WHO guidelines on the transfer of technologyin pharmaceutical manufacturing

WHO制药生产技术转移指南

Background

背景

1. Introduction

介绍

2. Scope

范围

3. Glossary

术语

4. Due diligence and gap assessments

尽职调查和差距评估

5. Organization and management

组织和管理

6. Quality management and quality risk management

质量管理和质量风险管理 

7. Documentation

文件

8. Premises

厂房

9. Equipment and instruments

设备和仪器

10. Qualification and validation

确认与验证

11. Product life cycle and project management principles

产品生命周期和项目管理原则

12. Phases of a technology transfer project

技术转移项目阶段

Phase I: Project initiation

阶段1：项目启动

Phase II: Project proposal

阶段2：项目计划

• Establishing a team

• 建立团队

• Risk assessment

• 风险评估

• Project plan

• 项目计划

• Control strategy

• 控制策略

Phase III: Project transfer

阶段3项目转移

• Production: transfer (processing, packaging)

• 生产：转移（工艺、包装）

• Starting materials

• 起始物料

• Active pharmaceutical ingredients

• 活性药物成分

• Excipients

• 辅料

• Information on process and finished pharmaceutical products information

• 关于工艺和药物成品的信息

• Packaging

• 包装

• Quality control: analytical method transfer

• 质量控制：分析方法转移

• Cleaning

• 清洁

Phase IV: Project review

阶段4：项目回顾

References

参考文献

Further reading

拓展阅读

Abbreviations

缩略语

Appendix 1. Example of documentation commonly required for the transferof technology

附录1. 技术转移通常需要的文件示例

Appendix 2. Example of possible experimental designs and acceptancecriteria for analytical testing

附录2. 分析测试可能的实验设计和接受标准示例

4. Due diligenceand gap assessments

尽职调查和差距评估

4.1.         A process of duediligence, gap assessment or audits of the SU and RU should be one of the firststeps when considering a technology transfer project.

在考虑技术转移项目时，首先应对转移方和接收方进行尽职调查、差距评估或审计。

4.2. The suitability and degree of preparedness of the RU should beassessed prior to the start of the transfer. The procedure to be followedshould be documented.

接收方的适当性和准备程度应在转移开始之前进行评估。应将应遵循的程序形成文件。

4.3. The assessment should be done by a team of appropriately qualifiedpersons with knowledge and experience in the field of GxP and the activity tobe transferred.

评估应由一个具有GxP领域知识和经验的适当资质的人员组成的团队来完成。

4.4. The assessment should further cover resources including personnel,premises, equipment and instruments, utilities, QC, documentation, computerizedsystems, qualification and validation and waste management.

评估应进一步涵盖资源，包括人员、厂房、设备和仪器、公用设施、质量控制、文件、计算机化系统、确认与验证以及废弃物管理。

4.5. The assessment to determine feasibility and readiness for technologytransfer may include technical, business, regulatory and legal aspects.

确定技术转移的可行性和准备情况的评估可能包括技术、商业、监管和法律方面。

5. Organization and management

组织和管理

5.1. All technology transfer activities should be organized andplanned.

所有技术转移活动均应得到组织和计划。

5.2. There should be a formal agreement between the parties whichspecifies the responsibilities of each party before, during and after transfer.The agreement should cover, for example, data management, data integrity,documentation and validation.

双方之间应有一份正式协议，具体规定双方在转移之前、期间和之后的责任。协议应包括，例如，数据管理，数据完整性，文件记录和验证。

5.3. All the necessary activities to be executed during thetechnology transfer project should be identified, organized and documented atthe start of the project. Responsibilities should be defined.

在技术转移项目开始时，应确定、组织和记录技术转让项目期间执行的所有必要活动。应该定义责任。

5.4. The SU should provide the necessary documentation relating tothe process, product or procedure to be transferred.

转移方应提供与所转移的工艺、产品或程序有关的必要文件。

5.5. The SU should provide criteria and information on inherentrisks, hazards and critical steps associated with the process, product orprocedure to be transferred. This may serve as a basis for the risk assessmentexercise.

转移方应提供与所转移的工艺、产品或程序相关的固有风险、危害和关键步骤的标准和信息。这可作为风险评估工作的基础。

5.6. The technology transfer should be managed by responsiblepersons from the SU and RU. A technology transfer team may be appointed withidentified and documented responsibilities.

技术转让应由转移方和接收方的负责人管理。可以任命一个技术转移小组，其职责应明确并形成文件。

5.7. The team members should have the necessary qualifications andexperience to manage the particular aspects of the transfer.

团队成员应该具备必要的资质和经验来管理转移的特定方面。

5.8. The SU should make all the necessary information and knowledgewith regard to the product, process or procedure available in relevantdocuments in order to ensure a successful transfer.

转移方应在相关文件中提供与产品、工艺或程序有关的所有必要信息和知识，以确保成功的转移。

5.9. A training programme should be implemented specific to theprocess, product or procedure to be transferred.

应针对待转移的工艺、产品或程序实施培训计划。

5.10. Any changes and adaptations made during the course of theproject should be fully documented and agreed to by both parties.

在项目过程中所作的任何变更和调整都应形成充分的文件，并经双方同意。

5.11. The execution of the technology transfer project should bedocumented in a report which is supported by the relevant data.

技术转移项目的执行情况应记录在一份报告中，并有相关数据支持。

5.12. Data should meet ALCOA+ principles.

数据应符合ALCOA+原则。

6. Quality management and quality riskmanagement

质量管理和质量风险管理

6.1. The SU and RU should each have an appropriately designed,clearly defined and documented quality system.

转移方和接收方都应该有一个适当设计、明确定义和书面的质量体系。

6.2. The quality system should be adequately resourced,implemented and maintained.

质量体系应有足够的资源，充分实施和维护。

6.3. The quality system should incorporate GxP which should beapplied to the life cycle stages of the products and processes, including thetechnology transfer.

质量体系应包含GxP，应应用于产品和工艺生命周期的各个阶段，包括技术转移。

6.4. The quality system should ensure that:

质量体系应确保：

• responsibilities are clearly specified inwriting;

• 职责有明确的书面规定

• operations are clearly defined in writing;

• 操作有明确的书面定义;

• there is a system for quality riskmanagement; and

• 有一个质量风险管理系统

• arrangements are made for the documentedtechnology transfer.

• 已就书面的技术转移作出安排。

6.5. Quality risk management should be implemented as a systematicprocess for the assessment, control, communication and review of risks.

质量风险管理的实施应包括对风险进行评估、控制、沟通和审核的系统过程。

6.6. The system for quality risk management should be described inwriting and cover appropriate areas such as, but not limited to, premises,equipment, materials, products, production, processes, QC, qualification,validation and the process of technology transfer.

质量风险管理体系应以书面形式描述，包括但不限于，厂房、设备、物料、产品、生产、工艺、QC、确认、验证和技术转移过程等适当领域。

6.7. The evaluation of the risk should be based on scientificknowledge and experience including that of the process and product.

风险评估应以科学知识和经验为基础，包括公司和产品的知识和经验。

6.8. The level of effort, formality and documentation of thequality risk management process should be commensurate with the level of risk.

质量风险管理过程的努力水平、正式程度和文件化程度应该与风险水平相适应。

6.9. The procedures and records for quality risk management shouldretained.

应保留质量风险管理的程序和记录。

7. Documentation

文件

Note: A list with examples ofdocuments commonly required in technology transfer is presented in Appendix 1.

注:附录1列有技术转移通常需要的文件示例。

7.1. An authorized technology transfer document should list theintended sequential phases and activities of the transfer. The document shouldinclude, for example, the following:

应有经批准的技术转移文件列出转移的预定阶段和活动。例如，该文件应包括下列内容:

• title;

• 标题

• objective;

• 目的

• scope;

• 范围

• name and addresses of the SU and RU;

• 转移方和接收方的名称和地址

• names of key personnel and theirresponsibilities;

• 关键人员的名字及其职责

• phases of the project and actions;

• 项目的阶段和活动

• a parallel comparison of premises,equipment, instruments, materials, procedures, and methods;

• 对厂房、设备、仪器、物料、程序和方法的平行比较

• experimental design, quality attributes,process parameters and acceptance criteria;

• 实验设计、质量属性、工艺参数和接受标准;

• information on trial production batches,qualification batches and process validation;

• 有关试产批、确认批和工艺验证的信息;

• change and deviation management;

• 变更和偏差管理

• arrangements for keeping retention samplesof active ingredients, intermediates and finished products, and information onreference substances where applicable; and

• 活性成分、中间体和成品留样的保存，以及有关对照物质的信息(如适用);和

• review of the transfer, outcome, signature(s)and date of conclusion of the transfer.

• 转移、结果、转移结论签字/日期的审核。

7.2. Standard operating procedures (SOPs) should be followed,describing actions to be taken during the technology transfer process.

应遵循描述在技术转移过程中应采取行动的标准操作规程(SOPs)。

7.3. Records should be maintained for the activities performedduring the technology transfer process (e.g. a technology transfer report). Thereport content should reflect the protocol and SOPs that were followed. Thereport should summarize the scope of the transfer, the critical parameters asobtained in the SU and RU, and the final conclusions of the transfer. The discrepanciesand appropriate actions taken to resolve them should be recorded. Supportive documentswith data, results and other relevant information should be referenced in thereport and be readily available.

技术转移过程中进行的活动应保持记录(如技术转移报告)。报告内容应反映所遵循的方案和SOP。报告应总结转移的范围，在转移方和接收方中获得的关键参数，以及转移的最终结论。应记录偏差和为解决偏差而采取的适当措施。数据、结果和其他相关信息的支持性文件应在报告中引用，并随时可用。

8. Premises

厂房

8.1. The RU should haveappropriate premises with the layout, construction and finishing to suit the intendedoperations. Utilities such as heating, ventilation and air conditioning, aswell as gas and water systems, should be appropriate for the intended process,product or procedure to be transferred.

接收方应该有适当的布局、建筑和修整，以适应预期的操作。公用设施，如暖通空调，以及气体和水系统，应该适合待转移的工艺，产品或程序。

8.2. The SU should provide the RU with information on relevant health,safety and environmental issues, including:

转移方应向接收方提供有关健康、安全和环境问题的信息，包括:

• inherent risks of the manufacturing processes (e.g. reactive chemicalhazards, exposure limits, fire and explosion risks);

• 制造过程的固有风险(例如反应性化学危害、接触限度、火灾和爆炸风险);

• health and safety requirements to minimize operator exposure (e.g.atmospheric containment of pharmaceutical dust);

• 健康和安全要求以减少操作人员暴露(例如，空气中药物粉尘的控制);

• emergency planning considerations (e.g. in case of gas or dust release,spillage, fire and firewater run-off); and

• 应急计划考虑(例如，气体或灰尘释放、泄漏、火灾和消防水溢出);和

• identification of waste streams and provisions for re-use, recyclingand/or disposal.

• 识别废物流及可再用、回收及/或处置的规定。

9. Equipment and instruments

设备和仪器

9.1. The SU should provide a list of equipment and instrumentsinvolved in the production, filling, packing and QC testing. The list shouldinclude the makes and models of the relevant equipment and instruments.

转移方应提供一份生产、分装、包装和QC测试所涉及的设备和仪器清单。清单应包括相关设备和仪器的制造商和型号。

9.2. Other relevant documentation may include, on a case-by-casebasis as required, drawings; manuals; maintenance procedures and records;calibration procedures and records; as well as procedures such as equipmentset-up, operation and cleaning.

其他相关文件可能包括图纸(视具体情况而定);手册;维护程序和记录;校正程序和记录;以及设备设置、操作和清洗等的程序。

9.3. A review and a side-by-side comparison of equipment andinstruments of the SU and RU should be carried out in terms of their workingprinciple, make and models.

对转移方和接收方的设备和仪器进行工作原理、制造、型号等方面的审查和平行对比。

9.4. Where the review and comparison identify any gaps ordifferences, appropriate action should be taken. This may include theadaptation of existing equipment or acquisition of newequipment. Such action should be taken by following a changemanagement procedure which should be documented.

当审查和比较发现任何差距或差异时，应采取适当的措施。可能包括改造现有设备或购置新设备。这些措施应通过变更管理程序来进行，并应形成文件。

9.5. Production volumes and batch sizes at the SU and RU should becompared. Where batch sizes are different, the impact should be assessed andthe appropriate action planned and taken. Other factors relating to equipmentto be reviewed may include:

转移方和接收方的生产量和批量大小应进行比较。当批量大小不同时，应评估其影响，计划并采取适当的措施。与待审查设备有关的其他因素可能包括:

• minimum and maximum capacity;

• 最小和最大能力

• material of construction of contactsurfaces;

• 接触表面的构造材料

• critical operating parameters;

• 关键操作参数

• components (e.g. filters, screens, andtemperature/pressure sensors); and

• 组件(例如过滤器、筛和温度/压力传感器);和

• range of intended use.

• 预计使用范围

9.6. The impact of the potential product to be transferred, on existingproducts manufactured on site, should be assessed.

应评估待转移产品对现场生产的现有产品的影响。

10. Qualification and validation

确认与验证

10.1. The extent of qualification and validation to be performedshould be determined on the basis of risk management principles.

应根据风险管理原则确定确认和验证的范围。

10.2. The qualification of premises, utilities and equipmentshould be done in accordance with a qualification master plan and protocols.

厂房、公用设施和设备的确认应按照确认主计划和方案进行。

10.3. Validation, such as process validation, should be done inaccordance with a validation master plan and protocols.

验证，例如工艺验证，应该按照验证主计划和方案进行。

10.4. Where technology is transferred to commercial sites, thequalification of equipment and instruments should be completed prior to theactual technology transfer.

技术转移到商业化工厂的，应当在实际技术转移前完成设备、仪器的确认。

10.5. Process validation usually starts in research anddevelopment facilities either as prospective validation (traditional approach)or as stage I process validation (see references regarding the new approachesin process validation; and the life cycle approach). Note: Process validationshould be done according to current guidelines as published incurrent WHO Technical Report Series (3).

工艺验证通常从研发设施开始，或作为前瞻性验证(传统方法)，或作为第一阶段工艺验证(参见有关工艺验证新方法及生命周期方法的参考文献)。注:工艺验证应根据当前WHO技术报告系列(3)中发布的现行指南进行。

10.6. Procedures including processing and analytical procedures,should be appropriately validated at the SU and transferred to the RU followingdocumented procedures. Verification and validation, as appropriate, should becontinued at the RU as identified and documented in the technology transferprotocol.

程序，包括加工和分析程序，应在转移方进行适当的验证，并按照书面的程序移交给接收方。应在接收方继续进行确认和验证。

10.7. For cleaning procedures, development and validation shouldbe done in accordance with the guidelines as published in current WHO TechnicalReport Series (6). Points to consider when using HBEL in cleaning validation (14) should be taken into account in establishing cleaning procedures,cleanability studies and setting acceptance limits.

对于清洁程序，开发和验证应按照当前WHO技术报告系列(6)中发布的指南进行。在建立清洁程序、可清洁能力研究并设置可接受限度时，应考虑《在清洁验证中应用HBEL(14)的考量》。

10.8. Analytical procedures should be validated according to theguidelines as published in current WHO Technical Report Series (7).

分析程序应根据当前WHO技术报告系列(7)中发布的准则进行验证。

10.9. Qualification and validation procedures, protocols, data andresults should be appropriately recorded. The documents should be retained asdefined in procedures.

应适当地记录确认和验证程序、方案、数据和结果。文件应按照程序规定予以保存。

11. Product life cycle and project managementprinciples

产品生命周期和项目管理原则

11.1. The relevant stage of the life cycle of the facility,equipment, instrument, utility, product, process or procedure to be transferredshould be taken into consideration when the transfer is planned and executed.

在计划和实施转移时，应考虑转移的设施、设备、仪器、公用系统、产品、工艺或程序的生命周期的相关阶段。

Appendix 1 Example of documentation commonlyrequired for the transfer of technology

附录1技术转移通常需要的文件示例

* Thetable below provides an example of documentation commonly required for thetransfer of technology.

下表提供了技术转移通常需要的文件示例。

*Note: These are examples. All therequired documents should be identified for the different tasks.

注意:以上为示例。针对不同的任务，应该识别出所有需要的文件。

Appendix 2 Exampleof possible experimental designs and acceptance criteria for analytical testing

附录2. 分析测试可能的实验设计和接受标准示例

The table below provides an example of possible experimental designs andacceptance criteria for analytical testing. The numbers in the table are givenas examples only and should not be considered as recommendations. Methodtransfers should account for the variability and sensitivity of the method andthe specifications for the quality parameter. Alternative procedures andacceptance criteria may be applied based on science and the characteristics ofthe analytical method and the analyte.

下表提供了分析测试可能的实验设计和接受标准的示例。表内的数字只是举例，不应视为建议。方法转移应该考虑方法的可变性和灵敏度以及质量参数的标准。基于科学和分析方法、被分析物的特点，可以采用其他的程序和接受标准。