Date of implementation: 1 March 2010
Introduction:
The holder of a Certificate of suitability shall inform the EDQM of any change to the information in the certification dossier by sending an application form and all necessary documents demonstrating that the conditions laid down in the present guideline are met.
Classification of changes
The changes have been classified in three categories (notification/minor/major) depending on the potential impact of the change on the quality of the final substance. These three categories are based on those (IA-IAIN/IB/II) of the Commission Regulation (EC) No 1234/2008 concerning the examination of variations to the terms of marketing authorisation for medicinal products for human use and veterinary medicinal products.
Any change not classified as a notification or a major change should be classified as a minor change except in the following cases where a new application should be submitted:
- addition of a new route of synthesis and/or a new manufacturing site where the specifications of the fi
nal substance are different from the one already approved
- transfer to a new holder that is not the same legal entity as the approved one, where the transfer does not occur because of a merger or because the company is sold, and where the manufacturer does not take out the Certificate of suitability in their own name.
The changes related to Ph. Eur. monograph revisions or any other regulatory requirements are treated separately and generally initiated by the EDQM.
执行日期：2010年3月1日
介绍：
欧洲药典适用性证书持有人必须向EDQM报告所有与申报文件有关的变更，申报时应填写申请表格和所有必要的资料，证明变更符合现行指南的规定。 变更分类
根据变更对最终产品可能产生的影响程度，变更分为三类（通知/微小/重大）。
分类原则是根据EC法规1234/2008 (IA-IAIN/IB/II)：EC成员国审核人用和兽用制剂销售许可证变更规定
所有未划为通知或者重大变更的变更都是微小变更，但以下情形必须按新证书申请办理：
- 增加新合成途径或新生产场地，而且成品质量标准发生变化。 - 持有人转让，新持有人与现行法人不同，这种转让不是公司合并、出售的结果，生产厂也没有以自己名义获取原有证书。
欧洲药典修订或其它法规要求而产生的变更另论，通常由EDQM发起。
Documentation to be provided
For any revision the documentation should consist of:
- a cover letter
- the application form, duly filled and listing all the changes applied for
- a description of each change together with a justification
- data showing, when applicable, that the conditions have been met
- update of the relevant section(s) of the dossier (presented in EU-CTD format).
- the specific documents described below for each change and supporting the change
- supportive information, including comparative data with the previous version of the dossier (in tabular format), showing the approved and the proposed section and highlighting the changes
Consequential changes should be identified and the relation between the changes should be described.
1100.laEach time batch data are needed:
- they should be in accordance with the specifications of the current Ph. Eur. monograph and when relevant with the additional requirements included in the Certificate of suitability
- the manufacturing site, the manufacturing date and the size of the batches should be specified.
- quan titative results should be presented numerically (i.e. not in general terms such as “complies”) and with the appropriate number of decimal places.
需要申报的文件
所有变更的申报文件必须包括以下内容：
- 附函
- 申请表，列出申请的变更
- 变更内容并说明变更的合理性
- 若适用的的话，表明符合条件的数据
- 更新申报文件相关的章节（按EU-CTD格式）
- 下述各种变动所要求的具体文件
- 支持性信息，包括与原版本的对比数据（以表格格式），表明原内容及现内容，强调变更应该识别间接的变更，并描述变更之间的关系。
所有变更都需要申报批分析数据：
- 而且必须现行欧洲药典标准、以及CEP证书附加的有关要求。
- 必须说明生产场地、生产日期和生产批量。社会经济
- 应以数字形式表示定量结果（即：不得笼统表达为“合格”等），数位应合理。
The changes are presented in five sections:
- Notifications (N and T)
- Typical minor revisions for Certificates of suitability for chemical purity and microbiological quality or for TSE Certificates of suitability
- Major revisions (MAJ)
- Renewal
- Transfer of holdership
Editorial changes should not be submitted as separate variations but should be reported at the same time as changes concerning the respective part of the dossier. In any case, a declaration should be provided that the content of the concerned part of the dossier has not been changed by the editorial changes (except for the change itself).
以下分五节讨论各种变更情况：
通知（N和T）
化学纯度和微生物质量的CEP证书或TSE证书的典型微小变更
重大变更（MAJ）
更新
证书持有人转让
文字性变更不应作为单独的变更提交，但当文件相关部分变更时应当同时报告。不管怎么样，应该申明：除了变更本身之外，文件相关部分的内容没有因文字性的变更而发生变更。NOTIFICATIONS (IN/AN)
Notifications are split into immediate notifications and notifications with annual reporting.
1. Immediate notifications (IN):
IN1) Change in the name and/or address of the certificate holder of the final substance (former N1)
Conditions:
- the certificate holder shall remain the same legal entity (except where the company is sold or in case of a merger).
Specific Documentation:
- a formal document from a relevant official body (e.g. Chamber of Commerce) in which the new name or the new address is mentioned
- all updated declarations (annexes to the application form).
通知（（IN/AN）
碎纸片拼接通知分为立即通知和年度报告的通知
1. 立即通知IN
IN1 原料药证书持有人名称或地址变更（以前的N1） 条件：
- 证书持有人法人地位不变（公司出让或被兼并除外）。
文件要求：
- 官方出具（如：商会）的有关新名称和新地址的正式文件
- 所有更新的声明（见申请表附录）
IN2) Change in the name and/or address of the manufacturing site for the final substance (former N2)
Conditions:
- the location of the manufacturing site shall remain the same.
Specific Documentation:
- a formal document from a relevant official body (e.g. Chamber of Commerce) in which the new name or the new address is mentioned
基因工程抗体- updated declarations of manufacture in accordance with the dossier and according to GMP rules a
nd of willingness to be inspected.
IN2 原料药生产场所名称或地址变更（以前的N2）
条件：生产场所具体位置应保持不变。
文件要求：
- 官方出具（如：商会）的有关新名称和新地址的正式文件
- 更新的声明：按申报文件和GMP法规组织生产及愿意接受检查的声明
IN3) Deletion of any manufacturing site for the final substance (former N3)
Conditions:
- the deletion should not be due to critical deficiencies concerning manufacturing.
Specific Documentation:
- the justification of the deletion.
IN3 原料药生产场地的取消（以前的N3）
条件：取消不应该是由于与生产有关的严重缺陷
文件要求：证明取消的合理性。
马鞍山化工厂爆炸IN4) Change or addition of a manufacturer of a starting material or intermediate used in the manufacturing process of the final substance when the proposed manufacturer is part of the same group as the currently approved manufacturer
Conditions:
- the specifications and the route of synthesis (including In-Process Controls, methods of analysis of all materials used) of the concerned material are identical to those already approved
- the final substance is not a biological substance or a sterile substance.
Specific Documentation:
- a declaration from the holder of the Certificate of suitability that the specifications of the final substance are the same as those already approved
- a declaration from the holder of the Certificate of suitability that the synthetic route (or in case of herbal material, where appropriate, the method of preparation, geographical source and production), the specifications and the quality control procedures of the starting material or intermediate are the same as those already approved
- a list of approved and proposed sites
- batch analysis data (in a comparative tabular format) for at least two batches (minimum pilot scale) of the final substance from the approved and proposed sites.
IN4 变更或增加原料药生产工艺过程中所使用的起始物料或中间体生产厂家，新厂家与原厂家同属一个集团
条件
- 相关物料的质量标准和合成路线（包括中控、所有原料的分析方法）与已批准的相同
- 原料药不是生物制品或无菌制品
文件要求：
- CEP证书持有者申明原料药的质量标准与已批准的一致
- CEP证书持有者申明起始物料或中间体的合成路线（或当原料为草药时，其制备方法，地理来源和制造）、质量标准和检测方法与已批准的一致
- 新旧地址的清单
- 新旧地址至少两批（至少为中试批次）原料药的批分析数据（对比表格）。
IN5) Change or addition of a manufacturing site/workshop for the final substance when the proposed manufacturer is part of the same group as the currently approved manufacturer
Conditions:
氯酸钠
- the specifications of the final substance (including in process controls, methods of analysis of all materials), method of preparation (including batch size) and detailed route of synthesis are identical to those already approved
- the final substance is not a biological substance or a sterile substance.
Specific Documentation:
- a declaration from the holder of the Certificate of suitability that the synthetic route (or in case of herbal material, where appropriate the method of preparation, geographical source and production), quality control procedures and specifications of the final substance are the same as those already approved
- a list of approved and proposed sites
- batch analysis data (in a comparative tabular format) for at least two batches (minimum pilot scale) of the final substance from the approved and proposed sites
- updated declarations of manufacture in accordance with the dossier and according to GMP rules and of willingness to be inspected for the new site.
IN5 变更或增加原料药的生产地址/车间，新厂家与原厂家同属一个集团
条件
- 原料药的质量标准（包括中控、所有原料的分析方法）和制备方法（包括批量）及详细的合成路线与已批准的相同
- 原料药不是生物制品或无菌制品
文件要求：
- CEP证书持有者申明原料药的合成路线（或当原料为草药时，其制备方法，地理来源和制造）、质量标准和检测方法与已批准的一致
-新旧地址的清单
-新旧地址至少两批（至少为中试批次）原料药批分析数据（对比表格）
- 更新的声明：按申报文件和GMP法规组织生产及愿意接受检查的声明
IN6) Tightening of the specification limits for the final substance (former N8) Conditions:
- the change does not result from unexpected events arising during manufacture
- any change should be within the range of currently approved limits
- the test procedure remains the same, or changes in the test procedure are minor.
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