INTERNATIONAL CONFERENCE ON HARMONISATION OF TECHNICAL REQUIREMENTS FOR REGISTRATION OF PHARMACEUTICALS FOR HUMAN USE人用药物注册技术要求国际协调会议

ICH Harmonised Tripartite Guideline  ICH三方协调指南

Pharmaceutical Development药物开发

Q8

Recommended for Adoption at Step 4 of the ICH Process on 10 November 2005 by the ICH Steering Committee      ICH指导委员会2005年11月10日ICH第四阶段推荐采用

  This Guideline has been developed by the appropriate ICH Expert Working Group and has been subject to consultation by the regulatory parties, in accordance with the ICH Process.  At Step 4 of the Process the final draft is recommended for adoption to the regulatory bodies of the European Union, Japan and USA. 本指南根据ICH规程由合适的ICH专家工作组起草并经向法规部门咨询。在规程的第4步，建议欧洲共同体、日本和美国的药政部门采用其最终的草案。 

TABLE OF CONTENTS目录

1.       INTRODUCTION简介... 1

1.1     Objective of the Guideline指南目的... 1

1.2     Scope范围... 1

2.       PHARMACEUTICAL DEVELOPMENT药物开发... 1

2.1     Components of the Drug Product制剂产品的组分... 4

2.1.1      Drug Substance活性成分... 4

2.1.2      Excipients辅料... 4

2.2     Drug Product制剂... 5

2.2.1      Formulation Development配方开发... 5

2.2.2      Overages超量... 6

2.2.3      Physicochemical and Biological Properties物化和生化性质... 7

2.3     Manufacturing Process Development制造工艺开发... 7

2.4     Container Closure System容器系统... 9

2.5     Microbiological Attributes微生物属性... 9

2.6     Compatibility兼容性... 10

3.       GLOSSARY术语... 11

1.    INTRODUCTION 简介

1.1 Objective of Guideline 指南目的

The Pharmaceutical Development section provides an opportunity to present the knowledge gained through the application of scientific approaches and quality risk management (for definition, see ICH Q9) to the development of a product and its manufacturing process. It is first produced for the original marketing application and can be updated to support new knowledge gained over the lifecycle of a product. The Pharmaceutical Development section is intended to provide a comprehensive understanding of the product and manufacturing process for reviewers and inspectors. The guideline also indicates areas where the demonstration of greater understanding of pharmaceutical and manufacturing sciences can create a basis for flexible regulatory approaches. The degree of regulatory flexibility is predicated on the level of relevant scientific knowledge provided. 药物开发一章给申请企业提供了一个机会，来阐述其应用科学的方法和风险管理手段，在产品及其生产工艺的开发过程中所获得的知识。它既可以被用于原始的制剂上市申请，又可以经过更新后被用于支持产品生命周期内所获得的新知识。本指导文件也说明了在什么情况下，药物和生产方面的最大程度的理解可以形成灵活的药政管理办法的基础。药物开发一章旨在为审核官和检查官就产品和生产工艺提供更详尽的理解。

1.2 Scope 范围

This guideline is intended to provide guidance on the contents of Section 3.2.P.2 (Pharmaceutical Development) for drug products as defined in the scope of Module 3 of the Common Technical Document (ICH guideline M4). The guideline does not apply to contents of submissions for drug products during the clinical research stages of drug development. However, the principles in this guideline are important to consider during those stages as well. This guideline might also be appropriate for other types of products. To determine the applicability of this guideline to a particular type of product, applicants can consult with the appropriate regulatory authorities. 本指导文件就 CTD 模块3（ICH 标题 M4）中所定义的制剂的第3.2.P.2（药物开发）一章中的内容提供了指南。本指导文件不适用于临床研究阶段制剂递交文件的内容。然而，在这些阶段对本指导文件中的原则进行考虑也是重要的。本指南可能也适用于其他一些类型的产品。申请者向合适的药政管理当局进行咨询来确定本指导文件是否适用于某一特定类型的产品。

2. PHARMACEUTICAL DEVELOPMENT 药物开发

The aim of pharmaceutical development is to design a quality product and its manufacturing process to consistently deliver the intended performance of the product. The information and knowledge gained from pharmaceutical development studies and manufacturing experience provide scientific understanding to support the establishment of the design space, specifications, and manufacturing controls.   药物开发的目的在于设计符合质量要求的产品及符合重复生产模式的制造工艺。在药物开发和研究过程中所获得的信息和知识将为建立质量标准和生产控制提供科学的依据。

Information from pharmaceutical development studies can be a basis for quality risk management. It is important to recognize that quality cannot be tested into products; i.e., quality should be built in by design. Changes in formulation and manufacturing processes during development and lifecycle management should be looked upon as opportunities to gain additional knowledge and further support establishment of the design space. Similarly, inclusion of relevant knowledge gained from experiments giving unexpected results can also be useful. Design space is proposed by the applicant and is subject to regulatory assessment and approval. Working within the design space is not considered as a change. Movement out of the design space is considered to be a change and would normally initiate a regulatory post approval change process. 药物开发研究过程中所获得的信息是风险评估的基础。质量是通过设计建立起来的，而不是通过对产品的检测得来的，认识这一点是很重要的。开发过程中的配方和生产工艺的变更应当被看成是获得更多额外知识的机会，以进一步支持设计空间的建立。包括从失败实验中获得的知识也是有用的，也可以用于支持所选择的产品及其生产工艺。

The Pharmaceutical Development section should describe the knowledge that establishes that the type of dosage form selected and the formulation proposed are suitable for the intended use. This section should include sufficient information in each part to provide an understanding of the development of the drug product and its manufacturing process. Summary tables and graphs are encouraged where they add clarity and facilitate review. 药物开发一章应当阐述为满足申请中所规定的目的，建立所选择的剂型和拟定的配方的知识基础。在本章节中的每一个部分都应当要包括足够的资料用以理解制剂及其生产工艺的开发。鼓励使用表格和图表进行概述。At a minimum, those aspects of drug substances, excipients, container closure systems, and manufacturing processes that are critical to product quality should be determined and control strategies justified. Critical formulation attributes and process parameters are generally identified through an assessment of the extent to which their variation can have impact on the quality of the drug product. 至少，应当要对关键的且能很大程度上影响产品质量的方面进行确定和讨论，它们包括原料药，赋形剂和生产工艺，这些方面也是需要检测和控制的。通过评估它们的变化程度对制剂质量的影响可确定这些关键的配方属性和工艺参数。

In addition, the applicant can choose to conduct pharmaceutical development studies that can lead to an enhanced knowledge of product performance over a wider range of material attributes, processing options and process parameters. Inclusion of this additional information in this section provides an opportunity to demonstrate a higher degree of understanding of material attributes, manufacturing processes and their controls. This scientific understanding facilitates establishment of an expanded design space. In these situations, opportunities exist to develop more flexible regulatory approaches, for example, to facilitate: 此外，申请者也可以选择进行一些其它的药物开发研究以在更广的物料属性范围，操作选项范围和工艺参数范围内对产品的性能有更深的了解。将这些更多的信息包括在本章节使得可以对生产工艺和过程控制有更高的理解。这样的科学理解确立了设计空间。这些情况为建立更灵活的药政管理办法提供了可能，比如，便于：

·         risk-based regulatory decisions (reviews and inspections); 基于风险管理的药政决议（审核和现场检查）；

·         manufacturing process improvements, within the approved design space described in the dossier, without further regulatory review; 生产工艺改进，在文件所述的已批准的设计空间范围内，不需要进一步的药政审核；

·         reduction of post-approval submissions; 减少预审批呈递

·         real-time quality control, leading to a reduction of end-product release testing. “实时”质量控制，导致最终产品的放行检测的减少

To realise this flexibility, the applicant should demonstrate an enhanced knowledge of product performance over a range of material attributes, manufacturing process options and process parameters. This understanding can be gained by application of, for example, formal experimental designs, process analytical technology (PAT), and/or prior knowledge. Appropriate use of quality risk management principles can be helpful in prioritising the additional pharmaceutical development studies to collect such knowledge. 为了实现这种灵活性，申请者应当要在物性（如：粒径分布、水分、流动性），操作选项和工艺参数等的某一范围内对产品性能进行更高层次的论述。可以通过实行规范的实验设计或工艺分析技术（PAT）来获得这些知识。适当地应用风险管理原则，有助于按其优先性进行排序额外的药物开发研究，以获得这些知识。The design and conduct of pharmaceutical development studies should be consistent with their intended scientific purpose. It should be recognized that the level of knowledge gained, and not the volume of data, provides the basis for science-based submissions and their regulatory evaluation. 药物开发研究的设计和实施应当要和其拟定的科学目的和产品开发阶段相一致。需要认识到的是所获知识的层次，而不是数据量，为科学的申请文件及其药政评审提供了基础。

2.1 Components of the Drug Product制剂产品的组分
      2.1.1 Drug Substance活性成分

      The physicochemical and biological properties of the drug substance that can influence the performance of the drug product and its manufacturability, or were specifically designed into the drug substance (e.g., solid state properties), should be identified and discussed.  Examples of physicochemical and biological properties that might need to be examined include solubility, water content, particle size, crystal properties, biological activity, and permeability. These properties could be inter-related and might need to be considered in combination.  应当要对原料药的能对制剂的性质及其生产能力产生影响的，或是已被专门设计在原料药方面的（如：晶体工程学）物化性质和生物学特性进行说明和讨论。可能需要检查的物化属性和生物特性有：溶解性、水分、粒径、晶体特性、生物活性、和渗透性等。这些性质可能相互之间是有联系的，因此可能需要综合起来考虑。有些性质会随着时间而改变的，或是和供应商相关。

    To evaluate the potential effect of drug substance physicochemical properties on the performance of the drug product, studies on drug product might be warranted. For example, the ICH Q6A Specifications: Test Procedures and Acceptance Criteria for New Drug Substances and New Drug Products: Chemical Substances describes some of the circumstances in which drug product studies are recommended (e.g., Decision Tree #3 and #4 (Part 2)). This approach applies equally for the ICH Q6B Specifications: Test Procedures and Acceptance Criteria for Biotechnology/Biological Products. The knowledge gained from the studies investigating the potential effect of drug substance properties on drug product performance can be used, as appropriate, to justify elements of the drug substance specification (3.2.S.4.5). 为了评估原料药的物理化学性质对制剂产品性能的潜在影响，应当要提供制剂的研究资料。比如说，ICH Q6A 质量标准：新化学原料药及新制剂的检验方法及合格标准中建议的一些情况下需要进行制剂研究（如决策树#3 和#4（第2 部分））。对原料药性质可能会对制剂性能产生的影响进行研究所获得的知识，如果合适，可被用于论证原料药的质量标准建立的原因（3.2.S.4.5）。

    The compatibility of the drug substance with excipients listed in 3.2.P.1 should be evaluated. For products that contain more than one drug substance, the compatibility of the drug substances with each other should also be evaluated. 需讨论原料药与第 3.2.P.1 章中所列辅料的兼容性。对于含有多个原料药的制剂，还应讨论各原料药间的兼容性。

    2.1.2 Excipients辅料
The excipients chosen, their concentration, and the characteristics that can influence the drug product performance (e.g., stability, bioavailability) or manufacturability should be discussed relative to the respective function of each excipient. This should include all substances used in the manufacture of the drug product, whether they appear in the finished product or not (e.g., processing aids). Compatibility of excipients with other excipients, where relevant (for example, combination of preservatives in a dual preservative system), should be established. The ability of excipients (e.g., antioxidants, penetration enhancers, disintegrants, release controlling agents) to provide their intended functionality, and to perform throughout the intended drug product shelf life, should also be demonstrated. The information on excipient performance can be used, as appropriate, to justify the choice and quality attributes of the excipient, and to support the justification of the drug product specification (3.2.P.5.6). 可以影响制剂产品的性能（例如，稳定性和生物利用度）或是制剂产品的工艺性的辅料选择，辅料的浓度和特性必须按各自的功效逐一讨论。在相关的情况下（比如双防腐剂系统中的防腐剂），还需确定各赋形剂间的兼容性。还应阐述各种辅料（如防氧化剂、穿透增强剂、分解质、释放控制剂）在整个制剂保质期内实现其预期作用的能力。可适当应用辅料性能方面的资料来论证辅料选择及其质量特性的合理性，以支持制剂质量标准的合理性说明（3.2.P.5.6）。
    Information to support the safety of excipients, when appropriate, should be cross-referenced (3.2.P.4.6).适当时，还应交叉引用相关资料以支持辅料的安全性论证（3.2.P.4.6）。

2.2 Drug Product制剂
2.2.1 Formulation Development处方开发
    A summary should be provided describing the development of the formulation, including identification of those attributes that are critical to the quality of the drug product, taking into consideration intended usage and route of administration. Information from formal experimental designs can be useful in identifying critical or interacting variables that might be important to ensure the quality of the drug product. 应综述配方的开发过程，包括那些对制剂产品质量很重要的属性，并考虑拟定用途和给药途径。
    The summary should highlight the evolution of the formulation design from initial concept up to the final design. This summary should also take into consideration the choice of drug product components (e.g., the properties of the drug substance, excipients, container closure system, any relevant dosing device), the manufacturing process, and, if appropriate, knowledge gained from the development of similar drug product(s). 该综述应着重说明配方设计从最初概念到最终设计的发展过程。该综述还应当要考虑各制剂组分的选择（如：原料药，赋形剂，包装系统和相关剂型装置），生产工艺和类似制剂产品开发过程中所获得的经验（如果合适的话）。
    Any excipient ranges included in the batch formula (3.2.P.3.2) should be justified in this section of the application; this justification can often be based on the experience gained during development or manufacture.  正式的实验设计所获得的资料可用于确定关键的或有相互作用的变量，这些变量对于确保制剂产品的质量可能是重要的。在申请文件的此章节中应对批配方（3.2.P.3.2）中的辅料范围进行合理性说明。通常，该合理性说明会建立在配方和生产工艺的开发所获得的经验这个基础上。

    A summary of formulations used in clinical safety and efficacy and in any relevant bioavailability or bioequivalence studies should be provided. Any changes between the proposed commercial formulation and those formulations used in pivotal clinical batches and primary stability batches should be clearly described and the rationale for the changes provided. 应综述在临床安全性和有效性，生物利用度研究或生物等效性研究中所用到的所有配方。对于拟定的市售配方和临床研究与稳定性实验所用批次的配方间的变更都应当进行明确地说明，并提供这些变更的合理性说明。

    Information from comparative in vitro studies (e.g., dissolution) or comparative in vivo studies (e.g., bioequivalence) that links clinical formulations to the proposed commercial formulation described in 3.2.P.1 should be summarized and a cross-reference to the studies (with study numbers) should be provided. Where attempts have been made to establish an in vitro/in vivo correlation, the results of those studies, and a cross-reference to the studies (with study numbers), should be provided in this section. A successful correlation can assist in the selection of appropriate dissolution acceptance criteria, and can potentially reduce the need for further bioequivalence studies following changes to the product or its manufacturing process. 应综述和市售配方（如3.2.P.1 中所描述）相关联的对比性体外研究（如：溶出度）或对比性体内研究（如：生物等效性）所获得的信息，并参引这些研究（研究序号）。如果已试图确立体外实验和体内实验之间的相关性，则在此章节中应提供这些研究的结果并参引这些研究（研究序号）。成功的相关性有助于合适的溶出度可接受标准的选择，并可能减少在产品和生产工艺出现变更的情况下，进一步进行生物等效性研究的需要。

    Any special design features of the drug product (e.g., tablet score line, overfill, anti-counterfeiting measure as it affects the drug product) should be identified and a rationale provided for their use. 需应标明制剂的所有设计特性（如：药片标记线、过度充填、反伪造措施），并提供使用他们的理由。应提供这些特性的适宜性的支持信息。

2.2.2 Overages超量
In general, use of an overage of a drug substance to compensate for degradation during manufacture or a product’s shelf life, or to extend shelf life, is discouraged. 总体来说，不鼓励加入过量原料药以补偿生产过程或产品存贮期中原料药的降解，或用以延长保存期。
Any overages in the manufacture of the drug product, whether they appear in the final formulated product or not, should be justified considering the safety and efficacy of the product. Information should be provided on the 1) amount of overage, 2) reason for the overage (e.g., to compensate for expected and documented manufacturing losses), and 3) justification for the amount of overage. The overage should be included in the amount of drug substance listed in the batch formula (3.2.P.3.2).对于制剂生产过程中出现的过量现象，无论其是否是出现在最终制剂中，都应当要从产品的安全性和有效性方面对其进行合理性说明。应提供如下信息：1）过量的量；2）过量的原因（如，补偿生产过程中出现的损失）；3）超出量的合理性说明。在典型批配方（3.2.P.3.2）所列的原料药量中应包括超出量。

2.2.3 Physicochemical and Biological Properties物化和生化性质
The physicochemical and biological properties relevant to the safety, performance or manufacturability of the drug product should be identified and discussed. This includes the physiological implications of drug substance and formulation attributes. Studies could include, for example, the development of a test for respirable fraction of an inhaled product. Similarly, information supporting the selection of dissolution vs. disintegration testing, or other means to assure drug release, and the development and suitability of the chosen test, could be provided in this section. See also ICH Q6A Specifications: Test Procedures And Acceptance Criteria For New Drug Substances And New Drug Products: Chemical Substances; Decision Tree #4 (Part 3) and Decision Tree #7 (Part 1) or ICH Q6B Specifications: Test Procedures and Acceptance Criteria for Biotechnology/Biological Products. The discussion should cross-reference any relevant stability data in 3.2.P.8.3. 应确定和制剂产品的性能或工艺性能相关的物理化学特性和生物学特性，并对它们进行讨论。可以包括如下配方属性：pH 值、摩尔渗透压浓度、离子浓度、亲油性、溶出度、再分散作用、重构、粒径分布、颗粒形状、聚集作用、多晶形、流变性质、乳剂的颗粒尺寸、生物活性/功效、和/或免疫活性。配方属性的生理性质如pH 值也应当要说明。需参引3.2.P.8.3 中的相关稳定性资料。在申请文件中的此章节（3.2.P.2.2.3）中，应综述为了研究物理化学特性和生物学性质对制剂的潜在影响及制剂可接受限度的合适性开展的开发研究。这些研究包括：比如，溶出度实验或释放度实验的开发，吸入制剂的可吸入组分的实验开发。应说明原料药的生理适应性和配方属性。比如说可以包括研究是否需要在制剂质量标准中加入多晶型的合格标准所获得的信息。类似的，关于溶出度VS 崩解实验或其他确保制剂释放的方法的选择，以支持配方和生产工艺的耐用性的信息也可以包括在该章节。也可参见ICH Q6A 质量标准：新原料药和新制剂的测试方法和认可标准：化学物质。决策树#4（Part 3）和决策树#7（Part 1）。
2.3 Manufacturing Process Development制造工艺开发
The selection, the control, and any improvement of the manufacturing process described in 3.2.P.3.3 (i.e., intended for commercial production batches) should be explained. It is important to consider the critical formulation attributes, together with the available manufacturing process options, in order to address the selection of the manufacturing process and confirm the appropriateness of the components. Appropriateness of the equipment used for the intended products should be discussed. Process development studies should provide the basis for process improvement, process validation, continuous process verification* (where applicable), and any process control requirements. Where appropriate, such studies should address microbiological as well as physical and chemical attributes. The knowledge gained from process development studies can be used, as appropriate, to justify the drug product specification (3.2.P.5.6). 关于 3.2.P.3.3 中所述的生产工艺（拟用于市售生产批次），应解释其选择、控制和优化。对关键的配方属性及可获得的生产工艺选项（如：干式制粒法VS 湿式制粒法，终端灭菌VS 无菌工艺）进行考虑是很重要的，这样可以说明生产工艺的选择并确认各组分（例如辅料）的合适性。应讨论用于产品生产的设备的合适性。工艺研究开发要为工艺优化，工艺验证和工艺控制要求提供基础。在合适的情况下，这些研究需要说明微生物学，物理和化学属性。工艺开发研究中所获得的知识，可被适当地用于制剂质量标准的合理性说明（3.2.P.5.6）。
The manufacturing process development programme or process improvement programme should identify any critical process parameters that should be monitored or controlled (e.g., granulation end point) to ensure that the product is of the desired quality.   应当要对工艺能在不同的工艺条件下，在不同的生产规模下，或使用不同的设备这些情况下，能可靠地生产出有指定质量的产品的能力进行评估。生产工艺开发程序应确认需要进行监测和控制的以确保产品有理想质量的那些关键工艺参数。
For those products intended to be sterile an appropriate method of sterilization for the drug product and primary packaging material should be chosen and the choice justified.对于无菌制剂，应当要选择合适的灭菌方法和初级包装材料，并论证说明选择的理由。
Significant differences between the manufacturing processes used to produce batches for pivotal clinical trials (safety, efficacy, bioavailability, bioequivalence) or primary stability studies and the process described in 3.2.P.3.3 should be discussed. The discussion should summarise the influence of the differences on the performance, manufacturability and quality of the product. The information should be presented in a way that facilitates comparison of the processes and the corresponding batch analyses information (3.2.P.5.4). The information should include, for example, (1) the identity (e.g., batch number) and use of the batches produced (e.g., bioequivalence study batch number), (2) the manufacturing site, (3) the batch size, and (4) any significant equipment differences (e.g., different design, operating principle, size). 生产临床安全性和有效性、生物利用度、生物等效性、或初始稳定性实验批次的生产工艺与第3.2.P.3.3 章中所述生产工艺之间有明显差异的话，应对其进行讨论。该讨论应简述这些差异对产品的性能和工艺性能的影响。资料的编排方式应当要便于比较工艺和其相对应的批分析信息（3.2.P.5.4）。这些信息应当包括，比如说，（1）标识（如批号）和使用指定设备生产出来的批次的使用（如生物等效性研究的批号），（2）生产地点，（3）批量和（4）明显的设备差异（如不同的设计，不同的操作原理和不同的尺寸）。
In order to provide flexibility for future process improvement, when describing the development of the manufacturing process, it is useful to describe measurement systems that allow monitoring of critical attributes or process end-points. Collection of process monitoring data during the development of the manufacturing process can provide useful information to enhance process understanding. The process control strategies that provide process adjustment capabilities to ensure control of all critical attributes should be described.  为了给将来的工艺优化提供灵活性，在叙述生产工艺的开发时，对用于关键属性或工艺终点监控的测量系统进行叙述是有用的。收集生产工艺开发过程中的工艺监控资料可以提供有用的资料以增强对工艺的理解。应叙述能提供工艺控制能力以确保了所有关键属性控制的工艺控制。这些为风险控制策略提供了方法。
An assessment of the ability of the process to reliably produce a product of the intended quality (e.g., the performance of the manufacturing process under different operating conditions, at different scales, or with different equipment) can be provided. An understanding of process robustness* can be useful in risk assessment and risk reduction (see ICH Q9 Quality Risk Management glossary for definition) and to support future manufacturing and process improvement, especially in conjunction with the use of risk management tools (see ICH Q9 Quality Risk Management). 工艺耐用性的评估是有助于风险评估和风险降低的，能支持将来的生产和工艺优化，特别是结构化的风险管理工具的联合使用。
2.4 Container Closure System容器系统
The choice and rationale for selection of the container closure system for the commercial product (described in 3.2.P.7) should be discussed. Consideration should be given to the intended use of the drug product and the suitability of the container closure system for storage and transportation (shipping), including the storage and shipping container for bulk drug product, where appropriate. 应对市售产品的包装系统（3.2.P.7）的选择及选择理由进行讨论。应考虑制剂的用途和包装系统的储存及运输适宜性，包括大包装制剂的储存和运输包装。
The choice of materials for primary packaging should be justified. The discussion should describe studies performed to demonstrate the integrity of the container and closure. A possible interaction between product and container or label should be considered. 内包材的选择应恰当。对内包材的讨论应叙述为了论证包装系统的完整性而开展的研究。应考虑产品和包装或标签之间可能存在的相互作用。
The choice of primary packaging materials should consider, e.g., choice of materials, protection from moisture and light, compatibility of the materials of construction with the dosage form (including sorption to container and leaching), and safety of materials of construction. Justification for secondary packaging materials should be included, when relevant. 内包装材料的选择应考虑，比如，材质的选择，防潮和避光，材质和剂型的兼容性（包括包装的吸附和浸析），材质的安全性。
If a dosing device is used (e.g., dropper pipette, pen injection device, dry powder inhaler), it is important to demonstrate that a reproducible and accurate dose of the product is delivered under testing conditions which, as far as possible, simulate the use of the product. 如果使用了定量装置（如滴管、笔式注射器、干粉吸入器），论证产品在测试条件下（尽可能地模拟产品使用时的条件）能重复得到准确的剂量非常重要。
2.5 Microbiological Attributes微生物属性
Where appropriate, the microbiological attributes of the drug product should be discussed in this section (3.2.P.2.5). The discussion should include, for example: 在适当的情况下，本章节（3.2.P.2.5）还应论述制剂产品的微生物属性。该讨论应包括如：
? The rationale for performing or not performing microbial limits testing for non sterile drug products (e.g., Decision Tree #8 in ICH Q6A Specifications: Test Procedures and Acceptance Criteria for New Drug Substances and New Drug Products: Chemical Substances and ICH Q6B Specifications: Test Procedures and Acceptance Criteria for Biotechnology/Biological Products); 是否对非无菌制剂进行微生物限度检测的理由（如，ICH Q6A 质量标准：新原料药和新制剂可接受标准和检测程序：化学原料药，和ICH Q6B 质量标准：生物技术/生物药品的检测程序和可接受标准的决策树#8）；
? The selection and effectiveness of preservative systems in products containing antimicrobial preservative or the antimicrobial effectiveness of products that are inherently antimicrobial; 产品中防腐系统的选择和效果，包括抗菌防腐剂或本身就有抗菌作用的产品的抗菌效果；
? For sterile products, the integrity of the container closure system as it relates to preventing microbial contamination. 无菌产品包装系统的完整性，因其关系到能否防止微生物污染。
Although chemical testing for preservative content is the attribute normally included in the drug product specification, antimicrobial preservative effectiveness should be demonstrated during development. The lowest specified concentration of antimicrobial preservative should be demonstrated to be effective in controlling micro-organisms by using an antimicrobial preservative effectiveness test. The concentration used should be justified in terms of efficacy and safety, such that the minimum concentration of preservative that gives the required level of efficacy throughout the intended shelf life of the product is used. Where relevant, microbial challenge testing under testing conditions that, as far as possible, simulate patient use should be performed during development and documented in this section. 尽管通常制剂的质量标准中会有防腐剂含量的化学检测，但在开发中还是应该要对抗菌防腐剂的效果进行论述。需通过抗菌防腐剂效果实验论述抗菌防腐剂在所规定的最低浓度下能有效地控制微生物。使用的浓度应根据效果和安全进行判断，以采用可以保证指定的保存期限内均维持有效防腐水平的最低浓度。相应地，开发过程中应进行检测条件下的微生物挑战性试验（尽可能模拟病人使用情况）并写入本部分的文件。
2.6 Compatibility兼容性
The compatibility of the drug product with reconstitution diluents (e.g., precipitation, stability) should be addressed to provide appropriate and supportive information for the labelling. This information should cover the recommended in-use shelf life, at the recommended storage temperature and at the likely extremes of concentration. Similarly, admixture or dilution of products prior to administration (e.g., product added to large volume infusion containers) might need to be addressed. 应说明制剂与稀释剂或定量装置之间的兼容性（如：原料药在溶液中沉淀，注射装置的吸附性，稳定性等），以便在标签上提供适当的支持性信息。这些信息需包含整个建议的保质期，所建议的储存温度，可能的极限浓度。如果标签上建议在使用之前对固体剂型进行稀释或混合（如，饮用药物），则需要对适当的兼容性实验进行叙述。
3. GLOSSARY术语
Continuous Process Verification:持续工艺确认
An alternative approach to process validation in which manufacturing process performance is continuously monitored and evaluated. 工艺验证的一种替代方式，指对生产工艺的情况进行持续的监控和评估。
Design Space: 设计空间
The multidimensional combination and interaction of input variables (e.g., material attributes) and process parameters that have been demonstrated to provide assurance of quality. Working within the design space is not considered as a change. Movement out of the design space is considered to be a change and would normally initiate a regulatory post approval change process. Design space is proposed by the applicant and is subject to regulatory assessment and approval. 已被证明可以保证质量的输入变数（如原料）和工艺参数的多维结合及及相互作用。在设计空间内运行通常不被认为是变更。超出了设计空间就会被看作是变更，通常会需要启动规定的事后批准变更程序。设计空间由申请人提议，通过规定的评估和批准程序生效。
Formal Experimental Design: 正式实验设计
A structured, organized method for determining the relationship between factors affecting a process and the output of that process. Also known as “Design of Experiments”. 一个结构化的有组织的方法，用于确定工艺影响因素和工艺产物之间的关系。也被称为“实验设计”。
Lifecycle生命周期:
All phases in the life of a product from the initial development through marketing until the product’s discontinuation.产品从最初的开发，经过市场周期，直至产品废止所经历的所有阶段。
Process Analytical Technology (PAT): 工艺过程分析技术（PAT）
A system for designing, analyzing, and controlling manufacturing through timely measurements (i.e., during processing) of critical quality and performance attributes of raw and in-process materials and processes with the goal of ensuring final product quality.  通过对原料和中控物料及所保证最终产品质量为目的的工艺的关键质量和性能属性的实时测量（例如，在工艺过程进行中），来对制造进行设计、分析和控制的系统。
Process Robustness工艺耐受性:
Ability of a process to tolerate variability of materials and changes of the process and equipment without negative impact on quality. 工艺可以承受原料不稳定、工艺和设备改变而不会对质量产生影响的能力。
Quality:  质量
The suitability of either a drug substance or drug product for its intended use. This term includes such attributes as the identity, strength, and purity (from ICH Q6A Specifications: Test Procedures and Acceptance Criteria for New Drug Substances and New Drug Products: Chemical Substances). 一个原料药或制剂对其使用目的的适合性。本术语包括这样一些属性如鉴别、剂量和纯度（源自ICH Q6A 质量标准： 新原料药和新制剂药的检验方法和可接受标准：化学物质）。