EMA工艺验证指南

1

月

15

日

Date for coming into effect

6 months after publication

生效日期

公布后

6

个月

This

guideline

replaces

the

note

for

guidance

on

process

validation

(CPMP/QWP/848/96,

EMEA/CVMP/598/99) including annex II

–

non-standard processes (CPMP/QWP/2054/03).

本指南替代工艺验证注释（

CPMP/QWP/848/96,

EMEA/CVMP/598/99

）

，包括附录二

----

非标准工艺

（< /p>

CPMP/QWP/2054/03

）

。

Process

validation,

continuous

process

verification,

on-going

process

verification,

critical

Keywords

process parameter, critical quality attribute, lifecycle, change control

关键词

工艺验证、 持续工艺确认、关键工艺参数、关键质量属性、生命周期、变更控制

Table of contents

目录

Executive summary

实施摘要

1. Introduction (background)

2. Scope

3. Legal basis

4. General considerations

5. Process validation

5.1. Traditional process validation

5.2. Continuous process verification

介绍（背景）

范围

法规依据

一般考虑

工艺验证

传统工艺验证

持续工艺确认

5.3. Hybrid approach

5.4. Design space verification

6. Scale-up

7. Post approval change control

混合方案

设计空间确认

放大生产

批准后变更控制

8. Standard vs. non-standard methods of manufacture < /p>

标准

VS

非标准生产方法

Definitions

定义

References

Annex I: Process validation scheme

参考文献

附录

I

：工艺验证计划

Annex II: Standard/non-standard processes

附录< /p>

II

：标准

/

非 标工艺

Executive summary

实施摘要

This

guideline

replaces

the

previous

note

for

guidance

on

process

validation

(CPMP/QWP/848/96,

EMEA/CVMP/598/99).

The

guideline

is

brought

into

line

with

ICH

Q8,

Q9

and

Q10

documents

and

the

possibility to use continuous process verification in addition to, or

instead of, traditional process validation

described in the previous guideline has been added and is encouraged. This guideline does not introduce new

requirements on medicinal products already authorised and on the market, but clarifies how companies can

take advantage of the new possibilities given when applying enhanced process understanding coupled with

risk management tools under an efficient quality system as described by ICH Q8, Q9 and Q10.

本指南替代之前的工艺验证指南解释

(CPMP/QWP/848/96, EMEA/CVMP/598/99)

。本指南与

ICH

Q8

，

Q9

和

Q10

文件相一致，提供在之前加入和鼓励采用的传统工艺验证这外 ，提供了使用持续工艺确认

的可能性。本指南对已批准上市的药品未引入新要求，但阐述 了公司在

ICH

Q8,

Q9

和

Q10

中描述的

有 效质量体系下，应用强化工艺理解与风险管理工具时，如何抓住所给的新的可能性。

1. Introduction (background)

介绍（背景）

Process

validation

can

be

defined

as

documented

evidence

that

the

process,

operated

within

established

parameters,

can

perform

effectively

and

reproducibly

to

produce

a

medicinal

product

meeting

its

predetermined

specifications

and

quality

attributes

(ICH

Q7).

Continuous

process

verification

has

been

introduced

to

cover

an

alternative

approach

to

process

validation

based

on

a

continuous

monitoring

of

manufacturing performance. This approach is based on the knowledge from product and process development

studies and / or previous manufacturing experience.

工 艺可定义为证明在建立的参数范围内操作的工艺可以重复有效地生产出符合其预定质量标准和质量

属性的药品的书面证据

(ICH

Q7)

。持续工艺验证被引入替代基于对工艺性能持续监测的工艺验证。这

种方法是 依据来自于产品和工艺研发和

/

或之前生产经验的知识。

Continuous

process

verification

may

be

applicable

to

both

a

traditional

and

enhanced

approach

to

pharmaceutical development. It may use extensive in-line, on-line or at-line monitoring and / or controls to

evaluate

process

performance.

It

is

intended

that

the

combination

of

the

advice

provided

in

the

Note

for

Guidance

on

Development

Pharmaceutics

(CPMP/QWP/155/96)

and

the

Note

for

Guidance

on

Pharmaceutical

Development

(ICH

Q8R2)

together

with

this

guideline

should

cover

all

of

the

critical

elements in manufacturing process for inclusion in the dossier for regulatory submission for a pharmaceutical

product

for

human

use.

For

veterinary

medicinal

products,

the

applicable

guidance

is

that

provided

in

the

Note for Guidance on Development Pharmaceutics for Veterinary Medicinal Products (EMEA/CVMP/315/98)

together

with

this

guideline.

Although

the

ICH

Q8

guideline

is

not

applicable

to

veterinary

medicinal

products the principles detailed in this guideline may be applied to veterinary medicinal products should an

applicant

choose

to

apply

an

enhanced

approach

to

pharmaceutical

development

and

process

validation.

Process

validation

should

not

be

viewed

as

a

one-off

event.

Process

validation

incorporates

a

lifecycle

approach linking product and process development, validation of the commercial manufacturing process and

maintenance of the process in a state of control during routine commercial production.

持续工艺确认既适 用于传统药品研发方法，也适用于加强药品研发方法。它采用广泛的在线监测和

/

或控制来评估工艺的性能。将研发药物指南解释

(CPMP/QWP/ 155/96)

、药物研发指南解释

(ICH

Q8R2)

与本指南相结合，应可以覆盖人用药法规申报文件所需包括的生产工 艺的关键因素。对于兽药产品，

适用的指南为

“

兽药研发指南解释

”

(EMEA/CVMP/315 /98)

与本指南。尽管

ICH

Q8

指南不适用兽药产

品，本指南中的原则可以应用于兽药产品，申 请人应选择性采用更好的方法来进行药品研发和工艺验

证。工艺验证不应该作为是一次性 的事情。工艺验证应将产品生命周期结合工艺研发、商业生产工艺

验证、在常规商业化生 产中控制状态的工艺维护相结合。

2. Scope

范围

This document is intended to provide guidance on the process validation information and data to be provided

in

regulatory

submissions

for

the

finished

dosage

forms

of

chemical

medicinal

products

for

human

and

veterinary use. The general principles also apply to active substances.

本文件意在提 供关于人用和兽用化学药品制剂的申报时所需提交的工艺验证资料和数据的指南。一般

原 则也适用于活性物质。

However, information on validation of non-sterile active substances is not required in the dossier.

但是，在申报文件中并不要求提交非无菌原料药的验证信息。

In

addition,

expectations

for

active

substances

are

contained

in

ICH

Q11

and

so

the

information

is

not

repeated in this document.

另外，

ICH Q11

< br>中包括了对原料药的建议，因此本文件中不再重复这些信息。

The

principles

described

are

also

applicable

to

biological

medicinal

products.

However,

these

should

be

considered on a case by case basis in view of the complex nature and inherent variability of the biological

substance.

本文所述的原则也适用于生物制品。< /p>

但是，

生物制品的工艺验证应根据其复杂性和内在变因各案考查。

It is expected that the information / data requested in this guideline be present in the dossier at the time of

regulatory submission.

在本指南中 所要求的资料

/

数据应该包括在法规申报的文件中。

This document provides guidance on the validation of the manufacturing process, which can be considered as

the second stage in the product lifecycle. The first stage (process design) is covered in the note for guidance

on

pharmaceutical

development

(ICH

Q8R2/

EMEA/CVMP/315/98)

and

the

third

stage

(on-going

process

verification) is covered under

GMP

(Annex 15).

本文件提供生产工艺验证指南，工艺验证可以当作产品生命周期的第二阶段。 第一阶段（工艺设计）

包括在药物研发指南解释（

ICH Q8R2/ EMEA/CVMP/315/98

）中，第三阶段（持续工艺确认）包括 在

GMP

（附录

15

< br>）中。

3. Legal basis

法律依据

This guideline has to be read in conjunction with the introduction and general principles section (4) of Annex

I to Directive 2001/83/EC as amended and the introduction and general principles section (2) of Annex I to

Directive 2001/82/EC as amended.

本指南应与指令

2001/83/EC

修订版本附录

1

第（

4

）部 分中的介绍和一般原则，以及指令

2001/82/EC

修订版附录

1

第（

2

）部分中的介绍和一般原则一起解读。

4. General considerations

一般考虑

Irrespective of whether a medicinal product is developed by a traditional approach or an enhanced approach,

the

manufacturing

process

should

be

validated

before

the

product

is

placed

on

the

market.

In

exceptional

circumstances concurrent validation may be accepted. Please refer to GMP Annex 15 for further guidance.

Process validation should confirm that the control strategy is adequate to the process design and the quality of

the

product.

The

validation

should

cover

all

manufactured

strengths

and

all

manufacturing

sites

used

for

production of the marketed product. A bracketing approach may be acceptable for different strengths, batch

sizes and pack sizes.

However, validation must cover all proposed sites.

Process

validation data should

be

generated

for

all

products

to

demonstrate

the

adequacy

of

the

manufacturing

process

at

each

site

of

manufacture.

Validation

should

be

carried

out

in

accordance

with

GMP

and

data

should

be

held

at

the

manufacturing location and made available for inspection if not required in the dossier (see section 8).

工艺验证应确认控制策略对于工 艺设计和产品质量来说已足够。验证应覆盖生产上市产品的所有生产

场所和所有剂量产品 。不同剂量、不同批量和包装规格可以括号法。但是，验证必须覆盖所有拟生产

的场所。 每个生产场所所有产品均应有工艺验证数据，以证明生产工艺的充分性。工艺验证应符合

GMP

，数据应保留在生产场所，如果申报文件中未要求（参见第

8

部分）则应该在检查过程中随时可

提供。

< br>

Process validation can be performed in a traditional way, as described below, regardless of the approach to

development taken. However, there is also the possibility to implement continuous process verification if an

enhanced approach to development has been performed or where a substantial amount of product and process

knowledge

and

understanding

has

been

gained

through

historical

data

and

manufacturing

experience.

A

combination

of

traditional

process

validation

and

continuous

process

verification

may

be

employed.

The

in-line,

on-line

or

at-line

monitoring

that

is

often

utilised

for

continuous process

verification

(discussed

in

section 5.2) provides substantially more information and knowledge about

the process

and might

facilitate

process improvements.

如下所述，不管采用了什么研发方法，工艺验证都可以采 用传统方法。但是，如果已采用加强研发方

法，或通过历史数据和生产经验已获得大量产 品和工艺知识和理解，也存在实施持续工艺确认的可能

性。可能要采用传统工艺验证和持 续工艺确认相结合的方法。在线监控经常用于持续工艺确认（在第

5.2

部分中已讨论）

，提供大量的关于工艺的信息和知识，可能有利于工艺改进。< /p>

5. Process validation

工艺验证

5.1. Traditional process validation

传统工艺验证

Traditional process

validation is

normally performed when the pharmaceutical

development

and/or process

development is concluded, after scale- up to production scale and prior to marketing of the finished product.

As part of the process validation lifecycle, some process validation studies may be conducted on pilot scale

batches if the process has not yet been scaled up to production scale.

传统工艺验证一般 在药物研发和

/

或工艺研发结束后，在放大至生产规模后，成品 上市前进行。作为工

艺验证生命周期的一部分，如果有些工艺还没有放大到生产规模，部 分工艺验证研究可能会在中试批

次进行。

It should be noted that pilot batch size should correspond to at least 10% of the production scale batch (i.e.

such that the multiplication factor for the scale-up does not exceed 10). For solid oral dosage forms this size

should

generally

be

10%

of

the

maximum

production

scale

or

100,000

units

whichever

is

the

greater

[1]

.

Where

the

intended

batch

size is

less

than

100,000

units,

the

predictive

value

of

the

pilot

batches

may

be

limited and a justified approach should be followed. For other dosage forms the pilot batch size should be

justified

taking

into

account

risk

to

the

patient

of

failure

of

the

dosage

form.

Since

it

is

not

generally

considered

useful

to

conduct

full

validation

studies

on

pilot

scale

batches,

the

process

validation

scheme

outlined

in

Annex

I

of

this

guideline

should

be

completed

for

each

product

for

subsequent

execution

at

production

scale;

bracketing

may

be

acceptable.

The

process

validation

scheme

to

be

followed

should

be

included in the dossier. The scheme should include a description of the manufacturing process, the tests to be

performed and acceptance criteria, a description of the additional controls in place and the data to be collected.

A justification

for the chosen process

validation scheme should be presented in

Module 3 and the Quality

Overall

Summary

for

human

medicines

and

in

Part

2.B

and

the

Pharmaceutical

Detailed

and

Critical

Summary for veterinary medicines.

要注意的是中试生产批应至少对应商业 生产批量的

10%

（即，放大生产倍数不应超过

10

）

。该规模的

固体口服剂 型一般应为最大生产批量的

10%

或

1 0

万个单位剂量，

取其中大者。

如果要 生产的批量小于

10

万剂型单位，中试批次预期值可能受限，则 需要采用经过评估的方法。对于其它剂型，中试批量的

论述要考虑剂型失败给患者带来的 风险。由于一般认为在中试规模批次进行全验证研究是没有用的，

因此在本指南附录

1

中列出的工艺验证计划应在之后的各产品生产规模时进行完善，< /p>

可以接受括号法。

申报文件中应包括要执行的工艺验证计划。计划 中应包括工艺描述、要实施的测试和可接受标准、附

加控制的描述和要收集的数据。要在 人药申报文件模块

3

和质量综述、兽药申报文件第

2.B

部分和药

品详情和关键摘要中放入为什么选择 该工艺验证计划的论述。

In

certain

cases

however,

it

is

considered

necessary

to

provide

production

scale

validation

data

in

the

marketing

authorisation

dossier

at

the

time

of

regulatory

submission,

for

example

when

the

product

is

a

biological / biotech product or where the applicant is proposing a non-standard method of manufacture (see

section 8 and Annex II). In these cases, data should be provided in the dossier on a number of consecutive

batches at production scale prior to approval. The number of batches should be based on the variability of the

process, the complexity of the process /product, process knowledge gained during development, supportive

data at commercial scale during technology transfer and the overall experience of the manufacturer. Data on a

minimum

of

3

production

scale

batches

should

be

submitted

unless

otherwise

justified.

Data

on

1

or

2

production scale batches may suffice where these are supported by pilot scale batches and a justification as

highlighted above.

在某些情况下，可能认为有必要在上市许可申报资料中提交生产批量的验证数据，例如，如果产 品是

生物

/

生物技术制品，或者申请人 所拟的工艺为非标生产方法（参见第

8

部分和附录二）

。这种情况下，

要在批准前在申报资料中包括采用生产批量所获得的连续 批次数据。批次数应基于工艺变动情况、工

艺

/

产品复杂程度、在研发阶段所获得的工艺知识、在技术转移中所获得的商业批量中的支持数据，以

及生产商的总体经验。除非另有论述，否则至少需要提交

3

据支持，以及上述高亮显示的论述 提供，则仅提供

1

或

2

批生产批量数据也是可以的。

译者：未见哪里有高亮显示的内容。

The studies should address critical steps of manufacture, by conducting additional testing as necessary.

研究应说明关键生产工艺步骤，必要时增加检测。

5.2. Continuous process verification

持续工艺确认

Continuous

process

verification

is

an

alternative

approach

to

traditional

process

validation

in

which

manufacturing process performance is continuously monitored and evaluated (ICH Q8).

持续工艺确认是传统工艺验证的一种替代方 式，是指生产工艺的性能被持续地监控和评估（

ICH Q8

）

。

Continuous process verification can be used in addition to, or instead of, traditional process validation.

持续工艺确认可以用于补充，或替代传统工艺验证。

It is a science and risk-based real- time approach to verify and demonstrate that a process that operates within

the

predefined

specified

parameters

consistently

produces

material

which

meets

all

its

critical

quality

attributes

(CQAs)

and

control

strategy

requirements.

In

order

to

enable

continuous

process

verification,

companies

should

perform,

as

relevant,

extensive

in-line,

on-line

or

at- line

controls

and

monitor

process

performance and product quality on each batch. Relevant data on quality attributes of incoming materials or

components,

in-process

material

and

finished

products

should

be

collected.

This

should

include

the

verification of attributes, parameters and end points, and assessment of CQA and critical process parameter

(CPP)

trends.

Process

analytical

technology

(PAT)

applications

such

as

NIR

spectroscopy

with

or

without

feedback loop

(e.g. end

point determination of blend homogeneity, determination of granules surface area,

determination

of

content

uniformity

with

large

sample

size)

and

Multivariate

Statistical

Process

Control

(MSPC) can be viewed as enablers for continuous process verification.

确认和证明一 个工艺如果在预定的特定参数范围内操作，即可以稳定生产出符合所有

CQA

略要求的物料是一个科学并基于风险的实时方法。为了进行持续工 艺确认，公司应相应地实施众多的

在线控制和工艺性能监控，以及各批产品质量监控。应 收集进厂物料或组件、制程中物料和成品的质

量属性相关数据，还应该包括对属性、参数 和终点，和

CQA

和

CPP

PAT

工具，如具有或 不具有反馈回路的

NIR

光谱（例如，混合均一性终点测试，颗 粒表面积测试，样品量

较大时含量均一性测试）

，和多变量统计 学工艺控制

MSPC

可以当作持续工艺确认的工具。

Sufficient

knowledge

and

understanding

of

the

process

is

required

in

order

to

support

continuous

process

verification. However, the scope and extent of continuous process verification will be influenced by a number

of factors including:

为了支持持续工艺确认，需要对工艺有足够的知识和理解。但是 ，持续工艺确认的程度会受到一些因

素的影响，包括

—

prior development and manufacturing knowledge from similar products and/or processes;

—

从同类产品和

/

或工艺中获得的研发生产前的知识

—

the

extent

of

process

understanding

gained

from

development

studies

and

commercial

manufacturing

experience;

—

在研发获 得的对工艺理解的程度，以及商业生产经验

—

the complexity of the product and/or manufacturing process;

—

产品和

/

或生产工艺的复杂性

—

the level of process automation and analytical technologies used;

—

工艺自动化水平和使用的分析技术水平

—

for legacy products, with reference to the product lifecycle, process robustness and manufacturing history

since point of commercialization as appropriate.

—

对于已有产品，参考产品生命周 期、工艺耐用性和自从商业化以来的生产历史（适用时）

A discussion on the appropriateness and feasibility of the continuous process verification strategy should be

included in the development section of the dossier and should be supported with data from at least laboratory

or

pilot

scale

batches.

A

description

of

the

continuous

process

verification

strategy

including

the

process

parameters

and

material

attributes

that

will

be

monitored,

as

well

as

the

analytical

methods

that

will

be

employed, should be included as described in Annex 1, with cross-reference to the validation section of the

dossier. Actual data generated during continuous process verification at production scale should be available

at the site for inspection. The applicant should define the stage at which the process is considered to be under

control and the validation exercise completed prior to release of the product to the market, and the basis on

which that decision will be made. The discussion should include a justification for the number of batches to

be

used

based

on

the

complexity

and

expected

variability

of

the

process

and

existing

manufacturing

experience

of

the

manufacturing

site.

Continuous

process

verification

would

be

considered

the

most

appropriate method for validating continuous processes.

在申报资料的 研发部分，应包括持续工艺确认策略的适当性和可行性讨论，并使用至少是实验室规模

或 中试规模批次的数据加以支持。持续工艺确认策略的内容应包括：要监控的工艺参数和物料属性、

要采用的分析方法，应该如附录

1

中所述，交叉引用至 申报文件的验证部分。在生产规模持续工艺确

认中所产生的实际数据应受检查现场可以获 得。申请人应定义工艺步骤受控起始点，和将产品放行上

市销售前所完成的验证工作，以 及做出该决定的根据。讨论应包括根据工艺复杂性和预期变化，以及

在生产场所内已有生 产经验来决定批次数的论述。在验证连续生产的工艺时，持续工艺确认被认为是

最适当的 方式。

Continuous process verification can be introduced at any time in the lifecycle of the product. It can be used

for the initial commercial production, to re-validate commercialised products as part of process changes or to

support continual improvement.

持续工艺确认可以在产品生命周期的任何时间引入。它可以 用于初始的商业化生产，作为工艺变更的

一部分对商业产品进行再验证，或用于支持持续 改进。

Continuous process verification is dependent on compliance with GMP principles and requirements.

持续工艺确认是独立于

GMP

原则和要求符合性的。

Pharmaceutical

quality

systems

(PQS)

as

described

in

ICH

Q10

can

complement

GMP

requirements.

However, GMP matters and PQS should not be included in the submission as they are assessed and handled

by GMP inspectors as appropriate.

在

ICH

Q10

里所述药品质量体系

PQS

可以补充

GMP

要求，但是，

GMP

事宜和< /p>

PQS

不应该包括在申

报资料中，因为它 们是由

GMP

审计官在适当时进行评估的。

5.3. Hybrid approach

混合方案

It

may

be

necessary

to

use

either

the

traditional

process

validation

or

the

continuous

process

verification

approach

for

different

steps

within

the

manufacturing

process.

It

should

be

clear

in

the

dossier

which

approach to validation has been taken for which steps in the manufacturing process.