ISPE Guidance Documents

• Topic I: Overview of Product Realization
• 1 Introduction
• 1.1 Objective
• 1.2 Scope
• 1.3 Benefits
• 2 Structure of the Guide Series, Product Quality Lifecycle Implementation from Concept to Continual Improvement
• 3 Product Realization using QbD
• 3.1 Quality Target Product Profile
• 3.2 Product and Process Outline
• 3.3 Prior Knowledge
• 3.4 Product Critical Quality Attributes
• 3.5 Product and Process Development
• 3.5.1 Objectives of Work
• 3.5.2 Multi-Disciplinary Working
• 3.5.3 Scale of Studies
• 3.5.4 Study Designs
• 3.5.5 Iterative Nature of Product and Process Development
• 3.5.6 Use of PAT Tools
• 3.5.7 Linking Material Attributes and CPPs to CQAs
• 3.5.8 Knowledge Management
• 3.6 Design Space
• 3.7 Control Strategy
• 4 Continual Improvement
• 5 Benefits of Using QbD in Development
• 5.1 Making Development More Efficient
• 5.2 Improving Manufacturing Efficiency
• 5.3 Proposing Regulatory Flexibility
• 5.4 Business Strategy
• 5.5 Environment
• Topic II: Criticality
• 6 Introduction
• 6.1 Overview
• 6.2 Objective
• 6.3 Scope
• 6.4 Benefits
• 6.5 Key Concepts
• 6.6 Structure of This Topic
• 7 Assignment of Criticality
• 7.1 Background
• 7.1.1 Review of Industry Experience
• 7.1.2 The Context for Criticality
• 7.1.3 The Importance of Criticality
• 7.2 Use of Quality Risk Management in Assignment of Criticality
• 7.2.1 Severity
• 7.2.2 Uncertainty
• 7.2.3 Probability
• 7.2.4 Detectability
• 7.2.5 Risk Evaluation
• 7.3 Approaches to Assigning Critical Quality Attributes and Critical Process Parameters
• 7.3.1 Target Product Profile
• 7.3.2 Quality Target Product Profile and Critical Quality Attributes (CQA)
• 7.3.3 Critical Quality Attributes of a Drug Product
• 7.3.4 Critical Process Parameters and Critical Material Attributes
• 8 Use of Criticality throughout the Product Lifecycle
• 8.1 Use of Criticality for Process Validation
• 9 Examples of Criteria to Assess Severity
• 9.1 Example of Severity Scale Showing Impact on the Patient
• 9.2 Examples of Severity Scales Showing Impact on Product Quality
• 10 Exampls of Criteria to Assess Probability
• 11 Examples of Criteria to Assess Detectability
• 12 Examples of Target Product Profile and Quality Target Product Profile
• Topic III: Design Space
• 13 Introduction
• 13.1 Overview13.2 Objectives13.3 Scope13.4 Benefits13.5 Key Concepts13.6 Structure of this Topic
• 14 Development of Design Space
• 14.1 Introduction
• 14.1.1 Procedure for Determining a Design Space
• 14.2 Objective
• 14.3 Scope of Design Space Development
• 14.4 Risk Assessment Procedures
• 14.4.1 Failure Mode and Effect Analysis (FMEA)
• 14.4.2 Cause and Effect Analysis
• 14.4.3 Preliminary Hazard Assessment/Hazards and Operability Studies/"What If" Reviews
• 14.5 Experiment Design
• 14.6 Modeling and Presentation of Design Space
• 14.6.1 First Principle Models - Thermodynamic Phenomena
• 14.6.2 Mechanistic Model-Rate Phenomena
• 14.6.3 Use of Correlations in Development of Process Understanding
• 14.6.4 Example 4: First Principle Approaches for Formulations
• 14.6.5 Managing Model Uncertainty
• 14.7 Design Space Confirmation and Scale Considerations
• 15 Design Space Updating/Continual Improvement
• 15.1 Capability Analysis
• 16 Relationship of Design Space to Control Strategy
• 17 Examples
• 17.1 Example 1
• 17.2 Example 2
• 17.3 Example 3
• 17.4 Example 4
• 17.5 Example 5
• 17.6 Example 6
• 17.7 Example 7
• 17.8 Example 8
• 17.9 Example 9
• 17.10 Example 10
• Topic IV: Control Strategy
• 18 Introduction
• 18.1 Overview
• 18.2 Objectives
• 18.3 Scope
• 18.4 Benefits
• 18.5 Key Concepts
• 18.6 Structure of this Topic
• 19 Lifecycle Approach to Control Strategy
• 19.1 Control Strategy throughout the Drug Product Lifecycle
• 19.1.1 Control Strategy in Pharmaceutical Development
• 19.1.2 Preparing the Control Strategy for Technology Transfer
• 19.1.3 Executing the Control Strategy in Manufacturing
• 19.1.4 Discontinuing the Product
• 20 Control Strategy Options
• 20.1 When to Start Developing and Defining the Control Strategy
• 20.2 Factors Influencing the Selection of Control Strategy
• 20.2.1 Business Influence on Control Strategy Selection
• 20.2.2 Process Control Based on Attributes and Parameters
• 20.2.3 The Influence of Business Drivers on the Development of a Control Strategy
• 20.3 Control Strategy and Continual Improvement over the Product Lifecycle
• 20.3.1 Example 3: Interaction between Drug Substance and Drug Product for Continual Improvement
• 20.3.2 Example 4: Interaction between Drug Product and Excipients for Continual Improvement
• 21 Implementation of the Control Strategy into Manufacturing
• 21.1 The Link between Design Space and Control Strategy
• 21.2 Implementation of Control Strategy
• 21.2.1 Establishment of Specifications for Material Attributes
• 21.2.2 Establishment of Specification for Drug Substance
• 21.2.3 Set-Points for Process Parameters
• 21.2.4 Applying Control Strategy to Manufacturing
• 21.3 Manufacturing/Site Capabilities
• 21.3.1 Equipment
• 21.3.2 Operations
• 21.3.3 Pharmaceutical Quality System (PQS)
• 21.3.4 Site Selection
• 21.3.5 Execution and Data Management
• 21.4 Documentation of the Control Strategy
• 22 Process Analytical Technology and Real Time Release Testing in Manufacturing
• 22.1 Process Analytical Technology in Manufacturing
• 22.2 Real Time Release Testing and Control Strategy for Solid Dose Manufacturing
• 22.2.1 Elements of a Control Strategy Derived from Enhanced, QbD Approach for Real Time Release Testing
• 22.3 Sampling and Acceptance Criteria
• 22.3.1 Determination of Sample Size
• 22.4 Maintaining Control if Failure of PAT Systems
• 22.5 Validation/Verification of PAT Analytical Tools for RTRT
• 22.6 Process Monitoring
• 23 Control Strategy and Process Validation
• 23.1 Link Between Enhanced, QbD Approach to Control Strategy and the Lifecycle of Process Validation
• 23.2 Continued Process Verification
• 23.3 Verification of the Control Strategy
• 24 Examples
• 24.1 Example 1: Establishing a Control Strategy Meeting Business Objectives
• 24.2 Example 2: Establishing a Control Strategy Using PAT and Meeting Business Objectives
• 24.3 Example 3: Interaction between Drug Substance and Drug Product for Continual Improvement
• 24.4 Example 4: Interaction between Drug Product and Excipients for Continual Improvement
• Appendices
• 25 Appendix 1 - References
• 25.1 References
• 25.2 Further Reading
• 26 Appendix 2 - Glossary
• 26.1 Acronyms
• 26.2 Definitions

• Eric Ahuja, Merck, USA
• Joanne Barrick, Eli Lilly & Company, USA
• John Berridge, Consultant and PQLI Project Manager, United Kingdom
• Chris Brook, GlaxoSmithKline, USA
• Mette Bryder, H. Lundbeck A/S, Denmark
• Sue Busse, Eli Lilly & Company, USA
• Graham Cook, Pfizer, United Kingdom
• Bruce Davis, Global Consulting, United Kingdom
• Ranjit Deshmukh, MedImmune, USA
• John Donaubauer, Abbott Laboratories, USA
• Tom Garcia, Pfizer, USA
• Jeff Givand, Merck, USA
• John Groskoph, Pfizer, USA
• Theodora Kourti, GlaxoSmithKline, United Kingdom
• Mette Kraemer-Hansen, Novo Nordisk, Denmark
• Jay Lakshman, Novartis, USA
• Steve Laurenz, Abbot Laboratories, USA
• John Lepore (Co-Lead), Merck, USA
• Line Lundsberg-Nielsen (Co-Lead), NNE Pharmaplan, United Kingdom
• Vincent McCurdy, Pfizer, USA
• Gordon Muirhead, GlaxoSmithKline, United Kingdom
• Roger Nosal (Co-Lead), Pfizer, USA
• Gary O’Connor, Pfizer, United Kingdom
• Wim Oostra, MSD, Netherlands
• Chris Potter, Consultant and PQLI Technical Project Manager, United Kingdom
• Tom Schultz, Johnson & Johnson, USA
• Kevin Siebert, Eli Lilly & Company, USA
• Shailesh Singh, Sandoz, USA
• Chris Sinko (Co-Lead), Bristol-Myers Squibb, USA
• William Spanogle, Johnson & Johnson, USA
• Jim Spavins, Pfizer, USA
• Paul Stott, AstraZeneca, United Kingdom
• Mani Sundararajan, AstraZeneca, USA
• Stephen Tyler, Abbott Laboratories, USA
• Hedinn Valthorsson, Novartis, Switzerland
• Kim Vukovinsky, Pfizer, USA
• Tim Watson, Pfizer, USA

The global pharmaceutical industry and regulators are responding to the challenge of significantly improving the way drug development and manufacturing is managed. New concepts are being advanced and applied, including enhanced, quality by design approaches to product and process development and introduction into manufacturing with a focus on product and process understanding.

The international regulatory community has outlined their position on these new “Science- and Risk-Based Approach” concepts in the ICH Q8, Q9, Q10, and Q11 quality guidelines, where guidance is given on applying these concepts to drug substance and drug product across the entire drug life cycle.

Part 1 – Product Realization using Quality by Design (QbD): Concepts and Principles provides an overview as an introduction to and a summary of the Guide Series, and elaborates on the concepts of criticality, design space, and control strategy as introduced in ICH Q8, Q9, Q10, and Q11. How these concepts are applied during development and in manufacturing is discussed and exemplified.

Benefits of using enhanced, quality by design approaches are also discussed.

This Guide is solely created and owned by ISPE. It is not a regulation, standard, or regulatory guideline document, and products and processes designed in conformance with this Guide Series may or may not meet FDA or other global regulatory requirements.