11月11日，世界卫生组织（WHO）发布了“研究和开发设施的良好实践” 指南（Good practices for research and development facilities）的征求意见稿。WHO指出，就开发批、中试批生产以及相应的稳定性数据，目前没有相关的法规指南对稳定性、工艺验证和分析方法的开发和验证提出具体要求，因此开发本文件非常有必要。本文件为研发机构提供了有关GMP方面的指南，目的是确保遵循正确的系统，保证产品、工艺、程序和数据的适当性、可靠性和质量。

 

本指南主体部分分为22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.卫生

7.确认与验证

8.外包活动

9.自检和质量审计

10.人员

11.培训

12.设施

13.设备和仪器

14.物料

15.文档

16.加工和工艺验证

17.质量控制

18.稳定性研究

19.分析程序的制定

20.技术转移

21.生命周期方法

22.清洁程序的开发和清洁验证

 

以下是该指南的背景、简介和范围方面的内容：

 

1. Background 背景

 

In view of the recent need for the unprecedented fast 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 batches and the sequential stability data that is submitted in product applications (dossiers) for marketing authorization and the prequalification of medical products.

 

鉴于最近迫切需要快速开发用于新冠治疗的健康产品，WHO资格预审检查小组（PQT INS）提出了开发GMP文件的紧迫性，以指导开发批、中试批生产以及相应的稳定性数据，这些信息是在产品申请（申报资料）中提交，用于上市许可和医疗产品资格预审。

 

There are currently no regulatory guidelines which address this matter, although the data collected from these batches influence the following aspects of the product:

 stability;

 process validation; and

 analytical method development and validation.

 

尽管从这些批次中收集的数据会影响产品的以下几个方面，但是目前没有解决这些问题的法规指南：

•稳定性；

•工艺验证；

•分析方法的开发和验证。

 

2. Introduction 简介

 

2.1. The modern era of the pharmaceutical industry, in particular focusing on chemical synthesis, began in the 19th century. The use of computerized systems in production and control is increasing rapidly. The ongoing evolution and advancement in the pharmaceutical industry is fundamental in the control and elimination of disease around the world.

 

制药业的现代化始于19世纪，主要专注于化学合成药物。在生产和控制中，计算机系统的使用正在迅速增加。制药行业的不断发展和进步，对于控制和消除全球疾病至关重要。

 

2.2. With an ever increasing awareness of the risks in pharmaceutical production and control, and the life cycle approaches being followed, more and more emphasis is being placed on ensuring that the research and development of products are appropriately controlled and documented.

 

随着人们对药品生产和控制风险的认识不断提高，并且遵循了生命周期方法，越来越多的重点聚焦于：对产品的研究和开发，确保进行适当的控制和记录。

 

2.3. Furthermore, as regulators request and review data and information such as the development data of products and processes, design of experiments, validation and stability results, it has become necessary to ensure that the facilities, quality systems, data and information meet the appropriate standards and good practices.

 

此外，随着监管机构对数据和信息的索要和审查，例如产品和工艺的开发数据、实验设计、验证和稳定性结果，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实践。

 

2.4. This document intends to provide guidance on GMP to research and development facilities. 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 the requirements for safety, efficacy and quality that they purport to possess.

 

本文档旨在为研发机构提供有关GMP的指南。它还旨在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。进一步有助于确保产品满足声称具有的安全性、功效和质量要求。

 

2.5. In addition to product development, other activities including the production of investigational products and pilot scale batches; process validation; cleaning procedure development; cleaning validation studies; as well as stability studies, are often undertaken in such facilities.

 

除产品开发外，其他活动包括试验用产品和中试批的生产；工艺验证；清洁程序的开发；清洁验证研究；以及稳定性研究，通常都是在此类设施中进行的。

 

2.6. The WHO document titled Good manufacturing practices for investigational pharmaceutical  products for clinical trials in humans (1) specifically addresses the requirements and recommendations for products used in clinical trials. Other WHO guidelines address specific requirements and recommendations including but not limited to stability testing, analytical method validation, cleaning validation and the transfer of technology (TOT). (See the References  and Further Reading sections).

 

WHO题为“试验用药品的GMP”的文件专门针对临床试验中使用的产品提出了要求和建议。世卫组织的其他指南还针对具体要求和建议，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（TOT）。

 

3. Scope 范围

 

3.1. This guideline is applicable to research and development facilities of products manufactured by chemical synthesis, extraction, cell culture or fermentation, by recovery from natural sources, or by any combination of these processes. It further covers development of procedures and processes intended for transfer and use in marketing authorization applications, process validation, TOT (10)-related activities, validation (7), quality control laboratory activities (11), such as stability testing and development, and validation of cleaning procedures (see Figure 1 and section 4 below).

 

本指南适用于研发设施，其通过化学合成、提取、细胞培养或发酵、天然来源回收或通过这些工艺的任何组合来生产产品。它进一步涵盖程序和流程的开发，涉及转移和用于上市许可申请、工艺验证、TOT相关的活动、验证、QC实验室活动（例如稳定性检验和开发），以及清洁程序的验证（请参见下面的图1和第4章）。

 

3.2. This guide excludes all vaccines, whole cells, whole blood and plasma, blood and plasma derivatives (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（血浆分级分离）、医用气体、商业产品、放射性药物和基因治疗产品。

 

3.3. The good practices outlined below are to be considered general guides and they may be adapted to meet individual needs. The equivalence of alternative approaches, however, should be proven.

 

以下概述的良好实践应被视为通用指南，可以对其进行调整以满足特别需求。但是，应证明替代方法的等效性。

 

3.4. In this guide, the term “should” indicates recommendations that are expected to apply unless shown to be inapplicable or replaced by an alternative demonstrated to provide an acceptable level of control.

 

本指南中，术语“应该”表示预期将适用的建议，除非显示为不适用，或被证明可以使用替代方案替代（需提供可接受的控制水平）。

 

3.5. This guide, as a whole, does not cover safety aspects for the personnel engaged in the research and development nor the aspects of protection of the environment. These controls are inherent responsibilities of the manufacturer and are governed by national laws.

 

总体而言，本指南未涵盖从事研发的人员的安全方面，也未涵盖环境保护的方面。这些控制是生产商的固有责任，并受国家法律约束。

 

3.6. This guide is not intended to define registration requirements or modify pharmacopoeial requirements or other guideline recommendations. For details on process development, it is recommended that other guidelines, such as those published by The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH), be read in conjunction with this document.

 

本指南无意定义注册要求，或修改药典要求，或其他指南建议。有关工艺开发的详细信息，建议与本文档一起阅读其他指南，例如ICH出版的相关指南。

 

3.7. This guide does not affect the ability of the responsible regulatory agency to establish specific registration or filing requirements. All commitments in registration and filing documents must be met. This document provides information to consider for a risk- and science-based approach in the research and development of medical products.

 

本指南不影响负责的监管机构建立特定注册或备案要求的能力。必须遵守注册和提交文件中的所有承诺。本文档提供了：在医疗产品研发中，考虑基于风险和科学的方法的信息。

 

3.8. The main focus of the document is on pharmaceutical formulation and development. The principles described in this document may however be applied in facilities where other products such as vaccines, veterinary products and biopharmaceutical products are developed. The principles may also be considered, where appropriate, in facilities where medical devices are manufactured.

 

该文件的主要重点是药物制剂和开发。但是，本文档中描述的原理可能适用于开发其他产品（如疫苗、兽药和生物制品）的设施。在适当的情况下，也可以在生产医疗器械的设施中考虑这些原则。

 

3.9. Due to the nature of research work, and an increasing expectation for compliance with standards in manufacture, the guidance in this document would normally be applied based on risk assessment, in an increasing manner, from research to commercial batch manufacturing. The stringency of GMP in research and development should increase as the process proceeds from early research work to the final steps of development and formulation, stability testing, process validation and cleaning validation.

 

由于研究工作的性质、以及对生产标准合规性的期望越来越高，因此通常基于风险评估，随着从研究到商业批生产这一过程的推进，本指南中的内容越来越多地应用。随着从早期研究工作到最终步骤的过程，如开发与配方、稳定性测试、工艺验证和清洁验证，GMP在研究和开发中的严格性应逐渐增加。

 

Figure 1. Application of this guide

 

Early research – Research – Development/formulation – Registration batches

Increased compliance with Good Manufacturing Practices*

 

图1.本指南的应用

 

早期研究–研究–开发/处方–注册批次

 

更好地遵守GMP*

 

*The principles described in this guideline are applied, based on risk management principles, in an increased manner from early research to development to registration batches

 

*本指南中描述的原则基于风险管理原则，从早期研究，到开发、再到注册批次，其应用越来越多。

 

4. 质量管理

 

Quality management 

 

4.1. There should be a quality management system encompassing adequate resources, a written organizational structure and procedures to follow.

 

应该有一个质量管理体系，包括充分的资源、书面话的组织结构和可以遵循的程序。

 

4.2. The necessary resources should include, for example:

a) a sufficient number of appropriately qualified, trained personnel;

b) adequate premises and space;

c) suitable equipment and services;

d) appropriate materials, containers and labels；and

e) suitable storage and transport.

 

必要的资源应包括，例如：

a）足够数量的经过适当培训的有资质人员；

b）充分的场所和空间；

c）合适的设备和服务；

d）适当的材料、容器和标签；

e）适当的储存和运输。

 

4.3. Roles, responsibilities and authorities should be defined, communicated and implemented.

 

角色、职责和权限应定义、沟通和实施。

 

4.4. The quality system should facilitate innovation and continual improvement and strengthen the link between pharmaceutical development and manufacturing activities.

 

质量体系应促进创新和持续改进，并加强药物开发与生产活动之间的联系。

 

4.5 All parts of the quality system should be adequately resourced and maintained, including with sufficient competent personnel, suitable premises, equipment and facilities.

 

质量体系的所有部分应有充分的资源和维护，包括有充分的有资质人员，合适的场所、设备和设施。

 

4.6 Initial research, as well as development activities, should be defined and documented. The detail should be in accordance with risk assessment and the increasing scale of GMP requirements from early to final stages of development.

 

应该定义和记录初步研究以及开发活动。其详细程度，应与风险评估、以及从开发的早期到最终阶段不断增加的GMP要求相一致。

 

4.7 The quality system should ensure, as applicable and according to the stage of research and development, that:

 

质量体系应根据研究和开发阶段的要求，确保：

 

•managerial responsibilities are clearly specified in job descriptions;

 

在岗位说明书中明确规定管理职责；

 

•instructions and procedures are written in clear and unambiguous language;

 

指导和程序以清晰明确的语言编写；

 

•procedures are correctly carried out;

 

正确执行程序；

 

•records are made (manually and/or by recording instruments) during production and quality control;

 

在生产和质量控制期间（手动和/或通过记录仪器）进行记录；

 

•any significant deviations are recorded, investigated and the appropriate action taken;

 

记录、调查任何重大偏差，并采取适当措施；

 

•records are maintained;

 

保持记录；

 

•there is a system for quality risk management (QRM);

 

有质量风险管理（QRM）系统；

 

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

 

对于生产、供应和使用正确的起始和包装材料，进行相应的安排；

 

•all necessary controls on starting materials, intermediate products, bulk products and other in-process controls are carried out;

 

对原材料、中间体、半成品和其它中制措施，进行所有必要的控制；

 

•calibrations and validations are carried out where appropriate;

 

适当时，进行校准和验证；

 

•the product and process knowledge is managed;

 

产品和工艺知识得到管理；

 

•products are designed and developed in accordance with applicable good practices (GxP);

 

根据适用的良好实践（GxP）设计和开发产品；

 

•production and control operations are clearly specified in written form;

 

以书面形式，明确规定生产和控制操作；

 

•continual improvement is facilitated through the implementation of quality improvements appropriate to the current level of process and product knowledge;

 

通过实施适合于当前工艺和产品知识水平的质量改进，来促进持续改进；

 

•product realization is achieved;

 

完成产品的可实现化；

 

•cleaning procedures are developed and validated;

 

制定并验证清洁程序；

 

•stability testing is done following written procedures and protocols；and

 

按照书面程序和草案进行稳定性测试；

 

•data meet ALCOA+ requirements.

 

•数据符合ALCOA +要求。

 

4.8 There should be periodic management review with the involvement of senior management.

 

应在高级管理层的参与下，进行定期的管理层审查。

 

5.质量风险管理

 

 Quality risk management 

 

5.1. A system of quality risk management (QRM) should be implemented. The system should ensure that risks are identified based on scientific knowledge and experience. The appropriate controls should be identified and implemented to mitigate risks.

 

应实施质量风险管理（QRM）系统。该系统应确保根据科学知识和经验确定风险。应确定并实施适当的控制措施，以减轻风险。

 

5.2. The level of effort, formality and documentation of the QRM process is commensurate with the level of risk and the stage from research to development, to commercial batch manufacturing and control (see Figure 1).

 

QRM流程的工作量、形式和文件记录的水平，应与风险水平以及从研究、到开发再到商业批生产和控制的阶段相对应（见图1）。

 

5.3. Systems should be in place to manage and minimize the risks inherent in research and development in order to ensure the ultimate quality, safety and efficacy of products；and the reliability of data.

 

应建立系统来管理和减少研发中固有的风险，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. Risk assessments should be periodically reviewed in light of improvements, current technology, scientific knowledge and experience.

 

应根据改进情况、当前技术、科学知识和经验，定期审查风险评估。

 

6. 清洁与卫生

 

Sanitation and hygiene 

 

6.1. Procedures should be implemented to maintain sanitation and hygiene. The scope of sanitation and hygiene covers personnel, premises, equipment and apparatus, production materials and containers, and products for cleaning and disinfection.

 

应执行程序，以保持清洁与卫生。清洁和卫生范围包括人员、场所、设备和器具、生产材料、容器，以及清洁和消毒产品。

 

6.2. Potential sources of contamination should be eliminated.

 

应消除潜在的污染源。

 

7.  确认与验证

 

Qualification and validation

 

7.1. Qualification and validation required should be identified based on risk assessment and, in addition, should be appropriate to the stage of research and development.

 

应基于风险评估来确定所需的确认与验证，此外，还应适合于研发阶段。

 

7.2. The qualification and validation policy and approach should be defined and documented, for example, in a validation master plan.

 

例如，应在验证主计划中，定义和记录确认与验证的策略及方法。

 

7.3. Where qualification and validation is carried out, the responsibility of performing validation should be clearly defined.

 

在进行确认与验证时，应明确规定执行验证的责任。

 

7.4. Qualification and validation should provide documentary evidence that specifications and other requirements are met. Protocols and reports should be made available, when required.

 

确认与验证应提供证明，即满足质量标准和其它要求的书面证据。必要时，应提供草案和报告。

 

7.5. Where process validation, cleaning validation and analytical procedure validation is done as a part of development, procedures and protocols should be followed. Reports should be available and retained.

 

在开发过程中，进行工艺验证、清洁验证和分析方法验证时，应遵循程序和草案。报告应可查，并进行保留。

 

8.外包活动

 

Outsourced activities

 

8.1. Outsourced activities should be correctly defined, agreed and controlled through a written agreement.

 

应通过书面协议，正确定义、约定和控制外包活动。

 

8.2. All responsibilities and arrangements for activities, such as quality control testing and technology transfer, should be clearly described.

 

所有活动的职责和安排，例如QC检验和技术转让，都应予以明确说明。

 

委托方

 

The contract giver

 

8.3. The contract giver is responsible for assessing the suitability and competence of the contract acceptor to successfully carry out the work or tests required and for approval of the contract activities.

 

委托方负责评估受托方成功完成所需工作或检验的适用性和能力，并负责批准合同活动。

 

8.4. The contract giver should provide the contract acceptor with all the information necessary to carry out the contracted operations correctly.

 

委托方应向受托方提供正确执行合同规定的操作所需的所有信息。

 

8.5. The contract giver should ensure that the contract acceptor is fully aware of any hazards associated with the product, work or tests.

 

委托方应确保受托方充分意识到与产品、工作或检验有关的任何危险。

 

8.6. The contract giver should review and assess the records and results related to the outsourced activities.

 

委托方应审查和评估与外包活动有关的记录和结果。

 

8.7. The contract giver is responsible for ensuring that the contract accepter understands that his or her activities may be subject to inspection by the competent authorities.

 

委托方有责任确保受托方了解：其活动可能受到主管当局的检查。

 

受托方

 

The contract accepter

 

8.8. The contract accepter must have adequate premises, equipment, knowledge, experience and competent personnel to satisfactorily carry out the work ordered by the contract giver.

 

受托方必须具有充分的场所、设备、知识、经验和胜任的人员，方能成功地执行委托方所下令的工作。

 

8.9. The contract accepter should not pass to a third party any of the work entrusted under the contract without the contract giver’s prior evaluation and approval of the arrangements.

 

未经委托方的事先评估和批准，受托方不得将合同所委托的任何工作交给第三方。

 

协议

 

The agreement

 

8.10. The technical aspects of the agreement should be drawn up by competent persons suitably knowledgeable in the field of research, development and GMP.

 

该协议的技术方面应由在研究、开发和GMP领域具有适当知识的主管人员起草。

 

8.11. The agreement should describe the handling of materials, such as samples and products, if they are out of specification or rejected.

 

该协议应描述材料（例如样品和产品）的处理方法（如不合格或被拒绝时）。

 

8.12. The agreement should permit the contract giver to audit the facilities 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. 自检和质量审计

 

Self-inspection and quality audits

 

9.1. There should be a written self-inspection programme.

 

应该有一个书面的自检计划。

 

9.2. Self-inspections should be performed routinely and may be, in addition, performed on special occasions.

 

自检应常规进行，此外，还可以在特殊情况下进行。

 

9.3 The team responsible for self-inspection should consist of personnel with the appropriate knowledge and experience, free from bias.

 

负责自检的团队应由具有适当知识和经验、且没有偏见的人员组成。

 

9.4 Self-inspections should cover at least the following items:

 

自检应至少包括以下几项内容：

a) personnel;

b) premises including personnel facilities;

c) maintenance of buildings and equipment;

d) storage of starting materials and finished products;

e) equipment;

f) production and in-process controls;

g) quality control;

h) documentation;

i) sanitation and hygiene;

j) qualification and validation;

k) calibration of instruments or measurement systems;

l) control of labels；and

m) results of previous self-inspections and any corrective steps taken.

a）人员；

b）包括人员设施在内的场所；

c）厂房和设备的维修；

d）原材料和成品的储存；

e）设备；

f）生产和过程控制；

g）质量控制；

h）文件；

i）清洁与卫生；

j）确认和验证；

k）仪器或测量系统的校验；

l）标签控制；

m）先前自检的结果以及采取的任何纠正措施。

 

9.5 The outcome of the self-inspection should be documented. Corrective actions and preventive actions should be identified and implemented. There should be an effective follow-up programme.

 

自检的结果应形成文件。应确定和实施纠正和预防措施。应该有一个有效的后续计划。

 

9.6 Self-inspections may be supplemented by quality audits.

 

质量审计可以补充自检。

 

10.人员

 

Personnel

 

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

 

有关人员应明确定义和理解个人责任，并记录为书面说明。

 

10.2 All personnel should be aware of the principles of this guideline and other applicable GxPs.

 

所有人员均应了解本指南和其它适用的GxP原则。

 

10.3 Steps should be taken to prevent unauthorized people from entering storage, production and quality control areas.

 

应采取措施防止未经授权的人员进入存储、生产和质量控制区域。

 

10.4. The heads of production and quality unit should be independent of each other.

 

生产主管和质量主管应相互独立。

 

10.5. Smoking, eating, drinking, chewing and keeping plants, food, drink, smoking material and personal medicines should not be permitted in any area where they might adversely influence product quality.

 

禁止在任何可能对产品质量产生不利影响的区域吸烟、进食、饮用、咀嚼和储存植物、食物、饮料、吸烟材料和个人药品。

 

11. 培训

 

Training

 

11.1. Training should be provided in accordance with a written programme that covers topics such as the theory and practice of GMP and the duties assigned to them.

 

应按照书面计划提供培训，其中应涵盖GMP的理论和实践以及分配给他们的职责等主题。

 

11.2. The effectiveness of training should be assessed.

 

应评估培训的有效性。

 

11.3. Training and assessment records should be kept.

 

应保留培训和评估记录。

 

11.4. Where appropriate, specific training should be given on the handling of highly active, toxic, infectious or sensitizing materials.

 

在适当时，应进行有关高活性、有毒、传染性或致敏性物质处理的专门培训。

 

12. 设施

 

Premises

 

12.1. Premises should be located, designed, constructed, adapted and maintained to suit the operations to be carried out.

 

设施的位置、设计、构造、调整和维护应适合要执行的操作。

 

12.2. The layout and design should aim to minimize the risk of errors and permit effective cleaning and maintenance in order to avoid cross-contamination, build-up of dust or dirt and, in general, any adverse effect on the products and activities.

 

布局和设计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，并且通常避免对产品和活动产生不利影响。

 

12.3. Where product dust is generated, measures should be taken to avoid cross-contamination and to facilitate cleaning.

 

在产生产品粉尘的地方，应采取措施避免交叉污染并促进清洁。

 

12.4. Premises should be cleaned according to detailed written procedures. Records should be maintained.

 

设施应按照详细的书面程序进行清洁。记录应予以保留。

 

12.5. Electrical supply, lighting, temperature, humidity and ventilation should be appropriate.

 

应有适当的电源、照明、温度、湿度和通风。

 

12.6. Toilets, rest and refreshment rooms should be separate from production and control areas.

 

厕所、息室和休闲室应与生产和控制区域分开。

 

12.7. Animal houses should be well isolated from other areas, with a separate entrance (animal access) and air-handling facilities.

 

动物房应与其它区域隔离开，并有单独的入口（动物通道）和空气处理设施。

 

12.8. Storage areas should be of sufficient capacity with proper separation and segregation between materials, based on risk assessment.

 

根据风险评估，存储区域应具有充分的容量，并在物料之间进行适当的隔离和分离。

 

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.

 

储存区域应清洁干燥，通过设计或调整，确保维持所需的储存条件。在适当情况下，应控制、监测和记录条件。

 

12.10. Segregation should be provided for the storage of quarantined, released and rejected materials and products.

 

应有不同的分区，以存储隔离、释放和拒收的材料和产品。

 

12.11. Certain materials, such as highly active, radioactive materials and narcotics, should be stored in safe and secure areas.

 

某些材料，例如高活性、放射性材料和麻醉品，应存储在安全的地方。

 

12.12. Materials identified for testing should be sampled in accordance with written procedures and analysed for compliance with their specifications.

 

对于确定要进行检验的材料，应按照书面程序进行取样，并分析其是否符合质量标准。

 

12.13. The stages in production, including weighing, compounding, and packaging, should be done in a manner to prevent contamination, cross-contamination and mix-ups.

 

对于生产的各个阶段（包括称重、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. There should be sufficient space, instruments, equipment and the appropriate reference materials, solvents and reagents.

 

质量控制（QC）实验室应与生产区域分开。它们的设计应适合要在其中执行的操作。应该有充分的空间、仪器、设备以及适当的标准品、溶剂和试剂。

 

13.设备与仪器

 

Equipment and instruments

 

13.1. Equipment and instruments should be located, designed, constructed, adapted and maintained to suit the operations to be carried out. They should allow for effective cleaning and maintenance in order to avoid cross-contamination and a build-up of dust or dirt.

 

设备和仪器的放置、设计、构造、改装和维护应适合要执行的操作。它们应进行有效的清洁和维护，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、仪器和设备应适当标记。

 

13.3. Balances and other measuring equipment of an appropriate range and precision should be available for production and control operations and should be calibrated on a scheduled basis.

 

应有适当范围和精度的天平和其它测量设备，可用于生产和控制操作，并应按计划进行校验。

 

13.4. Equipment and 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 be removed from operational areas or be clearly labelled as defective in order to prevent use.

 

有缺陷的设备和仪器应从操作区域移开，或清楚地标记为有缺陷的，以防止误用。

 

14.物料

 

Materials

 

14.1. Materials should be purchased from approved suppliers.

 

材料应从批准的供应商处购买。

 

14.2. Materials, identified through risk assessment, should be quarantined immediately after receipt, sampled and tested in accordance with specifications.

 

通过风险评估识别的材料，应在收到后立即进行隔离，并按照质量标准进行取样和检验。

 

14.3. Materials released by the quality department and within their shelf life should be used.

 

应使用质量部门放行的且在有效期内的材料。

 

14.4. Materials identified through risk assessment should be stored under the appropriate conditions as specified on their labels and in an orderly fashion to permit segregation, stock rotation and a first-expire, first-use rule.

 

对于通过风险评估识别的材料，应在标签上规定的适当条件下，以有条理的方式存储，以实现区别管理、库存更新和先到期先使用的规则。

 

14.5. The dispensing of materials for the production of a batch should be done according to a written procedure. Materials should be accurately weighed or measured into clean and properly labelled containers.

 

用于批生产的材料分配应按照书面程序进行。材料应准确称量或测量，放入干净且贴有标签的容器中。

 

14.6. No materials used for operations, such as cleaning, the lubrication of equipment and pest control, should come into direct contact with the product. Where possible, such materials should be of a suitable grade (e.g. food grade) to minimize health risks.

 

勿将用于操作的材料（例如清洁、设备润滑和病虫害防治）直接与产品接触。在可能的情况下，此类材料应采用合适的等级（例如食品等级），以最大程度地降低健康风险。

 

14.7. Water used should be suitable for its intended use.

 

使用的水应适合其预期用途。

 

14.8. Packaging materials should be stored in secure conditions so as to exclude the possibility of unauthorized access.

 

包装材料应存放在安全的条件下，以防止未经授权的使用。

 

14.9. Intermediate and bulk products should be kept under appropriate conditions.

 

中间产品半成品应保持在适当的条件下。

 

14.10. Finished products should be stored under suitable conditions.

 

成品应在适当的条件下存储。

 

14.11. Rejected materials and products should be clearly marked as such and stored separately in restricted areas. They should be handled in an appropriate and timely manner. Whatever action is taken should be approved by authorized personnel and recorded.

 

拒收的材料和产品应清晰标明，并分别存放在限制区域中。应该以适当和及时的方式处理它们。采取的任何措施均应由授权人员批准并记录。

 

14.12. Toxic substances and flammable materials should be stored in suitably designed, separate, enclosed containers and, as required, by national legislation. All waste materials should be stored in a safe manner and disposed of at regular intervals to avoid accumulation.

 

有毒物质和易燃材料应存储在适当设计的单独的密闭容器中，并应根据国家法规进行存储。所有废物均应以安全的方式进行存储，并应定期进行处置，以免积累。

 

15. 文档

 

Documentation

 

15.1. Documentation includes specifications and procedures for materials and methods of production and control. The design and use of documents depend upon the research and development facility. The scope and extent should be established based on risk assessment and the stage of research and development (see Figure 1).

 

文件包括材料的质量标准、程序和生产及控制方法。文件的设计和使用取决于研发机构。应根据风险评估和研发阶段来确定范围和程度（见图1）。

 

15.2. Documents should be designed, prepared, reviewed and authorized for use.

 

文件应经过设计、准备、审核和授权使用。

 

15.3. Documents should be reviewed periodically and kept up-to-date. Superseded documents should be retained for a defined period of time.

 

文件应定期审查，并保持最新状态。被取代的文件应在规定的时间内进行保留。

 

15.4. Entries of data and information should be clear and legible.

 

数据和信息输入应清晰易读。

 

15.5. Data (and records for storage) may be recorded by electronic data-processing systems or by photographic or other reliable means. Batch production and control records should be protected throughout the defined period of retention.

 

数据（以及用于存储的记录）可以通过电子数据处理系统、或图片或其它可靠方式进行记录。在规定的保留期内，批生产和控制记录应受到保护。

 

15.6. Labels should be clear, unambiguous and in the company’s agreed format.

 

标签应清晰、明确，并采用公司批准的格式。

 

15.7. There should be appropriately authorized and dated specifications, including tests on identity, purity and quality, for starting materials and for finished products.

 

应有适当的授权和标注日期的质量标准，包括对原材料和成品的鉴别、纯度和质量的检验项目。

 

15.8. Pharmacopoeias, reference standards, reference spectra and other reference materials should be available in the QC laboratory.

 

在质量控制实验室内，应有药典、标准品、参考光谱和其它参考材料。

 

15.9. Specifications should contain appropriate information such as the designated name; internal code reference; and qualitative and quantitative requirements with acceptance limits. Other data may be added to the specification.

 

质量标准应包含适当的信息，例如指定的名称；内部代码参考；定性和定量要求，以及可接受限度。可以添加其它数据到质量标准中。

 

15.10. The packaging material should be examined for compliance with the specification.

 

应检查包装材料是否符合质量标准。

 

15.11. Specifications for intermediate and bulk products should be available where the need has been identified.

 

确定需求后，应提供中间体和半成品的质量标准。

 

15.12. Specifications for finished products should be available and include the required information.

 

应有成品质量标准，并包括必需的信息。

 

15.13. A master formula, containing the relevant information, should be available for the product and batch size to be manufactured.

 

应有包含相关信息的主配方，并可用于要生产的产品和批量。

 

15.14. Packaging instructions should exist for the products to be packed.

 

包装产品应有包装指导。

 

15.15. A batch processing record should be kept for each batch processed. It should be based on the relevant parts of the current specifications on record.

 

对于每个已加工的批次，应保留一个批记录。它应基于当前质量标准（出现在记录上）的相关部分。

 

15.16. During processing, detailed information should be recorded at the time each action is taken and, after completion, the record should be dated and signed by the person responsible for the processing operations.

 

在加工过程中，应在执行每个操作时记录详细信息；操作完成后，记录应标注日期并由加工操作的负责人签名。

 

15.17. A batch packaging record should be kept for each batch or part batch processed.

 

对于每个加工批次或部分加工批次，应保留批包装记录。

 

15.18. Standard operating procedures (SOP) and corresponding records, where required, should be available. These include, but are not limited to, for example:

a) equipment assembly and cleaning;

b) personnel training, clothing and hygiene;

c) maintenance;

d) sampling;

e) analytical apparatus and instrument calibration;

f) testing;

g) release and rejection；and

h) pest control.

如果需要，应提供标准操作程序（SOP）和相应的记录。这些包括但不限于例如：

a）设备组装和清洁；

b）人员培训、更衣和卫生；

c）维护；

d）取样；

e）分析仪器和仪器校验；

f）检验；

g）放行和拒放；

h）虫害防治。

 

15.19. Cross-contamination should be avoided by taking the appropriate technical or organizational measures.

 

应通过采取适当的技术或组织措施，来避免交叉污染。

 

15.20. Before any processing operation is started, steps should be taken to ensure that the work area and equipment are clean and free from any starting materials, products, product residues, labels or documents not required for the current operation.

 

在开始任何加工操作之前，应采取步骤，以确保工作区域和设备清洁，且没有当前操作不需要的任何起始原料、产品、产品残留物、标签或文件。

 

15.21. To prevent cross-contamination and mix-ups, different products should not be packaged in close proximity.

 

为避免交叉污染和混淆，不同产品包装时不应过于靠近。

 

16.加工和工艺验证

 

Processing and process validation

 

Note: For details on process validation, see WHO Technical Report Series, No. 1019, Annex 3, Appendix  7, 2019.

 

注：有关工艺验证的详细信息，请参阅WHO技术报告系列第1019号，附录3，附件7（2019年）。

 

加工

 

Processing

 

Note: For more details on specific aspects relating to process development, see ICH Q 11.

 

注意：有关与工艺开发相关的特定方面的更多详细信息，请参阅ICH Q 11。

 

16.1. The selection of the starting materials and manufacturing process should be carefully considered in order to ensure that the intended product will meet the intended standards of safety, efficacy and quality in a consistent manner.

 

应仔细考虑原材料和生产工艺的选择，以确保目标产品以一致的方式满足安全、功效和质量的目标标准。

 

16.2. Knowledge management and risk assessment principles should be applied. Quality attributes, critical quality attributes, process parameters and critical process parameters should be defined and documented.

 

应该使用知识管理和风险评估原则。应定义和记录质量属性、关键质量属性，工艺参数和关键工艺参数。

 

16.3. The design of experiments should cover identified variables.

 

实验设计应涵盖已识别的变量。

 

工艺验证

 

Process validation

 

16.4. Process validation is usually initiated by research and development organizations. During this stage, the validation is also referred to as “process design”. (In a traditional or historical approach, this was often referred to as “prospective validation”).

 

工艺验证通常由研发组织发起。在此阶段，验证也称为“工艺设计”。（在传统或历史方法中，这通常被称为“预验证”）。

 

16.5. Product development activities provide key inputs to the process design stage. Laboratory or pilot-scale models designed to be representative of the commercial process can be used to estimate variability.

 

产品开发活动为工艺设计阶段提供了重要的输入信息。设计实验室或中试规模模型，以代表商业工艺，可用于估计变异性。

 

16.6. Process design should normally cover the design of experiments, process development, the manufacture of products for use in clinical trials, pilot-scale batches and technology transfer.

 

设计通常应涵盖：实验设计、工艺开发、用于临床试验的产品生产、中试规模的批次和技术转移。

 

16.7. Process design should be verified during product development. Process design should cover aspects for the selection of materials; expected production variation; selection of production technology/process and qualification of the unitary processes that form the manufacturing process as a whole; selection of in-process controls; tests；inspection; and its suitability for the control strategy.

 

在产品开发过程中，应确认工艺设计。工艺设计应涵盖材料选择的各个方面；预期产量变化；选择生产技术/工艺，并对构成整个生产工艺的单一工艺进行确认；选择过程控制；检验；检查;及其对控制策略的适用性。

 

16.8. As the validation data are intended to be used in applications for marketing authorizations, all batch data, results and related information should be clear, detailed and in compliance with ALCOA+.

 

由于验证数据将用于上市许可的申请，因此所有批次数据、结果和相关信息应清晰、详细，且符合ALCOA +的要求。

 

17.质量控制

 

Quality control

 

17.1 The QC unit should be independent from production.

 

质量控制单元应独立于生产。

 

17.2 There should be adequate resources available to ensure that all the QC arrangements are effectively and reliably carried out.

 

应有充分的资源，来确保有效且可靠地执行所有质量控制安排。

 

17.3 Activities and responsibilities of the QC unit include:

 

质量控制部门的活动和职责包括：

a) sampling and testing (e.g. starting materials, packaging materials, intermediate products, bulk products and finished products);

b) performing the necessary qualification and validation;

c) evaluating, maintaining and storing reference standards for substances;

d) ensuring that stability programme and testing is done;

e) participating in environmental monitoring; and

f) participating in QRM programmes.

 

a）取样和检验（例如原材料、包装材料、中间体、半成品和成品）;

b）进行必要的确认和验证；

c）评估、维护和存储标准品；

d）确保完成稳定性计划和检验；

e）参与环境监测；

f）参加QRM计划。

 

17.4 Appropriate records should be kept, demonstrating that all the required activities were performed.

 

应保留适当的记录，以表明已完成所有必需的活动。

 

17.5 Sufficient samples of materials and products should be retained for a defined period of time.

 

应在规定的时间内，保留足够的材料和产品样品。

 

17.6 Appropriate reference standards should be used. Standards should be stored in an appropriate way.

 

应使用适当的标准品。标准品应以适当的方式存储。

 

17.7. Whenever official reference standards exist, these should preferably be used.

 

只要存在官方标准品，就应优先使用。

 

17.8. Where secondary and working standards are established and used, these should be tested at regular intervals to ensure that they are fit for their intended use.

 

在建立和使用二级和工作标准品时，应定期检验这些标准品，以确保它们适合其预期用途。

 

17.9. Reference standards should be appropriately labelled with at least the following information:

a) name of the material;

b) batch or lot number and control number;

c) date of preparation;

d) shelf life;

e) potency; and

f) storage conditions.

 

标准品至少应适当标记以下信息：

a）材料名称；

b）批号以及控制号；

c）准备日期；

d）有效期；

e）活性；和

f）储存条件。

 

18. 稳定性研究

 

Stability studies

 

Note: See guideline on stability testing of active pharmaceutical ingredients and finished  pharmaceutical products , WHO Technical Report Series, No. 1010, Annex 10, 2018.

 

注：见《关于活性药物成分和成品的稳定性测试指南》，世卫组织技术报告系列，第1010号，附录10，2018年。

 

18.1. Where stability determination is initiated by research and development organizations, a written programme should be developed and implemented to include elements such as:

 

由研究和开发组织发起稳定性研究时，应制定并实施书面计划，包括以下内容：

a) a complete description of the medicine involved in the study；

b) the complete set of testing procedure, parameters and limits;

c) attributes such as potency or assay and physical characteristics；

d) evidence that these tests indicate stability;

e) the testing schedule for each medicine;

f) provision for special storage conditions; and

g) provision for adequate sample retention.

a）研究中所涉及药物的完整描述；

b）整套检验程序、参数和限度；

c）活性或含量和物理特性等属性；

d）这些检验可以表明稳定性的证据；

e）每种药物的检验时间表；

f）特殊存储条件的规定；

g）提供充分的留样能力。

 

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 and followed. Any deviations from the procedures should be clearly documented.

 

样品制备和检验程序应详细说明，并得到遵循。与程序的任何偏差均应清楚进行记录。

 

18.4. The results and data generated should be documented and include the evaluation and the conclusions of the study.

 

产生的结果和数据应形成文件，包括评估和研究的结论。

 

18.5. Where stability data are intended to be used in applications for marketing authorizations, all batch data, results and related information should be clear, detailed and in compliance with ALCOA+.

 

如果计划在上市许可申请中使用稳定性数据，则对于所有批次数据、结果和相关信息，应清晰、详细，且符合ALCOA +。

 

18.6. Records should be maintained for a defined period of time.

 

在规定的时间内，应对记录进行维护。

 

19.分析程序开发

 

Analytical procedure development

 

19.1. Analytical procedures developed by research and development organizations should be appropriately recorded.

 

研发组织制定的分析程序应适当记录。

 

19.2.   As the procedures are usually intended to be transferred to quality control units in manufacturing facilities of commercial batches, procedures and records should be sufficiently detailed to ensure that TOT will be successful.

 

通常要将程序转移到商业批生产设施中的QC单元，因此程序和记录应足够详细，以确保TOT成功。

 

19.3. Analytical procedures should be appropriately validated.

 

分析程序应适当验证。

 

Note: For details on analytical procedure validation, see WHO Technical Report Series, No. 1019, Annex 3, Appendix 4, 2019.

 

注：有关分析程序验证的详细信息，请参阅WHO技术报告系列第1019号附录3，附件4，2019年。

 

20.技术转移

 

Transfer of technology

 

Note: For details on transfer of technology, see WHO Technical Report Series, No. 961, Annex 7, 2011  (update in progress).

 

注意：有关技术转移的详细信息，请参阅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 and development organizations, may be transferred to production and quality control sites.

 

开发工作，包括计划、程序、草案、质量标准和研发组织的验证，可以转移到生产和质量控制场所。

 

20.2. Data and information relating to equipment, instruments, manufacturing, and testing should be detailed, traceable and available.

 

与设备、仪器、生产和检验有关的数据和信息，应详细、可追溯，具备可及性。

 

20.3. Authorized procedures should be followed when transferring technology from research and development organizations to production and quality control facilities.

 

将技术从研发组织转移到生产和质量控制设施时，应遵循已批准的程序。

 

21.生命周期方法

 

Life cycle approach

 

21.1. Industry should implement policies and procedures that will encourage science-based and risk-based approaches in product research and development.

 

行业应实施政策和程序，以鼓励在产品研发中采用基于科学和基于风险的方法。

 

21.2. Continual improvement should be encouraged across the entire product life cycle.

 

在整个产品生命周期中应鼓励持续改进。

 

21.3. Knowledge gained from the commercial manufacturing of a product, as well as knowledge  gained from other products, can be used to further improve process understanding and process performance.

 

从产品的商业生产中获得的知识，以及从其它产品中获得的知识，可用于进一步改善工艺理解和工艺性能。

 

21.4. New technologies and the review and interpretation of statistical evaluation of results from validation and other processes, as well as other applicable data and information, should be considered in order to encourage continual improvement during the process development stage of the life cycle of the product.

 

为了鼓励在产品生命周期的工艺开发阶段不断改进，应考虑使用新技术；并对验证和其它工艺结果的统计评估、以及其它适用的数据和信息，进行审查和解释。

 

21.5. Where appropriate, these should be shared and transferred to commercial manufacturing facilities.

 

在适当情况下，应将这些共享并转移到商业生产设施中。

 

22.清洁程序的开发和清洁验证

 

Cleaning procedure development and cleaning validation

 

Note: For details on cleaning validation, see WHO Technical Report Series, No. 1019, Annex 3, Appendix  3, 2019 and the WHO Points to consider when including HBELs in cleaning validation, TRS XXX, Annex 2,  2021.

 

注意：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，附件3，2019年；以及将HBEL纳入清洁验证时要考虑的重点，TRS XXX，附录2，2021年。

 

22.1. Research and development facilities are often involved in the development and validation of cleaning procedures. QRM principles should be applied in cleaning procedure development and cleaning validation.

 

研究和开发设施经常参与清洁程序的开发和验证。QRM原则应应用于清洁程序开发和清洁验证。

 

22.2. The development of cleaning procedures should include cleanability.

 

清洁程序的制定应包括可清洁性。

 

22.3. Health Based Exposure Limits (HBELs) should be considered in the approach to cleaning validation.

 

在进行清洁验证的方法中，应考虑基于健康的暴露限度（HBEL）。

 

22.4. The sampling of procedures should include swab and rinse samples. Maximum Safe Residue, Maximum Safe Surface Residue and Visible Residue Limits should be considered in the new cleaning validation approach.

 

程序的取样应包括棉签和冲洗样品。在新的清洁验证方法中，应考虑最大安全残留物、最大安全表面残留物和可见残留物限度。

 

22.5. The development of the analytical procedures to be used in the testing for residues should be appropriately documented. The procedures should be validated.

 

应适当记录用于残留检验的分析程序的开发。该程序应经过验证。

 

22.6. Procedures for sampling and testing, and the results obtained, should meet ALCOA+ principles. The data and information should be retained over the life cycle of the product.

 

取样和检验程序，以及获得的结果应符合ALCOA +原则。数据和信息应在产品的生命周期内保留。

 

22.7. Procedures and protocols should be followed for the TOT to commercial manufacturing sites. Records should be maintained.

 

在向商业生产场所技术转移过程中，应遵守程序和草案。记录应予以保留。