WHO《研发设施GxP规范》（中英文对照版）！
近日，WHO发布了Working document QAS/20.865 《研发设施GxP规范》，现将翻译版发给大家，如下：
Workingdocument QAS/20.865
November2020
Good practices for research and development facilities
研发设施GxP规范
1. Introductionand background
介绍和背景
2. Scope
范围
3. Qualitymanagement
质量管理
4. Qualityrisk management
质量风险管理
5. Sanitationand hygiene
清洁卫生
6. Qualificationand validation
确认与验证
7. Outsourcedactivities
外包活动
8. Self-inspectionand quality audits
自检和质量审计
9. Personnel
人员
10. Training
培训
11. Premises
厂房
12. Equipmentand instruments
设备和仪器
13. Materials
物料
14. Documentation
文件记录
15. Processingand process validation
工艺和工艺验证
16. Qualitycontrol
质量控制
17. Stabilitystudies
稳定性研究
18. Analyticalprocedure development
分析方法开发
19. Transferof technology
技术转移
20. Lifecycle approach
生命周期方法
21. Cleaningprocedure development and cleaning validation
清洁程序开发和清洁验证
Glossary
术语
Abbreviations
缩写
References
参考文献
Further reading
拓展阅读
1. Background
背景
In view of the recent need for the unprecedentedfast development of health products for the treatment of COVID-19 therapies,the World Health Organization (WHO) Prequalification Inspection Services Team(PQT INS) raised the urgency for the development of good manufacturing practice(GMP) text to address the manufacturing of developmental batches, pilot batchesand the sequential stability data that is submitted in product applications(dossiers) for marketing authorization and the prequalification of medicalproducts.
鉴于最近医药产品治疗COVID-19的前所未有的快速发展的需要，世界卫生组织(WHO)预确认检查服务团队(PQT INS)提出了发展的紧迫性良好生产规范(GMP)文本解决发展的生产批次,为上市批准和医药产品预确认而提交的产品申请(档案)中的中试批次和序列稳定性数据。
There are currently no regulatory guidelines whichaddress this matter, although the data collected from these batches influencethe following aspects of the product:
目前还没有针对这一问题的监管指南，尽管从这些批次收集的数据影响了产品的以下方面:
stability
稳定性
processvalidation; and
工艺验证
analyticalmethod development and validation
分析方法开发和验证
2. Introduction
介绍
2.1. The modern era of the pharmaceutical industry, inparticular focusing on chemicalsynthesis,began in the 19th century. The use of computerized systems inproduction and control is increasing rapidly. The ongoing evolution andadvancement in the pharmaceutical industry is fundamental in the control andelimination of disease around the world.
现代制药业开始于19世纪，尤其是化学合成。计算机化系统在生产和控制方面的使用正在迅速增加。制药工业的不断发展和进步是全世界控制和消除疾病的基础。
2.2. With an ever increasing awareness of the risks inpharmaceutical production and control, and the life cycle approaches beingfollowed, more and more emphasis is being placed on ensuring that the researchand development of products are appropriately controlled and documented.
随着人们对药品生产和控制的风险的认识不断增强，以及对生命周期方法的遵循，人们越来越重视确保产品的研究和开发得到适当的控制和记录。
2.3. Furthermore,as regulators request and review data and information such as the developmentdata of products and processes, design of experiments, validation and stabilityresults, it has become necessary to ensure that the facilities, qualitysystems, data and information meet the appropriate standards and goodpractices.
此外，由于监管机构要求并审查数据和信息，如产品和工艺的开发数据、实验设计、验证和稳定性结果，因此有必要确保设施、质量体系、数据和信息符合适当的标准和良好规范。
2.4. Thisdocument intends to provide guidance on GMP to research and developmentfacilities. It further aims to ensure that the correct systems are followed,ensuring appropriateness, reliability and the quality of products, processes,procedures and data. It further helps to help ensure that products meet therequirements for safety, efficacy and quality that they purport to possess.
本文件旨在为研发机构提供GMP方面的指导。它的进一步目标是确保遵循正确的系统，确保产品、工艺、程序和数据的适当性、可靠性和质量。它还有助于确保产品符合其声称拥有的安全、功效和质量要求。
2.5. In additionto product development, other activities including the production ofinvestigational products and pilot scale batches; process validation; cleaningprocedure development; cleaning validation studies; as well as stabilitystudies, are often undertaken in such facilities.
除产品开发外，其他活动包括试验产品和中试批的生产；工艺验证；清洁程序开发；清洁验证研究；以及稳定性研究，通常也在这些设施中进行。
2.6. The WHOdocument titled Good manufacturingpractices for investigational pharmaceutical products for clinical trials in humans (1) specifically addressesthe requirements and recommendationsfor products used in clinical trials. Other WHO guidelines address specificrequirements and recommendations including but not limited to stabilitytesting, analytical method validation, cleaning validation and the transfer oftechnology (TOT). (See the Referencesand Further Reading sections).
WHO题为《人用临床试验用药良好生产规范》的文件(1)专门阐述了用于临床试验的产品的要求和建议。WHO的其他指南提供了，包括但不限于稳定性测试、分析方法验证、清洁验证和技术转移的具体要求和建议（参见参考文献和拓展阅读)。
2.7. Thisdocument should be read in conjunction with other WHO GMP guidelines, asreferenced in the document (2-9). Other documents of interest are also listedunder the section “Further reading”.
本文件应与参考文献(2-9)中的其他WHO GMP指南一起阅读。其他相关的文件也列在“拓展阅读”一节中。
3. Scope
范围
3.1. Thisguideline is applicable to research and development facilities of productsmanufactured by chemical synthesis, extraction, cell culture or fermentation,by recovery from natural sources, or by any combination of these processes. Itfurther covers development of procedures and processes intended for transferand use in marketing authorization applications, process validation, TOT (10)-relatedactivities, validation (7), quality control laboratory activities (11), such asstability testing and development, and validation of cleaning procedures (see Figure 1 and section 4 below).
本指南适用于通过化学合成、提取、细胞培养或发酵、从自然资源中回收或通过这些工艺的任何组合生产的产品的研究和开发设施。包括用于转移的程序和工艺的开发，以及用于上市许可申请、工艺验证、TOT（技术转移）(10)相关活动、验证(7)、质量控制实验室活动(11)（如稳定性测试和开发），以及清洁程序验证的程序和工艺的开发(见图1和下面的第4节)。
3.2. This guideexcludes all vaccines, whole cells, whole blood and plasma, blood and plasmaderivatives (plasma fractionation), medical gases, commercial products,radiopharmaceuticals and gene therapy products.
本指南不包括所有疫苗、全细胞、全血和血浆、血液和血浆衍生物(血浆分离物)、医用气体、商业产品、放射性药物和基因治疗产品。
3.3. The goodpractices outlined below are to be considered general guides and they may beadapted to meet individual needs. The equivalence of alternative approaches,however, should be proven.
以下概述的良好做法将被视为一般指南，并可加以修改以满足个别需要。但是，替代方法的等效性应以证明。
3.4. In thisguide, the term “should” indicates recommendations that are expected to applyunless shown to be inapplicable or replaced by an alternative demonstrated toprovide an acceptable level of control.
在本指南中，“应”一词表示除非被证明不适用或被证明能提供可接受控制水平的替代方案所取代，否则应适用的建议。
3.5. This guide,as a whole, does not cover safety aspects for the personnel engaged in theresearch and development nor the aspects of protection of the environment. Thesecontrols are inherent responsibilities of the manufacturer and are governed bynational laws
总体上，本指南不包括从事研发的人员的安全方面，也不包括环境保护方面。这些控制是制造商固有的责任，受国家法律管辖。
3.6. This guideis not intended to define registration requirements or modify pharmacopoeialrequirements or other guideline recommendations. For details on processdevelopment, it is recommended that other guidelines, such as those publishedby The International Council for Harmonisation of Technical Requirements forPharmaceuticals for Human Use (ICH), be read in conjunction with this document.
本指南无意规定注册要求或修改药典要求或其他指南建议。关于工艺开发的细节，建议其他指南，如ICH指南，与本文件一起阅读。
3.7. This guidedoes not affect the ability of the responsible regulatory agency to establishspecific registration or filing requirements. All commitments in registrationand filing documents must be met. This document provides information toconsider for a risk- and science-based approach in the research and developmentof medical products.
本指南不会影响负责监管机构制定具体注册或备案要求的能力。必须遵守注册备案文件中的各项承诺。本文件就在医药产品研究和开发中采用基于风险和科学的方法提供考量信息。
3.8. The mainfocus of the document is on pharmaceutical formulation and development. Theprinciples described in this document may however be applied in facilitieswhere other products such as vaccines, veterinary products andbiopharmaceutical products are developed. The principles may also beconsidered, where appropriate, in facilities where medical devices aremanufactured.
本文件主要关注药物制剂和开发。然而，本文件中描述的原则可能适用于其他产品(如疫苗、兽药产品和生物制药产品)开发的设施。在适当的情况下，生产医疗器械的设施也可以考虑这些原则。
3.9. Due to thenature of research work, and an increasing expectation for compliance withstandards in manufacture, the guidance in this document would normally be appliedbased on risk assessment, in an increasing manner, from research to commercialbatch manufacturing. The stringency of GMP in research and development shouldincrease as the process proceeds from early research work to the final steps ofdevelopment and formulation, stability testing, process validation and cleaningvalidation.
由于研究工作的性质，以及对生产合规的期望越来越高，本文件中的指南通常基于风险评估进行应用，以越来越多的方式，从研发到商业生产。从前期研究工作到开发、制剂、稳定性测试、工艺验证、清洁验证等最后阶段，研发过程中GMP的严格程度不断提高。
Figure 1.Application of this guide
图1. 本指南应用
*The principles described in this guideline areapplied, based on risk management principles, in an increased manner from earlyresearch to development to registration batches
*本指南中所描述的原则基于风险管理原则，从前期研究到开发再到注册批次，应用方式不断增加
4. Quality management
质量管理
4.1. Thereshould be a quality management system encompassing adequate resources, awritten organizational structure and procedures to follow.
应有一个包含足够资源的质量管理体系，一个书面的组织结构和可遵循的程序。
4.2. The necessary resources should include, for example:
需要的资源应包括，例如：
a) asufficient number of appropriately qualified, trained personnel;
足够数量的经适当确认、培训的人员
b) adequatepremises and space;
足够的厂房和空间
c) suitableequipment and services;
合适的设备和服务
d) appropriatematerials, containers and labels; and
适当的物料、容器和标签
e) suitablestorage and transport.
适当的储存和运输
4.3. Roles, responsibilities and authorities should be defined,communicated and implemented.
角色、职责和权限应明确、沟通和实施
4.4. The qualitysystem should facilitate innovation and continual improvement and strengthenthe link between pharmaceutical development and manufacturing activities.
质量体系应促进创新和持续改进，并加强制药开发和生产活动之间的联系。
4.5. All partsof the quality system should be adequately resourced and maintained, includingwith sufficient competent personnel, suitable premises, equipment andfacilities.
质量体系的所有部分都应有充足的资源和维护，包括有足够能力的人员、适当的场所、设备和设施。
4.6. Initialresearch, as well as development activities, should be defined and documented.The detail should be in accordance with risk assessment and the increasingscale of GMP requirements from early to final stages of development.
最初的研究，以及开发活动，应予以定义和记录。其详细程度应与风险评估和从开发早期到最后阶段不断增长的GMP要求相一致。
4.7. The qualitysystem should ensure, as applicable and according to the stage of research anddevelopment, that:
质量体系应根据研发的阶段，在适用时确保:
a) managerialresponsibilities are clearly specified in job descriptions;
在工作说明书中明确规定管理职责;
b) instructionsand procedures are written in clear and unambiguous language;
说明和程序以清晰和明确的语言编写;
c) proceduresare correctly carried out;
程序得到正确地执行
d) records aremade (manually and/or by recording instruments) during production and qualitycontrol;
在生产和质量控制过程中进行记录(人工和/或使用记录仪器);
e) anysignificant deviations are recorded, investigated and the appropriate actiontaken;
任何重大偏差均得到记录、调查，并采取适当行动;
f) records aremaintained;
记录得到保存
g) there is asystem for quality risk management (QRM);
具备质量风险管理的体系
h) arrangementsare made for the manufacture, supply and use of the correct starting andpackaging materials;
对正确的起始材料和包装材料的制造、供应和使用作出安排;
i) allnecessary controls on starting materials, intermediate products, bulk productsand other in-process controls are carried out;
对起始物料、中间产品、待包装产品和其他工艺控制进行了所有必要的控制;
j) calibrationsand validations are carried out where appropriate;
进行了适当的校准和验证;
k) the productand process knowledge is managed;
产品和工艺知识得到管理
l) productsare designed and developed in accordance with applicable good practices (GxP);
产品根据适当的良好规范（GxP）进行设计和开发；
m) production and control operationsare clearly specified in written form;
生产和控制操作以书面的形式进行了明确的规定
n) continualimprovement is facilitated through the implementation of quality improvementsappropriate to the current level of process and product knowledge;
推行与现行工艺及产品知识水平相适应的质量改善，以促进持续改善;
o) productrealization is achieved;
产品得到实现
p) cleaningprocedures are developed and validated;
清洁程序得到开发并验证
q) stabilitytesting is done following written procedures and protocols; and
根据书面的程序和方案进行了稳定性测试
r) data meetALCOA+ requirements.
数据符合ALCOA+要求
4.8. There should be periodic management reviewwith the involvement of senior management.
应定期进行管理评审，并由高级管理人员参与。
5. Quality risk management
质量风险管理
5.1. A system ofquality risk management (QRM) should be implemented. The system should ensurethat risks are identified based on scientific knowledge and experience. Theappropriate controls should be identified and implemented to mitigate risks.
应实施质量风险管理体系(QRM)。系统应确保风险根据科学知识和经验得到识别。应建立并实施适当的控制，以减轻风险。
5.2. The levelof effort, formality and documentation of the QRM process is commensurate withthe level of risk and the stage from research to development, to commercialbatch manufacturing and control (seeFigure 1).
质量风险管理过程的努力程度、正式程度和文件化程度应与风险的水平以及自研究到开发、商业生产和控制的所在阶段相适应(见图1)。
5.3. Systemsshould be in place to manage and minimize the risks inherent in research anddevelopment in order to ensure the ultimate quality, safety and efficacy ofproducts; and the reliability of data.
应有系统来管理和减少研发过程的固有风险，以确保产品的最终质量、安全性和有效性;以及数据的可靠性。
5.4. Riskassessments should be periodically reviewed in light of improvements, currenttechnology, scientific knowledge and experience.
风险评估应根据改进的情况、当前技术、科学知识和经验定期审查。
6. Sanitation and hygiene
清洁卫生
6.1. Proceduresshould be implemented to maintain sanitation and hygiene. The scope ofsanitation and hygiene covers personnel, premises, equipment and apparatus,production materials and containers, and products for cleaning anddisinfection.
应执行程序以保持环境卫生和个人卫生。清洁卫生的范围包括人员、厂房、设备和仪器、生产物料和容器以及用于清洁消毒的产品。
6.2. Potential sources of contamination should beeliminated.
应消除潜在的污染源。
7. Qualification and validation
确认与验证
7.1. Qualificationand validation required should be identified based on risk assessment and, inaddition, should be appropriate to the stage of research and development.
所需的确认和验证应基于风险评估确定，此外，还应与所处的研发阶段相适应。
7.2. Thequalification and validation policy and approach should be defined anddocumented, for example, in a validation master plan.
应定义和记录确认和验证的方正和方法，例如，在验证主计划中。
7.3. Wherequalification and validation is carried out, the responsibility of performingvalidation should be clearly defined.
在进行确认和验证时，应明确定义执行验证的责任。
7.4. Qualificationand validation should provide documentary evidence that specifications andother requirements are met. Protocols and reports should be made available,when required.
确认和验证应提供符合标准和其他要求的书面证据。需要时，应能提供方案和报告。
7.5. Whereprocess validation, cleaning validation and analytical procedure validation isdone as a part of development, procedures and protocols should be followed.Reports should be available and retained.
当工艺验证、清洁验证和分析方法验证作为开发的一部分时，应遵循程序和方案。应有报告并保存。
8. Outsourced activities
外包活动
8.1. Outsourcedactivities should be correctly defined, agreed and controlled through a writtenagreement.
外包活动应通过书面协议正确定义、协定和控制。
8.2. Allresponsibilities and arrangements for activities, such as quality controltesting and technology transfer, should be clearly described.
所有的职责和活动安排，例如质量控制测试和技术转移，都应明确加以说明。
Thecontract giver
委托方
8.3. The contractgiver is responsible for assessing the suitability and competence of thecontract acceptor to successfully carry out the work or tests required and forapproval of the contract activities.
委托方负责评估受托方成功完成所需的工作或测试的适用性和能力，并对委托活动进行批准。
8.4. The contractgiver should provide the contract acceptor with all the information necessaryto carry out the contracted operations correctly.
委托方应向受托方提供正确实施合同操作所需的所有信息。
8.5. Thecontract giver should ensure that the contract acceptor is fully aware of anyhazards associated with the product, work or tests.
委托方应确保受托方完全清楚任何与产品、工作或测试相关的风险。
8.6. Thecontract giver should review and assess the records and results related to theoutsourced activities.
委托方应审查和评估与外包活动相关的记录和结果。
8.7. Thecontract giver is responsible for ensuring that the contract accepterunderstands that his or her activities may be subject to inspection by thecompetent authorities.
委托方有责任确保受托方明白其活动可能受到主管当局的检查。
The contract accepter
受托方
8.8. Thecontract accepter must have adequate premises, equipment, knowledge, experienceand competent personnel to satisfactorily carry out the work ordered by thecontract giver.
受托方必须具备足够的厂房、设备、知识、经验和足够能力的人员，以圆满完成委托方委托的工作。
8.9. Thecontract accepter should not pass to a third party any of the work entrustedunder the contract without the contract giver’s prior evaluation and approvalof the arrangements.
未经委托方事先评估和批准，受托方不得将合同项下委托的任何工作转交给第三方。
The agreement
协议
8.10. The technical aspects of the agreement should be drawn up bycompetent persons suitably knowledgeable in the field of research, developmentand GMP.协议的技术方面应由在研发和GMP领域有适当知识的有足够能力的人员起草。
8.11. The agreement should describe the handling of materials, such assamples and products, if they are out of specification or rejected
协议应描述物料（如样品和产品）在出现OOS或不合格时的处理，。
8.12. The agreement should permit the contract giver to audit thefacilities and activities of the contract acceptor.
该协议应允许委托方对受托方的设施和活动进行审计。
9. Self-inspection and quality audits
自检和质量审计
9.1. There should be a written self-inspection programme.
应有书面的自检程序。
9.2. Self-inspectionsshould be performed routinely and may be, in addition, performed on specialoccasions.
自检应定期进行，并可在特殊情况下额外进行。
9.3. The teamresponsible for self-inspection should consist of personnel with theappropriate knowledge and experience, free from bias.
负责自检的团队应由具有适当知识和经验的人员组成，不存在偏见。
9.4. Self-inspectionsshould cover at least the following items:
自检至少应包括下列各项:
a) personnel;
人员
b) premisesincluding personnel facilities;
设施，包括个人设施
c) maintenanceof buildings and equipment;
厂房和设备的维护
d) storage of startingmaterials and finished products;
起始物料和成品的储存
e) equipment;
设备
f) productionand in-process controls;
生产和过程控制
g) qualitycontrol;
质量控制
h) documentation;
文件记录
i) sanitationand hygiene;
清洁卫生
j) qualificationand validation;
确认与验证
k) calibrationof instruments or measurement systems;
仪器或测试系统的校准
l) control oflabels; and
标签的控制
m) results of previousself-inspections and any corrective steps taken.
前次自检的结果以及所采取的任何整改措施
9.5. The outcomeof the self-inspection should be documented. Corrective actions and preventiveactions should be identified and implemented. There should be an effectivefollow-up programme.
自检的结果应记录在案。应确定和执行纠正措施和预防措施。应有一个有效的跟踪程序。
9.6. Self-inspectionsmay be supplemented by quality audits.
自检应可以由质量审计补充。
10.Personnel
人员
10.1. Individual responsibilities should be clearlydefined and understood by the persons concerned and recorded as writtendescriptions.
应明确定义人员的职责，并应被相关人员理解，并以书面形式记录。
10.2. All personnel should be aware of theprinciples of this guideline and other applicable GxPs.
所有人员应了解本指南的原则和其他适用的GxPs。
10.3. Steps should be taken to prevent unauthorizedpeople from entering storage, production and quality control areas.
应采取措施防止未经授权的人员进入储存、生产和质量控制区域。
10.4. The headsof production and quality unit should be independent of each other.
生产和质量部门的负责人应该彼此独立。
10.5. Smoking, eating, drinking, chewing and keepingplants, food, drink, smoking material and personal medicines should not bepermitted in any area where they might adversely influence product quality.
在任何可能对产品质量产生不利影响的区域，都不允许吸烟、吃、喝、嚼和保存植物、食品、饮料、吸烟材料和个人药品。
11.Training
培训
11.1. Training should be provided in accordance witha written programme that covers topics such as the theory and practice of GMPand the duties assigned to them.
培训应根据书面计划提供，涵盖诸如GMP理论和实践以及所分配工作职责等主题。
11.2. The effectiveness of training should beassessed.
应评估培训的效果。
11.3. Training and assessment records should bekept.
应保存培训和评估记录。
11.4. Where appropriate, specific training should begiven on the handling of highly active, toxic, infectious or sensitizingmaterials.
适当时，应就如何处理高活性、毒性、传染性或致敏性物料进行专门培训。
12.Premises
厂房
12.1. Premises should be located, designed, constructed,adapted and maintained to suit the operations to be carried out.
房地的选址、设计、建造、改造和维护应适合所进行的操作。
12.2. The layout and design should aim to minimizethe risk of errors and permit effective cleaning and maintenance in order toavoid cross-contamination, build-up of dust or dirt and, in general, anyadverse effect on the products and activities.
布局和设计应尽量减少差错风险，并允许有效的清洁和维护，以避免交叉污染，灰尘或污垢的积聚，以及对产品和活动的任何不利影响。
12.3. Where product dust is generated, measuresshould be taken to avoid cross-contamination and to facilitate cleaning.
对于易产尘的产品，应采取措施避免交叉污染并便于清洗。
12.4. Premises should be cleaned according todetailed written procedures. Records should be maintained.
厂房应按照详细的书面程序进行清洁。记录应保存。
12.5. Electricalsupply, lighting, temperature, humidity and ventilation should be appropriate.
电气供应、照明、温度、湿度和通风应适当。
12.6. Toilets,rest and refreshment rooms should be separate from production and controlareas.
厕所、休息和茶点室应与生产和控制区域分开。
12.7. Animal houses should be well isolated fromother areas, with a separate entrance (animal access) and air-handlingfacilities.
动物房应与其他区域良好隔离，有单独的入口(动物通道)和空气处理设施。
12.8. Storage areas should be of sufficient capacitywith proper separation and segregation between materials, based on riskassessment.
储存区域应足够使用，并根据风险评估，在物料之间进行适当的间隔和隔离。
12.9. Storage areas should be clean and dry,designed or adapted to ensure the required storage conditions are maintained.Conditions should be controlled, monitored and recorded where appropriate.
储存区域应洁净干燥，设计或适合确保维持所需的储存条件。适当时，应控制、监测和记录储存条件。
12.10.Segregation should be provided for the storage of quarantined, released andrejected materials and products.
对已检验、已放行和不合格的物料和产品的存放应实行隔离。
12.11.Certain materials, such as highly active, radioactive materials and narcotics,should be stored in safe and secure areas.
某些物质，如高活性、放射性物料和麻醉品，应存放在安全的地方。
12.12.Materials identified for testing should be sampled in accordance with writtenprocedures and analysed for compliance with their specifications.
确定用于测试的物料应按照书面程序取样，并进行分析，以确保符合其标准。
12.13. Thestages in production, including weighing, compounding, and packaging, should bedone in a manner to prevent contamination, cross-contamination and mix-ups.
在生产过程中，包括称量、配料和包装，应以防止污染、交叉污染和混淆的方式进行。
12.14.Quality control (QC) laboratories should be separated from production areas.They should be designed to suit the operations to be carried out in them. Thereshould be sufficient space, instruments, equipment and the appropriatereference materials, solvents and reagents.
质量控制(QC)实验室应与生产区域分开。它们的设计应该适合所进行的操作。应有足够的空间、仪器、设备和适当的对照物料、溶剂和试剂。
13.Equipment and instruments
设备和仪器
13.1. Equipment and instruments should be located,designed, constructed, adapted and maintained to suit the operations to becarried out. They should allow for effective cleaning and maintenance in orderto avoid cross-contamination and a build-up of dust or dirt.
设备和仪器的安装、设计、制造、改造和维护应适合所进行的操作。它们应该允许有效的清洁和维护，以避免交叉污染和灰尘或污垢的堆积。
13.2. Pipework,instruments and devices should be adequately marked.
管道、仪器和装置应适当标识。
13.3. Balancesand other measuring equipment of an appropriate range and precision should beavailable for production and control operations and should be calibrated on ascheduled basis.
生产和控制操作应备有量程和精度合适的天平和其他测量设备，并应定期校准。
13.4. Equipmentand instruments should be thoroughly cleaned on a scheduled basis.
设备和仪器应定期进行彻底清洁。
13.5. Defective equipment and instruments should beremoved from operational areas or be clearly labelled as defective in order toprevent use.
有缺陷的设备和仪器应移出操作区域，或清楚地标明有缺陷，以防止使用。
14.Materials
物料
14.1. Materials should be purchased from approvedsuppliers.
材料应从认可的供应商处购买。
14.2. Materials, identified through risk assessment,should be quarantined immediately after receipt, sampled and tested inaccordance with specifications.
物料，通过风险评估确定，应在收到后立即隔离，并按照规程取样和检验。
14.3. Materialsreleased by the quality department and within their shelf life should be used.
应使用质量部发放的材料，并在其保质期内使用。
14.4. Materials identified through risk assessmentshould be stored under the appropriate conditions as specified on their labelsand in an orderly fashion to permit segregation, stock rotation and afirst-expire, first-use rule.
通过风险评估确定的物料应按照标签上规定的适当条件储存，以允许隔离、库存轮换和近效期先使用的原则。
14.5. The dispensing of materials for the productionof a batch should be done according to a written procedure. Materials should beaccurately weighed or measured into clean and properly labelled containers.
用于生产批次的物料的分发应按照书面程序进行。物料应准确称量或计量，装入干净并贴有适当标签的容器中。
14.6. No materials used for operations, such ascleaning, the lubrication of equipment and pest control, should come intodirect contact with the product. Where possible, such materials should be of asuitable grade (e.g. food grade) to minimize health risks.
清洁、设备润滑、虫害控制等操作中使用的物料不得与产品直接接触。如有可能，这些物料应有适当的等级(例如食品级)以降低健康风险。
14.7. Water used shouldbe suitable for its intended use.
使用的水应该适合其预期用途。
14.8. Packaging materials should be stored in secureconditions so as to exclude the possibility of unauthorized access.
包装材料应储存在安全的条件下，以避免未经授权的进入。
14.9. Intermediateand bulk products should be kept under appropriate conditions.
中间体和待包装产品应储存在适当的条件下。
14.10. Finished products should be stored undersuitable conditions.
成品应储存在适当条件下。
14.11.Rejected materials and products should be clearly marked as such and storedseparately in restricted areas. They should be handled in an appropriate andtimely manner. Whatever action is taken should be approved by authorized personneland recorded.
不合格的物料和产品必须有明确的标识，并单独存放在受限区域内。应妥善、及时地处理。无论采取什么措施，都应得到授权人员的批准并加以记录。
14.12.Toxic substances and flammable materials should be stored in suitably designed,separate, enclosed containers and, as required, by national legislation. Allwaste materials should be stored in a safe manner and disposed of at regularintervals to avoid accumulation.
有毒物质和易燃材料应储存在设计适当、隔离、封闭的容器中，并按国家法律的要求储存。所有废弃物应以安全的方式储存，并定期处置，以避免堆积。
15.Documentation
文件记录
15.1. Documentation includes specifications andprocedures for materials and methods of production and control. The design anduse of documents depend upon the research and development facility. The scopeand extent should be established based on risk assessment and the stage ofresearch and development (see Figure 1).
文件包括物料的标准和程序以及生产和控制的方法。文件的设计和使用取决于研发机构。其范围和程度应根据风险评估和研发阶段来确定(见图1)。
15.2. Documents should be designed, prepared,reviewed and authorized for use.
文件应设计、准备、审核和批准以供使用。
15.3. Documents should be reviewed periodically andkept up-to-date. Superseded documents should be retained for a defined periodof time.
文件应定期审查并保持更新。被取代的文件应在规定的时间内保存。
15.4. Entries ofdata and information should be clear and legible.
数据和信息的输入应清晰易读。
15.5. Data (and records for storage) may be recordedby electronic data-processing systems or by photographic or other reliable means.Batch production and control records should be protected throughout the definedperiod of retention.
数据(和存储记录)可由电子数据处理系统或摄影或其他可靠的方法记录。批生产和控制记录应在规定的保存期内得到保护。
15.6. Labelsshould be clear, unambiguous and in the company’s agreed format.
标签应清晰、明确，并采用公司所规定的格式。
15.7. There should be appropriately authorized anddated specifications, including tests on identity, purity and quality, forstarting materials and for finished products.
应有适当的批准和生效日期的固定，包括对起始物料和成品的鉴别、纯度和质量的测试。
15.8. Pharmacopoeias, reference standards, referencespectra and other reference materials should be available in the QC laboratory.
QC实验室应有药典、对照标准品、对照光谱和其他对照物质。
15.9. Specifications should contain appropriateinformation such as the designated name; internal code reference; andqualitative and quantitative requirements with acceptance limits. Other datamay be added to the specification.
质量标准应包含适当的信息，如指定的名称；内部编号；以及带有接受标准的定性和定量要求。可以将其他数据添加到标准中。
15.10. The packaging material should be examined forcompliance with the specification.
应检查包装材料以符合标准。
15.11.Specifications for intermediate and bulk products should be available where theneed has been identified.
必要时，应提供中间产品和待包装产品的标准。
15.12. Specifications for finished products shouldbe available and include the required information.
应有成品的标准，并包含所要求的信息。
15.13. Amaster formula, containing the relevant information, should be available forthe product and batch size to be manufactured.
应有包含适用于所生产产品和批量大小相关信息的主配方。
15.14. Packaging instructions should exist for theproducts to be packed.待包装的产品应有包装说明。
15.15. Abatch processing record should be kept for each batch processed. It should bebased on the relevant parts of the current specifications on record.
应保存每一加工批次的批加工记录。应基于现行规程的相关部分进行记录。
15.16. Duringprocessing, detailed information should be recorded at the time each action istaken and, after completion, the record should be dated and signed by theperson responsible for the processing operations.
在加工过程中，应详细记录每项操作的执行情况，并在完成后由负责加工操作的人员填写日期和签名。
15.17. A batch packaging record should be kept foreach batch or part batch processed.
应保存所处理的每个批次或分批的批包装记录。
15.18.Standard operating procedures (SOP) and corresponding records, where required,should be available. These include, but are not limited to, for example:
必要时，应提供标准操作规程(SOP)和相应的记录。包括但不限于，例如:
a) equipmentassembly and cleaning;
设备组装和清洁
b) personneltraining, clothing and hygiene;
人员培训、更衣和卫生
c) maintenance;
维护
d) sampling;
取样
e) analyticalapparatus and instrument calibration;
分析仪器校准
f) testing;
检验
g) release andrejection; and
放行和拒签
h) pestcontrol.
虫害控制
15.19.Cross-contamination should be avoided by taking the appropriate technical ororganizational measures.
应采取适当的技术或组织措施避免交叉污染。
15.20.Before any processing operation is started, steps should be taken to ensurethat the work area and equipment are clean and free from any startingmaterials, products, product residues, labels or documents not required for thecurrent operation.
在任何加工操作开始前，应采取步骤确保工作区域和设备是清洁的，没有当前操作不需要的起始物料、产品、产品残留物、标签或文件。
15.21. Toprevent cross-contamination and mix-ups, different products should not bepackaged in close proximity.
为了防止交叉污染和混淆，不同的产品不应近距离包装。
16.Processing and process validation
工艺和工艺验证
Note: Fordetails on process validation, see WHO Technical Report Series, No. 1019, Annex3, Appendix 7, 2019.
注:有关工艺验证的详情，见WHO技术报告第1019号，附录3，附件7，2019年。
Processing
工艺
Note: For more details on specific aspects relatingto process development, see ICH Q 11.
注：有关工艺开发的具体方面的更多详情，请参阅ICH Q11。
16.1. The selection of the starting materials andmanufacturing process should be carefully considered in order to ensure thatthe intended product will meet the intended standards of safety, efficacy andquality in a consistent manner.
起始物料和生产工艺的选择应予以谨慎考虑，以确保预期产品以一致的方式满足预期的安全性、有效性和质量标准。
16.2. Knowledge management and risk assessmentprinciples should be applied. Quality attributes, critical quality attributes,process parameters and critical process parameters should be defined anddocumented.
应应用知识管理和风险评估原则。应定义质量属性、关键质量属性、工艺参数和关键工艺参数并形成文件。
16.3. The designof experiments should cover identified variables.
实验设计应包括已识别的变量。
Process validation
工艺验证
16.4. Process validation is usually initiated by researchand development organizations. During this stage, the validation is also referredto as “process design”. (In a traditional or historical approach, this wasoften referred to as “prospective validation”).
工艺验证通常由研发组织发起。在这个阶段，验证也被称为“工艺设计”。(在传统的或历史的方法中，这通常被称为“前瞻性验证”)。
16.5. Product development activities provide key inputsto the process design stage. Laboratory or pilot-scale models designed to be representativeof the commercial process can be used to estimate variability.
产品开发活动为工艺设计阶段提供关键的输入。可以使用用以代表商业化工艺的实验室或中试规模的模型来估计变异性。
16.6. Process design should normally cover thedesign of experiments, process development, the manufacture of products for usein clinical trials, pilot-scale batches and technology transfer.
工艺设计通常应包括实验设计、工艺开发、临床试验产品生产、中试批量和技术转移。
16.7. Process design should be verified duringproduct development. Process design should cover aspects for the selection ofmaterials; expected production variation; selection of production technology/processand qualification of the unitary processes that form the manufacturing processas a whole; selection of in-process controls; tests; inspection; and itssuitability for the control strategy.
工艺设计应在产品开发过程中进行确认。工艺设计应包括物料选择的各个方面；预期的生产变异性；生产技术/工艺的选择，对整个生产过程的单个工艺进行确认；过程控制的选择；测试；检查；以及其对控制策略的适用性。
16.8. As the validation data are intended to be usedin applications for marketing authorizations, all batch data, results andrelated information should be clear, detailed and in compliance with ALCOA+.
由于验证数据将用于上市许可申请，所有批次数据、结果和相关信息都应清晰、详细，并符合ALCOA+要求。
17.Quality control
质量控制
17.1. The QC unit should be independent fromproduction.
QC部门应独立于生产。
17.2. There should be adequate resources availableto ensure that all the QC arrangements are effectively and reliably carriedout.
应该有足够的资源来确保所有的QC工作均得到有效和可靠地执行。
17.3. Activities and responsibilities of the QC unitinclude:
QC的活动和职责包括：
a) samplingand testing (e.g. starting materials, packaging materials, intermediateproducts, bulk products and finished products);
取样和检验（例如，起始物料、包装材料、中间产品、待包装产品和成品）
b) performingthe necessary qualification and validation;
执行必要的确认与验证
c) evaluating,maintaining and storing reference standards for substances;
评估、维护和保存对照标准
d) ensuring thatstability programme and testing is done;
确保稳定性计划和测试得到执行
e) participatingin environmental monitoring; and
参与环境监测
f) participatingin QRM programmes.
参与质量风险管理程序
17.4. Appropriate records should be kept, demonstrating that all therequired activities were performed
应保存适当的记录，以证明所有必需的活动都已执行。
17.5. Sufficient samples of materials and products should be retained fora defined period of time.
应保留足够的物料和产品留样在规定的时间内。
17.6. Appropriate reference standards should be used. Standards should bestored in an appropriate way.
应使用适当的对照标准。标准应以适当的方式储存。
17.7. Wheneverofficial reference standards exist, these should preferably be used.只要有官方对照标准，就最好使用这些标准。
17.8. Where secondary and working standards are established and used,these should be tested at regular intervals to ensure that they are fit fortheir intended use.
在建立和使用二级标准和工作标准时，应定期对这些标准进行测试，以确保它们适合其预期用途。
17.9. Reference standards should be appropriately labelled with at leastthe following information:
对照标准应至少适当标明以下信息:
a) name of thematerial;
物料名称
b) batch orlot number and control number;
批号和控制编号
c) date ofpreparation;
配制日期
d) shelf life;
有效期
e) potency;and
效价
f) storageconditions.
储存条件
18.Stability studies
稳定性研究
Note: See guideline on stabilitytesting of active pharmaceutical ingredients and finished pharmaceuticalproducts , WHO Technical Report Series, No. 1010, Annex 10, 2018.
注:参见WHO技术报告 第1010号附录10《药品活性成分和成品稳定性试验指南》，2018年。
18.1. Where stability determination is initiated by research and developmentorganizations, a written programme should be developed and implemented toinclude elements such as:
研发组织在确定稳定性时，应制定和执行一项书面方，其中应包括以下要素:
a) a completedescription of the medicine involved in the study;
所研究的药物的完整描述;
b) thecomplete set of testing procedure, parameters and limits;
一套完整的测试程序、参数和限度;
c) attributessuch as potency or assay and physical characteristics;
属性，如效价或含量和物理特性
d) evidencethat these tests indicate stability;
这些测试表明稳定性的证据;
e) the testingschedule for each medicine;
每种药物的测试时间表;
f) provisionfor special storage conditions; and
特殊储存条件的规定;和
g) provisionfor adequate sample retention.
足够的留样样品的规定
18.2. Sampling should be done in accordance with written procedures.
取样应按照书面程序进行。
18.3. Sample preparation and testing procedures should be detailed andfollowed. Any deviations from the procedures should be clearly documented.
样品制备和检测程序应详细并遵循。任何与程序的偏差都应清楚记录在案。
18.4. The results and data generated should be documentedand include the evaluation and the conclusions of the study.
产生的结果和数据应记录在案，包括评价和试验的结论
18.5. Where stability data are intended to be usedin applications for marketing authorizations, all batch data, results andrelated information should be clear, detailed and in compliance with ALCOA+.
当稳定性数据用于上市许可申请时，所有批次数据、结果和相关信息应清晰、详细并符合ALCOA+要求。
18.6. Recordsshould be maintained for a defined period of time.
记录应在规定时间内保存。
19.Analytical procedure development
分析方法开发
19.1. Analytical procedures developed by researchand development organizations should be appropriately recorded.
应适当记录研发组织开发的分析程序。
19.2. As the procedures are usually intended to betransferred to quality control units in manufacturing facilities of commercialbatches, procedures and records should be sufficiently detailed to ensure thatTOT will be successful.
由于分析方法通常需要移交给商业批次生产工厂的QC部门，因此程序和记录应足够详细，以确保TOT（技术转移）的成功。
19.3. Analyticalprocedures should be appropriately validated.
分析方法应适当验证。
Note: For details on analyticalprocedure validation, see WHO Technical Report Series, No. 1019, Annex 3,Appendix 4, 2019.
注:有关分析方法验证的详情，见WHO技术报告系列，第1019号，附录3，附件4，2019年。
20.Transfer of technology
技术转移
Note: For details on transfer oftechnology, see WHO Technical Report Series, No. 961, Annex 7, 2011 (update inprogress).
注:有关技术转移的详情，见WHO技术报告系列，第961号，附录7，2011年(正在更新)。
20.1. Development work, including programmes,procedures, protocols, specifications and validation from research anddevelopment organizations, may be transferred to production and quality controlsites.
开发工作，包括研发组织的计划、程序、方案、标准和验证，可转移到生产和质量控制工厂。
20.2. Data and information relating to equipment,instruments, manufacturing, and testing should be detailed, traceable andavailable.
与设备、仪器、生产和检验有关的数据和信息应详细、可追溯和可用。
20.3. Authorized procedures should be followed whentransferring technology from research and development organizations toproduction and quality control facilities.
在将技术从研发机构转移到生产和质量控制工厂时，应遵循经批准的程序。
21.Life cycle approach
生命周期方法
21.1. Industry should implement policies andprocedures that will encourage science-based and risk-based approaches inproduct research and development.
企业应实施政策和程序，鼓励以科学和风险为基础的方法进行产品研究和开发。
21.2. Continualimprovement should be encouraged across the entire product life cycle.
应鼓励在整个产品生命周期内进行持续改进。
21.3. Knowledge gained from the commercial manufacturingof a product, as well as knowledge gained from other products, can be used tofurther improve process understanding and process performance.
从一个产品的商业制造中获得的知识，以及从其他产品中获得的知识，可以用于进一步提高对工艺的理解和提高工艺性能。
21.4. New technologies and the review and interpretationof statistical evaluation of results from validation and other processes, aswell as other applicable data and information, should be considered in order toencourage continual improvement during the process development stage of thelife cycle of the product.
应考虑新技术、验证和其他工艺结果的统计评价的评审和解释，以及其他适用的数据和信息，以支持在产品生命周期的工艺开发阶段进行持续改进。
21.5. Where appropriate, these should be shared andtransferred to commercial manufacturing facilities.
适当时，应共享并转移给商业生产设施。
22.Cleaning procedure development and cleaning validation
清洁程序开发和清洁验证
Note: Fordetails on cleaning validation, see WHO Technical Report Series, No. 1019,Annex 3, Appendix 3, 2019 and the WHO Points to consider when including HBELsin cleaning validation, TRS XXX, Annex 2, 2021.
注:有关清洁验证的详细信息，请参阅WHO技术报告系列第1019号，附录3，2019和WHO《清洁验证中应用HBEL的考量》，TRS XXX，附录2，2021。
22.1. Research and development facilities are ofteninvolved in the development and validation of cleaning procedures. QRMprinciples should be applied in cleaning procedure development and cleaningvalidation.
研发设施经常涉及到清洁程序的开发和验证。应在清洁程序的制定和清洁验证中应用QRM原则。
22.2. Thedevelopment of cleaning procedures should include cleanability.
清洁程序的开发应包括清洁能力。
22.3. Health Based Exposure Limits (HBELs) should beconsidered in the approach to cleaning validation.
在进行清洁验证时，应考虑基于健康的暴露限。
22.4. The sampling of procedures should include swaband rinse samples. Maximum Safe Residue, Maximum Safe Surface Residue andVisible Residue Limits should be considered in the new cleaning validationapproach.
取样程序应包括擦拭和淋洗样品。在新的清洁验证方法中，应考虑最大安全残留、最大安全表面残留和可见残留限度。
22.5. The development of the analytical proceduresto be used in the testing for residues should be appropriately documented. Theprocedures should be validated.
用以检测残留物的分析方法的开发应有适当的记录。这些程序应该经过验证。
22.6. Proceduresfor sampling and testing, and the results obtained, should meet ALCOA+principles.The dataand information should be retained over the life cycle of the product.
取样和测试的程序，以及得到的结果，应符合ALCOA+原则。这些数据和信息应该在产品的生命周期中保存。
22.7. Procedures and protocols should be followedfor the TOT to commercial manufacturing sites.Records should be maintained.
应遵循TOT（技术转移）到商业生产工厂的程序和方案。记录应保存。
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