该问答文件阐明了制剂预认证批准后有关变更常被咨询的问题。   

This Q&A document aims to provide clarification, and additional information, as needed, and should be read in conjunction with the WHO guidelines on variationsto a prequalified product and other guidance documents. This document will be updated regularly to reflect new developments.   

该问答文件旨在提供分类和额外信息，应与《WHO已批准产品的变更指南》和其他指南一起阅读，该文件也会定期更新以反映最新的发展。   

1. What is thetimeline for implementation and review of a variation? Where can thesetimelines be found?   

变更实施和审评的期限是什么？在哪儿可以找到此类期限？   

The implementation and assessment timelines for the various change categories areprovided in the section for Variations to FPP on the Prequalification of Medicines website. Each type of variation has its own approval mechanism and timeline, as summarized in the Variations Approval Mechanism and Timelines(PDF) table.   

不同变更的实施和审评期限在WHO药品预认证网站的“Variations to FPP”栏目中可获取。每种变更均有各自的批准机制和期限，见变更批准机制和期限表（pdf）中总结。   

（注解：WHO的变更类型主要有

annualnotification 年度通知(AN)；

immediatenotification立即通知(IN)；

minorvariation微小变更 (Vmin)；

majorvariation 重大变更(Vmaj) 四类）   

For changes to an Innovator or Multisource (Generic) FPP Prequalified on the basisof SRA approval, please refer to SRA-approved Multisource (generic) or Innovator FPPs. The timelines are subject to change and will be updated, as and when appropriate. Whenever there is conflict, the timeline published onPrequalification of Medicines website prevails over the timeline included inthe variation guideline.   

基于严格药监部门（SRA）而对预认证的原研药或仿制药成品制剂进行变更，请参阅SRA-批准的仿制药或原研药成品制剂。适宜时，该时限会变更并更新。如果出现冲突，则WHO药品预认证官网上的期限为准，而非变更指南中的期限。   

2. Should data tosupport the annual notification be submitted?   

年度通知的支持性数据需要提交么？

   Anannual notification should be submitted with a completed annual notificationform, including a summary of the change(s) and the date(s) of implementation.The summary should be sufficiently detailed to enable the assessor to easily determine whether the appropriate reporting category has been used. 

  提交年度通知应含填写完整的年度通知单，包括变更的总结和实施的日期。总结应充分详细，令审评员能轻松地确定是否使用了适宜的报告类别。 

  Whenan annual notification involves a change in specifications or standard testprocedures (STP) for an API or FPP, the signed and dated version of the revised specification and STP including the change history should be attached to the notification form.   

若年度包括包含API或FPP质量标准或标准检测规程（STP）的变更，则签字并注明日期的修改的质量标准和STP版本（含变更历史）应附在通知单后。

   For FPPs that have an agreed-upon Quality of Information Summary (QIS), the QIS should be revised and submitted with the revised sections highlighted. See morediscussion on the QIS under (3) below.   

对于成品制剂商定一致的质量信息概述（QIS），QIS应进行修订并高亮标注修订部分。更多有关QIS的讨论见下(3)。

   Additional associated documentation is not required to be submitted. However, the information used to support the change must be generated prior to distributing the product manufactured with the change, and should be available on request,or to WHO inspectors during an inspection. A summary of studies performed to assess the impact of each change on product quality should be provided in the application form, if applicable.  

 额外相关的文件不需要进行提交。然而，用于支持变更的信息必须在分销生产变更产品之前产生，并一经请求可获取或在检查中对WHO检查员获取。若适用，用以评估每个变更对产品质量而开展的研究总结应以申请表的形式进行提供。  

 3. Do I need toupdate the quality information summary (QIS)for each variation application? 

针对每个变更申请，申请人是否需要每次都更新质量信息概述（QIS）   The QIS provides asummary of the key quality information from the product dossier which has been accepted by WHO PQ. It is a useful tool for post-prequalification activities,e.g. GMP inspections, variations and requalification of the product. The finalQIS also facilitates the information exchange between WHO and nationalregulatory authorities participating in the WHO collaborative registration procedure.   QIS提供了产品申报资料中关键质量信息的综述，且获得WHO-PQ的批准。QIS是批准后活动如产品的GMP检查、变更或重新预认证的一项有益工具。最终版的QIS能便利WHO和参与WHO注册互认程序中的国家药品监管当局交换信息。  

 The QIS is a living document which needs to be revised each time a particular section is affected by a proposed change, and submitted as part of the variation package with any revised sections highlighted and the change history updated.  

 QIS是一个动态的文件，若特定的章节受到拟议变更的影响，它需要每次都修改，高亮标注变更部分，更新变更历史，作为变更包的一部分进行提交   

The applicant isrequired to update the “Applicant’s date of preparation or revision” section ofthe QIS whenever a revision is made to the QIS. 

  当对QIS进行修订时，申请人需要更新“申请人起草或修订日期”部分。   

After a change isaccepted, the QIS represents the approved quality data in the product dossier,which should be used as the basis for any future application submissions.   If there is nochange to the QIS as a result of the variation, a statement should be made in the variation application form to this effect.   

当某个变更被接受时，QIS代表了产品申报资料中被批准的质量数据，其会被作为未来申请递交的依据。若变更不需要变更QIS，则在变更申请表中应为此进行声明。  

 Pleasenote that if no agreed QIS was made available at the time of prequalification of the FPP concerned, a QIS is not required for submission of a variation.However, if a QIS was made available through requalification of the FPP concerned, a revised QIS should be submitted with the variation, if applicable.  

请注意若相关成品制剂预认证时，未获及公认的QIS（申请人和WHO-PQ之间认可），则在递交变更时不需要提交QIS。然而，若成品制剂通过重新预认证可获取QIS，则修订的QIS应随变更一起递交，若适用。   4. For a groupedvariation, should I file an application form for each change separately?   针对组合变更，申请人应该对每个变更单独填写一份申请表？ 

  Groupingof variations is acceptable only under the following circumstances.   组合变更仅在以下情况下被接受：  

  (1) the variations are consequential to each other, e.g. introduction of a new impurity specification that requires a new test method   

变更是相互影响的，如引入新的杂质标准需要新的检测方法   

 (2) the same change affects multiple FPPs from the same applicant e.g. addition of a new API manufacturing site for multiple FPPs   

相同的变更影响同一个申请人的多个成品制剂，如针对多个成品制剂增加新的API生产场地     

  (3) each of the changes is of the AN type.   每个变更都为年度报告类型   Agrouped variation should be filed in one application form, and will be reviewed as one application. For the purpose of classification, an application involving two or more types of variations will be considered to be of the highest risktype. For example, additional manufacturing site for an FPP for all the manufacturing processes (the new site has been satisfactorily inspected by WHO)with scale up of batch size at the new site (up to 10 times to the biobatch) should be submitted as a grouped variation of variation no.28c (Vmin) andvariation no. 30a(IN). The overall variation type is a minor variation, and the implementation and assessment timelines will therefore be those for a minor variation. The conditions and documentation for both changes should be considered and submitted in the application.   

组合变更应填写在一个申请表内，并将视为一个申请进行审阅。出于分类目的，含两个或以上的变更类型的申请将被视为最高风险型。比如，成品制剂针对所有生产工艺增加额外的生产场地（新场地已经被WHO.检查符合GMP规范），在新场地放大生产批量（生物批量的10倍）应以变更28c (Vmin,微小变更)和变更no. 30a(IN，立即通知)进行组合申报。整体的百年更类型为微小变更，因此实施和评估时限依据微小变更进行。在此次递交中应考虑两项变更需满足的条件和文件。   

5. For anadditional FPP manufacturing site, a minor variation may be submitted if the proposed site has been inspected and found GMP compliant by WHO or an SRA inthe last three years (variation no.28). Should a major variation be used if the GMP inspection for the proposed site was conducted more than 3 years ago?   针对额外的成品制剂生产场地，若拟议的场地在近三年内经检查且符合WHO GMP规范或SRA要求（变更号28），则上述变更是否以微小变更提交？若GMP检查在三年前开展，则上述变更是否以重大变更提交？   It is recommended that the applicant consults WHO PQ in advance when planning the submission(address enquiry to: prequalvariation@who.int).   建议申请人在计划此类递交前提前咨询WHO PQ（咨询邮箱：prequalvariation@who.int）   6. May a batchsize that has been accepted for one of the approved manufacturing sites of the product be implemented at the other approved FPP site? What change category should be applied for?   适用哪个变更分类？   If a batch size hasbeen accepted for one of the FPP sites, it may be implemented at other approved FPP sites, and be notified to WHO as an Annual notification. The followingconditions should be fulfilled:   如果在成品制剂的某个产地的产品批量已被批准，则可在另一个已批准的成品制剂场地上实施，并以年度通知形式通知WHO。但必须满足下述条件： 

  1) The change pertains only to immediate-release oral pharmaceuticalforms and to non-sterile liquid forms.   

该变更仅适用于速释口服制剂和非无菌液体制剂。   

2) Manufacturing equipment used at these sites is similar, exceptcapacity differences.   

场地之间的生产设备除生产能力差异外相似。   

3) Formulation, controls on starting materials, manufacturing process,in-process controls, specifications and packaging materials remain the same atboth sites.   

处方、对起始物料的控制、生产工艺和中控、质量标准、包材在两个场地间一致。 

4) The necessaryvalidations/qualifications at the other (proposed) site must be carried out asper cGMP prior to distributing the product and the data generated should bemade available for verification by the WHO inspection team or for evaluation byassessors when requested.   

在分销产品前，在拟定生产场地上依据cGMP规范开展必要的验证和确认工作。所产生的数据应在WHO检查组确认时可获及或应审评员评估所需进行提供。   

7. What is thevariation requirement when the heavy metals test is removed from API and/orexcipient specifications?  

 API或辅料质量标准中删除重金属检测的变更要求是什么？  

 The change can be implemented and be notified to WHO as annual notification or when submitting arelated variation application for the affected product. The revised specifications of API and/or excipient (with version history) should besubmitted with the notification.   

变更的实施应以年度通告形式通知WHO或对受影响的产品递交相关的变更申请。修订的API或辅料质量标准（含修订历史）应与通知一并进行提交。   Information aboutthe elemental impurities in API or excipients should be available to the FPP manufacturer. The FPP manufacturer should conduct associated risk assessment on elemental impurities which should be available in case requested by assessorsor for verification by the WHO inspection team.  

 成品制剂生产商应可获及API或辅料中的元素杂质信息。成品制剂生产商应开展相关的元素杂质风险评估，应在WHO检查组确认时可获及或应审评员评估所需进行提供  

 8. There is nochange category for a change in the variation guideline, what should I do? 

若变更未在变更指南中有分类，申请人应怎么办？   A change that is notaddressed in the WHOguidelines on variations to a prequalified product (variation guideline) should be considered as a major change bydefault as per the guideline. This is to give WHO enough time to review the unclassified change. However, if the applicant believes that the change is unlikely to have major effects on the overall safety, efficacy and quality ofthe product, WHO can be consulted for classification of the particular change,by email addressed toprequalvariation@who.int. The email should contain sufficient details of the proposed change toenable WHO to provide advice.   

若某项变更未在《WHO预认证产品变更指南》（变更指南）中有说明，则根据指南该变更应被默认为重大变更。这能给予WHO充分时间来评估未进行分类的变更。然而，若申请人认为该变更不可能显著影响产品整体的安全性、有效性和质量，则可以就某个特定的变更分类发邮件至prequalvariation@who.int咨询WHO。邮件应包含拟定变更的充分细节以使得WHO提供建议。

   Examplesof changes which are not described in the Variation guideline that should be submitted as major, or be reclassified as minor or notification, are given inappendix I and appendix II. Examples of changes that do not need to be filed as variation applications but should be handled as per GMP change control aregiven in appendix III. The appendices will be updated regularly to reflect new developments. 

  变更指南中未进行描述但应作为重大变更或重新分类为微小变更或通知的变更实例已经在附录1，附录2中进行论述。对于一些不需要以变更申请但需要以GMP变更进行控制的变更实例在附录3中进行论述。上述附录会定期更新以体现最新进展。   Appendix I:Examples of changes that should be submitted as major variations  

 附录I：作为重大变更进行提交的变更实例 

  (It remains the responsibility of the applicant to submit relevant documentation to justify that the change will not have a negative impact on the quality, safety and efficacy of the product)

   申请人承担递交相关文件，论证此类变更不会影响产品的质量、安全性和有效性的职责。  

 1. Addition of new API source with a new APIMF.   

新的APIMF文件，以增加新的API来源   

2. Qualitative or quantitative changes in composition of the product that may have a significant effect on the quality, safety, orefficacy of the product (required to be supported by a bioequivalence study). 

 制剂组成成分上定性或定量的变更，可能会显著影响产品的质量、安全性和有效性（需要开展生物等效性试验）   

3. Addition of a new manufacturing site and/or new production block which has not been satisfactorily inspected by WHO or by an SRA.   

增加新的生产场地或新的生产楼，这些区域之前未获得WHO或SRA的检查批准。   

4. Major change in the manufacturing process ofproduct that requires a new bioequivalence study, e.g. from dry to wet granulation, from one type of drying process to another for products containinginsoluble APIs.  

生产工艺的重大变更(需要开展生物等效性试验)，如从干法制粒变更未湿法制粒，对含有不溶性APIs的制剂产品改变了其干燥工艺。   

5. Change inmanufacturing process that may affect the sterility assurance of a sterileproduct (e.g. change from aseptic processing to terminal sterilization or viceversa), including changes in the sterilization method for packaging materials(e.g. gas, dry heat, irradiation).   

可能影响灭菌产品灭菌保障的生产工艺变更（如从无菌加工变更至终末灭菌，反之亦然），包括对包装材料灭尽方法的变更（如气体灭菌，干热灭菌和辐射灭菌）   

6. Change in thelimit of an impurity exceeding the ICH qualification threshold which requires supportive toxicological data.   超过ICH的定量限、且需要支持性毒理学数据的杂质限度变更   

7. Change in the qualitative/quantitative composition of primary packaging of a sterile product.   

无菌制剂内包装组成成分的定性或定量变更。

   AppendixII: Examples of changes which are not described in the Variation guideline andcan be classified as minor change or notification.   

附录II：变更指南未描述、可作为微小变更或年度通知进行提交的变更实例    (The category and required conditions, if applicable, are given for each specifiedchange. It remains the responsibility of the applicant to submit relevant documentation to justify that the change will not have a negative impact on thequality, safety and efficacy of the product)   

（若适用，规定每个特定变更的分类和满足的条件。申请人承担递交相关文件，论证此类变更不会影响产品的质量、安全性和有效性的职责。）  

 1. Change in the manufacturing process of the FPP - Change in the holding time of anintermediate (Vmin)   

成品制剂的生产工艺变更——变更中间体的储存期（Vmin，即微小变更）   

Conditions:Supportive hold time study data are available.   

满足条件：支持性的储存期研究数据   

2. Change inin-process limits (relaxation) for immediate release products based on trend data for a minimum of 10 consecutive commercial batches, e.g. hardness, blendfines, bulk density (IN)   

基于最少10批次的商业化批次的趋势数据，变更中控限度（放宽限度），如硬度、总混颗粒、松密度（IN，立即通知）   Conditions: 

满足条件 ：

  i. No change in the manufacturing process and specifications of the final product (except hardness,if applicable);   成品制剂的生产工艺和质量标准未变更（若适用，硬度除外） 

  ii. Similarity of dissolution profile to the biobatch dissolution profile is demonstrated under routine dissolution condition (in the case of change in hardness)   论证溶出曲线与生物批溶出曲线在常规溶出条件下的相似性（如变更硬度的情况下）   

3. Change in FPP specification - introduction of skip testing of microbial limit for non-sterile dosage forms (IN)   变更成品制剂的标准——如对非无菌制剂的微生物限度项目引入跳检（IN，立即通知）   Conditions: Results for at least 5 commercial batches showing compliance with the acceptance criteria. At least one batch should be fully tested at regular intervals (onebatch for every 10 batches or one batch in a year, whichever is sooner). Full testing must be reinstated as soon as any batch failure is observed or conditions under which skip testing was approved are no longer met.   

满足条件：至少5个批次的商业化批次数据论证符合接受限度。至少1批定期全检（如每10批每1批或一年一批进行全检，取较快的频率）。若任何一批检测结果失败或不再符合跳检的条件，则应恢复全检。   

4. Elimination or reduction of an overage from the batch formula which was previously used to compensate for presumed manufacturing losses (IN)   

消除或减少批处方的过量投料，之前为补偿假定的生产损耗（IN，立即通知）  

 Conditions: N/A   

满足条件：不适用   

5. Change inlocation of manufacturing (including terminal sterilization of finished product) within the accepted facility or site with no changes to currently accepted formulation, batch size(s), manufacturing process, equipment,in-process controls, finished product specifications, and packaging materials.The Quality systems, standard operating procedures, and manufacturing batch records will remain the same except for administrative information (AN)   

现行处方、批量、生产工艺、设备、中控、成品质量标准和包装材料无变更的情况下，在已认可场地内变更生产地点（包括终末灭菌）。质量体系、标准操作规程和生产批记录除行政信息外均保证一致（AN，年度变更）。   

Conditions:The accepted facility or site, including the proposed location, has a satisfactory GMP status confirmed by WHO or by an SRA. Please note that such changes should follow proper change control procedures which should include but not belimited to risk assessment, qualification of new facility, equipment andprocess validation.   

满足条件：已认可工厂或场地，包括拟定的地点，应为WHO或严格监管机构确认过符合规范GMP状态。请注意，此类变更应遵循正确的变更控制程序，应包括并不局限于风险评估，对新工厂和设备的资质确认和工艺评估。   

AppendixIII: Examples of changes that do not need to be filed as variation applicationsbut should be implemented as per GMP change control   

附录3：:不需要以变更申请但需要以GMP变更进行控制的变更实例   

1. Reduced testing frequency of API, excipients, packaging materialetc. by the finished product manufacturer on receipt of batches, whether the finished product manufacturer performs all of the tests listed in the approved specifications or accepts some of the results (except Identification) based on the certificate of analysis provided by the suppliers. The specifications should remain unchanged (a complete specification must be maintained for full periodic retesting). The reduced testing scheme should be documented and willbe subject to review during a GMP inspection. Normally periodic or skip testingshould only be implemented for the testing of regular commercial batches. 

 成品生产商在接收物料批次时，降低API ,辅料和包装材料的检测频率，不管是成品生产商开展已批准质量标准上所有的检测项目或接受供应商提供的分析报告上的部门结果（除定性检测）。质量标准应保持不变（在完整的定义复验时，应维持完整的质量标准）。降低频率的检测计划应进行记录并供GMP检查时审阅。通常，定期检测或跳检应仅在检测常规商业化批次时进行实施。       

2. Reduced testingfrequency of in-process controls of intermediates (e.g. final blend, coretablets) based on trend data of a sufficient number of commercial batches (e.g.more than 10 batches). The specifications of intermediates should remain unchanged. The reduced testing scheme should be documented and will be subject to review during a GMP inspection.   基于足够数量的商业化批次（超过10批）的趋势数据，降低中间产品的中控检测频率（如总混颗粒，素片）。中间产品的质量标准不变。降低频率的检测计划应进行记录并供GMP检查时审阅。   The manufacturer needs to perform continued process verification to demonstrate that process iswell controlled. Full testing must be reinstated as soon as any batch failureis observed or if there is a change in the validated manufacturing process which might have a possible impact on the quality of product.   生产商应开展持续性的工艺确认，论证工艺控制良好。若任何一批检测结果失败或生产工艺验证中的某项变更可能对产品质量有潜在影响，则应恢复全检。   

3. Changes to the dossiers including spelling mistakes, editorial revisions made to documents such as Validation protocol and/or Reports,Analytical Procedures, SOPs, Batch manufacturing records, for added clarity that have no impact on the safety, efficacy and quality of the product.  变更申报资料，包括拼写错误和文件上编辑修订，如验证方案或报告，分析规程，SOPs，批生产记录，为说明清楚表明其对产品的有效性、安全性和质量无影响。   

4. Change in the in-process controls performed at non-critical manufacturing steps (e.g. a process/step that has no impact upon purity and impurity profile or requires no specific facility considerations, such as,buffer and media preparation, storage of intermediates, and packaging)  对于非关键生产步骤中控的变更（如某项工艺或步骤对纯度或杂质无影响或对场地无特殊的注意事项，如缓冲液或溶媒的制备，中间体的储存和包装）。   

5. Replacement of equipment with that of the same design and operating principle, when there is no change in the approved process methodology or in-process control limits. Anequivalency study is recommended.   替代具有相同设计和操作原理的设备，且不变更已批准的工艺方法学或中控限度。推荐一致性研究。   However, for terminal sterilization of product, change from a qualified sterilizationchamber to another, the new chamber and load configurations are required to bevalidated to operate within the previously validated parameters. This will be verified during a GMP inspection.   然而，对于制剂的终末灭菌，从符合资质的灭菌箱变更至另一个新的灭菌箱，则新灭菌箱和加载配制均需要在之前已经验证过的参数下运行完成验证。这在GMP检查中将会被确认。   

6. Addition of a new GMP compliant storage warehouse for raw materials,and drug substance, packaging materials.  增加新的符合GMP规范的原辅料和包材仓储间   

7. Change in supplier of excipients without a risk of TSE contamination and without change in the technical grade and specification.  变更辅料供应商且无TSE污染风险，在辅料技术级别和质量标准上无变更  

 8. Change in dimensions of secondary packaging.  外包装尺寸变更  

 9. Change in tertiary packaging components (including tertiary packsize) of drug substance or drug product that do not affect stability.  原料药或成品制剂的三级包装组分变更（包括三级包装的包装尺寸），但不影响稳定性。   

10. Change in thecolor, design of label art work without change in the contents   标签的内容不变，但其颜色、设计改变  

 原文参考：   

1.Variations to prequalified pharmaceutical products Frequently asked questions(FAQ)   

https: // extranet.who.int/prequal/sites/default/files/documents/FAQ_Variations_Sept2018.pdf