Quality by DesignPutting Theory into Practice

Siegfried Schmitt

PDABethesda, MD, USADHI Publishing, LLCRiver Grove, IL, USA

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ISBN: 1-933722-48-7Copyright © 2011 Siegfried SchmittAll rights reserved.

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CONTENTS

Preface xiiiGlossary xv

1 Introduction 1Siegfried Schmitt

2 The Regulatory Framework 5Siegfried Schmitt

The Early Days 5PAT and QbD 8Pilot Programs 10ICH 13Quality ImplementationWorking Group (Q-IWG) Q&A 14

Design space 15Real time release testing (RTRT) 17Knowledge management 17Lifecycle approach 18Benefits of applying ICH Q8, Q9 and Q10 18Attendees’ understanding of the ICH Guidance Documents 18

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Questions and answers 18Current Legislative Situation 20Industry Organisations and Their Roles 22References 28About the Author 30

3 The Roadmap to QbD 31Siegfried Schmitt

Getting Started 31Thought leaders 32

PDA and ISPE 33Regulatory agencies 33

Conferences and seminars 36Online forums an special interest groups 36Tools 37

The Business Case 38Design Space 45

Control strategies 45Concept 47The relationship between validation and QbD 50Link to pharmacokinetics and pharmacodynamics 50Examples 52

Outlook 53References 54About the Author

4 Simplified Process Development and Commercialization 57Girish Malhotra

Introduction 57Chemistry 58Physical Properties 60Consideration of Process Alternates for Process Scale Up 66Alternative Processing Methods 75Phase Separation 80Removal of the Reaction Product 81Other Considerations 83Good Manufacturing Practices 85References 87About the Author 88

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5 Change Management Associated withQbD Implementation 89

Michael Schousboe and Irwin HirshIntroduction 89

Putting theory into practice 90Discovering QbD as a Concept 91

Lessons from PAT implementation projects (2004–2006) 92Focus started with the future state of validation 92Management realization of the need for implementation 93

Setting up the Implementation Project 93Realizing that you cannot eat the entire elephant in

one bite — multi-step planning 94Choosing implementation strategy — managing the change 95Understanding that creates clarity — getting to the

definition of QbD 96Securing buy-in and gathering the project group 97

Selling QbD Implementation — Creation of a Strong Business Case 101The basic case for quality risk management 101Quality by redesign — and a mini-paradigm shift 103The high science approach — process understanding

that enables control 105The QbD business case for our entire industry 107

Realization — Results from a Focused Implementation 109QbD becomes a strategic focus in CMC development 109Securing the competences for QbD lifecycle management 110Working with the quality management system 111

Concluding Remarks 112References 113About the Authors 114

6 QbD and ProcessValidation — ComplementaryLifecycle Approaches 115

Paul L. PlutaIntroduction 115QbD Basics 117

QbD vs. QbT 118Process Validation Basics 119

Stage 1 Process Design — understanding the productand process 120

Stage 2 Process Qualification — manufacturing thevalidation conformance lots 120

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Stage 3 Continued Process Verification — maintainingthe validated state 121

The “process” of process validation 121Lifecycle approach to process validation —

organizational approach 121Quality risk management 122Terminology 123

Basis and Expectations for the Lifecycle Approachto Process Validation 123Expectations for validated processes 127

QbD and Process Validation Stage 1 — Process Design 127Design and development 129

Quality target product profile 129API and excipient pharmaceutics 130Quality attributes 131Formulation and process development 131Process parameters 132Design space 132

Pilot scale, technology transfer, and commercial scale-up 133Identification of input variables 133Strategy to control variables 134

QbD and Process Validation Stage 2 — Process Qualification 135Considerations prior to process performance 136

Lifecycle approach to process validation 136Validation process performance = confirmation 136Collaboration — function roles and responsibilities 137

Pre-process performance documents 137VMP and site policy documents 138Process understanding documents specific to theproduct/process to be validated 138Validation plan for specific process validation 139Validation protocol 141Manufacturing batch record 142

Manufacturing of PPQ lots 142Communication 143Preparation for process validation 143PPQ batch manufacturing 144

Post-process performance documents 144Executed manufacturing batch record 145Conformance lots test results 145Validation performance final report 145Amendments and mistakes 146Plan for maintaining the validated state 146

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QbD and Process Validation Stage 3 — Continued ProcessVerification 146Factors supporting maintenance of the validated state 147

Lifecycle approach to process validation 148Functional group collaboration — rolesand responsibilities 148Quality systems development and implementation 148Resource allocation 150Management responsibilities 150Risk analysis of product and associated processes 151

Activities for maintaining the validated state 152Trend and assess data 152Change management and control 153Periodic evaluation 154

Additional Process Validation Considerations 154Equipment/facilities/utilities qualification 154Analytical methods 155Statistical methods 155Documentation 156

Summary and Conclusions 157References 159About the Author 162

7 The Analytical Challenge in QbD — From Data toInformation and to Knowledge — From (Bioprocess)Development to Manufacturing 163

Christoph HerwigIntroduction 163Information and Knowledge Needs in Development

and Manufacturing 164What is process understanding? 164What entities are gathered, what do we measure? 164

Process Development Phases: Goals and Data Needs 166Early screening 167Quantitative screening 167Bioprocess development 167Piloting 168

Instrumentation Impact: Sensors in BiopharmaceuticalProcesses 170Data Consistency, Soft Sensors and Extraction of Information 173

Information from raw data 173

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Influence of measurement accuracy and frequency onextraction of information 173

Variables reflecting information 175Knowledge-based methods 176

Analytical methods 177Application of the hybrid method approach 181

Real-time Approaches for Deriving Information and Knowledge:Process Understanding 182DoE set-up 182Scale-down models and metabolic modelling 182Knowledge generation cycle 183

From Development to Manufacturing 183Generic strategy 183Requirements for data management 188

Pharmaceutical development 188Generating a business process for knowledgemanagement 189

Conclusions 189References 190About the Author 194

8 Applying QbD Design to Pharmaceutical Microbiology 195Jeanne Moldenhauer

What is Pharmaceutical Microbiology? 195Introduction 196Applying a QbD Approach for Analytical Methods 199

Method development 199Method validation or qualification 199Method transfer, if required 200Method use or operation 200Lifecycle management 200

Applying QbD to Pharmaceutical Microbiology Analytical Methods 201Applying QbD to Pharmaceutical Microbiology 203Getting Regulatory Flexibility 204Conclusion 214References 214About the Author 215

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9 The QbD Challenge for Analytical Laboratories 217Terry Hopper

Introduction 217Quality Programs and QbD 219The Analytical Laboratory and QbD 222

Reliability of the analytical laboratory examples 225Laboratory error 227Operational analysis of the analytical laboratory by QbD 229SPC/SQC and continuous improvement in the

analytical laboratory 233Monitoring and reducing laboratory error 237Summary 243

QbD for Analytical Methods 244Overview of design of experiments 249DoE approach for a HPLC method example 252DoE for analytical methods examples 253Automated methods 261Quality function deployment 261Summary 266

Space Structures in QbD 267Knowledge space 272Summary 274

Developing QbD in the Analytical Laboratory 274Conclusions 283References 284About the Author 285

10 Compliance by Design (CbD) and ComplianceMaster Plan (CMP) — Lifecycle Approach toQuality Systems and Compliance 287

Paul L. Pluta, Richard Poska and Timothy J. FieldsIntroduction — Can Pharmaceutical Compliance be Improved? 287

Quality systems and GMPs 288Approaches and Methods to Improve Compliance and

Quality Systems 289Quality by Design (QbD) 290

Process Analytical Technology (PAT) 291Risk analysis 291

Process validation lifecycle approach 292Validation Master Plan (VMP) 292

Quality by Design (QbD) and Compliance by Design (CbD) 292

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CbD design and objectives 293CbD critical compliance parameters 294CbD variables control strategy 294CbD monitoring and maintenance 295Associated concepts — PAT and risk analysis 295

Process Validation Lifecycle Approach and Quality SystemsLifecycle Approach 296

Validation Master Plans (VMP) and Compliance MasterPlans (CMP) 296

CbD/CMP Implementation Strategy and Approach 298CbD implementation process 298Example: material system business process 300

Material system subsections 301Subsection analysis and evaluation 301Performance measurement 301

CMP implementation process 305CbD/CMP Implementation Benefits —Why Implement CbD/CMP? 305

Organized and comprehensive focus on quality systemsand compliance 305

Cross-function thinking 306Consistent prioritized mitigation activities across functions 306Proactive variation identification and control strategy 306Standardized audit expectations and documentation 307Centralized tracking of commitments 307Organization commitment, transparency, and credibility 307

CbD/CMP Implementation — Practical Advice 308How to successfully implement CbD/CMP 308How not to implement CbD/CMP 309

Conclusions 310References 311About the Authors 313

11 The Regulatory Perspective for Small MoleculesRelated toVariations 315

Salma MichorRegulatory Information — CTD/eCTD 315

Format of the CTD 316Module 1 317Module 2 317Module 3 — the quality section (M4Q) 317Module 4 — the safety section (M4S) 318

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Module 5 — the efficacy section (M4E) 318Handling of Variations 318

Quality system elements 319Change management 319Regional aspects 321

QbD and Regulatory Information 323Location of information 323Design space and variations 324

Conclusion 324References 325About the Author 326

12 Role of the University inTeaching QbD 327Siegfried Schmitt

About the Author 334

Index 335

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PREFACE

The global pharmaceutical industry has experienced great advances in developmentand control of pharmaceutical products in the recent past. Quality by Design (QbD)has been at the forefront of this effort. The QbD concept became widely knownduring the 2000s and has evolved to emphasize and clarify the most importantelements of new product development. QbD emphasizes product and processunderstanding with technical focus based on risk analysis. QbD has integratedestablished and reliable methods (e.g., DOE) with newer concepts such as designspace, critical quality attributes (CQAs), critical process parameters (CPPs), andcritical material attributes (CMAs). QbD has encouraged a proactive approach toidentification and control of variation. The QbD initiative has successfullyorganized and structured these methods and applied them throughout the entireproduct lifecycle in a logical systematic approach.

The pharmaceutical scientific community has responded to the QbD initiativethrough professional association collaborations and as individuals in publishingconceptual approaches, methods, and research. This effort has resulted in clarifiedQbD approaches, more sophisticated new product development, and technicalinnovations. QbD has facilitated implementation of technology that is nowcommonplace in the pharmaceutical manufacturing environment. The QbDapproach has evolved from origins in small molecule dosage form developmentto applications far beyond its original scope. Opinion leaders now espouse theQbD approach to small molecule and biotech API manufacturing, analytical

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methods, pharmaceutical microbiology, computer systems, and various qualitysystem compliance applications. Such widespread application clearly demonstratesthat QbD has evolved and is accepted as a proven strategic methodology.

The publication of Quality By Design — Putting Theory into Practice by Dr.Siegfried Schmitt and coauthors is appropriate, relevant, and timely. Many of theinitial questions and concerns raised with QbD have been resolved. Several pilotdevelopment programs with regulatory submissions have been completed.Experiences have been communicated at international forums. The industry is nowpoised for increasing implementation of QbD methods. A compilation of thebackground, regulatory guidances, strategies and approaches, experiences, andapplications of QbD will be a useful and relevant resource in support of this nextphase of QbD implementation.

Quality By Design — Putting Theory into Practice is a comprehensivereference on QbD useful to new and experienced professionals in regulatedindustries. Further, it is a “how-to” book with useful and practical advice. This bookprovides a thorough and complete treatise on the subject including potentialapplications beyond the original scope of QbD. The regulatory basis of QbDincluding international guidance documents are discussed. Several chapters discussvarious aspects of implementation including organizational considerations, businessissues, connection to associated disciplines, and related concerns are presented. Anorganizational decision to implement QbD is a significant undertaking; thesechapters provide practical direction. Chapters on applications of QbD principles tothe bioprocess development, analytical laboratory and analytical methods, and topharmaceutical microbiology demonstrate the utility of the QbD methodology.Aspects of QbD in CTD regulatory submissions are discussed. The volume endswith discussion of the role of the university in teaching QbD and associated content.

Readers of Quality By Design — Putting Theory into Practice will find thisbook to be greatly valuable. This book provides comprehensive information that isclearly written and well-referenced. Chapter authors are knowledgeable andexperienced. Readers will learn the philosophy and fundamentals of QbD, know itshistory, understand regulatory status, appreciate the scope of implementation,develop a lifecycle perspective, and see many possible applications in theirorganizations. Discussion topics providing author experiences are extremelyuseful. Readers of this book will be well-prepared for the future direction of thedevelopment, manufacturing, quality, regulatory, and associated areas in the globalpharmaceutical industry.

Siegfried Schmitt

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