继美国 FDA 于 9 月 20 日发布针对浙江华海药业的检查 483报告之后，FDA 与欧洲药品管理局（EMA）于 9 月 28 日分别发布广泛的进口禁令和不合规报告，采取扩大范围的禁止进口、取缔上市许可等严厉措施。
这对于作为中国制剂出口龙头华海药业是严重打击，对于中国制剂出口影响也是意义深远。
FDA places Zhejiang Huahai Pharmaceuticals on import alert
FDA将浙江华海药业列入进口禁令
Update [9/28/2018] FDA placed Zhejiang Huahai Pharmaceuticals on import alert on September 28, 2018, to protect U.S. patients while the active pharmaceutical ingredient (API) manufacturer fully determines how impurities were introduced into its API and remediates its quality systems. The import alert stops all API made by ZHP and finished drug products made using ZHP’s API from legally entering the United States. FDA’s action follows a recent inspection at ZHP’s facility.
更新日期【20180928】FDA已于2018年9月28日将浙江华海药业置于进口禁令中，以在API生产商完全确定杂质是如何进入其API以及补救其质量体系期间保护美国患者。该进口禁令将叫停合法进口ZHP生产的所有API，以及使用ZHP的API生产的制剂至美国。FDA的措施是在最近对ZHP设施进行检查的基础上做出的。
FDA reminds manufacturers that it is their responsibility to develop and use suitable methods to detect impurities, including when they make changes to their manufacturing processes. If amanufacturer detects new or higher levels of impurities, they should fully evaluate the impurities and take action to ensure the product is safe for patients.
FDA提醒生产商有义务开发和使用适当的方法检出杂质，包括在对其生产工艺进行变更的时候。如果生产商检出了新杂质或更高水平的杂质，应该全面评估这些杂质，并采取措施确保其产品对患者来说是安全的。
EudraGMDP 不合规报告
发布官方：Italian Medicines Agency 意大利药监局
检查日期：2018-09-13
发布日期：2018-09-28
报告编号：IT/NCR/API/2/2018
受检公司：ZHEJIANG HUAHAI PHARMACEUTICAL CO., LTD. 浙江华海药业有限公司
受检地址：Chuannan Duqiao,Linhai, Zhejiang, 317016, China 浙江临海川南杜桥
受影响产品：缬沙坦原料药
不符合情况：
The joint EMA/EDQM inspection was initiated as “for-cause” inspection in the context of the NDMA/NDEA Valsartan contamination issue. Nine “Major” and eight “Other” deviations were identified. The Major deficiencies were found in the following areas:
EMA/EDQM检查对缬沙坦的NDMA/NDEA污染事件启动了有因检查。九个主要观察项和8个其他观察项被发现。发现的主要缺陷如下：
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The investigations conducted in the context of the NDMA/NDEA contamination of Valsartan showed significant flaws; 对于缬沙坦中的NDMA/NDEA污染的调查显示出重大的缺陷。
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. The company’s risk assessment performed in the context of the development/implementation of the optimised Valsartan process, conducted in July/August 2018, was not satisfactory; moreover, the company did not identify the need to develop a control strategy to reduce the new risks introduced with the optimised process; 该公司在2018年7月和8月在开发和实施优化缬沙坦工艺中执行的风险评估不符合要求，而且，该公司并没有识别出需要开发一个控制策略来降低因为优化工艺会带来的新的风险。
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. Several gaps were identified in the context of the development of the Valsartan process as revised in 2011/2012. N.B.: the changes introduced with this modified process led to the formation of the NDMA impurity; 在2011/2012年升级缬沙坦工艺研发中发现了几个差异。在改变工艺时引入的变更导致了NDMA杂质的生成。
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Observations related to the handling of the complaints, with specific focus on the NDMA contamination issue; 处理因为NDMA污染投诉相关的观察项
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Management of out-of-specification results; OOS结果的管理
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Recall management: no recall was formally initiated to manage the actions related to the contaminated Valsartan batches; 召回管理，没有正式地启动召回程序来管理被污染的缬沙坦批次的召回行动。
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Reprocessing/blending operations including traceability of reprocessed/blended material ; 包含返工和混合物料的追溯的返工/混合操作。
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Data integrity issues in relation to GC-FID analysis; GC-FID分析相关的数据完整性问题。
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Inadequate investigation of unknown peaks detected in GC-MS analysis of batches of Valsartan manufactured with the new process as optimized in July/August 2018.在使用2018年7月/8月优化的新工艺生产的缬沙坦批次的GC-MS分析中检测到未知峰的不充分的调查。
内容来源：FDA、EMA，药研编辑整理