人用药品中使用的原料药流通质量管理规范基本原则指引精品文档32

1、人用药品中使用的原料药流通质量管理规范基本原则指南（徐禾丰翻译）Ref. Ares(2019)148102 - 05/02/2019参考编号(2019)148102-2019 年02月05日EUROPEAN COMMISSION欧盟委员会HEALTH AND CONSUMERS DIRECTORATE-GENERAL健康与消费者总司Health Systems and Products健康体系与产品Medic inal Products - Quality, safety and efficacy药品-质量、安全性与有效性Brussels,布鲁塞尔，SANCO/D/6/SF/mg/ddg1.d

2、.6(2019)179367GUIDELINES ON THE PRINCIPLES OF GOOD DISTRIBUTION PRACTICES FORACTIVE SUBSTANCES FOR MEDICINAL PRODUCTS FOR HUMAN USE人用药品中使用的原料药流通质量管理规范基本原则指南DRAFT SUBMITTED FOR PUBLIC CONSULTATION用于公共征求意见的草案Stakeholders are invited to comment on this draft by 30 April 2019at the latest.Responsesshoul

3、d be sent preferably by e-mailto san co-pharmaceuticalsd6ec.europa.eu , or by post to UnitSANCO/D/6, DM24 02/050, BE-1049 Brussels.诚邀各利益相关方于 2019年4月30日前将对本草案的意见发送至邮箱 sanco-pharmaceuticalsd6ec.europa.eu ， 或用 信函由E 寄至 Unit SANCO/D/6, DM24 02/050, BE-1049 Brussels 。When sending your comments and respons

4、es, you should state whether you are a stakeholder associati on or a private in dividual. If youreprese nt an associati on,please in dicateclearly what type ofassociati on this is (activesubsta nee manu facturer,medic inalproducts manufacturer,importer etc.). If you represent a company,please state

5、whether itfalls within the EU definition of a smalland medium-sizedenterprise(i.e. less than?50millionannualturno ver and fewer tha n 250 employees).当回复意见时，请注明您是利益相关的社会团体或是个人。如果您代表社 会团体，请明确注明类型(原料药制造商、药品制造商、进口商等 )。如果 您代表公司，请注明其是否属于欧盟定义的中小企业(即，年营业额小于5千万欧圆且雇员少于250人)。All comme nts and resp on ses will

6、be made publicly available on the Europa website on pharmaceuticals once the consultation period is over. If you do not wish yourcontribution to be madepublic please in dicate this clearly and specifically in thedocume ntati on you sendus (i.e. not just in the coveringletter or e-mail). In thiscase,

7、only an indication of the contributor will be disclosed.征集期结束后，所有意见与回复将在“ Europa网站”的制药部分公布。如 果您不希望将意见公幵，请在您发送的文件上特别注明(即，而不仅是在首页函或电子邮件中注明)。此种情况下，只公幵投稿人。Professi onalorga ni sati onsare in vitedto register in th e Un io n sRegisterforIn terestReprese ntatives(http:/europa.eu/tra nspare ncy-register/)

8、set up as part of theEuropea nTran spare ncy In itiative to provide the Commissio n and thepublic at largewith in formati onabout the objectives, funding andstructures of in terest represe ntatives.我们邀请专业组织在欧盟注册页面进行登记(http:/europa.eu/transparency-register/)将其作为欧洲透明倡议的一部分，来向欧洲委员会以及公众提供其代表利益的目标、资金与结构的

9、 详细信息。Scope范围I. For the purpose of these guideli nes, the distributi on of activesubstances for medicinal products for humanuse (hereafter activesubstances ) is the procuring, import, holding,supplyingorexport ing active substa nces.本指南中的人用药品使用的活性物质 （以下简称“原料药”）流通包括：原 料药的采购、进口、持有、供应或出口。2. Activities

10、con sist ing of re-packag ing, re-labelli ng or divid ing up of active substa nces are manu factur ing activities and as such are subject to the guideli nes on Good Manu facturi ng Practice of active substa nces.对原料药进行重新包装、重新贴标签或分装属制造范畴，受原料药生产质 量管理规范指南的约束。Quality System质量体系3. Distributors of active

11、substa nces should develop and maintain a quality system setting out responsibilities, processes and riskman ageme nt prin ciples.原料药流通企业应当制定并保持一个质量体系，建立职责、流程及风险管理的基本原则。4. The quality system should be adequately resourced with compete ntpersonnel,and suitable and sufficientpremises, equipment andfac

12、ilities.该质量体系应当有充足的胜任人员、适当且足够的房屋、设备与设施等资源。5. The size, structure and complexity of distributor s activitiesshould be take n into con sideratio n whe n develop ing or modify ing the quality system.在制定或修订质量体系时，应当考虑流通企业活动的规模、结构与复杂性。Pers onnel人员6. A man ageme nt represe ntative should be appo in ted in

13、each distributen point, who should have defined authority and responsibility for ensuring that a quality system is implementedand mai ntai ned. He should fulfil his resp on sibilitiespers on ally.各流通现场应当指定一名管理者代表，应当规定其职权与职责，确保质量 体系的实施与保持。管理者代表应当亲自履行其职责。7. Key pers onnel in volved in the warehous ing

14、 of active substa ncesshould have the appropriate ability and experienee to guarantee thatactive substa nces are properly stored and han dled.原料药仓储中所涉及到的关键人员应当具备恰当的能力与经验，以保证原料药正确存储与处理。8. Pers onnel should be trained in relati on to the duties assig ned to them and the tra ining sessi ons recorded.应当

15、针对人员职责进实施培训，且应当有培训记录Docume ntati on文件9. AII docume ntatio n should be madeavailable on request of compete nt authorities. Electr onic docume ntati on should comply with Chapter5.4 of Part II of Eudralex, the Rules Gover ning Medic inal Productsin the Europea n Un io n, Volume 4 (EU Guideli nes to Go

16、odMa nu facturi ngPractice for Medic inal Products for Huma n and Veteri nary Use -hereafter EUGMP), or its Annex 11 (Guidelines on Computerised Systems).应当按主管官方要求提供所有文件。电子文件应当符合欧盟药品法规第四卷第二部分的第5.4章（欧盟人用与兽用药品生产质量管理规范指南-以下简称“欧盟药品生产质量管理规范”）或其第11附录（计算机化系统指南） 要求。Orders订货10. Where active substances are pr

17、ocured from a distributor of activesubstances, that distributor should be registeredaccording toArticle 52(a) of Directive 2019/83/EU.若从流通企业采购原料药，此流通企业应当已经按第2019/83/EU法令第52(a)条进行注册。Procedures规程11. Writtenprocedures should describe the differentoperationswhich may affect the quality of the active sub

18、sta nces or of the distribution activity:receipt and checking of deliveries, storage,cleaning and maintenance of the premises (includingpest control),recording of the storage conditions,security of stocks on site andof con sig nments in tran sit, withdrawal from saleable stock, records, including re

19、cords of clients orders, returned products, recall pla ns, etc. These procedures should be approved, sig ned and dated by the pers on resp on sible for the quality system.应当有书面规程来描述可能会影响原料药质量或流通活动的不同操作：交 付物品的接收与检查、储存，厂房清洁与维护(包括虫害控制)、存储条件记录、现场库存与委托运输安全性、从可供出货库存收回、记录，包括记录客户订单、退回产品、召回计划等。这些规程应当由质量体系负责人

20、来批准、签署并注明日期。Records记录12. Records should be made at the time each operation is taken andin such a way that all significantactivities or events are traceable.Records should be clear and readily available. They should be reta ined for a period of five years at least.应当在每次操作时进行记录，并且以能对所有重要活动或事件可追溯的方 式进行

21、记录。记录应当清晰易得，并且至少保留五年。13. Records should be kept of each purchase and sale, show ing the date of purchase or supply, n ame of the active substa nee, batch nu mber and qua ntity received or supplied, and n ame and address of the orig inal manu facturer. Records should en sure the traceability of the o

22、rigin and destinationof products, so that all the suppliersof, or those supplied with, an active substa nee can be ide ntified.Docume nts that should be reta ined and available in clude:应当保存好历次采购与销售记录， 标明采购或供应的日期、原料药的名称、 接收或供应的批号与数量、原始制造企业的名称与地址。记录应当确保产 品原产地与目的地可追溯性，以便能对所有的原料药供应商或其供应产品 进行识别。应当获取并保留的

23、文件包括：Identity of original manufacturer原始制造企业的身份Address of orig inal manu facturer原始制造企业地址Purchase orders采购订单Bills of lading, transportation and distribution records提单、运输与流通记录Receipt docume nts接收文件Name or desig nati on of active substa nee原料药名称或命名Manufacturer s batch number制造企业批号All authe ntic Certif

24、icatesof An alysis, i ncludi ng those of theoriginal manufacturer所有可信的分析证明，包括原制造企业的分析证明Retest or expiry date复验期或有效期Premises and equipme nt厂房与设备en sure14. Premises and equipment should be suitable and adequate to proper con servati on, protect on (e.g. n arcotics) and distribute nof active substa nce

25、s. Mon itori ng devices, where used, should becalibrated.应当有适当并且充足的厂房与设备，确保原料药的保存、防护(如,*品)与流通。如使用监控设备，应当对其进行校准。Receipt接收15. Areas for receivingactive substances should protect deliveriesfrom bad weather during unioading. The reception area should be separate from the storage area. Deliveries should

26、be exam ined at receipt in order to check that containers are not damaged, all security seals are prese nt and that the active substa nee and the con sig nment corresp ond to the order.原料药接收区域应当能够在恶劣天气下对交付物卸载提供防护。接收区域 应当与存储区域相分离。应当在接收时对交付物进行检查，确定容器没有 损坏、具有所有安全性铅封，并且原料药与发运物与订单相符。16. Active substa nce

27、s subject to specific storage measures (e.g.narcotics, products requiring a specific storage temperature orhumidity) should be immediately identifiedand stored in accordaneewith writte n in structi ons and with releva nt legislativeprovisi ons.需要特殊存储措施的原料药（如，麻醉品、需要特定存储温度或湿度的产品等），应当立即进行标识并按照书面指示和相关法规

28、条款进行存储。17. Where the distributor suspects that an active substanee procured or imported by him is falsified, he should inform the n atio nal compete nt authority in which he is registered.流通企业如怀疑其采购或进口的原料药是伪造的，其应当通知流通企业注册国主管官方。Storage存储18. Active substa nces should n ormally be stored apart from oth

29、ergoods and under the conditions specifiedby the manufacturer (e.g.con trolled temperature and humiditywhe n n ecessary).These conditions should be monitored periodically and records maintained. The records should be reviewed regularly by the person responsible for the quality system.原料药通常应当在制造企业所指定

30、的条件（如，必要的受控温度和湿度）下与其它货物分幵储存。应当对这些条件进行定期监测，并保存记录。应当 由质量体系负责人对记录进行定期审核。19. Whe n specific temperature or humidity storage con diti ons arerequired, storage areas should be equipped with recorders or other devices that will indicate whenthe specific temperature or humidity range has not been maintained

31、.Controlshould be adequate tomai ntai n all parts of the releva nt storage area within the specified temperature or humidity ran ges.若储存条件对温度或湿度有特殊要求，存储区应当配备记录仪器或其它设 备，对未能满足特定温度或湿度范围的情况予以显示。应当将储存区域的 所有相关部分充分控制在特定温度或湿度的范围内。2O.The storage facilities should be clean and free from litter, dust and pests

32、. Adequate precautio ns should be take n aga inst spillage or breakage, attack by micro-orga ni sms and cross con tam in ati on.存储设施应当保持清洁，无垃圾、灰尘与虫害。应当采取充分的预防措施, 防止泄漏或破损、微生物侵害与交叉污染等。21. There should be a system to ensure stock rotation( first expiry(retest date) first out ) with regular and frequent

33、checks thatthe system is operating correctly. Products beyond their expiry date or shelf-life should be separated from usable stock and not be supplied.应当该有一个系统，确保存货周转(“先到有效期先出(先到复验期先出)”)，并且定期而经常性检查系统是否正常运行。超出有效期或保质期 的产品应当与可使用库存相隔离，而且不能供应。22. Active substa nces with broke n seals, damaged packag ing

34、, or suspected of possible contamination should be withdrawn from saleable stock, and if not immediately destroyed, they should be kept in a clearly separated area so that they cannot be sold in error or con tam in ate other goods.应当将铅封损坏、包装破损，或怀疑可能受到污染的原料药从可销售库存 中收回，并且如果不能立即销毁，应当将其保存在清晰的隔离区域，使其能不能错

35、误销售或污染其它货物23.Shortages that requires registered importers to no tifyreleva ntcustomers of any interruptionto supply that the importer ordistributor becomes aware of.注册的进口企业需要通知相关客户有关进口企业或流通企业已经觉察到 的任何因中断供应所导致的短缺。Deliveries to customers客户交付24.Supplies within the EU should be made only to registered d

36、istributors of activesubstances accordingto Article 52a ofDirective 2019/83/EU or to authorised manu facturers accord ing to Article 40 of Directive 2019/83/EU.欧盟范围内，仅可供应给已经按照第2019/83/EU号法令的第52a条注册的原料药流通企业，或根据第 2019/83/EU号法令的第40条获得授权的制 造企业。25. Active substa nces should be tra nsported in such a way

37、that:原料药应当以如下方式运输:a) their identification is not lost;不丢失其标识；b) theydo not con tam in ate,and are not con tam in ated by otherproducts or materials;不污染其它产品或物料，也不被其它产品或物料污染；c)adequate precauti onsare taken against spillage,breakage ortheft;采取适当预防措施，防止泄漏、破损或被盗窃；d)they are secure and not subjected to u

38、nacceptable degrees of heat,cold, light, moisture or other adverse in flue nee, nor to attack by micro-orga ni sms or pests. 确保运输安全并切不会遭受不可接受程度的热、冷、光、水分或其它不良影响，也不会遭受微生物或害虫侵害。26. Where tra nsportati on of the active substa nee is con tracted outthe distributor should en sure that the eon tract accept

39、or knows and follows the appropriate tra nsport and storage con diti ons.在原料药委托运输时，应当确保合同受方了解并遵循适当的运输与贮存条件。27. Activesubsta ncesrequir ingcon trolledtemperature storageshould also be tra nsported by appropriately specialized means.需要控制存储温度的原料药应当用特定的方式进行运输。28. A system should be in place by which the

40、 distribution of eachbatch of active substance can be readily determined to permit its recall.应当有适当的系统，确保所流通的每个批次原料药能容易判断其是否需要 召回。Tran sfer of In formatio n信息传递29. Distributorsshouldtran sferall quality or regulatoryin formatio n received from an active substa nee manu facturer to the customer, and

41、from the customer to the active substanee manufacturer.流通企业应当将所有从原料药制造企业收到的质量或药政信息传递给客户，并将客户的质量或药政信息传递给原料药制造企业。30. The distributor who supplies the active substanee to the customer should provide the nameand address of the original active substanee manufacturer and the batch number(s) supplied. A co

42、py of the orig inal Certificate of An alysis from the manu facturer should beprovided to the customer.为客户供应原料药的流通企业应当提供原始原料药制造企业的名称与地 址以及批号。应当将来自制造企业的原始分析证明一份副本提供给客户。31. The distributor should also provide the identity of the originalactivesubsta neemanu facturerto regulatory authorities uponrequest

43、. The orig inal manu facturer can resp ond to the regulatoryauthority directly or through its authorised agents, depending onthe legalrelationshipbetween the authorisedage ntsand theorig inalactivesubsta neemanu facturer.(Inthiscon text authorisedrefers to authorised by the manufacturer.)如药政主管官方需要，流

44、通企业还应当提供原始原料药制造企业身份。根 据授权代理以及原始制造企业的法律关系，原始制造企业可以直接或通过 其授权的代理人向药政主管官方进行回复（此处的“授权”是指制造企业进行的授权）。32. The specific guida nee for Certificates of An alysis is in cluded in Section 11.4 of Part II of the EU-GMP.分析证明的具体指南见欧盟药品生产质量管理规范第二部分的第11.4节Retur ns退货33. Retur ned active substa nces should be ide ntifi

45、ed as such and quara nti ned.应当对已经退回的原料药进行标识并且进行并待检隔离。34.lf the con diti ons un der which retur ned active substa nces havebeen stored or shipped before or during their return or the conditionof their contain ers casts doubt on their quality, they should bedestroyed by appropriate means.如果怀疑退回的原料药在退

46、回前或退回过程中的储存或运输条件或其容器条件对原料药质量产生不利影响，应当用恰当方式对其进行销毁。35. Active substa nces which have left the care of the distributor, should only be retur ned to saleable stock if:如果原料药已经脱离流通企业控制，仅仅在下列情况下才可将其退回到可供销售库：a)the active substanee is in the originalunopened container(s)andin good con diti on;原料药处于原始未幵封容器中并且

47、处于良好的条件下；b)it is dem on strated that the active substa nee have bee n stored and han died un der proper eon diti ons;可证明原料药在适当条件下存储与处理；e)the rema ining shelf life period is acceptable;余下的保质期是可以接受的；d)they have bee n exam ined and assessed by a pers on authorised to do so.经授权人员检验并评估合格。36. This assessm

48、e nt should take in to acco unt the n ature of the active substanee, any special storage conditions it requires, and the time elapsed since it was supplied. Special attention should be givento products requiri ng special storage con diti on s. If n ecessary,advice should be sought from the manufactu

49、rerof the activesubsta nee.评估应当考虑原料药的性质、其要求的特定储存条件，以及其从供应幵始 经过的时间。应当特别注意产品需要的特殊贮存条件。如必要，应当征询 原料药制造企业的建议。For37. Records of returned active substances should be maintained, each retur n, docume ntati on should in clude:应当保留原料药的退回记录。每次的退货记录应当包括：Name and address of the con sig nee收货人名称与地址Active substa n

50、ee batch nu mber and qua ntity retur ned退回的原料药批号与数量Reas on for return退货理由Use or disposal of the retur ned active substa nee退回原料药的使用或处理38.Only appropriately trained and authorised personnel should release active substances to be returned to stock. Active substances retur ned to saleable stock should

51、be placed such that the firstexpiry (re- test date) first out system operates effectively.只有经过适当培训并授权的人员才能将退回的原料药放行入库。退回到可 销售库存的原料药，应当按照“先到期先出 (先到复验期先出)”系统有效 运作。Complai nts and Recalls投诉与召回39.AII quality related complaints, whether received orally or inwriting,should be recorded and investigated acc

52、ording to a writtenprocedure.所有与质量有关的投诉，无论口头的还是书面投诉，都应当按书面规程进 行记录与调查。40pla int records should in elude:投诉记录应当包括：Name and address of compla inant投诉人的名称与地址Name (and, where appropriate, title) and phone number of personsubmitt ing the compla int提交投诉人员的姓名(如果适当，头衔)与电话号码Compla int n ature (in clud ing n a

53、me and batch nu mber of the activesubsta nee)投诉性质(包括原料药的名称与批号)Date the compla int is received收到投诉的日期第31页Actio n in itially take n (in clud ing taking the acti on)dates and ide ntityof pers on最初米取的措施（包括米取行动的日期和行动人员身份 ）Any follow-up acti on take n采取的任何后续措施Resp onse provided to the orig in ator of comp

54、la int (in clud ing date resp onse sent)提供给原始投诉企业的回复(包括发送回复日期)Final decisi on on active substa nee batch or lot对原料药批次的最终决定41.Records of compla in ts should be reta ined in order to evaluate tren ds, product related freque ncies, and severity with a view to taking additi on al,and if appropriate, immediate correctiveactio n.These should be made available to compete nt authorities of the Member States on whose territory the products were distributed.应当保存投诉记录，以评价趋势、与产品相关的频率、严重性及采取而外 的措施