是什么意思Q3A(R2)-新原料药中的杂质(中英文)-finial

2021年1月28日发(作者：amex)

Impurities In New Drug Substances

新原料药中的杂质

INTERNATIONAL

CONFERENCE

ON

HARMONISATION

OF

TECHNICAL

REQUIREMENTS

FOR

REGISTRATION OF PHARMACEUTICALS FOR HUMAN USE

ICH

H

ARMONISED

T

RIPARTITE

G

UIDELINE

I

MPURITIES

I

N

N

EW

D

RUG

S

UBSTANCES

Q3A(R2)

Current

Step 4

version

dated 25 October 2006

This Guideline has been developed by the appropriate ICH Expert Working Group and has been

subject to consultation by the regulatory parties, in accordance with the ICH Process. At Step 4

of

the

Process

the

final

draft

is

recommended

for

adoption

to

the

regulatory

bodies

of

the

European Union, Japan and USA.

Page 1 of 24

Impurities In New Drug Substances

新原料药中的杂质

Q3A(R2)

Document History

First

Codification

New

Codification

November

2005

History

Date

Q3

Approval by the Steering Committee under

Step 2

and release for

public consultation.

Approval

by

the

Steering

Committee

under

Step

4

and

recommendation for adoption to the three ICH regulatory bodies.

Q3 was renamed Q3A.

15

March

1994

30

March

1995

7

October

1999

6 February

2002

Q3A

Q3A

Q3A

Q3A(R)

Approval

by

the

Steering

Committee

of

the

first

Revision

under

Step 2

and release for public consultation.

Approval

by

the

Steering

Committee

of

the

first

Revision

under

Step

4

and

recommendation

for

adoption

to

the

three

ICH

regulatory bodies.

Q3A(R1)

Q3A(R)

Q3A(R1)

Current

Step 4

version

Q3A(R2)

Approval

by

the

Steering

Committee

of

the

revision

of

the

Attachment

2

directly

under

Step

4

without

further

public

consultation.

25

October

2006

Q3A(R2)

Page 2 of 24

Impurities In New Drug Substances

新原料药中的杂质

I

MPURITIES

I

N

N

EW

D

RUG

S

UBSTANCES

ICH Harmonised Tripartite Guideline

Having reached

Step 4

of the ICH Process at the ICH Steering Committee meeting

on 7 February 2002, this guideline is recommended for

adoption to the three regulatory parties to ICH.

Attachment 2 has been revised on 25 October 2006.

TABLE

OF

CONTENTS

1.

PREAMBLE .............................. .................................................. ................................................

4

2.

CLASSIFICATION OF IMPURITIES .......... .................................................. ..................................

4

3.

RATIONALE FOR THE REPORTING AND CONTROL

OF IMPURITIES ......................... .................................................. ..............................................

6

3.1

Organic Impurities

.

< br>............................................... .................................................. ..........

6

3.2

Inorganic Impurities ....................................... .................................................. ................

7

3.3

Solvents .... .................................................. .................................................. ....................

7

4.

ANALYTICAL PROCEDURES ....................................... .................................................. ..............

8

5.

REPORTING IMPURITY CONTENT OF BATCHES

.

................................................. ......................

9

6.

LISTING OF IMPURITIES IN SPECIFICATIONS ..................... .................................................. ...

1

1

7.

QUALIFICATION OF IMPURITIES

.

............. .................................................. .............................

1

3

8.

GLOSSARY

< p>
.

................................ .................................................. ............................................

1

5

ATTACHMENT 1

.

... .................................................. .................................................. ......................

1

8

ATTACHMENT 2

.

... .................................................. .................................................. ......................

1

9

ATTACHMENT 3

.

... .................................................. .................................................. ......................

2

2

Page 3 of 24

Impurities In New Drug Substances

新原料药中的杂质

I

MPURITIES

I

N

N

EW

D

RUG

S

UBSTANCES

新原料药中的杂质

1.

PREAMBLE

序言

This document is intended to provide guidance for registration applications on the content and

qualification

of

impurities

in

new

drug

substances

produced

by

chemical

syntheses

and

not

previously

registered

in

a

region

or

member

state.

It

is

not

intended

to

apply

to

new

drug

substances used during the clinical research stage of development. The following types of drug

substances

are

not

covered

in

this

guideline:

biological/biotechnological,

peptide,

oligonucleotide,

radiopharmaceutical,

fermentation

product

and

semi-synthetic

products

derived therefrom, herbal products, and crude products of animal or plant origin.

本文件旨在为那些尚未在任何地区或成员国注册的化 学合成的新原料药在注册时，对其

杂质的含量和界定的申报提供指导。本报导原则不适用 于临床研究期间所用的新原料

药，不涵盖生物及生物技术产品、肽、寡聚核苷酸、放射性 药物、发酵和半合成产品、

草药以及来源于动植物的粗制品。

Impurities in new drug substances are addressed from two perspectives:

新原料药中的杂质分两个方面阐述：

Chemistry

Aspects

include

classification

and

identification

of

impurities,

report

generation,

listing

of

impurities

in

specifications,

and

a

brief

discussion

of

analytical

procedures; and < /p>

化学方面：包括对杂质的分类和鉴定、报告生成、规范中杂质的检查项目以及对分

析方法的简要讨论。

Safety

Aspects

include

specific

guidance

for

qualifying

those

impurities

that

were

not

present, or were present at substantially lower levels, in batches of a new drug substance

used in safety and clinical studies.

安全性方面：对用于 安全性研究和临床研究的新原料药批次中不存在或含量很低的

那些杂质的界定的指南。< /p>

2.

CLASSIFICATION OF IMPURITIES

杂质的分类

Impurities can be classified into the following categories:

杂质可分为下列类型

:

?

?

?

Organic impurities (process- and drug-related)

有机杂质（与工艺和药物有关的）

Inorganic impurities

无机杂质

Residual solvents

残留溶剂

Page 4 of 24

Impurities In New Drug Substances

新原料药中的杂质

Organic impurities can arise during the manufacturing process and/or storage of the new drug

substance. They can be identified or unidentified, volatile or non-volatile, and include:

有机杂质可能会在新原料药 的生产过程和（或）储存期间有所增加。这些杂质可能是已鉴定的或

者是未鉴定的、挥发 性的或者非挥发性的。它包括：

?

?

?

Starting materials

起始物

By-products

副产物

Intermediates

中间体

?

Degradation products

降解产物

?

Reagents, ligands and catalysts

试剂、配位体、催化剂

Inorganic impurities can result from the manufacturing process. They are normally known and

identified and include:

无机杂质可能来源于生产过程，它们一般是已知的和已鉴定的。包括：

?

?

?

?

Reagents, ligands and catalysts

试剂、配位体、催化剂

Heavy metals or other residual metals

重金属或其他残留金属

Inorganic salts

无机盐

Other materials (e.g., filter aids, charcoal)

其他物质（例如：过滤介质、活性炭等）

Solvents

are

inorganic

or

organic

liquids

used

as

vehicles

for

the

preparation

of

solutions

or

suspensions

in

the

synthesis

of

a

new

drug

substance.

Since

these

are

generally

of

known

toxicity, the selection of appropriate controls is easily accomplished (see ICH Guideline Q3C on

Residual Solvents).

溶剂是在新原料药 合成过程中用于制备溶液或混悬液的有机或无机液体，由于它们一般

具有已知毒性，故容 易选择控制方法（见

ICH

指导原则

Q 3C

残留溶剂项下）。

Excluded from this document are: (1) extraneous contaminants that should not occur in new

drug substances and are more appropriately addressed as Good Manufacturing Practice (GMP)

issues, (2) polymorphic forms, and (3) enantiomeric impurities.

不包括在本文件中的杂质为：（

1

）外源性污染物（不应该存 在于新原料药中，可以用

GMP

来控制）；（

< br>2

）多晶型；（

3

）对映体杂质 。

Page 5 of 24

Impurities In New Drug Substances

新原料药中的杂质

3.

RATIONALE FOR THE REPORTING AND CONTROL OF IMPURITIES

杂质报告和控制的说明

3.1

Organic Impurities

有机杂质

The applicant should summarise the actual and potential impurities most likely to arise during

the

synthesis,

purification,

and

storage

of

the

new

drug

substance.

This

summary

should

be

based

on

sound

scientific

appraisal

of

the

chemical

reactions

involved

in

the

synthesis,

impurities

associated

with

raw materials

that

could

contribute

to

the

impurity

profile

of

the

new drug substance, and possible degradation products. This discussion can be limited to those

impurities that might reasonably be expected based on knowledge of the chemical reactions

and conditions involved.

申报者应对新原料药在合成、精制和储存过程中最可能产生的那些实际存在的和潜在的

< p>
杂质进行综述。该描述应建立在对合成所涉及的化学反应、由原材料引入的杂质及可能

的降解产物进行合理地、科学地评估的基础上。可以局限于根据化学反应以及相关条件

下可能会产生的杂质进行讨论。

In

addition,

the

applicant

should

summarise

the

laboratory

studies

conducted

to

detect

impurities

in

the

new

drug

substance.

This

summary

should

include

test

results

of

batches

manufactured

during

the

development

process

and

batches

from

the

proposed

commercial

process,

as

well

as

the

results

of

stress

testing

(see

ICH

Guideline

Q1A

on

Stability)

used

to

identify potential impurities arising during storage. The impurity profile of the drug substance

batches intended for marketing should be compared with those used in development, and any

differences discussed.

此外，申报 者还应对新原料药中杂质检测的实验室研究工作进行综述，其内容包括对研

制期间和模拟 上市的所有批次产品的试验结果、以及为鉴定在储存期间可能产生的潜在

杂质而进行强力 破坏试验的结果（见

ICH

指导原则

Q 1A

稳定性项下）。同时应对那些模

拟上市的原料批次中的杂质 概况和用于研制开发过程的原料批次中的杂质概况进行比

较，任何不同之处均应加以讨论 。

The

studies

conducted

to

characterise

the

structure

of

actual

impurities

present

in

the

new

drug substance at a level greater than (>) the identification threshold given in Attachment

1

(e.g., calculated

using

the

response

factor

of

the

drug

substance)

should

be

described.

Note

that

any

impurity

at

a

level

greater

than

(>)

the

identification

threshold

in

any

batch

manufactured

by

the

proposed

commercial

process

should

be

identified.

In

addition,

any

degradation product observed in stability studies at recommended storage conditions at a level

greater

than

(>)

the

identification

threshold

should

be

identified.

When

identification

of

an

impurity is not feasible, a summary of the laboratory studies demonstrating the unsuccessful

effort

should

be

included

in

the

application.

Where

attempts

have

been

made

to

identify

Page 6 of 24

Impurities In New Drug Substances

新原料药中的杂质

impurities present at levels of not more than (

?

) the identification thresholds, it is useful also

to report the results of these studies.

申报资料中还应对那些在新原料药中实际存在的、含量大于（＞）附录

< br>1

中鉴定阈值的

杂质（例如：以原料药的响应因子计算） 的结构特征进行描述。应该注意，在模拟上市

生产的批次中，所有出现的大于（＞）鉴定 阈值的杂质应予鉴定；也应同样鉴定在推荐

的放置条件下的稳定性研究中发现大于（＞） 鉴定阈值的降解产物；当某个杂质无法鉴

定时，申报资料中应包括对该杂质所进行的不成 功的试验研究的概述。如果已尝试过鉴

定含量不大于（

≤

）鉴定阈值的杂质，那么把这些研究结果也报告进去是很有用的。

Identification of impurities present at an apparent level of not more than (

?

) the identification

threshold

is

generally

not

considered

necessary.

However,

analytical

procedures

should

be

developed for those potential impurities that are expected to be unusually potent, producing

toxic or pharmacological effects at a level not

more

than

(

?

)

the

identification

threshold.

All

impurities should be qualified as described later in this guideline.

通常没 有必要对含量在阈值以下（

≤

）的杂质进行鉴定。然而，对那些 含量不大于（

≤

）

阈值但可能产生不寻 常功效或毒性药理作用的潜在杂质，仍应建立分析方法。所有杂质

均应按照本指导原则后 续章节中的要求来界定。

3.2

Inorganic Impurities

无机杂质

Inorganic

impurities

are

normally

detected

and

quantified

using

pharmacopoeial

or

other

appropriate procedures. Carry-over of catalysts to the new drug substance should be evaluated

during

development.

The

need

for

inclusion

or

exclusion

of

inorganic

impurities

in

the

new

drug

substance

specification

should

be

discussed.

Acceptance

criteria

should

be

based

on

pharmacopoeial standards or known safety data.

无机杂质通常按药典或其他适当的方 法来检测和定量。在新药的研制过程中应对遗留在

新原料药中的催化剂进行评估。在新原 料药规范中是否收载无机杂质检查项目，应进行

讨论。认可标准应根据药典标准或已知的 安全性数据来制定。

3.3

Solvents

溶剂

The

control

of

residues

of

the

solvents

used

in

the

manufacturing

process

for

the

new

drug

substance should be discussed and presented according to the ICH Q3C Guideline for Residual

Solvents.

应按

ICH

Q3C“

残留溶剂

”

指导原则的要求，对新原料药生产过程中所 用的溶剂的残留量的

控制进行讨论和申报。

Page 7 of 24

Impurities In New Drug Substances

新原料药中的杂质

4.

ANALYTICAL PROCEDURES

分析方法

The

registration

application

should

include

documented

evidence

that

the

analytical

procedures are validated and suitable for the detection and quantification of impurities

(see

ICH Q2A and Q2B Guidelines for Analytical Validation). Technical factors (e.g., manufacturing

capability and control methodology) can be considered as part of the justification for selection

of

alternative

thresholds

based

on

manufacturing

experience

with

the

proposed

commercial

process. The use of two decimal places for thresholds (See Attachment 1) does not necessarily

reflect the precision of the analytical procedure used for routine quality control purposes. Thus,

the

use

of

lower

precision

techniques

(e.g.,

thin-layer

chromatography)

can

be

acceptable

where

justified

and

appropriately

validated.

Differences

in

the

analytical

procedures

used

during development

and

those

proposed

for

the

commercial

product

should

be

discussed

in

the registration application.

注册申请中应提供书面文件 ，证明分析方法是经过论证并适用于杂质的检测和定量（见

ICH Q2A

及

Q2B

分析方法论证指导原则项下），技术因素（ 如生产能力与质控方法）可用

于说明为什么在拟上市产品中采用其他的阈值。阈值采用两 位小数（见附录

1

）并不代表

常规质量 控制中分析方法的精度。因此，只需经过验证和论证，可以使用较低精度的技

术（如薄层 色谱法）。如果研发中所采用的分析方法和准备上市产品的分析方法不同，

在申报资料中 应予以讨论。

The quantitation limit for the analytical procedure should be not more than (

?

) the reporting

threshold.

分析 方法的定量限度应不大于（

≤

）报告阈值。

Organic

impurity

leve

ls

can

be

measured

by

a

variety

of

techniques,

including

those

that

compare an analytical response for an impurity to that of an appropriate reference standard or

to the response of the new drug substance itself. Reference standards used in the analytical

procedures for control of impurities should be evaluated and characterised according to their

intended

uses.

The

drug

substance

can

be

used

as

a

standard

to

estimate

the

levels

of

impurities.

In

cases

where

the

response

factors

of

the

drug

substance

and

the

relevant

impurity

are

not

close,

this

practice

can

still

be

appropriate,

provided

a

correction

factor

is

applied or the impurities are, in fact, being overestimated. Acceptance criteria and analytical

procedures

used

to

estimate

identified

or

unidentified

impurities

can

be

based

on

analytical

assumptions

(e.g.,

equivalent

detector

response).

These

assumptions

should

be

discussed

in

the registration application.

可用各种技术测定有机杂质的含量，这些技术包括把杂质的响应值与适当的参比标准品

的响应值比较或与药物本身的响应值比较。应根据使用目的，对分析过程中用于控制杂

质的参比标准品进行定性和定量。可用原料药作为标准物质来估计杂质的量，如果原料

药 和杂质的响应因子不接近，只要应用了校正因子或测得的杂质量高于实际的杂质量，

Pa ge 8 of 24

Impurities In New Drug Substances

新原料药中的杂质

该方法仍是可行的。用于评估已鉴定或未鉴定杂质的认可标准和分析方法可基于分析的

假设（例如：相同的检测响应等）。为此，这些假设也应在注册申请中加以讨论。

5. REPORTING IMPURITY CONTENT OF BATCHES

各批次产品杂质含量的报告

Analytical

results

should

be

provided

in

the

application

for

all

batches

of

the

new

drug

substance used for clinical, safety, and stability testing, as well as for batches representative of

the proposed commercial process. Quantitative results should be presented numerically, and

not in general terms such as “complies”, “meets limit” etc. Any impurity at a level greater than

(>) the reporting threshold (see Attachment 1) and total impurities observed in these batches

of the new drug substance should be reported with the analytical procedures indicated. Below

1.0%, the results should be reported to two decimal places (e.g., 0.06%, 0.13%); at and above

1.0%,

the

results

should

be

reported

to

one

decimal

place

(e.g.,

1.3%).

Results

should

be

rounded using conventional rules (see Attachment 2). A tabulation (e.g., spreadsheet) of the

data is recommended. Impurities should be designated by code number or by an appropriate

descriptor, e.g., retention time. If a higher reporting threshold is proposed, it should be fully

justified. All impurities at a level greater than (>) the reporting threshold should be summed

and reported as total impurities.

注册申请应提供用于临床、安全性研究、稳定性试验的所有新原料药批次产品的分析结

< p>
果以及用于准备上市产品的分析结果。定量测定结果应数字化，不应用

“< /p>

符合规定

”

，

“

符

合限度

”

等 一般性术语。在新原料药的所有批次中，应报告检测到的大于（＞）报告阈值

（见附录< /p>

1

）的任何杂质和总杂质，并附所用的分析方法。若低于

1.0%

，结果应报告至

小数点后两位（如

0.06%

，

0.13%

< br>），若大于或等于

1.0%

，结果报告至小数点后

1

位（如

1.3%

） 。结果应按传统规则修约（见附录

2

）。建议使用数据表格（如 电子数据表），各

杂质均应以编号或合适的描述表示（如保留时间）。如果采用较高的报 告阈值，应进行

充分论证。所有大于（＞）报告阈值的杂质应进行累加，报告为

“

总杂质

”

。

When analytical procedures change during development, reported results should be linked to

the

procedure

used,

with

appropriate

validation

information

provided.

Representative

chromatograms should be provided. Chromatograms of representative batches from analytical

validation studies showing separation and detectability of impurities (e.g., on spiked samples),

along

with

any

other

impurity

tests

routinely

performed,

can

serve

as

the

representative

impurity

profiles.

The

applicant

should

ensure

that

complete

impurity

profiles

(e.g.,

chromatograms) of individual batches are available, if requested. < /p>

若在研制期间，分析方法发生了变化，报告测试结果应附上所用的分析方法。并提供相

应的方法学论证资料。应提供有代表性的色谱图。方法学论证中，显示杂质分离度和检

测灵敏度的、具有代表性批次（例如：加样试验）的色谱图和常规杂质检测得到的色谱

Page 9 of 24

Impurities In New Drug Substances

新原料药中的杂质

图，可以反映出有代表性的杂质概况。申报者应保证：如需要，可提供各个批次产品的

< p>
完整的杂质概况（例如；色谱图）。

Page 10 of 24

Impurities In New Drug Substances

新原料药中的杂质

A tabulation should be provided that links the specific new drug substance batch to each safety

study and each clinical study in which the new drug substance has been used.

另外，申报者还应提供应用在每 个安全性研究和临床研究中的新原料药的每个批次一一

对应的名单。

For each batch of the new drug substance, the report should include:

对每批新原料药、报告内容应包括：

?

Batch identity and size

批号与批量

?

?

?

?

?

?

6.

Date of manufacture

生产日期

Site of manufacture

生产地点

Manufacturing process

生产工艺

Impurity content, individual and total

单个杂质含量和总杂质含量

Use of batches

批次的用途

Reference to analytical procedure used

所采用分析方法的阐释

LISTING OF IMPURITIES IN SPECIFICATIONS

规范中所列的杂质检查项目

The specification for a new drug substance should include a list of impurities. Stability studies,

chemical

development

studies,

and

routine

batch

analyses

can

be

used

to

predict

those

impurities

likely

to

occur

in

the

commercial

product.

The

selection

of

impurities

in

the

new

drug substance specification should be based on the impurities found in batches manufactured

by

the

proposed

commercial

process.

Those

individual

impurities

with

specific

acceptance

criteria included in the specification for the new drug substance are referred to as

impurities

在新原料药的规范中应包括杂质检查项目。稳定性 研究、化学方面的开发研究以及日常

批次分析检验的结果有助于预测在市售产品中可能出 现的杂质。在新原料药规范中收载

的杂质应根据在拟上市生产的批次中所发现的杂质来选 择。在本指导原则中。列入新原

料药规范中、具有特定的认可标准的各个杂质称为特定杂 质。特定杂质可以是已鉴定

的，也可以是未鉴定的。

A rationale for the inclusion or exclusion of impurities in the specification should be presented.

This rationale should include a discussion of the impurity profiles observed in the safety and

clinical development batches, together with a consideration of the impurity profile of batches

manufactured by the proposed commercial process. Specified identified impurities should be

included along with specified unidentified impurities estimated to be present at a level greater

than

(>)

the

identification

threshold

given

in

Attachment

1.

For

impurities

known

to

be

unusually

potent

or

to

produce

toxic

or

unexpected

pharmacological

effects,

the

quantitation/detection

limit

of

the

analytical

procedures

should

be

commensurate

with

the

Page 11 of 24

Impurities In New Drug Substances

新原料药中的杂质

level at which the impurities should be controlled. For unidentified impurities, the procedure

used and assumptions made in establishing the level of the impurity should be clearly stated.

Specified, unidentified impurities should be referred to by an appropriate qualitative analytical

descriptive label (e.g., “unidentified A

acceptance criterion of not more than (

?

) the identification threshold (Attachment 1) for any

unspecified impurity and an acceptance criterion for total impurities should be included.

应对用于安全性和临床研究中的批次中所发现杂质情况，以及对拟上市生产的原料中杂< /p>

质概况综合进行考虑后，再对规范中列入或不列入哪些杂质的理由进行说明。特定的已

鉴定杂质应与特定的其含量估计大于（＞）鉴定阈值（附录

1

）的未鉴定杂质一起考虑。

对于那些具有特殊功效或产生毒性或为预料 到的药理作用的杂质，其分析方法的定量限

或检测限度必须与该杂质应被控制的量相当。 对于未鉴定的杂质，所使用的检测方法和

确定杂质量时所采用的假设应予明确说明。特定 的未鉴定的杂质应采用适当的方法描述

标记（例如：

“

未鉴定杂质

A”“

相对保留时间为

0.9

的杂质

”

）。对于任 何一个非特定杂质

应有一个不大于（

≤

）鉴定阈值（附录

1

）的认可标准，对总杂质也应建立一个认可 标

准。

Acceptance criteria should be set no higher than the level that can be justified by safety data,

and

should

be

consistent

with

the

level

achievable

by

the

manufacturing

process

and

the

analytical capability. Where there is no safety concern, impurity acceptance criteria should be

based on data generated on batches of the new drug substance manufactured by the proposed

commercial

process,

allowing

sufficient

latitude

to

deal

with

normal

manufacturing

and

analytical

variation

and

the

stability

characteristics

of

the

new

drug

substance.

Although

normal manufacturing variations are expected, significant variation in batch-to-batch impurity

levels can indicate that the manufacturing process of the new drug substance is not adequately

controlled

and

validated

(see

ICH

Q6A

Guideline

on

Specifications,

Decision

Tree

#1,

for

establishing an acceptance criterion for a specified impurity in a new drug substance). The use

of

two

decimal

places

for

thresholds

(See

Attachment

1)

does

not

necessarily

indicate

the

precision of the acceptance criteria for specified impurities and total impurities.

建立认可标准不能高于经安全资料界定合理的水 平，并且必须与生产工艺和分析能力所

能达到的水平一致。如果没有安全性方面的问题， 杂质认可标准应根据拟上市生产的新

原料药批次测定的数据来建立，并应为常规生产和分 析上的正常变异及药物的稳定性特

性留有足够的余地。尽管常规生产中的变化是可以预料 的，然而批与批之间杂质水平的

显著变化可能预示着新原料药的生产工艺尚未得到充分的 控制和论证（见

ICH

Q6A

“< /p>

规范

”

指南判断流程图

< br>1

，建立新原料药中的特殊杂质的认可标准）。阈值的两位小数（见附录

1

）并不代表特定杂质和总杂质认可标准的精度。

In

summary,

the

new

drug

substance

specification

should

include,

where

applicable,

the

following list of impurities:

Page 12 of 24