近日，ICH重磅发布了新的《ICH Q1稳定性试验指南》（草案），该指南将原ICH 稳定性指南系列 Q1A-F 和Q5C进行修订并整合，增加使用过程中的稳定性研究、短期稳定性研究、中间产品/中间体加工和保持时间、标准品稳定性研究、产品生命周期和建模等内容，同时，示例了一系列产品类型的标准稳定性数据包，用于监管提交，并包括对在药品质量体系 （PQS） 内管理的研究的建议。堪称史上最强稳定性试验指南！

在最近一期的“药审云课堂”上，CDE建议关注ICH近期发布的ICH Q1原料药与制剂的稳定性草案。现在，国家药监局审评中心已发布其中文翻译，中英文对照如下：

INTERNATIONAL COUNCIL FOR HARMONISATION OF TECHNICAL REQUIREMENTS FOR PHARMACEUTICALS FOR HUMAN USE
国际人用药品注册技术协调会

ICH HARMONISED GUIDELINE
ICH 三方协调指导原则

STABILITY TESTING OF DRUG SUBSTANCES AND DRUG PRODUCTS Q1

原料药和制剂的稳定性试验（Q1）

1.INTRODUCTION1 

1.简介

1.1 OBJECTIVES OF THE GUIDELINE

1.1 指导原则的目的

1.2 SCOPE OF THE GUIDELINE

1.2 指导原则的适用范围

1.3 INTRODUCTION TO GUIDELINE AND GENERAL PRINCIPLES

1.3 指导原则和一般原则简介

2.DEVELOPMENT STABILITY STUDIES UNDER STRESS AND FORCED CONDITIONS

2.影响因素和强制降解条件下的开发稳定性研究

2.1 DEVELOPMENT STUDIES UNDER STRESS CONDITIONS

2.1 影响因素条件的开发研究

2.2 DEVELOPMENT STUDIES UNDER FORCED DEGRADATION CONDITIONS

2.2 强制降解条件的开发研究

2.3 ANALYSIS AND INTERPRETATION OF RESULTS

2.3 结果分析与解读

3.PROTOCOL DESIGN FOR FORMAL STABILITY STUDIES

3.正式稳定性研究的方案设计

3.1 GENERAL PRINCIPLES

3.1 一般原则

3.2 STABILITY DATA TO SUPPORT THE INITIAL RE-TEST PERIOD AND SHELF LIFE ACCORDING TO THE STANDARD APPROACH

3.2 根据标准方法支持初始复检期和有效期的稳定性数据

3.3 STABILITY-INDICATING CRITICAL QUALITY ATTRIBUTES

3.3 稳定性指示关键质量属性

3.3.1 Recommendations for Establishing a Re-Test Period or Shelf life

3.3.1 关于确定复检期 / 有效期的建议

3.3.2 Recommendations for Lifecycle Stability Protocols

3.3.2 生命周期稳定性方案建议

3.4 SPECIFICATIONS

3.4 质量标准

3.4.1 Tests and Analytical Procedures

3.4.1 测试和分析程序

3.4.2 Acceptance Criteria

3.4.2 可接受标准

3.4.3 Pharmacopoeial Critical Quality Attributes and Analytical Procedures

3.4.3 药典关键质量属性和分析方法

3.5 ADDITIONAL CONSIDERATIONS FOR VACCINES

3.5 关于疫苗的其他考虑因素

3.6 ADDITIONAL CONSIDERATIONS FOR THE COMBINATION OF A DRUG PRODUCT WITH A MEDICAL DEVICE

3.6 药械组合的其他考虑因素

3.7 RISK MANAGEMENT

3.7 风险管理

4.SELECTION OF BATCHES

4.批次选择

4.1 CONSIDERATIONS FOR SELECTION OF PRIMARY STABILITY BATCHES

4.1 注册稳定性批次选择的考虑因素

4.2 CONSIDERATIONS FOR MULTIPLE PRODUCTION SITES IN THE INITIAL REGULATORY SUBMISSION

4.2 首次注册申报中对多个生产场地的考虑因素

4.3 CONSIDERATIONS FOR VACCINES

4.3 疫苗的考虑因素

4.4 CONSIDERATIONS FOR CONTINUOUS MANUFACTURING PROCESSES

4.4 连续制造工艺的考虑因素

5.CONTAINER CLOSURE SYSTEM

5.容器密封系统

6.TESTING FREQUENCY

6.检测频率

10.SHORT - TERM STORAGE CONDITIONS

10.短期贮存条件

11.IN - USE STABILITY
11.使用中稳定性

11.1 PURPOSE OF IN - USE STABILITY TESTING
11.1 使用中稳定性试验的目的

11.2 IN - USE STABILITY STUDY PROTOCOL DESIGN
11.2.1 批次选择

11.2.1 Selection of Batches

11.2.1 批次选择

11.2.2 Selection of Analytical Procedures and Acceptance Criteria
11.2.2 使用分析方法和可接受标准的选择

11.2.3 Labelling of the In - Use Period and Storage Conditions

11.3 使用期间允许时接受贮存条件的标签

12.REFERENCE MATERIALS, NOVEL EXCIPIENTS AND ADJUVANTS

12.参比物质、新型辅料和佐剂

12.1 REFERENCE MATERIALS
12.1 参比物质

12.1.1 Considerations for Synthetic Chemical Reference Materials
12.1.1 化学药物参比物质的注意事项

12.1.2 Considerations for Biological Reference Materials
12.1.2 生物制品参比物质的注意事项

12.2 NOVEL EXCIPIENTS
12.2 新型辅料

12.3 VACCINE ADJUVANTS

12.3 疫苗佐剂

13.DATA EVALUATION

13.数据评价

13.1 GENERAL CONSIDERATIONS

13.1 一般考虑因素

13.1.1 Re - Test Period
13.1.1 复检期

13.1.2 Start of Shelf Life for Synthetic Chemical Entity Drug Products
13.1.2 化学合成实体制剂有效期起始

13.1.3 Start of Shelf Life for Biological Drug Products
13.1.3 生物制剂有效期起始

13.2 STATISTICAL EVALUATION OF THE LONG - TERM STORAGE CONDITION STABILITY PROFILE TO ESTABLISH THE RE - TEST PERIOD OR SHELF LIFE
13.2 确定复检期或有效期的长期条件稳定性特征的统计评价

13.2.1 Linear Regression for an Individual Batch
13.2.1 单一批次的线性回归

13.2.2 Combining Batches

13.2.2 合并批次

13.2.3 Scale Transformation of Data
13.2.3 数据规模转换

13.2.4 Extrapolation and Stability Modelling
13.2.4 外推和稳定性建模

13.2.5 Extrapolation for Synthetic Chemical Entities
13.2.5 化学合成实体的外推

13.2.6 No Significant Change at Accelerated Condition
13.2.6 在加速条件下无明显变化

13.2.7 Significant Change at Accelerated Condition
13.2.7 加速条件下的显著变化

13.2.8 Extrapolation for Chemical Entities when Stored Frozen

13.2.8 冷冻保存时化学实体的外推

13.2.9 Extrapolation for Biological Entities when Stored Frozen
13.2.9 生物制品外推

13.3 DATA EVALUATION FOR MULTI - FACTOR, FULL - DESIGN STUDIES
13.3 多因素、完整设计研究的数据评估

13.3.1 Testing to Combine Batch Data per Individual Combination
13.3.1 用于每个单独组合批次数据的合并测试

13.3.2 Testing to Combine Data for All Factors and Factor Combinations
13.3.2 综合所有因素和因素组合数据的测试

13.4 DATA PRESENTATION
13.4 数据呈现

14.LABELLING

14.说明书及标签

14.1 EXCURSIONS OUTSIDE OF A LABELLING CLAIM

14.1 超出说明书及标签要求的偏离

15 STABILITY CONSIDERATIONS FOR COMMITMENTS AND PRODUCT LIFECYCLE MANAGEMENT

15.关于承诺和产品生命周期管理的稳定性考虑因素

15.1 COMMITMENT STABILITY STUDIES

15.1 稳定性研究承诺

15.2 ONGOING STABILITY STUDIES

15.2 持续稳定性研究

15.3 PRODUCT LIFECYCLE STABILITY STUDIES

15.3 产品生命周期稳定性研究

15.4 STABILITY STUDIES TO SUPPORT NEW DOSAGE FORMS AND NEW STRENGTHS/CONCENTRATIONS

15.4 支持新剂型和新规格 / 浓度的稳定性研究

16.GLOSSARY

16.术语表

17.REFERENCES

17.参考文献

18.ANNEXES

18.附录

ANNEX 1 REDUCED STABILITY PROTOCOL DESIGN

附录 1 - 简化稳定性方案设计

ANNEX 2 STABILITY MODELLING

附录 2 稳定性建模

ANNEX 3 STABILITY OF ADVANCED THERAPY MEDICINAL PRODUCTS (ATMPs)

附录 3 先进治疗药品（ATMP）的稳定性

1   INTRODUCTION

1   简介

1.1  Objectives of the Guideline

1.1  指导原则的目的 

The following guideline outlines the stability data expectations for drug substances and drug products.This guideline is applicable to marketed drug products, including those associated with registration andlifecycle/post-approval changes and, when applicable, master files. These applications are hereaftercollectively referred to in the guideline as regulatory submissions. ICH Q1 is a consolidated revisionthat supersedes ICH Q1A-F and Q5C guidelines and provides additional guidance on principles relatingto stability.

本指导原则概述了原料药（生物制品也称原液）和制剂的稳定性数据要求，适用于已上市产品，包括注册申报、生命周期/批准后变更相关的产品及主文件（如适用）。本指导原则统称此类申请为注册申报。ICH Q1为整合修订版，取代了ICH Q1A-F 和Q5C指导原则，并为稳定性相关原则提供了更多指导。

1.2  Scope of the Guideline

1.2  指导原则的适用范围

This guideline applies to synthetic and biological drug substances and drug products, including thefollowing:

本指导原则适用于由合成技术和生物技术制备的原料药及制剂，包括：

Chemically synthesised drug substances including oligonucleotides, polysaccharides and polypeptides (collectively referred to as ‘synthetic chemical entities’ or ‘synthetics’ in this guideline), semi-synthetic drug substances and fermentation-derived drug substances.

化学合成原料药，包括寡聚核苷酸、多糖和多肽类（在本指导原则中统称为“化学合成实体”或“合成品”）、半合成原料药以及发酵原料药。Therapeutic  proteins/polypeptides,  polysaccharides  and  proteoglycans  produced  usingrecombinant DNA (rDNA) technology or isolated from human, animal or plant tissues, othernatural sources, including body fluids (such as plasma-derived products), or cell cultures.

采用重组DNA（rDNA）技术生产或从人体、动物或植物组织，其他天然来源（包括体液，如血浆衍生产品）或细胞培养物中分离的治疗性蛋白/多肽、多糖和蛋白聚糖。 

Conjugated products that are made up of proteins/polypeptides linked to another moiety (e.g.,antibody-drug conjugate).

由蛋白/多肽与其他分子偶联形成的制品（如抗体药物偶联物）。

Vaccines, allergenic products, and adjuvants.

疫苗、过敏原产品和佐剂。

Autologous and allogenic cell-based substances, including those which may be geneticallymodified ex-vivo (refer to Annex 3 – Stability of Advanced Therapy Medicinal Products(ATMPs)).•       自体和异体细胞类物质，包括体外基因修饰产品（见附录3-先进治疗药品（ATMP）的稳定性）。 

Gene therapy products that mediate their effect by the expression (transcription or translation)of transferred genetic materials and genome editing products used to modify cells (refer toAnnex 3 – Stability of Advanced Therapy Medicinal Products (ATMPs)).

通过遗传物质的表达（转录或翻译）介导其作用的基因治疗产品，以及用于细胞修饰的基因编辑产品（见附录3-先进治疗药品（ATMP）的稳定性）。

The drug constituent part of a combination of a drug product with a medical device (both integral or co-packaged).

药械组合（单一实体或组合包装）的药物组成部分。

Co-packaged solvents/diluents.

组合包装的溶剂/稀释剂。

Natural health products that are regulated as drug products.

按药品监管的天然保健品。

The guideline is applicable to all regulatory submissions and, in accordance with regional regulations,can apply to prescription and non-prescription drug products (e.g., regulated over-the-counter products),original drug products (e.g., new entities), new product presentations, abbreviated/abridged applications(e.g., generics) and biosimilars.

本指导原则适用于所有注册申报，同时根据地区法规，可适用于处方药品和非处方药品（如受监管的非处方药品）、原研药品（如新化学实体）、新剂型、简化申请（如仿制药）及生物类似药。

The principles outlined in this guideline are applicable to support post-approval changes (PACs) thatrequire supportive and confirmatory stability studies, including those that are discussed within ICHQ12.

本指导原则适用于需要进行支持性和确证性稳定性研究的批准后变更（PAC），包括ICHQ12中讨论的情形。

Although this guideline is not directly applicable to drug substances and drug products during clinicaldevelopment stages, the concepts can apply proportionate to increasing level of product and processunderstanding during pharmaceutical development. The data from development batches that meetprimary stability requirements may be used to support a regulatory submission and for product lifecyclemanagement. Refer to Section 15 - Stability Considerations for Commitments and Product LifecyleManagement.

本指导原则虽然不直接适用于临床开发阶段的原料药和制剂，但随着药学开发中对产品和工艺的认知加深可逐渐适用。符合的开发批次的数据可用于支持注册申报及产品生命周期管理。见第15节“稳定性承诺和产品生命周期管理的考量”）。

The guideline is not applicable to device constituent parts, radiopharmaceuticals and whole bloodproducts.

本指导原则不适用于器械组成部分、放射性药物和全血制品。

1.3  Introduction to Guideline and General Principles

1.3  指导原则和一般原则简介

The purpose of stability testing is to provide evidence on how the quality of a drug substance or drugproduct varies with time under the influence of a variety of environmental and physical factors such astemperature, humidity, light, or agitation. Stability testing establishes and confirms a re-test period orshelf life for the drug substance or a shelf life for the drug product in the proposed container closuresystem under the recommended storage conditions. Shelf life is also referred to as dating period orexpiry period in some regions. This guideline provides comprehensive guidance to establish stabilityfor all molecule types within its scope and includes recommendations on how science- and risk-basedprinciples may be applied. A standard approach to assess each stability-related topic is provided bydescribing the general principles and strategies to assess stability. In addition, the principles of Qualityby Design described within ICH Q8-Q11 and Q14, through enhanced understanding of critical quality attributes (CQAs) and the impact that the manufacturing process can have on these attributes, areapplicable to the design of an overall stability strategy.

稳定性试验的目的在于提供证据，以说明在温度、湿度、光照或搅拌等各种环境因素和物理因素的影响下，原料药或制剂的质量如何随时间变化。稳定性研究旨在建立并确认在拟定贮藏条件下及拟定的包装系统中原料药的复检期或有效期，或制剂的有效期。某些地区，有效期（Shelf life）也称为有效日期（dating period）或失效日期（expiry period）。本指导原则为其适用范围内的所有分子类型提供全面的稳定性研究指导，并就如何应用基于科学和风险的原则提出了建议。通过阐述稳定性评估的一般原则和策略，本指导原则提供了评估各稳定性相关议题的标准方法。此外，ICH Q8-Q11和Q14综述了质量源于设计的原则，因其对关键质量属性（CQAs）以及生产工艺对这些属性影响的深入理解，可将其应用于整体稳定性策略的设计。

This guideline should be considered in its entirety for a comprehensive approach to stability studies.

在制定稳定性研究的综合方法时，应全面考虑本指导原则。

The guideline exemplifies the standard stability data package for drug substances and drug productsand provides guidance on alternative and scientifically justified approaches that encompass the varietyof different situations that may be encountered due to specific scientific considerations and characteristics of the data being evaluated. Alternative strategies based on science- and risk-based principles (e.g., as described in ICH Q8-Q11 and section IX of ICH Q12) for drug substances and drug products may be proposed by the applicant of a regulatory submission, leveraging quality risk management principles, pharmaceutical development data (e.g., as discussed in Section 2 – Development Studies Under Stressed and Forced Conditions), prior knowledge and modelling, (e.g., as discussed in Annex 2 -Stability Modelling). Examples are provided under specific sections to illustrate how science- and risk-based strategies may be applied.

本指导原则通过示例形式，说明了原料药和制剂的标准稳定性数据包，并为替代性及科学论证的方法提供指导，这些方法涵盖了因被评估数据的特定科学考量和特性而可能遇到的各种不同情况。注册申报的申请人可基于对原料药和制剂的科学和风险原则（如ICH  Q8-Q11和ICH Q12 的IX部分所述），利用质量风险管理原则、产品开发数据（如第2节“影响因素条件和强制降解条件下的开发研究”所述）、先验知识和建模，（如附录2-稳定性建模所述），提出替代策略。具体章节提供的示例说明了如何应用基于科学和风险的策略。

Unless otherwise specified, the recommendations described in this guideline apply to both drug substance and drug products. Additionally:

除非另有说明，本指导原则中的建议同时适用于原料药和制剂。此外：

 Each section may include guidance for specific product types (e.g., synthetics, biologicals,vaccines or a combination drug product with a medical device) where relevant.

 各章节在适用时可包含针对特定产品类型的指导（如，合成药物、生物制品、疫苗或药械组合）。

 For semi-synthetics, fermentation and conjugated products, the recommendations for syntheticsand biologicals would apply, as appropriate.

 对于半合成、发酵和偶联产品，酌情适用合成药物和生物制品的建议。

 Where “products” is mentioned by itself in this guideline, this is to be interpreted as “drugsubstances and drug products”.

本指导原则中提及的“产品”，应理解为“原料药和制剂”。

 Recommendations on the general principles for stability studies and data expectations for drugsubstances and drug products apply across all climatic zones for regulatory submissions andlifecycle management. The mean kinetic temperature in any part of the world can be derivedfrom climatic data, which divides the world into four climatic zones, I-IV (13, 14). The fourzones are distinguished by their characteristic prevalent annual climatic conditions based on theconcept originally described by W. Grimm (15), updated in W. Grimm (16) and adopted underWHO Technical Reports (13, 14). This guideline addresses all four climatic zones. Theprinciple has been established that if the stability information is generated under a more severeclimatic zone storage condition, it would be acceptable in the other climatic zones, providedthe information is consistent with this guideline and the labelling and storage statements are inaccordance with regional requirements.

关于原料药和制剂稳定性研究的一般原则及数据要求的建议，适用于所有气候带的注册申报与生命周期管理。基于气候数据可推导全球任何地区的平均动力学温度，据此将全球划分为I-IV四个气候带（13、14）。四个气候带的划分基于W.Grimm（15）最初提出的理论框架，该分类依据各地区显著的全年普遍气候条件特征，后续在W.Grimm（16）的更新研究中得到完善，并被WHO技术报告（13、14）所采纳。

本指导原则涵盖全部四个气候带，确定如下原则：若稳定性信息是在更严苛的气候带贮藏条件下生成，且符合本指导原则要求，同时说明书及标签的贮藏声明符合地区要求，则可接受用于其他气候带。

The recommendations may be applicable to drug substance intermediates and drug productintermediates. Intermediates that are stored as part of manufacturing process activities (e.g.,unprocessed bulk harvest, granulations) should be evaluated in accordance with Section 9 -Stability Considerations for Processing and Holding Times for Intermediates. For those

intermediates that are packaged and stored outside of manufacturing process activities, a

holding time may be established or it may be appropriate to establish a re-test period or shelf

life as per the applicable sections of this guideline (e.g., antibody prior to conjugation and a

spray dried dispersion).

本指导原则的建议可适用于原料药中间产品和制剂中间产品。作为生产工艺活动（如未加工的原液、颗粒混合物）组成部分贮藏的中间产品，应根据第9节“中间产品加工和保持时限的稳定性考量”进行评估。对于在生产工艺活动外进行包装和贮藏的中间产品，可依据本指导原则的适用章节（如偶联前的抗体和喷雾干燥分散体）建立保持时限，或适当设定复检期或有效期。

The recommendations may be applicable to reference materials as well as to drug productscontaining certain excipients and adjuvants where the stability of these components cansignificantly impact drug product performance. Refer to Section 12- Reference Materials,

Novel Excipients and Adjuvants for detailed guidance. Co-packaged solvents/diluents should

follow the recommendations for drug products.

本指导原则的建议可适用于标准物质，以及含有特定辅料与佐剂的制剂，其成分的稳定性可能显著影响制剂的性能。具体指导见第12节“标准物质、新型辅料与佐剂”。

组合包装的溶剂/稀释剂应遵循制剂的相关建议。

Regulatory expectations for the stability data package in this guideline are also applicable todrug substances and drug products made using continuous manufacturing (CM) processes.

本指导原则对稳定性数据包的监管要求同样适用于通过连续制造（CM）工艺生产的原料药和制剂。

Annexes are intended to either supplement the guideline with specific guidance on enhancedapproaches or to provide product-specific guidance for product types with specific and uniquestability considerations. Annex 1 provides guidance on Reduced Protocol Design; Annex 2provides guidance on Stability Modelling; and Annex 3 provides Additional Considerations forATMPs.

The main types of stability studies are graphically represented in Figure 1.

附录旨在通过以下方式补充本指导原则：提供针对强化方法的具体指导，或为具有

特殊和独特稳定性考量的产品类型提供专项指导。附录1提供了简化方案设计的指导；附录2提供了稳定性建模的指导；附录3提供了先进治疗产品（ATMP）的其他考量。

稳定性研究的主要类型如图1所示。

Figure 1: Stability Study Types

1 稳定性研究类型

Formal stability studies are primary, commitment, ongoing and product lifecycle stability studies conducted under the accelerated, intermediate, or long-term storage conditions (as applicable) to establish or confirm a re-test period or a shelf life. Supportive stability studies are those stability studies that are conducted (as applicable) to support the practical use of the product (including label claims) or a re-test period or a shelf life (e.g., photostability, in-use, short-term storage condition studies and studies to support excursions or modelling). Formal and supportive stability studies and their purposes are described in various sections of this guideline. In addition to formal stability studies, guidance is provided on studies that inform stability knowledge and product understanding (refer to Section 2 – Development Studies Under Stressed and Forced Conditions).These development studies are introduced in Section 2 because some of this information is utilised to develop the primary stability protocol and the validation of stability-indicating methodologies.

正式稳定性研究系指在加速条件、中间条件和长期条件下（如适用）开展的所有注册、承诺、持续或产品生命周期稳定性研究，以建立或确认复检期或有效期。支持性稳定性研究系指为支持产品的实际使用（包括说明书及标签声明）或复检期或有效期而开展的稳定性研究（如适用）（如光稳定性、使用期间、短期贮存条件研究和支持偏离或建模的研究）。本指导原则各章节对正式与支持性稳定性研究及其目的进行了阐述。除正式稳定性研究外，本指导原则还提供增强稳定性认知与产品理解的研究指导（见第2节“影响因素条件和强制降解条件下的开发研究”）。第2节对此类开发研究进行了介绍，因其中部分信息用于制定注册稳定性方案和验证稳定性的指示方法。

The guideline discusses strategies for protocol design within Section 3 - Stability Protocol Design to Section 7 - Storage Conditions. The recommendations in these sections are applicable to primary stability studies. However, the principles of protocol design are intended to apply to any stability protocol (e.g., commitment, ongoing and product lifecycle stability studies, including those to support changes).

本指导原则在第3节“稳定性方案设计”至第7节“贮藏条件”讨论了方案设计策略。上述章节的建议适用于注册稳定性研究。但方案设计的原则拟适用于所有稳定性方案（如承诺、持续和产品生命周期稳定性研究，以及变更支持性研究）。

The concept of a ‘representative batch’ to support establishing the re-test period or shelf life is referenced throughout this guideline. The justification that a batch is representative will vary depending on the drug substance and drug product types, their complexity and manufacturing processes. This is discussed in detail within Section 4 - Selection of Batches.

本指导原则全文引用了“代表性批次”概念以支持确定复检期或有效期。批次具有代表性的论证因原料药和制剂的类型、复杂程度和生产工艺而异，详见第4节“批次选择”。

The applicant should consider all available stability knowledge when designing stability protocols and defining information for inclusion on the product labelling (e.g., storage statements). This includes considerations of the impact of holding times, the primary stability data and supportive stability data to inform long-term, short-term and in-use storage conditions. In many cases, stability protocol designs may be dependent on the potential impact on the final product quality and therefore based on quality risk management.

申请人在设计稳定性方案和制定产品说明书及标签信息（如贮藏声明）时，应综合考虑所有可用的稳定性知识，包括保持时限的影响、注册稳定性数据和支持性稳定性数据对长期、短期和使用期间的贮藏条件。多数情况下，稳定性方案的设计可能取决于对终产品质量的潜在影响，因此应基于质量风险管理原则。

This guideline does not specify filing mechanisms or regional requirements.

本指导原则不涉及具体的申报机制或区域要求。

2  DEVELOPMENT STABILITY STUDIES UNDER STRESS AND FORCED CONDITIONS

2  影响因素和强制降解条件下的开发稳定性研究

Product knowledge is useful in the design of formal stability study protocols. Development studies may be useful to characterise the physical, chemical and biological changes likely to occur with storage, to establish the degradation profile and intrinsic stability of the product, to confirm and validate the stability-indicating nature of the analytical procedures, to inform specifications and to determine whether unexpected exposures to conditions other than those defined in the label are deleterious to the product (refer to Section 14 – Excursions Outside of a Labelling Claim). In addition, these development studies can be used to help design the primary stability protocol and may also be applied to protocols used to support changes during the product lifecycle (refer to Section 3 - Stability Protocol Design and Section 15 - Stability Considerations for Commitments and Product Lifecyle Management).

产品认知有助于设计正式稳定性研究的方案。开发研究可能有助于表征贮藏期间可能发生的潜在的物理、化学和生物特性变化，以建立产品的降解特性谱和固有稳定性，确认并验证分析方法的稳定性指示能力，作为制定质量标准的依据，并评估偏离说明书及标签贮藏条件对产品的危害（见第14节“超出说明书及标签声明的偏离”）。此外，开发研究可用于帮助设计注册稳定性方案，也可应用于支持产品生命周期变更的方案（见第3节“稳定性方案设计”和第15节“稳定性承诺和产品生命周期管理的稳定性考量”）。

In the context of generating product knowledge, studies may be performed under accelerated and/or stress conditions, including forced conditions. The nature of this testing should be proportionate to the knowledge available, the type of the drug substance or drug product being evaluated and the quality attribute(s) being investigated.

已有产品认知的前提下，可以在加速和/或影响因素条件下（包括强制降解条件）进行研究。试验的性质应与现有认知水平、所评价原料药或制剂的类型以及所研究的质量属性相称。

Accelerated conditions (temperature and when applicable, humidity), over a defined time period, are intended to increase the rate of chemical degradation, physical change and/or biochemical change in the product. Data generated under accelerated conditions can be used to gain product knowledge and to support extrapolation, re-test or shelf life determination and to evaluate the impact of excursions outside the label storage conditions. Accelerated testing is typically included as part of the formal stability program as described in Sections 3 – Stability Protocol Design through Section 7 – Storage Conditions.

在规定时间内，加速条件（温度和湿度，如适用）旨在提高产品的化学降解、物理变化和/或生化反应的速率。加速条件下的数据可用于获取产品认知，支持外推、复检期或有效期的确定，并评估偏离说明书及标签贮藏条件的影响。如第3节“稳定性方案设计”至第7节“贮藏条件”所述，加速试验通常作为正式稳定性计划的一部分。

Development studies undertaken to assess the effect of stress on the drug substance and/or drug product can be divided into two categories:

为评估影响因素条件对原料药和/或制剂的影响进行的开发研究可分为两类：

1)  Studies conducted under stress conditions: Conditions are more severe than the accelerated conditions but not necessarily intended to deliberately degrade the sample.

1)  影响因素条件研究：条件比加速条件严苛，但非刻意诱导样品降解。

2) Studies conducted under forced degradation conditions: Conditions are intended to deliberately degrade the sample (such as elevated temperature, humidity, pH, oxidation, agitation and light).

2)  强制降解研究：刻意诱导样品降解（如高温、高湿、pH值、氧化、搅拌和光照）。

The purpose of this section is to describe the principles of development studies under stress and forced conditions. This section provides clarity on the concepts, study design and considerations for interpreting the results.

本节旨在介绍影响因素条件和强制降解条件下开发研究的基本原则。阐明了概念、研究设计和结果解释的考虑因素。

2.1  Development Studies Under Stress Conditions

2.1  影响因素条件的开发研究

Studies under stress conditions can contribute to an understanding of product knowledge and the data gathered from these studies can be useful in addressing unexpected excursions outside of the conditions defined on the labelling (refer to Section 14.1 – Excursions Outside of a Labelling Claim).

影响因素条件研究有助于增进产品认知，其数据可用于应对超出说明书及标签规定条件的意外偏离（见第14.1节“超出说明书及标签声明的偏离”）。

Stress condition studies can include temperature and humidity levels above accelerated conditions,thermal cycling and freeze-thaw studies, as appropriate. For synthetic chemicals entities, these studies may be conducted on one batch of the drug product and where relevant one batch of the drug substance directly exposed or in a container closure system, as applicable. For biologicals, at a minimum, stress studies may be performed on a single batch of drug product, however, it may be possible to justify using a single batch of drug substance if it is representative of the drug product.

影响因素条件研究可以包括高于加速条件的温度和湿度水平、热循环和冻融试验（如适用）。对于化学合成实体，上述研究可采用一批制剂进行（必要时可同时采用一批原料药进行，原料药可采用直接暴露方式或置于容器密封系统，如适用）。对于生物制品，至少应对一批制剂进行影响因素研究，但如果原料药批次能代表制剂特性，则可以提供合理性论证后使用该批原料药。

2.2  Development Studies Under Forced Degradation Conditions

2.2  强制降解条件的开发研究

Forced degradation studies may be utilised to investigate potential degradation pathways; gain product knowledge; understand the intrinsic stability of product and used to develop and confirm stability-indicating nature of the analytical procedure (refer to ICH Q2 and ICH Q14). It is acceptable to leverage product knowledge when data is available on identified degradation products and pathways, including scientific literature.

强制降解研究可用于研究潜在的降解途径；获取产品知识；了解产品的固有稳定性，并用于开发和确认分析方法具有稳定性指示特性（见ICH Q2和ICH Q14）。当可获得已鉴定的降解产物和降解途径的数据时（包括科学文献），可以利用现有产品知识。

It is recommended to assess forced conditions on a single batch of the drug substance. It should include the effect of elevated temperatures, humidity (e.g., 75% Relative Humidity (RH) or greater) where appropriate, oxidation and photodegradation on the drug substance. Testing should evaluate the susceptibility of the drug substance to hydrolysis across a range of pH values. Also, a combination of forced conditions may be appropriate to test under certain circumstances (e.g., agitation and heat).

建议对单批原料药的强制降解条件进行评估，评估应包括温度、湿度（如≥75%  相对湿度（RH），如适用）、氧化和光降解的影响。应评估原料药在一定pH值范围内对水解的敏感性。此外，在某些情况下（如搅拌和加热），可能需要组合使用强制降解条件进行试验。

For drug products, testing under forced conditions is recommended on a single batch of exposed drug product. It should include the effect of temperature, humidity (e.g., 75% RH or greater) where appropriate and light. Additional forced conditions for specific types of products and dosage forms may be appropriate.

对于制剂，建议对单批制剂开展强制降解条件，试验应包括温度、湿度（如≥75%  RH，如适用）和光照的影响。对于特定类型的产品和剂型，可能需要进行额外的强制降解条件。

For biologicals, studies under forced degradation conditions should be performed on a single batch of drug substance; alternatively, it may be possible to justify using a single batch of drug product.

对于生物制品，应对单批原料药进行强制降解条件的研究，或者，如果能证明制剂批次具有代表性，也可使用单批制剂。

The forced photodegradation condition can be an integral part of forced degradation studies. The purpose of forced photodegradation studies is to evaluate the overall photosensitivity of the product. A forced photodegradation study requires exposure to light conditions which are more extreme than the light conditions utilised in confirmatory studies (refer to Section 8 – Photostability).

强制光降解条件可作为强制降解研究的组成部分，其目的是评估产品的整体光敏性。强制光降解研究需要采用比确证性研究更严苛的光照条件（见第8节“光稳定性”）。

With forced degradation studies, the conditions and duration may need to be varied depending on the sensitivity of the product. For development and analytical procedure validation purposes, it is appropriate to limit the exposure and end the forced degradation study if extensive decomposition occurs. Similarly, for stable materials, studies may be terminated after an appropriate exposure level has been used. The design of these experiments is left to the applicant’s discretion although the exposure levels used should be justified.

强制降解研究的条件和持续时间可根据产品的敏感性进行调整。开发和分析方法验证时，若发生显著性的分解，则可适当限制暴露并终止研究。同样地，对于稳定的样品，在达到适当暴露水平后可终止研究。申请人可自主设计试验方案，但应对所用的暴露水平进行论证。

2.3  Analysis and Interpretation of Results

2.3  结果分析与解读

When testing under stressed conditions, including forced degradation, samples should be examined at the end of the exposure period for any changes in physical, chemical, or biological properties (e.g., physical state, clarity, colour, degradation products, particle size, potency), as applicable, by a procedure suitable to detect any evidence of change.

在影响因素条件下（包括强制降解）进行试验时，应采用适当的检测方法，在暴露期结束时评估样品的物理、化学或生物学特性的变化（如物理状态、澄清度、颜色、降解产物、粒度、效价）（如适用）。

Changes in attributes that are unlikely to occur under normal storage conditions may occur under forced conditions and possibly under stress conditions (e.g., the formation of degradation products). This information may be useful in developing and validating suitable analytical procedures and can be part of a comprehensive approach to justify the overall control strategy.

在常规贮藏条件下不太可能发生的属性变化，但在强制降解条件和影响因素条件下可能发生（如形成降解产物）。这些信息有助于开发和验证分析方法，并可作为综合方法的一部分，用以证明整体控制策略的合理性。

The data obtained from these development studies may also inform product understanding and help identify the potential stability-indicating CQAs that should be monitored during stability testing,assisting in the design of the stability protocol (refer to Section 3 - Stability Protocol Design). Although forced degradation studies are not part of the formal stability studies, results from the forced degradation studies are an integral part of the information provided to regulatory authorities (e.g., support analytical procedure validation, product characterisation, specifications or packaging considerations). Data from development studies under stress condition should be included in regulatory submissions if they support a claim on the product labelling.

这些开发研究数据可增进产品认知，帮助识别稳定性研究中需监测的稳定性指示CQA，从而协助设计稳定性方案（见第3节“稳定性方案设计”）。虽然强制降解研究不属于正式稳定性研究，但其结果是提交给监管机构的重要组成部分（如支持分析方法验证、产品表征、质量标准或包装的筛选）。若影响因素条件下的开发研究数据支持药品说明书及标签的声明，则应将其纳入注册申报资料中。

3  PROTOCOL DESIGN FOR FORMAL STABILITY STUDIES

3  正式稳定性研究的方案设计

This section provides guidance that is intended to be used in conjunction with Section 4 – Selection of Batches through Section 7 – Storage Conditions to establish a formal stability study protocol. Figure 2 illustrates how an applicant may approach the design and development of a formal stability protocol.The “available stability data” in the figure refers to knowledge gained from long-term and accelerated stability studies conducted earlier in development and from development studies discussed in Section 2 – Development Studies Conducted on Stressed and Forced Conditions.

本节提供了旨在与第4节“批次选择”至第7节“贮藏条件”配合使用的指导，以建立正式稳定性研究的方案。图2说明了申请人如何设计和制定正式稳定性研究的方案。图中的“现有稳定性数据”是指从开发早期进行的长期和加速稳定性研究以及第2节“强力条件和强制降解条件下的开发研究”中获得的知识。

Where noted, these sections provide specific guidance for establishing a primary stability protocol to determine a re-test period or shelf life (refer to Section 13 - Data Evaluation). When applicable, the guidance in these sections should be utilised in conjunction with Section 15 - Stability Considerations for Commitments and Product Lifecyle Management (for commitment stability studies, ongoing stability studies and lifecycle stability studies) and Annex 1 - Reduced Stability Protocol Design (where reduced study designs may be appropriate).

如有注明，这些章节提供了关于制定注册稳定性方案的具体指导，以确定复检期/有效期（见第13节“数据评估”）。在适用的情况下，这些章节中的指导应与第15节“关于承诺与产品生命周期管理的稳定性考虑因素”（适用于承诺稳定性研究、持续稳定性研究和生命周期稳定性研究）和附录1-简化稳定性方案设计（可能适合简化研究设计）配合使用。

3.1  General Principles

3.1  一般原则

A summary of the stability protocol should be provided in a regulatory submission when a re-test period or shelf life is to be established or confirmed. The stability protocol incorporates all necessary information to establish or confirm the stability of the drug substance or drug product under the recommended storage conditions throughout the re-test period or shelf life. This includes consideration of data from primary stability studies and supporting data to inform long-term storage, short-term storage, excursions and in-use conditions.

当需要建立或确认复检期/有效期时，应在注册申报资料中纳入稳定性方案的摘要。稳定性方案应包含所有必要的信息，以确认原料药或制剂在其整个复检期/有效期内在推荐的贮藏条件下的稳定性。这包括对注册稳定性研究的数据和支持性数据的考虑，以告知长期贮藏、短期贮藏、偏离和使用期间条件。

An illustration of the general process for the development, design and execution of a stability protocol is shown in Figure 2. The applicant is responsible for building knowledge and understanding during pharmaceutical development, leading to the identification of those CQAs that are or have the potential to be stability-indicating under appropriate storage conditions and using this information to design the protocol to support the formal stability studies. Stability studies should include testing of those attributes that are susceptible to change during storage and can potentially influence quality, safety and efficacy.During the product’s lifecycle, as knowledge is gained, stability protocol designs may be optimised. Changes to the stability protocol to extend a re-test period or shelf life should be established in accordance with Section 15 - Stability Considerations for Commitments and Product Lifecyle Management.

稳定性方案的开发、设计和执行的一般过程如图2所示。申请人负责在产品开发过程中积累知识和理解，从而确定在适当贮藏条件下具有或可能指示稳定性的CQA，并使用该信息设计方案，以支持正式稳定性研究。稳定性研究应包括对贮藏期间易发生变化且可能影响质量、安全性和有效性的属性进行检测。在产品的生命周期中，随着知识的不断获取，可以不断优化稳定性方案设计。为延长复检期/有效期而对稳定性方案进行的变更，应根据第15节“关于承诺和产品生命周期管理的稳定性考虑因素”进行确定。

Figure 2: General Process Flow for the Development, Design and Execution of a Stability Protocol

图2 稳定性方案开发、设计和执行的一般流程

The principles detailed for protocol design should be applied from initial regulatory submission through product lifecycle. The precise protocol design will depend on the drug substance/drug product, study purpose and the available prior knowledge.

方案设计的详细原则应涵盖从首次注册申报到产品生命周期的所有内容。方案设计精确与否将取决于原料药/制剂、研究目的和可用的先验知识。

Additional protocol considerations for photostability, excursions, short-term storage and in-use conditions are described in the respective sections (refer to Section 8 – Photostability, Section 14.1 –Excursions Outside of a Labelling Claim, Section 10 - Short-Term Storage Conditions and Section 11– In-Use Stability). 

关于光稳定性、偏离、短期贮藏和使用期间条件的其他方案考虑因素，在相应章节中均有描述（见第8节“光稳定性”、第14.1节“超出说明书及标签声明的偏离”、第10节“短期贮存条件”和第11节“使用中稳定性”）。

A full design stability protocol is a protocol where at least three batches of the drug substance or at least three batches of each strength of the drug product covering the proposed container closure systems for every combination of all design factors are included and tested at all time points. Alternative approaches to stability protocol design, such as bracketing, matrixing, knowledge- and risk-based protocol reductions and stability models are described in Annex 1 – Reduced Stability Protocol Design and Annex 2 – Stability Modelling. Additional considerations for ATMPs are provided in Annex 3 – Stability of Advanced Therapy Medicinal Products (ATMPs).

完整稳定性设计方案是指在所有时间点纳入并检测至少三批原料药或每种规格至少三批制剂（涵盖所有设计因素的每种组合的拟定容器密封系统）的方案。稳定性方案设计的替代方案，如括号法、矩阵设计、基于知识和风险的方案简略以及稳定性模型，见附录1-简化稳定性方案设计和附录2-稳定性建模。附录3-先进治疗产品（ATMP）的稳定性中介绍了ATMP的其他考虑因素。

3.2  Stability Data to Support the Initial Re-test Period and Shelf Life According to the Standard Approach

3.2  根据标准方法支持初始复检期和有效期的稳定性数据

This section provides guidance on establishing the re-test period, shelf life and storage conditions using data from the primary stability study (refer to Section 4 – Selection of Batches). This is considered the standard approach. When the standard approach is adopted, the recommendations provided in Table 1 establish an appropriate minimum dataset at the time of the initial regulatory submission to assign a re- test period and shelf life in accordance with the guidance provided in Section 13 – Data Evaluation.Alternative approaches to the principles and practices described in this section may be acceptable if they are supported by adequate justification, including an enhanced knowledge of product performance from prior knowledge, as per ICH Q8 - Q11 and modelling as discussed in Annex 2 - Stability Modelling.

本节对使用注册稳定性研究数据确定复检期、有效期和贮藏条件提供了指导（见第4节“批次选择”）。这被认为是标准方法。当采用标准方法时，表1中的建议是在首次申报时建立一个适当的最小数据集，以便根据第13节“数据评估”中提供的指导确定复检期/有效期。如果有充分的依据支持，包括根据ICH Q8-Q11和附录2-稳定性建模中讨论的建模，从先验知识中增强对产品性能的了解，则可以使用本节所述原则和实践的替代方案。

The stability package provided in the regulatory submission should be sufficient to support the proposed re-test period or shelf life and storage conditions. The long-term stability protocol should, at a minimum, ensure testing continues for the duration of the proposed re-test period or shelf life.

注册申报资料中提供的稳定性数据包应足以支持拟定的复检期/有效期和贮藏条件。长期稳定性方案至少应确保检测在建议的复检期/有效期内持续进行。

Data from the accelerated storage conditions and, if appropriate, from the intermediate storage conditions can be used to evaluate the effect of short-term excursions outside the labelled storage conditions (e.g., during shipping). For synthetics, data from the accelerated storage condition are also needed to enable extrapolation in accordance with Section 13.2.5 – Extrapolation for Synthetic Chemical Entities. For biologicals, data from the accelerated storage condition is utilised for product understanding and may be used to support analytical comparability. Even though data generated under accelerated storage conditions are not used to establish a re-test period or shelf life for biologicals, it is strongly suggested to include these data in the regulatory submission.

来自加速条件和中间条件（如适用）的数据可用于评估短期偏离标签上的贮藏条件（比如运输期间）的影响。对于化学合成实体，还需要加速条件下的数据，以便根据第13.2.5节“化学合成实体的外推法”进行外推。对于生物制品，加速条件下的数据用于产品理解，并可用于支持分析可比性。尽管加速条件下生成的数据不用于建立生物制品的复检期/有效期，但本指导原则强烈建议将这些数据纳入注册申报资料中。

Refer to Section 4 – Selection of Batches, Table 2 for guidance on selection of primary batches. For synthetics and for biologicals, a primary batch may be a production batch but does not need to be a production batch.

有关注册稳定性批次选择的指导，请参阅第4节“批次选择”中的表2。对于化学合成实体和生物制品，注册稳定性批次可以是生产批次，但不必须是生产批次。

Biological drug substances and drug products usually require stringent conditions for their storage to ensure maintenance of biological activity and to avoid degradation, because of dependence of molecular conformation and biological activity on noncovalent as well as covalent forces, resulting their high sensitivity to environmental factors (e.g., temperature changes, oxidation, light, ionic content and shear). The evaluation of their stability may necessitate complex analytical methodologies including physicochemical, biochemical and immunochemical methods, and consideration of many external conditions which can affect the product’s potency, purity and quality. For biological drug substances and drug products, data from three primary batches that cover the duration of the proposed shelf life should be submitted unless an alternative approach is justified. When these primary batches are not

production scale, a minimum of 6 months of data from production batches should also be submitted to support the evaluation of the regulatory submission. A minimum of 6 months stability data from primary batches should be submitted in cases where shelf life is greater than 6 months. For drug substances and drug products with a shelf life of less than 6 months, the minimum amount of stability data in the initial regulatory submission should be determined on a case-by-case basis. Refer to Section 15 - Stability Considerations for Commitments and Product Lifecyle Management for guidance on providing commitment stability data after marketing authorisation.

生物制品原液和制剂通常需要严格的贮藏条件，以确保维持生物活性并避免降解，这是因为其分子构象和生物活性依赖于共价和非共价力，使其对环境因素（如温度变化、氧化、光照、离子含量和剪切力）极为敏感。对其稳定性的评估可能需要采用复杂的分析方法，包括理化、生化和免疫化学方法，也需要考虑许多可能影响产品效价、纯度和质量的外部条件。对于生物制品原液和制剂，应提交涵盖拟定的有效期的三个注册批次的数据，除非可以解释替代方案的合理性。当这些注册稳定性批次的规模不是生产规模时，还应提交至少6个月的生产批次数据，以支持对注册申报的审评。如果有效期超过6个月，应提交注册稳定性批次至少6个月的稳定性数据。对于有效期小于6个月的原液和制剂，首次注册申报时的稳定性数据最低数量应视具体情况而定。关于在获得上市许可后提供承诺稳定性数据的指导，请参阅第15节“关于承诺和产品生命周期管理的稳定性考虑因素”。

A stability study to establish a re-test period or shelf life should include at least three batches of the drug substance or at least three batches of each strength of the drug product covering the proposed container closure systems. Reduced designs may be applied where justified (refer to Annex 1 – Reduced Stability Protocol Design). 

旨在确定复检期/有效期的稳定性研究应包含使用拟定容器密封系统的至少三个原料药/原液批次或每种规格、装量或浓度的至少三个制剂批次。在合理的情况下，可采用简化设计（见附录1-简化稳定性方案设计）。

For synthetic chemical entities and biologicals, if primary batches are not production scale or not all at production scale, the applicant should commit to continuing or initiating and completing a commitment stability study to establish and confirm the re-test period or shelf life in accordance with Section 15.1 - Commitment Stability Studies.

对于化学合成实体和生物制品，如果注册稳定性批次不是生产规模或并非全部处于生产规模，申请人应承诺继续或启动并完成承诺稳定性研究，以根据第15.1节“承诺稳定性研究”建立并确认复检期/有效期。

Table 1: Recommended Core Stability Data for the Standard Approach at Submission to

Support the Initial Re-test Period or Shelf Life1

表1  在申报时用于支持初始复检期/有效期标准方法的建议核心稳定性数据1

1 For testing frequency guidance refer to Section 6 – Testing Frequency

1有关检测频率的指导，请参阅第6节“试验频率”

2 For a full design, at least 3 batches of the drug substance or at least 3 batches of each strength of the drug product covering the proposed container closure systems are tested. Reduced designs may be applied where justified (refer to Annex 1 – Reduced Stability Protocol Design).

2对于完整设计，至少三个原料药/原液批次或至少每种规格或装量生产3个制剂批次，包含建议的容器密封系统。在合理的情况下，可采用简化设计（见附录1-简化稳定性方案设计）

3 If a significant change (refer to Section 13 - Data Evaluation) or an out of specification result occurs at accelerated conditions within the first 3 months, it is considered unnecessary to continue to test through 6 months.

3如果在加速条件下的前3个月内出现显著变化（见第13节“数据评估”）或超标结果，则认为没有必要继续进行为期6个月的试验。

4 In principle, stability protocols for new dosage forms and new strengths/concentrations should follow the guidance for a new drug. However, a reduced stability dataset at submission time (e.g., 6 months accelerated and 6 months long term data) may be acceptable in certain justified cases (refer to Section 15.3 - Stability Studies to Support New Dosage Forms and New Strengths/Concentrations).

4原则上，新剂型和新规格/浓度的稳定性方案应遵循新药的指导。但在某些合理的情况下（见第15.3节“支持新剂型和新规格/浓度的稳定性研究”），申报时简略的稳定性数据集（例如6个月加速试验和6个月长期试验的数据）或许是可以接受的。

5 There should be a commitment to continue stability studies for production batches corresponding to the proposed re-test period or shelf life.

5与拟定复检期/有效期相对应的生产批次，应承诺继续进行稳定性研究。

6 A primary batch can be a production batch but does not need to be a production batch. If the re-test period or shelf life proposed from non-production primary batch data is greater than 6 months, stability data from production batches should be a minimum of 6 months. The shelf life would generally be supported by three primary batches having stability data through to shelf life.

6注册稳定性批次可以是生产批次，但不必须是生产批次。如果非生产注册稳定性批次数据建议的复检期/有效期大于6个月，则生产批次的稳定性数据应至少为6个月。有效期通常由三个具有有效期内稳定性数据的注册稳定性批次支持。

7 Testing under accelerated storage conditions is strongly suggested when appropriate for the storage condition and product type and the minimum time period should be justified by the applicant in accordance with the selected storage conditions. A minimum of three time points, including the initial and final, is recommended.

7当贮藏条件和产品类型适当时，本指导原则强烈建议在加速条件下进行试验，申请人应根据选定的贮藏条件证明最短时间期限的合理性。建议至少设置三个时间点，包括初次时间点和末次时间点。

For drug substances and drug products with intended storage periods of less than the recommendations in Table 1, the minimum amount of stability data in the initial regulatory submission should be determined based on the product-specific risks and in accordance with Section 6 – Testing Frequency.

对于预期的贮藏期比表1中的推荐期限更短的原料药和制剂，在首次注册申报时，应根据产品特定风险，并按照第6节“试验频率”确定最低的稳定性数据量。

3.3  Stability-Indicating Critical Quality Attributes

3.3  稳定性指示关键质量属性

CQAs should be identified using the principles outlined in ICH Q6A, Q6B and ICH Q8-Q11. When designing a stability protocol in support of a drug substance or drug product, information on the CQAs and their target acceptance criteria should already be available. Based on prior knowledge and development data, the applicant should identify the stability-indicating CQAs, which are those attributes that may change upon storage and may impact the functionality and/or quality of the drug substance or drug product.

应根据ICH Q6A, Q6B和ICH Q8-Q11中概述的原则鉴别CQA。在设计支持原料药或制剂的稳定性方案时，应已获得关于CQA及其目标可接受标准的信息。根据先验知识和开发数据，申请人应确定指示稳定性的CQA，这些属性可能在贮藏后发生变化，并可能影响原料药或制剂的功能性和/或质量。

3.3.1  Recommendations for Establishing a Re-Test Period or Shelf life.

3.3.1  关于确定复检期/有效期的建议

The stability protocol to establish a re-test period or shelf life should include stability-indicating CQAs and compile a suitable dataset to demonstrate product quality through storage and use. For synthetic chemical drug substances and drug products, the stability protocol should consider appropriate, physical and chemical attributes. For biological drug substances and drug products, the protocol should assess changes in CQAs that affect physicochemical properties, purity and impurity levels, immunochemical properties and the biological activity of the product, as appropriate. For both synthetics and biologicals, microbiological attributes and product performance characteristics should be confirmed on stability as applicable. For products that are particularly sensitive to changes in temperature, oxidation, light, moisture content and shear forces, quality attributes that may be impacted should be assessed. For additional information on attributes to be included in the drug substance or drug product specification, refer to ICH Q6A and Q6B.

用于确定复检期/有效期的稳定性方案应包括指示稳定性的CQA，并汇编适当的数据集以证明在贮藏和使用过程中的产品质量。对于合成化学原料药和制剂，稳定性方案应酌情考虑理化属性。对于生物制品的原液和制剂，方案应酌情评估影响产品理化性质、纯度和杂质水平、免疫化学性质和生物活性的CQA的变化。对于化学合成实体和生物制品，应酌情确认稳定性的微生物属性和产品性能特征。对于对温度、氧化、光照、水分含量和剪切力变化特别敏感的产品，应评估其可能受影响的质量属性。有关原料药或制剂质量标准中包含的质量属性的其他信息，请参考ICH Q6A和Q6B。

Where excipient levels or their properties may change on stability, potentially impacting drug product CQAs, they should be evaluated as part of drug product stability testing, (e.g., levels of surfactant, preservative content). In cases where stabilisers are needed for a biological drug substance, the same considerations should be applied. Co-packaged diluents should follow the recommendations for drug products. A risk-based approach is recommended, where development data and excipient prior knowledge can be used to understand whether additional drug substance and/or drug product stability data are appropriate to support the re-test period or shelf life.

如果辅料水平或其特性在稳定性期间可能发生变化，从而可能影响制剂CQA，则应将其作为制剂稳定性试验的一部分进行评估（比如表面活性剂的水平和防腐剂含量）。对于生物制品需要使用稳定剂的情况，也应进行同样的考量。合并包装的稀释剂将遵循针对制剂的建议。建议采用基于风险的方法，其中开发数据和辅料先验知识可用于了解是否需要额外的原料药和/或制剂稳定性数据, 合理支持复检期或有效期。

In accordance with the principles outlined in ICH Q3D and Q3E, stability-indicating CQAs

considerations should include potential interaction with the respective storage container, contact with administration or delivery devices (e.g., syringe walls, catheters and injection needle) and dispersion media (such as solvents for reconstitution or dilution).

根据ICH  Q3D和Q3E中概述的原则，指示稳定性的CQAs考虑因素应包括与相应贮藏容器的潜在相互作用、与给药或递送装置（如注射器壁、导管和注射针）和分散介质（如复溶溶剂或稀释剂）之间的接触。

3.3.2  Recommendation for Lifecycle Stability Protocols

3.3.2  生命周期稳定性方案建议

After additional knowledge is gained following establishment of the re-test period or shelf life, data may confirm that some CQAs do not change on stability and stability protocols to support the product lifecycle may be updated accordingly (refer to Section 15 – Stability Considerations for Commitments and Product Lifecyle and Annex 1 - Reduced Stability Protocol Design)

在确定复检期/有效期并获得更多信息后，数据可确认某些CQAs是否在稳定性研究中未发生变化，并相应更新支持产品生命周期的稳定性方案（见第15节“关于承诺和产品生命周期管理的稳定性考虑因素”

3.4  Specifications

3.4  质量标准

3.4.1   Tests and Analytical Procedures

3.4.1   测试和分析程序

Before a formal stability study protocol is initiated, the suitability of the proposed analytical procedures to detect changes in the stability-indicating CQAs should be assessed in accordance with ICH Q2 and ICH Q14. The analytical procedures used to monitor changes in the stability-indicating CQAs should be chosen and validated to provide assurance that changes to product quality will be detected, measured and understood over the expected re-test period or shelf life. Establishment of potential degradation pathways (refer to Section 2.3 -Analysis and Interpretation of Results) is important when developing and validating suitable analytical procedures. When feasible for synthetic chemical entities, the mass

balance relationship between tested attributes should be observed when selecting appropriate stability- indicating tests. For example, for solid drug substances or drug products, an apparent decrease in the active moiety could be caused by an increase in degradation products and/or an increase in moisture content.

在启动正式稳定性研究的方案之前，应根据ICH Q2和ICH Q14评估用建议的分析方法检测指示稳定性的CQA变化的适用性。应选择并验证用于监测指示稳定性的CQA变化的分析方法，以确保在预期的复检期/有效期内检测、测量和理解产品质量的变化。在开发和验证合适的分析方法时，确定潜在的降解途径（见第2.3节“结果分析与解读”）非常重要。如果对于化学合成实体可行，在选择适当的指示稳定性试验时，应观察被测属性之间的质量平衡关系。例如，对于固体原料药或制剂，活性部分的明显减少可能是由降解产物的增加和/或水分含量的增加引起的。

When justified, the analytical procedures used for stability testing may differ from the release analytical procedure for the same quality attribute (e.g., container closure integrity testing may be used instead of sterility testing during stability). In situations where stability-indicating quality attributes are not tested as part of release testing (e.g., the relevant CQAs are measured and controlled during processing as described in ICH Q8), additional analytical procedures should be established to support stability studies.

在合理的情况下，用于稳定性测试的分析程序可与相同质量属性的放行分析程序不同（比如在稳定性研究期间可能使用容器密封完整性测试代替无菌测试）。在未将指示稳定性的质量属性作为放行检测的一部分进行检测的情况下（比如按照ICH Q8所述在处理过程中测量和控制相关CQA），应建立额外的分析方法来支持稳定性研究。

3.4.2   Acceptance Criteria

3.4.2   可接受标准

The shelf life acceptance criteria should consider all available stability information from development and manufacture of the drug substance through final drug product shelf life in accordance with ICH Q6A and Q6B. As per these guidelines, when a stability-indicating CQA changes over time, it may be appropriate to establish a release specification that is more stringent than the shelf life specification to ensure that the drug substance and/or drug product quality is maintained through to the end of shelf life.

In general, any differences between the release and shelf life acceptance criteria should be justified with data. In case a re-test period is assigned to a drug substance, generally the acceptance criteria are the same as at release.

根据ICH Q6A和Q6B，有效期可接受标准的制定应考虑从原料药/原液开发和生产到最终制剂有效期的所有可用稳定性信息。根据这些指导原则，当指示稳定性的关键质量属性随时间变化时，可能需要建立比有效期质量标准更为严格的放行标准，以确保原料药和/或制剂能够在有效期结束前一直维持良好质量。一般来说，放行标准和有效期可接受标准之间的任何差异都应该用数据来证明。如果为原料药指定了复检期，则其可接受标准通常与放行标准相同。

3.4.3   Pharmacopoeial Critical Quality Attributes and Analytical Procedures

3.4.3   药典关键质量属性和分析方法

When drug substance and/or drug product monographs or general procedures are available and relevant to the region(s) where the regulatory submission is to be filed, the monographed CQAs and analytical procedures are an appropriate starting point in designing a product-specific stability protocol. Any differences in the proposed analytical procedures from those in the pharmacopeia should be scientifically justified (e.g., including demonstration of equivalency). A knowledge- and risk-based approach should then be applied to ensure that any differences in stability behaviour are properly controlled.

当原料药/原液和/或制剂专论或常规方法在拟提交注册申报的地区可用并相关时，专论CQA和分析方法可以作为设计产品特定稳定性方案的合适起点。建议的分析方法与药典方法的任何差异都应有科学依据（比如包括等效性证明）。应该采用基于知识和风险的策略，以确保任何稳定性行动之间的差异都能得到有效控制。

3.5   Additional Considerations for Vaccines

3.5   关于疫苗的其他考虑因素

In cases where the potency of the product is dependent on conjugation and/or adsorption of the active ingredient to another moiety (e.g., carrier), applicants should evaluate potential dissociation of the active ingredient(s) from the carrier during storage (e.g., in conjugate vaccines).

如果制剂的效价取决于活性成分与另一个部分（如载体）的结合和/或吸附，申请人应评估在贮藏期间活性成分与载体可能的解离情况（比如在结合疫苗中解离）。

In cases where the potency of the product is dependent on the inclusion of an adjuvant, the CQAs for the adjuvant should be evaluated during stability studies.

如果产品的效价取决于是否含有佐剂，则应在稳定性研究期间评估佐剂的CQA。

It is strongly recommended that stability studies for vaccines include mechanisms to evaluate the potency (i.e., the specific ability or capacity to achieve its intended effect using suitable methods) of the product.

本指导原则强烈建议在关于疫苗的稳定性研究中纳入评估产品效价的机制（即用适当方法达到预期效果的特定能力或容量）。

3.6   Additional Considerations for the Combination of a Drug Product with a Medical Device

3.6   药械组合的其他考虑因素

The stability of a combination of a drug product with a medical device considers (a) drug product CQAs and (b) drug device combination performance characteristics through storage to the completion of administration (refer to Section 11 – In Use Stability). The functional performance characteristics of the device constituent alone are outside of the scope of this guideline and are addressed through device design verification studies.

药械组合的稳定性考虑因素包括：（a）制剂CQA和（b）从贮藏至给药完成期间的药械组合性能特征（见第11节“使用中稳定性”）。设备组件单独的功能性能特征不在本指导原则的范围内，需通过组件设计验证研究加以解决。

The stability protocol design for a combination of a drug product with a medical device (integral or co-packaged) should follow the same principles as described for a drug product, including a risk assessment and compatibility with contact materials. Stability-indicating attributes of the drug constituent may impact the medical device functional performance characteristics, and stability studies and conclusions should account for these interactions. Considerations should be made for the administration-dependent functional performance characteristics of the fully assembled combination of a drug product with a medical device that may be impacted by long-term storage (i.e., CQAs that can only be assessed after

assembly). The storage orientation may be established based on a risk assessment. The shelf life of a co-packaged combination of a drug product with a medical device should be based on the shorter of either the device constituent part or the drug constituent part shelf life. For integrated device-drug products, the shelf life should be based on the shorter of either of the constituent part or the final combination of a drug product with a medical device.

药械组合（单一实体或组合包装）的稳定性方案设计应遵循与制剂相同的原则，包括风险评估以及与直接接触材料的相容性。药物成分的稳定性指示属性可能会影响医疗器械功能性能特征，稳定性研究和结论应对这些相互作用做出解释。应该考虑制剂与医疗器械完全组装后的组合在给药依赖下的功能性能特征，这些特征可能会受到长期贮藏的影响（即只能在组装后评估的关键质量属性）。可根据风险评估确定贮藏考量。组合包装的药械组合的有效期应以器械组成部分或制剂有效期中的较短者为准。对于一体式包装的药械组合，有效期应以器械组成部分或最终药械组合制剂有效期中的较短者为准。

制剂与医疗器械的每种组合类型都有其独特的质量属性和基于给药方式的功能性能特征列表。

Each type of combination of a drug product with a medical device should have its own unique list of quality attributes and administration-dependent functional performance characteristics. Attributes should be risk assessed according to the specific design of that product to identify the critical attributes or characteristics. The risk assessment may include data from device design development studies and prior knowledge from similar combinations of a drug product with a medical device. The stability protocol should use the assembled (integral or co-packaged) product representative of the product proposed for marketing. If the stability studies were not performed with the combination of a drug product with a medical device as proposed for marketing, the changes made should be assessed and justified with respect to the impact on stability.

应根据产品的具体设计对其属性进行风险评估，以确定关键属性或特性。风险评估可能包括器械设计开发研究的数据以及制剂与医疗器械类似组合的先验知识。稳定性方案应使用代表拟上市产品的组装（一体式包装或组合包装）产品。如果未以拟上市组合形式进行稳定性研究，则应对相应变更进行评估，并说明其对稳定性的影响。

3.7  Risk Management

3.7   风险管理

A science- and risk-based approach should be used to inform the different aspects of protocol design outlined in Section 4 - Selection of Batches through Section 7 - Storage Conditions.

应采用基于科学和风险的方法，为第4节“批次选择”至第7节“贮藏条件”中概述的方案设计的提供不同的决策依据。

The inclusion of risk management information with a registered stability protocol is not mandatory, but in cases where it forms the basis of a justification for enhanced/reduced protocol approaches, information on the risk assessment process, outcome and the connection to the stability protocol should be described.

尽管不强制要求在注册稳定性方案中纳入风险管理信息，但如果该信息构成扩充或简略方案方法的依据，则应描述风险评估过程、风险评估结果及其与稳定性方案的关联信息。

4   SELECTION OF BATCHES

4   批次选择

To establish a re-test period or shelf life for the drug substance and drug product, stability data should generally be provided on three primary batches. Alternative approaches for batch requirements may be supported when justified. The manufacturing process for the primary batches of drug substance and drug product should be similar or representative, but not necessarily identical to the manufacturing process used for production batches. Hence, a primary batch may be but is not necessarily a production batch. Differences in the manufacturing processes for the primary batches and those proposed for production batches should be justified. Specific considerations for primary stability batches are provided in Table 2.

为建立原料药和制剂的复检期或有效期，通常应提供三个注册稳定性批次的稳定性数据。在合理的情况下，可支持批量要求的替代方案。原料药和制剂注册稳定性批次的生产工艺应当相似或具有代表性，但不一定与用于生产批次的生产工艺完全相同。因此，注册稳定性批次可以是生产批次，但不一定是生产批次。注册稳定性批次和拟生产批次的生产工艺差异应合理。注册稳定性批次的具体考虑因素见表2。

For studies that are not a primary study (e.g., in-use stability, photostability, supportive studies and stability studies to support post-approval changes) and use non-production batches, the batches should be representative as described below:

对于非主要研究（例如，使用中稳定性、光稳定性、支持性研究和支持批准后变更的稳定性研究）和使用非生产批次的研究，使用的批次应具有代表性，如下所述：

Synthetic chemical entities: Chemically synthesised drug substances should be manufactured by the same synthetic route. Changes to manufacturing process parameters should be scientifically justified. Drug products should be of the same formulation and method of manufacture.

化学合成实体：化学合成的原料药应采用相同的合成路线进行生产。生产工艺参数

的变更应有科学依据。制剂的处方和生产方法应相同。

Biologicals: The quality of all drug substance and drug product batches placed in a stability program should be manufactured using a similar process to the proposed production manufacturing process and be analytically comparable to the production batches (refer to ICH Q5E). The analytical comparability for the clinical batches and the non-production batches to the production batches should be demonstrated. A comprehensive analytical comparability exercise may include additional characterisation testing.

生物制品：稳定性计划中的所有原液和制剂批次应采用与建议生产工艺相似的工艺

进行生产，并在分析上与生产批次具有可比性（见ICH  Q5E）。应证明临床批次和

非生产批次与生产批次的分析可比性。全面的分析可比性研究可能包括额外的特性

鉴定试验。

4.1   Considerations for Selection of Primary Stability Batches

4.1   注册稳定性批次选择的考虑因素

Where possible, batches of drug product included in stability testing should be derived from different batches of drug substance to account for variability in drug substance batches. Stability studies should be performed on each individual strength, fill volume and container closure system of the drug product unless a reduced protocol design is applied (refer to Annex 1 – Reduced Stability Protocol Design).

在可能的情况下，稳定性试验中包含的制剂批次应来自不同的原料药批次，以将原料药批次的变异性纳入考虑。应对制剂的每种规格、装量和容器密封系统进行稳定性研究，除非采用了简略方案设计（见附录1-简化稳定性方案设计）。

The primary stability batches of the drug substance and drug product should be representative of the clinical and production batches as described above. Additional development batches that are representative of the primary and production batches may also be included as supporting stability data.

原料药/原液和制剂的注册稳定性批次应代表上述临床和生产批次。代表申报批次和生产批次的其他开发批次也可作为支持性稳定性数据。

Refer to Table 2 below for additional considerations at time of selection of primary stability batches.

选择注册稳定性批次时的其他考虑因素见下表2。

Table 2: Considerations for Primary Stability Batches of Drug Substance and Drug Product

表2  原料药和制剂注册稳定性批次的考虑因素

1Refer to Annex 1 – Reduced Stability Protocol Design for details around when exceptions may apply 

1有关可能适用例外情况的详细信息，请参阅附录1-简化稳定性方案设计

2In accordance with ICH Q13, the definition of a pilot batch for synthetics does not apply for continuous manufacturing.

2根据ICH Q13，化学合成实体中试批次的定义不适用于连续生产。

When the long-term stability data do not cover the proposed re-test period or shelf life at the time the marketing application is submitted, refer to Section 15 - Stability Considerations for Commitments and Product Lifecycle Management for relevant commitments.

在提交上市申请时，长期稳定性数据未包含建议的复检期/有效期，相关承诺见第15节“关于承诺和产品生命周期管理的稳定性考虑因素”。

4.2  Considerations for Multiple Production Sites in the Initial Regulatory Submission

4.2  首次注册申报中对多个生产场地的考虑因素

The stability data from each site, provided in the initial regulatory submission should be proportionate to the overall product, process and facility risk and in accordance with regional requirements. For both synthetics and biologicals, when the product, process and production site are comparable, the re-test period and/or shelf life would not need to be re-established at an additional production site. An additional production site refers to any production site proposed in the initial regulatory submission other than the drug substance and drug product site where the original production scale batches are manufactured.

首次注册申报中提供的每个场地的稳定性数据应与整体的产品、工艺和设施风险成比例，并符合地区要求。对于化学合成实体和生物制品，当产品、工艺和生产场地具有可比性时，不需要在其他生产场地重新确定复检期和/或有效期。额外生产场地是指除用于生产初始生产规模批次的原料药和制剂场地外的，首次注册申报时建议的任何生产场地。

For synthetic chemical entities, a comparison of batch data of the primary batches with data from each production site should be provided in the regulatory submission. The amount of stability data provided for each production site depends on the risk associated with implementing each additional production site for the drug substance or drug product. A commitment stability study should be established for each production site in accordance with Section 15.1 - Commitment Stability Studies.  The number of production batches from each site in the commitment stability study can be fewer than three with a supporting scientific justification and risk assessment.

对于化学合成实体，应在注册申报中提供注册稳定性批次的批次数据与每个生产场地数据的比较情况。为每个生产场地提供的稳定性数据批次数量取决于与实施原料药或制剂的每个额外生产场地相关的风险。应根据第15.1节“承诺稳定性研究”，为每个生产场地建立承诺稳定性研究。在承诺稳定性研究中，每个生产场地的生产批次数量可以少于三个，但需要具有支持性的科学依据和风险评估。

For biologicals, the default minimum stability data presented for each production site, should be as outlined in Table 1 of Section 3.2 -Recommended Minimum Core Stability Data for the Standard Approach at Submission to Support Initial Re-test Period or Shelf Life. However, for biologicals with an enhanced level of product and process understanding, an alternative science- and risk-based approach may be justified for those additional sites that are receiving the transferred manufacturing process from an originating production site. A comparability assessment inclusive of accelerated and/or stressed condition stability results for commercial scale production batches manufactured at the proposed additional site relative to primary batches from the original production site should be provided (refer to ICH Q5E). Based on risk assessment that considers analytical comparability, process comparability and production site history for the manufacture of similar product types, sites receiving the transferred manufacturing process may initially propose a reduced number of production scale stability studies in the regulatory submission. When a reduced data set is justified, a commitment should be made to continue stability studies at each site through the proposed re-test period or shelf life for a total of three production scale batches in accordance with Section 15.1 - Commitment Stability Studies.

对于生物制品，每个生产场地的默认最低稳定性数据应如第3.2节中的表1“在申报时用于支持初始复检期/有效期标准方法的建议最低核心稳定性数据”所述一致。然而，对于产品和工艺已得到深入理解的生物制品而言，其他的、从初始生产场地接收和转移制造工艺的生产场地采用科学的、基于风险的替代方案却可能是更合理的。应提供可比性评估，包括在建议的额外场地生产的商业规模生产批次相对于初始生产场地的注册稳定性批次在加速和/或强力条件下的稳定性结果（见ICH Q5E）。根据风险评估，并考虑到分析的可比性、工艺的可比性和生产类似产品类型的生产场地历史，接收生产工艺转移的场地起初可在注册申报中建议减少生产规模稳定性研究的数量。如果简化的数据集是合理的，则应承诺按照第15.1节“承诺稳定性研究”，继续在每个生产场地进行总共三个生产规模批次的稳定性研究至拟定复检期/货架期。

4.3  Considerations for Vaccines

4.3  疫苗的考虑因素

In general, production scale batches are expected to be used to set shelf life of vaccines.  If non- production scale batches are used as primary batches, a justification should be based on product knowledge, comparability studies and risk. The remaining recommendations for primary batches for biologicals in Table 2 are also applicable to vaccines.

一般来说，使用生产规模批次来设定疫苗的有效期。如果使用非生产规模批次作为注册稳定性批次，则应根据产品知识、可比性研究和风险进行论证。表2中关于生物制品注册稳定性批次的其余建议也适用于疫苗。

4.4  Considerations for Continuous Manufacturing Processes

4.4  连续制造工艺的考虑因素

For guidance on selection of batches from a CM process, refer to ICH Q13 guideline. For recombinant protein biologicals, the use of a single start-up/shutdown sequence (refer to ICH Q13) to manufacture multiple primary drug substance stability batches is typically not applicable. Primary drug substance stability batches should be obtained from multiple harvests/cell bank thaws and should cover the entire cell culture duration. The drug product primary stability batches manufactured by CM processes should incorporate the variability described for different drug substance batches.

关于从连续制造（CM）工艺中批次选择的指导，请参考ICH  Q13指导原则。对于重组蛋白生物制品，使用单一启动/关闭顺序（见ICH Q13）来生产多个原液注册稳定性批次的方法通常不适用。原液注册稳定性批次应从多次收获/细胞库解冻中获得，并应涵盖整个细胞培养过程所用时间。通过CM工艺生产的制剂注册稳定性批次应包括不同原液批次的变异性。

5  CONTAINER CLOSURE SYSTEM

5  容器密封系统

A container closure system comprises the primary (in contact with the product) and the secondary packaging if the latter are functional (e.g., combination of a drug product with a medical device) or intended to provide additional protection to the drug product. The stability study design should consider and include the secondary package when it is protective or directly impacts the chemical, physical, or functional attributes, unless otherwise justified.

容器密封系统包括内包装（与产品直接接触）和次级包装，前提是后者具有一定功能（比如药械组合），或旨在为药品提供额外的保护。除非另有说明，否则当次级包装具有保护性或直接影响产品的化学、物理或功能属性时，稳定性研究设计应考虑并纳入次级包装。 

The primary stability studies for the drug substance should be conducted in a container closure system that is the same or representative of the packaging proposed for storage and distribution. The container closure system should be the same type and constructed of the same material as production batches (dimensions may be smaller). For the drug product, the commercial container closure is recommended to ensure that the proposed container closure system can adequately protect the dosage form, is compatible with the dosage form and will function in the manner for which it is designed through a product's intended shelf life. When applicable, impact of packaging components from which matter may migrate into the product (e.g., ink or adhesive from labels) should also be considered.

原料药的注册稳定性研究应在与拟用于贮藏和分销的包装相同或具有代表性的容器密封系统中进行。容器密封系统的类型和材质应与生产批次相同（尺寸可能更小）。对于制剂，建议采用商业容器密封系统，以确保建议的容器密封系统能够充分保护剂型、与剂型相容，并在产品预期有效期内按照设计的方式发挥作用。在适用的情况下，还应考虑可能迁移到产品中的物质的包装组件的影响（比如标签上的墨水或粘合剂）。

Changes in the quality of a product may occur due to the interactions between the drug substance or drug product and the respective container closure system, and the effect of such interactions on product stability should be evaluated. Any impact of container orientation on the critical quality attributes of the drug product should be assessed based on prior knowledge gained through development and/or as part of stability studies. For primary batches of liquids, solutions, semi-solids and suspensions, the product should be placed into an inverted (or horizontal) position and an upright (or vertical) position unless a worst-case orientation is justified with supporting data. However, when drug product-container closure

interactions cannot be excluded, stability studies should include samples maintained in both the inverted (or horizontal) position, as well as in the upright (or vertical) position (e.g., when storage orientation can have a significant effect on the delivered dose/repriming period of pressurised metered dose inhalers).

原料药或制剂同相应的容器密封系统之间的相互作用可能会导致产品质量发生变化，应评估这种相互作用对产品稳定性的影响。应根据通过开发获得的先验知识和/或作为稳定性研究的一部分，评估容器放置方向对制剂关键质量属性有何影响。对于液体、溶液、半固体和悬浮液的注册稳定性批次，产品应以倒置（或水平）放置和直立（或垂直）方式放置，除非有支持性数据证明提出的最差情况下的方向是合理的。然而，当无法排除制剂-容器密封系统相互作用时，稳定性研究应包括样品在倒置（或水平）位置和直立（或垂直）位置的贮藏（比如当贮藏方向对加压定量吸入器的剂量/再启动期有显著影响时）。

6  TESTING FREQUENCY

6  检测频率

The proposed protocol should align with the principles outlined in Section 13 - Data Evaluation and include sufficient timepoints to verify any proposed extrapolation or stability model, where appropriate for the product type.

建议方案应符合第13节“数据评价”中概述的原则，并包括足够的时间点，以验证适用于产品类型的任何建议外推或稳定性模型。

For primary stability studies, the frequency of testing should be sufficient to establish the stability profile of the drug substance or drug product. For a drug substance or drug product with a proposed re-test period/shelf life of 12 months or less, the frequency of testing at the long-term storage condition is recommended monthly for the first 3 months and at 3-month intervals thereafter. For cases when an intended re-test period/shelf life is very short, sufficient time points should be considered. For a drug substance or drug product with a proposed re-test period/shelf life greater than 12 months, the recommended frequency of testing at the long-term storage condition should normally be every 3 months over the first year, every 6 months over the second year and annually thereafter through to the end of the proposed re-test period/shelf life. Sterility testing or alternatives (e.g., container closure integrity testing) should be performed at a minimum annually, including initially and at the end of the proposed re-test period or shelf life.

对于注册稳定性研究，检测频率应足以建立原料药或制剂的稳定性特征。对于建议复检期/有效期为12个月或更短的原料药或制剂，在长期条件下建议前3个月每月检测一次，以后每隔3个月检测一次。对于预期的复检期/有效期较短的情况，应考虑足够的时间点。对于建议复检期/有效期大于12个月的原料药或制剂，在长期条件下的建议试验检测频率通常为第一年每3个月一次，第二年每6个月一次，此后每年一次，直至建议复检期/有效期结束。无菌测试或替代测试（如容器密封完整性测试）应至少每年进行一次，包括初始和建议的复检期/有效期结束时。

For studies under accelerated conditions, a minimum of three time points, including the initial and final time points, is recommended (e.g., 0, 3 and 6 months is recommended for a 6-month study). Where an expectation (e.g., based on development experience) exists that results from accelerated studies are likely to approach significant change criteria (refer to Section 13 – Data Evaluation) or likely to be out of specification, increased testing is recommended. Increased testing could be conducted either by (a) including an additional less severe temperature condition (i.e., intermediate) that may be better predictive of the long-term stability and /or (b) including an additional time point in the accelerated study design which may be earlier than the final time point. Note that this would not preclude following the recommendations in Section 13 - Data Evaluation, when deciding whether extrapolation is

applicable. At the intermediate storage condition, a minimum of four time points, including the initial and final time points (e.g., 0, 6, 9 and 12 months, from a 12-month study) is recommended.

对于加速条件下的研究，建议至少设置三个时间点，包括初次时间点和末次时间点（比如对一项考察期为6个月的研究而言，建议将时间点设置为0、3和6个月）。如果预计（比如基于开发经验）加速研究的结果可能接近显著变化标准（见第13节“数据评估”）或可能超出质量标准，则建议增加试验。增加的试验可通过以下方式进行：（a）纳入一个额外的不太严格的温度条件（即中间温度），这可能更好地预测长期稳定性；和/或（b）在加速研究设计中纳入一个额外的时间点，该时间点可能早于末次时间点。请注意，在决定外推是否适用时，并不排除要遵循第13节“数据评估”中的建议。在中间条件下，建议至少设置四个时间点，包括初次和末次时间点（比如对一项考察期为12个月的研究而言，建议将时间点设置为0、6、9和12个月）。

As discussed in Annex 1 - Reduced Stability Protocol Design and Section 15.3 - Product Lifecycle Stability Studies, a reduced testing frequency may be justified when potential stability-indicating CQAs show no change over time. The minimum testing frequency recommended in this section may not be applicable if alternative strategies are applied (refer to Section 13 – Data Evaluation and Annex 2 –Stability Modelling).

如附录1-简化稳定性方案设计和第15.3节“产品生命周期稳定性研究”中所述，当潜在指示稳定性的CQA未随时间变化时，可证明降低试验频率是合理的。如果采用替代策略，本节中推荐的最低试验频率可能不适用（见第13节“数据评估”和附录2-稳定性建模）。

7   STORAGE CONDITIONS

7   贮藏条件

7.1   General Considerations

7.1   一般考虑因素

 Stability of drug substances and drug products should be evaluated under storage conditions with appropriate tolerances that test for thermal and moisture stability and, if applicable, sensitivity to potential solvent loss. For sensitivity to light, refer to Section 8 – Photostability. The storage conditions and the duration of studies chosen should cover the intended storage and use, including considerations for shipment and any short-term storage condition (refer to Section 10 – Short-Term Storage Conditions). Advice on storage conditions to support an in-use period is detailed in Section 11 - In-Use Stability.

应在具有适当耐受性的贮藏条件下对原料药和制剂的稳定性进行评估，以检测其热稳定性和湿度稳定性，以及对潜在溶剂损失的敏感性（如适用）。关于对光的敏感性，请参阅第8节“光稳定性”。所选择的贮藏条件和研究持续时间应涵盖预期的贮藏和情况，包括对运输以及任何短期贮存条件的考虑（见第10节“短期条件”）。第11节“使用中稳定性”中详细介绍了支持使用中保存条件建议。

Testing at accelerated conditions or stress testing is essential to establish product stability information, such as to establish the degradation pathways and the intrinsic stability of the molecule, to confirm the stability-indicating nature of the analytical procedures (refer to Section 2 – Development Studies Under Stress and Forced Conditions and Section 3.3 – Stability-Indicating Critical Quality Attributes) and unintended excursions in storage conditions. Data generated under accelerated conditions may enable stability modelling. Accelerated conditions data may support extrapolation of the intended re-test period

and shelf life (refer to Section 13 – Data Evaluation).

加速条件下的试验或强制降解试验对于确定产品稳定性信息至关重要，例如确定降解途径、和分子的固有稳定性、确认分析方法的稳定性指示性质（见第2节“强力条件和强制降解条件下的开发研究”和第3.3节“指示稳定性的关键质量属性”）和贮藏条件下的非预期偏离。在加速条件下生成的数据可以实现稳定性建模。加速条件数据可支持对预期的复检期和有效期进行外推（见第13节“数据评估”）。

Since most biologicals are sensitive to physical conditions, data obtained under accelerated conditions may confirm the stability-indicating nature of the analytical procedures or help elucidate the degradation profile of a biological drug substance or drug product. Data from accelerated conditions could also support that a manufacturing change did not impact the stability profile.

由于大多数生物制品都对贮藏条件敏感，因此在加速条件下获得的数据可证实分析方法的稳定性指示性质，或有助于了解生物原料药或制剂的降解产物谱。加速条件下的数据也可为生产变更没有影响稳定性特征提供支持。

Where it can be justified that a proposed container closure system and conditions of storage afford sufficient protection against high and low humidity conditions, stability studies at different relative humidities can usually be omitted. Appropriate stability data under recommended storage conditions should be provided if containers other than impermeable containers are used.

如果能够证明建议的容器密封系统和贮藏条件在高湿度和低湿度条件下提供了足够的保护，则通常可以省略不同相对湿度下的稳定性研究。如果使用非渗透性容器以外的容器，应提供推荐贮藏条件下的适当稳定性数据。

The storage conditions to be applied to the different stability studies are detailed in the sections below.The equipment utilised should be capable of controlling the storage condition within the ranges defined in this guideline. The actual temperature and humidity (when controlled) should be monitored during stability storage. Short-term spikes due to opening of doors of the storage facility are accepted as unavoidable. The effect of excursions due to equipment failure should be addressed and reported if judged to affect stability results. Excursions that exceed the defined tolerances for more than 24 hours should be described in the study report and their effect assessed.

适用于不同稳定性研究的贮藏条件详见以下章节。所使用的设备应能将贮藏条件控制在本指导原则规定的范围内。在稳定性贮藏期间，应在实际温度和湿度（得到控制时）对其进行监测。由于贮藏设施的门打开而导致出现的短期峰值被认为是不可避免的。如果判断设备故障导致的偏移影响到稳定性结果，则应说明并报告该偏移的影响。应在研究报告中描述超过规定24小时的偏移，并评估其影响。

Alternative storage conditions can be used if justified. Recommendations are applicable to both synthetic chemical entities and biological products, unless otherwise specified.

如果合理，可以使用其他贮藏条件。除非另有规定，否则建议适用于化学合成实体和生物制品。

7.2   Considerations for Products Intended to be Stored at Room Temperature

7.2   拟在室温下贮藏产品的注意事项

The recommended storage conditions that are applicable to each climatic zone are outlined in the table below.

下表列出了适用于每个气候带的推荐贮藏条件。

Table 3: Storage Condition Recommendations for Each Climatic Zone1

表 3各气候带的贮藏条件建议 

1Specific regional requirements for more severe storage conditions may however apply

1然而，对于更苛刻贮藏条件，可能适用特定区域要求

2Refer to Section 1.3 – Introduction to Guideline and General Principles

2参见第1.3节-指导原则和一般原则简介

The applicant should determine and justify the long-term stability studies conditions to be performed.

申请人应确定并证明要进行的长期试验的条件。

In general, it is acceptable for stability information to be generated under a more severe climatic zone storage condition already defined in Table 3 to support the labelling. Testing at a more severe long-term condition (e.g., 30°C ±2°C/75% RH ±5% RH) could be justified as it encompasses all climate zones that a drug substance or drug product may be exposed to. However, if it is demonstrated that the drug substance or drug product will not remain within its acceptance criteria when stored at the more severe condition (e.g., 30°C ±2°C/75% RH ±5% RH) for the duration of the proposed re-test period or shelf life, the following are some approaches to consider:

一般而言，在表3中定义的更严酷的气候带贮藏条件下生成的稳定性信息是可以接受的，以支持说明书及标签。在更苛刻的长期条件下（如30°C±2°C/75%RH±5%RH）进行试验是合理的，因为该条件涵盖了原料药或制剂可能暴露的所有气候带。但是，如果证明原料药或制剂在更苛刻的条件下（如30°C±2°C/75%RH±5%RH）在建议的复检期或有效期内贮藏时不能保持在其可接受标准范围内，则应考虑以下方法：

alternative long-term storage condition for the intended climatic zone.

预期气候带的替代长期条件

a minimal reduction in re-test period or shelf life.

复检期或有效期的最小缩减 

evaluation of stability in an alternative container closure system.

替代容器密封系统的稳定性评估 

evaluation of formulation and manufacturing process options.

剂型和生产工艺方案的评估

When long-term studies are conducted at 25°C ±2°C/60% RH ±5% RH and a significant change occurs at any time during 6 months’ testing under accelerated conditions, additional testing at the intermediate storage condition should be conducted and evaluated against significant change criteria (refer to Section 13 – Data Evaluation).

当在25°C±2°C/60%RH±5%RH条件下进行长期研究，并在加速条件下6个月的试验期间的任何时间发生显著性变化时，应在中间条件下进行额外试验，并根据显著性变化标准进行评估（参见第13节-数据评估）。

If 30°C ±2°C/65% RH ±5% RH or 30°C ±2°C/75% RH ±5% RH is the long-term condition, there is no intermediate condition defined.

如果30°C±2°C/65%RH±5%RH或30°C±2°C/75%RH±5%RH为长期条件，则无需定义中间条件。

For Climatic Zone III stability studies, an alternative approach to studying at the reference relative humidity (e.g., 35% RH ± 5% RH) can be achieved by performing the stability studies under higher relative humidity (e.g., 65% RH ± 5% or 75% RH ± 5%) through mathematical calculation. This can be achieved by experimentally determining the permeation coefficient for the container closure system (e.g., refer to Example 1 in Section 7.2.2 – Storage Conditions for Products Packaged in Semi- Permeable Containers).

对于气候带III 的稳定性研究， 可以通过数学计算在较高相对湿度（ 如65%RH±5% 或

75%RH±5%）下进行稳定性研究，从而实现参考相对湿度（如35%RH±5%RH）下的替代研究方法。这可以通过实验确定容器密封系统的渗透系数来实现（例如，参考第7.2.2节“包装在半渗透性容器中的产品的贮藏条件”中的示例1）。

7.2.1   Storage Conditions for Products Packaged in Impermeable Containers

7.2.1   包装在非渗透性容器中的产品的贮藏条件

Since drug substance and drug products packaged in impermeable containers (e.g., aluminium /aluminium foil blister, sealed glass container) provide a permanent barrier to passage of moisture or solvent, sensitivity to moisture or potential for solvent loss is not a concern. Thus, stability studies for products stored in impermeable containers can be conducted under any humidity condition.

由于包装在非渗透性容器（如铝/铝箔泡罩、密封玻璃容器）中的原料药和制剂为水分或溶剂通过提供了永久性屏障，因此对水分的灵敏度或溶剂损失的可能性不是问题。 因此，对于贮藏在非渗透性容器中的产品，可以在任何湿度条件下进行稳定性研究。

7.2.2  Storage Conditions for Products Packaged in Semi-Permeable Containers

7.2.2  包装在半渗透性容器中的产品的贮藏条件

Sensitivity to moisture or potential for solvent loss is a concern for drug substance and drug products packaged in semi permeable containers. Semi-permeable containers can allow the passage of moisture, solvent, or gases while preventing solute loss. The mechanism for solvent transport occurs by absorption into one container surface, diffusion through the bulk of the container material and desorption from the other surface. Transport across the container wall is driven by a partial pressure gradient.

对于包装在半渗透性容器中的原料药和制剂，对水分的灵敏度或溶剂损失的可能性是一个问题。半渗透性容器可以允许水分、溶剂或气体通过，同时防止溶质损失。溶剂运输的机制是通过吸收到一个容器表面、通过容器材料的本体扩散以及从另一个表面解吸而发生的。通过容器壁的运输是由分压梯度驱动的。

Aqueous-based products packaged in semi-permeable containers should be evaluated for potential water loss in addition to physical, chemical, biological and microbiological stability. This evaluation should be carried out under conditions of low relative humidity, as discussed below. Ultimately, it should be demonstrated that aqueous-based products stored in semi-permeable containers can withstand low relative humidity environments.

除物理、化学、生物和微生物稳定性外，还应评估包装在半渗透性容器中的水基产品的潜在失水情况。应在低相对湿度条件下进行该评估，如下所述。最终，应证明贮藏在半渗透性容器中的水基产品能够承受低相对湿度环境。

For non-aqueous, solvent-based products, comparable approaches can be developed and applied.

对于非水性溶剂型产品，可以开发和应用类似的方法。

Table 4: Storage Condition Recommendations for Semi-Permeable Containers

表 4   半渗透性容器的贮藏条件建议

在更严苛的长期条件下进行试验是合理的，如30°C±2°C/35%RH±5%RH。

A 5% loss in water from its initial value is considered a significant change for a product packaged in a semi-permeable container after an equivalent of 3 months’ storage at 40°C ± 2°C /NMT 25% RH.However, for small containers (1 mL or less) or unit-dose products, a water loss of 5% or more after an equivalent of 3 months’ storage at 40°C ± 2°C /NMT 25% RH may be acceptable, if justified.

对于包装在半渗透性容器中的产品，在40°C±2°C/NMT 25% RH条件下贮藏3个月后，其水分含量与初始值相比损失5%被视为显著变化。但是，对于小容器（1  mL或更少）或单位剂量制剂，在40°C±2°C/NMT 25% RH条件下贮藏3个月后，失水量≥5%是可以接受的（如果证明合理）。

A significant change in water loss alone under the accelerated condition does not necessitate testing at the intermediate storage condition. However, data should be provided to demonstrate that no significant water loss has been observed throughout the proposed re-test period / shelf life if stored at 25°C ±2°C / 40% RH ±5% RH.

仅在加速条件下失水量发生显著变化时，无需在中间条件下进行试验。但是，应提供数据证明在25°C±2°C/40%RH±5%RH条件下贮藏时，在整个拟议的复检期/有效期内未观察到显著的失水。

When long-term studies are conducted at 25°C ± 2°C/40% RH ± 5% RH, additional testing at the intermediate storage condition should be performed to evaluate the temperature effect at 30°C if significant change other than water loss occurs during the 6 months testing at the accelerated condition.

当在25°C±2°C/40%RH±5%RH条件下进行长期研究时，如果在加速条件下的6个月试验期间发生失水以外的显著变化，则应在中间条件下进行额外试验，以评估30°C下的温度影响。

If 30°C ±2°C/35% RH ±5% RH is the long-term condition, there is no intermediate condition.

如果长期条件为30°C±2°C/35%RH±5%RH，则无需设置中间条件。

An alternative approach to performing studies at the reference relative humidity as recommended in Table 5 is performing the stability studies under higher relative humidity and deriving the water loss at the reference relative humidity through calculation. This can be achieved by experimentally determining the permeation coefficient for the container closure system (e.g., as shown in the illustrative example below, using the calculated ratio of water loss rates for the container closure system between the two relative humidity conditions at the same temperature). The permeation coefficient for a container closure system can be experimentally determined by using the worst-case scenario (e.g., the most diluted of a series of concentrations) for the proposed drug product.

在表5中推荐的参考相对湿度下进行研究的另一种方法是在较高相对湿度下进行稳定性研究，并通过计算得出在参考相对湿度下的失水量。这可以通过实验确定容器密封系统的渗透系数来实现（例如，如以下说明性示例所示，通过计算在相同温度下两种相对湿度条件下容器密封系统的失水率的比率）。容器密封系统的渗透系数可以通过使用拟申报制剂的最差情况（例如，一系列浓度的最大稀释度）进行实验确定。

Example 1. An approach for determining water loss:

示例1测定失水的方法：

For a product in a given container closure system, container size and fill, an appropriate approach for deriving the water loss rate at the reference relative humidity is to multiply the water loss rate measured at an alternative relative humidity at the same temperature by a water loss rate ratio determined experimentally shown in Table 5 below. A linear water loss rate at the alternative relative humidity over the storage period should be demonstrated.

对于在特定容器密封系统、容器尺寸和装量的产品，推导参考相对湿度下的失水率的适当方法是将相同温度下在替代相对湿度下测得的失水率乘以通过实验确定的失水率比（见下表5）。应证明贮藏期间在替代相对湿度下的线性失水率。

For the below illustrative example, at a given temperature (e.g., 40°C) the water loss rate determined experimentally for the proposed container closure system during storage at NMT 25% RH is the water loss rate measured at 75% RH multiplied by 3.0, the corresponding water loss rate ratio.

对于下面的说明性示例，在设定的温度（例如40°C）下，通过实验确定的拟定的容器密封系统在不超过25%RH下贮藏期间的失水率是在75%RH下测得的失水率乘以3.0，即相应的失水率比。

Table 5: Example of Ratio of Water Loss Calculations

表 5失水率计算示例

1失水率= （100 - 参考%RH） / （100 - 替代%RH）

The ratios described in Table 5 above are for illustrative purposes. Actual ratios for water loss rates determined experimentally for the proposed container closure system under various relative humidity conditions should be provided.

上述表5中描述的比率仅用于说明目的。应提供在各种相对湿度条件下，通过实验测定的拟定容器密封系统失水率的实际比率。

7.3  Considerations for Refrigerated Temperature Storage

7.3  冷藏温度贮藏的注意事项

Recommendations for drug substance and drug products intended for long-term storage under

refrigerated conditions are provided below. Accelerated conditions are intended to demonstrate the effect of temperature, and active humidity control may not be needed when justified.

对拟在冷藏条件下长期贮藏的原料药和制剂的建议如下。加速条件旨在证明温度和主动湿度控制的影响，如果合理，可能不需要。

Table 6: Storage Under Refrigerated Conditions

表 6 冷藏条件下的贮藏

For an aqueous-based product packaged in a semi-permeable container, appropriate information should be provided to assess the extent of water loss.

对于包装在半渗透性容器中的水性产品，应提供适当的信息以评估失水程度。

For products stored under refrigerated conditions, when a significant change or out of specification occurs within the first 3 months of testing under accelerated conditions, a discussion should be provided to address the effect of shipment and handling (refer to Section 14 – Labelling).

对于在冷藏条件下贮藏的产品，当在加速条件下试验的前3个月内发生显著变化或超标时，应进行讨论以说明运输和搬运的影响（参见第14节 - 说明书及标签）。

For synthetics, it is considered unnecessary to continue to test a product under accelerated conditions through 6 months when a significant change has occurred within the first 3 months.

对于合成制剂，当在前3个月内发生显著变化时，则认为无必要在加速条件下继续检测产品直至6个月。

7.4  Considerations for Frozen Temperature Storage

7.4  冷冻温度贮藏的注意事项

Recommendations for drug substance and drug products intended for long-term storage under frozen conditions (as determined for the product) are provided below.

对拟在冷冻条件下长期贮藏的原料药和制剂（根据产品确定）的建议如下。

Table 7: Storage in a Freezer or below -20°C

表 7 冷冻柜或-20°C 以下贮藏

Testing at accelerated or stress conditions (e.g., 5°C ± 3°C or 25°C ± 2°C or 30°C ± 2°C or any appropriate condition based on the intrinsic properties of the drug substance or drug product) for an appropriate time period should be conducted to address the effect of short-term excursions outside the proposed label storage condition (refer to Section 14.1- Excursions Outside of a Labelling Claim).

应在加速或下（如5°C±3°C、25°C±2°C、30°C±2°C或基于原料药或制剂内在特性的任何适当条件）进行适当的时间周期的试验，以研究短期偏移拟定说明书及标签贮藏条件的影响（参见第14.1节 - 说明书及标签声明之外的偏移）。

8   PHOTOSTABILITY

8   光稳定性

8.1   Purpose of Photostability Testing

8.1   光稳定性试验的目的

This section addresses the principles governing the generation of photostability information in initial regulatory submission and for lifecycle management changes.

本节介绍了初始注册申报和全生命周期管理中的中光稳定性信息的指导原则。

The intrinsic photostability characteristics of a product should be evaluated to demonstrate that light exposure does not result in unacceptable change that could compromise product efficacy or patient safety. Normally, photostability testing is carried out on a single representative batch suitable for the purpose of the study. Repeating a photostability study may be required in response to relevant changes (e.g., in the formulation, container closure system and in-use conditions) when the photostability characteristics and controls established at the time of the initial regulatory submission are assessed to be impacted (refer to Section 15.3 – Product Lifecycle Stability Studies).

应评估产品的固有的光稳定性特性，以证明光暴露不会导致可能危及产品有效性或患者安全性的不可接受的变化。通常，光稳定性试验是在适合研究目的的单个代表性批次上进行的。当评估初始监管申报时建立的光稳定性特征和控制措施会受到影响时，可能需要重复光稳定性研究以应对相关变化（例如剂型、容器密封系统和使用条件的变化）（参见第15.3节-产品生命周期稳定性研究）。

Two specific studies are performed to generate and evaluate photostability data:

为生成和评估光稳定性数据，进行了两项特定研究：

Forced photodegradation study – A study that may be an integral part of forced degradation evaluation and may be undertaken in the development phase. This information may be used to evaluate the overall photosensitivity of the drug substance and drug product for method development purposes, degradation pathway elucidation and to inform control strategies (refer to Section 2-Development Stability Studies Under Stress and Forced Conditions).

强制光降解研究 - 可能是强制降解评估的一个组成部分，并可在开发阶段进行。该

信息可用于评估原料药和制剂的整体光敏性，用于方法开发、降解途径阐明和控制策略（参见第2节 - 影响因素和强制降解条件下的开发稳定性研究）。

Confirmatory photostability studies – Studies performed when a risk of photodegradation has been identified. The purpose of the studies is to establish the photostability characteristics to understand the ability of the primary or secondary packaging material to protect light-sensitive products and the impact of light on product quality through manufacture, storage, transportation and in-use. These data may also support labelling (e.g., storage statements).

确认光稳定性研究 - 当确定存在光降解风险时进行的研究。研究的目的是确定光稳

定性特性，了解内包装或外包装材料在生产、贮藏、运输和使用过程中保护光敏感产品的能力以及光对产品质量的影响。这些数据也可支持说明书及标签信息（例如，存储说明）。

A systematic approach to photostability testing is recommended, covering as appropriate:

建议采用系统方法进行光稳定性试验，包括（如适用）：

i)  Tests on the drug substance and/or drug product directly exposed; and if necessary.

i）  对直接暴露的原料药和/或制剂的检测；如有必要。

ii)  Tests on the drug substance and/or drug product in the primary packaging; and if necessary.

ii） 对内包装中的原料药和/或制剂的检测；如有必要。

iii) Tests on the drug substance and/or drug product in the secondary packaging.

iii）对外包装中原料药和/或制剂的检测。

Normally, the studies are carried out in a sequential manner starting with testing the sample directly exposed then progressing as necessary to the drug substance and/or drug product in the primary packaging and then in the secondary packaging, if applicable. If the product is known to be photosensitive, e.g., most biologicals, parallel testing can be carried out as a science- and risk -based approach. The extent of testing should be established by assessing whether acceptable change or no change has occurred at the end of the light exposure testing. Acceptable change is a change within limits previously justified by the applicant. If a non-acceptable change is observed, a change in the packaging or the formulation should be proposed. Testing should progress until the results demonstrate that the drug substance and/or drug product is adequately protected from exposure to light (refer to Figure 3 - Decision Flow Chart for Systematic Photostability Testing).

通常情况下，研究是按顺序进行的，首先测试直接暴露的样品，然后根据需要对内包装中的原料药和/或制剂进行检测，然后对外包装中的原料药和/或制剂进行检测（如适用）。如果已知产品（例如大多数生物制品）具有光敏性，则可以基于科学和风险进行平行试验。应通过评估光暴露试验结束时是否发生可接受的变化或无变化来确定试验范围。可接受的变化是指在申请人先前证明的限度范围内的变化。如果观察到不可接受的变化，应提议对包装或剂型进行变更。试验应持续进行，直至结果证明原料药和/或制剂充分避光（参见图3 - 系统光稳定性试验的决策流程图）。

Figure 3: Decision Flow Chart for Systematic Photostability Testing

图 3 系统光稳定性试验的决策流程图

8.2  Forced Photodegradation

8.2  强制光降解

As forced photodegradation is an integral part of forced degradation strategy, details on the concepts,study design considerations and interpretation of results can be found in Section 2- Developmental Studies Under Stress and Forced Conditions.  For details on radiation sources and light exposure conditions for forced photo degradation studies refer to Section 8.4 – Radiation Source and Light Exposure.

由于强制光降解是强制降解策略的组成部分，有关概念、研究设计注意事项和结果分析的详细信息，请参见第2节 – 影响因素和强制降解条件下的开发研究。有关强制光降解研究的辐射源和光暴露条件的详细信息，请参见第8.4节 - 辐射源和光暴露。

If the forced photodegradation study is combined with the confirmatory photostability study, the specific sample considerations provided in Section 8.3 - Confirmatory Photostability should be considered, e.g., for solid substances.

如果结合强制光降解研究与确认光稳定性研究，应考虑第8.3节 - 确认光稳定性中提供的特定样本考虑因素，例如对于固体物质。 

8.3  Confirmatory Photostability

8.3  确认光稳定性

The confirmatory studies are used to determine whether special precautionary measures are needed in manufacturing, formulation of the product, long-term storage or in-use period (refer to Section 11 - In-Use Stability) and if a light-resistant container closure system and/or special labelling information are needed. Guidance is provided on determining whether a confirmatory study should be performed, study design and interpretation of results (refer to Figure 3- Decision Flow Chart for Systematic Photostability Testing).

确认研究用于确定在生产、产品剂型、长期贮藏或使用期间是否需要采取特殊预防措施（参见第11节 - 使用中稳定性），以及是否需要避光容器密封系统和/或特殊说明书及标签信息。为确定是否应进行确认研究、研究设计和结果分析提供了指导（参见图3 - 系统光稳定性试验的决策流程图）。

For synthetic chemical entities, confirmatory photostability testing is generally performed on one batch of the drug substance and the drug product, while for biologicals, testing is generally performed on one batch of the drug product. Confirmatory testing is typically conducted in the primary container closure system and including, if necessary, secondary packaging. Alternative science- and risk-based approaches may be considered when appropriately justified and may include scenarios where confirmatory photostability testing is not required. For example, if no photodegradation is observed in the fully exposed drug substance sample or the fully exposed drug product sample, no further testing as part of the confirmatory study is needed. For some products where it has been demonstrated that the

primary packaging is completely impenetrable to light (e.g., aluminium tubes cans or foil/foil blisters) testing should normally only be conducted on directly exposed drug product.

对于化学合成实体，通常对一批原料药和制剂进行确认光稳定性试验，而对于生物制品，通常对一批制剂进行试验。通常在内容器密封系统中进行确认试验，如有必要，包括外容器密封系统。在适当证明合理时，可以考虑替代科学和基于风险的方法，并且可能包括无需进行确认光稳定性试验的情况。例如，如果在完全暴露的原料药样品或完全暴露的制剂样品中未观察到光降解，则无需作为确认研究一部分进行进一步试验。对于某些已证明内包装完全不透光的产品（如铝管、罐或箔/箔泡罩），通常仅对直接暴露的制剂进行试验。

If the results from the confirmatory study batch are not conclusive in terms of photostability or photolability, testing of additional batches or a new study design should be considered.

如果确认研究批次的结果在光稳定性或光敏性方面无法得到结论，则应考虑对其他批次进行试验或采用新的研究设计。

As a direct challenge for samples of solid products, an appropriate amount of sample should be taken and placed in a glass or plastic dish spread in a single layer and protected with a suitable transparent cover, if considered necessary. Tablets and capsules should be spread in a single layer. Solids, except tablets or capsules, should be spread across the dish to give a thickness of typically not more than 3 millimetres. When direct exposure is not feasible (e.g., liquids, or products sensitive to non-light induced oxidation), the sample should be placed in a suitable protective inert transparent container (e.g., quartz). In general, the samples should be positioned to provide maximum area of exposure to the light source.

作为对固体产品样品的直接挑战，应采集适量的样品，并将其放置在单层铺开的玻璃或塑料皿中，并在必要时用适当的透明盖保护。片剂和胶囊应单层铺开。固体样本（除片剂或胶囊外）应在培养皿上铺开，厚度通常不超过3毫米。当直接暴露不可行时（例如，液体或对非光致氧化敏感的产品），样品应放置在合适的保护性惰性透明容器中（如石英）。一般而言，样品应放置在能提供最大光源区域面积的位置。

If testing of the drug product in the primary or secondary packaging is needed, the samples should be placed horizontally or transversely with respect to the light source, providing the most uniform exposure of the samples. Some adjustment of testing conditions may have to be made when testing large-volume containers (e.g., dispensing packs). In general, samples with the greatest light exposure surface in the container should be tested.

如果需要对内包装或外包装中的制剂进行检测，样品应相对于光源水平或横向放置，以使样品暴露最均匀。在测试大体积容器（例如，分发包装）时，可能需要对测试条件进行一些调整。一般而言，应检测容器中受光面最大的样品。

At the end of the exposure period, representative samples (taking homogeneity of light exposure into consideration) should be examined by analytical procedures (suitable for intended purpose) for any changes in physical, chemical or biological properties, including assay or potency and degradants that are determined from the characterisation studies that are likely to arise from photochemical degradation.

When powder samples are involved, sampling should ensure that a representative portion is used in individual tests. For solid oral dosage form products (e.g., tablets, capsules), testing should be conducted on a suitable number of units (statistical sampling approaches may be used). Similar sampling considerations, such as homogeneity or solubilisation of the entire sample, apply to other materials that may not be homogeneous after exposure (e.g., creams, ointments, suspensions).

在暴露期结束时，应采用分析方法（适用于预期目的）检查代表性样品（考虑光暴露的均一性），以确定物理、化学或生物特性、包含含量或效价以及降解物的任何变化。这些变化由特性鉴定研究确定，可能由光化学降解引起。当涉及粉末样品时，取样应确保在单个试验中使用具有代表性的部分。对于固体口服剂型产品（如片剂、胶囊），应在适当数量的单位上进行检测（可采用统计抽样方法）。类似的取样考虑因素，如整个样品的均匀性或溶解性，适用于暴露后可能不均匀的其他材料（如乳膏、软膏、混悬液）。

暴露样品的分析应与用作暗对照的任何受保护样品（如果在试验中使用）的分析同时进行。

The analysis of the exposed sample should be performed concomitantly with that of any protected samples used as dark controls if these are used in the test. When evaluating the results of photostability studies to determine whether change due to exposure to light is acceptable, it is important to consider the results obtained from other formal stability studies to assure that the product will be within proposed specifications during the re-test period or shelf life. Depending on the extent of change or failure to meet acceptance criteria, special precautions may be needed to mitigate exposure to light, like formulation change, redesign of container closure system (including secondary packaging), a reduced re-test period or shelf life of drug substance or drug product (in conjunction with long term stability data) or change in labelling for storage and use (refer to Figure 3 - Decision Flow Chart for Systematic Photostability Testing).

在评价光稳定性研究结果以确定是否可以接受光暴露引起的变化时，重要的是要考虑从其他正式稳定性研究中获得的结果，以确保产品在复检期或有效期内符合拟定的质量标准。根据变化程度或不符合可接受标准的情况，可能需要采取特殊的预防措施来减少光暴露，如剂型变更、重新设计容器密封系统（包括外包装）、缩短原料药或制剂的复检期或有效期（结合长期稳定性数据）或贮藏和使用说明书及标签的变更（参见图3 - 系统光稳定性试验的决策流程图）。

8.4   Radiation Source and Light Exposure

8.4   辐射源和光暴露

This section describes the radiation source and light exposure that can be used to support forced photodegradation studies and confirmatory photostability studies. For forced degradation studies a variety of exposure conditions may be used, depending on the photosensitivity of the product and the intensity of the light sources used.  Confirmatory photostability studies should be based on light exposure possible during manufacture, storage, distribution and in-use.

本节描述了可用于支持强制光降解研究和确认光稳定性研究的辐射源和光暴露。对于强制降解研究，可以使用各种暴露条件，具体取决于产品的光敏性和所用光源的强度。确认光稳定性研究应基于生产、贮藏、运输和使用期间可能的光暴露。

In photostability studies, it is important to consider the spectral characteristics of the light, cumulative light exposure and temperature, as the combination of these factors will influence the rate of photodegradation and the design of the study.

在光稳定性研究中，重要的是考虑光的光谱特征、累积光暴露和温度，因为这些因素的组合将影响光降解速率和研究设计。

The light sources described below are considered appropriate for photostability testing. Alternative light sources may be applicable when justified. The applicant should either maintain appropriate temperature control to minimise the effect of localised temperature changes or include a dark control in the same environment unless otherwise justified. The applicant may rely on the spectral distribution specification of the light source manufacturer for the following options:

下述合适的光源可用于光稳定性试验。如合理，可采用替代光源。除非另有说明，否则申请人应保持适当的温度控制，以尽量减少局部温度变化的影响，或在相同环境中设置暗对照。申请人可根据光源制造商的光谱分布规范选择以下方案：

Option 1:

选项 1：

For light exposure similar to the D65 (outdoor daylight) emission standard (as currently defined in,ISO/CIE 18909:2022) (17), an artificial daylight fluorescent lamp combining visible and ultraviolet(UV) outputs, xenon or metal halide lamp, including appropriate filter(s) is recommended as radiation light source.

对于类似于D65（室外日光）排放标准（目前定义见ISO/CIE  18909:2022）（17）的光暴露，建议使用结合可见光和紫外线（UV）输出的人造日光荧光灯、氙气或金属卤化物灯，包括采用适当的滤光器作为辐射光源。

Option 2:

选项 2：

A combined exposure to both cool white fluorescent and near ultraviolet lamp, which is capable of producing a light exposure similar to the ID65 (indoor daylight) emission standard, for which the ultraviolet lamp has at least 25% of the ultraviolet-A between 320 and 360 nm and at least 25% is between 360 and 400 nm.

组合暴露于冷白色荧光灯和近紫外线灯，其能够产生类似于ID65（室内日光）发射标准的光暴露，对于该标准，紫外线灯在320 nm和360 nm之间具有至少25%的UV-A并且至少25%是在360和400nm之间。

Option 3:

选项 3：

Ambient/mild light conditions (predominantly light >400 nm during manufacturing, processing and in- use), for which a fluorescent or LED lamp is recommended.

采用环境/温和光照条件（制造、加工和使用过程中的主要光线>400 nm），建议使用荧光灯或LED灯。

Light exposure for forced photodegradation studies may require higher light intensity, such as doubling the levels used in confirmatory studies. However, depending on the photosensitivity of the product, milder conditions may be more suitable to avoid extensive decomposition. For example, samples might be exposed to ambient/mild light conditions, typically ranging from 43-260 ×103 lux hours for >400 nm and 0.3-3 Wh/m2 for 350 – 400 nm, over an exposure period of 1 to 7 days.

强制光降解研究的光暴露可能需要更高的光强度，例如将确认研究中使用的光强度水平加倍。然而，根据产品的光敏性，较温和的条件可能更为适宜，以避免过度分解。例如，样品可能暴露在环境/温和的光照条件下，暴露时间为1至7天，通常范围为43-260×103勒克斯小时（>400 nm）和0.3-3 Wh/m2（350-400 nm）。

In confirmatory studies, to assess the effects of light under controlled conditions during manufacturing, storage and in use, samples maybe exposed to light providing an overall illumination of not less than 1.2 million lux hours and an integrated near ultraviolet energy of not less than 200 Wh/m2. When justified, alternate approaches may also be appropriate depending on the photosensitivity of the product, the light source selected, manufacturing conditions and packaging. The overall light exposure during manufacture can be determined by measuring the light exposure and defining the average light exposure and UV energy (e.g., in Luxh and/or Wh/m2). The average light exposure reading, with the worst-case light exposure time, could be used to define light exposure time and distance to light source

considerations in the confirmatory study.

在确认研究中，为了评估在生产、贮藏和使用过程中受控条件下的光照影响，可将样品暴露于总照度不低于120万勒克斯小时且综合近紫外能量不低于200 Wh/m2的光照下。在合理的情况下，根据产品的光敏性、选择的光源、制造条件和包装，也可采用合适的替代方案。可以通过测量光暴露并定义平均光暴露和UV能量（例如，以Luxh和/或Wh/m2为单位）来确定制造过程中的总体光暴露。在确认性研究中，可使用最差情况下的光照暴露时间的平均光照读数来界定光照暴露时间和与光源的距离。

9   STABILITY CONSIDERATIONS FOR PROCESSING AND HOLDING TIMES FOR INTERMEDIATES

9   中间产品加工和贮藏时间的稳定性考虑因素

9.1  General Considerations

9.1  一般考虑因素

Good manufacturing practices (GMP) and good distribution practices (GDP) require that controls are in place to ensure that intermediates (i.e., drug substance intermediates and drug product intermediates(including bulk drug products)) are manufactured and stored under appropriate conditions. Storage and/or transportation arrangements should not have deleterious effects on the subsequent processing,stability, safety, or quality of intermediates, in accordance with good distribution practices.

药品生产质量管理规范（GMP）和良好分销规范（GDP）要求采取控制措施，以确保在适当的条件下生产和贮藏中间产品（即原料药中间产品和制剂中间产品（包括散装制剂））。根据良好分销规范，贮藏和/或运输安排不应对中间产品的后续加工、稳定性、安全性或质量产生不利影响。

The processing time can be considered as the established time period needed to perform a manufacturing step or series of steps and should take into consideration compatibility with manufacturing equipment.Whereas the holding time can be considered as the established time period for which materials (e.g.,dispensed raw materials, drug substance intermediates and drug product intermediates) are awaiting further processing or packaging in the final container closure system and may be held and/or transported under specified conditions. For such intermediates, maximum holding times should be established to ensure their quality and that they can be held, pending the next processing step, without having results outside the established control strategy. Intermediates should not be used beyond the established holding times. A written protocol, procedure or program for the holding time studies should be followed taking into consideration the principles described in Section 3.1 – General Principles.

加工时间可视为执行一个生产步骤或一系列步骤所需的既定时间段，并应考虑与生产设备的相容性。鉴于贮藏时间可视为物料（例如，分配的原料、原料药中间产品和制剂中间产品）在最终容器密封系统中等待进一步加工或包装并可在特定条件下保存和/或运输的既定时间段。对于此类中间产品，应确定最长贮藏时间，以确保其质量，并确保其可贮藏至下一个加工步骤之前，而不会产生超出既定控制策略的结果。中间产品的使用不应超过规定的贮藏时间。考虑到第3.1节 - 一般原则中描述的原则，应遵循贮藏时间研究的书面方案、规程或计划。

The data used to establish the holding time should cover the proposed holding times for the

intermediates and the stability studies should be performed at relevant temperature and humidity conditions to support the expected storage conditions for the drug substance or drug product intermediate. If the temperature and humidity conditions used during these studies do not correspond with the storage conditions described in Section 7 - Storage Conditions of this guideline, other conditions should be justified. If the product is sensitive to light exposure that may occur during storage, data should confirm that controls are sufficient to limit exposure to acceptable levels as described in Section 8 - Photostability. If more than one production site is involved, the stability studies should also consider transportation of the intermediates. For consideration of reduced design, the principles of Annex 1 - Reduced Stability Protocol Design may apply. Cumulative hold times are generally assessed as part of process validation. If a stability risk is identified, a cumulative holding time study may be necessary.

用于确定贮藏时间的数据应涵盖中间产品的建议贮藏时间，稳定性研究应在相关温度和湿度条件下进行，以支持原料药或制剂中间产品的预期贮藏条件。如果这些研究中使用的温度和湿度条件与本指导原则第 7 节 “贮藏条件”中描述的贮藏条件不一致，则应证明其他条件的合理性。如果产品对贮藏期间可能发生的光暴露敏感，则应提供数据确认控制措施足以将光暴露限制在可接受水平，如第8节 - 光稳定性中所述。如果涉及多个生产场地，稳定性研究还应考虑中间产品的运输。考虑简化设计时，附录1-简化稳定性方案设计的原则可能适用。累积贮藏时间通常作为工艺验证的一部分进行评估。如果发现稳定性风险，可能需要进行累积贮藏时间研究。

For drug substance and drug product intermediates that are packaged and stored outside of the

manufacturing process activities or that are purchased as such, it may be appropriate to establish a re-test period or shelf life, as applicable, rather than a holding time. In these situations, the recommendations described in the respective sections within this guideline should be followed for the stability studies conducted to support the re-test period or shelf life with the corresponding storage statements.

对于在生产工艺活动之外包装和贮藏的原料药和制剂中间产品，或以这种方式购买的原料药和制剂中间产品，可能适合确定复检期或有效期（如适用），而非贮藏时间。在这些情况下，稳定性研究应遵循本指导原则相应章节中所述的建议，以支持复检期或有效期以及相应的存储说明。

Stability recommendations for intermediates, including considerations that are specific for synthetic chemical entities and biologicals, are described below.

关于中间产品的稳定性建议，包括针对化学合成实体和生物制品的特定考虑因素，如下所述。

9.2   Considerations for Synthetic Chemical Entities

9.2   化学合成实体的考虑因素

The holding times of the drug substance intermediates should consider GMP principles and comply with written procedures. However, in situations where an in-process step for the drug substance has a holding time where the quality of the drug substance may be affected by the hold, then the principles in this section apply.

原料药中间产品的保持时限应考虑GMP原则，并遵循书面规程。但是，如果原料药的中间过程步骤有保持时限规定，而该保持时限可能会影响原料药的质量，则本节中的原则适用。

When established, the processing times and maximum holding times for drug product intermediates should be included in the description of the manufacturing processes. The risk assessment and control strategy for the drug product manufacturing processes should include an assessment of whether holding time studies should be performed. When applicable, the information to support the processing and holding times should be included in the regulatory submission.

制剂中间产品的加工时间和最长保持时限一经确定，应包含在生产工艺描述中。制剂生产工艺的风险评估和控制策略应包括是否应进行保持时限研究的评估。如适用，应在注册申报资料中纳入支持加工和保持时限的信息。

When the holding times of a drug product intermediate are prolonged (e.g., more than 30 days for solid dosage forms for the entire manufacturing process or more than 24 hours for non-solid dosage forms or sterile products), evidence of the suitability of the holding times, together with the proposed container that is representative of that for marketing, the storage period or transportation arrangements, should be included in the regulatory submission, when requested. Where intermediates are transported between production sites, the transportation arrangements and method of transportation should be described in general terms (e.g., intermediate container, storage and transportation conditions) in the description of the manufacturing processes.

当制剂中间产品的保持时限延长时（例如，在整个生产过程中固体剂型超过 30 天，或非固体剂型或无菌产品超过 24 小时），应根据要求在注册申报资料中纳入保持时限的适用性证据，以及代表上市包装的拟定容器、贮藏期或运输安排。当在生产场地之间运输中间产品时，应在制造工艺描述中以通用术语（例如中间产品容器、贮藏和运输条件）描述运输安排和运输方法。

For a drug substance or drug product produced by batch processes (i.e., not by continuous

manufacturing processes), it is expected that the data to support the holding times is generated and is representative of the overall process. If the data to support the holding times were not generated on production scale batches, these data should be verified in post-approval stability commitment to conduct these studies on production scale batches. If continuous manufacturing processes are used, the principles outlined in ICH Q13 guideline should be followed when selecting batches to support holding times.

对于通过分批工艺（即，非连续生产工艺）生产的原料药或制剂，预期会生成支持保持时限的数据，并代表整个工艺。如果生产规模批次没有生成支持保持时限的数据，则应在批准后稳定性承诺中确认这些数据，以对生产规模批次进行这些研究。如果使用连续生产工艺，在选择批次以支持保持时限时，应遵循ICH Q13指导原则中概述的原则。

9.3  Considerations for Biologicals

9.3  生物制品的注意事项

During the manufacture of biologicals, the quality and control of certain process intermediates may be critical to the production of the drug substance or drug product. In general, the manufacturer should identify process intermediates and generate data and define process limits and holding times that assure their stability within the conditions of the developed manufacturing process. Samples are periodically tested for product quality attributes that may be affected by the holding time.

在生物制品生产过程中，某些工艺中间产品的质量和控制可能对原液或制剂的生产至关重要。一般而言，生产商应确定工艺中间产品并生成数据，并定义工艺限度和保持时限，以确保其在已开发的生产工艺条件下的稳定性。定期检测样品可能受保持时限影响的产品质量属性。

A holding time study for a biological will typically consider two elements: (a) physicochemical stability and (b) microbial control strategy. The physicochemical stability part may be performed on small scale batches that are representative of production scale as part of process characterisation and should be assessed by monitoring relevant CQAs, such as purity and impurity. Microbial control should be demonstrated for the manufacturing process of production scale batches. The use of surrogate material as well as other approaches should be justified.

生物制品的保持时限研究通常会考虑两个因素：（a）理化稳定性和（b）微生物控制策略。作为工艺表征的一部分，理化稳定性部分可在代表生产规模的小规模批次中进行，并应通过监测相关CQA（如纯度和杂质）进行评估。应对生产规模批次的生产工艺进行微生物控制验证。应证明使用替代材料以及其他方法的合理性。

When physicochemical and microbial hold times are determined from separate studies, the established hold time would be the shorter of the two times.

当理化和微生物保持时限由不同的研究确定时，确定的保持时限应为两者中的较短者。

When analytical procedures cannot be applied to an intermediate to determine its holding time, the adequacy of the holding time could be supported by evaluating the quality of the later stage intermediates, drug substance, or drug product.

当无法用分析方法来确定中间产品的保持时限时，可通过评估后期中间产品、原液或制剂的质量来支持保持时限的充分性。

9.4   Examples of Holding Time Risk Assessment Considerations

9.4   保持时限风险评估考虑因素示例

The following are examples of the stages that may be considered during the risk assessment of two different types of drug product manufacturing process. Depending on the dosage form, other stages and considerations could be relevant.

以下是两种不同类型的制剂生产工艺风险评估期间可能考虑的阶段示例。根据剂型的不同，其他阶段和考虑因素也可能相关。

Non-Sterile, Solid Oral Dosage Form

非无菌固体口服剂型

The following are examples of the stages that may be considered during the risk assessment of the drug product manufacturing processes for a for a non-sterile, solid oral dosage form to identify potential processing and holding times for intermediates. Depending on the dosage form, other stages and considerations could be relevant.

以下是非无菌固体口服剂型的制剂生产工艺风险评估期间可能考虑的阶段示例，以确定中间产品的潜在加工和保持时限。根据剂型的不同，其他阶段和考虑因素也可能相关。

Table 8: Production steps and associated intermediates for non-sterile, solid oral dosage form

表 8非无菌固体口服剂型的生产步骤和相关中间产品

Sterile, Injectable Solution

灭菌的，注射用溶液

The following are examples of the stages that may be considered during the risk assessment of the manufacturing processes for a sterile, injectable solution to identify potential processing and holding times for intermediates:

以下是灭菌的，注射用溶液生产工艺风险评估期间可能考虑的阶段示例，以确定中间产品的潜在加工和保持时限：

Processing times at 15-25°C during drug substance process to bulk drug substance

原料药在15-25°C下分散溶解的工艺时间

Frozen in-process materials

工艺中物料的冷冻

Processing time at room temperature (e.g., 15-25°C) from start of drug product manufacturing(e.g., drug substance thaw) until end of fill

室温（如15-25°C）下从制剂生产开始（如原料药解冻）至灌装结束的工艺时间