technology and knowledge transfer

TECHNOLOGYAND KNOWLEDGE

TRANSFER

KEYS TO SUCCESSFULIMPLEMENTATION AND

MANAGEMENT

Mark Gibson and Siegfried Schmitt Editors

www.pda.org/bookstore

CONTENTS

1 INTRODUCTIONAND OBJECTIVES 1Mark Gibson and Siegfried SchmittPurpose of the Book 1Technology Transfer and the Drug Discovery and

Development Process 5Why is Technology Transfer Important? 11Scope of the Book 13References 18About the Authors 20

2 TECHNOLOGY TRANSFER AND KNOWLEDGEMANAGEMENT OVER THE DRUG LIFECYCLE 23Siegfried SchmittIntroduction 23From Data to Knowledge 25Transferring or Sharing Data and Knowledge 26Knowledge Sharing Standard Operating Procedure (SOP) 31Final Conclusions 32References 33About the Author 33

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3 TECHNOLOGY TRANSFER,THE REGULATORYAND BUSINESS PERSPECTIVE 35Alan Harris and Siegfried SchmittIntroduction 35Regulatory Requirements for Technology Transfer 36Electronic Records/Electronic Signatures (ER/ES) 42Safety, Health and Environmental (SHE) Regulations 42General Safety and Health Considerations 42Waste Disposal 44Potential Impact of the Regulations Concerning

Import/Export of Chemicals 45Economic Factors 46NewTechnology 47Social Aspects and the Impact on Technology Transfer 50Language 50Culture 52Team Building 52Conclusions 54References 55About the Authors 57

4 TECHNOLOGY TRANSFER ORGANISATIONSTRATEGY AND PLANNING 59Steve Burns and Mark GibsonIntroduction 59Stages of the Technology Transfer Process 62

Stage 1: pre-technology transfer preparation 63Stage 2: scale-up and establish process at commercial scale 71Stage 3: plan and perform process validation 73

Management of Change 76Organisation 77Teams Supporting the Technology Transfer Process 80

Global Technology Transfer Management Team (GTTMT) 80Sending site (R&D) drug substance project team 82Sending site (R&D) drug product project team 82Receiving site(s) project teams 85

Documentation Required to Support Technology Transfer 87Planning 89Timings 90References 93About the Authors 94

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5 CHEMICAL DRUG SUBSTANCE DEVELOPMENTANDTECHNOLOGYTRANSFER 97Alan HarrisIntroduction 97The Drug Substance Development Process 98

Introduction to drug substance process researchand development 98

The role of process R&D 100Good process design 103The challenge of discontinuous development 108Barriers to process changes 110

Introduction to Technology Transfer for Drug Substance 111Aims of Technology Transfer 113The Impact of Technology Transfer Issues on Process

Development Strategies 114Early development decisions 114Route selection, regulatory and sourcing strategies 116Process freeze 117

Potential Impact of REACH Regulations 118Applying Risk Analysis and Risk Management to Technology

Transfer Decisions 119Managing the Technology Transfer Programme 120

Principles for technology transfer 121The technology transfer team 122

Documentation to be Transferred or Generated DuringTechnology Transfer and Establishment of the Process 123

Success Criteria for Technology Transfer 124Process Validation 125Case Study 1: Remacemide Hydrochloride 129

Early process evaluation 129Process R&D work 131Early technology transfer of the process for DPAP 131Second source for DPAP 134Technology transfer of the final stages of the process 135Salt selection, polymorphism and particle size 136Lessons from case study 1 136

Case Study 2: Sibenadet Hydrochloride 138Synthesis and technology transfer of the benzothiazolone

amine intermediate 138Synthesis and technology transfer of the intermediate

benzoate ester 141Technology transfer of the final steps 141Control of physical form 143

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Crystallisation/drying issues 144Overall lessons from case study 2 145

Case Study 3: Gefitinib (Iressa®) 147Overall lessons from case study 3 151

Future Directions for Process Development and the Impacton Technology Transfer 152Microwave and ultrasonic reactors 152Micro-reactors technology and continuous processes 153Chromatographic purification techniques 153

Overall Conclusions 154References 157About the Author 160

6 CHEMICAL DRUG PRODUCT DEVELOPMENTAND TECHNOLOGY TRANSFER 161Mark GibsonIntroduction 161Product Design 168Product Optimisation 172Process Design and Optimisation 177Process Capability and Robustness 182Use of PAT to Aid Process Optimisation and Understanding 183Scale-up and Technology Transfer 187Process Validation 190

Clinical trials process validation 191Cleaning validation 192Process validation of the commercial process

— acceptance by production 194Post-validation and Post-regulatory Approval Changes 200Documenting the Drug Development Process 203Chemical (Small Molecules) Drug Product Technology

Transfer Case Studies 206Case study 1: immediate release film coated tablet 206Case study 2 211Case study 3: metered dose inhaler 213

References 215About the Author 218

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7 DRUG SUBSTANCE MANUFACTURINGPROCESS DEVELOPMENTANDTECHNOLOGYTRANSFERS — BIOPHARMACEUTICALS 219Lamine BouakazIntroduction 219Biopharmaceutical Drug Substances 221

Characteristics of biopharmaceutical drug substances 221Biopharmaceutical vs. chemical manufacture 223

Development Phases for Biopharmaceuticals 226Pre-clinical program for biopharmaceuticals 226Clinical trials program for biopharmaceuticals 229Registration of biopharmaceuticals 230Commercialization and product lifecycle: Phase IV 231

Development of Biopharmaceutical Drug SubstanceManufacturing Processes 232Overview of biopharmaceuticals drug substance

manufacturing processes 233The Quality Target Product Profile 235Process development for pre-clinical drug substance

manufacture 236Process development for Phase I/II biopharmaceutical

drug substance manufacture 240Phase III biopharmaceutical drug substance

manufacturing process development 249Process and product characterization studies 260Process validation 263Registration 266Knowledge management 268

Biopharmaceutical Drug Substance Manufacturing ProcessTechnology Transfer from Development to Commercial Scale 268Preclinical to Phase I/II manufacturing process

technology transfer 269Phase I/II to Phase III manufacturing process

technology transfer 274Biopharmaceutical Drug Substance Manufacturing

Process Technology Transfer between CommercialManufacturing Sites 278

References 284Abbreviations 286About the Author 288

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8 ANALYTICAL METHODOLOGYAND SPECIFICATIONS 289Mark HindleIntroduction 289

Method transfer scope 291Analytical technology transfer: what to do

before formal transfer starts 292QC involvement during method validation 295QC involvement post validation 296Analytical technology transfer: when does it start

and when does it end? 297Principles of analytical methodology transfer 299Change control 302Competition and timing 303

The Technology Transfer Process for AnalyticalMethodology and Specifications 303Stages of analytical method transfer 304

Stage 1: Analytical Strategy 306Analytical method transfer team 306Analytical transfer strategy document 309

Stage 2: Knowledge and Information Transfer 313Information package 314Knowledge transfer 315

Stage 3: Method Transfer Protocol 320Testing design 322Use of statistics 328Approval of method transfer protocol 330

Stage 4: Analytical Testing 331Stage 5: Summary Report 333

Transfer approval 333Post transfer monitoring 334Post approval changes 334Method transfer — potential problems

and how to avoid them 335Summary 345References 346About the Author 348

APPENDIX: SPECIAL CONSIDERATIONS FORTRANSFER OF BIOASSAY METHODS 349Sharon Longhurst and Ralf HessIntroduction 349Cell Based Assays 351

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Issues for Consideration with Respect to AnalyticalTransfer Strategy 352

Knowledge and Information Transfer 355Method Transfer Protocol 356Ligand Binding Assays 358Issues for Consideration with Respect to Analytical Transfer 359In Vivo Assays 359Issues for Consideration with Respect to

Analytical Transfer Strategy 360Knowledge and Information Transfer 360Method Transfer Protocol 361References 361About the Authors 362

9 TECHNOLOGY TRANSFER, OUTSOURCEDACTIVITIES MANAGEMENT 365Siegfried SchmittIntroduction 365

The purpose of technical/quality agreements 365What are technical/quality agreements? 366

Quality Agreements 367Applicable regulations

Minimum Requirements for Contentsof a Technical/Quality Agreement 371

Key Performance Indicators for Compliance ThroughQuality Agreements (PQA, premier-research.com) 375

Challenges to Companies in Developing Quality Agreements 377Summary 377Examples 378References 378About the Author 379

10 AUDITSAND INSPECTIONS 381Mark GibsonIntroduction 381The PAI Process 385Common PAI Deficiencies 390PAI —What will be Inspected? 392PAI — How to Prepare? 395

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Documented PAI policy 395Formation of PAI preparation team(s) 396Documentation, data review and retrieval 399Product development reports 402Good level of cGMP and compliance 406Training and awareness 406

PAI and Launch 408Technology Transfer: Final Conclusions 409References 411About the Author 412

11 TRAINING,AN ESSENTIAL ELEMENTOF TECHNOLOGY TRANSFER 415Siegfried SchmittIntroduction 415The Quality by Design Challenge 416Learning fromTechnology Transfer 417Developing a Training Strategy 418

Scope of training 418Prioritisation and context of training needs 419Detailed contents of training programmes 420Methods and tools for delivering training 421Management of training programmes 422Trainers 423Templates and style guidelines 423Training documentation 424Language used for training programmes 425

Measuring the Success of Training 425Auditing of Training 425Conclusions 426References 426About the Author 427

Glossary 429

Index 459

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technology and knowledge transfer

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