IN8) 增加原料药标准的参数

条件

- 该变动不是生产过程的异常引起

- 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[这句话怎样才能译得更为准确？]

- 检测方法不是生物方法或生物产品使用生物试剂的方法（不包括药典中标准的微生物方法）

- 变更不涉及基因毒性杂质

文件要求

- 变动前后质量标准对照表

- 若有，任何详细的新的检测方法和验证数据

- 包括相关原料药所有规格参数的两批正式生产的批检验数据



IN9) Removal/reduction of the re-test period from the Certificate of suitability / change to more restrictive storage conditions (former N11)

Conditions:

- the change should not be the result of unexpected events arising during manufacture or because of stability concerns



Specific Documentation:

- the justification of the removal/reduction of the re-test period

IN9 从CEP证书上取消/减少再检验日期/贮藏条件变为更严格（以前的N11）

条件： 该变更不是生产过程的异常或稳定性实验出现问题引起

文件要求：说明取消/减少再检验日期的合理性

IN10) Deletion of an approved change management protocol for design space submission

Conditions:

- the deletion of the approved change management protocol is not a result of unexpected events or out of specification results during the implementation of the change (s) described in the protocol.

Specific Documentation:

- amendment of the relevant section(s) of the dossier

IN10 删除已批准的设计空间提交的变更管理方案[这句话怎样才能译得更为准确？]

条件

- 删除已批准的变更管理方案不是由于异常结果，或在执行该方案所描述的变更过程中引起的OOS结果

文件要求：

- 修订文件相关的部分

- 验证结果对比，或仅对比检测结果表明新方法与原方法等同

2. Notification with annual reporting (AN):

AN1) Change in the name and/or address of a manufacturer of a starting material or intermediate used in the manufacture of the final substance

Conditions:

- the location of the manufacturing site shall remain the same

Specific Documentation:

- updat-ed list of manufacturers of starting material/intermediate



AN2) Deletion of a manufacturer of a starting material/intermediate used in the manufacture of the final substance (former N4)

Conditions:

- the deletion should not be due to critical deficiencies concerning manufacturing

Specific Documentation:

- the justification of the deletion

- updat-ed list of manufacturers of starting material/intermediate

2. 年度报告的通知 （AN）

AN1 原料药生产工艺过程中所使用的起始物料或中间体厂家名称和/或地址变更

条件

- 生产地址的地理位置不变

文件要求

-更新的起始物料/中间体厂家清单

AN2取消原料药生产工艺过程中所使用的中间体/起始物质的生产厂家

条件：取消不应该是由于与生产有关的严重缺陷 [以前的条件为无，此为增加内容]

文件要求：

-证明取消的合理性

-更新的起始物料/中间体厂家清单

AN3) Change in the code product/reference number and/or in the brand name of the final substance or any material used in its manufacture (former N9)

Condition:

- the change does not regard the quality of the final substance or the concerned material

Specific Documentation:

- approved and proposed code product / reference number / brand name

AN3 原料药或生产过程使用的任一物料的产品代码或索引号或商标名变更（以前的N9）

条件:

- 变更与原料药质量或相关的物料质量无关

文件要求

- 产品代码、索引号、商标名新旧对照表

AN4) Minor change in the manufacturing process of the final substance (former R1)

Conditions:

- the specifications of the final substance or intermediates are unchanged and there is no adverse change in qualitative and quantitative impurity profile

- the synthetic route remains the same, i.e. intermediates remain the same and there are no new reagents, catalysts or solvents used in the process. In the case of herbal products, the geographical source and production of the herbal material remain unchanged

- the final substance is not a biological substance.

Specific Documentation:

- batch analysis data (in comparative tabular format) of at least two batches (minimum pilot scale) manufactured according to the currently approved and proposed process.



AN4 原料药生产工艺的微小变化（以前的R1）

条件:

- 原料药或中间体标准不变，并且定性、定量的杂质概况均没有不利的变化

- 合成途径未变，即：中间体不变，而且工艺中未用到新试剂、催化剂或溶剂。对于植物制剂产品，其地理来源及生产操作不变

- 原料药不是生物制品

文件要求

- 工艺变动前后至少两个批号产品的批分析数据(对比表格) (至少应为中试批)

AN5) Change in batch size of final substance or intermediate up to 10-fold compared to the original batch size (former N5)

Conditions:

- any changes to the manufacturing methods are only those necessitated by scale-up, e.g. use of different-sized equipment

- test results of at least two batches of the final substance complying with the approved specifications should be available for the proposed batch size

- the substance is not a biological substance or a sterile substance

- the change does not affect the reproducibility of the manufacturing process

- the specifications of the final substance/intermediates remain the same

- the currently approved batch size was not approved via a notification

Specific Documentation:

- the batch numbers of the tested batches having the proposed batch size

- approved and proposed batch size

- updat-ed description of the full process specifying the proposed batch size

- a declaration from the certificate holder that the changes to the manufacturing methods are only those necessitated by scale-up, that the change does not adversely affect the reproducibility of the process, and that the specifications of the final substance/intermediates remain the same.

AN5 成品或中间体批量变动，但不超过原批量10倍（以前的N5）

条件

- 生产方法所有变动只与批量放大有关，如：使用不同大小的设备

- 至少有符合已批准质量标准的两个成品批号检验结果（新批量）

- 产品不是生物或无菌产品

- 变更不影响生产工艺的重现性

- 成品/中间体质量标准不变

- 原批量不是经过通知批准的

文件要求

- 新生产批号（新批量）

- 原批准批量和新批量

- 批量变动后，新的工艺描述

- 证书持有者申明：-生产方法所有变动只与批量放大有关；变动不影响生产工艺的重现性；成品/中间体质量标准不变

每次看到下面的这两种表示方法时总要想半天：

the currently approved (batch size, specification): 现行的已被批准的(批量，规格) ------也就是变更前已经过正式批准的批量、规格

the proposed (batch size, specification): 被提议的(批量，规格）------也就是想要变更尚未批准的新批量、新规格

AN6) Change in batch size of final substance or intermediate: downscaling (former N6)

Conditions:

- any changes to the manufacturing methods are only those necessitated by the downscaling, e.g. use of different-sized equipment

- test results of at least two batches of the final substance complying with the approved specifications should be available for the proposed batch size

- the substance is not a biological substance or a sterile substance

- the change does not affect the reproducibility of the manufacturing process

- the change should not be the result of unexpected events arising during manufacture or because of stability concerns

- the currently approved batch size was not approved via a notification.

Specific Documentation:

- the batch numbers of the tested batches having the proposed batch size

- approved and proposed batch size

- updat-ed description of the full process specifying the proposed batch size

- a declaration from the certificate holder that the changes to the manufacturing methods are only those necessitated by downscaling, that the change does not adversely affect the reproducibility of the process, that it is not the result of unexpected events arising during manufacture or because of stability concerns and that the specifications of the final substance/intermediates remain the same.

AN6 成品或中间体批量变更：变小（以前的N5）

条件:

- 生产方法所有变动只与批量变小有关，如：使用不同大小的设备

- 至少有符合已批准质量标准的两个成品批号检验结果（新批量）

- 产品不是生物或无菌产品

- 变更不影响生产工艺的重现性

- 该变动原因不是生产过程的异常或由于稳定性有关的问题引起的

- 原批量不是经过通知批准的

文件要求

- 新生产批号（新批量）

- 原批准批量和新批量

- 批量变动后，新工艺的完整描述

- 证书持有者申明：-生产方法所有变动只与批量变小有关；变动不影响生产工艺的重现性，不是生产过程的异常或由于稳定性有关的问题引起的；成品/中间体质量标准不变

AN7) Addition of a new in-process test and limit applied during the manufacture of the final substance

Conditions:

- the change does not result from unexpected events arising during manufacture

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

- the new test method is not a biological method or a method using a biological reagent for a biological substance (does not include standard pharmacopoeial microbiological methods).



Specific Documentation:

- comparative table of approved and proposed in-process tests

- details of any new non-pharmacopoeial analytical method and validation data, where relevant.

AN7) 成品制造增加新的中控检测和限度

条件

-该变动原因不是生产过程的异常引起的

- 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

- 新的检测方法不是生物方法或生物产品使用生物试剂的方法（不包括药典中标准的微生物方法）

文件要求：

- 新旧中控检测对比表

- 若有，任何新的非药典分析方法和验证数据详情

AN8) Deletion of a non significant in-process test applied during the manufacture of the final substance

Conditions:

- the change does not result from unexpected events arising during manufacture.

Specific Documentation:

- comparative table of approved and proposed in-process tests

- justification /risk-assessment from the certificate holder as appropriate showing that the parameter is non-significant.

AN8) 删除成品制造中不重要的中控检测和限度

条件

- 该变动原因不是生产过程的异常引起的

文件要求：

- 新旧中控检测对比表

- 证书持有者说明该参数不重要的证明/风险评估

AN9) Tightening of the limits of in-process tests applied during the manufacture of the final substance

Conditions:

- the change does not result from unexpected events arising during manufacture

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

Specific Documentation:

- comparative table of approved and proposed in-process tests.

AN9) 提高成品制造中中控检测限度



条件

-该变动原因不是生产过程的异常引起的

-检测程序不变，或检测程序变化较小

文件要求：

-新旧中控检测对比表

AN10) Addition of a specification parameter for a starting material/intermediate/reagent

Conditions:

- the change does not result from unexpected events arising during manufacture

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

- the test method is not a biological method or a method using a biological reagent for a biological substance (does not include standard pharmacopoeia microbiological methods).

Specific Documentation:

- comparative table of approved and proposed specifications

- details of any new analytical method and validation data, where relevant.

AN10)增加起始物料/中间体/试剂质量标准的参数

条件

- 该变动原因不是生产过程的异常引起的

- 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

- 检测方法不是生物方法或生物产品使用生物试剂的方法（不包括药典中标准的微生物方法）

文件要求：

- 新旧中控检测对比表

- 若有，任何新的分析方法和验证数据详情

AN11) Deletion of a non-significant specification parameter for the final substance/starting material/intermediate or deletion of a test procedure for a starting material/intermediate/ reagent

Condition:

- the change does not result from unex-pected events arising during manufacture

- the parameter is non-significant or an al-ternative test procedure is already approved.

Specific Documentation:

- comparative table of approved and proposed specifications

- justification/ risk-assessment from the holder of the certificate as appropriate showing that the parameter is non-significant.

AN11) 删除成品/起始物料/中间体一个不重要的质量标准参数，或删除起始物料/中间体/试剂检测程序

条件：

-该变动原因不是生产过程的异常引起的

- 该参数不重要或一个可替代的检测程序已被批准

文件要求：

-新旧质量规格对比表

-证书持有者说明该参数不重要的证明/风险评估

AN12) Minor changes to a test procedure for a starting material/intermediate/reagent used in the manufacturing process of the final substance (former N7)

Conditions:

- the method of analysis should remain the same (e.g. a change in column length or temperature, but not a different type of column or method)

- appropriate (re-)validation studies have been performed in accordance with relevant guidelines and show that the new updat-ed test procedure is at least equivalent to the former one

- the final substance is not a biological substance.

Specific Documentation:

- updat-ed method description.

AN12) 产品生产过程中所用到的起始物料/中间体/试剂分析方法的微小变更（以前的N7）

条件:

- 分析方法本身不变(如：柱长或柱温改变，但柱子类别或方法不变);

- 已按有关指南要求进行适当的（再）验证，证明新检验方法至少等同于原方法

- 成品不是生物产品

文件要求

- 更新后的方法描述