中国药厂GMP缺陷导致全球药品供应问题，WHO发布声明表面立场
The Chinese API manufacturer Qinhuangdao Zizhu Pharmaceutical Co., Ltd received a Warning Letter after an FDA inspection end of last year. This Warning Letter contains a list of serious violations of GMP. The deficiencies observed primarily cover the handling of data in the area of quality control (data manipulation, audit trail feature disabled, missing access controls, repeated analyses until the desired results be achieved) and the inappropriate exercising of the QC's responsibilities with regard to the release of products (incompletely filled in, unapproved batch records). The Warning Letter presents an impressive list of 17 items criticised and required by the FDA. The company now has to submit a lot of documents and statements to convince the FDA that the deficiencies observed during the inspection are corrected sustainably. Only when this is done, the Import Alert set in March this year will be repealed (an "Import Alert" entitles the FDA to block the further transport of goods within the US American borders without any further investigation).
中国原料生产商秦皇岛紫竹药业有限公司在FDA于去年的检查后收到了警告信。该警告信罗列了GMP严重违规。所发现的缺陷主要包括QC处理数据（数据篡改、审计追踪未激活、缺乏权限控制、重复检验直到合格）和QC就产品放行方面的职责未能行使（记录填写不完全、批记录未批准）。FDA在该警告信中罗列了令人印象深刻的17项批评和要求。该公司现在必须提交大量文件和声明来说服FDA，检查期间所发现的缺陷项已得到纠正并能持续。只有完成这些，今年3月的这份警告信才会被关闭。
Already before the issuance of this Warning Letter, the WHO published on its "Prequalification of Medicines Website" a statement on the Import Alert for products of the company Qinhuangdao Zizhu Pharmaceutical. The reason for this rapid and strong reaction of the WHO was a conflict due to this Import Alert with extensive and maybe even global consequences which can be described as follows:
在该警告信公布之前，WHO在其“药品网站预确认”中对进口禁令发布了一个声明。WHO之所以如此迅速强烈反应是因为该进口禁令的很大且甚至可能成为一个全球性的后果，描述如下：
In the course of the prequalification programme for APIs, representatives of the WHO's prequalification team (PQT) inspected the production sites of Qinhuangdao Zizhu Pharmaceutical in October 2015. The inspectors also discovered violations of the GMP-compliant handling with data and several minor deficiencies. After the company's responsible persons had communicated the CAPAs, the inspection was closed out and the site was classified as "compliant". The report is publicly accessible like any other inspection report of the PQT.
在原料药预确认程序的过程中，WHO的预确认团队代表于2015年10月检查了秦皇岛紫竹药业的生产现场。检查官也发现了数据处理方面的GMP符合性违规和一些小缺陷。在该公司的负责人沟通了CAPA之后，该检查关闭并且该工厂被列为符合。检查的报告与其他预确认团队（PQT）检查报告一样对外公开。
The objective of WHO's prequalification programme is to assess the quality, safety and efficacy of APIs and finished products with regard to the GMP-compliance of their production. The indication of those products concerns diseases particularly prevalent in the developing countries like HIV/ Aids, tuberculosis, malaria, diarrheal diseases among children as well as reproductive health. Products with the prequalification status are listed and are used by international official procurement agencies as a guide for the bulk purchase of medicinal products to be used in medicinal programmes in such countries. Quality control laboratories can also apply for a prequalification.
WHO的预确认程序的目的是就生产的GMP符合性方面评估原料药和成品的质量、安全和有效。这些产品主要集中在发展中国家普遍发生的疾病，如艾滋病毒/艾滋病、结核病、疟疾、儿童腹泻和生殖健康等疾病。经过预确认的产品被登记并被国际官方采购机构用作此类国家的医疗项目药品大宗采购的指南。质量控制实验室也可以申请预确认。
Qinhuangdao Zizhu Pharmaceuticals' prequalified products according to the WHO inspection were the hormones Mifepristone, Ethinylestradiol and Levonorgestrel, all of which are used in reproductive medicine. Root of the problem is: the last of the aforementioned is the only API the WHO classified as prequalified at all. The fact that due to the FDA inspection, Qinhuangdao Zizhu Pharmaceuticals' products are now placed on import alert, led to a precarious situation; US based official procurement entities can for now no longer obtain medicinal products containing the API Levonorgestrel from this source.
根据WHO的检查，秦皇岛紫竹药业得到预确认的产品为激素药米非司酮、乙炔雌二醇、左炔诺孕酮，均作为生殖医学用药。问题的根源是：上述最后一个药是唯一一个被WHO列入预确认清单的原料药。由于FDA的检查，秦皇岛紫竹药业的产品现在已被列入进口禁令，导致了严重的后果。美国官方采购机构从现在开始将不能够再获取包含秦皇岛紫竹药业左炔诺孕酮原料的药品。
In its statement, the WHO lists the following measures as "WHO action and advice":
在WHO的声明中，WHO罗列了如下措施作为WHO的行动和建议：
Consultation between Qinhuangdao Zizhu Pharmaceuticals and the FDA in order to find a solution for the problem.
联系秦皇岛紫竹药业和FDA以寻求解决该问题。
Close cooperation with the manufacturers of finished medicinal products containing Levonorgestrel with the goal of identifying alternatives for the API.
关闭与包含左炔诺孕酮药物成品的生产商的合作，以寻求该API的替代。
Appeal to manufacturers of Levonorgestrel preparations to undertake comprehensive quality controls on shipments of said API supplied by Qinhuangdao Zizhu Pharmaceutical.
呼吁左炔诺孕酮制剂生产商确保秦皇岛紫竹药业该原料药入库的全面质量控制。
Scheduling of a de novo inspection at the site of Qinhuangdao Zizhu Pharmaceuticals.
计划重新对秦皇岛紫竹药业进行检查。
Frequent updates of the current situation.
随时更新当前的状态
The WHO points out that there have been no quality problems in relation to Levonorgestrel tablets in the market so far. Therefore, the prequafilied status of Levonorgestrel and the two other preparations remain until revoked; international official procurement agencies may still include products from this source in their purchases.
WHO指出说，到目前为止市场上没有和左炔诺孕酮片相关的任何质量问题。因此，左炔诺孕酮和其他两种制剂的预确认状态仍然保留直到撤销。国际官方采购机构可能仍然会将此来源的药品纳入购买计划中。
公众号
GMP办公室
专业的GMP合规性研究组织
国内外（FDA、EMA、MHRA、CFDA、WHO、PIC/S等）GMP法规解读；
国内外制药行业GMP监管动态；
GMP技术指南（ISPE、PDA、ISO、ASTM等）分享