WHO第961号技术报告材料_附件7_药物生产技术转移指南设计(中英文)

WHO第961号技术报告 附件7 药物生产技术转移指南

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

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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。

1.2 Transfer of technology 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WHO指南中阐述了对此问题的推荐。

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

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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、生产和质量控制各方面。一般会有一个转出方(SU)，一个接收方和管理工艺的单位。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，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.

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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.

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。

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、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.

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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。

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

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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

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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）。

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，安装是正确的，并可以按既定的标准进行操作。

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

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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。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）。

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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

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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

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— 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).

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

 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。

4.12 Any changes and adaptations made during the course of the technology transfer should be fully documented.

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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）

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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;

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 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（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  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);

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 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）

 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  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

 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;

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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 change control (sometimes referred to as change management) reports which led to the current manufacturing process;

所有研发过程中的活动信息或报告，包括生产的批次数和处理，形成目前生产工艺的偏差和变更控制报告（有时引用变更管理）

 the change history and reasons, e.g. a change control log, indicating any changes to the

process or primary packaging or analytical methods as a part of process optimization or improvement; and

变更历史和原因，例如变更控制台帐，包括在工艺优化或改进中对工艺或内包装、检验方法的任何变更，以及

 information on investigations of problems and the outcomes of the investigations.

问题调查的信息，调查结果

5.10 The SU should provide to the RU information on any health, safety and environmental issues associated with the manufacturing processes to be transferred, and the implications, e.g. need for gowning or protective clothing.

转出单位应向接收单位提供所有与将要转移的工艺相关的卫生、安全、环境问题的信息，以及所有内含意义，例如更衣或保护性着装要求

5.11 The SU should provide to the RU information on current processing and testing, including but not limited to:

转出单位应向接收单位提供现行工艺和检测的信息，包括但不限于  a detailed description of facility requirements and equipment;

厂房设施和设备的要求的详细描述

 information on starting materials, applicable MSDS and storage requirements for raw

materials and finished products;

起始物料、适用的MSDS、原料、成品存贮条件的信息

 description of manufacturing steps (narrative and process maps or flow charts, and or

master batch records), including qualification of in processing hold times and conditions, order and method of raw material addition and bulk transfers between processing steps

生产工艺的描述（工艺描述、工艺图或流程图，批记录母版），包括确认工艺放置时间和条件、原料投加顺序和加入方法、不同工艺步骤间物料转移

 description of analytical methods;

分析方法的描述

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 identification and justification of control strategy (e.g. identification of critical performance

aspects for specific dosage forms, identification of process control points, product quality attributes and qualification of critical processing parameter ranges, statistical process control (SPC) charts);

控制策略的识别和论述（例如，识别特定剂型的关键表现方面、识别工艺控制点、产品质量属性和关键工艺参数范围的确认、统计工艺控制（SPC）图表）

 design space, in cases where this has been defined;

设计空间，如有

 validation information, e.g. validation plans and reports; 验证信息，例如验证计划和报告

 annual product quality reviews; 年度产品质量回顾

 stability information; 稳定性信息

 an authorized set of protocols and work instructions for manufacturing; and 批准过的方案和工作指令

 environmental conditions or any special requirement needed for the facility or equipment

depending on the nature of the product to be transferred.

根据所转移的产品的属性而提出的对环境条件、厂房和设备所有特殊要求

5.12 During the transfer process, the RU should identify any differences in facilities, systems and capabilities and communicate with the SU about these differences to understand the potential impact on ability to run the process to deliver good product quality. Differences should be understood and satisfactorily addressed to assure equivalent product quality. Based on the

information received from the SU, the RU should consider its own capability to manufacture and pack the product to the required standards and should develop relevant plant operating procedures and documentation before the start of production. Process development at the RU should address the following tasks:

在转移过程中，接收方应找出所有与转出方的不同点，包括厂房设施、系统和产能，与转出方进行沟通，以了解这些不同对形成产品质量的工艺的潜在影响。不同之处应让大家了解，并进行讨论说明，以保证等同的产品质量。基于从转出方收到的信息，接收方应考虑其自身按要求的标准进行生产和包装的能力，在生产开始前，建立相关的厂区操作程序和文件记录。接收方进行工艺发展时，应重点考虑以下任务：

 comparison and assessment of suitability and qualification of facility and equipment; 厂房和设备的适用性和确认的比较和评估

 description of manufacturing process and flow of personnel and of materials at the RU

(narrative and or process maps or flow charts);

接收方对生产工艺的描述、人流图、物流图（描述和/或工艺图或流程图）

 determination of critical steps in manufacture, including hold times, endpoints, sampling

points and sampling techniques (13);

生产关键步骤的确定，包括放置时间、终点、取样点和取样技术（13）

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 writing and approval of SOPs for all production operations (e.g. dispensing, granulation or

blending or solution preparation, tablet compression, tablet coating, encapsulation, liquid filling, primary and secondary packaging and in-process quality control), packaging, cleaning, testing and storage;

所有生产操作（例如分装、制粒或混合、溶液制备、片剂压制、片剂包及、胶囊封装、液体充填、

内包装和外包装、中控）、包装、清洁、检测和存贮均应有书面的经过批准的SOP。

 evaluation of stability information, with generation of site-specific stability data if required

(14); and

对稳定性信息进行评估，如果需要则应进行本场所的稳定性试验（14），以及

 compliance with regulatory requirements for any changes made, e.g. in terms of batch size. 如果有做出变更，应符合法规要求，例如批量变更

Packaging 包装

5.13 The transfer of packaging operations should follow the same procedural patterns as those of the production transfer.

包装操作的转移应采用与生产转移相同的程序。

5.14 Information on packaging to be transferred from the SU to the RU includes specifications for a suitable container or closure system, as well as any relevant additional information on design,

packing, processing or labelling requirements and tamper-evident and anti-counterfeiting measures needed for qualification of packaging components at the RU.

需要从转出方转移至接收方的包装信息包括适当的容器或密闭系统的质量标准，与设计、包装、处理或标签要求、接收单位包装确认所需的防拆封和防伪措施。

5.15 For QC testing of packaging components, specifications should be provided for drawings, artwork and material (for example, glass, card or fibre board).

包装组件、质量标准应提供画图、设计图和材质检测信息供QC（例如玻璃、卡或纤维板）。

5.16 Based on the information provided, the RU should perform a suitability study for initial

qualification of the packaging components. Packaging is considered suitable if it provides adequate protection (preventing degradation of the medicine due to environmental influences), safety (absence of undesirable substances released into the product), compatibility (absence of

interaction possibly affecting medicine quality) and performance (functionality in terms of drug delivery).

基于所收到的信息，接收单位应进行包装组件的初始稳定性试验。如果提供了充分的保护性（预防由于环境影响对产品造成的降解）、安全性（没有不希望的物质释放至产品中）、相容性（没有对药品质量可能产生影响的相互作用）和其表现信息，则可以认为该包装是适当的。

Cleaning 清洁

5.17 During the manufacturing process, pharmaceutical products and APIs can be contaminated by other pharmaceutical products or APIs if the plant is processing different products. To minimize the risk of contamination and cross-contamination, operator exposure and environmental effects, adequate cleaning procedures are essential.

如果工厂生产不同产品，则在生产过程中，制剂和原料药可能会受到其它制剂或原料药的污染。为最大程度减少污染和交叉污染，操作者暴露和环境影响，需要建立充分的清洁程序。

5.18 Cleaning procedures and their validation are site-specific. In order for the RU to define its cleaning strategy the SU should provide information on cleaning at the SU to minimize

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cross-contamination due to residues from previous manufacturing steps, operator exposure and environmental impact, including:

清洁程序和验证根据各工厂情况不同而不同。为使用接收单位可以制订其清洁策略，转出单位应提供在转出单位的清洁信息，以最大程度减少由于之前的生产带来的交叉污染，操作人员暴露和环境影响，包括

— information on solubility of active ingredients, excipients and vehicles; — 活性成份、辅料和赋形剂的溶解性信息

— minimum therapeutic doses of active ingredients; — 活性成份的最小治疗剂量

— therapeutic category and toxicological assessment; and — 治疗分析和毒性评估，以及 — existing cleaning procedures. — 已有清洁程序

Additional information should be provided, as appropriate and where available, e.g.: 如果需要并可以获得，还需要提供一些额外信息，例如

— cleaning validation reports (chemical and microbiological); — 清洁验证报告（化学残留和微生物情况）

— information on cleaning agents used (efficacy, evidence that they do not interfere with

analytical testing for residues of APIs, removal of residual cleaning agents); and

— 所使用的清洁剂（效价、与原料药残留的检测不会相互干扰的证据、清洁剂去除），和 — recovery studies to validate the sampling methodology. — 验证取样方法回收率

5.19 Before the transfer, the SU should provide information on limits for product residues, and the rationale for limit selection.

在转移前，转出方应提供产品残留限度信息，以及限度选择的合理性论述。

5.20 Based on the information provided by the SU, cleaning procedures should be designed at the RU, taking into account relevant characteristics of the starting materials (e.g. potency, toxicity, solubility, corrosiveness and temperature sensitivity), manufacturing equipment design and configuration, cleaning agent and products residue.

基于转出方提供的信息，接收方应设计清洁程序，并在其中考虑起始物料的相关特性（例如，效价、毒性、溶解性、腐蚀性、温度敏感性），生产设备设计和参数、清洁剂和产品残留。

Implementation of processing, packaging and cleaning systems 工艺、包装和清洁体系的实施

5.21 Trial batch(es) (“demonstration batches”) are normally produced to confirm process capability before initiating formal validation. Where trial batches are produced, at a minimum, all critical processing parameters and finished product specifications should be assessed.

一般会生产试验批（“模拟批”）以确认生产能力，然后再开始正式的验证。如果生产了试验批，则最少需要对所有关键工艺参数和成品质量标准进行评估。

5.22 Once process capability has been established at the RU, assuring that the product, process or method at the RU meets predefined and justified specifications, process validation and cleaning validation can be carried out.

一旦接收方建立自己的生产能力，保证产品、工艺或检验方法符合预定的经过论证的质量标准，就可以进行工艺验证和清洁验证。

6. Quality control: analytical method transfer 质量控制：分析方法转移

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6.1 Transfer of analytical methods should accommodate all the analytical testing required to demonstrate compliance of the product to be transferred with the registered specification (15). 分析方法转移应包括所有证明被转移产品符合注册标准（15）所需要的检测方法。

6.2 Analytical methods used to test pharmaceutical products, starting materials, packaging

components and cleaning (residue) samples, if applicable, should be implemented at the testing laboratory before testing of samples for process validation studies is performed by the RU. Process validation samples may be tested at the RU, the SU or a third laboratory.

用于检测药品、起始物料、包装材料和清洁残留样品的检验方法均应先在化验室试验，方可用于检测接收方的工艺验证中的样品。工艺验证样品可以在接收方进行检测，也可以在转出方或第三方化验室进行检测。

6.3 A protocol defining the steps should be prepared for transfer of analytical methods. The analytical methods transfer protocol should include a description of the objective, scope and

responsibilities of the SU and the RU; a specification of materials and methods; the experimental design and acceptance criteria; documentation (including information to be supplied with the results, and report forms to be used, if any); procedure for the handling of deviations; references; signed approval; and details of reference samples (starting materials, intermediates and finished products).

要准确一份分析方法转移方案，说明转移的步骤。分析方法转移方案应包括目的、范围、接收方和转出方责任、原料质量标准、检验方法、试验设计和可接受标准、文件记录（包括结果所需信息、要使用的报告格式，如有）、处理偏差的程序、签字批准、对照样品的详细信息（起始物料、中间体和成品）。

6.4 The SU’s responsibilities for the transfer of analytical methods are to: 转出单位在分析方法转出时的责任

 provide method-specific training for analysts and other quality control staff, if required; 给化验员和其它质量控制人员（如必要）提供专用方法的培训，

 assist in analysis of QC testing results; 帮助QC分析检验结果

 define all methods to be transferred for testing a given product, starting material or cleaning

sample;

定义所有将要转移的检验方法，包括产品、起始物料或清洁样品

 define experimental design, sampling methods and acceptance criteria; 定义实验设计、取样方法和可接受标准

 provide any validation reports for methods under transfer and demonstrate their robustness; 提供所有要转移的方法验证报告，考察其耐用性

 provide details of the equipment used, as necessary (part of validation report, if available)

and any standard reference samples;

提供所用设备详细信息（验证报告的一部分，如有），标准对照样品

 provide approved procedures used in testing; and 提供批准的检验程序

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 review and approve transfer reports. 审核和批准转移报告

6.5 The RU’s responsibilities are to: 接收单位的责任

 review analytical methods provided by the SU, and formally agree on acceptance criteria

before execution of the transfer protocol;

审核由转出单位提供的分析方法，在实施转移方案前对可接受标准表示正式同意

 ensure that the necessary equipment for QC is available and qualified at the RU site. The

equipment used by the RU during the analytical transfer should meet appropriate specifications to ensure the requirements of the method or specification are met;

保证接收单位QC有必须的仪器，并经过确认。接收单位在方法转移过程中所用的仪器应符合适

当的质量标准，以保证满足方法和质量标准的要求

 ensure that adequately trained and experienced personnel are in place for analytical testing; 保证有充分的培训，有经验的人员进行分析检测

 provide a documentation system capable of recording receipt and testing of samples to the

required specification using approved test methods, and of reporting, recording and collating data and designation of status (approved, rejected, quarantine);

应有适当的文件体系，保证记录以下信息：样品的接收、按照批准的检验方法进行检测，判断是

否符合质量标准、报告、记录和审核数据和最终状态（批准、不合格、待检）。

 execute the transfer protocol; 实施转移方案

 perform the appropriate level of validation to support the implementation of the methods; and 进行适当水平的验证以支持方法的实施，和

 generate and obtain approval of transfer reports. 起草并批准转移报告

6.6 Appropriate training should be provided and all training activities and outcomes should be documented.

应提供适当的培训，所有培训活动和结果均应有记录。

6.7 Reference to compendial monographs (e.g. The International Pharmacopoeia (15), European Pharmacopoeia, British Pharmacopoeia and United States Pharmacopeia), where available, is expected.

如果有相关的药典各论，应进行引用（例如国际药典（15），欧洲药典，英国药典和美国药典）。

6.8 Possible experimental designs and acceptance criteria for the main analytical testing methods are shown in Table 1. Note that this table represents high-level guidance to apply the general principle that method transfers should account for the variability and sensitivity of the method and the specifications for the quality parameter. Alternative procedures and acceptance criteria may be applied based on science and the characteristics of the analytical method and the analyte.

表1中给出了主要的分析检测项目可能的试验设计和可接受标准。注意该表格给出的在方法转移中，需要考虑质量参数的质量标准和方法的变动性和敏感性，是应用一般原则的高水平指南。公司可根据自身的分析方法和分析样品的科学和属性，制订相应的程序和可接受标准。

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实用文档 Table 1 Possible experimental designs and acceptance criteria for analytical testing 表1 分析方法可接受标准和可能的试验设计 Test Considerations for transfer 测试项目 转移考虑问题 Replication of tests 测试重复性 Set-up 硬件要求 Acceptance criteria 可接受标准 Direct 直接说明 Statistically derived 更满意的方法 Transfer should focus on sample preparation, On determination instruments, data usually sufficient interpretation. Acceptable Identity to demonstrate to include in assay transfer 鉴别 equivalence where relevant. 一般证明其对等性即转移应关注样品制备、仪器、数可 据诠释。需要时可以将含量转移包括在其中。 — non-specific assay should not be used for Different sets of At each site: 2 stability testing instruments and analysts×3lots, in — 非专属性含量方法不应columns Assay for triplicate (=18 per 用于稳定性测试 Independent potency site) — Bracketing maybe solution 效价含量 每一场所：2个化验员appropriate for multiple preparation 各3批，3次重复检测 strengths 不同仪器和色谱住、（=18结果/场所） — 对于多剂量情况可以采单独配制溶液 取矩阵方式 Different sets of If method is equivalent to instruments and At each site: 2 assay method, separate columns Content analysts×1 lot (= 2 transfer is not usually independent uniformity per site) required solution 含量均一性 每一场所：2个化验员如果方法与含量方法等同，则一preparation 各1批（=2结果/场所） 般不没有单独转移要求 不同仪器和色谱柱、单独配制溶液 Two one-sided t-tests with intersite Comparison of mean and variability differences≤2%, 95% 比较平均值和变动性 confidence 两次单边t测试95%置信区间同场所内差异≤3% Mean at RU within ±3% of mean at Two one-sided t-tests with SU; comparison of relative st. dev. intersite differences 接收单位平均值在转出单位平均值的≤3%, 95% confidence ±3%变动范围内 两次单边t测试95%置信区间比较RSD值 同场所内差异≤3% 文案大全

实用文档 6 units (12 if not routine at RU, and Compare profile (e.g. F2), Bracketing may be for extended Mean at RU within ±5% of mean at or appropriate for multiple Dissolution release products) SU Compare data at Q time strengths 溶出度 六组（如果在接受单接受单位的平均值在转出单位平均值points as for assay 对于多剂量情况可以采用矩阵位是非常规测试，则的±5%范围内 概况比较（例如F2），或含方法 需要12组，如为缓释量Q时间点数据比较 药品，也需要12组） Use spiked samples, with levels within Cleaning 3×validated st. — All samples spiked above verificatioConfirm that same swabbing dev. Or within specification should fail n (recovery material is used at sending ±10% of — 所有加样样品如超出限度则判of residues unit (SU) and receiving unit specification 定为失败 from (RU) (whichever is — 90% of samples spiked below surfaces) 确认转出单位与接收单位所用greater) specification should pass 清洁确认（从的擦拭材料相同 采用加样检测，3倍— 90%加样样品在限度以下则判表面上收集验证过的SD值水平，定为通过 残留） 或在限度的±10%范围内（取大者） — execute common on-site validation protocol: Micro-biolorationale; method gical — Qualitative; Demonstrate identity; validation testing recovery of micro-organisms parameters; data (qualitativUse different lots — Quantitative; Recovery summary; acceptance e and Validation in for each validation levels within acceptance criteria; methods of quantitativtriplicate exercise limits specified in protocol compiling and analyzing e limit 验证应重复3次 对各验证采用不同的 data; handling of out-o tests) 批次 — 定性，证明微生物回收能力 –specification 微生物检测 — 定量，回收水平在方案的可接results; follow-up （定性和定受限度内 requirements 量限度检测） — 实施一般的现场验证方案：合理、方法相同、验证文案大全

实用文档 参数、数据总结、可接受标准、数据分析和汇总方法、OOS结果处理、跟踪要求 — Use same materials, techniques, inoculum preparation — 采用相同材料、技术、接种制备 — Different days, different sets of instruments — Confirm response and columns factors for calculation — Use samples relative to drug peak; At each site: of similar age, — Confirm limit of 2 analysts × 3 homogeneity, (For low levels)Values at RU within (For moderately high quantization at RU; lots, in duplicate Impurity, packaging, ±25% of values at SU, or Mean at levels) Two one-sided — Compare chromatograms (in triplicate if degradationstorage RU within ±0.05% of mean at SU (5%) t-tests, differences — Compare accuracy and done together with , residual — Use spiked ≤10%, 95% confidence precision for spiking assay) solvents samples if （低水平下）接收单位的结果应为转 experiments 每一场所： 杂质、降解产necessary 出单位的±25%范围内，或接受单位的（对于中等水平杂质）两次— 确认相对于产品的响应2名化验员各3批各测物、残留溶剂 — 在不同天，采结果平均值为转出单位平均值（5%）单边t测试95%置信区间时差因子 两次 用不同仪器和不的±0.05%以内 异≤10% — 确认接收单位的定量限 （如果与含量一起同柱子 — 比较色谱系统 做，则各测3次） — 采用具有相似— 比较加样条件下准确度存放时长、均一和精密度 性、包装、存贮条件的样品 — 必要时使用加样样品 St.dev. standard deviation. SD标准偏差 Note: numbers in the table are given as examples only and should not be considered as recommendations 注：表中的数字仅作为例子给出，不是推荐值。 文案大全

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The SU and the RU should execute the transfer protocol and jointly prepare a transfer report. The points to be addressed in the analytical methods transfer report are listed in these guidelines. 转出方和接收方应实施转移方案，联合准备一个转移报告。分析方法转移报告中需要强调的问题也列在这些指南中。

7. Premises and equipment 设施和设备

Premises 设施

7.1 The SU should provide information to the RU on the layout, construction and finish of buildings and services (16,17) (heating, ventilation and airconditioning (HVAC), temperature, relative humidity, water, power, and compressed air), which have an impact on the product, process or method to be transferred.

转出单位应将建筑平面图、建造和完成情况，以及服务商的信息等，会对要转移的产品、工艺或方法造成影响的因素，提供给接受单位（16，17）（供暖、通风和净化空调（HVAC）、温度、相对湿度、供水、供电和压缩空气）。

7.2 The SU should provide information on relevant health, safety and environmental issues, including:

转出单位应提供与健康、安全和环境有关的信息，包括

 inherent risks of the manufacturing processes (e.g. reactive chemical hazards, exposure

limits, fire and explosion risks);

生产工艺内在的风险（例如，化学反应危害，暴露极限，火灾和爆炸风险）

 health and safety requirements to minimize operator exposure (e.g. atmospheric

containment of pharmaceutical dust);

减少操作暴露的健康和安全要求（例如药物粉末对大气影响）

 emergency planning considerations (e.g. in case of gas or dust release, spillage, fire and

firewater run-off); and

紧急处理计划的考虑因素（例如，如果气体或粉尘泄漏，散落，着火和消防水用完）；以及

 identification of waste streams and provisions for re-use, recycling and/ or disposal.  废弃途径和重复使用、循环和/或弃置规定

Equipment 设备

7.3 The SU should provide a list of equipment, makes and models involved in the manufacture, filling, packing and or control of the product, process or method to be transferred, together with existing qualification and validation documentation. Relevant documentation may include:

转出单位应提供一个用于生产、充填、包装和/或产品控制、工艺控制、或要转移的方法所用的设备清单，包括设备的品牌和型号，以及现有的确认和验证文件。相关文件可能包括

— drawings; 平面图 — manuals; 手册

— maintenance logs; 维护记录

— calibration logs; and 校正记录，和

— procedures (e.g. regarding equipment set-up, operation, cleaning, maintenance, calibration

and storage). 程序（例如，关于设备安装、操作、清洁、维护、校正和贮存）

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7.4 The RU should review the information provided by the SU together with its own inventory list including the qualification status (IQ, OQ, PQ) of all equipment and systems, and perform a

side-by-side comparison of equipment at the two sites in terms of their functionality, makes, models and qualification status.

接收单位应审核这些由转出单位提供的信息，以及自己的设备清单包括所有设备和系统的确认状态（IQ,OQ,PQ），并对两场所的设备进行一一比较，包括其功能、品牌、型号和确认状态。

7.5 The RU should perform a gap analysis to identify requirements for adaptation of existing equipment, or acquisition of new equipment, or a change in the process, to enable the RU to reproduce the process being transferred. GMP requirements should be satisfied and intended production volumes and batch sizes (e.g. same, scaled-up or campaign) should be considered. Factors to be compared include:

接收单位应进行差异分析以识别现有设备采用的标准，或对新设备的需求，或工艺的变更，以使接收单位能再现被转移的工艺。需要满足GMP要求，需要考虑目标的生产量、批量（例如等同、放大或生产周期）。要比较的因素包括

— minimum and maximum capacity; 最小和最大产能 — material of construction; 建造用原料

— critical operating parameters; 关键操作参数

— critical equipment components (e.g. filters, screens, and temperature/ pressure sensors); 关

键设备组件（例如过滤器、过筛机，和温度/压力探头） — critical quality attribute; and 关键质量特征，和 — range of intended use. 目的使用范围

7.6 The facility- and building-specific location of all equipment at the RU should be considered at the time of drawing up process maps or flow charts of the manufacturing process to be transferred, including flows of personnel and material.

在制作要转移的工艺图或生产工艺流程图时，要考虑接收单位的厂房建筑和所有设备的位置，包括人流和物流。

7.7 The impact of manufacturing new products on products currently manufactured with the same equipment should be determined.

要确认共用设备情况下新产品对已有产品的影响。

7.8 Any modification of existing equipment that needs to be adapted to become capable of reproducing the process being transferred should be documented in the transfer project plan. 为了能用于被转移的工艺的生产而对已有设备所做的任何改造都必须记录在转移项目计划中。

8. Documentation 文件

8.1 The documentation required for the transfer project itself is wide ranging. Examples of documentation commonly required are summarized in Table 2.

项目转移本身文件要求范围很宽。常规要求的文件举例归纳在表2中。

8.2 The documented evidence that the transfer of technology has been considered successful should be formalized and stated in a technology transfer summary report. That report should summarize the scope of the transfer, the critical parameters as obtained in the SU and RU

(preferably in a tabulated format) and the final conclusions of the transfer. Possible discrepancies should be listed and appropriate actions, where needed, taken to resolve them.

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一个技术转移被认为是成功的时候，证明其成功的文件证据需要正式化，并在技术转移总结报告中申明。该报告应总结转移的范围、转出单位和接收单位所获得的关键参数（最好以表格形式）、转移的最终结论。应列出可能的差异，如果需要时，应采取可能的措施解决并记录。

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实用文档 Table 2 表2 Examples of documentation for transfer of technology (TOT) 技术转移文件举例（TOT） Key task 关键任务 Project definition 项目定义 Documentation provided by SU 转出方提供的文件 Project plan and quality plan (where separate documents), protocol, risk assessments, gap analysis 项目计划和质量计划（如果文件分开），方案、风险评估、差异分析 Plans and layout of facility, buildings (construction, finish) 设施和厂房的平面图（建筑、处理方法） Qualification status (DQ, IQ, OQ) and reports 确认状态（DQ, IQ, OQ）和报告 Transfer documentation 转移文件 Project implementation plan 项目实施计划 TOT protocol TOT方案 Side-by-side comparison with RU facility and buildings; gap analysis 与接收单位设施、建筑进行一一对照比较，差异分析 Qualification protocol and report 确认方案和报告 Quality agreement 质量协议 Facility assessment 设施评价 Health & Safety assessment 卫生和安全评价 Skill set analysis and training 熟练程度分析和培训 Analytical method transfer 分析方法转移 Starting material evaluation 起始物料评价 Equipment selection and transfer 设备选择和转移 Process transfer: manufacturing and packaging 工艺转移生产和包装 Product-specific waste management plans 产品专用废物管理计划 Contingency plans 应急方案 SOPs and training documentation (product-specific operations, analysis, testing) SOP和培训文件（产品专用操作、分析检测） Analytical method specification and validation, including in-process quality control 分析方法质量标准和验证，包括中控质量控制 Specification and additional information on APIs, excipients 原料药和辅料的质量标准和额外信息 Inventory list of all equipment and systems, including makes, models, qualification status (IQ, OQ, PQ) 所有设备和系统清单，包括品牌、型号、确认状态（IQ, OQ, PQ） Drawings, manuals, logs, SOPs (e.g. set-up, operation, cleaning, maintenance, calibration, storage) 图纸、手册、日志、SOP（例如设定、操作、清洁、维护、校正、存储） Reference bathes (clinical, dossier, biobatches) 参考（临床，文件，生物批） Development report (manufacturing process rationale) 研发报告（生产工艺合理性） History of critical analytical data Training protocols, assessment results 培训方案，评价和结果 Analytical method transfer protocol and report 分析方法转移方案和报告 Side-by-side comparison with RU equipment (makes, models, qualification status) 与接收单位的设备一一对照比较（品牌、型号、确认状态） Gap analysis 差异分析 Qualification and validation protocol and report 确认和验证方案和报告 History of process development at RU 接收单位工艺研发历史 Experience at RU should be recorded for future reference 接收单位的经验应记录作为将来参考 文案大全

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Key task 关键任务

Cleaning 清洁

Documentation provided by SU 转出方提供的文件 关键分析数据历史

Rationale for specifications 质量标准论述

Change control documentation 变更控制文件

Critical manufacturing process parameters

关键生产工艺参数

Process validation reports 工艺验证报告 Drug master file 药物主文件

API validation status and report(s) 原料药验证状态和报告 Product stability data 产品稳定性数据

Current master batch manufacturing and packaging records

List of all batches produced 所有生产批次清单 Deviation reports 偏差报告

Investigations, complaints, recalls Annual product review

调查、客诉、召回、年度产品回顾 Cleaning validation, including solubility information, therapeutic doses, category (toxicology); existing cleaning SOPs; validation

reports---chemical and micro; agents used; recovery study 清洁验证，包括溶解性信息、治疗剂量、类别（毒性）、已有的清洁SOP，验证报告---化学和微生物、所用的试剂、回收率试验

Transfer documentation 转移文件

Provisional batch

manufacturing document (RU to develop)

临时批次生产文件（接收单位制订）

Provisional batch packaging document (RU to develop) 临时批次包装文件（接收单位负责制订）

Description of process at RU (narrative, process map, flow chart)

接收单位的工艺描述（叙述、 工艺图、流程图）

Process validation protocol and report

工艺验证方案和报告

Product and site-specific cleaning SOPs at RU

接受单位产品和场所专用清洁SOPs

Cleaning validation protocol and report

清洁验证方案和报告

DQ, design qualification; IQ, installation qualification; OQ, operational qualification; API, active pharmaceutical ingredient; SOPs, standard operating procedures; RU, receiving unit.

DQ 设计确认 IQ 安装确认 OQ 运行确认 API 活性药物成分 SOPs标准操作规程 RU 接收单位

9. Qualification and validation 确认和验证 General 一般说明

9.1 The extent of qualification and or validation (18) to be performed should be determined on the basis of risk management principles.

需要进行的确认和/或验证（18）的深度应在风险管理原则的基础上决定。

9.2 Qualification and validation should be documented. 确认和验证应有记录。

References 参考文件

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