技术领域technical field
本发明涉及临床凝血检验制剂的制备方法，具体凝血因子IX质控品制备方法。The invention relates to a preparation method of a clinical blood coagulation test preparation, in particular a preparation method of a blood coagulation factor IX quality control product.
背景技术Background technique
凝血因子IX测定具有重要的临床意义。随着凝血因子IX活性检验项目不断拓展到疾病诊断和治疗中的各个领域，使用凝血因子IX质控品对凝血因子IX活性检测进行室内质控和室间质评就显得尤其重要。目前针对凝血因子IX检测的试剂、仪器较多，不同的试剂和检测仪器、检测原理各不相同，导致其结果差别很大。无论采用何种方法，进行室内质控和参加室间质评是保障检测结果具有良好重复性和可比性的必要手段，而这些质量保证措施的开展都离不开凝血因子IX质控品。Determination of coagulation factor IX has important clinical significance. As the blood coagulation factor IX activity test project continues to expand to various fields in disease diagnosis and treatment, it is particularly important to use blood coagulation factor IX quality control products to conduct internal quality control and external quality assessment for blood coagulation factor IX activity detection. At present, there are many reagents and instruments for the detection of blood coagulation factor IX. Different reagents, detection instruments, and detection principles are different, resulting in great differences in the results. Regardless of the method used, internal quality control and external quality assessment are necessary means to ensure good repeatability and comparability of test results, and these quality assurance measures are inseparable from coagulation factor IX quality control products.
目前临床实验室使用的凝血质控物通常为多参数凝血质控品，其异常值凝血质控品除凝血因子IX水平异常外其它参数也为异常，难以保证病理性样本凝血因子IX测定结果的准确性，同时也难以保证凝血因子IX室内质控和室间质评的有效性。At present, the blood coagulation quality control substances used in clinical laboratories are usually multi-parameter blood coagulation quality control substances, and the abnormal values of the blood coagulation quality control substances are also abnormal except for the abnormal level of coagulation factor IX. At the same time, it is difficult to guarantee the effectiveness of the coagulation factor IX internal quality control and external quality assessment.
国内凝血质控品几乎被国外试剂厂商垄断，产品价格昂贵且水平单一，无法满足临床检验多活性水平的需求，因此，研发生产国内自主品牌的多个浓度水平的凝血因子IX质控品迫在眉睫。Domestic coagulation quality control products are almost monopolized by foreign reagent manufacturers. The products are expensive and have a single level, which cannot meet the needs of clinical testing with multiple activity levels.
发明内容Contents of the invention
针对上述技术问题，本发明提供一种制备凝血因子IX质控品的方法及获得凝血因子IX质控品。本发明方法制备的凝血因子IX质控品为凝血因子IX多个浓度水平，且其它凝血因子含量在正常范围；该产品均一性和稳定性较好，满足临床对凝血因子IX质控品检验的质量控制要求。In view of the above technical problems, the present invention provides a method for preparing a blood coagulation factor IX quality control product and obtaining a blood coagulation factor IX quality control product. The blood coagulation factor IX quality control product prepared by the method of the present invention has multiple concentration levels of blood coagulation factor IX, and the content of other blood coagulation factors is in the normal range; the product has good uniformity and stability, and meets the clinical requirements for the blood coagulation factor IX quality control product inspection. Quality control requirements.
为了实现上述发明目的，本发明提供以下技术方案：凝血因子IX质控品制备方法，包括以下步骤：In order to achieve the above-mentioned purpose of the invention, the present invention provides the following technical solutions: a method for preparing a blood coagulation factor IX quality control product, comprising the following steps:
(1)将人静脉采集的血液与抗凝剂以体积比为9∶1加入混合，在2℃～8℃条件下离心15分钟，相对离心力为2500g，分离吸取上层血浆，将多人份血浆混合，即得多人份混合血浆；抗凝剂为枸橼酸三钠溶液，其浓度为0.109mol/L～0.129mol/L。(1) Add and mix the blood collected from human veins and anticoagulant at a volume ratio of 9:1, centrifuge at 2°C to 8°C for 15 minutes, and the relative centrifugal force is 2500g, separate and absorb the upper layer of plasma, and separate the plasma from several people Mixing, that is, multiple servings of mixed plasma; the anticoagulant is trisodium citrate solution, and its concentration is 0.109mol/L to 0.129mol/L.
(2)免疫亲和层析柱预先用缓冲液在10℃～18℃条件下平衡，缓冲液包括0.02mol/L Tris、0.15mol/L NaCl、8mmol/L MgCl2，pH7.25。(2) The immunoaffinity chromatography column is pre-balanced with a buffer solution at 10°C to 18°C. The buffer solution includes 0.02mol/L Tris, 0.15mol/L NaCl, 8mmol/L MgCl2 , pH7.25.
(3)原料血浆加入MgCl2后，原料血浆中MgCl2浓度为4.5～5.5mmol/L。上免疫亲和层析柱，收集免疫亲和层析柱下方流出的血浆，即为缺乏凝血因子IX血浆。(3) After adding MgCl2 to the raw plasma, the concentration of MgCl2 in the raw plasma is 4.5-5.5 mmol/L. Put on the immunoaffinity chromatography column, and collect the plasma flowing out from the bottom of the immunoaffinity chromatography column, which is plasma lacking coagulation factor IX.
(4)将缺乏凝血因子IX血浆与多人份混合血浆按照要求比例混合，即可制备成不同浓度水平的凝血因子IX质控品。(4) By mixing the blood coagulation factor IX-deficient plasma and the mixed blood plasma of multiple parts according to the required ratio, the blood coagulation factor IX quality control products with different concentration levels can be prepared.
(5)将制备的凝血因子IX质控品加入冻干保护剂，分装，冷冻干燥。加入的冻干保护剂，包括质量比例占凝血因子IX质控品的0.5～1.5％Hepes、l～5％甘氨酸、0.5～5％甘露醇。(5) The prepared blood coagulation factor IX quality control substance was added into a lyoprotectant, subpackaged, and freeze-dried. The added lyoprotectant includes 0.5-1.5% Hepes, 1-5% glycine, and 0.5-5% mannitol whose mass proportion accounts for the coagulation factor IX quality control product.
本发明提供的凝血因子IX质控品制备方法，用抗人凝血因子IX单克隆抗体免疫亲和层析柱将多人份混合血浆进行亲和层析，去除多人份混合血浆中的凝血因子IX即为缺乏凝血因子IX血浆；再将多人份混合血浆与缺乏凝血因子IX血浆按照一定比例混合，制备成凝血因子IX含量为不同浓度水平的凝血因子IX质控品，加入冻干保护剂，分装，冷冻干燥，获得凝血因子IX质控品。The preparation method of the blood coagulation factor IX quality control product provided by the present invention uses an anti-human blood coagulation factor IX monoclonal antibody immunoaffinity chromatography column to perform affinity chromatography on the mixed plasma of multiple parts to remove the coagulation factor in the mixed plasma of multiple parts IX is blood coagulation factor IX-deficient plasma; then multiple parts of mixed plasma and coagulation factor IX-deficient plasma are mixed according to a certain ratio to prepare coagulation factor IX quality control products with different concentrations of coagulation factor IX, and add lyoprotectant , aliquoted, and freeze-dried to obtain a blood coagulation factor IX quality control substance.
本发明提供的制备方法中，抗人凝血因子IX单克隆抗体免疫亲和层析柱的制备方法为将一种能够高度特异性的连接凝血因子IX的单克隆抗体偶联至经CNBr活化的Sepharose4B琼脂糖凝胶上，组成免疫亲和层析柱。在Mg2+存在的条件下，当血浆通过该免疫亲和层析柱时，唯独凝血因子IX被吸附，其他凝血因子的活性基本未变。In the preparation method provided by the present invention, the preparation method of the anti-human coagulation factor IX monoclonal antibody immunoaffinity chromatography column is to couple a highly specific monoclonal antibody linked to coagulation factor IX to CNBr-activated Sepharose4B Immunoaffinity chromatography column on agarose gel. In the presence of Mg2+ , when plasma passes through the immunoaffinity chromatography column, only coagulation factor IX is adsorbed, and the activities of other coagulation factors remain basically unchanged.
本发明制备的凝血因子IX质控品，其产品均一性、稳定性及冻干品复融后稳定性好，可代替进口产品用于凝血因子IX检测的质量控制，有利于降低检测成本，提升我国对凝血因子IX检测的能力。The blood coagulation factor IX quality control product prepared by the present invention has good product uniformity, stability and stability after rethawing of the freeze-dried product, and can replace imported products for quality control of blood coagulation factor IX detection, which is beneficial to reduce detection costs and improve my country's ability to detect coagulation factor IX.
具体实施方式Detailed ways
结合实施例，进一步阐述本发明：In conjunction with embodiment, further set forth the present invention:
实施例以制备活性为30％的凝血因子IX质控品为例。The embodiment takes the preparation of a blood coagulation factor IX quality control product with an activity of 30% as an example.
(1)将人静脉采集的血液与抗凝剂以体积比为9∶1加入混合，在2℃～8℃条件下离心15分钟，相对离心力为2500g，分离吸取上层血浆，将多人份血浆混合，即得多人份混合血浆；抗凝剂为枸橼酸三钠溶液，其浓度为0.109mol/L～0.129mol/L。(1) Add and mix the blood collected from human veins and anticoagulant at a volume ratio of 9:1, centrifuge at 2°C to 8°C for 15 minutes, and the relative centrifugal force is 2500g, separate and absorb the upper layer of plasma, and separate the plasma from several people Mixing, that is, multiple servings of mixed plasma; the anticoagulant is trisodium citrate solution, and its concentration is 0.109mol/L to 0.129mol/L.
(2)免疫亲和层析柱预先用缓冲液在10℃～18℃条件下平衡，缓冲液包括0.02mol/L Tris、0.15mol/L NaCl、8mmol/L MgCl2，pH7.25。(2) The immunoaffinity chromatography column is pre-balanced with a buffer solution at 10°C to 18°C. The buffer solution includes 0.02mol/L Tris, 0.15mol/L NaCl, 8mmol/L MgCl2 , pH7.25.
(3)原料血浆加入MgCl2后，原料血浆中MgCl2浓度为4.5～5.5mmol/L。上免疫亲和层析柱，收集免疫亲和层析柱下方流出的血浆，即为缺乏凝血因子IX血浆。(3) After adding MgCl2 to the raw plasma, the concentration of MgCl2 in the raw plasma is 4.5-5.5 mmol/L. Put on the immunoaffinity chromatography column, and collect the plasma flowing out from the bottom of the immunoaffinity chromatography column, which is plasma lacking coagulation factor IX.
(4)将缺乏凝血因子IX血浆与多人份混合血浆按照要求比例混合，制备凝血因子IX活性为30％左右浓度水平的凝血因子IX质控品。(4) Mixing the blood coagulation factor IX-deficient plasma and the mixed blood plasma of multiple parts according to the required ratio, and preparing the blood coagulation factor IX quality control product with the activity of blood coagulation factor IX at a concentration level of about 30%.
(5)将制备的凝血因子IX质控品加入冻干保护剂。保护剂包括1％Hepes、2％甘氨酸、2％甘露醇。进行分装，冷冻干燥。(5) Add the prepared coagulation factor IX quality control substance into the lyoprotectant. Protectants include 1% Hepes, 2% Glycine, 2% Mannitol. Aliquot and freeze-dry.
产品性能检验测试：Product performance inspection test:
(1)产品活性检测(1) Product activity detection
用Sysmex CA-1500全自动血凝仪及配套凝血因子IX检测试剂对实施例凝血因子IX质控品活性进行检测。Use the Sysmex CA-1500 automatic coagulation instrument and the supporting coagulation factor IX detection reagent to detect the activity of the blood coagulation factor IX quality control product in the embodiment.
表1凝血因子IX质控品的凝血因子活性测定表Table 1 coagulation factor activity determination table of coagulation factor IX quality control product
由上表可知，本制备方法所得产品特异性好，能够特异性的去除凝血因子IX而对其它凝血因子含量基本无影响。It can be seen from the above table that the product obtained by the preparation method has good specificity, and can specifically remove blood coagulation factor IX without substantially affecting the content of other blood coagulation factors.
(2)产品均一性测定(2) Determination of product uniformity
在实施例制备的凝血因子IX质控品中分别随机抽取10支，进行准确的复溶重建。10 of the coagulation factor IX quality control products prepared in the examples were randomly selected for accurate reconstitution and reconstitution.
用Sysmex CA-1500全自动血凝仪及配套凝血因子IX检测试剂对实施例凝血因子IX质控品活性进行检测，结果依次如下：百分活性(％)29.9、30.2、30.0、29.8、29.0、29.5、30.3、30.1、30.2、29.7，平均值29.9。With Sysmex CA-1500 automatic coagulation instrument and supporting coagulation factor IX detection reagent, the activity of the blood coagulation factor IX quality control product of the embodiment is detected, and the results are as follows in order: percent activity (%) 29.9, 30.2, 30.0, 29.8, 29.0, 29.5, 30.3, 30.1, 30.2, 29.7, with an average of 29.9.
取实施例制备的凝血因子IX质控品3瓶，进行准确的复溶重建，混合后连续检测FIX活性10次，结果如下：百分活性(％)29.4、30.5、29.9、29.8、30.0、30.5、30.6、30.1、30.3、29.9；平均值30.1。Get 3 bottles of the blood coagulation factor IX quality control product prepared in the example, carry out accurate reconstitution and reconstitution, detect FIX activity continuously 10 times after mixing, the results are as follows: percent activity (%) 29.4, 30.5, 29.9, 29.8, 30.0, 30.5 , 30.6, 30.1, 30.3, 29.9; average 30.1.
经计算得，实施例凝血因子IX质控品瓶间重复性CV值CV瓶间为0.39％，说明该水平凝血因子IX质控品达到临床试验对于质控品均一性的通用要求(批内瓶间CV≤5.0％)。After calculation, the repeatability CV value between CV bottles of the coagulation factor IX quality control product bottle is 0.39%, which shows that this level of blood coagulation factor IX quality control product reaches the general requirements of clinical trials for the uniformity of quality control products (bottles in batches). Between CV≤5.0%).
(3)产品冻干品稳定性检测(3) Stability testing of freeze-dried products
将实施例制备的凝血因子IX质控品和SIEMENS P质控品置于37℃保存，分别于1天、3天、5天、7天取样，同时进行准确的复溶重建。The blood coagulation factor IX quality control substance and SIEMENS P quality control substance prepared in the example were stored at 37°C, and samples were taken at 1 day, 3 days, 5 days, and 7 days respectively, and accurate reconstitution was carried out at the same time.
用Sysmex CA-1500全自动血凝仪及配套凝血因子IX检测试剂对实施例凝血因子IX质控品活性进行检测，结果如下：Use Sysmex CA-1500 automatic coagulation instrument and supporting coagulation factor IX detection reagent to detect the activity of the blood coagulation factor IX quality control product of the embodiment, the results are as follows:
表2冻干品37℃稳定性Table 2 Stability of freeze-dried products at 37°C
实施例凝血因子IX质控品37℃放置7天，放置前后活性波动范围＜5％，与市售进口SIEMENS异常质控血浆相当，可以认为本发明制备的凝血因子VIII质控品37℃放置7天是稳定的。Example The coagulation factor IX quality control product was placed at 37°C for 7 days, and the activity fluctuation range before and after placement was <5%, which was equivalent to the commercially available imported SIEMENS abnormal quality control plasma. It can be considered that the coagulation factor VIII quality control product prepared by the present invention was placed at 37°C for 7 days. The sky is stable.
(4)产品复溶稳定性检测(4) Product reconstitution stability testing
将实施例制备的凝血因子IX质控品和SIEMENS P质控品进行准确的复溶重建，分成两份分别置于2℃-8℃和室温(20℃-25℃)保存，每隔一定时间取样进行凝血因子IX活性检测。The blood coagulation factor IX quality control product and SIEMENS P quality control product prepared in the example were accurately reconstituted and reconstituted, divided into two parts and stored at 2°C-8°C and room temperature (20°C-25°C), and kept at regular intervals Samples were taken for coagulation factor IX activity testing.
用Sysmex CA-1500全自动血凝仪及配套凝血因子IX检测试剂对实施例凝血因子IX质控品活性进行检测，结果如下：Use Sysmex CA-1500 automatic coagulation instrument and supporting coagulation factor IX detection reagent to detect the activity of the blood coagulation factor IX quality control product of the embodiment, the results are as follows:
表3复溶稳定性Table 3 reconstitution stability
实施例凝血因子IX质控品复溶后置于2℃～8℃和室温条件下，24小时与0小时FIX∶C无明显变化，且活性波动范围均＜5％，与市售进口SIEMENS异常质控血浆相当。可以认为本产品复溶后2℃～8℃和室温存放24小时内可保持稳定。由此可见，本发明制备的凝血因子IX具有较好的开瓶稳定性。Example The blood coagulation factor IX quality control product was reconstituted and placed at 2°C to 8°C and room temperature. There was no significant change in FIX:C between 24 hours and 0 hours, and the activity fluctuation range was less than 5%, which was abnormal with the commercially available imported SIEMENS. Quality control plasma was comparable. It can be considered that the product can remain stable within 24 hours after reconstitution at 2°C to 8°C and at room temperature. It can be seen that the blood coagulation factor IX prepared by the present invention has better stability when opening a bottle.
以上所述仅是以一个浓度水平为例，是本发明的优选实施方式，本发明保护的是整个技术过程和产品，应当指出，对于本技术领域的普通技术人员来说，在不脱离本发明原理的前提下，还可以做出若干改进和润饰，这些改进和润饰也应视为本发明的保护范围。The above is only an example of a concentration level, which is a preferred embodiment of the present invention. The present invention protects the entire technical process and products. It should be pointed out that for those of ordinary skill in the art, without departing from the present invention Under the premise of the principle, some improvements and modifications can also be made, and these improvements and modifications should also be regarded as the protection scope of the present invention.
| Application Number | Priority Date | Filing Date | Title |
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| CN201410449813.9ACN104181313B (en) | 2014-09-04 | 2014-09-04 | Factor IX quality-control product preparation method |
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| CN201410449813.9ACN104181313B (en) | 2014-09-04 | 2014-09-04 | Factor IX quality-control product preparation method |
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| CN201410449813.9AExpired - Fee RelatedCN104181313B (en) | 2014-09-04 | 2014-09-04 | Factor IX quality-control product preparation method |
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| CN107467013A (en)* | 2017-09-20 | 2017-12-15 | 上海贞元诊断用品科技有限公司 | A method for preparing a universal plasma matrix for quality control products that can be stored for a long time |
| CN110257358A (en)* | 2019-06-10 | 2019-09-20 | 广东双林生物制药有限公司 | A kind of production method of high-purity Complex |
| CN110257358B (en)* | 2019-06-10 | 2023-05-19 | 广东双林生物制药有限公司 | Production method of high-purity human coagulation factor IX preparation |
| CN110346582A (en)* | 2019-07-15 | 2019-10-18 | 三诺生物传感股份有限公司 | A kind of compound quality-control product of blood coagulation and preparation method thereof |
| CN110346582B (en)* | 2019-07-15 | 2022-10-25 | 三诺生物传感股份有限公司 | Blood coagulation composite quality control product and preparation method thereof |
| CN115327128A (en)* | 2022-07-01 | 2022-11-11 | 深圳市帝迈生物技术有限公司 | VIII factor activity determination kit and preparation method thereof |
| Publication number | Publication date |
|---|---|
| CN104181313B (en) | 2015-11-18 |
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| SE01 | Entry into force of request for substantive examination | ||
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| CF01 | Termination of patent right due to non-payment of annual fee | ||
| CF01 | Termination of patent right due to non-payment of annual fee | Granted publication date:20151118 Termination date:20180904 |