ISPE Guidance Documents

• 1 Introduction
• 1.1 Background
• 1.2 Purpose and Objectives
• 1.2.1 Benefit
• 1.2.2 Scope
• 1.3 Key Concepts
• 1.3.1 Current Considerations and Trends
• 1.3.2 Key Terms
• 2 Cleaning Regulations
• 3 Risk Management
• 3.1 Risk Management Description Overview and Regulatory Expectations
• 3.1.1 Regulatory Expectations
• 3.1.2 Risk Management Models
• 3.1.3 Sources of Variation
• 3.2 Risk Management Applied to the Cleaning Validation Program
• 3.2.1 Initial Cleaning Validation Assessments
• 3.2.2 Introduction of New Products Risk Assessments
• 3.2.3 Ongoing Monitoring Maintenance Risk Assessments
• 3.2.4 Routine Operation of Cleaning Process Risk Assessments
• 3.2.5 Additional Applications
• 3.3 Points to Consider When Using QRM Tools for Cleaning Programs
• 3.3.1 Severity
• 3.3.2 Probability
• 3.3.3 Risk Prioritization
• 4 Cleaning Validation Principles
• 4.1 Cleaning Validation Lifecycle
• 4.1.1 Cleaning Process Design
• 4.1.2 Cleaning Process Performance Qualification
• 4.1.3 Cleaning Process Continued Verification
• 4.2 Documentation
• 4.3 The Validation Master Plan
• 4.4 Creation and Execution of Validation Protocols
• 4.5 Periodic Reviews
• 4.6 Cleaning Revalidation
• 5 Cleaning Methodologies
• 5.1 Selection of Cleaning Process
• 5.2 Clean in Place (CIP)
• 5.2.1 Principles of CIP
• 5.2.2 CIP Defined
• 5.2.3 CIP-Cleanable Processes
• 5.2.4 CIP Systems
• 5.2.5 CIP Flow Rates in Piping
• 5.2.6 CIP Spray Devices
• 5.2.7 CIP Cycle Development
• 5.3 Clean Out of Place (COP)
• 5.3.1 COP Stations
• 5.3.2 Washers
• 5.4 Manual Cleaning
• 5.5 Cleaning Parameters and CPPs
• 5.6 Worst-Case Products
• 5.6.1 Residue Types
• 5.6.2 Laboratory Evaluation/Confirmation
• 5.6.3 Equipment Dirty Hold Time (DHT)
• 5.7 Detergents5.8 Inactivation and Denaturation
• 5.8.1 Limitations of the Conventional MACO Approach
• 5.8.2 Recommended Analytical Methods to Evaluate Fragmentation and Inactivation of API
• 6 Acceptance Criteria
• 6.1 Cleaning Residue Limits for Shared Facilities
• 6.1.1 Determining the MACO
• 6.1.2 Drug Substance and Drug Product MACO Calculations
• 6.1.3 Determining Cleaning Residue Safety Limits
• 6.1.4 Rinse and Swab Safety Limit Calculations
• 6.1.5 Cleaning Limits for Legacy Cleaning Processes
• 6.1.6 Acceptance Criteria for Dedicated Equipment
• 6.2 Acceptance Limits for Fragments of Human Therapeutic Proteins
• 6.2.1 Inactivation of HTPs during Cleaning and Steaming
• 6.2.2 Safety Profile of Inactive Fragments of HTPs
• 6.2.3 Comparable Quality Approach
• 6.2.4 Scientific Rationale for the Use of Gelatin as a Reference Impurity
• 6.2.5 Application of the CQ Approach to Biopharmaceutical Cleaning Validation
• 6.3 Visual Inspection and Criteria
• 6.3.1 Visible Residue Limit Studies
• 6.3.2 Visible Residue Limit and Safety Limits
• 6.3.3 Non-Accessible Areas and the Visual Inspection Process
• 6.3.4 Organoleptic Inspection
• 6.4 Process Consistency, Capability, and Control
• 6.5 Bioburden and Endotoxins
• 6.5.1 Microbial Acceptance Criteria Calculation
• 6.5.2 Non-Sterile Surface Bioburden Limits Calculations
• 6.5.3 Sterile Surface Bioburden Limits Calculations
• 6.5.4 Endotoxin Limits from Surface Sampling
• 6.6 Summary of Acceptance Criteria Approaches for Cleaning Process Performance Qualifications
• 7 Sampling
• 7.1 Swab Sampling
• 7.1.1 Advantages and Disadvantages of Swab Sampling
• 7.1.2 Swab Sampling Parameters
• 7.1.3 Swab Sampling Recovery Execution
• 7.2 Rinse Sampling
• 7.2.1 Advantages, Disadvantages, and Limitations of Rinse Sampling
• 7.2.2 Requirements for Rinse Sampling
• 7.2.3 Rinse Sample Parameters
• 7.2.4 Sample Recovery Testing
• 7.2.5 Rinse Solvent
• 7.3 Placebo Sampling
• 7.4 Sampling for Bioburden and Endotoxins
• 7.4.1 Cleaning Risk Assessment for Biological Contaminants
• 7.4.2 Bioburden Sampling Methods Consideration
• 7.4.3 Bioburden and Endotoxin Interaction with Surface Materials
• 7.4.4 General Overview of Bioburden Sampling Methods
• 7.4.5 Microbiological Direct and Indirect Sampling Method Objectives
• 8 Analytical and Biological Assay Methods
• 8.1 Analytical Methods
• 8.1.1 Validation Parameters
• 8.1.2 Methodology
• 8.2 Test Method Assessment for Bioburden and Endotoxin
• 8.2.1 Swab Recovery Method Assessment
• 8.2.2 Endotoxin Surface Sampling
• 8.3 Microbiological (Virus, Mycoplasma, and TSE) Studies to Support Cleaning Requirements
• 9 Equipment Issues and Challenges
• 9.1 Design Aspects of Cleanable Process Equipment
• 9.2 Solid Dosage Processing
• 9.3 Sterile Processing
• 9.4 Liquids, Creams, and Ointments
• 9.5 API Processing
• 9.6 Biotechnology Equipment
• 9.7 Clinical and Investigational Medicinal Products (IMPs)
• 9.8 Packaging Equipment
• 9.9 Dedicated Equipment
• 9.10 Single-Use Technology Equipment
• 10 Manufacturing Operational Approaches and Impact to Cleaning Practices and Requirements
• 10.1 Facility Layouts and Segregation
• 10.2 Manufacturing Process and Platforms
• 10.2.1 Manufacturing Platforms
• 10.2.2 Continuous Manufacturing
• 10.3 Equipment Selection
• 10.4 Non-Product and Indirect Product Contact Surfaces
• 10.5 Operational Philosophy
• 11 Change Control
• 11.1 Elements of Validated Cleaning Processes
• 11.2 Examples of Changes with Corresponding Actions
• 11.2.1 Technical Systems and Equipment Design
• 11.2.2 Cleaning Methods
• 11.2.3 Sampling
• 11.2.4 Analytical Methods and Testing
• 11.2.5 Residue Limits, Acceptance Criteria, and Specifications
• 12 Appendix 1 - Example: Swab Recovery Execution Studies
• 13 Appendix 2 - Example: Cleaning Residue Limits Calculations for a Shared Formulation Tank (Product A/B)
• 14 Appendix 3 - Example: Protocol for Development and Establishment of a Visible Residue Limit (VRL)
• 15 Appendix 4 - Example: Bioburden Swab and Rinse Recovery Methods
• 15.1 Swab Recovery Method
• 15.1.1 Test Method Assessment
• 15.1.2 Preparation of the Working Cultures
• 15.1.3 Spore Suspension Preparation
• 15.1.4 Swab Sampling Procedure
• 15.2 Contact Plates Recovery Method
• 15.2.1 Overview of Different Contact Plate Types
• 15.2.2 Recovery Study Using the Contact Method
• 15.3 Rinse Water
• 15.3.1 Recovery Study Using the Rinse Method
• 15.3.2 Diluting Samples, Plating, and Incubating
• 16 Appendix 5 - Example: Endotoxin Swab and Rinse Recovery Methods
• 16.1 Endotoxin Swab Recovery Method
• 16.2 Endotoxin Rinse Recovery Method
• 17 Appendix 6 - Case Study: Establishing Process Parameters for a Manual Cleaning Process
• 17.1 Introduction
• 17.2 Description of Parts and Tools to Be Cleaned
• 17.3 Equipment Design Points to Consider
• 17.4 Manufacturing Process and Product Description
• 17.4.1 Manufacturing Process Considerations
• 17.4.2 Residue Characteristics
• 17.5 Recommended Cleaning Process for Tools and Small Parts
• 17.5.1 Risk Assessment Considerations
• 17.5.2 Final Recommendations for Cleaning Process
• 18 Appendix 7 - Case Study: Establishing Process Parameters for a Clean In Place Cleaning Process
• 18.1 Introduction
• 18.2 System Description
• 18.3 Scenario 1 - Product A
• 18.3.1 Manufacturing Process Considerations
• 18.3.2 Residue Characteristics
• 18.3.3 Proposed Cleaning Cycles for Product A
• 18.4 Scenario 2 - Product B
• 18.4.1 Manufacturing Process Considerations
• 18.4.2 Residue Characteristics
• 18.4.3 Proposed Cleaning Cycles for Product B
• 18.5 Scenario 3 - Product C
• 18.5.1 Manufacturing Process Considerations
• 18.5.2 Residue Characteristics
• 18.5.3 Proposed Cleaning Cycles for Product C
• 18.6 In-Process Monitoring and Visual Inspection
• 18.7 Points to Consider
• 19 Appendix 8 - Case Study: Application of Quality Risk Management Tools - Introduction of a New Product into an Existing Multiproduct Facility
• 19.1 Background Information
• 19.2 Risk Assessment
• 20 Appendix 9 - References
• 21 Appendix 10 - Glossary
• 21.1 Acronyms and Abbreviations
• 21.2 Definitions

• Jose Caraballo (Co-Lead), Bayer U.S., USA
• Liz Dallison, Pfizer Ltd., United Kingdom
• Rich Forsyth, Forsyth Pharmaceutical Consulting, USA
• Trefor Jones, Bluehatch Consultancy Ltd., United Kingdom
• Beth Kroeger-Fahnestock, STERIS Corp., USA
• Sam Lebowitz, Electrol Specialties Co., USA
• Catherine Oakes, Oakes Group Global, Turkey/USA
• Fred Ohsiek, Novo Nordisk, USA
• Joseph Payne (Co-Lead), Tergus Pharma (formerly with Alcami Corp.), USA
• David W. Vincent, MPH, PhD, VTI Life Sciences, Inc., USA/Asia

Regulatory agencies expect the development and validation of a compliant cleaning program. This critical activity ensures that the risks of contamination, product carryover, and cross-contamination are controlled, minimized, and monitored to safeguard patient safety and product quality.

This ISPE Guide: Cleaning Validation Lifecycle – Applications, Methods, and Controls describes the application of the process lifecycle model to cleaning. This will aid organizations in developing and adopting scientifically sound approaches, resulting in a robust cleaning validation program.

An integral part of an effective cleaning program is using risk-based approaches in the design and management of the validation process; accordingly, this ISPE Guide is aligned with the principles described in the ISPE Baseline®Guide: Volume 7 – Risk-Based Manufacture of Pharmaceutical Products [Risk-MaPP] (Second Edition).

This ISPE Guide: Cleaning Validation Lifecycle – Applications, Methods, and Controls promotes the use of health-based exposure limits (HBEL) and offers guidance and examples for developing and/or transitioning to the determination of cleaning specifications using HBEL.

Created by a team of industry experts with global experience, this ISPE Guide is intended as a reference for the cleaning lifecycle model as well as a practical guide for applying the theory and concepts to help create compliant and effective cleaning programs.