CN112156194B - Removing method 177 Method for endotoxin in Lu solution - Google Patents
Removing method 177 Method for endotoxin in Lu solution Download PDFInfo
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- CN112156194B CN112156194B CN202011047931.9A CN202011047931A CN112156194B CN 112156194 B CN112156194 B CN 112156194B CN 202011047931 A CN202011047931 A CN 202011047931A CN 112156194 B CN112156194 B CN 112156194B
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/04—Antineoplastic agents specific for metastasis
Abstract
The invention provides a method for removing 177 A process for endotoxin in Lu solution comprising the steps of: (1) According to the initiation 177 Adding a nitric acid solution into the Lu solution according to the concentration and volume parameters of acid in the Lu solution to enable the concentration of the nitric acid in the solution to be more than 1M; (2) The flow rate of 0.1-2.0 BV/min is used for leading the mixture obtained in the step (1) to be mixed 177 Injecting the Lu solution into a resin column filled with DGA resin for leaching; the volume of DGA resin in the resin column is 0.2-2.0 cm 3 (ii) a (3) Injecting sterile water for injection into the resin column in the step (2) at the flow rate of 0.1-2.0 BV/min until the specified volume is reached; (4) Injecting dilute hydrochloric acid into the resin column in the step (3) at the flow rate of 0.1-2.0 BV/min for elution, wherein the concentration of the dilute hydrochloric acid is 0.01-0.5M, filtering the effluent liquid through a 0.02 mu M filter membrane, collecting filtrate, and obtaining the filtrate which is used for removing endotoxin 177 Lu solution. After treatment by the process of the invention 177 The Lu product has the advantages of high radiochemical purity, metallic impurities and specific activity, and is in good accordance with medical use 177 Lu requirements.
Description
Technical Field
The invention belongs to the technical field of preparation of medicinal radioactive isotopes, and relates to a radioactive nuclide without endotoxin 177 Research on Lu, in particular to a method for preparing 177 In-process removal of Lu 177 Method for endotoxin in Lu solution.
Background
177 Lu radionuclides can be used for production 177 Lu labeled targeted drugs have achieved remarkable effects in the treatment of various tumors in recent years. 177 The Lu nuclides are mainly of two kinds: ' Carrier 177 Lu (direct production) "and" Carrier-free 177 Lu (indirect method of production) ". The clinical application mainly uses the carrier-free agent 177 Lu, in particular using monoclonal antibodies and polypeptides as carriers 177 Lu nuclide tumor treatment field. With a carrier 177 Lu is rarely used in clinic, but has a good prospect in bone metastasis tumor pain medicines.
177 Lu nuclide is generally used for producing injection radiopharmaceuticals, and the endotoxin level needs to be controlled according to the general quality requirements of production raw materials of the injection radiopharmaceuticals. Control of endotoxin levels can be controlled during the production process or after production the endotoxin can be removed by some endotoxin removal method. Production of 177 The Lu process is complex, involves many processes (including target preparation, irradiation, target breaking, dissolution, purification, split charging, packaging, etc.), also involves a complex shielding and ventilation system for high radioactive operation, and needs to ensure that the whole production process is in a sterile environment. Namely, the current process flow is required to be ensured 177 The endotoxin level in Lu solution is not realistic from the economic cost and technical requirements, so that the endotoxin level in Lu solution is obtained 177 Endotoxin in Lu solution is effectiveRemoval is a more economical way.
Adsorption of endotoxin in solution with porous material has been a common method in the past, but because of the porous material 177 The Lu nuclide belongs to high-valence metal positive ions and is easily adsorbed by a porous material, so that common activated carbon, molecular sieves, pottery clay, a conventional chromatography and the like cannot be used, the requirement on an adsorption material is extremely high, and a higher requirement is put forward on a method for removing endotoxin. The high temperature dry heat method may cause leakage of highly radioactive solvents causing environmental emissions and radiation safety problems. Chromatography uses an elution mobile phase with a complex composition and requires a series of process steps to remove impurities introduced by the mobile phase after removal of endotoxin. Ultrafiltration membranes require high-speed centrifuges, require special shielded fields for highly radioactive solution operations, and are prone to adsorbing large amounts of radioactive positive ions. 177 Lu ions are precipitated or formed into a colloid under an alkaline condition, so that an alkaline immersion method cannot be used. The only conventional way of removing endotoxin is by acid soaking, but the acid soaking method is generally used for the treatment of the surface of the container, and the applicant of the present patent found in the previous studies that: the acid soaking method can destroy a part of the raw material 177 Endotoxin in Lu solution, but even when it takes a long time (>10h) Can not be stably and reliably used for producing the injection sold on the market at present 177 Lu solution endotoxin requirement (20 EU/mL), and the additional acid still needs a series of subsequent process to remove. Therefore, the existing methods have obvious problems, and it is urgent to provide an unconventional and special purpose 177 A method for removing endotoxin in Lu solution, which aims to solve the problem in the prior art.
Disclosure of Invention
The present invention is to solve the above technical problems and to provide a method for removing 177 Method for endotoxin in Lu solution, so that 177 The endotoxin level of Lu solution meets the requirement of raw materials for producing injection, and has the advantages of simple and easy operation, controllable operation, easily obtained materials, small heat chamber occupation area, and treatment by the method 177 The technical indexes required in the Lu product comprise liberationThe key indexes of purity, metal impurities, specific activity and the like can well accord with medical use 177 Lu requirements.
Specifically, the following are: the methods described herein are "carrier-free 177 Lu 'and' carriers 177 Lu "general endotoxin removal method, hereinafter unless specified otherwise, no distinction is made.
In order to achieve the purpose, the technical scheme adopted by the invention is as follows:
removing method 177 A process for endotoxin in Lu solution, said process comprising the steps of:
(1) According to the initiation 177 Acid concentration and volume parameters in Lu solution, starting with 177 Adding a certain amount of nitric acid solution into the Lu solution to ensure that the concentration of nitric acid in the solution is more than 1M;
(2) The flow rate of 0.1-2.0 BV/min is used for leading the mixture obtained in the step (1) to be mixed 177 Injecting the Lu solution into a resin column filled with DGA resin for leaching; the volume of DGA resin in the resin column is 0.2-2.0 cm 3 Preferably 0.4 to 1.0cm 3 ；
(3) Injecting sterile water for injection into the resin column in the step (2) at the flow rate of 0.1-2.0 BV/min until the specified volume is reached;
(4) Injecting dilute hydrochloric acid into the resin column in the step (3) at the flow rate of 0.1-2.0 BV/min for elution, wherein the concentration of the dilute hydrochloric acid is 0.01-0.5M, preferably 0.04-0.05M, filtering the eluted effluent liquid through a 0.02 mu M filter membrane, collecting filtrate until the specified volume is stopped, and obtaining the filtrate which is the' endotoxin removing filtrate 177 Lu solution ".
The above-described process of the present invention employs the principle of using DGA resin pairs 177 Adsorption of Lu in high concentration nitric acid, complete washing and displacement of adsorbed small amount of nitric acid solvent by sterile water for injection and removal of endotoxin, followed by elution with dilute hydrochloric acid 177 Lu product. After being treated 177 Other required technical indexes in the Lu product, including radiochemical purity, metal impurities, specific activity and other key indexes, all meet medical requirements 177 Lu requirements. Although the prior art DGA resins have been used for some radionuclidesHowever, the method of the present invention has been extensively studied and there is no report in the prior art on how to use DGA resin pairs 177 When endotoxin in Lu is removed, the invention provides a good method for removing endotoxin by DGA resin 177 The method for removing endotoxin in Lu has remarkable effect, and other methods cannot effectively remove endotoxin in the process of searching by the inventor 177 Endotoxin in Lu.
Further, the initiation in step (1) 177 The acid in the Lu solution is hydrochloric acid or nitric acid, and the concentration and the volume of the acid are not limited. The concentration and volume of the acid described herein are not limited and refer to the starting 177 The acid concentration and volume in the Lu solution can be any parameters and can be treated according to the method of the invention; when starting 177 When the concentration of the nitric acid in the Lu solution is more than 1M, the subsequent treatment step is directly carried out without adding a nitric acid solution.
Further, after adding the nitric acid solution in the step (1) 177 The concentration of the nitric acid solution in the Lu solution is 2-5M, and the nitric acid solution is added 177 The total volume of the Lu solution is not limited, and the total volume is preferably 2 to 50mL.
Further, the initiation in step (1) 177 Lu solution is carrier 177 Lu or without carrier 177 Lu, its total activity is unlimited; when starting 177 Lu solution as carrier 177 Lu, of which 177 Lu and nat the total chemical content of Lu (stable Lu nuclide) is not higher than the limit sample loading amount of the resin column packing.
Further, the initiation in step (1) 177 Lu solutions produced under non-sterile conditions 177 Lu solution, the dilute hydrochloric acid in step (4) is subjected to sterile treatment.
Further, the DGA resin in step (2) may refer to a resin obtained by supporting a DGA-based organic compound on a base resin.
Further, the DGA-based organic compound includes TODGA or TEHDGA. Wherein TODGA refers to N, N, N ', N' -tetracotyldiglycolamide, and wherein TEHDGA refers to N, N, N ', N' -tetrackis-2-ethylhexyldiglycolamide.
Further, the base resin includes resin materials of different materials capable of supporting the DGA-based organic compound, including but not limited to silica gel materials, silica materials, acrylic polymers, or styrene polymers.
Preferably, the flow rates in the steps (2), (3) and (4) are all 0.3 to 1 BV/min.
Preferably, the specified volume of the sterile water for injection in step (3) is 3 to 15BV, preferably 6 to 9BV, and the injection volume of the dilute hydrochloric acid solution in step (4) is 2 to 15BV, preferably 6 to 9BV.
The invention has the following beneficial effects: the method of the invention provides a simple and easy removal 177 A method for endotoxin in Lu solution; after being treated by the method of the invention 177 Other required technical indexes in the Lu product, including radiochemical purity, metal impurities, specific activity and other key indexes, all meet medical requirements 177 Lu requirement and the whole process flow 177 The recovery rate of Lu is as high as 92-99%.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more clearly understood, the present invention is described in detail with reference to the following embodiments, it should be noted that the following embodiments are only for explaining and illustrating the present invention and are not intended to limit the present invention. The invention is not limited to the embodiments described above, but rather, may be modified within the scope of the invention.
Example 1
Initiation of 177 Lu solution: carrier-free process for production of non-sterile products 177 Lu solution, total activity 1.61Ci, volume 1.6mL, solvent 0.05MHCl.
DGA resin column parameters: the resin column is made of quartz, and is filled with commercial general DGA resin (manufactured by Triskem, with a composition of acrylic polymer loaded TODGA) 0.4cm 3 Two ends of the filter are connected with a medical sterile PE peristaltic pump pipe, and the outlet of the peristaltic pump pipe is connected with a 0.02 mu m filter membrane. Placing in A-grade clean shielding box before performing process flow, and performing ultraviolet sterilizationFor 1h, and previously rinsed with 25mL of sterile water for injection.
Step a: starting from above 177 Adding 3.2mL3MHNO into a bottle of Lu solution 3 And (4) uniformly mixing.
Step b: the above solution was injected into a DGA resin column at a flow rate of 0.4mL/min, and stopped after the injection was completed.
Step c: sterile water for injection 3 mL was injected into the above resin column at a flow rate of 0.4 mL/min.
Step d: 0.05M hydrochloric acid solution was injected into the above resin column at a flow rate of 0.4mL/min, and the eluate was filtered through a 0.02 μ M filter, and 2mL of filtrate was collected in a 10mL vial.
Step e: adding a rubber plug and an aluminum cover, and pressing a cover. The activity tested was 1.57Ci. (recovery rate was 97.5%).
177 Lu ions are adsorbed by flow path materials such as pipelines, resin columns, filter membranes and the like in the production process, so that certain activity loss is caused in the production process (the recovery rate is generally 92-99% in actual production). The loss is the conventional loss in the column purification production process, and the use of the product per se is not influenced. The same applies below.
Tests show that the endotoxin in the product (about) is 3.8EU/mL, and meets the production requirement of injection (A)<20 EU/mL). The test results show that: the method of the invention can well remove the production under the non-aseptic condition 177 Endotoxin in Lu solution. In addition, in general, large amounts are easily caused for removing endotoxin 177 Lu loss, which is unacceptable, and the method of the present invention also gives good consideration to the removal of endotoxins 177 The recovery rate of Lu is as high as 97.5%.
Example 2
Initiation of 177 Lu solution: carrier-free process for production of non-sterile products 177 Lu solution, total activity 2.73Ci, volume about 45mL, solvent 3.5MHNO 3 。
DGA resin column parameters: the resin column is made of quartz, and is filled with commercially available branched DGA resin (produced by Triskem company, and composed of acrylic polymer loaded TEHDGA) 0.4cm 3 Two ends are connected with medical asepticThe outlet of the PE peristaltic pump tube is connected with a 0.02 mu m filter membrane. The column was UV-sterilized in a class A clean shielded chamber for 1h prior to running the protocol, and previously rinsed with 25mL sterile water for injection, and equilibrated with 3.5M nitric acid (5 mL).
A, step a: the above solution was injected into a DGA resin column at a flow rate of 0.4mL/min, and stopped after the injection was completed.
Step b: sterile water for injection 3 mL was injected into the above resin column at a flow rate of 0.4 mL/min.
Step c: 0.05M hydrochloric acid solution was injected into the above resin column at a flow rate of 0.4mL/min, and the eluate was filtered through a 0.02 μ M filter, and 2.7mL of filtrate was collected in a 10mL vial.
Step e: adding a rubber plug and an aluminum cover, and pressing a cover. The activity tested was 2.71Ci. (recovery ratio 99.3%)
Through tests, the endotoxin in the product is (about) 1.1EU/mL, and meets the production requirement of injection (< 20 EU/mL).
Example 3
Initiation of 177 Lu solution: carrier produced under non-aseptic conditions 177 Lu solution with a total activity of 2.18Ci (original target) 176 Lu (76.4% enriched target) 0.6mg, volume 1.5mL, solvent 1MHCl.
DGA resin column parameters: the resin column is made of quartz, and is filled with DGA resin (self-made resin, consisting of acrylic polymer loaded TEHDGA) 0.8cm 3 Two ends of the filter are connected with a medical sterile PE peristaltic pump tube, and the outlet of the peristaltic pump tube is connected with a 0.02 mu m filter membrane. The column was UV sterilized in a class A clean shielded chamber for 1h prior to running the protocol, and previously rinsed with 25mL sterile water for injection, and equilibrated with 2.0M nitric acid (5 mL).
Step a: starting from above 177 Adding 3.0mL2MHNO into bottle of Lu solution 3 And (4) uniformly mixing.
Step b: the above solution was injected into a DGA resin column at a flow rate of 1.0mL/min, and stopped after the injection was completed.
Step c: sterile water for injection 5mL was injected into the above resin column at a flow rate of 0.5 mL/min.
Step d: 0.04M hydrochloric acid solution was injected into the above resin column at a flow rate of 0.5mL/min, and the eluate was filtered through a 0.02 μ M filter, and 4.8mL of filtrate was collected in a 10mL penicillin bottle.
Step e: adding a rubber plug and an aluminum cover, and pressing a cover. The activity was tested at 2.09Ci (95.8% recovery).
Tests show that the endotoxin in the product is (about) 0.2EU/mL, which meets the production requirement of injection (less than or equal to 20 EU/mL).
It should be noted that in examples 1-3, the difference in endotoxin levels in the product was not due to the instability of the process of the present invention, but two main reasons were that the endotoxin levels per batch of feed solution varied due to the production of the feed solution under non-sterile conditions; secondly, the endotoxin level in the product treated by the method is far lower than the limit (less than or equal to 20 EU/mL), and the radioactive endotoxin test is the test after dilution, so the quality test precision cannot be accurate at the lower endotoxin content. The same applies below.
Example 4
Initiation of 177 Lu solution: carrier-free process for production of non-sterile products 177 Lu solution, total activity 4.15Ci, volume about 40mL, solvent 3.2MHNO 3 In order to compare the endotoxin removing effect with that of the comparative example, 3 additional bacterial endotoxin working standards (80 EU/lot, produced by the Chinese food and drug testing institute) were added.
DGA resin column parameters: the resin column is made of quartz, and is filled with DGA resin (self-made resin, consisting of acrylic polymer loaded TEHDGA) 0.6cm 3 Two ends of the filter are connected with a medical sterile PE peristaltic pump tube, and the outlet of the peristaltic pump tube is connected with a 0.02 mu m filter membrane. The column was UV-sterilized in a class A clean shielded chamber for 1h prior to running the protocol, and previously rinsed with 25mL sterile water for injection, and equilibrated with 3.2M nitric acid (5 mL).
Step a: the above was initiated at a flow rate of 0.5mL/min 177 The Lu solution was injected into the DGA resin column and stopped after the injection was completed.
Step b: sterile water for injection 5mL was injected into the above resin column at a flow rate of 0.6 mL/min.
Step c: 0.05M hydrochloric acid solution was injected into the above resin column at a flow rate of 0.5mL/min, and the eluate was filtered through a 0.02 μ M filter, and 4.0mL of filtrate was collected in a 10mL penicillin bottle.
Step d: adding a rubber plug and an aluminum cover, and pressing a cover. The activity tested was 4.10Ci. (recovery rate 98.8%)
The endotoxin in the product is tested. (about) 1.9EU/mL, meeting the production requirement of injection (< 20 EU/mL).
Comparative example 1
Initiation of 177 Lu solution: carrier-free process for production of non-sterile products 177 Lu solution, total activity 1.35Ci, volume about 40mL, solvent 3.2M HNO 3 In order to compare the endotoxin removal effect of example 4, 3 additional working standards (80 EU/lot, produced by the Chinese food and drug testing institute) for bacterial endotoxin were added.
DGA resin column parameters: the resin column is quartz, and is filled with DGA resin (self-made resin, consisting of acrylic polymer loaded TEHDGA) 0.6cm 3 The column was UV sterilized in a class A clean shielded chamber for 1h prior to running the protocol, and previously rinsed with 25mL sterile water for injection, and equilibrated with 3.2M nitric acid (5 mL).
Step a: the above was initiated at a flow rate of 0.5mL/min 177 The Lu solution was injected into the DGA resin column and stopped after the injection was completed.
Step b: sterile water for injection (0.5 mL, which is insufficient in the amount of water for sterile injection and causes incomplete endotoxin washing) was injected into the above resin column at a flow rate of 0.5 mL/min.
Step c: 0.05M hydrochloric acid solution was injected into the above resin column at a flow rate of 0.5mL/min, and the eluate was filtered through a 0.02 μ M filter, and 3.8mL of filtrate was collected in a 10mL penicillin bottle.
Step d: adding a rubber plug and an aluminum cover, and pressing a cover. The activity tested was 1.30Ci. (recovery rate 96.3%)
The endotoxin in the product was tested to be 31EU/mL, which is higher than the requirement for injectable drug manufacture (. Ltoreq.20 EU/mL), indicating that the conditions in this comparative example are not effective in removing endotoxin.
In this comparative example, the volume rinsed out of the sterile book for injection was mainly reduced (step b of this comparative example). The aseptic water for injection rinsing is used for removing endotoxin adsorbed and stained on a flow path (comprising a pipeline, a resin column and a filter membrane) in the loading process. This step reduces the amount of sterile water for injection, and thus endotoxin cannot be removed effectively.
Comparative example 2
Initiation of 177 Lu solution: supports produced under non-sterile conditions 177 Lu solution with a total activity of 1.55Ci (original target) 176 Lu (76.4% enriched target) 0.6 mg), a volume of about 1.1 mL, and a solvent of 0.05 mhz cl.
DGA resin column parameters: the resin column is made of quartz, and is filled with DGA resin (self-made resin, consisting of acrylic polymer loaded TEHDGA) 0.10cm 3 (reduce the amount of column packing, unable to effectively adsorb Lu), the column was placed in a class A clean shielding box and subjected to UV sterilization for 1h before the process flow was performed, and the column was previously rinsed with 25mL of sterile water for injection and equilibrated with 1.2M nitric acid (5 mL).
Step a: starting from above 177 Adding 3.0mL2MHNO into bottle of Lu solution 3 And (4) uniformly mixing.
Step b: the above was initiated at a flow rate of 0.5mL/min 177 The Lu solution was injected into the DGA resin column and stopped after the injection was completed.
Step c: sterile water for injection 5mL was injected into the above resin column at a flow rate of 0.5 mL/min.
Step d: 0.05M hydrochloric acid solution was injected into the above resin column at a flow rate of 0.5mL/min, and the eluate was filtered through a 0.02 μ M filter, and 4.0mL of filtrate was collected in a 10mL vial.
Step e: adding a rubber plug and an aluminum cover, and pressing a cover. The activity was tested at 1.03Ci (66.5% recovery).
The endotoxin in the product is tested. (about) 1.9EU/mL, meeting the production requirement of injection (< 20 EU/mL).
In this comparative example, the DGA resin column packing volume was mainly reduced. When the sample liquid is a carrier 177 Lu, because of its total chemical mass (0.6 mg, inclusive) 176 Lu and 177 lu) is high, so that it is not present during loadingThe method effectively retains the Lu element. Although endotoxin in the product meets the requirements (the product can be used for producing injection). However, the comparative method has an excessively low recovery rate and very high loss in production, which is unacceptable for production.
Claims (16)
1. Removing method 177 A process for endotoxin in Lu solution, which comprises the steps of:
(1) According to the initiation 177 Acid concentration and volume parameters in Lu solution, starting with 177 Adding a certain amount of nitric acid solution into the Lu solution to ensure that the concentration of nitric acid in the solution is more than 1M;
(2) The flow rate of 0.1 to 2.0BV/min is used for leading the flow rate obtained in the step (1) 177 Injecting the Lu solution into a resin column filled with DGA resin for leaching; the volume of DGA resin in the resin column is 0.2-2.0 cm 3 ；
(3) Injecting sterile water for injection into the resin column in the step (2) at the flow rate of 0.1-2.0 BV/min until the specified volume is reached;
(4) Injecting dilute hydrochloric acid into the resin column in the step (3) at the flow rate of 0.1-2.0 BV/min for elution, wherein the concentration of the dilute hydrochloric acid is 0.01-0.5M, filtering the eluted effluent liquid through a 0.02 mu m filter membrane, and collecting filtrate, wherein the obtained filtrate is the' endotoxin removing filtrate 177 Lu solution ".
2. Removal according to claim 1 177 The method for removing endotoxin in the Lu solution is characterized in that the volume of DGA resin in the resin column in the step (2) is 0.4-1.0 cm 3 。
3. Removal according to claim 1 177 The method for removing endotoxin from the Lu solution is characterized in that the concentration of the dilute hydrochloric acid in the step (4) is 0.04-0.05M.
4. Removal according to claim 1 177 Process for endotoxins in Lu solution, characterized in that the starting in step (1) 177 The acid in the Lu solution is hydrochloric acid or nitric acid, and the concentration and the volume of the acid are not limited; when starting 177 When the concentration of nitric acid in the Lu solution is more than 1M, the nitric acid solution does not need to be added.
5. Removal according to claim 1 177 The method for endotoxin in Lu solution is characterized in that nitric acid solution is added in the step (1) and then 177 The concentration of the nitric acid solution in the Lu solution is 2-5M, and the nitric acid solution is added 177 The total volume of the Lu solution is not limited.
6. Removal according to claim 5 177 A method for endotoxin in Lu solution, characterized in that after adding nitric acid solution 177 The total volume of the Lu solution is 2-50 mL.
7. Removal according to claim 1 177 Process for endotoxins in Lu solution, characterized in that the starting in step (1) 177 Lu solution as carrier 177 Lu or without carrier 177 Lu, its total activity is unlimited; when starting 177 Lu solution as carrier 177 Lu, of which 177 Lu and nat the total chemical content of Lu is not higher than the limit sample loading of the resin column packing.
8. Removal according to claim 1 177 Process for endotoxins in Lu solution, characterized in that the starting in step (1) 177 Lu solutions produced under non-sterile conditions 177 Lu solution, the dilute hydrochloric acid in step (4) is subjected to aseptic processing.
9. Removal according to claim 1 177 The method for endotoxin in Lu solution, wherein the DGA resin in the step (2) is a resin obtained by loading a DGA-based organic compound on a base resin.
10. Removal according to claim 9 177 Lu solution inA method for endotoxin, wherein said DGA-based organic compound comprises TODGA or TEHDGA.
11. Removal according to claim 9 177 The method for endotoxin in Lu solution is characterized in that the substrate resin is resin material which is different in material and can load DGA organic compound.
12. Removal according to claim 11 177 The method for removing endotoxin from Lu solution is characterized in that the material of the base resin comprises acrylic polymer or styrene polymer.
13. Removal according to claim 1 177 The method for removing endotoxin in the Lu solution is characterized in that the flow rates in the steps (2), (3) and (4) are all 0.3-1 BV/min.
14. Removal according to claim 1 177 The method for removing endotoxin in the Lu solution is characterized in that the designated volume of the sterile water for injection in the step (3) is 3-15 BV; the volume of the dilute hydrochloric acid solution injected in the step (4) is 2-15 BV.
15. Removal according to claim 14 177 The method for removing endotoxin from Lu solution is characterized in that the designated volume of the sterile water for injection in the step (3) is 6-9 BV.
16. Removal according to claim 14 177 The method for removing endotoxin in the Lu solution is characterized in that the volume of the dilute hydrochloric acid solution in the step (4) is 6-9 BV.
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