ISPE发布了新的清洁验证指南——《ISPE基准指南：清洁验证生命周期–应用，方法和控制 （ISPE Baseline Guide: Cleaning Validation Lifecycle: Applications, Methods, and Controls） 》。

该指南共236页，包含一下内容：

Table of Contents

目录

1 Introduction

介绍

1.1 Background

背景

1.2 Purposeand Objectives

目的

1.2.1 Benefit

好处

1.2.2 Scope

范围

1.3 KeyConcepts

关键概念

1.3.1 CurrentConsiderations and Trends

现行考虑和趋势

1.3.2 KeyTerms

关键术语

2 CleaningRegulations

清洁法规

3 RiskManagement

风险管理

3.1 RiskManagement Deion Overview and Regulatory Expectations

风险管理概述和监管期望

3.1.1 RegulatoryExpectations

监管期望

3.1.2 RiskManagement Models

风险管理模型

3.1.3 Sourcesof Variation

变异源

3.2 RiskManagement Applied to the Cleaning Validation Program

适用于清洁验证程序的风险管理

3.2.1 InitialCleaning Validation Assessments

初始清洁验证评估

3.2.2 Introductionof New Products Risk Assessments

引入新产品的风险评估

3.2.3 OngoingMonitoring Maintenance Risk Assessments

持续监测维护风险评估

3.2.4 Routine Operation of Cleaning Process Risk Assessments

清洁工艺风险评估

3.2.5 Additional Applications

其他应用

3.3 Pointsto Consider When Using QRM Tools for Cleaning Programs

使用QRM工具应用于清洁程序的考量

3.3.1 Severity

严重性

3.3.2 Probability

可能性

3.3.3 RiskPrioritization

风险优先级

4 CleaningValidation Principles

清洁验证原则

4.1 CleaningValidation Lifecycle

清洁验证生命周期

4.1.1 CleaningProcess Design

清洁工艺设计

4.1.2 CleaningProcess Performance Qualification

清洁工艺性能确认

4.1.3 CleaningProcess Continued Verification

清洁工艺持续确认

4.2 Documentation

文件记录

4.3 TheValidation Master Plan

验证主计划

4.4 Creationand Execution of Validation Protocols

验证方案的创建和执行

4.5 PeriodicReviews

定期审查

4.6 CleaningRevalidation

清洁再验证

5 CleaningMethodologies

清洁方法

5.1 Selectionof Cleaning Process

清洁工艺的选择

5.2 Cleanin Place (CIP)

在线清洗（CIP）

5.2.1 Principlesof CIP

CIP的原则

5.2.2 CIPDefined

定义的CIP

5.2.3 CIP-CleanableProcesses

CIP-可清洁的工艺

5.2.4 CIPSystems

CIP系统

5.2.5 CIPFlow Rates in Piping

CIP管道流量

5.2.6 CIPSpray Devices

CIP喷淋装置

5.2.7 CIPCycle Development

CIP程序开发

5.3 CleanOut of Place (COP)

离线清洗（COP）

5.3.1 COPStations

COP状态

5.3.2 Washers

清洗机

5.4 ManualCleaning

人工清洗

5.5 CleaningParameters and CPPs

清洁参数和CPP

5.6 Worst-CaseProducts

最差条件产品

5.6.1 ResidueTypes

残留类型

5.6.2 LaboratoryEvaluation/Confirmation

实验室评价啊/确认

5.6.3 EquipmentDirty Hold Time (DHT)

设备脏的保持时间

5.7 Detergents

清洁剂

5.8 Inactivationand Denaturation

变性与失活

5.8.1 Limitationsof the Conventional MACO Approach

传统MACO方法的局限性

5.8.2 RecommendedAnalytical Methods to Evaluate Fragmentation and Inactivation of API

评估API降解和失活的推荐分析方法

6 AcceptanceCriteria

接受标准

6.1 Cleaning Residue Limits for SharedFacilities

共用设施的清洁残留限度

6.1.1 Determining the MACO

确定MACO

6.1.2 Drug Substance and Drug Product MACOCalculations

药物成分和药物产品MACO计算

6.1.3 Determining Cleaning Residue SafetyLimits

确定清洁残留安全限度

6.1.4 Rinse and Swab Safety LimitCalculations

淋洗和擦拭安全限度计算

6.1.5 Cleaning Limits for Legacy CleaningProcesses

遗留清洁工艺的清洁限度

6.1.6 Acceptance Criteria for DedicatedEquipment

专用设备的接受标准

6.2 Acceptance Limits for Fragments ofHuman Therapeutic Proteins

人类治疗蛋白片段的接受限度

6.2.1 Inactivation of HTPs during Cleaningand Steaming

清洗和消毒过程中HTPs的失活

6.2.2 Safety Profile of Inactive Fragmentsof HTPs

HTPs非活性片段的安全性分析

6.2.3 Comparable Quality Approach

类似质量方法

6.2.4 Scientific Rationale for the Use ofGelatin as a Reference Impurity

使用明胶作为对照杂质的科学原理

6.2.5 Application of the CQ Approach toBiopharmaceutical Cleaning Validation

CQ方法在生物制药清洁验证中的应用

6.3 Visual Inspection and Criteria

目视检查和标准

6.3.1 Visible Residue Limit Studies

可见残留限度研究

6.3.2 Visible Residue Limit and SafetyLimits

可见残留限度和安全限度

6.3.3 Non-Accessible Areas and the VisualInspection Process

不可进入区域和目视检查流程

6.3.4 Organoleptic Inspection

感官检查

6.4 Process Consistency, Capability, andControl

过程一致性、能力和控制

6.5 Bioburden and Endotoxins

生物负荷和内毒素

6.5.1 Microbial Acceptance CriteriaCalculation

微生物接受标准计算

6.5.2 Non-Sterile Surface Bioburden LimitsCalculations

非无菌表面生物负荷计算

6.5.3 Sterile Surface Bioburden LimitsCalculations

无菌表面生物负荷限度计算

6.5.4 Endotoxin Limits from SurfaceSampling

表面样品的内毒素标准

6.6 Summary of Acceptance CriteriaApproaches for Cleaning Process Performance Qualifications

清洁工艺性能确认的接受标准和方法的总结

7 Sampling

取样

7.1 Swab Sampling

擦拭取样

7.1.1 Advantages and Disadvantages of SwabSampling

擦拭取样的优点和缺点

7.1.2 Swab Sampling Parameters

擦拭取样参数

7.1.3 Swab Sampling Recovery Execution

擦拭取样回收

7.2 Rinse Sampling

淋洗取样

7.2.1 Advantages, Disadvantages, andLimitations of Rinse Sampling

淋洗取样的优点和缺点

7.2.2 Requirements for Rinse Sampling

淋洗取样的要求

7.2.3 Rinse Sample Parameters

淋洗取样参数

7.2.4 Sample Recovery Testing

取样回收测试

7.2.5 Rinse Solvent

淋洗溶剂

7.3 Placebo Sampling

安慰剂取样

7.4 Sampling for Bioburden and Endotoxins

生物负荷和内毒素取样

7.4.1 Cleaning Risk Assessment forBiological Contaminants

生物污染的清洁风险评估

7.4.2 Bioburden Sampling Methods Consideration

生物负荷取样方法考量

7.4.3 Bioburden and Endotoxin Interactionwith Surface Materials

生物负荷和内毒素与表面材料的相互作用

7.4.4 General Overview of BioburdenSampling Methods

生物负荷取样方法的概述

7.4.5 Microbiological Direct and IndirectSampling Method Objectives

微生物直接和非直接取样方法

8 Analyticaland Biological Assay Methods

分析和生物分析方法

8.1 Analytical Methods

分析方法

8.1.1 Validation Parameters

验证参数

8.1.2 Methodology

方法

8.2 Test Method Assessment for Bioburdenand Endotoxin

生物负荷和内毒素测试方法评估

8.2.1 Swab Recovery Method Assessment

棉签回收方法评估

8.2.2 Endotoxin Surface Sampling

内毒素表面取样

8.3 Microbiological (Virus, Mycoplasma, andTSE) Studies to Support Cleaning Requirements

用以支持清洁要求的微生物（病毒、支原体和TSE）研究

9 EquipmentIssues and Challenges

设备问题和挑战

9.1 Design Aspects of Cleanable ProcessEquipment

可清洁工艺设备的设计

9.2 Solid Dosage Processing

固体制剂加工

9.3 Sterile Processing

无菌加工

9.4 Liquids, Creams, and Ointments

液体、乳剂和膏剂

9.5 API Processing

API加工

9.6 Biotechnology Equipment

生物技术设备

9.7 Clinical and Investigational MedicinalProducts (IMPs)

临床和试验用药品（IMPs）

9.8 Packaging Equipment

包装设备

9.9 Dedicated Equipment

专用设备

9.10 Single-Use Technology Equipment

一次性使用技术设备

10 ManufacturingOperational Approaches and Impact to Cleaning Practices and Requirements

生产操作方法和对清洁操作的影响和要求

10.1 Facility Layouts and Segregation

设施布局和隔离

10.2 Manufacturing Process and Platforms

生产工艺和平台

10.2.1 Manufacturing Platforms

制造平台

10.2.2 Continuous Manufacturing

连续制造

10.3 Equipment Selection

设备选择

10.4 Non-Product and Indirect ProductContact Surfaces

非产品接触和非直接接触表面

10.5 Operational Philosophy

运营理念

11 ChangeControl

变更控制

11.1 Elements of Validated CleaningProcesses

已验证清洁工艺的要素

11.2 Examples of Changes with CorrespondingActions

带有相应操作的变更示例

11.2.1 Technical Systems and EquipmentDesign

技术体系和设备设计

11.2.2 Cleaning Methods

清洁方法

11.2.3 Sampling

取样

11.2.4 Analytical Methods and Testing

分析方法和测试

11.2.5 Residue Limits, Acceptance Criteria,and Specifications

残留限度，接受标准和规范

12 Appendix1 – Example: Swab Recovery Execution Studies

附录1—示例：擦拭回收率试验

13 Appendix2 – Example: Cleaning Residue Limits Calculations for a Shared Formulation Tank(Product A/B)

附录2—示例：一个共用配制罐（产品A/B）的清洁残留限度计算

14 Appendix3 – Example: Protocol for Development and Establishment of a Visible ResidueLimit (VRL)

附录3—示例：可见残留限度（VRL）开发和制定方案

15 Appendix4 – Example: Bioburden Swab and Rinse Recovery Methods

附录4—示例：生物负荷擦拭和淋洗回收方法

15.1 Swab Recovery Method

擦拭回收方法

15.1.1 Test Method Assessment

测试方法评估

15.1.2 Preparation of the Working Cultures

工作培养基的准备

15.1.3 Spore Suspension Preparation

芽孢悬液的准备

15.1.4 Swab Sampling Procedure

擦拭取样程序

15.2 Contact Plates Recovery Method

接触皿回收方法

15.2.1 Overview of Different Contact PlateTypes

不同接触皿类型概述

15.2.2 Recovery Study Using the ContactMethod

使用接触方法回收试验

15.3 Rinse Water

淋洗水

15.3.1 Recovery Study Using the RinseMethod

使用淋洗方法回收试验

15.3.2 Diluting Samples, Plating, andIncubating

稀释样品，电镀和培养

16 Appendix5 – Example: Endotoxin Swab and Rinse Recovery Methods

附录5—示例：内毒素擦拭和淋洗回收方法

16.1 Endotoxin Swab Recovery Method

内毒素擦拭回收方法

16.2 Endotoxin Rinse Recovery Method

内毒素淋洗回收方法

17 Appendix6 – Case Study: Establishing Process Parameters for a Manual Cleaning Process

附录6—案例：建立人工清洁工艺参数

17.1 Introduction

介绍

17.2 Deion of Parts and Tools to BeCleaned

待清洁部件和工具的描述

17.3 Equipment Design Points to Consider

设备设计考量

17.4 Manufacturing Process and ProductDeion

生产工艺和产品描述

17.4.1 Manufacturing Process Considerations

生产工艺考虑

17.4.2 Residue Characteristics

残留特性

17.5 Recommended Cleaning Process for Toolsand Small Parts

建议的工具和小部件清洁工艺

17.5.1 Risk Assessment Considerations

风险评估考虑

17.5.2 Final Recommendations for CleaningProcess

清洁工艺的最终建议

18 Appendix7 – Case Study: Establishing Process Parameters for a Clean In Place CleaningProcess

附录7—案例：建立在线清洗工艺参数

18.1 Introduction

介绍

18.2 System Deion

系统描述

18.3 Scenario 1 – Product A

产品A

18.3.1 Manufacturing Process Considerations

生产工艺考虑

18.3.2 Residue Characteristics

残留特性

18.3.3 Proposed Cleaning Cycles for ProductA

拟定的针对产品A的清洁程序

18.4 Scenario 2 – Product B

产品B

18.4.1 Manufacturing Process Considerations

生产工艺考虑

18.4.2 Residue Characteristics

残留特性

18.4.3 Proposed Cleaning Cycles for ProductB

拟定的针对产品B的清洁程序

18.5 Scenario 3 – Product C

产品C

18.5.1 Manufacturing Process Considerations

生产工艺考虑

18.5.2 Residue Characteristics

残留特性

18.5.3 Proposed Cleaning Cycles for ProductC

拟定的针对产品C的清洁程序

18.6 In-Process Monitoring and VisualInspection

过程监测和目视检查

18.7 Points to Consider

考虑点

19 Appendix8 – Case Study: Application of Quality Risk Management Tools – Introduction ofa New Product into an Existing Multiproduct Facility

附录8—案例：质量风险管理工具的应用-多产品工厂中新产品的引入

19.1 Background Information

背景信息

19.2 Risk Assessment

风险评估

20 Appendix9 – References

附录9—参考文献

21 Appendix10 – Glossary

附录10—术语

21.1 Acronyms and Abbreviations

缩略语

21.2 Definitions