WHO最新指南：《药品生产技术转移指南》（中英文对照）

WHO最新指南：《药品生产技术转移指南》（中英文对照）

PharmLink指南组 
12月4日，世界卫生组织（WHO）于发布《药品生产技术转移指南》(WHO guidelines on the transfer of technology in pharmaceutical manufacturing)，提供了药品技术转让期间应考虑的指导原则。

Background 背景

During the Fifty-fifth World Health Organization (WHO) Expert Committee on Specifications for Pharmaceutical Preparations (ECSPP) meeting, Expert Committee members were updated on the annual consultation of Good Practices for Health Products and Inspection which took place in July 2020 in a series of virtual meetings due to the COVID-19 pandemic. During these virtual meetings, a group of experts made a series of proposals for future activities, one of which was how to determine whether or not the WHO guidelines on the transfer of technology in pharmaceutical manufacturing (1) should also be updated. This document was published in 2011 and it was considered that it should require updating, not least to support the inspections for COVID-19 therapeutics.

在第55届WHO药物制剂质量标准专家委员会（ECSPP）会议上，专家委员会成员听取了健康产品和检查良好实践年度咨询的最新信息，由于COVID-19大流行，这些系列会议于2020年7月以远程会议形式召开。会议期间，一些专家为未来的活动提出了一系列建议，其中之一是确定是否应更新WHO药品生产技术转移指南。该文件于2011年发布，被认为应该进行更新，尤其是为了支持对COVID-19治疗用品的检查。

The Expert Committee asked the WHO Secretariat to explore this proposal.

专家委员会请世卫组织秘书处探讨这一建议。


1. Introduction 简介

1.1. Production and control procedures, validation and other related activities may be transferred from one site to another site prior to obtaining a marketing authorization. In some cases, this transfer takes place after the approval of, for example, a product, by a regulatory authority. This transfer can be, for example, from drug discovery to product development; to clinical trials; or to full-scale commercialization and commercial batch manufacturing; cleaning and validation.

在获得上市许可之前，生产和控制程序、验证以及其它相关活动可以从一个场所转移到另一场所。在某些情况下，这种转移是在监管机构批准产品后进行的。这种转移可以是从药物发现到产品开发、再到进行临床试验；或是全面商业化和商业批生产、清洁和验证。

1.2. A technology transfer, particularly one between different companies, has legal and economic implications. If such issues, which may include intellectual property rights, royalties, pricing, conflicts of interest and confidentiality agreements, are expected to impact on the open communication of technical matters in any way, they should therefore be addressed before and during the planning and execution of the transfer.

技术转移，尤其是不同公司之间的技术转移，具有法律和经济内涵。如果此类问题（包括知识产权、特许权使用费、定价、利益冲突和保密协议）可能会影响技术方面的开放沟通，则应在计划和执行转移之前和过程中加以解决。

1.3. A technology transfer requires a planned approach by trained, knowledgeable personnel working within a quality system, with documentation, data and information covering all aspects of development, production and quality control (QC), as applicable.

技术转移要求采用计划性的方法，由具备丰富知识并在质量体系内工作的人员进行规划，其文档、数据和信息涵盖开发、生产和质量控制（QC）各个方面（如适用）。

1.4. A technology transfer takes place between a sending unit (SU) and a receiving unit (RU). In some cases, there may be a separate unit managing the project.

在转移方（SU）和接收方（RU）之间进行技术转移。在某些情况下，可能会有一个单独的部门来管理项目。

1.5. The technology transfer project should fulfil the following general principles and requirements. There should be:

技术转移项目应满足以下一般原则和要求。应该有：

• a documented project plan covering the relevant aspects of the project;

•涵盖项目相关方面的文件化项目计划；

• a detailed risk management plan;

•详细的风险管理计划；

• a comprehensive technical gap analysis, including due diligence performed covering technical and regulatory aspects;

•全面的技术差距分析，包括涵盖技术和法规方面的尽职调查；

• similar capabilities between the SU and RU, including but not limited to, facilities and equipment;

•SU和RU之间具有类似的能力，包括但不限于设施和设备；

• an adequate number of adequately trained personnel with suitable qualifications and experience; and

•有足够的经过适当培训的人员，具有适当资质和经验；

• effective process and product knowledge management.

•有效的工艺和产品知识管理。

1.6 A technology transfer should include relevant documentation, data, information and knowledge from the SU in order to enable the RU to effectively perform the specified process or procedure in, for example, production and QC. A successful transfer of technology should result in proof that the RU can routinely reproduce the transferred product, process or procedure against a predefined set of specifications as agreed between the SU and RU.

技术转移应包括来自SU的相关文档、数据、信息和知识，以使RU能够有效执行指定的工艺或程序，例如在生产和质量控制中。成功的技术转移应证明：按照SU和RU之间预先商定的标准，RU可以常规化重现所转让的产品、工艺或程序。

1.7 This document should be read in conjunction with other WHO guidelines as referenced below (2-14), as well as other regulatory guidelines which include The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) Q7, Q8, Q9, Q10 and Q11. This guideline does not intend to replace any of these guidelines.

应当结合参考文献（2-14）引用的其它WHO指南以及其它法规指南，一起阅读本文档，其中包括ICH Q7，Q8，Q9， Q10和Q11。本指南无意取代这些指南。

1.8 This version of the guideline provides updated requirements and expectations reflecting current good practices (GxP) in the transfer of technology and replaces the previous version published (1).

该指南版本提供了更新的要求和期望，反映了技术转移中的当前良好实践（GxP），并替代了先前发布的版本。


2. Scope 范围

2.1 This document provides guiding principles on technology transfer.

本文档提供了有关技术转移的指导原则。

2.2 This guideline should be applied when transferring the technology of processes and procedures relating to active pharmaceutical ingredients (APIs), in-process bulk materials, finished pharmaceutical products (FPPs), process validation, cleaning procedure development and validation and analytical procedures.

本指南应用于以下相关的工艺和方法技术转移：活性药物成分（API）、中间体、制剂成品（FPP）、工艺验证、清洁程序开发和验证，以及分析程序。

2.3 The guideline applies to all pharmaceutical dosage forms and may be adapted on a case-by- case basis by using risk management principles. Particular attention should be given to certain complex formulations such as, for example, sterile products and metered dose aerosols.

该指南适用于所有药物剂型，并可通过使用风险管理原则，根据具体情况进行调整。应特别注意某些复杂的制剂，例如无菌产品和定量喷雾剂。

2.4. Although this document focuses on pharmaceutical products, the principles can also be applied to the transfer of production, related processes and controls for other products such as biopharmaceutical products, vaccines, medical devices and vector control products.

尽管本文档的重点是药品，但是这些原则也可以应用于其它产品的生产、相关工艺和控制转移，这些产品如生物制品、疫苗、医疗器械和载体控制产品。

2.5. Because each transfer project is unique, the provision of a comprehensive set of guidelines specific to a product or process is beyond the scope of this document.

由于每个转移项目都是唯一的，因此针对产品或工艺提供的全面指导超出了本文档的范围。

2.6. This document does not provide guidance on any legal, financial or commercial considerations associated with technology transfer projects.

就与技术转移项目相关的任何法律、财务或商业考虑，本文档不提供指导。

2.7. This document addresses the following principal areas:

本文档涉及以下主要领域：

• organization and management of the transfer;

•转让的组织和管理；

• transfer of development information in production, including but not limited to processing and packaging;

•生产开发信息的转移，包括但不限于工艺和包装；

• transfer of development information and analytical procedures;

•开发信息和分析程序的转移；

• documentation, premises, equipment;

•文件、设施、设备；

• personnel qualification and training;

•人员资质和培训；

• quality management and risk management;

•质量管理和风险管理；

•life cycle approach;

•生命周期方法；

• control strategy; and

•控制策略；

• qualification and validation.

•确认和验证。

3. Glossary 术语

The definitions given below apply to the terms used in these guidelines. They have been aligned as far as possible with the terminology in related WHO guidelines and Good Practices and included in the WHO Quality Assurance of Medicines Terminology Database - List of Terms and related guideline https://www.who.int/docs/default-source/medicines/norms-and-standards/guidelines/mqa-terminology-sept-2020.pdf?sfvrsn=48461cfc_5 ), but may have different meanings in other contexts. 

以下定义适用于本指南中使用的术语。它们已尽可能与WHO相关指南和良好实践中的术语保持一致，并已包含在WHO药品质量保证术语数据库中，但在其它语境下可能具有不同的含义。


acceptance criteria. 

Measurable terms under which a test result will be considered acceptable.

可接受标准

可衡量的项目，在此之内测试结果被认为是可接受的。


active pharmaceutical ingredient (API). 

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.

活性药品成分（API）

准备用于生产制剂的物质或其混合物，使用时将成为该制剂的活性成分。此类物质旨在提供药理活性或其它直接作用，用于疾病的诊断、治愈、缓解、治疗或预防，或影响身体的结构和功能。


ALCOA+. 

A commonly used acronym for “attributable, legible, contemporaneous, original and accurate that puts additional emphasis on the attributes of being complete, consistent, enduring and available – implicit basic ALCOA principles.

“可归属、清晰、同步、原始和准确”的常用缩写，+号强调完整、一致、持久和可及的属性—基本ALCOA原则的暗含意思。


bracketing. 

An experimental design to test the extremes of, for example, dosage strength. The design assumes that the extremes will be representative of all the samples between the extremes.

分组

一种用于测试极端情况（例如剂量）的实验设计。设计假定极端情况将代表极端之间的所有样本。


change control. 

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.

变更控制 

一个正式的系统：在该系统下，对于可能影响已验证状态的提议或实际变更，具备资格的学科代表对此进行审查。目的是确定需要采取的措施，以确保将系统维护在已验证的状态。


control strategy.

 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 API and finished pharmaceutical 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.

控制策略

从当前产品和工艺了解中得出的一套计划内的控制措施，可确保工艺性能和产品质量。控制措施可以包括：与API和成品制剂的材料和组分有关的参数和属性、设施和设备的运行条件、过程控制、成品质量标准以及相关监控方法和频率。

corrective action. 
A## ny action to be taken when the results of monitoring at a critical control point indicate a loss of control.

纠正措施

当关键控制点的监测结果表明失去控制时，应采取的任何措施。


critical. 

Having the potential to impact on product quality or performance in a significant way.

关键的

有可能以显着方式影响产品质量或性能。


critical control point. 

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.

关键控制点

可以应用控制的步骤，对于防止或消除药品质量危害、或将其降低到可接受水平来说，是必要的。


design qualification. 

Documented evidence that, for example, the premises, supporting systems, utilities, equipment and processes have been designed in accordance with the requirements of good manufacturing practices (GMP). 

设计确认

书面证据，例如，设施、支持系统、公用系统、设备和工艺是根据良好生产规范（GMP）的要求设计的。


design space. 

The multidimensional combination and interaction of input variables (e.g. material attributes) and process parameters that have been demonstrated to provide assurance of quality.  

设计空间

输入变量（例如材料属性）和工艺参数的多维组合和交互作用，已证明可提供质量保证。


drug master file. 

Detailed information concerning a specific facility, process or product submitted to the medicines regulatory authority, intended for incorporation into the application for marketing authorization. 

药物主文件

提交给药监机构的有关特定设施、工艺或产品的详细信息，意在将其结合至上市许可申请中。


finished pharmaceutical product (FPP). 

A product that has undergone all stages of production, including packaging in its final container and labelling. An FPP may contain one or more active pharmaceutical ingredients (APIs). 

成品制剂（FPP）

产品经过了所有生产阶段，包括包装在最终容器中并贴有标签。FPP可能包含一种或多种活性药品成分（API）。


gap analysis. 

The identification of the critical elements of a process which are available at the sending unit (SU) but are missing from the receiving unit (RU).

差距分析

识别流程中的关键元素，这些元素在转移方（SU）存在，但在接收方（RU）中不存在。


good manufacturing practices (GMP). 

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.

良好生产规范（GMP）

质量保证的一部分，可确保始终如一地生产和控制药品，达到适合其预期用途的质量标准，并符合上市许可要求。


in-process control (IPC). 

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.

过程控制（IPC）

在生产中进行的检查，以监测并在必要时调整工艺，以确保产品符合其质量标准。环境或设备的控制也可以视为过程控制的一部分。


installation qualification (IQ).

Documented verification that the installations (such as machines equipment and instruments, computer system components, measuring devices, utilities and manufacturing) used in a processor system are appropriately selected and correctly installed, in accordance with established specifications. 

安装确认（IQ）

书面证明：表明根据已建立的标准，工艺或系统所用装置（例如，机器设备和仪器、计算机系统组件、测量仪器、公用系统和生产设施）已经恰当选择并正确安装。


intercompany transfer. 

A transfer of technology between the sites of different companies.

公司间转移

在不同公司场所之间进行技术转移。


intracompany transfer. 

A transfer of technology between sites of the same group of companies.

公司内部转移。

同一集团公司场所之间的技术转移。


operational qualification (OQ). 

Documented verification that the system or subsystem performs as intended over all anticipated operating ranges.

运行确认（OQ）

书面证明：系统或子系统在所有预期的工作范围内均按预期运行


performance qualification (PQ). 

Documented verification that the equipment or system performs consistently and reproducibly within defined specifications and parameters in its normal operating environment (i.e. in the production environment).

性能确认（PQ）

书面证明：在其正常操作环境（即生产环境）中，设备或系统在定义的质量标准和参数范围内可以一致且可重现地运行。


process validation. 

The collection and evaluation of data, from the process design stage through to commercial production, which establishes scientific evidence that a process is capable of continuously delivering the finished pharmaceutical product meeting its predetermined specifications and quality attributes.

工艺验证

从工艺设计阶段到商业生产的数据集合和评估，表明已建立了科学证据，证明工艺能够持续生产出满足其预定标准和质量属性的成品制剂。


qualification.

 Documented evidence that premises, systems or equipment are able to achieve the predetermined specifications when properly installed, and/or work correctly and lead to the expected results.

确认

书面化的证据，证明设施、系统或设备在正确安装后能够达到预定的质量标准，并且/或者正常运行，可达到预期的结果。


qualification batches. 

Those batches produced by the receiving unit (RU) to demonstrate its ability to reproduce the product .

确认批次

接收方（RU）生产的批次，用于证明其重现产品的能力。


quality assurance (QA).

 “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（QA）

“质量保证”是一个广泛的概念，涵盖了所有单独或共同影响产品质量的方面。这是所有工作的综合，目的是确保药品具备其既定用途所需的质量。


quality control (QC). 

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 (FPP) conform with established specifications for identity, strength, purity and other characteristics.

质量控制（QC）

针对起始原料、中间体、包装材料和成品制剂（FPP）所采取的所有措施，包括质量标准设定、取样、测试和分析清场，以确保符合其既定的鉴别、强度、纯度和其它属性标准。


quality planning. 

Part of quality management, focused on setting quality objectives and specifying necessary operational processes and related resources to fulfil the quality objectives.

质量计划

质量管理的一部分，侧重于设定质量目标，并指定必要的操作流程和相关资源，以实现质量目标。


quality policy. 

A brief statement that describes the organization’s purpose, overall intentions and strategic direction; provides a framework for quality objectives; and includes a commitment to meet applicable requirements.

质量方针

一个简要的声明，描述组织的目的、总体目标和战略方向；提供质量目标框架；并包括满足适用要求的承诺


quality risk management (QRM). 

A systematic process for the assessment, control, communication and review of risks to the quality of the pharmaceutical product throughout the product’s life cycle.

质量风险管理（QRM）

一个系统流程，在整个产品生命周期中评估、控制、沟通和回顾药品质量风险。


receiving unit (RU). 

The involved disciplines at an organization where a designated product, process or method is expected to be transferred.

接收方（RU）

一个组织中的相关机构，准备接收指定产品、工艺或方法。


sending unit (SU). 

The involved disciplines at an organization from where a designated product, process or method is expected to be transferred.

转移方（SU）

一个组织中的相关机构，准备转移指定产品、工艺或方法。


standard operating procedure (SOP). 

An authorized written procedure giving instructions for performing operations, not necessarily specific to a given product or material , but of a more general nature (for example, operation of equipment, maintenance and cleaning, validation, cleaning of premises and environmental control, sampling and inspection).  Certain standard operating procedures may be used to supplement product-specific master and batch production documentation.

标准操作程序（SOP）

经过批准的书面程序，提供执行操作的说明，不一定特定于某个具体的产品或材料，可能具有更一般的性质（例如，设备的操作、维护和清洁、验证、设施的清洁和环境控制、取样和检查）。可以使用某些标准操作程序，来补充特定于产品的主文件和批生产文件。


transfer of technology. 

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

在开发方和生产方之间，或在生产场所之间，对工艺及其文档和专业知识转移进行控制的逻辑化程序。这是一个供遵循的系统化程序，将开发和/或商业化期间获得的书面知识和经验转移给适当的、负责的许可方。


technology transfer report. 

A documented summary of a specific technology transfer project listing procedures, acceptance criteria, results achieved and conclusions.

技术转移报告

特定技术转移项目的一份书面总结文件，列出程序、可接受标准、取得的成果和结论。


validation. 

Action of proving and documenting that any process, procedure or method actually and consistently leads to the expected results.

验证

证明和记录工艺、程序或方法可以实际、并持续得到预期结果的活动。


validation master plan (VMP). 

A high-level document that summarizes the manufacturer’s overall philosophy and approach, to be used for establishing performance adequacy. It provides information on the manufacturer’s qualification and validation work programme and defines details of and timelines for the work to be performed, including a statement of the responsibilities of those implementing the plan.

验证主计划（VMP）

概述生产商总体理念和方法的高层次文件，用于建立性能的充分性。它提供了有关生产商确认和验证工作计划的信息，并定义了要执行工作的详细信息和时间表，包括对实施计划人员职责的说明。


validation protocol (VP). 

A document describing the activities to be performed during validation, including the acceptance criteria.

验证草案（VP）

描述验证期间要执行的活动的文件，包括可接受标准。


validation report (VR).

 A document in which the records, results and evaluation of validation are documented and summarized. It should also contain a conclusion of the outcome of the validation.

验证报告（VR）

记录和总结验证记录、结果和评估的文件。它还应包含验证结果的结论。


4. 尽职调查和差距评估

Due diligence and gap assessments

4.1. A process of due diligence, gap assessment or audits of the SU and RU should be one of the first steps when considering a technology transfer project. 

在考虑技术转移项目时，第一步应该是对SU和RU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 be assessed prior to the start of the transfer. The procedure to be followed should be documented. 

转移开始之前，应评估RU的适用性和准备程度。应记录要遵循的程序。

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

评估应由具有适当资质的人员组成的团队进行，这些人员具有GxP和待转移活动领域知识和经验。

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

评估应进一步涵盖资源方面，包括人员、设施、设备和仪器、公用系统、质量控制、文档、计算机系统、确认和验证以及废物管理。

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

确定技术转移的可行性和准备程度的评估可包括技术、业务、法规和法律方面。


5. 组织与管理

Organization and management

5.1. All technology transfer activities should be organized and planned.

所有技术转移活动均应进行组织和计划。

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

双方之间应该有一个正式协议，规定双方在转移之前、期间和之后的责任。该协议应涵盖例如数据管理、数据完整性、文档和验证。

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

在项目开始时，应确定、组织和记录技术转移项目期间要执行的所有必要活动。应确定相关职责。

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

SU应提供与待转移的工艺、产品或程序相关的必要文件。

5.5. The SU should provide criteria and information on inherent risks, hazards and critical steps associated with the process, product or procedure to be transferred. This may serve as a basis for the risk assessment exercise.

就待转移工艺、产品或程序相关的固有风险、危害和关键步骤，SU应提供有关的标准和信息。这可以作为风险评估活动的基础。

5.6. The technology transfer should be managed by responsible persons from the SU and RU. A technology transfer team may be appointed with identified and documented responsibilities. 

技术转移应由SU和RU的负责人进行管理。可以任命技术转移团队，该团队具有确定和文件化的职责。

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

团队成员应具有必要的资质和经验，以管理转移的特定方面。

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

SU应在相关文档中提供有关产品、工艺或程序的所有必要信息和知识，以确保成功转移。

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

针对要转移的工艺、产品或程序，应实施培训计划。

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

在项目进行工艺中进行的任何变更和调整均应完整记录下来，并征得双方的同意。

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

技术转移项目的执行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. 质量管理和质量风险管理

Quality management and quality risk management 

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

SU和RU应分别具有适当设计、明确定义和文件化的质量体系。

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

质量体系应有足够的资源，并得到实施和维护。

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

质量体系应包含GxP，将其应用于产品和工艺的生命周期阶段中，包括技术转移。

6.4 The quality system should ensure that:

• responsibilities are clearly specified in writing;

• operations are clearly defined in writing;

• there is a system for quality risk management; and

• arrangements are made for the documented technology transfer.

质量体系应确保：

•以书面形式明确规定职责；

•以书面形式明确定义操作要求；

•有质量风险管理系统；

•技术转移有文件记录安排。

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

质量风险管理应作为系统性流程来执行，以便评估、控制、沟通和回顾风险。

6.6 The system for quality risk management should be described in writing 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.

质量风险管理系统应以书面形式描述，并涵盖适当的领域，例如但不限于设施、设备、物料、产品、生产、工艺、QC、确认、验证和技术转移流程。

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

风险评估应基于科学知识和经验，包括工艺和产品方面的知识和经验。

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

质量风险管理过程的工作水平、正式程度和文件记录应与风险水平相称。

6.9 The procedures and records for quality risk management should retained.

质量风险管理的程序和记录应予以保存。


7.  文档

Documentation

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

注：附录1中列出了技术转移中通常需要的文档示例清单。

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

经过批准的技术转移文件应列出转移的预期顺序阶段和活动。该文件应包括例如以下内容：

• title;

标题；

• objective;

目标；

• scope;

范围;

• name and addresses of the SU and RU;

SU和RU的名称和地址；

• names of key personnel and their responsibilities;

关键人员的姓名及其职责；

• phases of the project and actions;

项目和行动的阶段；

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

对设施、设备、仪器、物料、程序和方法进行平行比较；

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

实验设计、质量属性、工艺参数和可接受标准；

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

有关试生产批次、确认批次和工艺验证的信息；

• change and deviation management;

变更和偏差管理；

• arrangements for keeping retention samples of active ingredients, intermediates and finished products, and information on reference substances where applicable; and

活性成分、中间体和成品的留样安排，对照品信息（如有）；

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

转移审核、结果、转移结束时的签名和日期。

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

应遵循标准操作程序（SOP），该程序描述在技术转移过程中要采取的措施。

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

应保存技术转移过程中进行活动的记录（例如技术转移报告）。报告内容应反映所遵循的协议和SOP。该报告应总结转移的范围，在SU和RU中获得的关键参数，以及转移的最终结论。对于差异和为解决这些差异而采取的适当措施，应进行记录。报告中应参考具有数据、结果和其它相关信息的支持性文件，并应确保随时可以获取。


8. 设施

Premises 

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

RU应具有适当的设施，其布局、构造和装修应适合预期的操作。公用设施，如加热、通风和空调以及气、水系统，应适合于要转移的预期工艺、产品或程序。

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

SU应向RU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 chemical hazards, exposure limits, fire and explosion risks);

生产工艺中的固有风险（例如，反应性化学危害、暴露限，火灾和爆炸风险）；

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

对健康和安全的要求，以最大程度地减少操作员的暴露（例如，在大气中药用粉尘的限制）；

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

应急计划考虑因素（例如，在气体或粉尘逸出、溅出、失火和消防用水用尽的情况下）；

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

识别废物流，以及重复使用、回收和/或处置的规定。


9. 设备和仪器

Equipment and instruments 

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

SU应提供涉及生产、灌装、包装和QC测试的设备和仪器清单。该清单应包括相关设备和仪器的品牌和型号。

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

其它相关文件可根据需要视情况提供，可包括图纸、手册、维护程序和记录、校验程序和记录；以及诸如设备设置、操作和清洁之类的程序。

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

对于SU和RU的设备与仪器的工作原理、品牌和型号，应进行审查和一对一比较。

9.4 Where the review and comparison identify any gaps or differences, appropriate action should be taken. This may include the adaptation of existing equipment or acquisition of new equipment. Such action should be taken by following a change management procedure which should be documented.

如果审查和比较发现任何差距或差异，则应采取适当的措施。这可能包括改造现有设备或购买新设备。应遵循变更管理程序，来采取此类措施，并有书面记录。

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

应该比较SU和RU的产量和批量。如果批量不同，则应评估影响，并计划和采取适当的措施。与需审核的设备有关的其它因素可能包括：

• minimum and maximum capacity;

最小和最大产能；

• material of construction of contact surfaces;

 接触面的构造材料；

• critical operating parameters; 

关键操作参数；

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

部件（例如过滤器、滤网和温度/压力传感器）；

• range of intended use.

既定用途范围。

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

应评估潜在转移产品对工厂生产的现有产品的影响。


10. 确认和验证

Qualification and validation 

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

应根据风险管理原则，确定要执行的确认与验证的程度。

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

设施、公用系统和设备的确认应根据确认主计划和草案执行。

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

验证（例如工艺验证）应按照验证主计划和草案执行。

10.4 Where technology is transferred to commercial sites, the qualification of equipment and instruments should be completed prior to the actual technology transfer.

如果将技术转移至商业场所，则在实际技术转移之前，应完成设备和仪器的确认。

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

工艺验证通常在研究和开发机构中开始，既可以作为前瞻性验证（传统方法），也可以作为第一阶段工艺验证（参见有关工艺验证新方法和生命周期方法的参考文献）。注：应根据现行WHO技术报告系列中发布的当前指南进行工艺验证。

10.6. Procedures including processing and analytical procedures, should be appropriately validated at the SU and transferred to the RU following documented procedures. Verification and validation, as appropriate, should be continued at the RU as identified and documented in the technology transfer protocol.

包括工艺和分析程序在内的程序应在SU处得到适当验证，再按照书面程序转移至RU处。必要时，RU应继续进行确认与验证，并记录在技术转移方案中。

10.7. For cleaning procedures, development and validation should be done in accordance with the guidelines as published in current WHO Technical Report 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，应根据现行WHO技术报告系列中发布的指南进行开发和验证。在建立清洁程序、清洁性研究和设定可接受限度时，应考虑清洁验证使用HBEL时的考量要点。

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

对于分析程序，应根据现行WHO技术报告系列中发布的指南进行验证。

10.9. Qualification and validation procedures, protocols, data and results should be appropriately recorded. The documents should be retained as defined in procedures.

确认和验证程序、草案、数据和结果应适当记录。应按照程序中的规定保存文件。 


11. 产品生命周期和项目管理原则

Product life cycle and project management principles

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

在计划和执行转移时，应考虑到要转移的设施、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。


12. 技术转移项目阶段

Phases of a technology transfer project

12.1. The technology transfer project plan may be divided into different phases. These may include, for example:

技术转移项目计划可以分为不同的阶段。这些可能包括，例如：




• Phase I: Project initiation;
第一阶段：项目启动；
• Phase II: Project proposal;
第二阶段：项目方案；
• 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; and
第三阶段：项目转移；
• Phase IV: Project review.
第四阶段：项目回顾
 第一阶段：项目启动

Phase I: Project initiation 

12.2. During the initiation phase of the project, a unit should normally identify the need for the technology transfer. This may be because of lack of capacity, transfer from development to commercial site or transfer from one company to another.

在项目的启动阶段，通常应由一方确定技术转移的需求。这可能是由于产能不足，从研发转移到商业场所，或从一家公司转移到另一家公司。

12.3. The units should establish initial discussion and identify whether or not there is any interest for such a project. (See also section on due diligence above).

双方应进行初步讨论，并确定是否对该项目感兴趣。（另请参见上面有关尽职调查的部分）。

12.4. The RU should be able to accommodate the intended activity.

RU应该有能力接收意向活动。

12.5. The RU should have the necessary technical expertise, technology and capability.

RU应该具有必要的技术专家、技术和能力。

12.6. A sufficient level and depth of detail to support the activity, and any further development and optimization at the RU, should be transferred.

对于转移，应该有足够的详细水平和深度，来支持RU的相关该活动、以及任何进一步开发和优化。


第二阶段：项目方案 

Phase II: Project proposal 

12.7. The SU and RU should jointly establish a team that will coordinate activities and execute the technology transfer exercise.

SU和RU应该共同建立一个团队，来协调活动并执行技术转移工作。

12.8. The team should perform a risk assessment based on the available data, information and knowledge of the premises, materials, products, procedures and other related information.

团队应进行风险评估，该评估基于设施、物料、产品、程序的现有数据、信息和知识及其它相关信息。

12.9. The team should prepare the technology transfer document.

团队应准备技术转移文件。

12.10. The team should develop a control strategy which includes, for example:

团队应制定控制策略，例如，包括：

• risks;

风险；

• material attributes;

物料属性；

• processing steps and stages in production;

生产中的工艺步骤和阶段；

• testing steps in QC;

QC检测步骤；

• equipment working principles and their impact on the process;

设备工作原理及其对工艺的影响；

• critical quality attributes (CQAs), critical process parameters (CPPs) and in-process controls;

关键质量属性（CQA）、关键工艺参数（CPP）和过程控制；

• QC instruments;

QC仪器；

• acceptance criteria and limits;

接受标准和限度；

• alarms and trends;

警报和趋势；

• personnel requirements, such as qualification and training; and

人员要求，例如资质和培训； 

• qualification and validation.

确认与验证。


 第三阶段：项目转移

Phase III: Project transfer 

 12.11. The team should execute the project in accordance with the procedures and agreed plan.

团队应按照程序和商定的计划执行项目。



Production生产:  

Starting materials 起始物料 

12.12. The specifications and relevant functional characteristics of the starting materials (APIs and excipients) to be used at the RU should be consistent with those materials used at the SU. Any properties which are likely to influence the process or product should be identified and/or characterized.

RU使用的起始原料（API和辅料）的质量标准和相关功能特性，应与SU中的一致。应识别和/或表征任何可能影响工艺或产品的特性。


Active pharmaceutical ingredients 活性药品成分
12.13. The SU should provide the RU with the open part of the Drug Master File (API master file), or equivalent information, as well as 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:

SU应向RU提供DMF（API主文件）的公开部分或等同信息，以及有关API的相关附加信息，这些信息对制剂生产非常重要。以下是通常可以提供的信息的示例；但是，应使用QRM原则，评估每种特定情况下所需的信息：

• manufacturer and associated supply chain;

生产商和相关的供应链；

• step of the API to be transferred;

要转移的API步骤；

• flow chart of synthesis pathway outlining the process, including entry points for raw materials, critical steps, process controls and intermediates;

概述工艺的合成路的流程图，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;

适当时，API确定的物理形式（包括显微照片和其它相关数据），以及所有晶型与溶剂化形态；

• solubility profile;

溶解度特性；

• if relevant, pH in solution;

溶液中的pH（如相关）；

• partition coefficient, including the method of determination;

分配系数，包括测定方法；

• intrinsic dissolution rate, including the method of determination;

固有溶出速率，包括测定方法；

• particle size and distribution, including the method of determination;

粒度和分布，包括测定方法；

• bulk physical properties, including data on bulk and tap density, surface area and porosity as appropriate;

体积物理性质，包括适当的体积和堆积密度、表面积和孔隙率数据；

• water content and determination of hygroscopicity, including water activity data and special handling requirements;

水分含量和吸湿性的测定，包括水活性数据和特殊处理要求；

• microbiological considerations (including sterility, bacterial endotoxins and bioburden  levels where the API supports microbiological growth) in accordance with national,  regional or international pharmacopoeia requirements;

基于国家、地区或国际药典的要求，对微生物学的考量（包括无菌性、细菌内毒素生物负荷水平——如果API支持微生物生长）；

• specifications and justification for release and end-of-life limits;

有关放行和货架期限度的质量标准和理由；

• summary of stability studies conducted in conformity with current guidelines, including conclusions and recommendations on retest date;

根据当前指南进行稳定性研究的摘要，包括结论和复验期建议；

• list of potential and observed synthetic impurities, with data to support proposed specifications and typically observed levels;

潜在和已发现的合成杂质清单，及支持拟议质量标准的数据和典型检出水平；

• information on degradants, with a list of potential and observed degradation products and data to support proposed specifications and typically observed levels;

有关降解物的信息：列出潜在的和已发现的降解产物，及支持拟议质量标准的数据和典型检出水平；

• potency factor, indicating observed purity and justification for any recommended  adjustment to the input quantity of API for product manufacturing, providing example  calculations; and

活性因子，指明已知晓的纯度，和生产中对API投料量调整建议的理由，并提供计算示例；

• 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.

对存储和/或处理有特殊考虑的因素，包括但不限于安全和环境因素（例如，物料安全数据表中规定的），以及对热、光或湿气的敏感性。


Excipients  辅料


12.14 The specifications and relevant functional characteristics of excipients should 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:

SU应提供辅料的质量标准和相关功能特性，以转移到RU场所。以下是通常可以提供的信息示例；但是，应使用QRM原则评估每种特定情况下所需的信息：

 • 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;

功能描述，加入任何抗氧化、防腐剂或辅料的理由；

 • definitive form (particularly for solid and inhaled dosage forms);

明确的形式（尤其是固体和吸入剂型）；

• solubility profile (particularly for inhaled and transdermal dosage forms);

溶解度特性（特别是对于吸入和透皮剂型）；

 • partition coefficient, including the method of determination (for transdermal dosage  forms);

分配系数，包括测定方法（对于透皮剂型）；

 • intrinsic dissolution rate, including the method of determination (for transdermal  dosage forms);

固有溶出速率，包括测定方法（对于透皮剂型）；

 • particle size and distribution, including the method of determination (for solid, inhaled  and transdermal dosage forms);

粒径和分布，包括测定方法（对于固体，吸入和透皮剂型）；

 • bulk physical properties, including data on bulk and tap density, surface area and  porosity as appropriate (for solid and inhaled dosage forms);

体积物理性质，包括体积和堆积密度、表面积和孔隙率数据（适用于固体和吸入剂型）；

 • compaction properties (for solid dosage forms);

压实特性（用于固体剂型）；

 • melting point range (for semi-solid or topical dosage forms);

熔点范围（对于半固体或局部剂型）；

 • pH range (for parenteral, semi-solid or topical, liquid and transdermal dosage forms);

pH范围（对于注射剂、半固体或局部、液体和透皮剂型）；

 • ionic strength (for parenteral dosage forms);

离子强度（对于注射剂）；

 • specific density or gravity (for parenteral, semi-solid or topical, liquid and transdermal  dosage forms);

特定的密度或比重（对于注射剂、半固体或局部、液体和透皮剂型）；

 • viscosity and or viscoelasticity (for parenteral, semi-solid or topical, liquid and  transdermal dosage forms);

粘度和/或粘弹性（对于注射剂、半固体或局部、液体和透皮剂型）；

 • osmolarity (for parenteral dosage forms);

渗透压（对于注射剂）；

 • water content and determination of hygroscopicity, including water activity data and  special handling requirements (for solid and inhaled dosage forms);

水分含量和吸湿性的测定，包括水活性数据和特殊处理要求（对于固体和吸入剂型）；

 • moisture content range (for parenteral, semisolid or topical, liquid and transdermal  dosage forms);

水分含量范围（对于注射剂、半固体或局部、液体和透皮剂型）；

• microbiological considerations (including sterility, bacterial endotoxins and bioburden levels where the excipient supports microbiological growth) in accordance with national, regional or international pharmacopoeia requirements, as applicable (for general and specific monographs);

基于适用的国家、区域或国际药典要求（通则和特定各论），对微生物学的考量（包括无菌性、细菌内毒素和的生物负荷水平——如辅料支持微生物生长的话）；

• specifications and justification for release and end-of-life limits;

有关放行和货架期限度的质量标准和理由；

• information on adhesives supporting compliance with peel, sheer and adhesion design criteria (for transdermal dosage forms);

有关支持符合剥离、透明和粘附设计标准的粘合剂信息（对于透皮剂型）；

• special considerations with implications for storage and or handling, including but not limited to, safety and environmental fa

       文章来源：药闻资讯

       本网站刊载的所有内容，包括文字、图片、音频、视频、软件等，如非标注为“原创”，则相关版权归原作者所有，如原作者不愿意在本网站刊登相关内容，请及时通知本站，我们将第一时间予以删除。

曜分享

分享精彩资讯