目的 考察國(guó)內(nèi)達(dá)肝素鈉注射液的質(zhì)量現(xiàn)狀及存在問題，對(duì)現(xiàn)行質(zhì)量標(biāo)準(zhǔn)的科學(xué)性及檢驗(yàn)方法進(jìn)行研究，為安全監(jiān)管提供參考。方法 對(duì)達(dá)肝素鈉注射液進(jìn)行國(guó)家評(píng)價(jià)性抽驗(yàn)，生產(chǎn)企業(yè)分別為常州千紅生化制藥股份有限公司、河北常山生化藥業(yè)股份有限公司、南京健友生化制藥股份有限公司、輝瑞制藥有限公司。采用法定標(biāo)準(zhǔn)方法和探索性研究方法對(duì)抽驗(yàn)樣品進(jìn)行檢驗(yàn)，對(duì)檢驗(yàn)結(jié)果進(jìn)行統(tǒng)計(jì)分析。建立并完善了多個(gè)檢驗(yàn)方法：寬分布標(biāo)樣法測(cè)定相對(duì)分子質(zhì)量與相對(duì)分子質(zhì)量分布；采用全自動(dòng)血凝儀終點(diǎn)法及動(dòng)力學(xué)法測(cè)定抗Xa因子和抗IIa因子效價(jià)；陰離子交換色譜法檢查有關(guān)物質(zhì)和游離硫酸根；細(xì)菌內(nèi)毒素檢查；拉曼光譜快檢模型。結(jié)果 4個(gè)廠家40批樣品法定檢驗(yàn)及探索性研究檢驗(yàn)合格率為100%，產(chǎn)品質(zhì)量較好。質(zhì)量標(biāo)準(zhǔn)中存在的主要問題是：企業(yè)注冊(cè)標(biāo)準(zhǔn)相對(duì)分子質(zhì)量測(cè)定方法不夠合理，使用的相對(duì)分子質(zhì)量對(duì)照品為已經(jīng)淘汰的歐洲藥典對(duì)照品或美國(guó)的依諾肝素鈉相對(duì)分子質(zhì)量對(duì)照品，實(shí)驗(yàn)操作復(fù)雜，計(jì)算誤差大；沒有對(duì)降解雜質(zhì)游離硫酸鹽進(jìn)行控制。產(chǎn)品質(zhì)量上的主要問題是：與原研產(chǎn)品相比，國(guó)產(chǎn)達(dá)肝素鈉重均相對(duì)分子質(zhì)量及大于8 000的級(jí)分控制的比較好，但重均相對(duì)分子質(zhì)量小于3 000的級(jí)分與原研產(chǎn)品（9.0%～10.0%）相比占比較高，為11.0%～13.0%，該項(xiàng)目限度為“不得過13.0%”；抗Xa因子效價(jià)國(guó)產(chǎn)達(dá)肝素鈉控制較好，原研企業(yè)在標(biāo)準(zhǔn)中還規(guī)定了抗IIa因子效價(jià)范圍，有部分國(guó)產(chǎn)廠家產(chǎn)品抗IIa效價(jià)偏高，因此抗Xa因子與抗IIa因子效價(jià)比偏低；游離硫酸鹽為降解雜質(zhì)，雖然企業(yè)注射液標(biāo)準(zhǔn)中沒有規(guī)定，但所有廠家產(chǎn)品的檢測(cè)結(jié)果均較低，小于0.02%，符合要求；原研產(chǎn)品沒有檢出硫酸皮膚素，國(guó)內(nèi)產(chǎn)品均檢出，但均小于2.0%，符合要求。結(jié)論 國(guó)產(chǎn)低分子肝素按生產(chǎn)工藝分類審批后，產(chǎn)品質(zhì)量大幅提高，但目前的企業(yè)注冊(cè)標(biāo)準(zhǔn)由于審批年代較早，質(zhì)控項(xiàng)目與方法較為落后，應(yīng)盡快建立統(tǒng)一的國(guó)家標(biāo)準(zhǔn)，進(jìn)一步提高我國(guó)低分子肝素類產(chǎn)品質(zhì)控水平與質(zhì)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