ICH M7(step4)基因毒性杂质评估和控制◆中英

列的评估。

对原料药、

中间体或起始物料的生产场所的变更，

或变更原料供应商则不需要对

< br>诱变性杂质风险重新进行评估。

When a new drug substance supplier is proposed, evidence that the drug substance

produced by this supplier using the same route of synthesis as an existing drug

product

marketed

in

the

assessor’s

region

is

considered

to

be

sufficient

evidence

of

acceptable

risk/benefit

regarding

mutagenic

impurities

and

an

assessment

per

this

guideline is not required. If this is not the case, then an assessment per this

guideline is expected.

如果拟提交一 个新的原料药供应商，

如有证据证明该供应商生产的原料药采用了与审评区域

/

利

益是可以接受的，

不需 要根据本指南进行评估。

如果不同这样，

则需要根据本指南进行 评估。

4.2

Post- Approval

Changes

to

the

Drug

Product

Chemistry,

Manufacturing,

and

Controls

上市后变 更

---

制剂研发、生产和控制

Post-approval

submissions

involving

the

drug

product

(e.g.,

change

in

composition,

manufacturing process, dosage form) should include an evaluation of the potential

risk associated with any new mutagenic degradation products or higher acceptance

criteria

for

existing

mutagenic

degradation

products.

If

appropriate,

the

regulatory submission would include an updated control strategy. Reevaluation of

the drug substance associated with drug products is not recommended or expected

provided

there

are

no

changes

to

the

drug

substance.

Changing

the

site

of

manufacture

of drug product will not require a reassessment of mutagenic impurity risk.

上市后申报如果涉及制剂（例 如、成分、生产工艺、剂型），则应包括对所有新的诱变性降

解产物或已有诱变性降解产 物更高的可接受标准进行评估。

适当时，

法规申报资料应包括对

控制策略的更新。

如果原料药并没有发生变更，

则不建议，

也不期望对制剂相关的原料药重

新进行评估 ，制剂生产场所变更不需要对诱变性杂质风险重新进行评估。

4.3 Changes to the Clinical Use of Marketed Products

上市后药品临床使用变更

Changes to the clinical use of marketed products that can warrant a reevaluation

of the mutagenic impurity limits include a significant increase in clinical dose,

an

increase

in

duration

of

use

(in

particular

when

a

mutagenic

impurity

was

controlled

above

the

lifetime

acceptable

intake

for

a

previous

indication

that

may

no

longer

be

appropriate

for

the

longer

treatment

duration

associated

with

the

new

indication), or for a change in indication from a serious or life threatening

condition

where

higher

acceptable

intakes

were

justified

(Section

7.5)

to

an

indication for a less serious condition where the existing impurity acceptable

intakes may no longer be appropriate. Changes to the clinical use of marketed

products associated with new routes of administration or expansion into patient

populations

that

include

pregnant

women

and/or

pediatrics

will

not

warrant

a

reevaluation, assuming no increases in daily dose or duration of treatment.

已上市药品的临床应用变更拒收情节包括，

变更所引起的对诱变杂质 限度的重新评估中会包

括临床使用剂量的显著增加、

用药时长的 增加

（特别是当根据之前的指征，

将诱变性杂质控

制在超出生命全程使用时可接受摄入量时，

可能采用新的指征，

其原定摄入量已不再适用于

更长的治疗时长。

）

或者是指征变更是从已论述的在病情较严重或危及生命的病患状态下采

用较高可接受摄入量的情况，

变成不那么严重的病患情况，

原 有的杂质可接受摄入量可能不

再适当了。如果已上市药品的临床应用变更包涵有使用新的 给药途径，或扩大使用患者群，

从而包括孕妇和

/

或小儿，假定日剂量或用药时长不增加，则无法保证重新评估符合要求。

4.4 Other Considerations for Marketed Products

已上市药物的其它需考虑问题

Application of this guideline may be warranted to marketed products if there is

specific cause for concern. The existence of impurity structural alerts alone is

considered

insufficient

to

trigger

follow-up

measures,

unless

it

is

a

structure

in

the cohort of concern (Section 3). However a specific cause for concern would be

new

relevant

impurity

hazard

data

(classified

as

Class

1

or

2,

Section

6)

generated

after

the

overall

control

strategy

and

specifications

for

market

authorization

were

established.

This

new

relevant

impurity

hazard

data

should

be

derived

from

high-quality

scientific

studies

consistent

with

relevant

regulatory

testing

guidelines, with data records or reports readily available. Similarly, a newly

discovered impurity that is a known Class 1 or Class 2 mutagen that is present in

a marketed product could also be a cause for concern. In both of these cases when

the

applicant

becomes

aware

of

this

new

information,

an

evaluation

per

this

guideline

should be conducted.

本指南在某些特殊原因考虑时可以适用于已上市的药品。

仅凭杂质存在警示结构 是无法启动

后续措施的，除非该结构具有队列方面的担忧

（第< /p>

3

部分）。所谓的一种特殊顾虑原因可以

是在上市产品已建立其总体控制策略和质量标准后所获得的新的相关杂质危害数据

（分类 为

第

1

或和

2

类，

第

6

部分 ）

。

这些新的相关杂质危害性数据所采用的研究方法应具有高质 量

科学性，且与相关的法规测试指南相一致，其数据记录或报告应易于获得。

市药品中发现一个新的杂质，< /p>

且被确知属于第

1

类或第

2

类诱变性，

则也属于一种特殊顾虑

< br>原因。上述两种情形下，一旦申报人知晓这些新的信息，则需要实施本指南所要求的评估。

5. DRUG

SUBSTANCE AND

DRUG

PRODUCT

IMPURITY

ASSESSMENT

原料药和制剂杂质评

估

Actual and potential impurities that are likely to arise during the synthesis and

storage

of

a

new

drug

substance,

and

during

manufacturing

and

storage

of

a

new

drug

product should be assessed.

实际存在和可能存在的杂质是可能在新原料药合成和存贮过程、

生产过程中生成。

对新制剂

的存贮条件应进行评估。

The impurity assessment is a two-stage process:

杂质评估可以分为两个阶段：

—

Actual impurities that have been identified should be considered

for their mutagenic potential.

—

已被鉴定的实际存在的杂质应考虑其潜在诱变性

—

An assessment of potential impurities likely to be present in the

final

drug

substance

is

carried

out

to

determine

if

further

evaluation

of

their

mutagenic potential is required.

—

对可能存在于原料药中的潜在杂质 进行评估，

以确定是否需要对其潜在诱

变性进行进一步评估

The

steps

as

applied

to

synthetic

impurities

and

degradation

products

are

described

in Sections 5.1 and 5.2, respectively.

适用于合成 杂质和降解产物的方法分别在第

5.1

和

5.2

部分进行了描述。

5.1 Synthetic Impurities

合成杂质

Actual impurities include those observed in the drug substance above the ICH Q3A

reporting thresholds. Identification of actual impurities is expected when the

levels

exceed

the

identification

thresholds

outlined

by

ICH

Q3A.

It

is

acknowledged

that

some

impurities

below

the

identification

threshold

may

also

have

been

identified.

实际杂质包括原料药中超出

ICH

Q 3A

报告阈的杂质。如果杂质水平超过了

ICH

Q3A

中所述的

鉴别阈，则需要进行鉴别。有些低于 鉴别阈的杂质可能也是经过鉴别的。

Potential

impurities

in

the

drug

substance

can

include

starting

materials,

reagents

and intermediates in

the route of synthesis from the starting material to the drug

substance.

原料药中潜在 杂质可以包括起始物料、试剂和从起始物料到原料药合成路线中的中间体，

The risk of carryover into the drug substance should be assessed for identified

impurities

that

are

present

in

starting

materials

and

intermediates,

and

impurities

that

are

reasonably

expected

by-products

in

the

route

of

synthesis

from

the

starting

material

to

the

drug

substance.

As

the

risk

of

carryover

may

be

negligible

for

some

impurities (e.g., those impurities in early synthetic steps of long routes of

synthesis), a risk-based justification could be provided for the point in the

synthesis after which these types of impurities should be evaluated for mutagenic

potential.

应评估起始物 料和中间体中的杂质，

以及从起始物料到原料药的合成路线中会生成的副产物

由于有些杂质被带入原料药的风险可以忽略

（例如，

很长的合成路线

中较早的合成步骤中的 杂质），可以提交对这些杂质在合成路线某一点时基于风险的论述。

在合成路线该点之后 ，此类杂质需要评估其诱变可能性。

For

starting

materials

that

are

introduced

late

in

the

synthesis

of

the

drug

substance

(and

where

the

synthetic

route

of

the

starting

material

is

known)

the

final

steps

of

the

starting

material

synthesis

should

be

evaluated

for

potential

mutagenic

impurities.

对于在原料 药合成路线后期才引入的起始物料

（以及如果已知起始物料的合成路线）

，

需要

评估起始物料合成的最终步骤中的潜在诱变性杂 质。

Actual

impurities

where

the

structures

are

known

and

potential

impurities

as

defined

above should be evaluated for mutagenic potential as described in Section 6.

已知其结 构的实际杂质和如上所述的潜在杂质应按第

6

部分要求评估其潜 在诱变性。

5.2 Degradation Products

降解产物

Actual

drug

substance

degradation

products

include

those

observed

above

the

ICH

Q3A

reporting

threshold

during

storage

of

the

drug

substance

in

the

proposed

long-term

storage

conditions

and

primary

and

secondary

packaging.

Actual

degradation

products

in the drug product include those observed above the ICH Q3B reporting threshold

during

storage

of

the

drug

product

in

the

proposed

long-term

storage

conditions

and

primary

and

secondary

packaging,

and

also

include

those

impurities

that

arise

during

the

manufacture

of

the

drug

product.

Identification

of

actual

degradation

products

is expected when the levels exceed the identification thresholds outlined by ICH

Q3A/Q3B.

It

is

acknowledged

that

some

degradation

products

below

the

identification

threshold may also have been identified.

原料药实际降解产物包括原料药在内 包装和外包装内，

在拟定的长期存贮条件下原料药存贮

期间观察 到的高于

ICH

Q3A

报告阈值的物 质。

制剂中实际降解产物包括制剂在内包装和外包

装内，在拟定 的长期存贮条件下原料药存贮期间观察到的高于

ICH

Q3B

报告阈值的物质，还

包括在制剂生产过程中产生的那些杂质。< /p>

如果降解产物的含量水平超过

ICH

Q 3A/Q3B

的鉴别

阈，则应进行鉴别。有些低于鉴别阈值的降 解产物可能也是经过鉴别的。

Potential

degradation

products

in

the

drug

substance

and

drug

product

are

those

that

may be reasonably expected to form during long term storage conditions. Potential

degradation products include those that form above the ICH Q3A/B identification

threshold during accelerated stability studies

(e.g., 40°C/75% relative humidity

for

6

months)

and

confirmatory

photo-stability

studies

as

described

in

ICH

Q1B

(Ref.

5),

but

are

yet

to

be

confirmed

in

the

drug

substance

or

drug

product

under

long-term

storage conditions in the primary packaging.

原料 药和制剂中潜在的降解产物是指经过合理推测，在长期存贮条件下可能会形成的物质。

潜 在降解产物包括在加速稳定性试验中（例如

40°C/75%下

6

个月）和

ICH

Q1B(

参考文

献

5)

光照稳定性试验中形成的超出

的鉴别限，但在原料药和制剂内包装长期存

Knowledge of relevant degradation pathways can be used to help guide decisions on

the selection of potential degradation products to be evaluated for mutagenicity

e.g., from degradation chemistry principles, relevant stress testing studies, and

development stability studies.

相关降解途径的知识有助于指导选择性地评 估潜在降解产物的诱变性，

例如，

从降解化学原

理、相关强降解试验和研发稳定性研究。

Actual and potential degradation products likely to be present in the final drug

substance or drug product and where the structure is known should

be evaluated

for

mutagenic potential as described in Section 6.

实际存在 和可能存在于最终原料药或制剂中的降解产物只要知道结构，

均应根据第

6

部分要

求评估其诱变可能性。

5.3 Considerations for Clinical Development

临床研发中要考虑的问题

It

is

expected

that

the

impurity

assessment

described

in

Sections

5.1

and

5.2

applies

to

products

in

clinical

development.

However,

it

is

acknowledged

that

the

available

information is limited. For example, information from long term stability studies

and photo-stability studies may not be available during clinical development and

thus information on potential degradation products may be limited. Additionally,

the

thresholds

outlined

in

ICH

Q3A/B

do

not

apply

to

products

in

clinical

development

and consequently fewer impurities will be identified.

要求在临床阶段应用第

5.1

和

部分对杂质进行评估。

但是，

众所周知可能获得的信息会

比较有限。

例如，

在临床阶段可能还没有长期稳定性研究和光照稳定性试验数据，

因此关 于

潜在降解杂质的资料可能比较有限。另外，在

ICH

Q3A/B

中列出的阈值不适用于临床阶段的

药品，因此被鉴别出的杂质会很少。

6. HAZARD

ASSESSMENT

ELEMENTS

危害性评估要素

Hazard assessment involves an initial analysis of actual and potential impurities

by conducting database and literature searches for carcinogenicity and bacterial

mutagenicity data in order to classify them as Class 1, 2, or 5 according to Table

1.

If

data

for

such

a

classification

are

not

available,

an

assessment

of

Structure-Activity

Relationships

(SAR)

that

focuses

on

bacterial

mutagenicity

predictions

should

be

performed.

This

could

lead

to

a

classification

into

Class

3,

4, or 5.

危害性分析会涉及采用数据库和诱变和细菌诱变数据文献 检索启动对实际和可能杂质的分

析，以根据表

1

将其分类为第

1

类、

第

2

类或第

5

类。如果 无法获得这样的分类数据，

则应

进行结构

-

活性关系（

SAR

）评估，该评估 应着重关注细菌诱变性预期。

这时可能会使得该杂

质被分入第< /p>

3

类、第

4

类或 第

5

类。

Table 1: Impurities Classification with Respect to Mutagenic and Carcinogenic

Potential and Resulting Control Actions

Class

Definition

Proposed action for control (details in

Section 7 and 8)

1

Known mutagenic carcinogens

Control at or below compound-specific

acceptable limit

2

Known

mutagens

with

unknown

Control at or below acceptable limits

carcinogenic

(bacterial

positive*,

potential

(appropriate TTC)

mutagenicity

no

rodent

carcinogenicity data)

3

Alerting structure, unrelated

Control at or below acceptable limits

to the structure of the drug

(appropriate TTC) or conduct bacterial

substance:

no

mutagenicity

mutagenicity assay:

data

If non-mutagenic = Class 5

If mutagenic = Class 2

4

Alerting

structure,

same

alert

Treat as non-mutagenic impurity

in

drug

substance

or

compounds

related to the drug substance

(e.g., process intermediates)

which

have

been

tested

and

are

non-mutagenic

5

No

structural

alerts,

or

Treat as non-mutagenic impurity

alerting

structure

with

sufficient

data

to

demonstrate

lack

of

mutagenicity

or

carcinogenicity

*Or

other

relevant

positive

mutagenicity

data

indicative

of

DNA-reactivity

related

induction of gene mutations (e.g., positive findings in

in vivo

gene mutation

studies)

表

1

：根据诱变性和致癌性及其控制措施对杂质分类

分类

1

2

定义

已知诱变致癌性

已知具有诱变性，致 癌效应未知

（细菌诱变呈阳性

*

，

无啮齿动物

致癌数据）

3

警示结构，与原料药结构无关，< /p>

无诱变性数据

控制不高于可接受限度（ 适当的

TTC

）或检

测细菌诱变含量：

如果非诱变性

=

第

5

类

如果具有诱变性

=

第

2

类

4

警示结构，与原料药或有关物质< /p>

有相同警示

（例如，

工艺中间体）

，

经测试为无诱变性

5

无警示结构，或警示结果具有充< /p>

与非诱变性杂质同等对待

与非诱变性杂质同等对待

拟定控制措 施（详见第

7

和

8

部分）

控制不高于化合物可接受限度

控制不 高于可接受限度（适当的

TTC

）

分的数据证明其不具备诱变性和

致癌性

*

或其它相关阳性诱变数据，说明与诱导基因变性的