AN13) Tightening of the specification limits for a starting material/ intermediate/reagent used in the manufacturing process of the final substance (former N8)

Conditions:

- the change should not be the result of 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.

Documentation

- comparative table of approved and proposed specifications



AN13)提高产品生产过程中所用到的起始物料/中间体/试剂质量标准（以前的N8）

条件:

- 该变动不是生产过程的异常引起

- 所有变动必须符合现行已经批准的质量标准范围

- 检测方法不变或检测方法变化较小

文件要求

- 变动前后质量标准对照表

AN14) Change in the composition of the immediate packaging

Conditions:

- the proposed packaging material must be at least equivalent to the approved material in respect of its relevant properties

- relevant stability studies have been started under ICH conditions and relevant stability parameters have been assessed in at least two pilot scale or industrial scale batches and at least three months satisfactory stability data are at the disposal at time of implementation.

NB: if the proposed packaging is more resistant than the existing packaging, the three months stability data do not yet have to be available.

These studies must be finalized and the data will be provided immediately to EDQM if outside specifications or potentially outside specifications at the end of the re-test period (with proposed action).

- the final substance is not a sterile, liquid or biological substance.

Specific Documentation:

- comparison of the approved and proposed immediate packaging specifications, if applicable

- appropriate data on the new packaging including a confirmation that the material complies with relevant pharmacopoeial requirements or EU legislation on plastic materials and objects in contact with foodstuffs

- a declaration from the holder of the certificate as appropriate that the required stability studies have been started under ICH conditions (with indication of the batch numbers concerned) and that, as relevant, the required minimum satisfactory stability data were at the disposal at time of implementation and that the available data did not indicate a problem. Assurance should also be given that the studies will be finalized and that data will be provided immediately to the competent authorities if outside specifications or potentially outside specifications at the end of the approved re-test period (with proposed action).

AN14)内包材成分变化

条件：

-在相关特性上，新旧包材至少等同

-按照ICH条件开始相应的稳定性实验，至少已有两批中试或正式生产批次进行了稳定性参数评估，执行时至少有符合质量标准的三个月的稳定性数据 [这个是新版增加的内容，也就是说三个月的稳定性数据合格后就可以申报变更了]

NB: 若新包装比原包装更严格，三个月的稳定性数据不是必须的

如果复测期结束（按新包装）后不符合标准或可能不符合标准，须尽快完成这些研究并立即将数据提交给EDQM。

- 产品不是无菌、液体或生物产品

文件要求：

- 若有的话，新旧内包装标准对比

-新包装的一些适当的数据，包括证明材料符合相关药典要求或欧盟对与食品接触的塑料材料与物体的法规

- 证书持有者申明：要求的稳定性实验已经按照ICH条件（指明批号）进行，执行时可提供符合要求的最少稳定性数据且数据没有问题。确定将完成实验，并且若在复测期（新标准）结束后出现不合格或可能不合格时会立即将数据上报给相关部门

AN15) Change in the specification parameters and/or limits of the immediate packaging of the final substance

Conditions:

- the change does not result from unexpected events arising during manufacture of the packaging material or during storage of the final substance

- the test procedure remains the same, or changes in the test procedure are minor

- any new test method does not concern a novel non-standard technique or a standard technique used in a novel way.

Specific Documentation:

- comparative table of approved and proposed specifications.



AN15)成品内包材质量标准参数和/或限度改变

条件

- 变化不是由于包材生产或产品储存过程的异常产生的

- 检测方法不变或变化较小

- 任何新的检测方法不涉及新的非标准技术或以新方式使用的标准技术

文件要求

- 新旧标准对比表

NOTIFICATIONS FOR TSE CERTIFICATES (TIN/TAN)

1. Immediate notifications (TIN):

TIN1) Deletion of a source country or change in source of a material used in the preparation of the final substance from a TSE risk material to a vegetable, synthetic, or non-TSE risk material (former N12)

Conditions:

- no change in the manufacturing process.

Specific Documentation:

- if applicable a declaration from the certificate holder or manufacturer of the material that it is purely of vegetable, synthetic or non-TSE risk origin.

TSE 证书通知(TIN/TAN)

1. 立即通知 (TIN):

TIN1)取消该物质来源，或将产品制备中所使用的、具TSE风险的原料更改为植物的、合成的或无TSE风险的来源（以前的N12）

条件： 生产工艺不得改变

文件要求： 适用时，证书拥有者或原料生产者声明原料仅仅来源于植物、合成或无TSE风险。

TIN2) Change or addition of a manufacturing site for the final substance when the proposed manufacturer is part of the same group as the approved manufacturer (former T1)

Conditions:

- no change in the manufacturing process, in the materials and in the origin of the material used in the process

- no other TSE risk material is processed in the new manufacturing site.

Documentation:

- a declaration from the holder of the certificate/manufacturer that the manufacturing process is identical to that already approved

- a declaration from the holder of the certificate/manufacturer that no other TSE risk material is processed in the new manufacturing site

- updat-ed declarations of manufacture in accordance with the dossier and according to GMP rules/quality system and of willingness to be inspected

- information on the quality assurance system (including traceability) applied in the new manufacturing site.

TIN2) 生产场地变动或增加，新厂家与原厂家同属一个集团（以前的T1）

条件:

- 生产工艺不变，工艺过程中所使用物料及其来源不变

- 新厂址不生产其它具TSE风险的产品

文件要求

- CEP证书持有人/生产厂声明：生产工艺与原来申报工艺完全相同

- CEP证书持有人/生产厂声明：新厂址不生产其它具TSE风险的产品

- 更新以下声明：按申报文件组织生产、符合GMP和愿意接受检查

- 质量保证体系适用于新厂址的信息（包括可追踪性）

TIN3) Change in the quality assurance system applied in the manufacturing site (Former T3)

Conditions:

- the new quality assurance system is at least equivalent to the former one

- no change in the manufacturing process (including process parameters) or in the specifications of the final substance.

Documentation

- updat-ed information on the quality assurance system (including traceability)

- updat-ed declarations of manufacture in accordance with the dossier and according to GMP rules/quality system and of willingness to be inspected.

TIN3)生产场所质量保证体系变更（以前的T3）

条件:

- 新质量体系至少与以前的体系具等同性

- 生产工艺（包括工艺参数）或产品质量标准不变

文件要求

- 更新的质量保证体系介绍（包括可追踪性）

- 更新以下声明：按申报文件组织生产、符合GMP法规/质量体系和愿意接受检查

2. Notifications with annual reporting (TAN):

TAN1) Minor change in the manufacturing process (including process parameters) or in the specifications of the final substance (Former T2)

Conditions:

- the change has no impact on the TSE risk

- the certificate of suitability covers only the TSE risk and does not cover the chemical purity and microbiological quality.

Documentation:

- comparison of the approved and proposed process

- a declaration from the holder of the certificate/manufacturer that the change has no impact on the TSE risk.

2. 每年报告的通知 (TAN):

TAN1) 生产工艺（包括工艺参数）或产品质量标准的微小变更（以前的T2）

条件:

- 变更不影响TSE风险

- TSE证书仅包括TSE风险，不涉及化学纯度及微生物质量

文件要求

- 变更前后的工艺对比

- 证书拥有者/生产者声明：变更不影响TSE风险

TYPICAL MINOR CHANGES FOR CERTIFICATES FOR CHEMICAL PURITY AND MICROBIOLOGICAL QUALITY

THIS IS A NON EXHAUSTIVE LIST OF MINOR CHANGES INTENDED TO HELP THE SUBMISSION AND THE PREPARATION OF THE DOCUMENTATION.

Change in batch size of the final substance or an intermediate more than 10-fold compared to the original batch size (former R2)
Specific Documentation:
- updat-ed description of the full process specifying the new batch size
- batch analysis data (in comparative tabular format) on a minimum of one production batch manufactured according to both the approved and the proposed sizes.
化学微生物质量产品的典型微小变更
这是为了帮助提交和文件准备而列出的非全面的微小变更清单
成品或中间体批量放大超过原申报批量10倍（以前的R2）
文件要求
- 变动后完整生产工艺描述，说明新的批量
- 批量变动前后至少一个批号的正式生产批分析数据(对比表格).
Change or addition of a manufacturer of a starting material or intermediate used in the manufacturing process of the final 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), 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
- for a manufacturer of intermediate, declarations of manufacture in accordance with the dossier and according to GMP rules and of willingness to be inspected for the proposed site
- batch analysis data (in comparative tabular format) on a minimum of one production batch manufactured with the approved and the proposed sources of material.
变更或增加产品生产工艺中所使用的起始物料或中间体生产厂家
- CEP证书持有者申明合成路线（或当产品为草药时，其制备方法，地理来源和制造）、起始物料或中间体的质量标准和检测方法与已批准的一致
- 新旧地址的清单
- 中间体生产厂家申明：按申报文件组织生产、符合GMP法规和愿意接受检查
- 使用新旧来源的物料正式生产的至少一个批次的产品批分析数据（对比表格）
Change or addition of a manufacturing site/workshop for the final 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
- updat-ed declarations of manufacture in accordance with the dossier and according to GMP rules and of willingness to be inspected for the proposed site
- batch analysis data (in comparative tabular format) on a minimum of one production batch manufactured in both the approved and the proposed sites.
变更或增加产品的生产地址/车间
文件要求：
- CEP证书持有者申明产品的合成路线（或当产品为草药时，其制备方法，地理来源和制造）、产品的质量标准和检测方法与已批准的一致
- 新旧地址的清单
- 生产者更新声明：按申报文件组织生产、符合GMP法规或新地址愿意接受检查的声明
- 新旧地址至少一批正式生产批次的成品批分析数据（对比表格）

For a “double” Certificate of suitability (for chemical purity and microbiological quality and for TSE risk), change in source of a material used in the preparation of the final substance from a TSE risk material to a vegetable, synthetic, or non-TSE risk material (former R5)
Specific Documentation:
- updat-ed specifications of the proposed source of the material
- 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 source of the material or intermediate
- a declaration from the manufacturer of the material that it is purely of vegetable, synthetic or non-TSE risk origin (specifying the origin)
- a declaration from the holder of the certificate that there is no change in the manufacturing process and that the specifications of the final substance remain the same.
双重CEP证书（化学微生物和TSE证书），将产品制备中所使用的TSE风险原料改为植物、合成或非TSE风险原料来源（以前的R5）
文件要求
- 新来源原料的质量标准
- 原料或中间体来源变更前后至少各两批产品（至少是中试批）批分析数据（对比表格）
- 原料生产厂声明：该原料仅仅来源于植物、合成或无TSE风险（说明来源）
- 证书持有者声明：产品生产工艺和质量标准不变
Extension/addition of the re-test period of the final substance and/or change in the storage conditions for the final substance (former R7)
Specific Documentation for addition of a re-test period:
- results of long-term and accelerated stability studies for at least two pilot or production scale batches
- appropriate data on the packaging material including a confirmation that the material complies with relevant pharmacopoeial requirements or EU legislation on plastic materials and objects in contact with foodstuffs.
Specific Documentation for an extension of the re-test period / change in the storage conditions for the final substance:
- updat-ed results of stability studies for at least two pilot or production scale batches.
延长/增加产品复测期/改变产品贮存条件（以前的R7）
增加复测期的文件要求：
- 提供至少两批中试或正式生产的长期和加速稳定性实验数据
- 关于包装材料的一些适当资料，包括证明材料符合相关药典要求或欧盟对与食品接触的塑料材料或物体的法规
延长复测期/改变产品贮存条件的文件要求：
- 更新至少两批中试或正式生产的稳定性实验数据

Change/addition of a manufacturer of starting material/intermediate used in the manufacturing process of a biological substance
Specific Documentation:
- a declaration from the holder of the certificate that the manufacturing process, quality control procedures and specifications of the final substance and of the concerned material are the same as those already approved
- a list of approved and proposed sites
- for a manufacturer of intermediate, declarations of manufacture in accordance with the dossier and according to GMP rules and of willingness to be inspected for the proposed manufacturer
- batch analysis data (in comparative tabular format) on 3 batches (minimum pilot scale) manufactured according to both the approved and the proposed manufacturers.

变更/增加生物产品生产工艺中所使用的起始物料/中间体生产厂家
文件要求
- CEP证书持有者声明产品和相关原料的合成路线、检测方法和质量标准与已批准的一致
- 新旧地址的清单
- 中间体生产厂家声明：按申报文件组织生产、符合GMP法规和愿意接受检查
- 新旧地址各三批（至少中试批次）的产品批分析数据（对比表格）

Change/addition of the manufacturer of a biological substance

Specific Documentation:
- a declaration from the holder of the certificate that the manufacturing process, quality control procedures and specifications of the final substance are the same as those already approved
- batch analysis data (in a comparative tabular format) for at least 3 batches (minimum pilot scale) of the final substance from the approved and the proposed sites
- updat-ed declarations of manufacture in accordance with the dossier and according to GMP rules and of willingness to be inspected.

变更/增加生物产品生产厂家
文件要求
- CEP证书持有者申明产品的合成路线、检测方法和质量标准与已批准的一致
- 新旧地址各至少三批（至少中试批次）的产品批分析数据（对比表格）
- 更新声明：按申报文件组织生产、符合GMP法规和愿意接受检查

Minor changes in the manufacturing process of a biological substance, including change in batch size
Specific Documentation:
- a direct comparison of the approved and the proposed process
- a declaration from the holder of the certificate that the specifications of the final substance are the same as those already approved
- batch analysis data (in comparative tabular format) of at least 3 batches (minimum pilot scale) of the final substance manufactured according to the approved and proposed process or according to both approved and proposed batch sizes, demonstrating that the change has no negative impact on the quality of the final substance.

生物产品生产工艺微小变更，包括批量改变
文件要求
- 新旧工艺直接对比
- CEP证书持有者申明产品的质量标准与已批准的一致
- 根据新旧工艺或新旧批量生产的各至少三批（至少中试批次）产品的批分析数据（对比表格），表明变更对产品质量无不良影响

Changes to a test procedure (including replacement or addition) for the biological substance/starting material/intermediate or changes to a biological method
Specific Documentation:
- description of the analytical method, a summary of validation data
- comparative analysis results showing that the approved and the proposed test are equivalent. This requirement is not applicable in case of an addition of a new test procedure.

生物产品/起始物料/中间体检测方法变更（包括取代或增加）或变更为生物方法
文件要求：
- 描述分析方法，验证数据总结
- 对比数据表明新旧方法是等同的。该条不适用于增加新检测方法的情况

MAJOR CHANGES (MAJ)

MAJ1 – Change/addition of the manufacturer of a starting material or intermediate, when the proposed manufacturer uses a substantially different route of synthesis or manufacturing conditions, which are likely to change the qualitative and/or quantitative impurity profile (eg. new reagents, solvents, materials are introduced in the synthesis)

MAJ2 - Change in the manufacturing process of the final substance that regards the sterilization step(s), including changes in batch size of a sterile substance

MAJ3 - Substantial change to the manufacturing process/addition of an alt-ernative manufacturing process for a starting material, intermediate or final substance likely to change the qualitative and/or quantitative impurity profile (eg. new reagents, solvents, materials are introduced in the synthesis)

MAJ4 - Changes in the manufacturing process of a herbal substance related to geographical source or production

MAJ5 - Widening or deletion of approved in-process test limits, which may have a significant effect on the overall quality of the final substance

MAJ6 – Widening of the approved specifications limits for the final substance

MAJ7- Widening of the approved specifications limits for starting materials/ intermediates, which may have a significant effect on the overall quality of the final substance

MAJ8 - Deletion of a specification parameter which may have a significant effect on the overall

quality of the final substance

MAJ9 - Change in the composition of immediate packaging for a sterile substance

MAJ10 - Introduction of a new design space or extension of an approved design space or of a post approval change management protocol related to the final substance

重大变更 (MAJ)

MAJ1 –变更/增加起始物料或中间体的生产厂家，新厂家使用的合成工艺或生产条件与原厂家的有很大不同，可能会改变产品定性和/或定量的杂质情况（如在合成工艺中引入新试剂、新溶剂、新物料）

MAJ2 –产品灭菌步骤的生产工艺变更，包括无菌制品的批量变更

MAJ3 – 起始物料、中间体或产品的生产工艺变化较大/增加一个替代的生产工艺，可能会改变定性和/或定量的杂质情况（如在合成工艺中引入新试剂、新溶剂、新物料）

MAJ4 - 与地理产地或制造相关的草药的生产工艺变更

MAJ5 -放宽或删除中控限度，可能对产品总体质量产生重大影响

MAJ6 –放宽产品质量标准的限度

MAJ7-放宽起始物料/中间体的质量标准的限度，可能对产品总体质量产生重大影响

MAJ8 – 删除质量标准参数，可能对产品总体质量产生重大影响

MAJ9 - 无菌产品内包材成分改变

MAJ10 – 引入新的设计空间或扩大已批准设计空间的范围，或引入与产品相关的批准后的变更管理计划 [搞不懂这句话具体是指什么？]



TSE changes

MAJ11 – Change/addition of a source country or tissues for TSE risk material

MAJ12 - Change/addition of a manufacturer of a starting material or intermediate

MAJ13 – Change/addition of a manufacturing site where other TSE materials than the substance are processed

MAJ14 - Substantial changes in the manufacturing process that are likely to affect the TSE risk

TSE 变更

MAJ11 –变更/增加TSE风险物质的来源国或组织

MAJ12 -变更/增加起始物料或中间体生产厂家

MAJ13 –变更/增加生产厂地，（此生产厂地）也生产其他TSE风险物质

MAJ14 -可能会影响TSE风险的生产工艺重大变更

RENEWAL

The Certificate of suitability is valid for five years from the date when the original certificate was granted. Regardless of any revisions treated in the meantime, the holder of a Certificate of suitability shall ask for the renewal of the Certificate of suitability six months prior to expiry date by providing an updat-e of the certification dossier.

If no change has been made since the last Certificate of suitability was granted

Documentation:

- a statement that no changes that may affect the quality, safety or efficacy of the final substance have been made

- certificates of analysis from at least two recent production batches

- updat-ed declarations as appendixes to the application form.

更新

CEP证书自首次签发之日起5年有效。失效前6个月，无论是否正在办理变更手续，CEP证书持有人必须提出更新申请，并上报更新后的文件。

如果自上次CEP证书签发后没有任何变动

文件要求：

- 声明没有发生任何影响产品质量、安全、效力的变更

- 并提供至少两个最近批号的分析证明（COA）

- 刷新申请表格后附的声明

If changes are included in the request for renewal

Documentation:

- an updat-ed dossier in CTD format and/or updat-ed sections affected by the changes

- list of changes introduced in the format of a comparative table

- relevant data supporting each change as described in this guideline

- certificates of analysis from at least two recent production batches

- updat-ed declarations as appendixes to the application form.

如果更新申请包含变更

文件要求：

- CTD格式的更新文件/或受变更影响的更新部分

- 所做变更的比较表格

- 按本指南要求，提供每一个变更的支持性数据资料

- 提供至少两个最近生产批号的分析证明（COA）

- 刷新申请表格后附的声明

TRANSFER OF HOLDERSHIP OF A CERTIFICATE OF SUITABILITY

A transfer of the holdership of the Certificate of suitability (i.e. change in the name of the certificate holder that is not the same legal entity and where the change does not occur following a sale or a merger) is feasible in exceptional cases with the below conditions:

- the current Certificate of suitability is held by another company than the manufacturer

- the manufacturer takes out the Certificate of suitability in their own name.

Documentation:

- a letter signed by both parties, i.e. the former holder and the manufacturer, agreeing that the holdership of the Certificate of suitability is passed on to the manufacturer from the date of the request

- updat-ed declarations as annex to the application form.

CEP证书持有人转让

CEP证书持有人的转让（即：证书持有人变更给原法人以外的团体，这种变更不是公司出售或合并的结果）在下面的条件下是可行的：

- 现行的CEP证书被另一个公司拥有，而不是该生产厂

- 生产厂以自己名义领取CEP证书

文件要求：

- 双方签字协议函，即：原持有人和生产厂同意自申请之日起，CEP证书转让给生产厂持有。

- 刷新申请表格附件的声明

这种申请属于重大变更。[不知道此话来自何处？？？]

明白了,前一版本中有这句话,此更新版本删掉了

真厉害，佩服佩服