WHO预认证药品变更常见问题

Variati** to prequalified pharmaceutical products

Frequently asked questi** (FAQ)

预认证药品变更常见问题

[url=]Julia法规翻译[/url] 2018-09-28

This questi** and answers (Q&A) document addresses the questi** most frequently asked by the applicants on matters related to variati** to finished pharmaceutical product (FPP) subsequent to prequalification.

本问答文件解决申请人关于成品制剂预认证后相关变更最常见的问题。

This Q&A document aims to provide clarification, and additional information, as needed, and should be read in conjunction with the WHO guidelines on variati** to a prequalified product and other guidance documents.

本问答文件旨在澄清和提供必需额外信息，应与WHO预认证制剂变更指南及其他指南共同解读。

This document will be updated regularly to reflect new developments.

该文件将会定期更新以反映新的问题。

1. What is the timeline for implementation and review of a variation? Where can these timelines be found?

变更实施和审核的时间线是什么？可以在哪里找到这些时间线？

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

不同变更类别的实施和评估时间线在药品预认证网站成品制剂的变更部分中可以找到。每种类型的变更都有其批准机制和时间线，在变更批准及其和时间表中有对这方面内容的总结。

For changes to an Innovator or Multisource (Generic) FPP Prequalified on the basis of SRA approval, please refer to SRA-approved Multisource (generic) or Innovator FPPs.

针对基于SRA批准而预认证的创新药或多源(通用)成品制剂变更, 请参阅经SRA批准的多源 (通用) 或创新FPP。

The timelines are subject to change and will be updated, as and when appropriate. Whenever there is conflict, the timeline published on Prequalification of Medicines website prevails over the timeline included in the variation guideline.

必要时，时间线不断变更并且更新。如果出现冲突，药品预认证网站上发布的时间线的效力超过《变更指南》上包括的时间线。

2. Should data to support the annual notification be submitted?

是否需要提交支持年度通知的数据？

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 assess or to easily determine whether the appropriate reporting category has been used.

年度通知应提交一份完整的年度通知表,包括对变更和执行日期的总结。该总结应足够详细,以使评估人员能够很容易地确定是否使用了适当的报告类别。

When an annual notification involves a change in specificati** or standard test procedures (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.

当年度通知涉及原料药或成品制剂的规格或标准测试程序(STP) 的更改时,签字和带有日期内容版本的标准和标准检测规程，包括变更历史应附于通知表后。

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

针对签订关键质量信息总结(QIS)的成品制剂，应修订QIS并且将修订部门重点强调后提交。详细信息见下（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.

不需要提交额外相关的文件。但是用于支持变更的信息必须在产品销售前产生，并且在有需要时或者WHO审计过程中需要时应能提供。如有必要，应申报表中提交用于评估每个变更对产品质量的影响的研究材料总结。

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

每次变更申请时我都需要更新关键质量信息QIS总结吗？

The QIS provides a summary 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 inspecti**, variati** and requalification of the product. The final QIS also facilitates the information exchange between WHO and national regulatory authorities participating in the WHO collaborative registration procedure.

QIS为产品档案中提供关键质量信息的概述，该产品档案被WHO P所接受。对于预认证前活动，例如GMP检查，产品变更和再确认来说，这是一项有用的工具。当国家当局监管机构参与WHO的写作的注册程序中时，QIS最终版本也便于WHO和国家当局监管机构之间的信息交换。

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 secti** highlighted and the change history updated.

QIS是一份灵活的文件，当提出变更时，应对其受影响的特定章节进行修订，并且作为变更提交文件包一起提交，且应重点突出修订的内容，并且需要更新该文件的变更历史。

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

修订QIS时，申请人应该按照要求更新“申请人准备或修订日期”章节。

After a change is accepted, the QIS represents the approved quality data in the product dossier, which should be used as the basis for any future application submissi**.

当变更接受以后，QIS在产品档案中应呈现经批准的质量数据，这些数据将会是未来申请提交的基础。

If there is no change to the QIS as a result of the variation, a statement should be made in the variation application form to this effect.

如果变更的结果不设计QIS内容的改变，在变更申请表应对这方面影响的内容进行陈述。

Please note 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.

应注意如果在成品制剂预认证时没有统一意见的QIS，变更时则不需要提交QIS。但是，如果成品制剂相关的再确认中制作了QIS，适当时，变更需要提交修订的QIS。

4. For a grouped variation, should I file an application form for each change separately?

对于一组变更，我需要为每个变更单独填写申请表吗？

Grouping of variati** is acceptable only under the following circumstances.

只接受以下情况的组变更：

•the variati** are c**equential to each other, e.g. introduction of a new impurity specification that requires a new test method

变更之间有因果关系的，例如：引入新的杂质需要新的检测方法

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

同一个申请的同一个变更影响多个成品制剂，例如：为不同的成品制剂增加新的一个原料药生产地址

•each of the changes is of the AN type.

每个变更都是AN类型

A grouped 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 variati** will be c**idered to be of the highest risk type. 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) and variation 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 conditi** and documentation for both changes should be c**idered and submitted in the application.

组变更应填写一个申请表，也会按照一个申请来审核。同一申请包含两个或两个以上变更的，将按照最高风险类型进行分类。例如,为所有生产过程(新的地址已被世卫组织检查并合格)的成品制剂增加生产地址, 在新地址上的批量大小（为生物批的10倍）应按照变更号No. o.28c (Vmin) 和变更号No. 30a(IN)按照组变更进行提交。整个变更类型应为次要变更，因此实施和评估时间线也按次要变更执行。应考虑两个变更的条件和文件，并在申请中提交。

5. For an additional 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 in the 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?

对于增加成品制剂生产地址，如果提议的地址在近3年内经过WHO或者SRA审计并且符合GMP规范(变更号no.28)，那么该变更可按照次要变更提交。如果提议的地址在3年多前被GMP审计合格了，应按照重大变更提交吗？

It is recommended that the applicant c**ults WHO PQ in advance when planning the submission (address enquiry to: prequalvariation@who.int).

我们建议申请人计划提交时，提前咨询WHO PQ（咨询邮箱：prequalvariation@who.int)）

6. May a batch size 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?

在经批准的生产地址生产的批量可以在其他批准的成品制剂的地址上生产吗？应申请哪一类变更类别？

If a batch size has been 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 following conditi** should be fulfilled:

如果在成品制剂的其中一个地址已经接受某一批量，该批量也可在另外的批准的FPP生产地址生产，可在年度通知中通知WHO，此时 应满足以下条件：

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

该变更只涉及速释口服药物和非无菌液体剂型。

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

在这些生产地址上使用的生产设备都是相似的，除了生产能力上有差异。

3)Formulation, controls on starting materials, manufacturing process, in-processcontrols, specificati** and packaging materials remain the same at both sites.

两个场地的配方、起始物料的控制、生产过程、中间控制、质量标准和包装材料保持相同。

4)The necessary validati**/qualificati** at the other (proposed) site must be carried out as per cGMP prior to distributing the product and the data generated should be made available for verification by the WHO inspection team or for evaluation by assessors when requested.

在销售产品前必须按照cGMP要求在另一个（建议的）生产地址实施必要的验证/确认，其产生的数据应提供给WHO检查团队核查，或当审评人员索取时提交供其评估。

7. What is the variation requirement when the heavy metals test is removed from API and/or excipient specificati**?

原料药和/或辅料质量标准中如果移除了重金属检测项目，变更要求是什么？

The change can be implemented and be notified to WHO as annual notification or when submitting a related variation application for the affected product. The revised specificati** of API and/or excipient (with version history) should be submitted with the notification. Information about the 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 assessors or for verification by the WHO inspection team.

这类变更可以实施，并且应该按照年度通知告知WHO或者提交受影响产品的相关变更时告知WHO。修订版的原料药和/或辅料的质量标准（包括版本历史）应随着通知一起提交。原料药和/或辅料中的元素杂质信息应对成品制剂生产商开放。成品制剂生产商应该开展关于元素杂质相关的风险评估，在评估员或者WHO检查团队要求提供时，应提供相关材料。

8. There is no change category for a change in the variation guideline, what should I do?

在变更指南中没有变更类别，我该怎么做？

A change that is not addressed in the WHO guidelines on variati** to a prequalified product (variation guideline) should be c**idered as a major change by default 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 of the product, WHO can be c**ulted for classification of the particular change, by email addressed to prequalvariation@who.int. The email should contain sufficient details of the proposed change to enable WHO to provide advice.

根据指南，在WHO预认证产品变更指南（变更指南）中没有提及到的变更应该考虑其为主要变更。这给与WHO足够的时间审核这个未分类的变更。然而，如果申请人认为该变更可能不会对产品安全、效用和质量产生重大影响，可咨询WHO有关这个特殊变更的分类情况。可发邮件至prequalvariation@who.int.邮件应包含关于提出的变更的足够信息以便WHO能够提供建议。

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

变更指南中未描述到的变更案例，其应该按照主要变更或者重新按照微小变更或者通知的类别提交，具体见附录1和附录2。不需要按照变更申请的变更案例应该按照GMP变更控制要求处理，具体见附录3。附件将会定期升级以反映最新的要求。

Appendix I: Examples of changes that should be submitted as major variati**

附录1：按照主要变更提交的变更示例

(It remains the resp**ibility 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)

申请人依然需要提交相关文件以评估该变更不会对产品质量、安全性和有效性产生负面影响。

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

采用新的原料药主文件增加新的原料药来源

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

产品成分的定性或定量变化可能对产品的质量、安全性或功效有显著影响(必须有生物等效性研究的支持)。

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

增加一个新的生产地点和/或新的生产区块, 且尚未被WHO或SRA验收合格。

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

产品生产过程的主要变更要求新的生物等效性研究，例如：干法制粒变更为湿法制粒，含有不溶性原料药的产品从一种干燥工艺变更为另一类型的干燥工艺。

5.Change in manufacturing process that may affect the sterility assurance of asterile product (e.g. change from aseptic processing to terminal sterilizationor vice versa), including changes in the sterilization method for packagingmaterials (e.g. gas, dry heat, irradiation).

生产过程变更可能影响到无菌产品的无菌保证（例如：从无菌生产工艺变更为最终灭菌，反之亦然），包括包装材料灭菌方法的变更（例如：气体、干热、辐射）

6.Change in the limit of an impurity exceeding the ICH qualification threshold which requires supportive toxicological data.

杂质限度超过ICH确认阈的变更需要支持性毒性数据。

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

无菌产品内包装组成部分的定性/定量变更

Appendix II: Examplesof changes which are not described in the Variation guideline and can beclassified as minor change or notification.

附录2：变更指南中未描述的，可以分为次要变更或者通知的变更示例

(The category and required conditi**, if applicable, are given for each specified change. It remains the resp**ibility 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)

（适用时，提供每个指定变更的类别和要求条件，申请人保留提供相关文件的责任，以证明变更不会对产品质量、安全性和有效性产生负面影响）

1.Change in the manufacturing process of the FPP - Change in the holding time of an intermediate (Vmin) Conditi**: Supportive hold time study data are available.

成品制剂生产过程的变更-中间产品储存时间(Vmin)的变更

条件：应具备支持性储存时间研究数据。

2.Change in in-process limits (relaxation) for immediate release products basedon trend data for a minimum of 10 c**ecutive commercial batches, e.g. hardness, blend fines, bulk density (IN)

基于至少10个连续生产的批次，对速释片中间过程控制限度（放松）的变更，例如：硬度、混粉细度、堆密度。

Conditi**:条件

i.No change in the manufacturing process and specificati** of the final product (except hardness, if applicable);

不涉及生产过程中以及成品质量标准的变化（不适用于硬度）

ii.Similarity of dissolution profile to the biobatch dissolution profile is dem**trated under routine dissolution condition (in the case of change in hardness)

在正常的溶解条件下，在常规溶出条件下,溶解材料与生物批溶解材料相似(在硬度变化情况下)。

3.Change in FPP specification - introduction of skip testing of microbial limit for non-sterile dosage forms (IN)

成品制剂质量标准变化-无菌制剂跳过微生物限度检测（IN）

Conditi**: Results for at least 5 commercial batches showing compliance with the acceptance criteria. At least one batch should be fully tested at regular intervals (one batch 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 conditi** under which skip testing was approved are no longer met.

条件：至少5个商业批次的记过是符合可接受标准的。至少定期对1批产品进行全检（每10批产品检1批，或者1年检1批，以间隔时间短的为准）。一旦发现某个批次失效或者跳过全检的条件不能满足检验要求，必须恢复全检。

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

降低或减少批配方的剩余，该剩余原先用于补偿预设的生产过程中的损失（IN）

Conditi**:N/A

条件：N/A

5.Change in location 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 specificati**, and packaging materials. The Quality systems, standard operating procedures, andmanufacturing batch records will remain the same except for administrative information (AN)

生产地址的变更（包括成品最终灭菌），变更至地址为合格的厂房或地址，但是不改变配方、批量、生产过程、设备、中间控制、成品制剂质量标准和包装材料。除了行政信息以外（AN），质量系统、标准操作规程和批生产记录均保持相同。

Conditi**: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 butnot be limited to risk assessment, qualification of new facility, equipment and process validation.

条件：合格的厂房或者地址，包括建议的位置已经被WHO或者SRA确认其满足GMP状态。请注意这种变更应遵循变更控制规程，应包括但不限于包括风险评估、新厂房、设备的确认和工艺验证。

Appendix III: Examples of changes that do not need to be filed as variation applicati** but should be implemented as per GMP change control

附录3：不需要按照变更申请但是需要按照GMP变更控制实施的变更示例

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

原料药、辅料、包装材料等降低检验频次，例如，成品制剂生产商在接受物料批次时，其是按照已经批准的质量标准对物料进行全检，还是基于供应商提供的**的分析接受其部分检测结果（除了鉴别）。质量标准应保持不变（因为应保持完整的质量标准用于定期的全部项目的重新检测）。减低检测的计划应记录下来并且应受GMP检查审查。通常的定期或者跳过项目检测应该只实施于定期商业批次的检测。

2.Reduced testing frequency of in-process controls of intermediates (e.g. final blend, core tablets) based on trend data of a sufficient number of commercial batches (e.g. more than 10 batches). The specificati** of intermediates should remain unchanged. The reduced testing scheme should be documented and will be subject to review during a GMP inspection.

中间产品中间控制降低检测频次（例如：终混、片芯）应基于足够商业批次的趋势数据（例如：对于10个批次）。中间产品的质量标准应保持不变，降低检测的方案应被记录并在GMP检查备查。

The manufacturer needs to perform continued process verification to dem**trate that process is well controlled. Full testing must be reinstated as soon as any batch failure is observed or if there is a change in the validated manufacturing process which might have a possible impact on the quality of product.

生产商需要实施持续工艺确认以展示过程处于良好的受控状态。一旦发现批次失效或者已经验证的工艺发生了可能影响产品质量的变更，必须恢复全检。

3.Changes to the dossiers including spelling mistakes, editorial revisi** made to documents such as Validation protocol and/or Reports, Analytical Procedures, SOPs, Batch manufacturing records, for added clarity that have no impact on thesafety, efficacy and quality of the product.

档案中的变更，包括拼写错误、对文件诸如验证方案和/或报告、分析规程、SOP、批记录的编辑性的修订，增加对药品安全性、有效性和质量无影响的条款。

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 orrequires no specific facility c**iderati**, such as, buffer and mediapreparation, storage of intermediates, and packaging)

非关键生产步骤中中间控制的变更（例如对纯度和杂质档案无影响，或者对厂房无特殊要求，例如缓冲液和培养基制备、中间产品的储存和包装）

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. An equivalency study is recommended.

当批准工艺方法或者中间控制限度没有变更时，将一设备替换成相同设计和操作原则的另一设备。推荐进行等效性试验。

However, for terminal sterilization of product, change from a qualified sterilization chamber to another, the new chamber and load configurati** are required to be validated to operate within the previously validated parameters. This will be verified during a GMP inspection.

然而，对于最终灭菌产品，由经过确认的灭菌柜变更为另一灭菌柜，要求在以前已经验证的参数范围内验证装载配置。在GMP检查中会确认该材料的实施情况。

6. Addition of a new GMP compliant storage warehouse for rawmaterials, and drug substance, packaging materials.

为原料、制剂和包装材料增加新的GMP合规的储存仓库。

7.    Change in supplier of excipients without arisk of TSE con**ination and without change in the technical grade and specification.

无TSE污染且没有技术等级或者质量标准上的变更的辅料供应商的变更。

8.    Change in dimensi** of secondary packaging.

二级包装大小的变更。

9.    Change in tertiary packaging components (including tertiary pack size) of drug substance or drug product that do not affect stability.

原料药或者制剂在不影响稳定性情况下进行的3J包装组分的变更（包括3J包装大小）

10.   Change in the color, design of label art work without change in the contents

标签内容不改变，仅在颜色、设计方面有变更

译者注：

SRA=stringent regulatory authority

FPP=finished pharmaceutical product

STP=standard test procedures

QIS=quality information summary

APIMF=active pharmaceutical ingridient master file

阅读原文：https://extranet.who.int/pqweb/news/frequently-asked-questi**-faq-variation-prequalified-pharmaceutical-products-published