APIC 原料药亚硝胺风险评估报告模板-2020年2月(中英文对照版)

REPORT ON THE RISK OF POTENTIAL PRESENCE

OF NITROSAMINE IMPURITIES

关于潜在存在亚硝胺杂质

的风险报告

Document ID:

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MATERIAL

物料

Name: ………………………………………………………………………………………………………………………………

名称

Material code(s) :……………………………………………………………………………………………………………………

材料代码

MANUFACTURER (refers to the manufacturing site)

制造商(指生产工厂)

Name:…………………………………………………………………………………………………………………………………

名称

Address:………………………………………………………………………………………………………………………………

地址

This report was completed by [person / central service]:

这份报告由

[

个人

/

中心事务

]

完成

:

▪ Name and position: …………………………………………………………………………………………………………………………………………….……………………

姓名和职位

▪ E-mail address: ………………………………………………………………………………………………………………………………………………………………………….

电邮地址

▪ Postal address: …………………………………………………………………………………………………………………………………………………………………………

邮寄地址

Declaration:

声明

:

The current manufacturing process of (the name of the substance) was assessed with respect to the risk of the presence of

Nitrosamine impurities.

(该物质的名称)当前生产工艺存在的亚硝胺杂质的风险评估已完成。

The signatory expressly recognizes that all information contained in this report is based on current knowledge and is true and

sincere to his / her actual knowledge considering available supplier information and likely chemical production processes where

information from the supplier is not available. The signatory further confirms that he / she has the authority to act on behalf of

the company they represent.

签字人明确承认，本报告所载的所有信息均以当前的知识为基础，其实际知识是真实和真诚的，考虑了供应商提供的

现有信息，以及在供应商未能提供信息的情况下可能的化学品生产过程。签字人进一步确认，他/她有权代表其所代表

的公司行事。

The information in this document may be updated as more information becomes available.

随着更多信息的出现，本文档中的信息可能会被更新。

Date, Signature and Company stamp

日期、签名及公司盖章

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Delete this page when issuing the letter.

发信时删除此页。

Instructions when using this template.

使用此模板时的说明。

1. Replace APIC logo by your company logo.

将APIC的logo替换为贵公司的logo。

2. In the footer, replace CEFIC logo by “This document was prepared based on

APIC template”.

在页脚，使用“此文件基于APIC模板编写”代替CEFIC logo。

3. In various places in the template, text appears in italics in square brackets, e.g. [Option

1, Option 2, Option3]. Keep the text that applies and remove the text that don’t apply to

the situation which is being described.

在模板的不同位置，有文字以斜体字出现在方括号内，例如[

选项

1

，选项

2

，选项

3]。保留适用的文本，删除不适用于所描述情况的文本。

4. In section 3, the detail would depend on the customer with whom the report will be

shared. The process description can be replaced by a workflow with the relevant

information for the assessment or just to reference the filing applicable section.

在第3节中，细节将取决于与之共享报告的客户。工艺描述可以用包含评估相关

信息的工作流程图取代，或者只是参考适用的归档章节。

5. In section 3, a description of the process step where the risk assessment was initiated,

e.g. from starting material or from intermediate, should be provided with a rationale

for the selection.

在第3节中，应说明启动风险评估的工艺步骤，例如从起始材料或中间材料开始，

并说明选择的理由。

6. For table in section 6, fill one line per nitrosamine which has been identified as

being possibly generated during the API manufacturing process.

对于第6节的表格，每一个已被确定为在API生产过程中可能产生的亚硝胺填

写一行。

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1 INTRODUCTION

引言

This document reports the outcome of the Risk Assessment on the above mentioned API based

on the requirements defined in the EMA notices Information on nitrosamines for marketing

authorisation holders EMA/189634/2019 and Questions and answers on ”Information on

nitrosamines for marketing authorisation holders” EMA/428592/2019 and following revisions

and other similar published by other Health Agencies.

本文件报告上述API的风险评估结果，评估依据的是EMA/189634/2019《提供上市许

可持有人使用的亚硝胺信息》和EMA/428592/2019《有关“提供上市许可持有人使用的

亚硝胺信息”的问答》及其后续版本，以及其他卫生机构公布的类似资料。

Such evaluation on the potential risk of presence of nitrosamine impurities in the APIs was

performed using quality risk management principles, as per ICH Q9 guideline and ICH M7.

Manufacturing processes are being reviewed to identify and, if found, to mitigate risk of

presence of N-nitrosamine impurities during manufacture and storage of the drug substance.

对API中存在亚硝胺杂质的潜在风险的评估是根据ICH Q9指南和ICH M7中的质量风

险管理原则进行的。通过审查生产工艺，以确定并，如有，降低在API的生产和储存过

程中出现N-亚硝胺杂质的风险。

2

SCOPE

范围

The Risk Assessment has evaluated the following items as potential sources of nitrosamines or

their precursors in line with root causes described in Questions and answers on Information on

nitrosamines for marketing authorisation holders EMA/428592/2019:

风险评估根据EMA/428592/2019《有关“提供上市许可持有人使用的亚硝胺信息”的问

答》中所述的根本原因，评估了下列物品作为亚硝胺或其前体的潜在来源:

1. Use of sodium nitrite or other nitrosating agents in presence of secondary, or tertiary

amines, or quaternary ammonium salts within the API manufacturing process either

within the same or at different process steps.

在API制造过程中，存在仲胺、叔胺或季铵盐的相同或不同的工序中使用亚硝酸钠

或其他硝化剂。

2. Use of sodium nitrite or other nitrosating agents in combination with reagents, solvents,

and catalysts, which are susceptible to degradation to secondary or tertiary amines,

within the same or different process steps.

在相同或不同的加工步骤中，将亚硝酸钠或其他硝化剂与易于降解为仲胺或叔胺的

试剂、溶剂和催化剂结合使用。

3. Use of contaminated raw materials (e.g. solvents, reagents, catalysts)

使用受污染的原料(例如溶剂、试剂、催化剂)

4. Use of recovered materials (e.g. solvents, reagents, catalysts)

使用回收物料(例如溶剂、试剂、催化剂)

5. Use of contaminated starting materials and intermediates supplied by vendors.

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使用由供应商提供的受污染起始材料和中间体。

6. Potential contamination due to risk for cross-contamination or carry over in

multipurpose plants

由于交叉污染风险或在共线工厂结转而造成的潜在污染

7. Degradation processes of starting materials, intermediates, or drug substances.

起始物料、中间体或药物成分的降解过程。

8. Primary packaging materials.

内包装材料。

3 MANUFACTURING / PROCESS STEPS COVERED BY RISK ASSESSEMENT

风险评估涵盖的3个制造/加工步骤

The Manufacturing Process described below may not contain some process details due to

Intellectual Property Protection as per Company Policy.

根据公司政策，由于知识产权保护，下面描述的制造过程可能不包含某些工艺细节。

4 RISK ASSESSMENT METHODOLOGY

4风险评估方法

The Risk Assessment methodology used has been [FMEA / Questionnaire / other]. The risk

assessment for potential presence of nitrosamines has been conducted taking into account the

following dimensions [severity, probability, detectability].

所采用的风险评估方法是[FMEA/

调查问卷

/

其他

]。在进行亚硝胺潜在存在的风险评估时，

已考虑到以下因素[

严重性、可能性、可检测性

]。

5 SUMMARY OF ITEMS REVIEWED FOR THE RISK ASSESSMENT

5.此风险评估审查的项目摘要

For each of the following items, indicate whether a risk for potential presence of nitrosamines has been

identified or not. As applicable, comment on the response provided whether the response is yes or no.

对于下列每一项，请说明是否已查明存在亚硝胺的潜在风险。适用时，对提供的回答作出说明，

不管回复是“是”还是“否”。

5.1 Use of sodium nitrite or other nitrosating agents in presence of secondary, or

tertiary

amines,

or quaternary ammonium salts within

the API manufacturing process either

within the same

or at different process steps.

在API的生产过程中，在存在仲胺、叔胺或季铵盐的相同或不同的工序，使用亚硝酸钠

或其他硝化剂。

Risk for presence of nitrosamines identified: YES ☐

识别出存在亚硝胺的风险:

NO ☐

Comment:

说明:

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5.2 Use of sodium nitrite or other nitrosating agents in combination with reagents, solvents, and

catalysts, which are susceptible to degradation to secondary or tertiary amines, within the

same or different process steps.

在相同或不同的工序中，将亚硝酸钠或其他硝化剂与易降解为仲胺或叔胺的试剂、溶剂

和催化剂混合使用。

Risk for presence of nitrosamines identified: YES ☐

识别出存在亚硝胺的风险:

NO ☐

Comment:

说明:

5.3 Use of contaminated raw materials (e.g. solvents, reagents, catalysts)

使用受污染的原材料(例如溶剂、试剂、催化剂)

Risk for presence of nitrosamines identified: YES ☐

识别出存在亚硝胺的风险:

Comment:

说明:

NO ☐

5.4 Use of recovered materials (e.g. solvents, reagents, catalysts)

使用回收物料(例如溶剂、试剂、催化剂)

Risk for presence of nitrosamines identified: YES ☐

识别出存在亚硝胺的风险:

Comment:

NO ☐

N/A ☐

说明:

5.5 Use of contaminated starting materials and intermediates supplied by vendors.

使用供应商提供的受污染的起始材料和中间体。

Risk for presence of nitrosamines identified:

识别出存在亚硝胺的风险:

Comment:

说明:

YES ☐

NO ☐

5.6 Potential contamination due to risk for cross-contamination or carry over in multipurpose

plants

由于交叉污染或结转到共用工厂而可能造成的污染

Risk for presence of nitrosamines identified:

YES ☐ NO ☐

识别出存在亚硝胺的风险:

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Comment:

说明:

5.7 Degradation processes of starting materials, intermediates, or drug substances.

起始物料、中间体或API的降解过程。

Risk for presence of nitrosamines identified:

YES ☐ NO ☐

确定存在亚硝胺的风险:

Comment:

说明:

5.8 Packaging materials

包装材料

Risk for presence of nitrosamines identified:

YES ☐ NO ☐

确定存在亚硝胺的风险:

Comment:

说明:

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6 RISK ASSESSMENT RESULT

6风险评估结果

Based on the risk assessment conducted, the risk for presence of nitrosamines is evaluated as:

根据所进行的风险评估，亚硝胺的风险评估如下:

☐

negligible

可忽略的

☐

potentially present

可能存在的

If the risk for contamination by nitrosamines is potentially present, indicate the possible

nitrosamine impurity, the origin of contamination and proposed mitigation measures:

如果可能存在亚硝胺污染的风险，请说明可能的亚硝胺杂质、污染的来源和计划的缓解

措施:

Possible Nitrosamine

(Name and Structure)

可能的亚硝胺

（名称和结构）

Origin of contamination

(specify nitrosating and

nitrosable agents)

污染的来源

（说明亚硝化过程和亚硝化剂）

Mitigation measures

缓解措施

7 ADDITIONAL INFORMATION TO SUPPORT THE RISK ASSESSMENT BY

THE DRUG PRODUCT MANUFACTURER / MARKETING

AUTHORIZATION HOLDER (MAH)

支持药品制造商/上市许可持有人(MAH)进行风险评估的附加信息

As the drug product manufacturer is responsible to evaluate whether any residual nitrosating or

nitrosable substances from the API may lead to potential formation of nitrosamines in the Drug

Product, the following information is provided.

由于药物制造商有责任评估API残留的硝化或可硝化物质是否会导致药物中亚硝胺的形

成，因此提供以下资料。

Based on the manufacturing process reviewed and on its related risk assessment for potential

presence of nitrosamines, the API manufacturer declares that there is

根据已审核的生产工艺及其对亚硝胺可能存在的相关风险评估，API生产商宣布

7.1

For nitrosating agents:

硝化剂:

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-

☐

Nitrosating agents are not likely to be present in the final API.

硝化剂不太可能出现在最终的API中。

-

☐ A risk for potential

presence of nitrosating agents in the final API (see table below

for details).

硝化剂可能存在于最终API中 (详情见下表)。

Table 1.

Nitrosating agents

表1.硝化剂

Potentially

present in

final API

可能存在于最终

API

Nitrosating agent (NO)*

硝化剂

Nitrite salts

Nitrate salts

Nitrous acid

Nitrous acidium ion

Nitric acid (contains N

2

O

4

)

Alkyl nitrites

Peroxynitrite

Nitrosonium ion

Nitro compounds

Nitrous anhydride

Dinitrogen tetroxide

Nitrosyl halides

Nitrosyl thiocyanate

Nitrosophenol

Nitrosothiol

Aqua regia

Nitryl chloride

Other (specify)

HCl + HNO3

NO

2

Cl

Structure

结构

MNO

2

MNO

3

HNO

2

+

H

2

O-NO

HNO

3

R-ONO

ONOO(-)

NO+

R-NO

2

N

2

O

3

N

2

O

4

Halide-NO

ONSCN

Phenol-NO

SH-NO

7.2

For Nitrosable substances:

7.2亚硝基物质:

-

☐

Nitrosable substances are not likely to be present in the final API.

亚硝基物质不大可能出现在最终的API中。

-

☐ A risk for potential

presence of nitrosable substances in the final API or as integral

part of the API (see table below for details).

硝基物质可能存在于最终API中或作为API的组成部分 (详情见下表)。

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Table 2.

Nitrosable substances

表2.亚硝基物质

Nitrosatable substance

Secondary

amines

(cyclic and acyclic)

Tertiary amines (cyclic

and acyclic)

Structure

R

1

-NH-R

2

byproducts (Potentially)

present in final

API

Hydrazine derivatives

N-methyl-2-

pyrrolidinone

Tertiary amides

N-Chloroalkylamines

N-alkylcarbamates

Other (specify)

NH

2

-NR

1

R

2

R

1

CONR

2

R

3

R

1

R

2

N-Cl

R

1

O-CO-NR

2

R

3

-

NHR

1

R

2

,

NHR

1

R

3,

or/and

NHR

2

R

3

NHR

1

R

2

N-methyl-4-

aminobutyric acid

NHR

2

R

3

NHR

1

R

2

NHR

2

R

3

8 CHANGES IN MANUFACTURING PROCESS WITH POTENTIAL IMPACT

ON NITROSAMINE IMPURITY FORMATION

生产工艺变更对亚硝胺杂质形成的潜在影响

In case of changes in the manufacturing process, starting materials, suppliers etc. that may affect

this risk assessment, we will evaluate the impact, revise this assessment when necessary and

inform our customers of the outcome.

如生产工艺、原料、供应商等方面的变更可能会影响风险评估，我们将评估影响，必要

时修订此评估，并将结果告知客户。

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