WHO新发布指南：试验用药品的GMP

11 月 5 日，世界卫生组织（WHO）发布了“试验用药品GMP” 指南（Good manufacturing practices for investigational products）的征求意见稿。

该文件是对WHO GMP附录7的修订，目前正处于收集意见期，截止日期为2021年1月。此后，将于2021年2-3月份提交专家工作组，进行讨论，完善后进行第2轮意见收集。最终修订稿计划于2021年10月份，提交第56药物制剂专家委员会（ECSPP）批准。

本指南主体部分分为18个章节，内容如下：

1.背景

2.简介

3.范围

4.质量管理

5.质量风险管理

6.人员

7.文件

8.设施

9.设备和公用系统

10.物料

11.生产

12.质量控制

13.确认和验证

14.投诉

15.召回

16.退货

17.运输

18.销毁

PharmLink计划进行翻译，供参考。

WHO新发布指南：试验用药品的GMP

试验用药品GMP，有什么文件要求？

临床样品，设施上有什么GMP要求？

试验用药品GMP，生产和QC有何要求？

1. Background 背景

1.1. In view of an old publication date, and the recent need for new guidelines arising from inspections carried out for COVID-19 therapeutics, the World Health Organization (WHO) Prequalification Team - Inspection Services (PQT INS) raised the urgency for a revision of the WHO Good manufacturing practices for investigational pharmaceutical products for clinical trials in humans (1). The Fifty-fifth Expert Committee on Specifications for Pharmaceutical Preparations (ECSPP) concurred with this proposal.

鉴于发布日期较旧，以及最近对COVID-19疗法进行检查时产生了新的指南需求，对WHO人体临床试验用药品的良好生产规范，世界卫生组织（WHO）资格预审小组-检查服务（PQT INS）提出了修订标准的紧迫性（1）。第55药物制剂专家委员会（ECSPP）同意该建议。

1.2. The objective of this update is to bring the guideline in line with current expectations and trends in good manufacturing practices and to harmonize the text with the principles from other related international guidelines.

本次更新的目的是使该指南与当前对良好生产规范的期望和趋势保持一致，并使文本与其他相关国际指南中的原则保持一致。

2. Introduction介绍

2.1. Investigational products are used for testing purposes; as a reference in a clinical trial; for an unauthorized indication; and to gain further information about the authorized form.

试验用药品用于测试目的；作为临床试验的参考；用于未经批准的适应症；以获得有关许可批准的更多信息。

2.2. In some cases, marketed products which have been re-packaged or modified in some way, are used for investigational purposes.

在某些情况下，市售产品，以某种方式重新包装或进行修改，可以用于试验目的。

2.3. The legal status of investigational products for human and veterinary use varies from country to country.

用于人类和兽医用途的试验用药品的法律地位，因国家而异。

2.4. These products are sometimes not covered by legal and regulatory provisions in the areas of good practices (GxP) and inspection. These complexities, such as lack of high level good manufacturing practices (GMP) requirements, risk of contamination and cross- contamination, clinical trial designs, blinding and randomization, increase the risk. In addition, there are also instances where there is incomplete knowledge of the potency and toxicity of the investigational product.

这些产品有时不在良好实践（GxP）和检查领域的法律和法规规定之列。这些产品存在诸多复杂性，例如缺乏高水平的良好生产规范（GMP）、污染和交叉污染的风险、临床试验设计、盲法和随机化，都会增加风险。另外，在某些情况下，对试验用药品的活性和毒性的了解不完整。

2.5. There are further risks associated with the production, validation, control, shipping, storage and use of investigational products.

对于试验用药品，存在着与生产、验证、控制、运输、存储和使用有关的其他风险。

2.6. To minimize risks and to ensure that the results of clinical trials are unaffected by inadequate safety, quality or efficacy arising from unsatisfactory manufacture, investigational products should be manufactured and managed in accordance with an effective quality management system and the recommendations contained in this guideline.

为了最大程度地降低风险，并确保临床试验的结果不受生产问题引起的安全性、质量或功效不足的影响，应根据有效的质量管理体系和本指南中的建议，来生产和管理试验用药品。

2.7. Other guidelines and GxP should be taken into account, where relevant and as appropriate, as to the stages of development, production and control of the product.

在产品开发、生产和控制阶段应酌情考虑其他指南和GxP。

2.8. Procedures should be flexible to provide for changes whenever necessary, as knowledge of the process increases over time, and in accordance with the stages of development of the product.

程序应灵活多变，以便在必要时进行更改，因为随着时间的推移，对工艺的了解会不断增加，并且要根据产品的开发阶段而定。

2.9. Investigational products should be manufactured in a manner:

that is compliant to GxP, as appropriate;

that ensures that subjects of clinical trials will be protected from poor quality products due to unsatisfactory manufacturing;

to assure consistency between and within batches of the investigational product; and

to assure consistency between the investigational product and the future commercial product.

试验用药品应采用以下方式生产：

适当时符合GxP；

确保不会由于生产问题，而使临床试验的受试者受到劣质产品的侵害；

确保试验用药品批次之间以及批次内的一致性；

确保试验用药品与未来商业产品之间的一致性。

2.10. The selection of an appropriate dosage form for clinical trials is important. While it is accepted that the dosage form may be very different from the anticipated final formulation (e.g. a capsule instead of a tablet) in early trials, in the pivotal Phase III studies, it should be similar to the projected commercial presentation; otherwise these trials will not necessarily prove that the marketed product is both efficacious and safe. If there are significant differences between the clinical and commercial dosage forms, data should be submitted to the registration authorities to demonstrate that the final dosage form is equivalent, in terms of bioavailability and stability, to that used in the clinical trials.

为临床试验选择合适的剂型很重要。虽然在早期试验中已经认识到剂型可能与预期的最终制剂（例如胶囊而不是片剂）有很大不同，但在关键的III期研究中，它应与预计的商业用途相似；否则，这些试验并不一定证明所上市的产品既有效又安全。如果临床剂型和商业剂型之间存在显着差异，则应将数据提交注册当局，以证明最终剂型在生物利用度和稳定性方面，与临床试验中的剂型具有等效性。

2.11. The quality of investigational products should be appropriate. For example, dosage forms in Phase III clinical studies should be characterized and assured at the same level, as for routinely manufactured products.

试验用药品的质量应适当。例如，III期临床研究中的剂型应与常规生产产品的特性和特征相同。

2.12 Where production and/or quality control is transferred from one site to another, the recommendations in the guideline for transfer of technology should be followed.

如果生产和/或质量控制从一个场所转移到另一个场所，则应遵循技术转移指南中的建议。

2.13 This document should be read in conjunction with other WHO GxP guidelines, including good clinical practice (GCP) (2).

该文件应与其他WHO GxP指南一起阅读，包括良好的临床实践（GCP）（2）。

3. Scope范围

3.1 The recommendations in this guideline are applicable to investigational products for human and veterinary use.

本指南中的建议适用于人类和兽医用途的试验用药品。

3.2 Although the focus is on medicinal (pharmaceutical) products, some of the principles may be applied to other investigational products.

尽管重点放在医药产品（药品）上，但某些原则可能适用于其他研究性产品。

4. Quality management 质量管理

4.1 There should be a comprehensively designed, clearly defined, documented and correctly implemented quality management system in place. Senior management should assume responsibility for this as well as the quality of the investigational product.

应该建立一个全面设计、明确定义、记录和正确实施的质量管理体系。高级管理人员应对此以及产品质量负责。

4.2 All parts of the quality system should be adequately resourced and maintained.

对于 质量体系的所有部分，都应有足够的资源和维护。

4.3 The quality system should incorporate GxP which would be applied to all the lifecycle stages of the products, including the transfer of technology, and the interface between the manufacture and the trial site (e.g. shipment, storage, labelling).

质量体系应纳入GxP，该GxP将应用于产品的所有生命周期阶段，包括技术转让以及生产商与试验场所之间的接口（例如运输、存储、标签）。

4.4 The quality system should ensure that:

质量体系应确保：

products are designed and developed in accordance with the requirements of this document and other associated guidelines such as good laboratory practice (GLP) (3), good clinical practice (GCP) (2) and good storage and distribution practices (GSDP) (4), where appropriate;

根据本文档和其他相关指南的要求，设计和开发产品，例如，良好的实验室规范（GLP）（3），良好的临床规范（GCP）（2）和良好的存储和分发规范（GSDP）（4 ）（在适当情况下）;

managerial responsibilities are clearly specified in job descriptions;

在岗位说明书中明确规定了管理职责；

operations are clearly specified in a written form;

以书面形式明确规定操作；

arrangements are made for the manufacture, supply and use of the correct starting and packaging materials;

安排生产、供应和使用正确的起始和包装材料；

all necessary controls on starting materials, intermediate products, bulk products and other in-process controls should be in place;

对原材料、中间产品、散装产品和其他过程中所有必要的控制措施应到位；

calibrations and validations are carried out where necessary;

必要时进行校验和验证；

the finished product is correctly processed and checked according to the defined procedures;

按照定义的程序，正确处理和检查了成品；

deviations and changes are investigated and recorded with an appropriate level of root cause analysis done and appropriate corrective actions and/or preventive actions (CAPAs) identified and taken;

对偏差和变更进行调查和记录，进行适当水平的根本原因分析，并确定并采取适当的纠正措施和/或预防措施（CAPA）；

there is a system for quality risk management (5); and

有质量风险管理系统（5）；

satisfactory arrangements exist to ensure, as far as possible, that the investigational products are stored, distributed and subsequently handled so that their quality is maintained.

存在充分的安排，以确保尽可能地确保试验用药品的存储、分发和后续处理，以保持其质量。

5. Quality risk management质量风险管理

5.1 There should be a system for quality risk management.

应该有一个质量风险管理系统。

5.2 The system for quality risk management should cover a systematic process for the assessment, control, communication and review of risks to the quality of the product and, ultimately, to the protection of the trial subject and patient.

质量风险管理系统应涵盖评估、控制、交流和审查风险的系统流程，这些风险与产品的质量以及试验对象和患者的最终保护有关。

5.3 The quality risk management system should ensure that:

5.3质量风险管理体系应确保：

the evaluation of the risk is based on scientific knowledge and experience with the process and product;

风险评估基于工艺和产品的科学知识和经验；

procedures and records for quality risk management are retained; and

保留质量风险管理的程序和记录；

the level of effort, formality and documentation of the quality risk management process is commensurate with the level of risk.

质量风险管理流程的工作水平、形式和文件记录，与风险水平相对应。

5.4. Quality risk management should be applied both proactively and retrospectively, when appropriate.

适当时，应主动和追溯应用质量风险管理。

6. Personnel 人员

6.1. There should be a sufficient number of appropriately qualified personnel available to carry out all the tasks for which the manufacturer of investigational products is responsible.

应该有足够数量的适当有资质的人员，来执行试验用药品生产商负责的相关活动。

6.2. Individual responsibilities should be clearly defined, recorded as written descriptions and understood by the persons concerned.

应明确界定个人责任，应以书面说明的形式进行记录，并为有关人员所理解。

6.3. A designated person, with a broad knowledge of product development and clinical trial processes should ensure that there are systems in place that meet the requirements of this guideline and other relevant GxP guidelines.

指定人员需具有产品开发和临床试验流程的广泛知识，并确保已建立符合本指南和其它相关GxP指南要求的系统。

6.4. Personnel involved in the development, production and control of investigational products should be appropriately trained in relevant GxP and the requirements specific to investigational products.

参与试验用药品开发、生产和控制的人员，应接受有关GxP和试验用药品特定要求的适当培训。

6.5. Production and quality control operations should be carried out under the control of clearly identified responsible persons who are separately designated and independent, one from the other.

生产和质量控制运营应在明确指定的负责人的控制下进行，这些负责人是彼此独立指定的。

7. Documentation 文件

7.1. Good documentation is an essential part of a quality management system. Documents should be appropriately designed, prepared, reviewed and distributed. They should also be appropriate for their intended use.

良好的文件记录是质量管理体系的重要组成部分。文件应适当设计、准备、审查和分发。它们还应该适合其预期用途。

7.2. Documents should be approved, signed and dated by the appropriate responsible persons. No authorized document should be changed without the prior authorization and approval of another.

文件应由适当的负责人批准，并具有署名日期。未经事先授权和批准，不得变更任何授权文件。

Specifications 质量标准

7.3. Specifications (for starting materials, primary packaging materials, intermediate, bulk and finished products) should be available.

应提供质量标准（用于起始物料、初级包装材料、中间产品、半成品和成品）。

7.4. In developing specifications, attention should be paid to the characteristics which affect the efficacy and safety of products, namely:

在制定质量标准时，应注意影响产品功效和安全性的特性，即：

• the accuracy of the therapeutic or unitary dose: homogeneity, content uniformity;

• the release of active ingredients from the dosage form: dissolution time, etc.;

• the package size should be suitable for the requirements of the trial, where applicable;

• the estimated stability, if necessary, under accelerated conditions; and

• the preliminary storage conditions and the shelf life of the product.

治疗剂量或单位剂量的准确性：均一性、含量均一性；

剂型中活性成分的释放：溶出时间等；

包装尺寸应适合试验要求（如适用）；

必要时在加速条件下的估计稳定性；

产品的初步储存条件和有效期。

7.5. As a result of new experience in the development of an investigational product, specifications may be changed by following a documented procedure. Changes should be authorized by a responsible person. Each new version should take into account the latest data and information, current technology, regulatory and pharmacopoeia requirements. There should be traceability of the previous version(s). The reasons for changes should be recorded. The impact of the change on any on-going clinical trials, on product quality, stability, bio-availability, and bio equivalence (where applicable) should be considered.

基于试验用药品开发获得的新经验，可以通过书面化的程序来变更质量标准。变更应由负责人授权。每个新版本均应考虑：最新数据和信息、当前技术、法规和药典要求。应该具有以前版本的可追溯性。变更的原因应记录下来。应该考虑该变更对任何正在进行的临床试验、产品质量、稳定性、生物利用度和生物等效性（如适用）的影响。

Order订购

7.6. An order should be available for the request of a certain number of units for processing, packaging, storage and their shipping.

对一定数量的单元进行加工、包装、储存和运输的要求，应有订单支持。

7.7. The order should be given by the sponsor to the manufacturer of an investigational product.

发起人应将该订单下发给试验用药品的生产商。

7.8. The order should be in writing (e.g. by paper or electronic means), be authorized and contain sufficient detail including the approved product specification file (see below) and the relevant clinical trial protocol, as appropriate, to avoid any ambiguity.

订单应为书面形式（例如，通过纸质或电子方式），并应包含足够的详细信息，包括批准的产品质量标准文件（请参阅下文）和相关的临床试验方案，以免产生歧义。

7.9. Where commercially available products are obtained to be used as reference products, such as for use in bio-equivalence studies, the relevant documentation, such as a purchase order, an invoice, storage and transport records, should be maintained and available for inspection.

如果获得了可作为参考产品使用的市售产品，例如用于生物等效性研究，则应保留相关文件，例如采购订单、发票、存储和运输记录，并可供检查。

Product specification file(s) 产品质量标准文件

7.10. A product specification file (or files) should contain the information necessary to prepare detailed written instructions on processing, packaging, quality control testing, batch release, storage conditions and/or shipping.

产品质量标准文件（一个或多个）应包含准备详细书面说明所必需的信息，涉及加工、包装、QC检验、批放行、储存条件和/或运输。

7.11. The product specification file should indicate who has been designated or trained as the designated responsible person(s) for the release of batches.

产品质量标准文件应指出批放行负责人，该人员谁已被指定或已接受培训。

7.12. The product specification file should be continuously updated while, at the same time, ensuring appropriate traceability to the previous version(s).

产品质量标准文件应在不断更新的同时，确保对先前版本的适当可追溯性。

7.13. The information should form the basis for assessment of the suitability for certification and release of a particular batch by the designated responsible person. It should include or refer to the following documents:

对于指定负责人，该信息应构成评估特定批认证和放行是否合适的基础。它应包括或参考以下文件：

• specifications for starting materials, packaging materials, intermediate, bulk and finished product;

• analytical methods for starting materials, packaging materials, intermediate, bulk and finished product;

• manufacturing methods;

• in-process testing and methods;

• approved label;

• relevant clinical trial protocols;

• randomization codes, as appropriate;

• relevant technical agreements, as appropriate;

• stability data; and

• storage and shipment conditions.

起始物料、包装材料、中间体、半成品和成品的质量标准；

起始物料、包装材料、中间体、半成品和成品的的分析方法；

生产方法；

过程测试和方法；

批准的标签；

相关的临床试验方案；

适当的随机码；

适当的相关技术协议；

稳定性数据；

储存和运输条件。

Note: The contents will vary depending on the product and stage of development.

注意：内容将根据产品和开发阶段而有所不同。

Manufacturing formulae and processing instructions

生产配方和加工指导

7.14. Normally, detailed manufacturing formulae, processing and packaging instructions and records should be available. Where this is not possible, other clear, written instructions and written records should be available for every manufacturing operation or supply.

通常，应提供详细的生产配方、加工和包装说明以及记录。如果无法做到这一点，则对于每个生产操作或供应，应为其提供其它明确的书面说明和书面记录。

7.15. As a result of new experience in the development of an investigational product, manufacturing formulae andprocessing instructions may be changed by following a documented procedure. Each new version should take into account the latest data and information, current technology, regulatory and other requirements. There should be traceability to previous versions. The reasons for changes should be recorded. The impact of the change on any on-going clinical trial, product quality, stability, bio-availability and bio equivalence (where applicable) should be considered. Changes should be authorized by a responsible person.

基于试验用药品开发获得的新经验，可以通过书面化的程序来变更生产配方和加工指导。每个新版本均应考虑：最新数据和信息、当前技术、法规和和其它要求。应该可以追溯到以前的版本。变更的原因应记录下来。应该考虑该变更对任何正在进行的临床试验、产品质量、稳定性、生物利用度和生物等效性（如适用）的影响。变更应由负责人授权。

7.16. These records should be used when preparing the final version of the documents to be used in routine manufacture.

准备常规生产文件的最终版本时，应使用这些记录。

7.17. Batch processing and packaging records should be retained for at least two years after the termination or discontinuance of the clinical trial, or after the approval of the investigational product.

在终止或中止临床试验后，或在试验用药品批准后，批处理和包装记录应保留至少两年。

7.18. Where the data are intended for inclusion in an application for product registration (marketing authorization) purposes, the records should be maintained until the end of the life cycle of the product.

如果数据打算包含在产品注册（上市许可）申请中，则记录应保留到产品生命周期结束。

Packaging instructions

包装指导

7.19. The number of units to be packaged should be specified before the start of the packaging operation. This should include the number of units necessary for carrying out quality controls and the number of samples from each batch used in the clinical trial to be kept as retention samples. Reconciliation should be carried out at defined intervals, where required, and at the end of the packaging and labelling process.

在开始包装操作之前，应指定要包装的单元数。这应该包括执行质量控制所必需的单位数量，以及在临床试验中用作留样的每批样品数量。衡算应在规定的时间间隔内进行，并应在包装和贴标签过程结束时进行。

7.20. Investigational products may be packed in an individual way for each subject included in the clinical trial, or as bulk if required.

对于临床试验中包括的每个受试者，试验用药品可以单独包装，也可以根据需要散装。

Labelling instructions

贴标说明

7.21. Investigational products should be labelled in accordance with relevant legislation or best practices. The label should contain information such as:

试验用药品应根据相关法律或最佳实践进行贴标。标签应包含以下信息：

• the name, address and telephone number of the sponsor, contract research organization or investigator;

• the statement: "For clinical research use only";

• a reference number indicative of the trial, site, investigator and sponsor, if not given elsewhere;

• a batch or code number;

• the trial subject or patient identification number;

• a reference to the directions for use;

• information on storage conditions;

• an expiry date, use-by date or re-test date (month and year);

• a dosage form and route of administration;

• the quantity of dosage units and, in the case of open trials, the name/identifier and

• strength/potency; and

• the statement: “Keep out of reach of children”.

发起人、合同研究组织或研究者的姓名、地址和电话号码；

声明：“仅用于临床研究”；

如果没有其它地方说明，则需要显示试验、研究地点、研究者和发起人的参考编号；

批号或编号；

试验对象或患者的识别号；

使用说明的参考信息；

有关储存条件的信息；

有效期、使用日期或再验期（月和年）；

剂型和给药途径；

剂量单位的数量，如果是公开试验，则包含名称/标识信息；

强度/活性；

声明：“勿让儿童接触”。

7. 22. Additional information may be displayed in accordance with the order (e.g. treatment period, standard warnings).

可以根据订单，显示其它信息（例如治疗期、标准警告）。

7.23. When necessary for blinding purposes, the batch number may be provided separately (see also "Blinding operations").

出于盲操作的目的，必要时可以单独提供批号（另请参见“盲操作”）。

7.24. A copy of each type of label should be kept in the batch packaging record.

在批包装记录中，应保存每种标签的副本。

7.25.The address and telephone number of the main contact for information on the product, clinical trial and for emergency unblinding need not appear on the label where the subject has been given a leaflet or card which provides these details and who has been instructed to keep this in their possession at all times.

标签上无需显示有关产品、临床试验和紧急揭盲的主要联系人地址和电话号码，可以为受试者（或其他相关人员）提供含这些详细信息的说明书或卡片。

7.26.Particulars should appear in the official language(s) of the country in which the investigational medicinal product is to be used.

试验用药品信息应使用所在国家的官方语言。

7.27.Where all the required information cannot be displayed on primary packaging, secondary packaging should be provided bearing a label with those particulars. The primary packaging should nevertheless contain information such as the name of sponsor, contract research organization or investigator; route of administration; batch and/or code number; trial reference code and the trial subject identification number.

如果不能在初级包装上显示所有必需的信息，则应提供次级包装，以涵盖这些详细信息。然而，初级包装应包含必要信息，诸如:发起人、合同研究组织或研究者的姓名；给药途径；批号和/或代码号；试验参考代码和试验对象识别号。

7.28.Symbols or pictograms may be included to clarify certain information. Warnings and/or handling instructions may be displayed.

可能包含符号或象形图以阐明某些信息。可能会显示警告和/或处理性指导。

7.29. If it becomes necessary to change the use-by date, an additional label should be affixed to the investigational medicinal product. This additional label should state the new use-by date and repeat the batch number. This labelling activity should be performed in accordance with GMP principles, standard operating procedures and should be checked by a second person. This additional labelling should be recorded in both the trial documentation and in the batch records.

如有必要变更使用日期，则应在研究用药物上贴上附加标签。此附加标签应注明新的使用日期，并重复批号信息。贴标活动应按照GMP原则和标准操作程序进行，并应由第二个人进行复核。此附加标签应记录在试验文件和批记录中。

Batch manufacturing records

批生产记录

7.30. Processing, packaging and testing records should be kept in sufficient detail for the sequence of operations to be accurately traced. They should contain any relevant remarks which increase the existing knowledge of the product, allow and reflect changes and improvements in the manufacturing operations, and justify the procedures used.

应以充分的细节信息，保留加工、包装和检验记录的，以准确追踪操作活动。它们应包含任何相关的说明，这些说明可以增加产品的现有知识，允许并反映生产操作中的变更和改进，并说明使用程序的合理性。

Coding (or randomization) systems

编码（或随机）系统

7.31. Procedures should be established for the generation, security, distribution, handling and retention of any randomization code used in packaging investigational products and code-break mechanisms. The appropriate records should be maintained.

就用于包装试验用药品随机代码的生成、安全性、分发、处理和保留，以及密码破解机制，应该建立程序。应保持适当的记录。

7.32. The coding system must permit the determination of the identity of the actual treatment product received by individual subjects, without delay, in an emergency situation.编码系统必须允许在紧急情况下，就各个受试者接收到的实际治疗产品，毫不拖延地确定具体信息。

8. 设施

Premises

8.1. Premises, where investigational products are manufactured, should be located, designed, constructed and maintained to suit the operations to be carried out.

生产试验用药品的设施应进行适当选址、设计、建造和维护，以适应要进行的操作。

8.2. The layout and design of premises should aim to minimize the risk of errors and mix-ups and permit effective cleaning and maintenance in order to avoid contamination, cross-contamination and, in general, any adverse effect on the quality of the products.

设施的布局和设计应旨在最大程度地减少错误和混淆的风险，并进行有效的清洁和维护，以避免污染、交叉污染、以及总体上对产品质量的任何不利影响。

8.3. Attention should be paid to line clearance in order to avoid mix-ups.

为了避免混淆，应注意生产线清场。

8.4. Because the toxicity of some materials may not be fully known, cleaning is of particular importance. Validated cleaning procedures should be followed in order to prevent cross- contamination. The visual inspection after cleaning, sampling and test procedures should be appropriate and the acceptance limits used after cleaning should be justifiable. Where cleaning agents are used, their selection should be justifiable.

由于某些物料的毒性可能尚不完全清楚，因此清洁尤为重要。应遵循经过验证的清洁程序，以防止交叉污染。清洁后的外观检查、取样和检验程序应适当，清洁后使用的可接受限度应合理。使用清洁剂时，应合理选择它们。

8.5. Where identified through risk assessment, campaign production should be considered. In other cases based on risk, dedicated and self-contained facilities should be used.

考虑开展阶段性生产时，应进行风险评估。在其它基于风险的情况下，应使用专用且设备齐全的设施。

9. 设备和公用系统

Equipment and utilities

9.1. Equipment and utilities should be selected, located, constructed and maintained to suit the operations to be carried out.

应选择、定位、构造和维护设备和公用系统，以适合要执行的操作。

9.2. The layout, design, installation and use of equipment and utilities should aim to minimize the risk of errors and permit effective cleaning and maintenance in order to avoid cross- contamination, a build-up of dust or dirt and, in general, any adverse effect on the quality of products.

对于设备和公用系统的布局、设计、安装和使用，应旨在最大程度地减少错误风险，并进行有效的清洁和维护，以避免交叉污染、灰尘或污垢的堆积，以及一般而言，应避免任何在产品质量上的不利影响。

10. 物料

Materials

Starting materials 起始物料

10.1. The consistency of the production of investigational products may be influenced by the quality of the starting materials. Their physical, chemical and, when appropriate, microbiological properties should therefore be defined, documented in their specifications, and controlled.

试验用药品生产的一致性可能会受到原材料质量的影响。因此，应该定义它们的物理、化学和适当的微生物特性，并在其质量标准中进行记录和控制。

10.2. Existing compendial standards, when available, should be taken into consideration.

现有的药典标准（如果有）应予以考虑。

10.3. Specifications for active ingredients should be as comprehensive as possible, given the current state of knowledge.

鉴于当前的知识水平，活性成分的质量标准应尽可能全面。

10.4. Specifications for both active ingredients and excipients should be periodically reassessed and updated as required.

活性成分和辅料的质量标准应定期重新评估，并根据需要进行更新。

10.5. Detailed information on the quality of active ingredients and excipients (as well as of packaging materials) should be available so as to make it possible to recognize and, as necessary, allow for any variation in production.

应提供有关活性成分和辅料（以及包装材料）质量的详细信息，以便可以识别并在必要时允许生产中的任何波动。

Chemical and biological reference standards for analytical purposes

用于分析目的的化学和生物学标准品

10.6. Reference standards from reputable sources (WHO or national standards) should be used, if available; otherwise the reference substance(s) for the active ingredient(s) should be prepared, tested and released as reference material(s) by the producer of the investigational pharmaceutical product, or by the producer of the active ingredient( s) used in the manufacture of that product.

如果可以的话，应使用信誉良好的标准品（世界卫生组织或国家标准）；否则，对于活性成分的参考物质，应由试验用药品的生产商或活性成分的生产者来制备、检验和放行。

Principles applicable to reference products for clinical trials

适用于临床试验参比产品的原则

10.7. In studies in which an investigational product is compared with a marketed product, steps should be taken in order to ensure the integrity and quality of the reference products (final dosage form, packaging materials, storage conditions, etc.).

在将试验用药品与市售产品进行比较的研究中，应采取步骤以确保参比产品的完整性和质量（最终剂型、包装材料、储存条件等）。

10.8. If significant changes are to be made in the product, data should be available (e.g. on stability, comparative dissolution) that demonstrate that these changes do not influence the original quality characteristics of the product.

如果要对产品进行重大变更，则应提供数据（例如稳定性，比较溶出度），以证明这些变更不会影响产品的原始质量特征。

11. 生产

Production

11.1. Products intended for use in clinical trials (late Phase II and Phase III studies) should, as far as possible, be manufactured at a licensed facility. The batch size for investigational products manufactured in a pilot plant or small-scale facility, as opposed to the commercial batch size, may vary widely.

对于计划用于临床试验（II期和III期后期）的产品，应尽可能在许可的工厂生产。在中试工厂或小型工厂中生产的试验用药品，在批量大小与商业批量大小不同。

11.2. The guidelines in this document are applicable to the following licensed facilities:

本文件中的准则适用于以下许可的设施：

a pilot plant, primarily designed and used for process development; and

a small-scale facility (sometimes called a "pharmacy"), separate both from the company's pilot plant and from routine production.

中试工厂，主要设计用于工艺开发；

小型工厂（有时称为“药房”），与公司的中试工厂和常规生产是分开的。

11.3. Facilities, as listed below, should be subject to all GMP requirements for pharmaceutical products;

下表列出的设施应符合药品的所有GMP要求；

a large-scale production line assembled to manufacture materials in larger batches (e.g. for late Phase III trials and first commercial batches); and

the normal production line used for licensed commercial batches, and sometimes for the production of investigational products if the number of, for example, ordered ampoules, tablets or other dosage forms, is large enough.

装配了大规模生产线，以大批量生产物料（例如，用于III期后期试验和第一批商业生产）；

用于许可用于商业批次的正常生产线，如果订购的安瓿、片剂或其它剂型的数量足够大，有时用于生产试验用药品。

11.4. Where activities are outsourced to contract facilities, the contract must then clearly state, inter alia, the responsibilities of each party, compliance with GMP or of this guideline, and that the product(s) to be manufactured or controlled are intended for use in clinical trials. Close cooperation between the contracting parties is essential.

如果将活动外包给合同设施，则合同必须明确说明各方的责任，遵守GMP或本指南，保证生产或控制的产品可以用于临床试验目的。合同双方之间的密切合作至关重要。

生产操作

Manufacturing operations

11.5. As process validation may not always be complete during the development phase of products, provisional quality attributes, process parameters and in-process controls should be identified, based on risk management principles and experience with analogous products.

由于在产品开发阶段工艺验证可能并不总是完整的，因此应基于风险管理原则和类似产品的经验，来识别临时质量属性、工艺参数和过程控制。

11.6. The necessary instructions should be identified and may be adapted based on the experience gained in production.

应该确定必要的指导，并可以根据在生产中获得的经验进行调整。

11.7. Where processes such as mixing have not been validated, additional quality control testing may be necessary.

如果未验证混合等过程，则可能需要进行其它QC检验。

11.8. For sterile investigational products, the assurance of sterility should be no less than for licensed products (see GMP for sterile products (6)).

对于无菌试验用药品，无菌保证应不低于许可产品的无菌水平（无菌产品参见GMP（6））。

包装和贴标

Packaging and labelling

11.9. The packaging and labelling of investigational products are likely to be more complex and more liable to errors (which are also harder to detect) when "blinded" labels are used than for licensed products. Supervisory procedures such as label reconciliation, line clearance, and so on, and the independent checks by quality unit personnel, should be intensified accordingly.

与使用许可产品相比，使用“盲”标签时，试验用药品的包装和贴标可能会更复杂，并且更容易出错（也更难以发现）。相应地应加强诸如标签衡算、生产线清场等的监督程序，以及质量部门人员的独立检查。

11.10. The packaging must ensure that the investigational product remains in good condition during transport and storage. Any opening of, or tampering with, the outer packaging during transport should be readily discernible.

包装必须确保试验用药品在运输和储存期间保持良好状态。在运输过程中任何打开或篡改外包装的情况，都应易于辨认。

盲操作

Blinding operations

11.11. In the preparation of "blinded" products, the blind should be maintained until it is required to allow for the identification of the “blinded” product. In-process control should include a check on the similarity in appearance and any other required characteristics of the different products being compared.

在准备“盲”产品时，应保持盲状态，直到需要识别“盲”产品为止。过程控制应包括检查外观的相似性，以及所比较的不同产品的任何其它所需特性。

11.12. A coding system should be introduced to permit the proper identification of "blinded" products. The code, together with the randomization list, must permit the proper identification of the product, including any necessary traceability to the codes and batch number of the product before the blinding operation.

应该引入编码系统，以正确识别“盲”产品。该代码以及随机列表必须允许正确识别产品，包括在盲操作之前对代码和产品批号的任何必要的可追溯性。

12. 质量控制

Quality control

12.1. Quality control should cover, for example, the sampling and testing of materials and products, ensuring that these are not released for use, sale or supply until their quality has been judged to be compliant with the specifications.

质量控制应包括，例如，物料和产品的取样和检验，确保在判定其质量符合质量标准之前，不放行这些物料以供使用、销售或供应。

12.2. Each batch of product should be tested in accordance with a Product Specification File and should meet its specification. Product release is often carried out in two stages; that is, before final packaging (bulk product testing) and after final packaging (finished product testing).

每批产品应按照产品质量标准文件进行检验，并应符合其质量标准。产品通常分为两个阶段：也就是说，在最终包装之前（半产品检验）和最终包装之后（成品检验）。

12.3. Bulk product testing should cover all relevant factors including production conditions, the results of in-process testing, a review of manufacturing documentation and compliance with the Product Specification File and the order. Finished product testing should cover, in addition to the bulk product assessment, all relevant factors including packaging conditions, the results of in-process testing, a review of packaging documentation and compliance with the Product Specification File and the order.

半产品检验应涵盖所有相关因素，包括生产条件、过程检验结果、生产文件审查，以及对产品质量标准文件和订单的符合情况。成品检验除对半成品的评估外，还应包括所有相关因素，包括包装条件、过程检验结果、包装文件审查，以及对产品质量标准文件和订单的符合情况。

12.4. When necessary, quality control should also be used to verify the similarity in appearance and other physical characteristics such as the odour of "blinded" investigational products.

必要时，还应通过质量控制来验证外观和其它物理特性（例如“盲”试验用药品的气味）是否相似。

12.5. End-product testing should be carried out in order to ensure that each batch meets its specification.

应当进行最终产品检验，以确保每个批次都符合其质量标准。

12.6 Reference and retention samples of each batch of product should be retained.

每批产品的参比样品和留样应保留。

12.7 Samples should be retained in the primary container used for the study or in a suitable bulk container for at least two years after the termination or completion of the relevant clinical trial. If the sample is not stored in the pack used for the study, stability data should be available to justify the shelf life in the pack used.

在相关临床试验终止或完成后，样品应保存在用于研究的主要容器中或合适的散装容器中，时间为至少两年。如果样品未保存在用于研究的包装中，则应提供稳定性数据以证明所用包装的有效期。

12.8 Retention samples should be kept until the clinical report has been prepared in order to enable the confirmation of product identity in the event of, and as part of an investigation into, inconsistent trial results.

留样应一直保存，直到准备好临床报告为止，以便在试验结果不一致时，作为调查的一部分，能够确认产品的鉴别。

12.9 The storage location of reference and retention samples should be defined in a technical agreement between the sponsor and manufacturer(s) and should allow for timely access by the competent authorities.

参比样品和留样的存放位置应在发起人与生产商之间的技术协议中规定，并应允许主管当局及时取用。

12.10The reference sample should be of sufficient size to permit the carrying out on, at least, two occasions of the full analytical controls on the batch in accordance with the Investigational Product dossier submitted for authorization in order to conduct the clinical trial.

参比样品应有足够的数量，以至少允许两次对批次进行全面的分析控制，该分析控制基于为获得临床试验许可而提交的试验用药品档案。

12.11 In the case of retention samples, it is acceptable to store information related to the final packaging as written or electronic records if such records provide sufficient information. In the case of reference samples, the system should comply with the requirements of WHO guidelines for computerized systems (7).

对于留样，如果能够提供了足够的信息，则可以书面或电子记录形式储存有关最终包装的信息。对于参比样品，系统应符合WHO对计算机系统指南的要求（7）。

12.12 The release of a batch of an investigational product should only occur after the designated responsible person has certified that the product meets the relevant requirements. These requirements include the assessment of, as appropriate:

仅在指定负责人证明产品符合相关要求后，才能放行该批试验用药品。这些要求包括对以下方面的评估：

batch records, including control reports, in-process test reports, changes, deviations and release reports demonstrating compliance with the product specification file, the order, protocol and randomization code;

批记录，包括控制报告、过程检验报告、变更、偏差和放行报告，证明它们符合产品质量标准文件、订单、草案和随机编码；

production conditions;

生产条件；

the validation status of facilities, processes and methods, as appropriate;

设施、工艺和方法的验证状态（如适用）；

the examination of finished packs;

成品包装的检查；

where relevant, the results of any analyses or tests performed after importation;

在相关的情况下，进口后进行的任何分析或检验的结果；

stability reports;

稳定性报告；

the source and verification of conditions of storage and shipment;

储存和运输条件的来源和确认；

audit reports concerning the quality system of the manufacturer, where applicable;

有关生产商质量体系的审计报告（如适用）；

documents certifying that the manufacturer is authorized to manufacture investigational medicinal products or comparators for export by the appropriate authorities in the country of export; and

就生产商已获得出口国有关当局授权生产试验用药品或参比品，其出口相关的证明文件；

where relevant, regulatory requirements for marketing authorization, GMP standards applicable and any official verification of GMP compliance.

适当时，有关上市许可的法规要求，适用的GMP标准，以及对GMP合规性的任何官方确认。

Note: The relevance of the above elements is affected by the country of origin of the product, the manufacturer and the marketed status of the product

注意：以上要素的相关性受产品原产国、生产商和产品市场状况的影响

13. 确认与验证

Qualification and validation

13.1 The extent of qualification and validation may be different to that necessary for a routine production operation.

确认与验证的范围可能不同于常规生产操作所必需的范围。

13.2 The scope of qualification and validation required should be determined based on risk assessment.

应根据风险评估，确定所需的确认与验证范围。

13.3 For sterile products, there should be no reduction in the degree of validation of sterilizing equipment required. Validation of aseptic processes presents special problems when the batch size is small since the number of units filled may be not adequate for a validation exercise. Filling and sealing, which is often done by hand, can compromise the maintenance of sterility. Greater attention should therefore be given to environmental monitoring

对于无菌产品，不应减少灭菌设备所需的验证水平程度。当批量较小时，会给无菌工艺验证带来特殊问题，因为灌装的单元数可能不足以进行验证。灌装和密封通常是手工完成的，可能会损害无菌性。因此，应更加重视环境监测。

14. 投诉

Complaints

14.1. There should be a written procedure describing the managing of complaints.

应该有描述投诉处理的书面程序。

14.2. Any complaint concerning a product defect should be recorded with all the original details and thoroughly investigated.

对于有关产品缺陷的任何投诉，应记录所有原始细节并进行彻底调查。

14.3. Where necessary, appropriate follow-up action, possibly including product recall, should be taken after investigation and evaluation of the complaint.

必要时，应在对投诉进行调查和评估之后，采取适当的后续措施，包括召回产品。

14.4. All decisions made and measures taken as a result of a complaint should be recorded and referenced to the corresponding batch records.

因投诉而做出的所有决定和采取的措施均应记录下来，并参考相应的批记录。

14.5. The competent authorities should be informed if a manufacturer is considering action following the identification of serious quality problems with a product that may be impacting trial subjects or patients.

在确定可能影响试验对象或患者的严重产品质量问题之后，就其是否正在考虑采取措施，生产商应告知主管当局。

14.6. The conclusions of the investigations carried out in response to a complaint should be discussed between the manufacturer and the sponsor (if different) or between the persons responsible for manufacture and those responsible for the relevant clinical trial in order to assess any potential impact on the trial and on the product development, in order to determine the cause, and to take any necessary corrective action.

应在生产商和发起人（如果有的话）之间，或在生产负责人与相关临床试验负责人之间，讨论针对投诉进行的调查结论，评估对试验和产品开发的任何潜在影响，确定原因，并采取任何必要的纠正措施。

15. 召回

Recalls

15.1. There should be a written procedure describing the managing of a recall of investigational products.

应该有一个书面程序来描述对试验用药品的召回管理。

15.2. Recall procedures should be understood by the sponsor, investigator and monitor, in addition to the person(s) responsible for recalls.

除召回负责人外，发起人、研究者和监测者还应了解召回程序。

15.3. The recall of a product should be documented and inventory records should be kept.

产品召回应形成文件，并应保存库存记录。

16. 退货

Returns

16.1. Investigational products should be returned under agreed conditions defined by the sponsor, specified in written procedures and approved by authorized staff members.

试验用药品应在发起人定义的同意条件下退回，该条件应在书面程序中说明，并经授权的工作人员批准。

16.2. Returned investigational products should be clearly identified and stored in a dedicated area in a controlled manner.

退回的试验用药品应清晰标识，并以可控方式储存在专用区域中。

16.3. Inventory records of returned products should be kept.

应保留退回产品的库存记录。

17. 运输

Shipping

17.1. The shipping of investigational products should be carried out in accordance with written procedures laid down in the protocol or shipping order given by the sponsor.

试验用药品的运输，应按照草案中规定的书面程序或发起人发出的运输指令进行。

17.2. A shipment is sent to an investigator after following the defined release procedures, for example, quality control and authorization by the sponsor. Both releases should be recorded.

按照规定的放行程序，例如，质量控制和发起人的授权，将货物发送给研究者。二者的放行都应记录。

17.3. The sponsor should ensure that the shipment will be received and acknowledged by the correct addressee as stated in the protocol.

按照草案中的规定，发起人应确保正确的收件人将收到并确认收货。

17.4. A detailed inventory of the shipments made by the manufacturer should be maintained and should make particular mention of the addressee's identification.

应保留生产商发货的详细清单，并应特别提及收件人的身份。

17.5. The transfer of investigational products from one trial site to another should be done in exceptional cases only. Such transfers should be justifiable, documented and carried out in accordance with a written procedure. Repackaging or relabelling should normally be done by the manufacturer. Records should be maintained and provide full traceability of the product and activities.

仅在特殊情况下，才可以将试验用药品从一个试验场所转移到另一试验场所。此类转移应有正当理由，形成文件并按照书面程序进行。重新包装或重新贴标签通常应由生产商完成。应保持记录，并提供产品和活动的完全可追溯性。

18. 销毁

Destruction

18.1. The sponsor is responsible for the destruction of unused investigational products. Unused products should normally not be destroyed by the manufacturer without prior authorization by the sponsor.

发起人负责销毁未使用的试验用药品。未经发起人事先授权，生产商通常不应销毁未使用的产品。

18.2. Destruction operations should be carried out in accordance with written procedures and environmental safety requirements.

销毁操作应按照书面程序和环境安全要求进行。

18.3. The delivered, used and recovered quantities of a product should be recorded, reconciled and verified by or on behalf of the sponsor for each trial site and each trial period. The destruction should be carried out only after any discrepancies have been investigated, satisfactorily explained and the reconciliation has been accepted.

对于产品的交付、使用和回收数量，应在每个试验场所和每个试验期间，由发起人或代表发起人的相关方进行记录、核对和确认。仅在对任何差异进行了调查、充分地说明，并接受衡算结果之后，方可进行销毁。

18.4. Destruction operations should be recorded in such a manner that all operations are accounted for. These records should be kept by the sponsor.

销毁操作应进行记录，以便可以追溯所有操作。这些记录应由发起人保存。

18.5. If the manufacturer is requested to destroy products, a Certificate of Destruction should be provided to the sponsor.

如果要求生产商销毁产品，则应向发起人提供销毁证明。

Ref.: [WHO][2020-11-07]DRAFT WORKING DOCUMENT FOR COMMENTS: Good manufacturing practices for investigational products

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