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ChineseHeparin Manufacturer again involved in Falsification and GMP Non-Compliance 中国肝素生产商又卷入造假和GMP不符合 The Heparin Scandal has changed theregulation and the enforcement actions against API manufacturers like noother case in the last 20 years. Now, it seems that falsification ofHeparin was detected again at a manufacturer in China. 肝素丑闻曾经改变了过去20年法规要求和对原料药生产商的强制措施，现在，貌似中国一家生产商又发现了肝素造假事件。 In 2008 adulterated Heparin from China caused thedeath of 81 people and 785 reports of serious injuries. The reason for theadverse reaction which caused the deaths and injuries was identifiedlater. The contaminant was an "over-sulphated derivativeof chondroitin sulfate, a closely related substance obtained from mammal orfish cartilage and often used as a treatment for arthritis. Sinceover-sulphated chondroitin is not a naturally occurring molecule, costs afraction of true heparin starting material, and mimics the in-vitro propertiesof heparin, the counterfeit was almost certainly intentional as opposed to anaccidental lapse in manufacturing. The raw heparin batches were found to havebeen cut from 2-60% with the counterfeit substance, and motivation for theadulteration was attributed to a combination of cost effectiveness and ashortage of suitable pigs in China." ( Source Wikipedia) 在2008年，来自中国的劣质肝素导致81人死亡，785例严重伤害报告。引发死亡和伤害不良反应的原因后来被找到。污染物是“硫酸软骨素衍生的超硫酸物，与哺乳动物或鱼软骨所得的物质非常接近，通常用作关节炎的治疗。由于超量硫酸软骨素并不是自然生成的分子，会消耗掉真正肝素起始物料的一部分，并且模拟肝素的体外特征，假冒行为几乎可以肯定是故意的而不是生产疏忽。原料肝素批次被发现使用假冒的物质替代了2-60%，假冒的动机是成本和中国适用的猪短缺的合并。”（来自维基） A comprehensive investigation of the US congressidentified weaknesses in the GMP Inspection by FDA. The UScongress discovered that the frequency of inspections was not asrequired by FDA's internal standards. FDA took multiple actions as aconsequence of the scandal. Among others the FDA opened overseas Inspectorates in India and China andinitiated a number of new regulatory initiatives. Also in the EU theHeparin scandal has impacted the regulation and inspections. The so-called Counterfeit Directive, the GDP Guidelines and changes in the EU GMP Guide (especially with regard to supplierqualification) have been havily impacted by the Heparin case.Today manufacturers of a medicinal products are obliged to controlthe GMP compliance of each API manufacturer. 美国议会一份全面调查找出了FDA在GMP检查中的弱点。美国议会发现检查频次并没有按照FDA内部标准执行。作为丑闻的结果，FDA采取了多项措施。其中一项是FDA启动了对中国和印度的海外检查，启动了大量新法规倡议。在欧洲的肝素丑闻也影响到了法规和检查。所谓的防伪法案、GDP指南和EU GMP指南的变更（尤其是关于供应商确认）都是受到肝素案例的严重影响。今天，一个药品生产商有义务控制每个原料药生产商的GMP符合性。 It was therefore a surprise when French Inspectorsjust recently found worrying details at Dongying Tiandong PharmaceuticalCo., Ltd., No. 1236, Nan-er Road, Dongying City, Shandong Provice, China.According to the non-compliance report published in the EudraGMDP Database: "Overall, 10 deficiencies wereobserved during the inspection, 2 Critical and 3 Major deficiencies: 因此，当法国检查员最近在东营天东制药有限公司，No.1236, Nan-er Road, Dongying City, 中国山东省，发现令人担忧的细节时，真是很令人惊讶。根据在欧洲GMDP数据库中公布的不符合报告，“检查中总共发现10项缺陷，其中2个关键3个主要缺陷： [Critical 1] PCR results of Crude Heparinshowing the presence of ruminant DNA received from approved suppliers weremanipulated. There was no evidence that the samples retested came from the samebatch tested initially; 【关键缺陷1】肝素粗品PCR结果显示从批准的供应商处接收的反刍动物类DNA是伪造的。没有证据证明复测样品与初测样品来自同一批次； [Critical 2] The quality system implementedby the company for ensuring the full traceability of crude Heparin wasidentified as very weak : e.g., the traceability from slaughterhouses/abattoirswas not available and not assessed during the audits of the suppliers (lack ofsupporting documents for the received lots)" 【关键缺陷2】公司执行的确保肝素粗品可追溯性的质量体系很差，例如，从屠宰场开始的可追溯性没有，对供应商审计期间并没有进行评估（接收批次缺乏支持性文件）； The inspectors also found out that 7 batches ofcrude Heparin received in 2014 and 2015 were obtained OOS for potency and usedfor the manufacturing of finished APIs without any OOS investigation. Newsuppliers of crude Heparin were not qualified in a systematic manner toguarantee the quality of the product. As a consequence of the findings EMApublished the GMP Non-Compliance Report on 25 February 2016. Also, the CEP2005-258 was suspended. Manufactures of Medicinal Products using the Heparinfrom Dongying Tiandong Pharmaceuticals should consider a recall of theirbatches based on a risk assessment. 检查员还发现2014-2015年间接收的7批肝素粗品效价检测结果是OOS，但没有OOS调查就用于成品原料药的生产。肝素粗品的供应商并没有采用系统化方式进行确认，来确保产品的质量。发现缺陷之后，EMA于2016年2月25日公布了GMP不符合报告。而CEP2005-258也被搁置。使用东营天东肝素的药品生产商应基于风险评估考虑召回其批次。 来源GMP不符合报告。
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