10 to 20° C., and even more preferably at an internal temperature of about 15° C. Here, "about 15° C." preferably means 13 to 17° C., more preferably 14 to 16° C., and even more preferably 15° C. When the average number of drug linkers bound per antibody in the antibody-drug conjugate to be produced is in the range of 3.5 to 4.5, step (iii) can be preferably carried out at 0 to 20° C., more preferably at 5 to 20° C., and even more preferably at 5 to 10° C. or about 10° C. When the average number of drug linkers bound per antibody in the antibody-drug conjugate to be produced is in the range of 7 to 8, the reaction time in step (iii) is preferably 0.5 to 2 hours. When the average number of drug linkers bound per antibody in the antibody-drug conjugate to be produced is in the range of 3.5 to 4.5, the reaction time in step (iii) is preferably 20 minutes to 4 hours, more preferably 0.5 to 2 hours. The reagent having a thiol group used in step (iv) can be used to react with the compound represented by formula (2) remaining in step (iii) In other words, the reagent having a thiol group used in step (iv) can be used to quench the excess compound represented by formula (2). The reagent having a thiol group used in step (iv) is not particularly limited as long as it can react with the maleimidyl group of the compound represented by formula (2). For example, N-acetylcysteine ​​or cysteine ​​can be used, and preferably N-acetylcysteine ​​can be used. When the average number of drug linkers bound per antibody in the antibody-drug conjugate to be produced is in the range of 7 to 8, the reagent having a thiol group used in step (iv) can be preferably used in an amount of 10 to 50 equivalents relative to one antibody molecule, and more preferably used in an amount of 10 to 30 equivalents. When the average number of drug linkers bound per antibody in the antibody-drug conjugate to be produced is in the range of 3.5 to 4.5, the reagent having a thiol group used in step (iv) can be preferably used in an amount of 2 to 8 equivalents, more preferably used in an amount of 3 to 7 equivalents, and even more preferably used in an amount of 3 to 5 equivalents. When the average number of drug linkers bound per antibody in the antibody-drug conjugate to be produced is in the range of 7 to 8, step (iv) can be preferably carried out at an internal temperature of 5 to 25° C., more preferably at an internal temperature of 10 to 20° C., and even more preferably at an internal temperature of about 15° C. Here, "about 15° C." preferably means 13 to 17° C., more preferably 14 to 16° C., and even more preferably 15° C. When the average number of drug linkers bound per antibody in the antibody-drug conjugate to be produced is in the range of 3.5 to 4.5, step (iv) can be preferably carried out at 0 to 20° C., more preferably at 5 to 20° C., and even more preferably at 5 to 10° C. or about 10° C. The reaction time in step (iv) is preferably 0.5 to 2 hours. The production method of the present invention may include the step (v) of adjusting the pH of the reaction solution. The pH of the solution adjusted in step (v) may be, for example, within the range of 4 to 6, and may be 4.2 to 5.8, 4.4 to 5.6, 4.6 to 5.4, 4.8 to 5.2, about 5, 5.0, 4.0 to 5.0, 4.1 to 4.9, 4.2 to 4.8, 4.3 to 4.7, 4.4 to 4.6, about 4.5, or 4.5, from the viewpoint of the stability of the antibody moiety and the stability of the drug linker moiety contained in the antibody-drug conjugate. The solution used to adjust the pH in step (v) is not particularly limited as long as it can be used to adjust the pH of the reaction solution. For example, an aqueous acetic acid solution, an aqueous hydrochloric acid solution, or a buffer solution can be used. Preferably, an aqueous acetic acid solution is used, and more preferably, a 10% aqueous acetic acid solution is used. In one embodiment of the present invention, when the antibody-drug conjugate produced by the present invention is an antibody-pyrrolobenzodiazepine derivative conjugate, conjugation of the antibody of the present invention to the drug linker intermediate can be performed by the methods described in WO 2019 / 065964, U.S. Patent Publication No. 2020 / 0261594, WO 2020 / 196474 or U.S. Patent Publication No. 2022 / 0168440, the disclosures of which are incorporated herein by reference. In one embodiment of the present invention, when the antibody-drug conjugate produced by the present invention is an antibody-cyclic dinucleotide derivative conjugate, the conjugation of the antibody of the present invention to the drug linker intermediate can be performed by the methods described in WO 2020 / 050406, U.S. Patent Publication No. 2022 / 0008549, WO 2021 / 177438 or U.S. Patent Publication No. 2023 / 0330248 (the disclosures of which are incorporated by reference herein). In certain embodiments of the invention, conjugation of an antibody of the invention to a drug linker intermediate can be carried out as described in WO 2014 / 057687 or U.S. Application Publication No. 2015 / 0297748, the disclosures of which are incorporated herein by reference. 6. Purification process using activated carbon materials The method for producing the antibody-drug conjugate of the present invention comprises the steps of: (i) removing by-products derived from the exatecan compound contained in a solution containing the antibody-drug conjugate using an activated carbon material. In one embodiment of the present invention, the step (i) is included after the step (iv). In general, in an antibody-drug conjugate, a drug with high cytotoxicity is bound to the antibody, and it is preferable to remove as much of the highly active impurities derived from the drug that is not bound to the antibody from the antibody-drug conjugate drug substance as possible, which is an extremely important requirement for the quality of the drug substance. The step (i) included in the present invention not only provides a method for efficiently purifying an antibody-drug conjugate from highly active impurities, but also reduces the amount of waste liquid containing highly active impurities compared to a conventional purification step by diafiltration (for example, the method described in WO 2020 / 022363). In addition, according to the step (i) included in the present invention, low molecular weight impurities can also be removed. Activated carbon (or activated charcoal) is a substance whose main component is porous carbon that has been subjected to chemical or physical treatment (activation, activation) to increase its adsorption efficiency. For example, it is used for the purpose of selectively separating, removing, and purifying specific substances. Activated carbon has a very large surface area-to-mass ratio and is capable of physical adsorption of solutes. The activated carbon used in the present invention preferably has a viscosity of 10 to 10,000 m 2 / g, more preferably 100 to 5000 m 2 / g, most preferably 1000 to 2000 m 2 / g surface area. The average particle size of the activated carbon used in the present invention is preferably 2 μm or more, more preferably 2 to 550 μm, and most preferably 5 to 40 μm. The particle size range of the activated carbon used in the present invention is, for example, such that the ratio of the average particle size of 5 to 40 μm is preferably at least 90% by weight, more preferably at least 95% by weight, and most preferably at least 98% by weight, based on the total weight of the activated carbon. The form of the activated carbon in step (i) is not particularly limited, and any form suitable for the production of pharmaceuticals can be used. Examples of the activated carbon include granular activated carbon such as crushed carbon, granular carbon, spherical carbon, or pelleted carbon, fibrous activated carbon such as fiber or cloth, specially formed activated carbon such as a sheet, molded body, or honeycomb shape, and powdered activated carbon. In one embodiment of the present invention, in step (i), a depth filter (activated carbon filter in the narrow sense) molded as a carrier that is filled with activated carbon material in advance and integrally formed is used. As the activated carbon filter, one made of activated carbon, cellulose fiber, etc. can be suitably used. In addition, filtering a solution containing a crude antibody-drug conjugate through an activated carbon filter is sometimes called activated carbon filtration. The activated carbon filter used in the present invention is not particularly limited, but examples of commercially available activated carbon filters include Millistak+ (registered trademark) Pod CR40 (Merck Millipore), Zeta Plus activated carbon adsorption depth filter (3M), SUPRAcap 50 Seitz (registered trademark) AKS filter (PALL), Supracap (registered trademark) 50 depth filter capsules activated carbon series AKS depth filter media (Cytiva), etc. The activated carbon filter of the present invention is preferably Millistak+ Depth Filter CR40 media, or a filter having an area of ​​5 cm2 composed of the same activated carbon, cellulose fiber, etc. 2 or Supracap® 50 depth filter capsules activated carbon series AKS depth filter media (Cytiva). The activated carbon filtration may be any of the following methods: (1) passing a solution containing a crude antibody-drug conjugate through an activated carbon filter only once; (2) passing a solution containing a crude antibody-drug conjugate that has been filtered with activated carbon one or more times through an activated carbon filter multiple times by recirculating the solution; (3) passing a solution containing a crude antibody-drug conjugate that has been filtered with activated carbon one or more times through the same activated carbon filter multiple times without recirculating the solution; and (4) passing a solution containing a crude antibody-drug conjugate that has been filtered with activated carbon one or more times through different activated carbon filters multiple times without recirculating the solution. However, a preferred embodiment of step (i) of the present invention is (1) passing a solution containing a crude antibody-drug conjugate through an activated carbon filter only once. In the examples of WO 2014 / 024514, a method for purifying an antibody from a cell culture supernatant containing the antibody using activated carbon in the production of the antibody is described. However, this technology is a technology for purifying an antibody, and the impurities to be removed are protein-derived substances such as host cell proteins (HCPs), and no technology is disclosed for purifying highly active drug-derived impurities from crude antibody-drug conjugates in which an antibody has been chemically modified. Matthew S., et al., Langmuir (2014), 30(27), 8046-8055 describes an activated carbon purification technology that sets an appropriate pH by focusing on the isoelectric point of a substance, but this document also targets protein-derived impurities such as HCPs for removal. The Examples of WO 2020 / 153390 describe a method for purifying an antibody by treating it with activated carbon after virus inactivation in the production of the antibody. This purification method is a technology that shows that activated carbon purification can function as an alternative to an anion exchange (AEX) chromatography step that has virus clearance capability, but does not disclose a technology for purifying a crude antibody-drug conjugate in which the antibody has been chemically modified. WO 2014 / 143622 describes a method for removing pyrrolobenzodiazepine-related impurities from a PBD-ADC product mixture using activated carbon. It is generally known that the adsorption of solutes by an activated carbon filter depends on the time of contact with the liquid, since the extraction efficiency depends on the flow rate (paragraph

[0060] of the same publication). Therefore, the flow rate of the mixture passing through the activated carbon filter needs to be increased or decreased according to the desired purity level (paragraph

[0060] of the same publication). In the case of activated carbon filtration of PBD-ADC, a flow rate of 6 L / min / m 2 It is described that at a high flow rate exceeding 1 L / min / m, the clearance of intermediates in the reaction process decreases (paragraph

[0061] of the same publication, paragraph

[0081] of Example 5, Figure 4). In step (i) of the present invention, the flow rate in the activated carbon filtration is unlikely to affect the efficiency of impurity removal, and for example, 2 ~10 L / min / m 2 The flow rate can be appropriately selected within the range of 6 L / min / m 2 ~10 L / min / m 2 , more preferably 7 L / min / m 2 ~10 L / min / m 2 , and even more preferably 8 L / min / m 2 ~10 L / min / m 2 , particularly preferably 9 L / min / m 2 ~10 L / min / m 2 It is. It has also been described that the main impurity in the product mixture of PBD-ADC is a compound in which N-acetylcysteine ​​is added to a drug linker (hereinafter also referred to as "PBD-NAC") (paragraph

[0072] of International Publication No. 2014 / 143622). N-acetylcysteine ​​is used to quench unreacted drug linkers. One of the main impurities of the present invention is a compound represented by formula (3), that is, a compound in which N-acetylcysteine ​​is added to a drug linker containing exatecan (hereinafter also referred to as "DXd-NAC"). It is generally known that the larger the LogPow and the more aromatic rings a compound has, the higher its adsorption rate to activated carbon. In particular, it is known that compounds with a LogPow of more than 3, containing aromatic rings, and having substituents on the aromatic rings with little steric hindrance tend to have a higher adsorption rate to activated carbon (Table 1 and Fig. 1 in Journal of Environmental Chemistry, Vol. 19, No. 4, pp. 519-525, 2009, etc.). Here, LogPow is the octanol-water partition coefficient, a physicochemical index that indicates the hydrophobicity of a chemical substance. cLogP (calculated LogP) is an index that is widely used as a predicted value of the LogPow of a molecule, and can be calculated even by ChemDraw, the most common software for drawing chemical structure formulas. Here, the cLogP (PCMODELS CLOGP, Daylight Version 4.82) of PBD-NAC is calculated to be 3.042, and the cLogP of DXd-NAC is calculated to be -0.203. From the calculation results of the cLogP and Table 1 and Fig. 1 described in the above literature, it would be expected that DXd-NAC has a significantly low adsorption to activated carbon or does not adsorb at all, since DXd-NAC has a lower fat solubility than PBD-NAC. However, the present inventors surprisingly found that DXd-NAC can be efficiently removed by activated carbon filtration. Furthermore, it has been described that a single filtration with an activated carbon filter is insufficient to reduce the concentration of the impurity PBD-NAC from the PBD-ADC product mixture (Paragraph

[0059] of International Publication No. 2014 / 143622). In order to sufficiently reduce the concentration of PBD-NAC, it is necessary to pass the PBD-ADC product mixture through an activated carbon filter multiple times. Since DXd-NAC has a lower lipid solubility than PBD-NAC, a person skilled in the art would assume that multiple activated carbon filtrations would be required to remove DXd-NAC, similar to or more than PBD-NAC, but the present inventors have surprisingly found that DXd-NAC can be efficiently removed by only one activated carbon filtration. The temperature (internal temperature) of the reaction solution containing the antibody-drug conjugate in step (i) is not particularly limited, but may be, for example, within the range of 0 to 30°C, and may be 2 to 28°C, 4 to 26°C, 6 to 24°C, 8 to 22°C, 10 to 20°C, 12 to 18°C, or 14 to 16°C, about 15°C, or 15°C, from the viewpoint of inhibiting the formation of aggregates of the antibody-drug conjugate. The pH of the solution containing the antibody-drug conjugate used in step (i) is not particularly limited, but may be within the range of 4 to 6, for example, and may be 4.2 to 5.8, 4.4 to 5.6, 4.6 to 5.4, 4.8 to 5.2, about 5, 5.0, 4.0 to 5.0, 4.1 to 4.9, 4.2 to 4.8, 4.3 to 4.7, 4.4 to 4.6, about 4.5, or 4.5, from the viewpoints of the stability of the antibody moiety and the stability of the drug linker moiety contained in the antibody-drug conjugate. The content of the by-product derived from the exatecan compound contained in the solution containing the antibody-drug conjugate used in step (i) is not particularly limited, and may be, for example, within the range of 0 to 300 μM for compound (3), and may be within the range of 0 to 150 μM, 0 to 140 μM, 0 to 130 μM, 0 to 120 μM, 0 to 110 μM, 0 to 100 μM, 0 to 90 μM, or 0 to 80 μM, and for compound (4), it may be within the range of 0 to 160 μM, and may be within the range of 0 to 80 μM, 0 to 75 μM, 0 to 70 μM, 0 to 65 μM, 0 to 60 μM, 0 to 55 μM, 0 to 50 μM, or 0 to 45 μM. The buffer solution contained in the solution containing the antibody-drug conjugate used in step (i) may be, for example, an acetate buffer, a histidine buffer, or a phosphate buffer, and may be, for example, an aqueous solution of sodium acetate, an aqueous solution of L-histidine, or an aqueous solution of disodium hydrogen phosphate. The solution containing the antibody-drug conjugate used in step (i) may or may not contain a surfactant. When a surfactant is contained, the surfactant is not particularly limited and may be, for example, polysorbate 20 or polysorbate 80. The method for producing an antibody-drug conjugate of the present invention may include a step (vi) of rinsing the activated carbon filter. The present invention preferably includes step (vi) following step (i). Here, "rinsing" refers to eluting a small amount of antibody-drug conjugate adsorbed to the activated carbon filter. When a solution containing an antibody-drug conjugate is filtered through activated carbon, the amount of the antibody-drug conjugate contained in the filtered solution is about 93-95% of the antibody-drug conjugate contained in the solution before filtration. This is because 5-7% of the antibody-drug conjugate may be adsorbed by the activated carbon and not eluted into the filtered solution. The present inventors have found that by rinsing the activated carbon filter used for filtration with a specific buffer solution, the antibody-drug conjugate of interest can be recovered without elution of by-products derived from the exatecan compound. That is, the present inventors have found a buffer solution suitable for rinsing the activated carbon filter, in which by-products derived from the exatecan compound are irreversibly adsorbed to the activated carbon and the antibody-drug conjugate of interest is reversibly adsorbed to the activated carbon. The recovery rate of the antibody-drug conjugate by rinsing is about 1-3%. The buffer used in step (vi) is not particularly limited as long as it allows the recovery of the antibody-drug conjugate of interest, and examples thereof include acetate buffer, histidine buffer, phosphate buffer, PIPES buffer, HEPES buffer, etc., but is preferably a buffer that allows the recovery of the antibody-drug conjugate of interest without elution of by-products derived from the exatecan compound, more preferably a histidine buffer, even more preferably a 5 to 15 mmol / L L-histidine buffer, and most preferably an 8.5 mmol / L L-histidine buffer. According to WO 2014 / 143622, in the purification process of PBD-ADC by activated carbon filtration, multiple activated carbon filtrations are required to sufficiently remove drug linker-derived impurities (paragraphs

[0010] and

[0011] , Example 4 of the same publication), and it is described that even after filtration, impurities are contained at least 0.06 μM (Table 1 in Example 4 of the same publication), and the recovery rate of the target PBD-ADC is at most 80% (Table 1 in Example 4 of the same publication). The solution used for activated carbon filtration contains an organic solvent such as propylene glycol to dissolve the drug linker (paragraph

[0054] , Example 1 of the same publication). In a solution containing an organic solvent that has high elution properties for the drug linker and impurities derived therefrom, it is considered difficult to irreversibly adsorb the drug linker-derived impurities to the activated carbon and reversibly adsorb the PBD-ADC to the activated carbon. Furthermore, Example 3 in paragraph

[0077] of the same publication describes that even if an activated carbon filter is filled with a buffer solution in advance, the target antibody-drug conjugate is adsorbed to the activated carbon, suggesting that recovery of the adsorbed antibody-drug conjugate is difficult even if it is rinsed with a buffer solution. For example, when the average number of drug linkers bound per antibody in the antibody-drug conjugate to be produced is in the range of 7 to 8, and the antibody is an anti-GPR20 antibody (preferably an antibody comprising a heavy chain consisting of the amino acid sequence set forth in amino acid numbers 20 to 472 in SEQ ID NO: 1 and a light chain consisting of the amino acid sequence set forth in amino acid numbers 21 to 234 in SEQ ID NO: 2, or an antibody lacking a lysine residue at the carboxyl terminus of the heavy chain), the buffer used in step (iv) is preferably a histidine buffer, more preferably a 5 to 15 mmol / L L-histidine buffer, and even more preferably an 8.5 mmol / L L-histidine buffer (pH 5.3). The method for rinsing with a buffer solution in step (vi) is not particularly limited, and may involve passing a fixed amount of the buffer solution through an activated carbon filter once or multiple times and recovering the resulting buffer solution containing the antibody-drug conjugate of interest; may involve circulating a fixed amount of the buffer solution through an activated carbon filter multiple times and recovering the resulting buffer solution containing the antibody-drug conjugate of interest; or may involve any other rinsing method. Furthermore, when the average number of drug linkers bound per antibody in the antibody-drug conjugate to be produced is in the range of 7 to 8, and the antibody is an anti-MUC1 antibody (preferably an antibody comprising a heavy chain consisting of the amino acid sequence set forth in amino acid numbers 1 to 447 of SEQ ID NO:5 or the amino acid sequence set forth in amino acid numbers 1 to 447 of SEQ ID NO:6 and a light chain consisting of the amino acid sequence set forth in amino acid numbers 1 to 219 of SEQ ID NO:7, or an antibody in which a lysine residue is deleted at the carboxyl terminus of the heavy chain of the antibody), the buffer used in step (iv) is preferably a histidine buffer, more preferably a 5 to 15 mmol / L L-histidine buffer, and even more preferably an 8.5 mmol / L L-histidine buffer (pH 5.3). The method for rinsing with a buffer solution in step (vi) is not particularly limited, and may involve passing a fixed amount of the buffer solution through an activated carbon filter once or multiple times and recovering the resulting buffer solution containing the antibody-drug conjugate of interest; may involve circulating a fixed amount of the buffer solution through an activated carbon filter multiple times and recovering the resulting buffer solution containing the antibody-drug conjugate of interest; or may involve any other rinsing method. Furthermore, when the average number of drug linkers bound per antibody in the antibody-drug conjugate to be produced is in the range of 7 to 8, and the antibody is an anti-CD37 antibody (preferably an antibody comprising a heavy chain consisting of the amino acid sequence set forth in amino acid numbers 20 to 468 of SEQ ID NO: 3 and a light chain consisting of the amino acid sequence set forth in amino acid numbers 21 to 234 of SEQ ID NO: 4, or an antibody lacking a lysine residue at the carboxyl terminus of the heavy chain), the buffer used in step (iv) is preferably a histidine buffer, more preferably a 5 to 15 mmol / L L-histidine buffer, and even more preferably an 8.5 mmol / L L-histidine buffer (pH 5.3). The method for rinsing with a buffer solution in step (vi) is not particularly limited, and may involve passing a fixed amount of the buffer solution through an activated carbon filter once or multiple times and recovering the resulting buffer solution containing the antibody-drug conjugate of interest; may involve circulating a fixed amount of the buffer solution through an activated carbon filter multiple times and recovering the resulting buffer solution containing the antibody-drug conjugate of interest; or may involve any other rinsing method. The purification method of by-products derived from compound (2) by steps (i) and (vi) of the present invention can reduce the amount of waste liquid containing highly active impurities at an industrial level, compared with the conventional purification method of by-products derived from compound (2) by diafiltration (for example, the method described in International Publication No. 2020 / 022363). For example, when 2 kg (20 g / L) of an antibody-drug conjugate solution is purified by diafiltration using tangential flow filtration, the diafiltration volume 1 DV (Diafiltration Volume) is generally 100 L. When it is necessary to use 5 DV to 15 DV of buffer to remove by-products derived from compound (2), it can be calculated that 500 L to 1500 L of waste liquid containing highly active impurities (hereinafter also referred to as "highly active waste liquid") is discharged. On the other hand, in the case of the purification step using the activated carbon material included in the production method of the present invention, after passing the process liquid body, only the buffer required for rinsing is used. That is, when 1 DV of buffer is used for rinsing and then concentrated to a predetermined concentration, the waste liquid remains at 100 L. When treating highly active waste liquid, a processing load is imposed on the process of detoxifying the liquid and removing water, so reducing the total amount of waste liquid leads to a reduction in the burden on the environment. When the highly active waste liquid generated by the conventional method needs to be stored for a certain period of time before being treated, not only is it necessary to secure space to store the waste liquid corresponding to the number of times the antibody-drug conjugate is produced, but it is also necessary to manage the waste liquid while taking into consideration the risk of leakage. The activated carbon filter used in step (i) of the present invention requires a relatively small storage space compared to the volume occupied by the waste liquid, and the highly active impurities adsorbed to the activated carbon filter have a relatively smaller risk of leakage than the waste liquid. The concentration of by-products derived from the exatecan compound (e.g., compounds represented by formula (3) and formula (4)) in the reaction solution after step (i) of the present invention is preferably about 1 μM or less, more preferably 0.1 μM or less, and even more preferably 0.06 μM or less. According to the present invention, a pharmaceutical composition can be provided that contains by-products derived from the exatecan compound at a concentration of preferably about 1 μM or less, more preferably 0.1 μM or less, and even more preferably 0.06 μM or less. According to the step (i) of the present invention, a solution containing an antibody-drug conjugate from which by-products derived from compound (2) have been removed can be produced. The solution containing an antibody-drug conjugate obtained by the production method of the present invention is characterized by containing 0.3% or less, preferably 0.1% or less, more preferably 0.05% or less, and even more preferably 0.03% or less of by-products derived from compound (2). According to the present invention, it is possible to provide a pharmaceutical composition containing an antibody-drug conjugate containing 0.3% or less, preferably 0.1% or less, more preferably 0.05% or less, and even more preferably 0.03% or less of by-products derived from compound (2). Such a content can be calculated, for example, by the method described below. The step (i) of the present invention can be used for both small-scale and large-scale production of the desired antibody-drug conjugate, for example, the step (i) of the present invention can be applied to the milligram to kilogram scale of the resulting antibody-drug conjugate. According to step (i) of the present invention, by-products derived from the exatecan compound can be removed, and therefore, as long as the structure of the by-products is common, the present invention can be applied regardless of the antibody portion of the target antibody-drug conjugate. In one embodiment of the present invention, the activated carbon material used in step (i) is powdered activated carbon. The antibody-drug conjugate can be purified by adding powdered activated carbon or a suspension thereof to a crude antibody-drug conjugate, and after a certain period of time, filtering or otherwise removing the mixture of the antibody-drug conjugate, by-products derived from the exatecan compound, and activated carbon to remove the activated carbon powder to which the by-products have been adsorbed. The concentration of the antibody-drug conjugate in the solution can be measured by known methods, for example, using the SoloVPE Variable Pathlength System (C Technologies, Inc., Bridgewater, NJ). In this specification, the measurement method using this device is sometimes referred to as the SoloVPE method. The antibody-drug conjugate concentration measured by this method is converted into the antibody concentration and is therefore equal to the antibody concentration in the antibody-drug conjugate. The concentration and content (%) of the by-product derived from compound (2), including the compound represented by formula (3) and the compound represented by formula (4), in the solution can be measured by a known method, for example, by the method shown below. Equipment: H-Class, Acquity Arc(Path 2), Agilent1290 Column: BioReslove RP mAb Polyphenyl (2.1×50 mm, 2.7 μm) Column temperature: 45℃, sample storage temperature: 10℃ Mobile phase A: 0.01 M ammonium sulfate phosphate buffer, pH 3.4 Mobile phase B: methanol / acetonitrile (1:1) Mobile phase C: Dilute perchloric acid (500 times diluted) Mobile phase D: Acetonitrile Wavelength: 370 nm, flow rate: 0.5 mL / min, sample injection volume: 2 μL Sampling rate: 5Hz (H-Class), 10Hz (Agilent1290) Elution mode: gradient, 40 min Gradient Program As a sample of the by-product derived from compound (2), for example, an aqueous solution of riboflavin prepared as follows can be used. 1) Accurately measure 40 mg of riboflavin standard. 2) Add water / acetonitrile mixture (1:1) to dissolve, then make up to exactly 200 mL. 3) Take 1 mL of the above solution and add a water / acetonitrile mixture (9:1) to make exactly 50 mL. When the above riboflavin solution is used, the concentration of the by-product derived from compound (2) can be calculated using the following formula. The drug concentration in the antibody-drug conjugate can be calculated from the antibody concentration in the antibody-drug conjugate obtained by the SoloVPE method using the following formula. Here, the average number of drugs bound per antibody molecule of an antibody-drug conjugate can be calculated, for example, by a method in which the UV absorbance of the antibody-drug conjugate and its conjugation precursor are measured at two wavelengths, 280 nm and 370 nm (UV method), or by a method in which the antibody-drug conjugate is treated with a reducing agent, and each of the resulting fragments is quantified by HPLC measurement and then calculated (HPLC method). The average number of drugs bound per antibody molecule of the antibody-drug conjugate can be calculated with reference to the descriptions in WO 2014 / 057687, WO 2015 / 098099, WO 2015 / 115091, WO 2015 / 155998, WO 2018 / 135501, WO 2018 / 212136, WO 2019 / 219891, WO 2020 / 022363, WO 2022 / 014698, and WO 2023 / 068226. The amount (%) of each by-product derived from compound (2) can be calculated from the concentration of the by-product derived from compound (2) and the drug concentration in the antibody-drug conjugate using the following formula. The content of TCEP in the solution containing the antibody-drug conjugate used in step (i) is not particularly limited, and may be, for example, within the range of 0 to 300 μg / mL, and may be within the range of 0 to 290 μg / mL, 0 to 280 μg / mL, 0 to 270 μg / mL, 0 to 260 μg / mL, 0 to 250 μg / mL, 0 to 240 μg / mL, 0 to 230 μg / mL, 0 to 220 μg / mL, 0 to 210 μg / mL, or 0 to 200 μg / mL. The present inventors have found that the step (i) of the present invention can remove not only by-products derived from the exatecan compound but also TCEP from the reaction solution. The concentration of TCEP in the solution can be measured by a known method, for example, it can be measured as tris(2-carboxyethyl)phosphine oxide (hereinafter also referred to as "TCEPO") by the method shown below. Equipment: Acquity UPLC H-Class and Qda (Waters) Detector:Mass spectormeter (ESI positivem Selected ion m / z 267 monitoring) Column: Inertsil AX (4.6 mm ID x 120 mm, 5 μm) Column temperature: 40℃ Mobile phase: A mixture of 250mM formic acid aq., 250mM ammonium formate aq. And methanol (19:19:2) Flow rate: 1.0 mL / min Dissolution mode: Isocratic, 15 min A TCEP standard can be prepared, for example, as follows. 1) Accurately measure 50 mg of TCEP. 2) Add purified water to dissolve completely, then make up to exactly 250 mL. 3) Add 10 μL of hydrogen peroxide to 1000 μL of solution 2) and incubate at room temperature for 10 minutes. 4) Add 7 μL of ammonia water and 983 μL of purified water to 3) to make a standard solution. The concentration of TCEP in the reaction solution after step (i) of the present invention is preferably 140 μg / mL or less. According to the present invention, it is possible to provide a pharmaceutical composition containing TCEP at 140 μg / mL or less. The removal rate of TCEP after step (i) of the present invention is preferably 16% or more, more preferably 20% or more, and even more preferably 24% or more. The content of NAC in the solution containing the antibody-drug conjugate used in step (i) is not particularly limited, but may be within the range of 0 to 300 μg / mL, and may also be within the range of 0 to 290 μg / mL, 0 to 280 μg / mL, 0 to 270 μg / mL, 0 to 260 μg / mL, 0 to 250 μg / mL, 0 to 240 μg / mL, 0 to 230 μg / mL, or 0 to 220 μg / mL, for example. The concentration of NAC can be measured by known methods, for example, by the method described below. Equipment: SpectraMax Spectra Maxi3x (Molecular Devices) Quantitative kit: Measure-IT Thiol Assay Kit The kit's usage method involves preparing standard and sample solutions and measuring them according to the experimental protocol described in the manual. The concentration of NAC in the reaction solution after step (i) of the present invention is preferably about 100 μg / mL or less, more preferably 70 μg / mL or less, and even more preferably 40 μg / mL or less. According to the present invention, a pharmaceutical composition containing NAC of preferably about 100 μg / mL or less, more preferably 70 μg / mL or less, and even more preferably 40 μg / mL can be provided. The removal rate of NAC by step (i) of the present invention is preferably 60% or more, more preferably 70% or more, and even more preferably 80% or more. The present invention may include a step of pre-washing the activated carbon filter used for the activated carbon filtration prior to step (i). It is recommended that the activated carbon filter be pre-washed with water before use to prevent contamination of the reaction solution with eluates from the activated carbon. The inventors have thoroughly investigated the solution used for pre-washing and have succeeded in improving the recovery rate of the desired antibody-drug conjugate without reducing the efficiency of removing by-products derived from the exatecan compound. The solution used for pre-washing is preferably an aqueous solution containing a surfactant, more preferably an aqueous solution of polysorbate 20 or polysorbate 80, and even more preferably an aqueous solution of polysorbate 80. The amount of solution used for the pre-use washing can be appropriately selected by a person skilled in the art depending on the amount of by-products derived from the exatecan compound eluted and the recovery rate of the desired antibody-drug conjugate. However, using an excessive amount of solution will result in a decrease in the amount of by-products derived from the exatecan compound adsorbed, making it impossible to obtain a sufficient purification effect, and therefore it is desirable to precisely adjust the amount of solution depending on the target amount of by-products to be removed and the recovery rate of the antibody-drug conjugate. As described above, the removal of by-products derived from the exatecan compound from a solution containing an antibody-drug conjugate using the exatecan compound has been described. However, the purification process using the activated carbon material is not limited to the removal of by-products derived from the exatecan compound, and can also be applied to the removal of by-products derived from other drugs different from the exatecan compound from a solution containing an antibody-drug conjugate using the other drug. In certain embodiments of the invention, the purification process using the activated carbon material of the invention can be carried out using, for example, antibody-pyrrolobenzodiazepine derivative conjugates described in WO 2019 / 065964, U.S. Patent Publication No. 2020 / 0261594, WO 2020 / 196474 or U.S. Patent Publication No. 2022 / 0168440 (the disclosures of which are incorporated by reference herein) or antibody-cyclic dinucleotide derivative conjugates described in WO 2020 / 050406, U.S. Patent Publication No. 2022 / 0008549, WO 2021 / 177438 or U.S. Patent Publication No. 2023 / 0330248 (the disclosures of which are incorporated by reference herein). In certain embodiments of the invention, the purification process using the activated carbon material of the invention can be carried out using antibody-drug conjugates, for example as described in WO 2014 / 057687 or US 2015 / 0297748, the disclosures of which are incorporated herein by reference, preferably having the following structure attached to the antibody as a drug-linker structural moiety: -(Succinimid-3-yl-N)-CH2CH2CH2CH2CH2-C(=O)-GGFG-NH-CH2-O-CH2-C(=O)-(NH-DX), -(Succinimid-3-yl-N)-CH2CH2CH2CH2CH2-C(=O)-GGFG-NH-CH2CH2-O-CH2-C(=O)-(NH-DX), -(Succinimid-3-yl-N)-CH2CH2-C(=O)-NH-CH2CH2O-CH2CH2O-CH2CH2-C(=O)-GGFG-NH-CH2CH2CH2-C(=O)-(NH-DX). 7. Preparation of pharmaceutical compositions The pharmaceutical composition of the present invention is a pharmaceutical composition comprising an antibody-drug conjugate of the present invention, a buffer and an excipient. Such pharmaceutical compositions further comprise an antibody-drug conjugate produced (including purification) by the above-mentioned method, (vii) adding a buffer solution to the solution containing the antibody-drug conjugate; (viii) concentrating the solution containing the antibody-drug conjugate; and (ix) adjusting the pH of the solution containing the antibody-drug conjugate to a predetermined value; At least one step selected from the group consisting of: and, (x) adding an excipient to the solution containing the antibody-drug conjugate; The present invention can be produced by carrying out a process including the steps of: The buffer added in step (vii) is preferably the same as the buffer used in step (ii), and therefore, the buffer used in step (vii) is preferably a histidine buffer. The adjustment of pH in step (ix) can be preferably carried out using an aqueous histidine solution when the buffer used in step (vii) is a histidine buffer. In the present invention, the term "excipient" refers to a substance added to make a pharmaceutical product have a certain size or concentration in order to improve the convenience of molding, handling, and taking the drug, etc. Such excipients are not particularly limited as long as they exhibit the effects of the present invention, and examples thereof include sucrose, trehalose, and sorbitol. As the excipient added in step (x), sucrose or trehalose can be preferably used. Furthermore, the pharmaceutical composition according to the present invention preferably further comprises a surfactant, i.e., the pharmaceutical composition according to the present invention is more preferably a pharmaceutical composition comprising an antibody-drug conjugate, a buffer solution, an excipient, and a surfactant. Such a pharmaceutical composition can be produced by carrying out a step including the step of (xi) adding a surfactant after the above step (x). As the surfactant added in step (xi), polysorbate 80 or polysorbate 20 can be suitably used. The concentrations of the buffer solution, excipient, surfactant, and antibody-drug conjugate in the pharmaceutical composition, as well as the pH of the pharmaceutical composition, can be appropriately selected depending on the average number of drug linkers bound per antibody in the antibody-drug conjugate to be produced and the type of antibody. For example, when the average number of drug linkers bound per antibody in the antibody-drug conjugate to be produced is in the range of 7 to 8, and the antibody is an anti-HER2 antibody (preferably an antibody comprising a heavy chain consisting of the amino acid sequence set forth in amino acid numbers 1 to 449 in SEQ ID NO: 8 and a light chain consisting of the amino acid sequence set forth in amino acid numbers 1 to 214 in SEQ ID NO: 9, or an antibody comprising a heavy chain consisting of the amino acid sequence set forth in SEQ ID NO: 1 and a light chain consisting of the amino acid sequence set forth in SEQ ID NO: 2), preferably, histidine buffer (preferably 25 mM histidine buffer), sucrose (preferably 9% sucrose), and polysorbate 80 (preferably 0.03% polysorbate 80) can be used as the buffer, excipient, and surfactant in the pharmaceutical composition, the concentration of the antibody-drug conjugate in the pharmaceutical composition is preferably 20 mg / mL, and the pH of the pharmaceutical composition is preferably 5.5. Furthermore, when the average number of drug linkers bound per antibody in the antibody-drug conjugate to be produced is in the range of 3.5 to 4, and the antibody is an anti-TROP2 antibody (preferably an antibody comprising a heavy chain consisting of the amino acid sequence set forth in amino acid numbers 20 to 470 in SEQ ID NO: 10 and a light chain consisting of the amino acid sequence set forth in amino acid numbers 21 to 234 in SEQ ID NO: 11, or an antibody in which a lysine residue at the carboxyl terminus of the heavy chain is deleted), preferably, histidine buffer (preferably 10 mM histidine buffer), sucrose (preferably 9% sucrose), and polysorbate 80 (preferably 0.02 or 0.03% polysorbate 80) can be used as the buffer, excipient, and surfactant in the pharmaceutical composition, the concentration of the antibody-drug conjugate in the pharmaceutical composition is preferably 20 mg / mL, and the pH of the pharmaceutical composition is preferably 6.0. Furthermore, when the average number of drug linkers bound per antibody in the antibody-drug conjugate produced is in the range of 7 to 8, and the antibody is an anti-HER3 antibody (preferably an antibody comprising a heavy chain consisting of the amino acid sequence set forth in SEQ ID NO: 12 and a light chain consisting of the amino acid sequence set forth in SEQ ID NO: 13, or an antibody in which a lysine residue at the carboxyl terminus of the heavy chain is deleted), preferably, histidine buffer (preferably 25 mM histidine buffer), sucrose (preferably 9% sucrose), and polysorbate 20 (preferably 0.03% polysorbate 20) can be used as the buffer, excipient, and surfactant in the pharmaceutical composition, the concentration of the antibody-drug conjugate in the pharmaceutical composition is preferably 20 mg / mL, and the pH of the pharmaceutical composition is preferably 5.4. Furthermore, when the average number of drug linkers bound per antibody in the antibody-drug conjugate to be produced is in the range of 3.5 to 4, and the antibody is an anti-B7-H3 antibody (preferably an antibody comprising a heavy chain consisting of the amino acid sequence set forth in amino acid numbers 20 to 471 in SEQ ID NO: 14 and a light chain consisting of the amino acid sequence set forth in amino acid numbers 21 to 233 in SEQ ID NO: 15, or an antibody in which a lysine residue at the carboxyl terminus of the heavy chain is deleted), preferably, histidine buffer (preferably 10 mM histidine buffer), sucrose (preferably 9% sucrose), and polysorbate 20 (preferably 0.02 or 0.03% polysorbate 20) can be used as the buffer, excipient, and surfactant in the pharmaceutical composition, the concentration of the antibody-drug conjugate in the pharmaceutical composition is preferably 20 mg / mL, and the pH of the pharmaceutical composition is preferably 5.9. Furthermore, when the average number of drug linkers bound per antibody in the antibody-drug conjugate to be produced is in the range of 7 to 8, and the antibody is an anti-GPR20 antibody (preferably an antibody comprising a heavy chain consisting of the amino acid sequence set forth in amino acid numbers 20 to 472 in SEQ ID NO: 1 and a light chain consisting of the amino acid sequence set forth in amino acid numbers 21 to 234 in SEQ ID NO: 2, or an antibody in which a lysine residue at the carboxyl terminus of the heavy chain is deleted), preferably, histidine buffer (preferably 10 mM histidine buffer), sucrose (preferably 9% sucrose), and polysorbate 80 (preferably 0.03% polysorbate 80) can be used as the buffer, excipient, and surfactant in the pharmaceutical composition, the concentration of the antibody-drug conjugate in the pharmaceutical composition is preferably 20 mg / mL, and the pH of the pharmaceutical composition is preferably 5.4. Furthermore, when the average number of drug linkers bound per antibody in the antibody-drug conjugate to be produced is in the range of 7 to 8, and the antibody is an anti-CDH6 antibody (preferably an antibody comprising a heavy chain consisting of the amino acid sequence set forth in amino acid numbers 20 to 471 in SEQ ID NO: 16 and a light chain consisting of the amino acid sequence set forth in amino acid numbers 21 to 233 in SEQ ID NO: 17, or an antibody in which a lysine residue at the carboxyl terminus of the heavy chain of the antibody is deleted), preferably, histidine buffer (preferably 10 mM histidine buffer), sucrose (preferably 9% sucrose), and polysorbate 80 (preferably 0.03% polysorbate 80) can be used as the buffer, excipient, and surfactant in the pharmaceutical composition, the concentration of the antibody-drug conjugate in the pharmaceutical composition is preferably 20 mg / mL, and the pH of the pharmaceutical composition is preferably 5.4. Furthermore, when the average number of drug linkers bound per antibody in the antibody-drug conjugate produced is in the range of 7 to 8, and the antibody is an anti-MUC1 antibody (preferably an antibody comprising a heavy chain consisting of the amino acid sequence set forth in amino acid numbers 1 to 447 in SEQ ID NO:5 or the amino acid sequence set forth in amino acid numbers 1 to 447 in SEQ ID NO:6 and a light chain consisting of the amino acid sequence set forth in amino acid numbers 1 to 219 in SEQ ID NO:7, or an antibody in which a lysine residue at the carboxyl terminus of the heavy chain of the antibody is deleted), preferably, histidine buffer (preferably 10 mM histidine buffer), sucrose (preferably 9% sucrose), and polysorbate 80 (preferably 0.03% polysorbate 80) can be used as the buffer, excipient, and surfactant in the pharmaceutical composition, the concentration of the antibody-drug conjugate in the pharmaceutical composition is preferably 25 mg / mL, and the pH of the pharmaceutical composition is preferably 5.2. Furthermore, when the average number of drug linkers bound per antibody in the antibody-drug conjugate to be produced is in the range of 7 to 8, and the antibody is an anti-CD37 antibody (preferably an antibody comprising a heavy chain consisting of the amino acid sequence set forth in amino acid numbers 20 to 468 in SEQ ID NO: 3 and a light chain consisting of the amino acid sequence set forth in amino acid numbers 21 to 234 in SEQ ID NO: 4, or an antibody in which a lysine residue at the carboxyl terminus of the heavy chain of the antibody is deleted), preferably, histidine buffer (preferably 8 mM histidine buffer), sucrose (preferably 9% sucrose), and polysorbate 80 (preferably 0.03% polysorbate 80) can be used as the buffer, excipient, and surfactant in the pharmaceutical composition, the concentration of the antibody-drug conjugate in the pharmaceutical composition is preferably 25 mg / mL, and the pH of the pharmaceutical composition is preferably 5.3. 8. Use of the Pharmaceutical Composition The pharmaceutical composition of the present invention can be applied to patients as a systemic therapy, and can also be applied locally to cancer tissues to be expected to have a therapeutic effect. The pharmaceutical composition of the present invention can be preferably used for mammals, and more preferably for humans. Examples of introduction routes that can be used to administer the pharmaceutical composition of the present invention include intravenous, intradermal, subcutaneous, intramuscular, and intraperitoneal routes, with intravenous being preferred. When the pharmaceutical composition of the present invention is an aqueous injection, it can be administered intravenously by drip infusion after being diluted with a suitable diluent, such as a glucose solution or saline, preferably a glucose solution, more preferably a 5% glucose solution. When the pharmaceutical composition of the present invention is a lyophilized injection, it is preferably dissolved in water for injection, and then diluted with a required amount of an appropriate diluent and administered intravenously by drip infusion. The diluent may be a glucose solution or a physiological saline solution, preferably a glucose solution, and more preferably a 5% glucose solution. In terms of the affinity of the antibody-drug conjugate of the present invention to an antigen, i.e., the dissociation constant (Kd value) for the antigen, the higher the affinity (the lower the Kd value), the more effective the pharmaceutical composition of the present invention can be even at a smaller dose. Therefore, the dose of the pharmaceutical composition of the present invention can be set based on the affinity with the antigen. When the pharmaceutical composition of the present invention is administered to a human, for example, about 0.001 to 100 mg / kg (here, "mg / kg" means the dose of the antibody-drug conjugate per kg of human body weight) of the antibody-drug conjugate may be administered once or multiple times at intervals of once every 1 to 180 days, and preferably, 0.8 mg / kg to 8 mg / kg may be administered once every three weeks. The dosage and administration interval of the antibody-drug conjugate can be appropriately selected depending on the average number of drug linkers bound per antibody in the antibody-drug conjugate to be produced and the type of antibody. For example, when the average number of drug linkers bound per antibody in the antibody-drug conjugate produced is in the range of 7 to 8, and the antibody is an anti-HER2 antibody (preferably an antibody comprising a heavy chain consisting of the amino acid sequence set forth in amino acid numbers 1 to 449 in SEQ ID NO: 8 and a light chain consisting of the amino acid sequence set forth in amino acid numbers 1 to 214 in SEQ ID NO: 9, or an antibody comprising a heavy chain consisting of the amino acid sequence set forth in SEQ ID NO: 8 and a light chain consisting of the amino acid sequence set forth in SEQ ID NO: 9), preferred methods include a method of administering 0.8 mg / kg, 1.6 mg / kg, 3.2 mg / kg, 5.4 mg / kg, 6.4 mg / kg, 7.4 mg / kg, or 8 mg / kg of the antibody-drug conjugate once every three weeks, more preferred methods include a method of administering 5.4 mg / kg, 6.4 mg / kg, 7.4 mg / kg, or 8 mg / kg of the antibody-drug conjugate once every three weeks, and even more preferred methods include a method of administering 5.4 mg / kg, 6.4 mg / kg, 7.4 mg / kg, or 8 mg / kg of the antibody-drug conjugate once every three weeks. An example of such a method is administration of mg / kg of the antibody-drug conjugate once every three weeks. Furthermore, when the average number of drug linkers bound per antibody in the antibody-drug conjugate produced is in the range of 3.5 to 4, and the antibody is an anti-TROP2 antibody (preferably an antibody comprising a heavy chain consisting of the amino acid sequence set forth in amino acid numbers 20 to 470 in SEQ ID NO: 10 and a light chain consisting of the amino acid sequence set forth in amino acid numbers 21 to 234 in SEQ ID NO: 11, or an antibody in which a lysine residue is deleted at the carboxyl terminus of the heavy chain), preferred methods include a method of administering 2 mg / kg, 3 mg / kg, 4 mg / kg, 5 mg / kg, 6 mg / kg, 7 mg / kg, 8 mg / kg, 9 mg / kg, or 10 mg / kg of the antibody-drug conjugate once every three weeks, and more preferred methods include a method of administering 4 mg / kg, 6 mg / kg, or 8 mg / kg of the antibody-drug conjugate once every three weeks. Furthermore, when the average number of drug linkers bound per antibody in the antibody-drug conjugate produced is in the range of 7 to 8, and the antibody is an anti-HER3 antibody (preferably an antibody comprising a heavy chain consisting of the amino acid sequence set forth in SEQ ID NO: 12 and a light chain consisting of the amino acid sequence set forth in SEQ ID NO: 13, or an antibody in which a lysine residue at the carboxyl terminus of the heavy chain is deleted), preferred methods include a method of administering 1.6 mg / kg, 3.2 mg / kg, 4.8 mg / kg, 5.6 mg / kg, 6.4 mg / kg, 8.0 mg / kg, 9.6 mg / kg, or 12.8 mg / kg of the antibody-drug conjugate once every three weeks, and more preferred methods include a method of administering 4.8 mg / kg, 5.6 mg / kg, or 6.4 mg / kg of the antibody-drug conjugate once every three weeks. Furthermore, when the average number of drug linkers bound per antibody in the antibody-drug conjugate produced is in the range of 7 to 8, and the antibody is an anti-B7-H3 antibody (preferably an antibody comprising a heavy chain consisting of the amino acid sequence set forth in amino acid numbers 20 to 471 in SEQ ID NO: 14 and a light chain consisting of the amino acid sequence set forth in amino acid numbers 21 to 233 in SEQ ID NO: 15, or an antibody lacking a lysine residue at the carboxyl terminus of the heavy chain), preferably, a single dose of 0.8 mg / kg, 1.6 mg / kg, 3.2 mg / kg, 4.8 mg / kg, 6.4 mg / kg, or 8.0 mg / kg can be administered at intervals of once every three weeks. Furthermore, when the average number of drug linkers bound per antibody in the antibody-drug conjugate produced is in the range of 7 to 8, and the antibody is an anti-CDH6 antibody (preferably an antibody comprising a heavy chain consisting of the amino acid sequence set forth in amino acid numbers 20 to 471 in SEQ ID NO: 16 and a light chain consisting of the amino acid sequence set forth in amino acid numbers 21 to 233 in SEQ ID NO: 17, or an antibody in which a lysine residue is deleted at the carboxyl terminus of the heavy chain of the antibody), preferably 0.1 to 50 mg / kg, more preferably 1 to 50 mg / kg, 1 to 30 mg / kg, 1 to 20 mg / kg, 1 to 15 mg / kg, 2 to 50 mg / kg, 2 to 30 mg / kg, 2 to 20 mg / kg, or 2 to 15 mg / kg may be administered multiple times at intervals of once every 1 to 4 weeks, preferably once every 2 to 3 weeks. The pharmaceutical composition of the present invention can be used for the treatment of cancer, and can be preferably used for the treatment of at least one cancer selected from the group consisting of breast cancer, gastric cancer (sometimes referred to as gastric adenocarcinoma), colon cancer (sometimes referred to as colorectal cancer, including colon cancer and rectal cancer), lung cancer (including small cell lung cancer and non-small cell lung cancer), esophageal cancer, head and neck cancer (including salivary gland cancer and pharyngeal cancer), gastroesophageal junction adenocarcinoma, biliary tract cancer (including bile duct cancer), Paget's disease, pancreatic cancer, ovarian cancer, uterine carcinosarcoma, urothelial cancer, prostate cancer, bladder cancer, gastrointestinal stromal tumor, cervical cancer, squamous cell carcinoma, peritoneal cancer, liver cancer, hepatocellular carcinoma, uterine cancer, kidney cancer, vulvar cancer, thyroid cancer, penile cancer, leukemia, malignant lymphoma, plasmacytoma, myeloma, glioblastoma multiforme, osteosarcoma, and melanoma. The pharmaceutical composition of the present invention can be selected and used as a drug for drug therapy, which is the main method of cancer treatment, and as a result, it can delay the growth of cancer cells, suppress their proliferation, and even destroy them. These actions can relieve cancer patients from symptoms caused by cancer and improve their QOL, and the therapeutic effect can be achieved while preserving the life of the cancer patient. Even if the destruction of cancer cells is not achieved, the inhibition and control of the proliferation of cancer cells can help cancer patients achieve a higher QOL and a longer life. In addition to the use of the drug alone in such drug therapy, the pharmaceutical composition of the present invention can also be used in adjuvant therapy in combination with other therapies, such as surgery, radiation therapy, hormone therapy, etc. Furthermore, it can also be used as drug therapy in neoadjuvant therapy. In addition to the above therapeutic uses, the pharmaceutical composition of the present invention can be expected to have a preventive effect of suppressing and even destroying the proliferation of minute metastatic cancer cells. For example, it can be expected to have an effect of suppressing and destroying cancer cells in body fluids during the metastasis process, and an effect of suppressing and destroying minute cancer cells immediately after implantation in any tissue. Therefore, it can be expected to have an effect of suppressing and preventing cancer metastasis, especially after surgical removal of cancer. The pharmaceutical composition of the present invention can be administered in combination with other cancer therapeutic agents, thereby enhancing the antitumor effect. The other cancer therapeutic agents used for such a purpose may be administered to an individual simultaneously with the pharmaceutical composition of the present invention, separately, or consecutively, or may be administered at different administration intervals.Such cancer therapeutic agents are not limited as long as they have antitumor activity, and examples thereof include irinotecan (CPT-11), cisplatin, carboplatin, oxaliplatin, fluorouracil (5-FU), gemcitabine, capecitabine, paclitaxel, docetaxel, doxorubicin, epirubicin, cyclophosphamide, mitomycin C, and the like. C), Tegafur / Gimeracil / Oteracil combination drug, Cetuximab, Panitumumab, Bevacizumab, Ramucirumab, Regorafenib, Trifluridine / Tipiracil combination drug, Gefitinib, Erlotinib, Afatinib, Methotrexate, Pemetrexed, Trastuzumab emtansine At least one selected from the group consisting of emtansin, trastuzumab, pertuzumab, tamoxifen, toremifene, fulvestrant, leuprorelin, goserelin, letrozole, anastrozole, and progesterone formulations may be mentioned. In this specification, unless the context requires otherwise, specifically and technically inconsistent, terms described in the singular also include the plural, and vice versa. The present invention will be described in more detail below with reference to examples, but the present invention is not limited to these examples. [Example 1] Removal of by-products derived from compound (2) using an activated carbon filter 1)-1 Reduction of antibody and conjugation of antibody with drug linker A solution (equivalent to 1.00 g of antibody) containing an anti-GPR20 antibody described in WO 2018 / 135501 (an antibody comprising a heavy chain consisting of the amino acid sequence described in amino acid numbers 20 to 472 in SEQ ID NO: 1 and a light chain consisting of the amino acid sequence described in amino acid numbers 21 to 234 in SEQ ID NO: 2) was placed in a glass flask, and a 150 mmol / L L-histidine aqueous solution (17 mL) containing 0.07 g / g polysorbate 80 and 2.0 mmol / L EDTA was added. Next, an aqueous solution containing 10 mmol / L TCEP hydrochloride (4.75 equivalents per antibody molecule) was added under stirring at 30°C, and an antibody having a thiol group was produced by stirring at the same temperature. After 3 hours, the reaction solution was cooled to an internal temperature of 15°C, and the following formula (2) was added under stirring. (8.90 equivalents per antibody molecule) was dissolved in an aqueous dimethyl sulfoxide solution containing acetic acid and added to react with the antibody having a thiol group. 1)-2 Quenching the reaction solution Next, a 0.03 mol / L N-acetylcysteine ​​aqueous solution (15.0 equivalents per antibody molecule) was added, and the mixture was stirred at the same temperature for 30 minutes to quench excess compound (2), and then the reaction solution was adjusted to pH 5.0 using a 10% aqueous acetic acid solution. (In the formula, A represents the binding site to the anti-GPR20 antibody.) A reaction solution containing an anti-GPR20 antibody-drug conjugate in which the drug linker represented by the formula: 1)-3 Rough purification of reaction solution using a filter The content of by-products derived from compound (2) in the resulting reaction solution was measured, and the reaction solution adjusted to 15°C was then passed through a Millistak+ (registered trademark) Depth Filter CR40 media (Merck), a depth filter formed using activated carbon powder as a carrier, and a filter having an area of ​​5 cm2, which is made of activated carbon and cellulose fibers, etc. 2 Filtration was performed using an activated carbon filter and a sterile filtration filter while pumping the liquid with a rotary pump. The reaction liquid after filtration was measured for the concentration of the anti-GPR20 antibody-drug conjugate and the content of by-products derived from compound (2), and the change in the content before and after filtration was tracked. For comparison, the content of by-products derived from compound (2) was measured when the activated carbon filter was not used. Here, the by-product derived from compound (2) is a compound in which tris(2-carboxyethyl)phosphine is added to the maleimidyl group of compound (2), that is, a compound represented by the following formula (3): and a compound in which N-acetylcysteine ​​is added to the maleimidyl group of compound (2), that is, a compound represented by the following formula (4): Examples of the compound include those represented by the following formula: 1)-4 Measurement of by-products derived from antibody-drug conjugates and compound (2) The concentrations of the anti-GPR20 antibody-drug conjugate before and after the activated carbon filter were measured and calculated by the SoloVPE method, and the contents of by-products derived from compound (2), including compound (3) and compound (4), were measured and calculated by the HPLC method. The contents of by-products derived from compound (2) and the recovery rates of the antibody-drug conjugates are shown in Table 2 and Figure 1. It was confirmed that compounds (3) and (4) could be almost completely removed by the activated carbon filter. In addition, the content (%) of by-products derived from compound (2) was calculated from the content of by-products derived from compound (2) and the drug concentration in the antibody-drug conjugate, and the results are shown in Table 3. [Example 2] Temperature study A reaction solution containing an anti-GPR20 antibody-drug conjugate was obtained by the method described in 1)-1 and 1)-2 of Example 1. The content of by-products derived from compound (2) in the obtained reaction solution was measured, and then the reaction solution was cooled to 0°C or heated to 30°C and then passed through a 5 cm2 filter made of activated carbon and cellulose fibers similar to Millistak+ (registered trademark) Depth Filter CR40 media (Merck), which is a depth filter molded using activated carbon powder as a carrier. 2 Filtration was performed using an activated carbon filter and a sterile filtration filter while pumping the solution with a rotary pump. The reaction solution after filtration was measured for the concentration of the anti-GPR20 antibody-drug conjugate and the content of by-products derived from compound (2), and the changes in the contents before and after filtration were tracked. The antibody-drug conjugate concentration and the content of by-products derived from compound (2) were measured before and after the activated carbon filter using the method described in 1)-4 of Example 1. The results of the content of by-products derived from compound (2) and the recovery rate of the antibody-drug conjugate are shown in Table 4 and Figure 2. Sufficient removal efficiency was confirmed in the liquid temperature range of 0 to 30°C. Although the difference was small, the removal efficiency was better at 30°C. [Example 3] pH study The antibody was reduced and the antibody was conjugated with a drug linker by the method described in 1)-1 of Example 1. Next, a 0.03 mol / L N-acetylcysteine ​​aqueous solution (15.0 equivalents per antibody molecule) was added, and the mixture was stirred at the same temperature for 30 minutes to quench excess compound (2), and the reaction solution was adjusted to pH 6.0 using a 10% aqueous acetic acid solution, or to pH 4.0 using a 10% aqueous acetic acid solution and acetic acid. This resulted in the formation of the compound represented by the following formula (1): (In the formula, A represents the binding site to the anti-GPR20 antibody.) A reaction solution containing an anti-GPR20 antibody-drug conjugate in which the drug linker represented by the formula: The resulting reaction solution was roughly purified using a filter by the method described in 1)-3 of Example 1, and the concentration of the antibody-drug conjugate and the content of by-products derived from compound (2) before and after the activated carbon filter were measured by the method described in 1)-4 of Example 1. The results of the content of by-products derived from compound (2) and the recovery rate of the antibody-drug conjugate are shown in Table 5 and Figure 3. Sufficient removal efficiency was confirmed in the solution pH range of 4.0 to 6.0. Although the difference was slight, the removal efficiency was higher at pH 4.0. [Example 4] Examination of the amount of by-products derived from compound (2) A solution containing the same anti-GPR20 antibody as the antibody used in Example 1 (corresponding to 1.00 g of antibody) was placed in a glass flask, and a 150 mmol / L L-histidine aqueous solution (17 mL) containing 0.07 g / g polysorbate 80 and 2.0 mmol / L EDTA was added. Next, an aqueous solution containing 10 mmol / L TCEP hydrochloride (6.00 equivalents per antibody molecule) was added under stirring at 30°C, and an antibody having a thiol group was produced by stirring at the same temperature. After 3 hours, the reaction solution was cooled to an internal temperature of 15°C, and compound (2) (10.00 equivalents per antibody molecule) was added under stirring to react with the antibody having a thiol group. The reaction solution was quenched by the method described in 1)-2 of Example 1, and the reaction solution was roughly purified using a filter by the method described in 1)-3 of Example 1. The concentration of the antibody-drug conjugate and the content of by-products derived from compound (2) were measured before and after the activated carbon filter by the method described in 1)-4 of Example 1. The results of the content of by-products derived from compound (2) and the recovery rate of the antibody-drug conjugate are shown in Table 6 and Figure 4. Even when the concentration of by-products derived from compound (2) was more than twice that of the standard experiment of Example 1, sufficient removal efficiency was observed. [Example 5] Study of aqueous solution A solution containing the same anti-GPR20 antibody as the antibody used in Example 1 (corresponding to 1.00 g of antibody) was placed in a glass flask, and a 1 mol / L aqueous sodium acetate solution (17 mL) containing 0.07 g / g polysorbate 80 and 2.0 mmol / L EDTA, or a 28 mmol / L aqueous disodium hydrogen phosphate solution (17 mL) containing 0.07 g / g polysorbate 80 and 2.0 mol / L EDTA was added. Next, an aqueous solution containing 10 mmol / L TCEP hydrochloride (4.75 equivalents per antibody molecule) was added under stirring at 30°C, and an antibody having a thiol group was produced by stirring at the same temperature. After 3 hours, the reaction solution was cooled to an internal temperature of 15°C, and compound (2) (8.90 equivalents per antibody molecule) was added under stirring to react with the antibody having a thiol group. The reaction solution was quenched by the method described in 1)-2 of Example 1, and the reaction solution was roughly purified using a filter by the method described in 1)-3 of Example 1. The antibody-drug conjugate concentration and the amount of by-product derived from compound (2) were measured before and after the activated carbon filter by the method described in 1)-4 of Example 1. The results of the amount of by-product derived from compound (2) and the recovery rate of the antibody-drug conjugate are shown in Table 7 and Figure 5. Sufficient removal efficiency equivalent to that of the histidine buffer was also confirmed in acetate buffer and phosphate buffer. [Example 6] Examination of additives A solution containing the same anti-GPR20 antibody as that used in Example 1 (corresponding to 1.00 g of antibody) was placed in a glass flask, and a 150 mmol / L L-histidine aqueous solution (17 mL) containing 2.0 mmol / L EDTA or a 150 mmol / L L-histidine aqueous solution (17 mL) containing 0.07 g / g polysorbate 20 and 2.0 mmol / L EDTA was added. Next, an aqueous solution containing 10 mmol / L TCEP hydrochloride (4.75 equivalents per antibody molecule) was added under stirring at 30°C, and an antibody having a thiol group was produced by stirring at the same temperature. After 3 hours had passed, the reaction solution was cooled to an internal temperature of 15°C, and compound (2) (8.90 equivalents per antibody molecule) was added and reacted with the antibody having a thiol group. The reaction solution was quenched by the method described in 1)-2 of Example 1, and the reaction solution was roughly purified using a filter by the method described in 1)-3 of Example 1. The antibody-drug conjugate concentration and the content of by-products derived from compound (2) before and after the activated carbon filter were measured by the method described in 1)-4 of Example 1. The results of the content of by-products derived from compound (2) and the recovery rate of the antibody-drug conjugate are shown in Table 8 and Figure 6. A sufficient removal effect was confirmed regardless of the type and presence or absence of additives (polysorbate 20 or polysorbate 80). [Example 7] Study of activated carbon filter rinsing method 1 A reaction solution containing an anti-GPR20 antibody-drug conjugate was obtained by the method described in 1)-1 and 1)-2 of Example 1. The reaction solution was roughly purified using an activated carbon filter by the method described in 1)-3 of Example 1. Then, 8.5 mmol / L L-histidine buffer (pH 5.3) (6.0 mL) was pumped to the activated carbon filter used for the crude purification, and the pump tube and the activated carbon filter were rinsed. The antibody-drug conjugate concentration and the content of by-products derived from compound (2) in the reaction solution before and after the activated carbon filter, as well as the antibody-drug conjugate concentration and the content of by-products derived from compound (2) in the rinse solution after the activated carbon filter, were measured by the method described in 1)-4 of Example 1. The results of the content of by-products derived from compound (2) and the recovery rate of the antibody-drug conjugate are shown in Table 9 and FIG. 7. It was confirmed that the anti-GRP20 antibody-drug conjugate could be recovered without elution of impurities by rinsing with 8.5 mmol / L L-histidine buffer (pH 5.3). The recovery rate of the antibody-drug conjugate was 97.3% when the reaction solution after filtration and the rinse solution were combined. [Example 8] Removal of by-products derived from compound (2) using an activated carbon filter 2 8)-1 Reduction of antibody and conjugation of antibody with drug linker A solution (equivalent to 1.00 g of antibody) containing an anti-CD37 antibody described in WO 2023 / 068226 (an antibody comprising a heavy chain consisting of the amino acid sequence described in amino acid numbers 20 to 468 in SEQ ID NO: 3 and a light chain consisting of the amino acid sequence described in amino acid numbers 21 to 234 in SEQ ID NO: 4) is placed in a glass flask, and a 120 mmol / L L-histidine aqueous solution (17 mL) containing 0.07 g / g polysorbate 80 and 2.0 mmol / L EDTA is added. Next, an aqueous solution containing 10 mmol / L TCEP hydrochloride (4.75 equivalents per antibody molecule) is added under stirring at 30°C, and an antibody having a thiol group is produced by stirring at the same temperature. After 3 hours, the reaction solution is cooled to an internal temperature of 15°C, and the following formula (2) is obtained under stirring. (8.90 equivalents per antibody molecule) is dissolved in an aqueous dimethyl sulfoxide solution containing acetic acid and added to react with the antibody having a thiol group. 8)-2 Quenching the reaction solution Next, a 0.03 mol / L N-acetylcysteine ​​aqueous solution (15.0 equivalents per antibody molecule) is added, and the mixture is stirred at the same temperature for another 30 minutes to quench excess compound (2), and then the reaction solution is adjusted to pH 5.0 using a 10% aqueous acetic acid solution. This results in the reaction of the following formula (1) (wherein A represents the binding site for the anti-CD37 antibody) A reaction solution containing an anti-CD37 antibody-drug conjugate in which the drug linker represented by the formula (I) is linked to the anti-CD37 antibody via a thioether bond is obtained. 8)-3 Rough purification of reaction solution using a filter The content of by-products derived from compound (2) in the resulting reaction solution was measured, and the reaction solution adjusted to 15°C was then passed through a 5 cm2 filter made of activated carbon and cellulose fibers similar to Millistak+ (registered trademark) Depth Filter CR40 media (Merck), which is a depth filter formed using activated carbon powder as a carrier. 2 The reaction solution after filtration is filtered using an activated carbon filter and a sterile filter while being pumped with a rotary pump. The concentration of the anti-CD37 antibody-drug conjugate and the content of the by-product derived from compound (2) are measured for the reaction solution after filtration, and the change in the content before and after filtration is tracked. Here, the by-product derived from compound (2) is a compound in which tris(2-carboxyethyl)phosphine is added to the maleimidyl group of compound (2), that is, a compound represented by the following formula (3): and a compound in which N-acetylcysteine ​​is added to the maleimidyl group of compound (2), i.e., a compound represented by formula (4): Examples of the compound include those represented by the following formula: 8)-4 Measurement of by-products derived from antibody-drug conjugates and compound (2) The concentration of the anti-CD37 antibody-drug conjugate before and after the activated carbon filter is measured by the SoloVPE method, and the content of by-products derived from compound (2), including compound (3) and compound (4), is measured by the HPLC method. [Example 9] Temperature study 2 A reaction solution containing an anti-CD37 antibody-drug conjugate is obtained by the method described in 8)-1 and 8)-2 of Example 8. The content of by-products derived from compound (2) in the obtained reaction solution is measured, and then the reaction solution is cooled to 0°C or heated to 30°C and then passed through a 5 cm2 filter made of activated carbon and cellulose fibers similar to Millistak+ (registered trademark) Depth Filter CR40 media (Merck), which is a depth filter molded using activated carbon powder as a carrier. 2 The reaction solution after filtration is filtered using an activated carbon filter and a sterile filter while being pumped with a rotary pump. The concentration of the anti-CD37 antibody-drug conjugate and the content of the by-product derived from compound (2) are measured for the reaction solution after filtration, and the change in the content before and after filtration is tracked. The concentration of the antibody-drug conjugate and the content of by-products derived from compound (2) before and after the activated carbon filter are measured by the method described in 8)-4 of Example 8. [Example 10] pH Study 2 The antibody is reduced and the antibody is conjugated with a drug linker by the method described in 8)-1 of Example 8. Next, a 0.03 mol / L N-acetylcysteine ​​aqueous solution (15.0 equivalents per antibody molecule) is added, and the mixture is stirred at the same temperature for 30 minutes to quench excess compound (2), and the reaction solution is adjusted to pH 6.0 using a 10% aqueous acetic acid solution, or to pH 4.0 using a 10% aqueous acetic acid solution and acetic acid. This results in the formation of the compound represented by the following formula (1): (wherein A represents the binding site for the anti-CD37 antibody) A reaction solution containing an anti-CD37 antibody-drug conjugate in which the drug linker represented by the formula (I) is linked to the anti-CD37 antibody via a thioether bond is obtained. The resulting reaction liquid is roughly purified through a filter by the method described in 8)-3 of Example 8, and the concentrations of the antibody-drug conjugate before and after the activated carbon filter and the contents of by-products derived from compound (2) are measured by the method described in 8)-4 of Example 8. [Example 11] Examination of the amount of by-products derived from compound (2) 2 A solution containing the same anti-CD37 antibody as that used in Example 8 (corresponding to 1.00 g of antibody) is placed in a glass flask, and a 120 mmol / L L-histidine aqueous solution (17 mL) containing 0.07 g / g polysorbate 80 and 2.0 mol / L EDTA is added. Next, an aqueous solution containing 10 mmol / L TCEP hydrochloride (6.00 equivalents per antibody molecule) is added under stirring at 30°C, and the antibody having a thiol group is produced by stirring at the same temperature. After 3 hours, the reaction solution is cooled to an internal temperature of 15°C, and compound (2) (10.00 equivalents per antibody molecule) is added under stirring to react with the antibody having a thiol group. The reaction solution is quenched by the method described in 8)-2 of Example 8, and the reaction solution is roughly purified using a filter by the method described in 8)-3 of Example 8. The concentrations of the antibody-drug conjugate before and after the activated carbon filter and the contents of by-products derived from compound (2) are measured by the method described in 8)-4 of Example 8. [Example 12] Study of activated carbon filter rinsing method 2 A reaction solution containing an anti-CD37 antibody-drug conjugate is prepared and the resulting reaction solution is roughly purified by the method described in Example 8, 8)-1 to 8)-3, and the concentration of the antibody-drug conjugate and the content of by-products derived from compound (2) are measured by the method described in Example 8, 8)-4. Next, 8.5 mmol / L L-histidine buffer (pH 5.3) (1.5 mL) is pumped into the activated carbon filter to rinse the pump tube and the activated carbon filter. The antibody-drug conjugate concentration and the content of by-products derived from compound (2) in the rinse solution obtained before and after the activated carbon filter are measured by the method described in 8)-4 of Example 8. This operation is repeated three times. [Example 13] Study of activated carbon filter rinsing method 3 A reaction solution containing an anti-CD37 antibody-drug conjugate is prepared and the resulting reaction solution is roughly purified by the method described in Example 8, 8)-1 to 8)-3, and the concentration of the antibody-drug conjugate and the content of by-products derived from compound (2) are measured by the method described in Example 8, 8)-4. Next, 8.5 mmol / L L-histidine buffer (pH 5.3) (4.5 mL) is circulated for 10 minutes to rinse the activated carbon filter and the pump tube. The antibody-drug conjugate concentration and the content of by-products derived from compound (2) in the obtained rinse solutions before and after the activated carbon filter are measured by the method described in 8)-4 of Example 8. [Example 14] Preparation of antibody-drug conjugate drug substance including a purification step using an activated carbon filter A reaction solution containing an anti-CD37 antibody-drug conjugate is prepared and the resulting reaction solution is roughly purified by the methods described in 8)-1 to 8)-3 of Example 8. Next, the pump tube and the activated carbon filter are rinsed with 8.5 mmol / L L-histidine buffer (pH 5.3) (4.7 mL). Next, the obtained reaction solution is ultrafiltered using a Pellicon 3 (registered trademark) Cassette Ultracel (registered trademark) ultrafiltration membrane while circulating with a diaphragm pump to concentrate the antibody-drug conjugate. The concentrated reaction solution is diafiltered using a 5-fold amount of 10.8 mmol / L L-histidine buffer (pH 5.2), and then concentrated again by ultrafiltration to obtain a solution containing the anti-CD37 antibody-drug conjugate. To the resulting reaction solution, a histidine buffer solution (pH 5.3) containing sucrose and a histidine buffer solution (pH 5.3) containing polysorbate 80 are added to adjust the anti-CD37 antibody-drug conjugate concentration to 25 g / L, thereby obtaining an anti-CD37 antibody-drug conjugate drug substance. [Example 15] Removal of by-products derived from compound (2) using an activated carbon filter 3 An experiment similar to that of Example 1 was performed using the anti-CD37 antibody described in WO 2023 / 068226 (an antibody comprising a heavy chain consisting of the amino acid sequence set forth in amino acid numbers 20 to 468 in SEQ ID NO: 3 and a light chain consisting of the amino acid sequence set forth in amino acid numbers 21 to 234 in SEQ ID NO: 4). The contents of by-products derived from compound (2) and the recovery rates of the anti-CD37 antibody-drug conjugates are shown in Table 10 and Figure 25. It was confirmed that compounds (3) and (4) could be almost completely removed by the activated carbon filter. In addition, the content (%) of by-products derived from compound (2) was calculated from the content of by-products derived from compound (2) and the drug concentration in the antibody-drug conjugate, and the results are shown in Table 11. [Example 16] Removal of by-products derived from compound (2) using an activated carbon filter 4 An experiment similar to that in Example 1 was carried out using the anti-MUC1 antibody described in WO 2023 / 068226 (an antibody comprising a heavy chain consisting of the amino acid sequence described in amino acid numbers 20 to 468 in SEQ ID NO: 3 and a light chain consisting of the amino acid sequence described in amino acid numbers 21 to 234 in SEQ ID NO: 4). The contents of by-products derived from compound (2) and the recovery rates of the anti-MUC1 antibody-drug conjugates are shown in Table 12 and Figure 26. It was confirmed that compounds (3) and (4) could be almost completely removed by the activated carbon filter. In addition, the content (%) of by-products derived from compound (2) was calculated from the content of by-products derived from compound (2) and the drug concentration in the antibody-drug conjugate, and the results are shown in Table 13. [Example 17] Effect of pre-use washing with polysorbate 80 aqueous solution 1 A reaction solution containing an anti-CD37 antibody-drug conjugate was obtained by the method of Example 15. Before subjecting the solution to "crude purification of the reaction solution using a filter", the activated charcoal filter was washed with an aqueous polysorbate 80 solution before use, and the effect of washing was evaluated. It is recommended that the activated carbon filter be washed with water before use to prevent contamination of the reaction solution with eluates from the activated carbon. In all of Examples 1 to 7, 15, and 16, the activated carbon filter was washed with 80 mL of water before use, but in this experiment, a part of this 80 mL was replaced with a 1% polysorbate 80 aqueous solution to perform washing before use. That is, 50 mL of water was pumped using a rotary pump to wash the activated carbon filter, and then 15 mL of a 1% polysorbate 80 aqueous solution and 15 mL of water were pumped to the activated carbon filter in this order to perform washing. Thereafter, crude purification of the reaction solution using a filter and measurement of the antibody-drug conjugate and by-products derived from compound (2) were performed using the method of Example 15. The results of the content of by-products derived from compound (2) and the recovery rate of the anti-CD37 antibody-drug conjugate are shown in Table 14 and Figure 27. It was confirmed that compounds (3) and (4) can be almost completely removed by the activated carbon filter. By washing before use with an aqueous polysorbate 80 solution, the recovery rate of the anti-CD37 antibody-drug conjugate was improved compared to Example 15, while the content of compound (3) was maintained at the same level as in Example 15. [Example 18] Effect of pre-use washing with polysorbate 80 aqueous solution 2 The conditions for pre-use washing were partially changed from those in Example 17. That is, in the step of washing the activated carbon filter before use, 80 mL of water was pumped by a rotary pump to wash the activated carbon filter, and then 40 mL of a 1% polysorbate 80 aqueous solution and 10 mL of water were pumped in this order to the activated carbon filter for washing. The results of the content of by-products derived from compound (2) and the recovery rate of the anti-CD37 antibody-drug conjugate are shown in Table 15 and Figure 28. It was confirmed that compounds (3) and (4) can be removed by the activated carbon filter. By increasing the amount of polysorbate 80 aqueous solution, the content of compound (3) increased compared to Example 17, but the recovery rate of the anti-CD37 antibody-drug conjugate was improved compared to Example 17. [Example 19] Removal of low molecular weight impurities The TCEP, TCEPO, and NAC contents in the reaction solutions were measured for the reaction solution containing the anti-GPR20 antibody-drug conjugate before and after activated carbon filter filtration obtained in Example 1)-3, the reaction solution containing the anti-CD37 antibody-drug conjugate before and after activated carbon filter filtration obtained in Example 15, and the reaction solution containing the anti-MUC1 antibody-drug conjugate before and after activated carbon filter filtration obtained in Example 16. In addition, as a comparison, the TCEP, TCEPO, and NAC contents in the reaction solution containing the anti-GPR20 antibody-drug conjugate before and after filtration without using an activated carbon filter obtained in Example 1)-3 were similarly measured. The contents of each impurity are shown in Table 16. It was confirmed that TCEP, TCEPO, and NAC can be removed by the activated carbon filter. The production method of the present invention enables lower production costs and / or less labor than conventional production methods for antibody-drug conjugates. A purification step that can remove impurities more efficiently than conventional purification steps for antibody-drug conjugates, particularly a purification step that replaces ultrafiltration in the purification step for antibody-drug conjugates, and a production method for antibody-drug conjugates including said purification step are provided. The production method of the present invention makes it possible to reduce the amount of waste liquid discharged during the production of antibody-drug conjugates. The antibody-drug conjugates produced by the present invention are useful as pharmaceuticals. SEQ ID NO: 1: Amino acid sequence of anti-GPR20 antibody heavy chain (h046-H4e) SEQ ID NO: 2: Amino acid sequence of anti-GPR20 antibody light chain (h046-L7) SEQ ID NO: 3: Amino acid sequence of anti-CD37 antibody heavy chain (hmAb-H541) SEQ ID NO: 4: Amino acid sequence of anti-CD37 antibody light chain (hmAb-L11) SEQ ID NO: 5: Amino acid sequence of anti-MUC1 antibody heavy chain (N54Q) SEQ ID NO: 6: Amino acid sequence of anti-MUC1 antibody heavy chain (PankoMab) SEQ ID NO: 7: Amino acid sequence of anti-MUC1 antibody light chain (N54Q and PankoMab) SEQ ID NO: 8: Amino acid sequence of the anti-HER2 antibody heavy chain SEQ ID NO: 9: Amino acid sequence of the anti-HER2 antibody light chain SEQ ID NO: 10: Amino acid sequence of anti-TROP2 antibody heavy chain (hTINA1-H1) SEQ ID NO: 11: Amino acid sequence of anti-TROP2 antibody light chain (hTINA1-L1) SEQ ID NO: 12: Amino acid sequence of the anti-HER3 antibody heavy chain SEQ ID NO: 13: Amino acid sequence of the anti-HER3 antibody light chain SEQ ID NO: 14: Amino acid sequence of anti-B7-H3 antibody heavy chain (M30-H1) SEQ ID NO: 15: Amino acid sequence of anti-B7-H3 antibody light chain (M30-L4) SEQ ID NO: 16: Amino acid sequence of anti-CDH6 antibody heavy chain (hH01) SEQ ID NO: 17: Amino acid sequence of anti-CDH6 antibody light chain (hL02)

Claims

1. Equation (1) (wherein A represents a binding position to the antibody) is a drug linker represented by the formula: (wherein A represents a binding position to the antibody), and the antibody is bound to the drug linker via a thioether bond, the method comprising: (i) removing by-products derived from the exatecan compound contained in a solution containing the antibody-drug conjugate using an activated carbon material.

2. The method according to claim 1, wherein step (i) is a step of filtering a solution containing the antibody-drug conjugate using an activated carbon filter.

3. The method according to claim 1 or 2, wherein step (i) is a step of filtering a solution containing an antibody-drug conjugate using an activated carbon filter, and the solution is passed through the activated carbon filter only once.

4. The method according to claim 2 or 3, further comprising, prior to step (i), a step of cleaning the activated carbon filter prior to use.

5. The manufacturing method according to claim 4, wherein an aqueous solution containing a surfactant is used in the step of washing before use.

6. The method according to claim 4 or 5, wherein an aqueous solution of polysorbate 20 or an aqueous solution of polysorbate 80 is used in the step of washing before use.

7. The method according to claim 4 or 5, wherein an aqueous solution of polysorbate 20 is used in the pre-use washing step.

8. The method according to claim 4 or 5, wherein an aqueous solution of polysorbate 80 is used in the pre-use washing step.

9. The activated carbon contained in the activated carbon material has a capacity of 10 to 10,000 m 2 The method according to any one of claims 1 to 8, having a surface area of ​​ / g.

10. The method according to any one of claims 1 to 9, wherein the activated carbon contained in the activated carbon material has an average particle size of 2 μm or more.

11. The method according to any one of claims 1 to 10, wherein at least 90% by weight of the activated carbon contained in the activated carbon material has an average particle size of 5 to 40 μm.

12. A manufacturing method according to any one of claims 1 to 11, wherein the temperature of the solution containing the antibody-drug conjugate used in step (i) is between 0°C and 30°C.

13. A manufacturing method according to any one of claims 1 to 12, wherein the temperature of the solution containing the antibody-drug conjugate used in step (i) is 10°C to 20°C.

14. The method of any one of claims 1 to 13, wherein the temperature of the solution containing the antibody-drug conjugate used in step (i) is about 15°C.

15. The manufacturing method according to any one of claims 1 to 14, wherein the pH of the solution containing the antibody-drug conjugate used in step (i) is 4.0 to 6.

0.

16. The method of any one of claims 1 to 15, wherein the pH of the solution containing the antibody-drug conjugate used in step (i) is about 5.

17. The method of any one of claims 1 to 15, wherein the pH of the solution containing the antibody-drug conjugate used in step (i) is about 4.

5.

18. (ii) reducing the antibody with a reducing agent; and (iii) reacting the antibody with a compound represented by the formula (2). (iv) adding a reagent having a thiol group and reacting it with the compound represented by formula (2) remaining in step (iii).

19. The manufacturing method according to any one of claims 1 to 18, comprising step (i) after step (iv).

20. A method for producing the exatecan compound according to any one of claims 1 to 19, wherein the by-product derived from the exatecan compound includes a compound in which the reducing agent used in step (ii) is added to the maleimidyl group of the compound represented by formula (2), and / or a compound in which the reagent having a thiol group used in step (iv) is added to the maleimidyl group of the compound represented by formula (2).

21. A by-product derived from the exatecan compound is represented by the formula (3) and / or a compound represented by formula (4) The method according to any one of claims 1 to 20, comprising the compound represented by the formula:

22. The method according to claim 21, wherein the content of the compound represented by formula (3) in the solution containing the antibody-drug conjugate used in step (i) is 300 μM or less.

23. The manufacturing method described in claim 21 or 22, wherein the content of the compound represented by formula (3) in the solution containing the antibody-drug conjugate used in step (i) is 0 to 150 μM.

24. The manufacturing method according to any one of claims 21 to 23, wherein the content of the compound represented by formula (4) in the solution containing the antibody-drug conjugate used in step (i) is 160 μM or less.

25. The manufacturing method according to any one of claims 21 to 24, wherein the content of the compound represented by formula (4) in the solution containing the antibody-drug conjugate used in step (i) is 0 to 80 μM.

26. A method for producing according to any one of claims 1 to 25, wherein the solution containing the antibody-drug conjugate obtained by step (i) contains 0.3% or less of a by-product derived from compound (2).

27. A method according to any one of claims 1 to 26, wherein the reducing agent used in step (ii) is tris(2-carboxyethyl)phosphine or a salt thereof.

28. A process according to any one of claims 1 to 27, wherein the reducing agent used in step (ii) is tris(2-carboxyethyl)phosphine hydrochloride.

29. A method according to any one of claims 1 to 28, wherein step (ii) is carried out in a buffer solution.

30. The method of claim 29, wherein the buffer is a histidine buffer.

31. The method according to claim 29 or 30, wherein the buffer solution is an aqueous L-histidine solution.

32. The method of claim 29, wherein the buffer solution is an aqueous solution of disodium hydrogen phosphate.

33. The method of claim 29, wherein the buffer is an acetate buffer.

34. The method of claim 29 or 33, wherein the buffer solution is an aqueous sodium acetate solution.

35. A process according to any one of claims 1 to 34, wherein step (ii) is carried out in the presence of a chelating agent.

36. The method of claim 35, wherein the chelating agent is ethylenediaminetetraacetic acid.

37. A method according to any one of claims 29 to 36, wherein the buffer used in step (ii) contains a surfactant.

38. The method of claim 37, wherein the surfactant is polysorbate 20.

39. The method of claim 37, wherein the surfactant is polysorbate 80.

40. A method according to any one of claims 29 to 36, wherein the buffer used in step (ii) does not contain a surfactant.

41. The method according to any one of claims 1 to 40, wherein the amount of the compound represented by formula (2) used in step (iii) is 2.0 to 10.0 equivalents.

42. The method according to any one of claims 1 to 41, wherein the amount of the compound represented by formula (2) used in step (iii) is 8.0 to 10.0 equivalents.

43. The method according to any one of claims 1 to 42, wherein the amount of the compound represented by formula (2) used in step (iii) is 8.9 to 10.0 equivalents.

44. A method according to any one of claims 1 to 41, wherein the amount of the compound represented by formula (2) used in step (iii) is 4.0 to 6.0 equivalents.

45. A method according to any one of claims 1 to 44, wherein the reagent having a thiol group used in step (iv) is N-acetylcysteine.

46. ​​A method for producing a product according to any one of claims 1 to 45, comprising the step of (v) adjusting the pH of the reaction solution.

47. A method for producing a product according to any one of claims 1 to 46, comprising step (v) following step (iv).

48. The method according to claim 46 or 47, wherein step (v) is a step of adjusting the pH of the reaction solution to a range of 4 to 6.

49. The method of any one of claims 46 to 48, wherein step (v) is a step of adjusting the pH of the reaction solution to about 5.

50. The method of any one of claims 46 to 48, wherein step (v) is a step of adjusting the pH of the reaction solution to about 4.

5.

51. A method according to any one of claims 46 to 50, wherein step (v) is a step in which the pH of the reaction solution is adjusted using an aqueous acetic acid solution.

52. The process of any one of claims 1 to 51, further comprising the step of (vi) rinsing the activated carbon filter.

53. The method of claim 52, comprising step (i) followed by step (vi).

54. A method according to claim 52 or 53, wherein a histidine buffer is used in step (vi).

55. A manufacturing method described in any one of claims 52 to 54, wherein 8.5 mmol / L L-histidine buffer is used in step (vi).

56. The method of any one of claims 1 to 55, wherein the average number of drug linkers bound per antibody in the antibody-drug conjugate is in the range of 7 to 8.

57. The method of any one of claims 1 to 56, wherein the average number of drug linkers bound per antibody in the antibody-drug conjugate is in the range of 7.5 to 8.

58. The method of any one of claims 1 to 57, wherein the antibody is an anti-GPR20 antibody.

59. The method for producing the anti-GPR20 antibody described in claim 58, wherein the anti-GPR20 antibody is an antibody comprising a heavy chain consisting of the amino acid sequence set forth in amino acid numbers 20 to 472 of SEQ ID NO: 1 and a light chain consisting of the amino acid sequence set forth in amino acid numbers 21 to 234 of SEQ ID NO:

2.

60. The method of claim 58 or 59, wherein the lysine residue at the carboxyl terminus of the heavy chain of the anti-GPR20 antibody is deleted.

61. The method of any one of claims 1 to 57, wherein the antibody is an anti-CD37 antibody.

62. The method for producing the anti-CD37 antibody described in claim 61, wherein the anti-CD37 antibody is an antibody comprising a heavy chain consisting of the amino acid sequence set forth in amino acid numbers 20 to 468 of SEQ ID NO: 3 and a light chain consisting of the amino acid sequence set forth in amino acid numbers 21 to 234 of SEQ ID NO:

4.

63. The method of claim 61 or 62, wherein the lysine residue at the carboxyl terminus of the heavy chain of the anti-CD37 antibody is deleted.

64. The method of any one of claims 1 to 57, wherein the antibody is an anti-MUC1 antibody.

65. The method of claim 64, wherein the anti-MUC1 antibody is an antibody comprising a heavy chain consisting of the amino acid sequence set forth in amino acid numbers 1 to 447 of SEQ ID NO:5 or the amino acid sequence set forth in amino acid numbers 1 to 447 of SEQ ID NO:6, and a light chain consisting of the amino acid sequence set forth in amino acid numbers 1 to 219 of SEQ ID NO:

7.

66. The method of claim 64 or 65, wherein the lysine residue at the carboxyl terminus of the heavy chain of the anti-MUC1 antibody is deleted.

67. A method of production according to any one of claims 1 to 57, wherein the antibody is an anti-HER2 antibody.

68. The method for producing the anti-HER2 antibody described in claim 67, wherein the anti-HER2 antibody is an antibody comprising a heavy chain consisting of the amino acid sequence set forth in amino acid numbers 1 to 449 of SEQ ID NO: 8 and a light chain consisting of the amino acid sequence set forth in amino acid numbers 1 to 214 of SEQ ID NO:

9.

69. The method of production described in claim 67 or 68, wherein the anti-HER2 antibody is an antibody comprising a heavy chain consisting of the amino acid sequence set forth in SEQ ID NO: 8 and a light chain consisting of the amino acid sequence set forth in SEQ ID NO:

9.

70. A method of production according to any one of claims 1 to 57, wherein the antibody is an anti-HER3 antibody.

71. The method for producing the anti-HER3 antibody described in claim 70, wherein the anti-HER3 antibody is an antibody comprising a heavy chain consisting of the amino acid sequence set forth in SEQ ID NO: 12 and a light chain consisting of the amino acid sequence set forth in SEQ ID NO:

13.

72. The method of claim 70 or 71, wherein the lysine residue at the carboxyl terminus of the heavy chain of the anti-HER3 antibody is deleted.

73. The method of any one of claims 1 to 57, wherein the antibody is an anti-CDH6 antibody.

74. The method for producing the anti-CDH6 antibody described in claim 73, wherein the anti-CDH6 antibody is an antibody comprising a heavy chain consisting of the amino acid sequence set forth in amino acid numbers 20 to 471 of SEQ ID NO: 16 and a light chain consisting of the amino acid sequence set forth in amino acid numbers 21 to 233 of SEQ ID NO:

17.

75. The method of claim 73 or 74, wherein the lysine residue at the carboxyl terminus of the heavy chain of the anti-CDH6 antibody is deleted.

76. The method of any one of claims 1 to 55, wherein the average number of drug linkers bound per antibody in the antibody-drug conjugate is in the range of 3 to 4.

77. A method for producing according to any one of claims 1 to 55 and 76, wherein the average number of drug linkers bound per antibody in the antibody-drug conjugate is in the range of 3.5 to 4.

78. The method of any one of claims 1 to 55, 76 and 77, wherein the antibody is an anti-TROP2 antibody.

79. The method for producing the anti-TROP2 antibody described in claim 78, wherein the anti-TROP2 antibody is an antibody comprising a heavy chain consisting of the amino acid sequence set forth in amino acid numbers 20 to 470 of SEQ ID NO: 10 and a light chain consisting of the amino acid sequence set forth in amino acid numbers 21 to 234 of SEQ ID NO:

11.

80. The method of claim 78 or 79, wherein the lysine residue at the carboxyl terminus of the heavy chain of the anti-TROP2 antibody is deleted.

81. The method of any one of claims 1 to 55, 76 and 77, wherein the antibody is an anti-B7-H3 antibody.

82. The method for producing the anti-B7-H3 antibody described in claim 81, wherein the anti-B7-H3 antibody is an antibody comprising a heavy chain consisting of the amino acid sequence set forth in amino acid numbers 20 to 471 of SEQ ID NO: 14 and a light chain consisting of the amino acid sequence set forth in amino acid numbers 21 to 233 of SEQ ID NO:

15.

83. The method of claim 81 or 82, wherein the lysine residue at the carboxyl terminus of the heavy chain of the anti-B7-H3 antibody is deleted.

84. A method for producing a compound according to any one of claims 1 to 83, characterized in that it does not include a chromatographic purification step.

85. The method of claim 84, wherein the chromatography is at least one selected from the group consisting of gel filtration chromatography, ion exchange chromatography, hydrophobic interaction chromatography, and affinity chromatography.

86. Formula (1) (wherein A represents the binding position to the antibody) and an antibody are bound via a thioether bond, the method comprising the steps of: (ii) reducing the antibody with tris(2-carboxyethyl)phosphine hydrochloride in the presence of ethylenediaminetetraacetic acid in an aqueous L-histidine solution containing or not containing polysorbate 20 or polysorbate 80; and (iii) reducing the antibody with tris(2-carboxyethyl)phosphine hydrochloride in the presence of ethylenediaminetetraacetic acid in an aqueous L-histidine solution containing or not containing polysorbate 20 or polysorbate 80. (iv) adding N-acetylcysteine ​​to react with the compound represented by formula (2) remaining in step (iii); (v) adjusting the pH of the reaction solution to about 5 or about 4.5 using an aqueous acetic acid solution; (i) filtering the solution containing the antibody-drug conjugate by passing it through an activated charcoal filter at about 15° C. only once to obtain the compound represented by formula (3). and a compound represented by formula (4) (vi) rinsing the activated carbon filter with 8.5 mmol / L L-histidine buffer, in that order.

87. A method for producing a pharmaceutical composition comprising an antibody-drug conjugate, a buffer solution, and an excipient, comprising producing an antibody-drug conjugate by the production method according to any one of claims 1 to 86, and further carrying out steps comprising: (vii) at least one step selected from the group consisting of a step of adding a buffer solution to a solution containing the antibody-drug conjugate, (viii) a step of concentrating the solution containing the antibody-drug conjugate, and (ix) a step of adjusting the solution containing the antibody-drug conjugate to a predetermined pH, and (x) a step of adding an excipient to the solution containing the antibody-drug conjugate.

88. The method of claim 87, wherein the buffer is a histidine buffer.

89. The method of claim 87 or 88, wherein the excipient is sucrose.

90. The method of claim 87 or 88, wherein the excipient is trehalose.

91. A method for producing a pharmaceutical composition comprising an antibody-drug conjugate, a buffer solution, and an excipient, by the production method according to any one of claims 87 to 90, and further comprising the steps of: (xi) adding a surfactant to the pharmaceutical composition.

92. The method of claim 91, wherein the surfactant is polysorbate 80.

93. The method of claim 91, wherein the surfactant is polysorbate 20.

94. The method of any one of claims 87 to 93, wherein the pharmaceutical composition contains 0.3% or less of by-products derived from compound (2).

95. 10-10,000 m for removing by-products from the exatecan compound 2 3. An activated carbon material comprising an activated carbon having a surface area of ​​1 / g.

96. The activated carbon material of claim 95, wherein the activated carbon has an average particle size of 2 μm or more.

97. The activated carbon material of claim 95 or 96, wherein at least 90% by weight of the activated carbon contained therein has an average particle size of 5 to 40 μm.