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检查方：西班牙 检查日期：2016-6-4 发布时间：2016-9-19
产品：3个厂区（外沙、岩头和东厂区）生产的所有原料药、中间体和制剂 厂址1：东厂区，台州椒江海正路1号 厂址2：岩头，台州椒江滨海路56号 56Binhai Road, Jiaojiang District, taizhou City, Zhejiang province, Taizhou,Zheijiang, 318000, China 厂址3：外沙，台州椒江区外沙路46号 46Waisha Road Jiaojiang District. Taizhou City, Zhejiang, 318000, China 不符合情况：Natureof non-compliance : Overall 57 deficiencies were observedduring the inspection, 3 critical and 17 major. 在检查期间共发现57个缺陷，其中3个关键，17个主要缺陷。 [Critical 1] The cross-contaminationrisk was not fully identified and mitigated. Fipronil API (ectoparasiticide forexternal application to animal) was produced in the same building, same areasand same equipment than another active ingredient (Clorsulon) and in the samebuilding and same area than Praziquantel. Fipronil was stored in the same roomin warehouse than other active ingredients for human use and veterinary use.HVAC systems, dust extraction systems and cleaning validation were notadequate. Additionally, there were three Penem intermediates stored in the coldstorage room located in warehouse Y05. The material was sampled in the samesampling room as other solid materials. 【关键缺陷1】未完全识别并降低交叉污染风险。原料药非泼罗尼（兽用外用杀外寄生虫药）与另一原料药（克洛索隆）共用同一建筑、同一区域和相同设备，与吡喹酮共用相同建筑和相同区域。非泼罗尼与其它人用和兽用原料药存贮在仓库里同一房间。HVAC系统、除尘系统和清洁验证不充分，另外，有3个青霉烯中间体存贮在仓库Y05的低温库。该物料与其它固体物料使用相同的取样间。 译者注：非泼罗尼为剧毒兽药，青霉烯为β-内酰胺类抗生素，克洛索隆为兽用抗寄生虫药。 [Critical 2] The three Fipronil APIintermediates were not manufactured at Hisun Pharmaceutical site. In SiteMaster File and other documents it is falsely stated that the manufacture ofthe three intermediates took place at Zhejiang Hisun Pharmaceutical Site. 【关键缺陷2】3个非泼罗尼原料药中间体并不在海正公司厂内生产。在工厂主文件和其它文件中，公司谎称这3个中间体是在浙江海正制药公司的工厂里生产的。 [Critical 3] Bad documentation practiceand deficient material management, specifically, uncontrolled documents werefound in a warehouse intended for other purposes and uncontrolled packagingmaterials bearing variable data as batch number and expire date were found in awarehouse intended for other purposes. 【关键缺陷3】不良文件规范和有缺陷的物料管理，具体有，在仓库里发现不受控的文件，而仓库并非用于存贮文件。不是用于包材存贮的仓库里发现未受控的包材已经印有不同的日期作为批号和有效期。 [Majordeficiencies] The 17 major deficiencies observed were identified in the areasof quality pharmaceutical system and senior management responsibilities,cleaning validation, medicinal product identification, filter usage andmaintenance, deviations and re-testing of stability studies, computerisedsystem validation, audit trail of computerised systems, document control, rawmaterial dispensing, handling of expired products, material sterilization,intermediate holding times, nitrogen and compressed air testing frequency, ventfilter integrity testing, reference standards used for testing and non-accurateinformation provided in Site Master File. 【主要缺陷】共发现17个主要缺陷，覆盖药品质量体系、高层管理职责、清洁验证、药品识别、过滤器使用和维护、稳定性试验偏差和复测、计算机化系统验证、计算机化系统审计追踪、文件控制、原料分装、过期产品处理、物料灭菌、中间体保存时间、氮气和压缩空气测试周期、排气过滤器完整性测试、检测用对照品以及SMF里提供的不准确信息。 Action taken/proposed by the NCA : NCA建议/采取的措施 Requested Variation of the marketing authorisation(s) 上市许可变更要求
1. This manufacturer should not be authorised in any new/ongoing marketingauthorization or variation applications. 在所有新的/正在进行的上市许可或变更申报中，均不应再批准此生产商。 2. The submission of a variation application forintroducing alternative manufacturers of active ingredients, intermediateproducts and finished products is recommended. 建议提交变更申报，引入原料药、中间体和制剂替代生产商。 Recall of batches already released 已放行批次的召回
No recall of the active ingredients, intermediate products and finishedproducts manufactured in the site is presently recommended. However, in caseout of specification results (OOS) are obtained as a result of testingrecommended as interim measures B1 and B2, these results should be communicatedby MAH to NCA. The decision to be made by NCA, following an assessment betweenthe NCA and MAHs, whether to recall a batch of a particular product or notshould be based on a risk assessment and on the criticality of the product.Evaluation should take into account if there are alternative suppliers andpotential risk of shortage. 未建议对此厂址所生的原料药、中间体和制剂实行召回。但是，如果作为临时措施B1和B2所建议的检查中发现OOS结果，则MAH应与NCA沟通这些检验结果。NCA和MAH进行评估之后，由NCA给出决定。应根据风险评估对特定产品批次做出是否召回的决定。评估时应考虑是否有替代供应商，以及潜在的短缺风险。 Prohibition of supply 禁止供应
Prohibition of supply is recommended, unless there are not alternativesuppliers and there is a risk of shortage. 建议禁止供应，除非没有替代供应商，有短缺风险。 Others 其它
Due to the number and severity of the findings detected, current valid GMPcertificates should be withdrawn. The following additional measures are recommended: 鉴于发现了大量严重的缺陷，将收回目前有效的GMP证书。建议采取以下附加措施： A. Due to the number and severity of the findingsdetected, current valid GMP certificates should be withdrawn. 鉴于发现了大量严重的缺陷，将收回目前有效的GMP证书。 B.1. To oblige medicinal product manufacturers locatedboth in EU and third countries to perform full analytical testing of everybatch of active substances manufactured at Hisun, including impurities,residual solvents and microbial burden. This measure is not applicable forbatches that are currently on the market. 强制EU境内外药品生产商对海正所生产的每批原料药均进行全检，包括杂质、残留溶剂和微生物负载。此措施不适用于目前已在销售的批次。 B.2. To oblige European manufacturers and/or importers toperform full analytical testing of every batch of intermediate products andfinished products sourced from Zhejiang Hisun or containing APIs orintermediates sourced from Hisun, including impurities, residual solvents andmicrobial burden. This measure is not applicable for batches that are currentlyon the market. 强制欧洲生产商和/或进口商对来自浙江海正的所有批次中间体和制剂，以及含有来源于海正的中间体和原料药的药品进行全检，包括杂质、残留溶剂和微生物负载。此措施不适用于目前已在销售的批次。 Additional comments : Due to their nature, the observed deficiencies are considered to apply to allactive substances, intermediate products and medicinal products manufactured atthe three campuses of Zhejiang Hisun Pharmaceutical, Co., Ltd. site (WaishaCampus, Yantou Campus and East Factory Campus). The inspection findings have apotential to impact on all the active ingredients, intermediate products andfinished products manufactured in the site. Marketing authorisation holders arerequested to contact the relevant National Competent Authority to verifywhether their products are considered critical, for which there are notalternative suppliers and there is a risk of shortage in their territory, andtherefore outside the scope of the non-compliance statement. 额外建议：鉴于缺陷性质，所发现的缺陷被认为适用于浙江海正3个厂区生产的所有原料药、中间体和制剂（外沙厂区、岩头厂区和东厂区）。检查发现的缺陷对在工厂生产的所有原料药、中间体和制剂均有潜在影响。要求上市许可持有人联系相关国家药监核对其产品是否关键，是否有替代供应商，是否在其国内有短缺风险，从而确定是否在不符合声明范围以内。 | 
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