-
WHO
第
961
号技术
报告
附件
7
药物生产技术
转移指南（中英文
1/4
）
2013-09-29 14:16:27|
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World Health
Organization
WHO Technical Report
Series, No. 961, 2011
WHO
第
961
号技术报告
附件
7
药物生产技术转移指南
Annex 7
附件
7
WHO guidelines on transfer of
technology in pharmaceutical
manufacturing
WHO
药物生产技术转移指南
1. Introduction
介绍
2. Scope
范围
3. Glossary
术语
4.
Organization and management
组织和管理
5.
Production: transfer (processing, packaging and
cleaning)
生产：
转移
（工
艺、
包装和清洁）
6.
Quality control: analytical method
transfer
质量控制：分析方法转移
7.
Premises and equipment
厂房设施和设备
8.
Documentation
文件
9. Qualification and validation
确认和验证
References
参考文献
1.
Introduction
介绍
These guiding
principles on transfer of technology are intended
to serve as a
framework which can be
applied in a flexible manner rather than as strict
rigid
guidance. Focus has been placed
on the quality aspects, in line with WHO’s
mandate.
本指南中关于技术转移的原则意在作为一个
框架，
以不同方式应用，
而不是一个
需
要严格遵守的指南。指南重点在于质量方面，与
WHO
的任务一
致。
1.1 Transfer of processes
to an alternative site occurs at some stage in the
life-cycle of most products, from
development, scale-up, manufacturing,
production and launch, to the post-
approval phase.
将工艺转移至一个可替代的场所发生在大多数产品的
生命周期的某些阶段，
从研
发、放大、生产、到上市后阶段。<
/p>
1.2 Transfer of
technol
ogy is defined as ―a logical
procedure that controls the
transfer of
any process together with its documentation and
professional
expertise between
development and manufacture or between manufacture
sites‖. It is a systematic procedure
that is followed in
order to pass the
documented knowledge and experience
gained during development and or
commercialization to an appropriate,
responsible and authorized party.
技术转移被
定义为
―
控制研发方和生产方，或两个生产场所之间所有工艺关
其文
件和专业技术转移的逻辑程序
‖
。
技术转移是一个系统性的程序，遵守该程序是
为了能将在研发过程中已记录的知识和经验
转移给一个适当的，
承担责任的经过
授权的主体方。
Technology transfer embodies
both the transfer of documentation and the
demonstrated ability of the receiving
unit (RU) to effectively perform the critical
elements of the transferred technology,
to the satisfaction of all parties and any
applicable regulatory bodies.
技术转移包括文件转移和接收单位的重现能力，
以使用得转移技术的关键要素得
以有效实施，满足参与各方和所有适用法规的要求。
1.3 Literature searches revealed little
information on the subject originating
from national or regional regulatory
bodies. Guidance on intracompany
transfers was prepared by the
International Society for Pharmaceutical
Engineering (ISPE)
(
1
).
文献查阅显示来自于国家或
地区药监部门关于本主题的信息非常少。
ISPE
（
I
）
有一份关于跨公司转移指南。
1.4 The ever changing business
strategies of pharmaceutical companies
increasingly involve intra- and
intercompany transfers of technology for
reasons such as the need for additional
capacity, relocation of operations or
consolidations and mergers. The WHO
Expert Committee on Specifications for
Pharmaceutical Preparations, therefore,
recommended in its forty second
report
that WHO address this issue through preparation of
WHO guidelines on
this matter
(
2
).
制药企业的经营策略导致在
公司间、
公司内进行技术转移日益增加，
原因各种各
样，例如增加产能的需求、寻求新的生产场所、合并和收购。因此，
WHO
制剂
质量标准专家委员会在
WHO
第
42
期报告中对制剂的
< br>WHO
指南中阐述了对此
问题的推荐。
< br>
1.5 Transfer of technology requires
a documented, planned approach using
trained and knowledgeable personnel
working within a quality system, with
documentation of data covering all
aspects of development, production and
quality control. Usually there is a
sending unit (SU), a receiving unit and the
unit managing the process, which may or
may not be a separate entity. For
―contract manufacturing‖ please see
good manufacturing practices (GMP)
(
3
).
技术转移需要一种记录的计
划方式，
人员应经过培训、
有知识背景，
在一个质量
体系下工作，
数据记录应覆盖研发、
和平和质量控制各方面。
一般会有一个转出
方
(SU)
，
一个接收方和管理工艺的单位。<
/p>
管理工艺的单位可以是一个独立的主体，
也可不是。关于
―
合同制造
‖
，请参见
GMP
（
3
）
。
1.6 For the transfer to be
successful, the following general principles and
requirements should be met:
为使转移成功，应符合以下一般原则和要求
?
the
project plan should encompass the quality aspects
of the project and
be based upon the
principles of quality risk management;
?
项目计划应基于质量风险管理，对项目的质量方面起到指导作用，
?
the
capabilities of the SU and at the RU should be
similar, but not
necessarily identical,
and facilities and equipment should operate
according to similar operating
principles;
?
接收单位和转出单位的产能应相似，
但不是必须的，
设施和设备应根据相似
的操作原则进行操作
?
a comprehensive technical gap analysis
between the SU and RU
including
technical risk assessment and potential regulatory
gaps, should
be performed as needed;
?
如有需要，
应对转出单位和接收单位进行综合技术差异分析，
< br>包括技术风险
评估和潜在法规差异
?
adequately trained staff should be
available or should be trained at the
RU:
?
接收单位应具有经过充分培训地员工，或培训其员工
—
regulatory requirements in the
countries of the SU and the RU, and in
any countries where the product is
intended to be supplied, should be
taken into account and interpreted
consistently throughout any transfer
programme project; and
—
接收单位和转出单位的所在国法规要求，以及任何该产品将要销售的国
家的法规要求
，均应进行考虑，并在整个转移程序项目期间有一致的解
释
—
there
should be effective process and product knowledge
transfer.
—
工艺和产品知识转移应有效果
1.7
Technology transfer can be considered successful
if there is documented
evidence that
the RU can routinely reproduce the transferred
product, process
or method against a
predefined set of specifications as agreed with
the SU.
如果有文件化的证据证明接收单位可以正常地再次生产出所转移的产品
、
工艺或
方法，
使用其符合与转出单位
协商同意的一系列既定的规格，
则可以认为技术转
移已经成功。
1.8 In the event that the
RU identifies particular problems with the process
during the transfer, the RU should
communicate them back to the SU to
ensure continuing knowledge management.
如果接收单位在转移过程中发现工艺有一些特别的问题，
应反馈
回转出单位，
以
保证继续进行知识管理。
1.9 Technology transfer projects,
particularly those between different
companies, have legal and economic
implications. If such issues, which may
include intellectual property rights,
royalties, pricing, conflict of interest and
confidentiality, are expected to impact
on open communication of technical
matters in any way, they should be
addressed before and during planning and
execution of the transfer.
技
术转移项目，
是那些不同公司间转移的项目，
牵涉到法律和经济
方面。
如果这
些方面，可能会包括知识产权、版税、价格、利益
和保密的冲突，将会影响到技
术问题的公开交流，那么在计划和实施技术转移之前和过程
中应进行说明。
1.10 Any lack of
transparency may lead to ineffective transfer of
technology.
缺乏透明度可能会导致技术转移没有效果
1.11 Some of the principles outlined in
this document may also be applicable
to
manufacturing investigational pharmaceutical
products for clinical trials as
part of
research and development, but this is not the main
focus of this
guidance and has been
excluded due to the complexity of the processes. <
/p>
在本文件中列出的有些原则可能也适用于作为生产临床药品，
作为
研发的一部分，
但这不是本指南主要关注点，并由于其过程太复杂因此未包括在其中。<
/p>
1.12 Some of the
responsibilities outlined in this document for the
SU may also
be considered to be part of
the management unit responsibilities.
在
本文件件中列出的转出单位的一些职责可能也可以考虑作为管理单位的职责。
2.
Scope
范围
Note
: This section
specifically provides for transfer of quality
control (QC)
methods where a technical
agreement exists (SU manufacturer to RU
manufacturer or SU manufacturer to RU
QC laboratory). Where no such
technical
agreements exist (e.g. testing by national
laboratories or testing for
procurement
agencies) a number of the points listed in section
2.4 may not
be workable,and alternative
approaches may be required.
注：
本部分特别提供给有技术协议存在时，
质量控制方法的转移
（转出生产方给
接收生产单位生产方或转出单位生产方给接收单位
QC
化验室）
。
如果没有这样
的技术协议存在
（例如，
由一个国家化验室进
行检查，
或由采购代理进行检测）
，
在
2.4
部分列出的一些项可能用不上，那么可能需要替代的方法
。
2.1 This document gives
guidance in principle and provides general
recommendations on the activities
necessary to conduct a successful intraor
intersite transfer of technology as
described in the Introduction to these
guidelines. The intention is to address
the basic considerations needed for a
successful transfer in order to satisfy
the regulatory authority defined for the
transfer process.
本文件给出了原则性指
南，
如本指南介绍中所述，
提供了在工厂内、
< br>不同工厂间
成功进行支持转移所需的活动建议，
意在说明
进行成功的技术转移所需的基本考
虑，以满足在工艺转移中涉及的法规当局的要求。
2.2 The guidelines will be
applied to manufacturing active pharmaceutical
ingredients (APIs), manufacturing and
packaging of bulk materials,
manufacturing and packaging of finished
pharmaceutical products (FPPs)
and/or
performing analytical testing.
本指南适用于原料
药生产活动、散装物料的生产和包装、制剂成品和
/
或的生产<
/p>
和包装、分析所用的检验方法。
2.3
The recommendations provided in these guidelines
apply to all dosage
forms but need to
be adjusted on a case-by-case basis (e.g. by using
risk
management principles).
Particularly close control of certain aspects will
be
required for certain formulations
such as sterile products, and metered dose
aerosols. WHO guidance on manufacture
of specific pharmaceutical
products
(4,5)
will be useful in this
regard.
本指南中的推荐适用于所有剂型，
但需要根据
具体案例进行调整
（例如采用风险
管理原则）。对某些特殊剂型
，例如无菌产品、单剂量气溶胶进行特殊控制。
WHO
对特殊药
品的生产指南（
4.5
）对此会有指导作用。
< br>
2.4 The guidelines address the
following areas at the SU and the RU:
—
transfer
of development and production (processing,
packaging and
cleaning);
—
研发和生产转移（工艺、包装和清洁）
—
transfer
of analytical methods for quality assurance and
quality control;
—
质量保证和质量控制的分析方法转移
—
skills
assessment and training;
—
技能评价和培训
—
organization and management of the
transfer;
—
转移的组织和管理
—
assessment of premises and equipment;
—
前提和设备评价
—
documentation; and
—
文件，和
—
qualification and validation.
—
确认和验证
2.5 Because
each transfer project is unique, the provision of
a comprehensive
set of guidelines is
beyond the scope of this document.
由于每个
技术转移项目都是独特的，
本文件并不提供一个综合性的整套指南条款。
2.6 These guidelines do not
provide guidance on any legal, financial or
commercial considerations associated
with technology transfer projects.
这些指南
并不提供与技术转移项目相关的任何法律、财务或商业方面的考虑。
3.
Glossary
术语
The
definitions given below apply to the terms used in
these guidelines.
以下给出的术语定义仅限用于本指南中。
They may have different meanings in
other contexts.
在其它上下文中可能有不同的含义。
acceptance criteria
可接受标准
Measurable
terms under which a test result will be considered
acceptable.
一个可以测量的标准，符合这个标准时检测结果被认为是可以
接受的。
active pharmaceutical
ingredient (API)
活性药物成份（原料药）
Any substance or mixture of substances
intended to be used in the
manufacture
of a pharmaceutical dosage form and that, when so
used,
becomes an active ingredient of
that pharmaceutical dosage form. Such
substances are intended to furnish
pharmacological activity or other direct
effect in the diagnosis, cure,
mitigation, treatment, or prevention of disease or
to affect the structure and function of
the body.
任何物质或混合物，
用于药品制剂的生产
，
成为这个制剂的一种活性成份。
这种
物质用于产生生物学活性，或用于治愈、缓解、治疗，或防止疾病，影响人体结
构和功能
。
Bracketing
正交
An
experimental design to test only the extremes of,
for example, dosage
strength. The
design assumes that the extremes will be
representative of all
the samples
between the extremes.
一种试验设计方法。用来检查，例如，
剂量的极限。设计假定上下极限能代表极
限之间的所有样品。
change control (C/C)
变更控制
A formal
system by which qualified representatives of
appropriate disciplines
review proposed
or actual changes that might affect a validated
status. The
intent is to determine the
need for action that would ensure that the system
is
maintained in a validated state.
一个正式的体系，
根据这个体系，
有资质相关
学科的代表对建议的或实际的，
可
能会对验证过的状态产生影响
的变更进行审核。
变更控制的目的是决定是否需要
采取行动来保
证体系维持在被验证的状态。
Commissioning
调试
The setting
up, adjustment and testing of equipment or a
system to ensure that
it meets all the
requirements, as specified in the user requirement
specification,
and capacities as
specified by the designer or developer.
Commissioning is
carried out before
qualification and validation.
对设备或一个系统进
行设置、
调整和检测，
以保证其符合在用户需求手册中列出
的所有要求，
以及由设计者或研发人员所指定的能力。
调试应在确认和验证之前
实施。
control strategy
控制策略
A planned
set of controls, derived from current product and
process
understanding, that assures
process performance and product quality. The
controls can include parameters and
attributes related to materials and
components related to drug substances
and drug product materials and
components, facility and equipment
operating conditions, in-process controls,
finished product specifications, and
the associated methods and frequency of
monitoring and control
(
6
).
一个计划的控制系列，
它来自于现行产品和对工艺的理解，
它保证工艺性能和产
品质量。
控制可以包括与参数和原料属性，
以及与
原料药有关的组件、
制剂原料
和组件、设施和设备操作条件、中
控、成品质量标准、相关的检验方法和监控的
频次。
corrective action (C/A)
纠正措施
Any action
to be taken when the results of monitoring at a
critical control point
indicate a loss
of control.
当对关键控制点的监控显示其失控时将要采取的任何措施。
Critical
关键
Having the potential to impact on
product quality or performance in a
significant way.
会显著影响产品质量或性能的潜在可能性。
critical control point (CCP)
关键控制点
A step at
which control can be applied and is essential to
prevent or eliminate a
pharmaceutical
quality hazard or to reduce it to an acceptable
level.
一个步骤，
通过控制这个步骤可以从根本上阻止
或消除对药品质量的危害，
或将
其降低到可以接受的水平。
design qualifi cation (DQ)
设
计确认
Documented evidence that the premises,
supporting systems, utilities,
equipment and processes have been
designed in accordance with the
requirements of good manufacturing
practices (GMP).
文件化的证据，证明设施、支持系统、公用系统、
设备和工艺已经根据
GMP
要
求进行设
计。
design space
设计空间
The
multidimensional combination and interaction of
input variables (e.g.
material
attributes) and process parameters that have been
demonstrated to
provide assurance of
quality (
7
).
多维组合
和输入变量
（例如原料属性）
与工艺参数的互动，
其已被证明可以保证
产品质量（
7
< br>）。
drug master file
(DMF)
药物主文件
Detailed information concerning a
specific facility, process or product
submitted to the medicines regulatory
authority, intended for incorporation into
the application for marketing
authorization.
某个公用系统、
工艺或产品的
详细信息，
它被申报给药品法规当局，
用于支持制
剂的上市批准申请。
finished
pharmaceutical product (FPP)
成品药
A product
that has undergone all stages of production,
including packaging in
its fi nal
container and labelling. An FPP may contain one or
more APIs.
一个经过了生产的所有环节，
包括最终
包装和贴标签的产品。
一种成品药可能包
含一种或多种原料药。
gap analysis
差异分析
Identification of critical elements of
a process which are available at the SU but
are missing from the RU.
识别在转出方有，但接收方没有的关键工艺要素。
good manufacturing practices (GMP)
优良制造规范
That part
of quality assurance which ensures that
pharmaceutical products are
consistently produced and controlled to
the quality standards appropriate to
their intended use and as required by
the marketing authorization
(
3
).
质量保证的一部分，
用以保证药品被持续生产和控制，
达到既定使用目的所需的
质量标准，符合上市许可要求。
in-
process control (IPC)
中间控制
Checks performed during production in
order to monitor and, if necessary, to
adjust the process to ensure that the
product conforms to its specifications.
The control of the environment or
equipment may also be regarded as a part of
in-process control.
在生产过程中实施
的检查，
用以监控和，
必要时调查工艺以保证产品符合其质量<
/p>
标准。环境控制或设备控制也可以认为是中控的一部分。
installation qualification (IQ)
安装确认
The
performance of tests to ensure that the
installations (such as machines,
measuring devices, utilities and
manufacturing areas) used in a manufacturing
process are appropriately selected and
correctly installed and operate in
accordance with established
specifications.
对生产工艺中所使用的（例如机器、计量装置、公用
系统和生产区域）安装进行
的测试，
以保证其选择是适当的，<
/p>
安装是正确的，
并可以按既定的标准进行操作。
< br>
intercompany transfer
公司间转移
A transfer
of technology between sites of different
companies.
在不同公司的工厂间进行的技术转移。
intracompany transfer
公司内转移
A transfer
of technology between sites of the same group of
companies.
在公司同一集团内工厂间进行的技术转移。
operational qualification (OQ)
运行确认
Documented
verification that the system or subsystem performs
as intended
over all anticipated
operating ranges.
系统或子系统在需要的操作范围内进行运行的确认及其记录
performance qualifi cation (PQ)
性能确认
Documented
verification that the equipment or system operates
consistently
and gives reproducibility
within defined specifications and parameters for
prolonged periods. (In the context of
systems, the term ―process validation‖
may also be used.)
证明设备或系统能持
续运行，
能在延长的时间内重复实现既定的质量标准和参数
的确
认性文件。（在讨论系统时，可能会使用术语
―
工艺验证
‖
）
process validation
工
艺验证
Documented evidence which provides a
high degree of assurance that a
specific process will consistently
result in a product that meets its
predetermined specifications and
quality characteristics.
证明某工艺能持续稳定生产出符
合既定质量标准和质量特性的文件和记录。
qualification
确认
Action of proving and documenting that
any premises, systems and equipment
are
properly installed, and/or work correctly and lead
to the expected results.
Qualification
is often a part (the initial stage) of validation,
but the individual
qualification steps
alone do not constitute process validation.
证明和记录所有设施、系统和设备已适当安装，和
/
或正确运行，能达到期望的
结果的动作。确认通常是验证的一部分（初始阶段），但单个
验证步骤不能形成
工艺验证。
qualification batches
确认批次
Those
batches produced by the RU to demonstrate its
ability to reproduce the
product
(1)
.
由接收单位生产的，证明其
具备生产能力的批次（
1
）。
quality assurance (QA)
质量保证
Quality
assurance is a wide-ranging concept covering all
matters that
individually or
collectively influence the quality of a product.
It is the totality of
the arrangements
made with the objective of ensuring that
pharmaceutical
products are of the
quality required for their intended use.
质量保证是一个宽范畴的概念，
涵盖所有单独或整体对产品质量造成影响的情况。<
/p>
它是保证药品具有其用途所需的品质所做的所有安排的总和。
quality control (QC)
质量控制
Quality
control covers all measures taken, including the
setting of
specifications, sampling,
testing and analytical clearance, to ensure that
starting materials, intermediates,
packaging materials and finished
pharmaceutical products conform with
established specifications for identity,
strength, purity and other
characteristics.
质量控制包括采取的所有措施，包括设定质量标准
、取样、检测和分析清场，以
保证起始物料、中间体、包材和制剂成品与所建立的均一性
、剂量、纯度和其它
特性相符合。
quality planning
质量计划
Part of
quality management focused on setting quality
objectives and
specifying necessary
operational processes and related resources to
fulfil the
quality objectives
(6)
.
质量管理的一部分，
重点关注质量目标的设置，
指出必要的操作流程，
和满足质
量目标所需的资源（
6
）
。
quality policy
质量方针
Overall
intentions and direction of an organization
related to quality as formally
expressed by senior management
(6)
.
高层管理人员正式表达的与
质量相关的组织目的和全面意图（
6
）。
quality risk management (QRM)
质量风险管理
Quality
risk management is a systematic process for the
assessment, control,
communication and
review of risks to the quality of the
pharmaceutical product
throughout the
product life-cycle.
质量风险管理是药品生命周期中对质量风险
进行评估、
控制、
沟通和回顾的一个
系
统性过程。
receiving unit (RU)
接收单位
The involved
disciplines at an organization where a designated
product,
process or method is expected
to be transferred.
接收被转移产品、工艺或方法所涉及的组织单位。
sending unit (SU)
转出单位
The involved
disciplines at an organization from where a
designated product,
process or method
is expected to be transferred.
将被转移产品、工艺或方法转移出去所涉及的组织单位。
Spiking
加样
The addition of a known amount of a
compound to a standard, sample or
placebo, typically for the purpose of
confirming the performance of an
analytical procedure.
他们标准品、
样品或空白样品中加入已知数量化合物，
典型地应用于确认分析
方
法的性能。
standard
operating procedure (SOP)
标准操作规程
An
authorized written procedure giving instructions
for performing operations
not
necessarily specific to a given product or
material (e.g. equipment
operation,
maintenance and cleaning, validation, cleaning of
premises and
environmental control,
sampling and inspection). Certain SOPs may be used
to supplement product-specific master
and batch production documentation.
批准的
书面程序，
在其中给出非产品或物料专用的操作指令
（例如设备
操作、
维
护和清洁、验证、设施清洁、环境控制、取样和检查）
。特定的
SOP
可能用于
对特定产品工
艺规程和批生产文件进行补充。
technology
transfer report
技术转移报告
A documented summary of a specific
technology transfer project listing
procedures, acceptance criteria,
results achieved and conclusions. Any
deviation should be discussed and
justified.
将特定的技术转移项目程序、可接受标准、达到的结果和结论进
行汇总的文件。
所有偏差均应有讨论和判定。
Validation
验证
Action of
proving and documenting that any process,
procedure or method
actually and
consistently leads to the expected results.
证明并记录所有工艺、程序或方法可以实际地获得一致的期望结果的动作。
validation master plan (VMP)
验证主计划
A high-
level document that establishes an umbrella
validation plan for the
entire project
and summarizes the manufacturer’s overall
philosophy and
approach, to be used for
establishing performance adequacy. It provides
information on the manufacturer’s
validation work programme and defines
details of and timescales for the
validation work to be performed, including a
statement of the responsibilities of
those implementing the plan.
高层次文件，
在其中对一个完整的项目建立一个总体验证计划，
并总结生产商的
总体验证理念和验证方法，
以达到要求的效率。
它提供生产商验证工作程序、
验
证工作时间表、实施人员职责
等信息。
validation protocol (or
plan) (VP)
验证方案（或计划）
A document describing the activities to
be performed in a validation, including
the acceptance criteria for the
approval of a manufacturing process
—
or a part
thereof
—
for
routine use.
描述在验证需要实施的活动的文件，包括批准一个生产工艺
-----
或其中一部分
------
常规使用的可接受标准。
validation report (VR)
验证报告
A document
in which the records, results and evaluation of a
completed
validation programme are
assembled and summarized. It may also contain
proposals for the improvement of
processes and or equipment.
包括完整的验证过程的记
录、
结果和评估整理和总结的文件。
也可以包括工艺和
/
或设备的改进方案。
4.
Organization and
management
组织和管理
4.1 Transfer comprises an SU and an RU.
In some circumstances there may
be an
additional unit which will be responsible for
directing, managing and
approving the
transfer.
转移包括一个转出方和一个接收方。
在有
些环境下，
可能会有更多单位参与指挥、
管理和批准转移。
4.2 There is a formal
agreement between the parties, which specifies the
responsibilities before, during and
after transfer.
双方应该有一个正式的协议，在其中说明在转移前、
转移中、转移后的责任。
4.3 Organization
and management of a successful technology transfer
need to
ensure that the main steps have
been executed and documented as described
in section 1.6.
成功的技术转移组织和管理
需要保证主要步骤进行实施，
并如
1.6
部分要求进行
记录。
4.4
There should be a project management plan which
identifies and controls
all the
necessary activities identified at the start of
the undertaking.
应该有一个项目管理计划，
在其中对开始时界定的一些必要的活动进行识别和控
制。
4.5 The transfer protocol should list
the intended sequential stages of the
transfer. The protocol should include:
转移方案应按顺序列出转移步骤。方案应包括
—
objective;
目的
—
scope;
范围
—
key personnel and their
responsibilities;
关键人员及其职责
—
a
parallel comparison of materials, methods and
equipment;
原料、方法和
设备的平行比较
—
the
transfer stages with documented evidence that each
critical stage has
been satisfactorily
accomplished before the next commences;
转移各步骤
均应有书面证据证明每个关键步骤圆满完成后，方可进入下一步骤
—
identification of critical control
points;
关键控制点的识别
—
experimental design and acceptance
criteria for analytical methods;
实验
设计和分析方法的可接受标准
—
information on trial production
batches, qualification batches and process
validation;
试生产批次的信息，确认批次和工艺验证
—
change
control for any process deviations encountered;
任何遇到的工艺
偏差的变更控制
—
assessment of end-product;
终成品的评价
—
arrangements for keeping retention
samples of active ingredients,
intermediates and finished products,
and information on reference
substances
where applicable; and
活性成份、中间体和制剂的留样的安排
，
适用时，对照品的信息，以及
—
conclusion, including signed-off
approval by project manager.
结论，包括
项目经理批准的签字
4.6 The SU should provide the necessary
validation documentation for the
process and its support functions.
Usually, an established process is
transferred, and such documentation is
already available.
转出方应提供必要的工艺验证文件，
及其支持的功能。
一般转移的工艺应该已建
立好
，这些文件应都是可以获得的。
4.7 The SU
should provide criteria and information on hazards
and critical
steps associated with the
product, process or method to be transferred, to
serve as a basis for a quality risk
management (QRM) exercise at the RU
(
7
–
10
). <
/p>
转出方应提供与将要转移的产品、
工艺或方法相关的安全标准和信
息，
以及关键
步骤，作为接收方进行质量风险管理的基础（
QRM
）。
4.8 The SU or third party should assess
the suitability and degree of
preparedness of the RU before transfer,
with regard to premises, equipment
and
support services (e.g. purchasing and inventory
control mechanisms,
quality control
(QC) procedures, documentation, computer
validation, site
validation, equipment
qualification, water for pharmaceutical production
and
waste management).
转出方或第
三方应在转移前对接收方准备情况进行评估，评估应包括基础设施、
设备和支持性服务（
例如采购和库存控制机制、质量控制（
QC
）程序、文件记
录、计算验证、厂房验证、设备确认、制药用水、废物管理）。
4.9 The SU and the RU should jointly
verify that the following, satisfactorily
completed, validation protocols are
available:
转出方和接收方应联合确认以下内容圆满完成，验证方案已完成
?
installation qualification (IQ) and
operational qualification (OQ) data for
manufacturing and packaging equipment
at the RU site and analytical
equipment; and
?
接收方工厂生产和包装设备、检验设施安装确认和运行确认数据，以及
< br>
?
qualification of the rooms for both
manufacture and packaging at the RU
site.
接受单位生产和包装房间确认
4.10 The SU and the RU should jointly
implement any training programmes
that
may be required specific to the product, process
or method to be
transferred, e.g. on
analytical methods or equipment usage, and assess
training outcomes.
转出方和接收方应联
合实施所有可能需要的与要转移的产品、
工艺或方法相关的
培训
项目，例如分析方法或设备使用，并对培训效果进行评估。
4.11 The SU and the RU should jointly
execute the transfer protocol according
to a checklist and or flow diagram
showing the sequence of steps to be carried
out to effect an efficient transfer.
转出方和接收方应根据表现步骤顺序的检查清单和
/
或流程图联合实施转移方案，
这些步骤的实施顺序可能会影响到转移的效率。<
/p>
4.12 Any changes and
adaptations made during the course of the
technology
transfer should be fully
documented.
所有在技术转移过程中进行的变更均应进行记录。
4.13 The SU and the RU should jointly
document the execution of the transfer
protocol in a transfer of technology
summary in a report.
转出方和接收方应一起记录对转移方案的
实施，在报告中记录技术转移总结。
Project
team
项目组
4.14 Any
transfer project will be managed by a team
comprising members with
clearly defined
key responsibilities. The team should be drawn
from members
of relevant disciplines
from both the SU and RU sites.
所有转移项目应由
项目组管理，
项目组人员主要职责均应明确。
项目组应从转出<
/p>
方和接收方相关学科人员中选出。
4.15 The team members should have the
necessary qualifications and
experience
to manage their particular aspect of the transfer.
项目组成员应具备必要的资质和经验，以管理转移中的不同方面。
5.
Production: transfer
(processing, packaging and cleaning)
生产：转移
（工艺、包装和清洁）
5.1 The RU should be able to
accommodate the intended production capacity.
If possible, it should be established
at the outset whether the intention is to
perform single-batch manufacture,
continuous production or campaigns.
接收方
应提出想要的生产规模。
可能时，
应在开始时即决定是单批生产
、
连续生
产还是周期生产模式。
5.2 Consideration should be given to
the level and depth of detail to be
transferred to support production and
any further process development and
optimization at the RU as intended
under the transfer project plan.
要考虑能支持
接收方的生产、
所有进一步工艺研发、
接收方优化工艺所需的转
移
的详细程度。
5.3
Consideration should be given to the technical
expertise, site technology
and site
capabilities for the RU. It should be identified
upfront by the SU of any
process
robustness issues so that plans may be put in
place at the RU.
需要考虑接收方的技术专业能力、
场所技术和场所产能。
转出方应识别出工艺耐
用性，这
样接收方可以制订计划。
5.4 The SU and
the RU should jointly develop a protocol for the
transfer of
relevant information
related to the process under consideration from
the SU to
the RU, as well as the
development of a comparable process at the RU.
转出方和接收方应基于共同考虑，
一起制订一份针对与工艺转移相关信
息的方案，
以及接收方研发可比性工艺的信息。
Starting materials
起始物料
5.5 The
specifications and relevant functional
characteristics of the starting
materials (APIs and excipients)
(
11,12
) to be used at the RU
should be
consistent with materials
used at the SU. Any properties which are likely to
influence the process or product should
be identified and characterized.
接收方会用作
起始物料（原料药或辅料（
11.12
））的质量标准和相关功
能性特
性应与转出方所用的一致。
所有可能会对工艺或产品产生
影响的特性均应进行识
别和描述。
Active pharmaceutical ingredients (API)
活性药物成分（原料药）
5.6
The SU should provide the RU with the open
(applicant’s) part of the API
master
file (APIMF or drug master file (DMF) or active
substance master file
(ASMF)), or
equivalent information and any relevant additional
information on
the API of importance
for the manufacture of the pharmaceutical product.
The
following are examples of the
information which may typically be provided;
however the information needed in each
specific case should be assessed
using
the principles of QRM:
转出方应向接收方提供原料药药物主
文件
（
APIMF
或
< br>DMF
或
ASMF
）
公开部分，
或等同的信息，
对制剂生产具有重要意
义的原料药的其它相关信息，
在每个单独
的个案中，应采用质量
风险管理的原则对所需要的信息进行评估：
?
manufacturer and associated supply
chain;
?
生产商和相关的供应链
?
step of
the API to be transferred;
?
将要转移的原料药的步骤
?
flow
chart of synthesis pathway, outlining the process,
including entry
points for raw
materials, critical steps, process controls and
intermediates;
?
合成路线流程图，
合成概述，包括原料加入点，关键步骤，工艺控制和
中间
体
?
where relevant, definitive physical
form of the API (including
photomicrographs and other relevant
data) and any polymorphic and
solvate
forms;
?
适用时，
原料药的最终物理形态
（包括显微图片和其它相关的数
据）
和所有
晶型和溶剂化形态
?
solubility profile;
?
溶解性概况
?
if
relevant, pH in solution;
?
必要时，溶液的
pH
值
?
partition coefficient, including the
method of determination;
?
分配比例，包括所用的检测方法
?
intrinsic dissolution rate, including
the method of determination;
?
特性溶出速率，包括所用的检测方法
?
particle size and distribution,
including the method of determination;
?
粒径分布，包括所用的检测方法
?
bulk
physical properties, including data on bulk and
tap density, surface
area and porosity
as appropriate;
?
散装物理特性，包括松密度和紧密度，表面积和孔隙度（适用时）
?
water
content and determination of hygroscopicity,
including water activity
data and
special handling requirements;
?
水份，吸湿性测试，包括水活性数据和特殊的处置要求
?
microbiological considerations
(including sterility, bacterial endotoxins and
bioburden levels where the API supports
microbiological growth) in
accordance
with national, regional or international
pharmacopoeial
requirements;
?
微生物（包括无
菌性、细菌内毒素，如果辅料支持微生物生长的话，还包括
生物负载水平）符合国家、地
区或国际药典要求
?
specifications and justification for
release and end-of-life limits;
?
放行标准和论证，生命终结期时的限度
?
summary
of stability studies conducted in conformity with
current
guidelines, including
conclusions and recommendations on retest date;
?
根据现行指南已
进行的稳定性研究的总结，包括复验期的结论和建议
?
list of
potential and observed synthetic impurities, with
data to support
proposed specifications
and typically observed levels;
?
潜在的和已观察
到的合成杂质清单，
满足所提议的质量标准的数据和代表性
观察
水平
?
information on degradants, with a list
of potential and observed
degradation
products and data to support proposed
specifications and
typically observed
levels;
?
降解物信息，
潜在的和已观察到的降解产物和满足所提议的限度的数据及典
型水平
?
potency factor, indicating observed
purity and justification for any
recommended adjustment to the input
quantity of API for product
manufacturing, providing example
calculations; and
?
效价因子，
包括观察到的纯度，
生产过
程中原料药加入调整量的推荐值的论
述，举例说明计算方式，以及
?
special considerations with
implications for storage and or handling,
including but not limited to safety and
environmental factors (e.g. as
specified in material safety data
sheets) and sensitivity to heat, light or
moisture.
?
关于存贮和处置的特殊考虑内容，
包括但不限于安全和环境因素
（例如，
在
MSDS
< br>中说明）和对热、光、湿的敏感性
Excipients
辅料
5.7 The excipients
(
11
) to be used have a
potential impact on the final product.
Their specifications and relevant
functional characteristics should, therefore,
be made available by the SU for
transfer to the RU site. The following are
examples of the information which may
typically be provided; however, the
information needed in each specific
case should be assessed using the
principles of QRM:
用于生产的辅料（<
/p>
11
）如果对成品有潜在影响，其质量标准和相关的功能性特
性应由转出方转移给接收方。
以下为代表性信息样例，
特殊情况下所需要的信息
应采用风险管理方法原则进行评估
< br>
?
manufacturer and associated supply
chain;
?
生产商和相关的供应链
?
description of functionality, with
justification for inclusion of any antioxidant,
preservative or any excipient;
?
如有添加抗氧剂、防腐剂或辅料，应有其功能描述及论证
?
definitive form (particularly for solid
and inhaled dosage forms);
?
最终的剂型（尤其是固体和吸入剂型）
?
solubility profile (particularly for
inhaled and transdermal dosage forms);
?
溶解性概况（尤其是对吸入和透皮剂型）
?
partition coefficient, including the
method of determination (for
transdermal dosage forms);
?
分配比例，包括所用的测试方法（透皮剂型）
?
intrinsic dissolution rate, including
the method of determination (for
transdermal dosage forms);
?
特性溶出速率，包括所用的检测方法（透皮剂型）
?
particle size and distribution,
including the method of determination (for
solid, inhaled and transdermal dosage
forms);
?
粒径分布，包括所用的测试方法（固体、吸入剂和透皮剂型）
?
bulk
physical properties, including data on bulk and
tap density, surface
area and porosity
as appropriate (for solid and inhaled dosage
forms);
?
散装物理特性，
包括松密度和紧密度，
适当时还包括表面积和
孔隙度
（固体
和吸入剂型）
?
compaction properties (for solid dosage
forms);
?
压制特性（固体剂型）
?
melting
point range (for semi-solid or topical dosage
forms);
?
熔点范围（半固体或局部用药）
?
pH
range (for parenteral, semi-solid or topical,
liquid and transdermal
dosage forms);
?
pH
范围（注射剂、半固体剂、局部用药、液体和透皮剂型）
?
ionic
strength (for parenteral dosage forms);
?
离子化强度（注射剂型）
?
specific density or gravity (for
parenteral, semi-solid or topical, liquid and
transdermal dosage forms);
?
密度或比重（注射剂、半固体或局部用药、液体和透皮剂型）
?
viscosity and or viscoelasticity (for
parenteral, semi-solid or topical, liquid
and transdermal dosage forms);
?
粘性和粒弹性（
注射剂、半固体剂或局部用药、液体、透皮剂型）
?
osmolarity (for parenteral dosage
forms);
?
摩尔浓度（注射剂型）
?
water
content and determination of hygroscopicity,
including water activity
data and
special handling requirements (for solid and
inhaled dosage
forms);
?
水分和吸湿性测
试，
包括水的活性数据和特殊的处置要求
（固体和吸入剂型）<
/p>
?
moisture content range (for parenteral,
semisolid or topical, liquid and
transdermal dosage forms);
?
水分控制范围（
注射剂、固体或局部用药、液体和透皮吸收剂型）
?
microbiological considerations
(including sterility, bacterial endotoxins and
bioburden levels where the excipient
supports microbiological growth) in
accordance with national, regional or
international pharmacopoeial
requirements, as applicable (for
general and specific monographs);
?
微生物特性（包
括无菌性、细菌内毒素，如果辅料支持微生物生长的话，还
包括生物负载水平）应符合国
家的、地区的或国际药典要求，适用时（通论
和各论）
?
specifications and justification for
release and end-of-life limits;
?
放行和生命终结时间点质量标准和论述
?
information on adhesives supporting
compliance with peel, sheer and
adhesion design criteria (for
transdermal dosage forms);
?
贴剂符合剥离性、透明和粘性设计要求的信息（经皮给药剂型）
?
special
considerations with implications for storage and
or handling,
including but not limited
to safety and environmental factors (e.g. as
specified in material safety data
sheets (MSDS)) and sensitivity to heat,
light or moisture; and
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关于存贮和处置
时的特殊考虑，包括但不仅限于安全和环境因素（例如，
MSDS
），和热敏性、光敏性、吸湿性，以及
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regulatory considerations, e.g.
documentation to support compliance with
transmissible animal spongiform
encephalopathy certification
requirements (where applicable).
?
法规要求方面的
考虑，例如，支持
TSE
认证要求的文件（适用时）
Information on process and
finished pharmaceutical products
information
工艺信息和成品信息
5.8 The
SU should provide a detailed characterization of
the product, including
its qualitative
and quantitative composition, physical
description, method of
manufacture, in-
process controls, control method and
specifications,
packaging components
and configurations, and any safety and handling
considerations.
转出方应提供产品的详细特
性，包括其定性和定量组成、物理描述、生产方法、
中控、
控制
方法和质量标准、
包装组件和参数、
以及所有安全的操作考虑事
项信
息。
5.9 The SU
should provide any information on the history of
process
development which may be
required to enable the RU to perform any further
development and or process optimization
after successful transfer.
转出方应提供工艺研发历史
信息，接收方可能需要这些信息来进行进一步研发，
或在转移成功后进行工艺优化
Such information may include
the following:
以上信息可以包括
?
information on clinical development,
e.g. information on the rationale for
the synthesis, route and form
selection, technology selection, equipment,
clinical tests, and product
composition;
?
临床研发信息，
例如合成的合理性、
给药途径和剂
型选择、
技术选择、
设备、
临床测试和
产品组成
?
information on scale-up activities:
process optimization, statistical
optimization of critical process
parameters, critical quality attributes, pilot
report and or information on pilot-
scale development activities indicating
the number and disposition of batches
manufactured;
?
放大生产的信息：
工艺优化、关键工艺参数统计学优化、关键质量属性、
中
试报告和
/
或中试研发活动信息，包
括生产的批次数和处理
?
information or report on full-scale
development activities, indicating the
number and disposition of batches
manufactured, and deviation and