WHO第961号技术报告_附件7_药物生产技术转移指南(中英文)

1、WHO第961号技术报告 附件7 药物生产技术转移指南World Health OrganizationWHO Technical Report Series, No. 961, 2011WHO第961号技术报告 附件7 药物生产技术转移指南 Annex 7 附件7WHO guidelines on transfer of technology in pharmaceutical manufacturingWHO药物生产技术转移指南1. Introduction 介绍2. Scope 范围3. Glossary 术语4. Organizatio

2、n 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 

3、;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 WHOs 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

4、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

5、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 knowledg

6、e 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 th

7、e 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 info

8、rmation 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 pharma

9、ceutical 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

10、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

11、 and knowledgeable personnel working within a quality system, with documentation of data covering all aspects of development, production and quality control. Usually there is a sending unit (SU), a receiving unit and the unit managing the process, which may or may not be a separate entity. For “cont

12、ract 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

13、 met:为使转移成功，应符合以下一般原则和要求l         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l         the

14、 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l         a comprehensive technical gap

15、 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l         adequately trained staff should be available or should be trained at

16、 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 proje

17、ct; 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 ca

18、n 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

19、 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, ha

20、ve 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 exec

21、ution of the transfer.技术转移项目，是那些不同公司间转移的项目，牵涉到法律和经济方面。如果这些方面，可能会包括知识产权、版税、价格、利益和保密的冲突，将会影响到技术问题的公开交流，那么在计划和实施技术转移之前和过程中应进行说明。1.10 Any lack of transparency may lead to ineffective transfer of technology.缺乏透明度可能会导致技术转移没有效果1.11 Some of the principles outlined in this document may also be applicable to

22、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

23、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 agreemen

24、t 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

25、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 inter

26、site 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

27、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

28、、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

29、as sterile products, and metered dose aerosols. WHO guidance on manufacture of specific pharmaceutical products (4,5)will be useful in this regard.本指南中的推荐适用于所有剂型，但需要根据具体案例进行调整（例如采用风险管理原则）。对某些特殊剂型，例如无菌产品、单剂量气溶胶进行特殊控制。WHO对特殊药品的生产指南（4.5）对此会有指导作用。2.4 The guidelines address the following areas at th

30、e 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

31、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;    &#

32、160;  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       

33、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 leg

34、al, 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

35、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 for

36、m 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 bo

37、dy.任何物质或混合物，用于药品制剂的生产，成为这个制剂的一种活性成份。这种物质用于产生生物学活性，或用于治愈、缓解、治疗，或防止疾病，影响人体结构和功能。Bracketing 正交An experimental design to test only the extremes of, for example, dosage strength. The design assumes that the extremes will be representative of all the samples between the extremes.一种试验设计方法。用来检查，例如，剂量的极

38、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

39、 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 capac

40、ities 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

41、 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 specificat

42、ions, 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

43、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 pharm

44、aceutical 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 g

45、ood manufacturing practices (GMP).文件化的证据，证明设施、支持系统、公用系统、设备和工艺已经根据GMP要求进行设计。design space 设计空间The multidimensional combination and interaction of input variables (e.g. material attributes) and process parameters that have been demonstrated to provide assurance of quality (7).多维组合和输入变量（例如原料属性）与工艺参

46、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。fini

47、shed 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

48、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 inten

49、ded 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

50、 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

51、 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 betwe

52、en sites of different companies.在不同公司的工厂间进行的技术转移。intracompany transfer 公司内转移A transfer of technology between sites of the same group of companies.在公司同一集团内工厂间进行的技术转移。operational qualification (OQ) 运行确认Documented verification that the system or subsystem performs as intended over all anticip

53、ated 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 “proc

54、ess 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 qu

55、ality 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

56、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（

57、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 require

58、d 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, pack

59、aging 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 qu

60、ality objectives and specifying necessary operational processes and related resources to fulfil the quality objectives (6).质量管理的一部分，重点关注质量目标的设置，指出必要的操作流程，和满足质量目标所需的资源（6）。quality policy 质量方针Overall intentions and direction of an organization related to quality as formally expressed by senio

61、r 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 transfer