目的 考察国内达肝素钠注射液的质量现状及存在问题，对现行质量标准的科学性及检验方法进行研究，为安全监管提供参考。方法 对达肝素钠注射液进行国家评价性抽验，生产企业分别为常州千红生化制药股份有限公司、河北常山生化药业股份有限公司、南京健友生化制药股份有限公司、辉瑞制药有限公司。采用法定标准方法和探索性研究方法对抽验样品进行检验，对检验结果进行统计分析。建立并完善了多个检验方法：宽分布标样法测定相对分子质量与相对分子质量分布；采用全自动血凝仪终点法及动力学法测定抗Xa因子和抗IIa因子效价；阴离子交换色谱法检查有关物质和游离硫酸根；细菌内毒素检查；拉曼光谱快检模型。结果 4个厂家40批样品法定检验及探索性研究检验合格率为100%，产品质量较好。质量标准中存在的主要问题是：企业注册标准相对分子质量测定方法不够合理，使用的相对分子质量对照品为已经淘汰的欧洲药典对照品或美国的依诺肝素钠相对分子质量对照品，实验操作复杂，计算误差大；没有对降解杂质游离硫酸盐进行控制。产品质量上的主要问题是：与原研产品相比，国产达肝素钠重均相对分子质量及大于8 000的级分控制的比较好，但重均相对分子质量小于3 000的级分与原研产品（9.0%～10.0%）相比占比较高，为11.0%～13.0%，该项目限度为“不得过13.0%”；抗Xa因子效价国产达肝素钠控制较好，原研企业在标准中还规定了抗IIa因子效价范围，有部分国产厂家产品抗IIa效价偏高，因此抗Xa因子与抗IIa因子效价比偏低；游离硫酸盐为降解杂质，虽然企业注射液标准中没有规定，但所有厂家产品的检测结果均较低，小于0.02%，符合要求；原研产品没有检出硫酸皮肤素，国内产品均检出，但均小于2.0%，符合要求。结论 国产低分子肝素按生产工艺分类审批后，产品质量大幅提高，但目前的企业注册标准由于审批年代较早，质控项目与方法较为落后，应尽快建立统一的国家标准，进一步提高我国低分子肝素类产品质控水平与质量。

Objective To investigate the quality status and existing problems of dalteparin sodium injection in China, and study the scientificity of the drug specifications and test methods, so as to provide reference for safety supervision. Methods The national evaluation sampling test of dalteparin sodium injection was carried out. The manufacturers are Changzhou Qianhong Biochemical Pharmaceutical Co., LTD., Hebei Changshan Biochemical Pharmaceutical Co., LTD., Nanjing Jianyou Biochemical Pharmaceutical Co., LTD., and Pfizer Pharmaceutical Co., LTD. The samples were tested by legal standard methods and exploratory research methods, and the test results were statistically analyzed. Several test methods were established and improved:determine molecular weight and molecular weight distribution by national wide distribution molecular standard, determine the anti-factor Xa and antifactor IIa activity by automatic coagulation analyzer, anion exchange chromatography was used to check related substances and free sulfate, bacterial endotoxin test, and fast detection model of Raman spectra. Results The pass rate of 40 batches of samples from four manufacturers through legal inspections and exploratory research inspections was 100%, and the product quality was good. The main problems in the drug specifications were:The molecular weight determination methods in current specifications were not reasonable, the molecular weight standards used was the obsolete European Pharmacopoeia Reference Substance or reference standard of enoxaparin sodium in the United States Pharmacopoeia, the experimental operation was complex and the calculation error was large. There was no control over the degradation impurity-free sulfate. The main problems in product quality were:Compared with the original product, the weight average molecular weight of domestic products and the fractions with weight average molecular weight greater than 8 000 were well controlled, the fractions with weight average molecular weight less than 3 000 account for 11.0%-13.0%, and the original product account for 9.0%-10.0%. The limit of this project is "no more than 13.0%". The activity of anti-factor Xa was well controlled by domestic products. The activity of anti-factor IIa of some domestic products was high, so the ratio of anti-factor Xa and anti-factor IIa was low. Free sulfate was a degradation impurity. Although it was not specified in the current specifications, the test results of all products were low, less than 0.02%, meeting the requirements. Dermatan sulfate was not detected in the original products, and it was detected in all domestic products, but it was less than 2.0%, meeting the requirements. Conclusion After the domestic low molecular weight heparin has been approved according to the production process, the product quality has been greatly improved. However, due to the early approval of the current specifications, the quality control items and methods are relatively backward. A unified national specification should be established as soon as possible to further improve the quality control level and quality of low molecular weight heparin products in China.

R927.11