Verfügbarkeit: The challenge of CMC regulatory compliance for biopharmaceuticals

The challenge of CMC regulatory compliance for biopharmaceuticals:

Gespeichert in:

Bibliographische Detailangaben
1. Verfasser:	Geigert, John (VerfasserIn)
Format:	Buch
Sprache:	English
Veröffentlicht:	New York, NY Kluwer Academic / Plenum Publishers 2004
Online-Zugang:	Inhaltsverzeichnis
Beschreibung:	Includes bibliographical references and index
Beschreibung:	XXII, 350 S.
ISBN:	0306480409

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245	1	0	\|a The challenge of CMC regulatory compliance for biopharmaceuticals \|c John Geigert
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Datensatz im Suchindex

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adam_text	Z831- THE CHALLENGE OF CMC REGULATORY COMPLIANCE FOR BIOPHARMACEUTICALS JOHN GEIGERT BIOPHARMACEUTICAL QUALITY SOLUTIONS CARLSBAD, CALIFORNIA KLUWER ACADEMIC / PLENUM PUBLISHERS NEW YORK, BOSTON, DORDRECHT, LONDON, MOSCOW CONTENTS LIST OF TABLES XIX LIST OF FIGURES XXIII CHAPTER 1 BIOPHARMACEUTICAL CMC REGULATORY COMPLIANCE: WHAT IS IT? 1. DEFINING OUR TERMS 1 1.1. WHAT IS A BIOPHARMACEUTICAL ? 2 1.2. WHAT IS CMC 2 1.3. WHAT IS CMC REGULATORY COMPLIANCE ? 3 2. UNDER THE BIOPHARMACEUTICAL UMBRELLA 3 2.1. RECOMBIRIANT DNA-DERIVED PROTEINS. 3 2.2. MONOCLONAL ANTIBODIES 5 2.3. GENE THERAPY 7 2.4. ANIMAL/PLANT TRANSGENICS 8 2.5. RAPID PACE OF BIOPHARMACEUTICAL DEVELOPMENT 8 3. REGULATORY DEVELOPMENT OF BIOPHARMACEUTICALS 9 3.1. THE DRUG DEVELOPMENT PROCESS 9 3.2. REGULATORY AGENCY REVIEW 10 3.2.1. U.S. FDA 10 3.2.2. EMEA 11 4. CMC REGULATORY COMPLIANCE TRACK RECORD 13 4.1. DRUGS AND BIOLOGIES 13 4.2. BIOPHARMACEUTICALS 14 IX X CONTENTS CHAPTER 2 ARE BIOPHARMACEUTICALS REALLY DIFFERENT? 1. PERCEPTION OR REALITY? 17 1.1. FIVE QUESTIONS FREQUENTLY ASKED 18 1.2. BOTTOM LINE QUESTION 18 2. REGULATORY AGENCIES SPEAK 18 2.1. U.S. FDA 19 2.2. EMEA 20 2.3. ICH 20 3. THREE UNIQUE CMC CHALLENGES FOR BIOPHARMACEUTICALS 21 3.1. THE USE OF LIVING RECOMBINANT ORGANISMS 21 3.2. THE PRODUCTS THEMSELVES 22 3.3. THE IMPACT OF THE MANUFACTURING PROCESS 22 4. CMC MEETINGS WITH THE FDA TAKE ON GREATER IMPORTANCE ..23 4.1. CMC COMMUNICATION WITH FDA IS CRITICAL 25 4.2. PREPARING FOR THE CMC MEETING 26 4.3. PRE-IND MEETING 27 4.4. END OF PHASE 2 (EOP2) MEETING 29 4.3. PRE-BLA/NDA MEETING 31 5. WHAT ABOUT CMC MEETINGS WITH EMEA? 33 6. BIOPHARMACEUTICALS NEED TO BE TREATED DIFFERENTLY 34 CHAPTER 3 DEVELOPING THE CORPORATE CMC REGULATORY COMPLIANCE STRATEGY 1. THREE KEY ELEMENTS FOR A COMPLETE CMC STRATEGY 35 1.1. ELEMENT 1: THE BROAD CMC SCOPE MUST BE CONSIDERED 36 1.2. ELEMENT 2: ANY UNIQUE CMC ISSUES MUST BE ADDRESSED 37 1.3. ELEMENT 3: MUST MEET MINIMUM CMC REGULATORY REQUIREMENTS 38 2. THE MINIMUM CMC CONTINUUM 39 3. MINIMUM CMC REQUIREMENTS FOR CLINICAL DEVELOPMENT 40 3.1. AN OVERVIEW 40 3.2. PHASE 1 46 3.3. PHASE 2 AND 3 47 4. FULL CMC REQUIREMENTS FOR DOSSIER FILING 48 4.1. COMPARISON OF BLA/NDA AND CTD CMC FORMATS 49 4.2. ADEQUATE RESOURCES REQUIRED TO COMPILE THE FULL CMC DOSSIER 51 4.3. QUALITY OF CMC CONTENT PRESENT IN DOSSIER IS CRITICAL 52 5. CASE-BY-CASE CMC STRATEGY SPECIFICS 54 CONTENTS XI CHAPTER 4 CAN T IGNORE CGMPS 1. NOT OPTIONAL 57 1.1 WHAT ARE CGMPS ? 57 1.2 THREE MAIN GMP QUESTIONS 58 2. GMPS FOR EVERYTHING 59 2.1. FOR FINISHED DRUG PRODUCTS 59 2.2. REQUIRED FOR APIS ALSO 63 2.3. EXTRA GMPS FOR BIOPHARMACEUTICALS 66 3. WHERE IN THE MANUFACTURING PROCESS SHOULD GMP BEGIN?...68 4. WHEN DURING CLINICAL DEVELOPMENT SHOULD GMP BEGIN? 70 4.1. API CLINICAL TRIAL MATERIALS 70 4.2. DRUG PRODUCT CLINICAL TRIAL MATERIALS 73 5. CONSEQUENCES OF NOT FOLLOWING GMPS 73 5.1. ISSUES WITH MARKET APPROVED BIOPHARMACEUTICALS 74 5.2. ISSUES DURING CLINICAL DEVELOPMENT 77 5.3. HOW TO AVOID GMP DIFFICULTIES WITH THE FDA 78 6. STRATEGIC CMC TIPS FOR GMP COMPLIANCE 80 CHAPTER 5 RECOMBINANT SOURCE MATERIAL: MASTER/WORKING BANKS 1. NEEDED: RELIABLE, CONTINUOUS, STABLE GENETIC SOURCE 83 1.1. THREE PRIMARY CMC CONCERNS FOR BANKS 84 1.2. GENETIC CONSTRUCTION OF A BANK 85 2. SO MANY HOSTS TO CHOOSE FROM 88 2.1. BANK TERMINOLOGY 88 2.2. CHOOSING THE HOST 89 2.2.1. DRIVERS TO REACH A DECISION 89 2.2.2. WHY CHOOSE RECOMBINANT CELLS? 90 2.2.3. WHY BIOENGINEERED ANIMALS OR PLANTS? 91 3. CMC GUIDANCE ON PREPARATION OF A BANK 92 3.1. ACCURATE AND THOROUGH DESCRIPTION OF PREPARATION 92 3.1.1. RECOMBINANT CELL BANKS 93 3.1.2. TRANSGENIC BANKS 95 3.2. WHY DOES THE FDA WANT SO MUCH CMC DOCUMENTATION? 98 3.3. WHEN IS FULL CMC DOCUMENTATION NEEDED? 99 3.4. WHAT IF CMC DOCUMENTATION IS MISSING? 100 3.5. DON T FORGET GMPS DURING PREPARATION OF THE BANK 100 4. CMC GUIDANCE ON CHARACTERIZATION OF A BANK 101 XII CONTENTS 4.1. APPROPRIATE AND SUFFICIENT CHARACTERIZATION 102 4.1.1. SIX KEY ELEMENTS FORA THOROUGH CHARACTERIZATION 102 4.1.2. RECOMBINANT CELL BANK CHARACTERIZATION 103 4.1.3. EXAMPLE OF CHARACTERIZATION OF A BACTERIAL CELL BANK 105 4.1.4. EXAMPLE OF CHARACTERIZATION OF A MAMMALIAN CELL BANK 106 4.2. HOW MUCH CHARACTERIZATION AND WHEN? 107 4.3. CRITICAL CONCERN FOR VIRUS SAFETY IN BANKS 109 4.4. MINIMIZING THE RISK OF TSES ILL 5. A SUCCESSFUL CMC STRATEGY FOR BANKS 113 CHAPTER 6 PRODUCTION: EXPANSION OF THE RECOMBINANT ORGANISM AND EXPRESSION OF THE BIOPHARMACEUTICAL 1. GOALS: IDENTITY, CAPACITY AND CONSISTENCY 115 1.1. TWO MAJOR CMC REGULATORY CONCERNS FOR PRODUCTION 116 1.2. NEED FOR HIGH AND CONSISTENT EXPRESSION OF THE BIOPHARMACEUTICAL 116 1.3. WHAT IS A PRODUCTION PROCESS ? 117 1.3.1. TYPES OF BIOREACTORS FOR CELL-BASED PRODUCTION 118 1.3.2. HARVESTING PROCEDURES FOR BIOPHARMACEUTICALS 119 1.4. PRODUCTION PROCESSES FAMILIAR TO THE FDA 119 2. ADEQUATE DESCRIPTION OF THE PRODUCTION PROCESS 122 2.1. DURING CLINICAL DEVELOPMENT 122 2.1.1. PHASE 1 IND SUBMISSION 122 2.1.2. PHASE 2 IND SUBMISSION 124 2.1.3. PHASE 3 IND SUBMISSION 124 2.2. PREPARING THE BLA/NDA SUBMISSION 125 3. VALIDATION OF A CELL-BASED PRODUCTION PROCESS 128 3.1. WHEN SHOULD VALIDATION OF THE PRODUCTION PROCESS OCCUR? 129 3.2. FIVE MAJOR AREAS INVOLVED IN VALIDATION OF THE PRODUCTION PROCESS 130 3.2.1. THE PRODUCTION FACILITY, UTILITIES AND PROCESS EQUIPMENT 130 3.2.2. MONITORING OF GROWTH PARAMETERS 132 3.2.3. IN-PROCESS CONTROLS 133 3.2.4. GENETIC STABILITY 136 3.2.5. CLEANING VALIDATION 137 3.3. FINAL COMMENTS ON PROCESS VALIDATION 140 4. ADDITIONAL PRODUCTION CONTROLS AND CONCERNS 140 4.1. CELL-BASED PRODUCTION PROCESSES 140 4.1.1. CELL CULTURE MEDIA ACCEPTANCE CRITERIA 141 4.1.2. AVOIDANCE OF ANIMAL- AND HUMAN-DERIVED RAW MATERIALS 141 4.1.3. CONTAINMENT OF THE RECOMBINANT ORGANISM 144 4.1.4. CONTAMINATION CONTROL FOR ASEPTIC PROCESSING OPERATIONS 144 4.2. GENE THERAPY PRODUCTION PROCESSES 146 4.2.1. CONTROL OF THE CELLS 146 CONTENTS XIII 4.2.2. RAC REVIEW AND APPROVAL OF THE PRODUCTION PROCESS 148 4.3. TRANSGENIC ANIMAL PRODUCTION PROCESSES 149 4.3.1. PRODUCTION-CONTROLS 149 4.3.2. PROTECTING THE GENE POOL 151 4.4. TRANSGENIC PLANT PRODUCTION PROCESSES 151 4.4.1. PHARMING CONTROLS 152 4.4.2. USDA/APHIS PROTECTING THE GENE POOL 155 5. WHAT CAN GO WRONG 157 6. STRATEGIC CMC TIPS FOR PRODUCTION 158 CHAPTER 7 PURIFICATION OF THE BIOPHARMACEUTICAL 1. GOALS: PURITY, RECOVERY AND CONSISTENCY 161 1.1. TWO MAJOR CMC REGULATORY CONCERNS FOR PURIFICATION 162 1.2. NEED FOR HIGH RECOVERY OF A PURE PRODUCT 162 1.3. WHAT IS A PURIFICATION PROCESS ? 163 1.3.1. PHYSICAL SEPARATIONS METHODS FOR BIOPHARMACEUTICALS 164 1.3.2. CHROMATOGRAPHIC PURIFICATION METHODS FOR BIOPHARMACEUTICALS 165 1.4. PURIFICATION PROCESSES FAMILIAR TO THE FDA 167 2. ADEQUATE DESCRIPTION OF THE PURIFICATION PROCESS 169 2.1. DURING CLINICAL DEVELOPMENT 170 2.1.1. PHASE 1 IND SUBMISSION 170 2.1.2. PHASE 2 IND SUBMISSION 171 2.1.3. PHASE 3 IND SUBMISSION 172 2.2. PREPARING THE BLA/NDA SUBMISSION 172 3. FACILITY AND UTILITY CONCERNS 174 3.1. DESIGN AND OPERATION 175 3.2. ENVIRONMENTAL MONITORING 176 4. PURIFICATION PROCESS VALIDATION 177 4.1. WHEN SHOULD PURIFICATION VALIDATION OCCUR? 177 4.2. PROCESS VALIDATION CONCERNS FOR A CHROMATOGRAPHIC STEP 178 4.3. PROCESS VALIDATION CONCERNS FOR A FILTRATION STEP 182 5. IN-PROCESS CONTROLS 1 83 6. PROCESS-RELATED IMPURITY PROFILE 185 7. VIRAL SAFETY EVALUATION 188 7.1. GENERAL STUDY DESIGN 189 7.2. JUSTIFICATION OF THE CHOICE OF VIRUSES 191 7.3. CALCULATION OF VIRUS REDUCTION FACTORS 193 7.4. VIRUS SAFETY CALCULATION 195 7.5. WORTH ALL THE TROUBLE AND COST? 196 7.6. WHEN SHOULD THE VIRAL CLEARANCE STUDIES BE PERFORMED? 196 8. PURIFICATION CONTROLS FOR GENE THERAPY PROCESSES 197 9. WHAT CAN GO WRONG 197 XIV CONTENTS 10. STRATEGIC CMC TIPS FOR PURIFICATION 199 CHAPTER 8 BIOPHARMACEUTICAL DRUG PRODUCT MANUFACTURING 1. THREE BASIC CMC REGULATORY CONCERNS 201 2. FORMULATION OF A BIOPHARMACEUTICAL 20 3 2.2. FORMULATIONS FAMILIAR TO FDA 203 2.3. CHEMCIAL MODIFICATION OF API PRIOR TO FORMULATION 205 3. BIOPHARMACEUTIAL MANUFACTURING PROCESSES 206 4. ADEQUATE DESCRIPTION OF THE MANUFACTURING PROCESS 208 4.1. DURING CLINICAL DEVELOPMENT 209 4.1.1. PHASE 1 IND SUBMISSION 209 4.1.2. PHASE 2 IND SUBMISSION 210 4.1.3. PHASE 3 IND SUBMISSION 211 4.2. BLA/NDA SUBMISSION 212 5. ADEQUATE CONTROL OVER THE MANUFACTURING PROCESS 213 5.1. REGULATORY REQUIREMENTS FOR MARKET APPROVED PRODUCTS 214 5.2. REGULATORY EXPECTATIONS DURING CLINICAL DEVELOPMENT 216 6. WHAT CAN GO WRONG 217 7. STRATEGIC CMC TIPS FOR DRUG PRODUCT MANUFACTURING 218 CHAPTER 9 PHYSICOCHEMICAL/BIOLOGICAL ANALYSIS OF THE BIOPHARMACEUTICAL PRODUCT 1. A CHALLENGING ANALYSIS 222 1.1. GOALS: CONSISTENT, SAFE, POTENT AND PURE PRODUCT 222 1.2. RELATIONSHIP BETWEEN PRODUCT CHARACTERIZATION AND QC TESTING 223 2. UNRAVELING THE MOLECULAR PROPERTIES 224 2.1. MOLECULAR VARIANTS FOR DNA 224 2.2. MOLECULAR VARIANTS FOR PROTEINS 224 2.3. PLETHORA OF ANALYTICAL METHODS AVAILABLE FOR PROTEINS 226 3. CHARACTERIZATION OF BIOPHARMACEUTICALS 229 3.1. REGULATORY EXPECTATIONS DURING CLINICAL DEVELOPMENT 229 3.1.1. PHASE 1 IND SUBMISSION 229 3.1.2. PHASE 2 IND SUBMISSION 230 3.1.3. PHASE 3 IND SUBMISSION 230 3.2 REGULATORY EXPECTATIONS FOR THE BLA/NDA SUBMISSION 231 3.3. FULL CHARACTERIZATION OF RECOMBINANT PROTEINS AND MONOCLONAL ANTIBODIES ....232 CONTENTS XV 3.3.1. WHAT IS FULL CHARACTERIZATION? 232 3.3.2. HOST-DEPENDENT GLYCOSYLATION 236 3.3.3. HOST-DEPENDENT IMPURITIES 237 3.3.4. IMPACT OF MOLECULAR VARIANTS ON BIOLOGICAL ACTIVITY 238 3.4. CHARACTERIZATION OF A GENE THERAPY BIOPHARMACEUTICAL 239 3.5. APPLYING THE MINIMUM CMC CONTINUUM TO CHARACTERIZATION 240 4. RELEASE TESTING AND SPECIFICATIONS 241 4.1. REGULATORY EXPECTATIONS DURING CLINICAL DEVELOPMENT 241 4.1.1. PHASE 1 IND SUBMISSION 241 4.1.2. PHASE 2 IND SUBMISSION 242 4.1.3. PHASE 3 IND SUBMISSION 242 4.2. REGULATORY EXPECTATIONS FOR THE BLA/NDA SUBMISSION 243 4.3. APPROPRIATE RELEASE TEST METHODS 244 4.3.1. NOT ALL RELEASE TESTING IS AT API OR DRUG PRODUCT STAGE 244 4.3.2. ELIMINATION OF RELEASE TESTING BY PROCESS VALIDATION 245 4.3.3. TEST METHOD PARAMETERS REQUIRED FOR RELEASE: PROTEINS 246 4.3.4. TEST METHOD PARAMETERS REQUIRED FOR RELEASE: DNA VECTORS 250 4.4. THE BIOASSAY - ABSOLUTE REQUIREMENT FOR A BIOPHARMACEUTICAL 252 4.5. TEST METHOD VALIDATION - HOW MUCH AND WHEN? 253 4.5.1. REGULATORY EXPECTATIONS FOR TEST METHOD VALIDATION 254 4.5.2. ASSAY QUALIFICATION DURING CLINICAL DEVELOPMENT 256 4.5.3. APPLYING THE MINIMUM CMC CONTINUUM TO TEST METHOD VALIDATION 257 4.6. THE ART OF SETTING A SPECIFICATION 258 4.6.1. DEVELOPMENT OF A SPECIFICATION 258 4.6.2. RELEASE VERSUS SHELF-LIFE SPECIFICATIONS 261 4.6.3. ARE THERE REQUIRED PURITY/IMPURITY LIMITS? 261 4.6.4. STRATEGIC CMC TIPS FOR SETTING SPECIFICATIONS 263 5. BIOPHARMACEUTICAL STABILITY AND EXPIRATION DATING 266 5.1. REGULATORY EXPECTATIONS DURING CLINICAL DEVELOPMENT 267 5.1.1. PHASE 1 IND SUBMISSION 267 5.1.2. PHASE 2 IND SUBMISSION 267 5.1.3. PHASE 3 IND SUBMISSION 268 5.2. REGULATORY EXPECTATIONS FOR THE BLA/NDA SUBMISSION 270 5.3. STABILITY-INDICATING TEST METHODS 272 5.4. SETTING AN EXPIRATION DATE 274 5.5. HOW MUCH CHANGE IS ACCEPTABLE? 277 5.6. APPLYING THE MINIMUM CMC CONTINUUM TO STABILITY 278 6. WHAT CAN GO WRONG 279 6.1. INCOMPLETE RELEASE/STABILITY TESTING REQUIREMENTS IN BLA/NDA FILING 280 6.2. FDA 483 INSPECTIONAL OBSERVATIONS 281 6.3. BIOPHARMACEUTICAL PRODUCT RECALLS 282 6.4. MISUSE IN THE CLINIC 284 7. STRATEGIC CMC TIPS FOR BIOPHARMACEUTICAL ANALYSIS 285 XVI CONTENTS CHAPTER 10 MANAGING PROCESS CHANGES - DEMONSTRATING PRODUCT COMPARABILITY 1. NOT AS EASY AS IT SEEMS! 287 2. REGULATORY MANAGEMENT OF PROCESS CHANGES 28 8 2.1. PRE-IND STAGE 289 2.2. IND CLINICAL DEVELOPMENT STAGES 289 2.3. BLA/NDA FILING STAGE 290 2.4. POST-APPROVAL MARKET STAGE 291 3. DEMONSTRATING PRODUCT COMPARABILITY 296 3.1 GUIDANCE DOCUMENTS ON PRODUCT COMPARABILITY 297 3.2. A THREE-TIERED TESTING HIERARCHY 297 3.3. DESIGNING THE COMPARABILITY STUDY - FOUR MAJOR FACTORS 300 3.3.1. FACTOR 1: CLINICAL DEVELOPMENT STAGE FOR THE CHANGE 301 3.3.2. FACTOR 2: WHERE IN THE PROCESS THE CHANGE IS INTRODUCED 301 3.3.3. FACTOR 3: QUALITY CRITERIA CONSIDERATIONS 302 3.3.4. FACTOR 4: SUITABILITY OF AVAILABLE ANALYTICAL METHODS 302 3.4. REGULATORY AGENCIES HAVE FINAL APPROVAL 302 3.5 IF IN DOUBT, ASK! 303 4. COMPARABILITY PROTOCOLS 304 5. CASE EXAMPLES OF BIOPHARMACEUTICAL COMPARABILITY 305 5.1. COMPARABILITY SUCCESS STORIES 306 5.2. COMPARABILITY SURPRISES 308 5.3. NOT COMPARABLE 309 CHAPTER 11 BIOPHARMACEUTICAL CMC OUTSOURCING 1. REGULATORY EXPECTATIONS FOR CONTRACTED WORK 311 1.1. WHY OUTSOURCE? 311 1.2. WRITTEN QUALITY AGREEMENTS REQUIRED 312 1.3. REGULATORY REQUIREMENTS DURING CLINICAL DEVELOPMENT 313 1.4. REGULATORY REQUIREMENTS FOR THE BLA/NDA SUBMISSION 313 1.5. REGULATORY REQUIREMENTS POST-MARKET APPROVAL 314 2. DEVELOPING THE INTERCOMPANY QUALITY AGREEMENT 315 2.1. TWO VIEWPOINTS 315 2.1.1. THE BIOPHARMACEUTICAL COMPANY SEEKING TO OUTSOURCE 315 2.1.2. THE CONTACT MANUFACTURER OFFERING OUTSOURCING 316 2.1.3. MAXIMUM LEVERAGE 316 2.2. CONTENTS OF AN IQA 316 3. STRATEGIC CMC TIPS FOR OUTSOURCING 319 CONTENTS XVII CHAPTER 12 CONCLUDING THOUGHTS ON BIOPHARMACEUTICAL CMC REGULATORY COMPLIANCE 1. MOST HELPFUL WEBSITES FOR BIOPHARMACEUTICALS 322 2. WEBSITE RESOURCES FROM FDA 323 3. RESOURCES FROM EMEA 329 4. RESOURCES FROM PROFESSIONAL ASSOCIATIONS 330 5. CONCLUSION 330 REFERENCES 331
adam_txt	Z831- THE CHALLENGE OF CMC REGULATORY COMPLIANCE FOR BIOPHARMACEUTICALS JOHN GEIGERT BIOPHARMACEUTICAL QUALITY SOLUTIONS CARLSBAD, CALIFORNIA KLUWER ACADEMIC / PLENUM PUBLISHERS NEW YORK, BOSTON, DORDRECHT, LONDON, MOSCOW CONTENTS LIST OF TABLES XIX LIST OF FIGURES \ XXIII CHAPTER 1 BIOPHARMACEUTICAL CMC REGULATORY COMPLIANCE: WHAT IS IT? 1. DEFINING OUR TERMS 1 1.1. WHAT IS A 'BIOPHARMACEUTICAL'? 2 1.2. WHAT IS'CMC 2 1.3. WHAT IS 'CMC REGULATORY COMPLIANCE'? 3 2. UNDER THE BIOPHARMACEUTICAL UMBRELLA 3 2.1. RECOMBIRIANT DNA-DERIVED PROTEINS. 3 2.2. MONOCLONAL ANTIBODIES 5 2.3. GENE THERAPY 7 2.4. ANIMAL/PLANT TRANSGENICS 8 2.5. RAPID PACE OF BIOPHARMACEUTICAL DEVELOPMENT 8 3. REGULATORY DEVELOPMENT OF BIOPHARMACEUTICALS 9 3.1. THE DRUG DEVELOPMENT PROCESS 9 3.2. REGULATORY AGENCY REVIEW 10 3.2.1. U.S. FDA 10 3.2.2. EMEA 11 4. CMC REGULATORY COMPLIANCE TRACK RECORD 13 4.1. DRUGS AND BIOLOGIES 13 4.2. BIOPHARMACEUTICALS 14 IX X CONTENTS CHAPTER 2 ARE BIOPHARMACEUTICALS REALLY DIFFERENT? 1. PERCEPTION OR REALITY? 17 1.1. FIVE QUESTIONS FREQUENTLY ASKED 18 1.2. BOTTOM LINE QUESTION 18 2. REGULATORY AGENCIES SPEAK 18 2.1. U.S. FDA 19 2.2. EMEA 20 2.3. ICH 20 3. THREE UNIQUE CMC CHALLENGES FOR BIOPHARMACEUTICALS 21 3.1. THE USE OF LIVING RECOMBINANT ORGANISMS 21 3.2. THE PRODUCTS THEMSELVES 22 3.3. THE IMPACT OF THE MANUFACTURING PROCESS 22 4. CMC MEETINGS WITH THE FDA TAKE ON GREATER IMPORTANCE .23 4.1. CMC COMMUNICATION WITH FDA IS CRITICAL 25 4.2. PREPARING FOR THE CMC MEETING 26 4.3. PRE-IND MEETING 27 4.4. END OF PHASE 2 (EOP2) MEETING 29 4.3. PRE-BLA/NDA MEETING 31 5. WHAT ABOUT CMC MEETINGS WITH EMEA? 33 6. BIOPHARMACEUTICALS NEED TO BE TREATED DIFFERENTLY 34 CHAPTER 3 DEVELOPING THE CORPORATE CMC REGULATORY COMPLIANCE STRATEGY 1. THREE KEY ELEMENTS FOR A COMPLETE CMC STRATEGY 35 1.1. ELEMENT 1: THE BROAD CMC SCOPE MUST BE CONSIDERED 36 1.2. ELEMENT 2: ANY UNIQUE CMC ISSUES MUST BE ADDRESSED 37 1.3. ELEMENT 3: MUST MEET MINIMUM CMC REGULATORY REQUIREMENTS 38 2. THE MINIMUM CMC CONTINUUM 39 3. MINIMUM CMC REQUIREMENTS FOR CLINICAL DEVELOPMENT 40 3.1. AN OVERVIEW 40 3.2. PHASE 1 46 3.3. PHASE 2 AND 3 47 4. FULL CMC REQUIREMENTS FOR DOSSIER FILING 48 4.1. COMPARISON OF BLA/NDA AND CTD CMC FORMATS 49 4.2. ADEQUATE RESOURCES REQUIRED TO COMPILE THE FULL CMC DOSSIER 51 4.3. QUALITY OF CMC CONTENT PRESENT IN DOSSIER IS CRITICAL 52 5. 'CASE-BY-CASE' CMC STRATEGY SPECIFICS 54 CONTENTS XI CHAPTER 4 CAN'T IGNORE CGMPS 1. NOT OPTIONAL 57 1.1 WHAT ARE'CGMPS'? 57 1.2 THREE MAIN GMP QUESTIONS 58 2. GMPS FOR EVERYTHING 59 2.1. FOR FINISHED DRUG PRODUCTS 59 2.2. REQUIRED FOR APIS ALSO 63 2.3. EXTRA GMPS FOR BIOPHARMACEUTICALS 66 3. WHERE IN THE MANUFACTURING PROCESS SHOULD GMP BEGIN?.68 4. WHEN DURING CLINICAL DEVELOPMENT SHOULD GMP BEGIN? 70 4.1. API CLINICAL TRIAL MATERIALS 70 4.2. DRUG PRODUCT CLINICAL TRIAL MATERIALS 73 5. CONSEQUENCES OF NOT FOLLOWING GMPS 73 5.1. ISSUES WITH MARKET APPROVED BIOPHARMACEUTICALS 74 5.2. ISSUES DURING CLINICAL DEVELOPMENT 77 5.3. HOW TO AVOID GMP DIFFICULTIES WITH THE FDA 78 6. STRATEGIC CMC TIPS FOR GMP COMPLIANCE 80 CHAPTER 5 RECOMBINANT SOURCE MATERIAL: MASTER/WORKING BANKS 1. NEEDED: RELIABLE, CONTINUOUS, STABLE GENETIC SOURCE 83 1.1. THREE PRIMARY CMC CONCERNS FOR BANKS 84 1.2. GENETIC CONSTRUCTION OF A BANK 85 2. SO MANY HOSTS TO CHOOSE FROM 88 2.1. BANK TERMINOLOGY 88 2.2. CHOOSING THE HOST 89 2.2.1. DRIVERS TO REACH A DECISION 89 2.2.2. WHY CHOOSE RECOMBINANT CELLS? 90 2.2.3. WHY BIOENGINEERED ANIMALS OR PLANTS? 91 3. CMC GUIDANCE ON PREPARATION OF A BANK 92 3.1. ACCURATE AND THOROUGH DESCRIPTION OF PREPARATION 92 3.1.1. RECOMBINANT CELL BANKS 93 3.1.2. TRANSGENIC BANKS 95 3.2. WHY DOES THE FDA WANT SO MUCH CMC DOCUMENTATION? 98 3.3. WHEN IS FULL CMC DOCUMENTATION NEEDED? 99 3.4. WHAT IF CMC DOCUMENTATION IS MISSING? 100 3.5. DON'T FORGET GMPS DURING PREPARATION OF THE BANK 100 4. CMC GUIDANCE ON CHARACTERIZATION OF A BANK 101 XII CONTENTS 4.1. APPROPRIATE AND SUFFICIENT CHARACTERIZATION 102 4.1.1. SIX KEY ELEMENTS FORA THOROUGH CHARACTERIZATION 102 4.1.2. RECOMBINANT CELL BANK CHARACTERIZATION 103 4.1.3. EXAMPLE OF CHARACTERIZATION OF A BACTERIAL CELL BANK 105 4.1.4. EXAMPLE OF CHARACTERIZATION OF A MAMMALIAN CELL BANK 106 4.2. HOW MUCH CHARACTERIZATION AND WHEN? 107 4.3. CRITICAL CONCERN FOR VIRUS SAFETY IN BANKS 109 4.4. MINIMIZING THE RISK OF TSES ILL 5. A SUCCESSFUL CMC STRATEGY FOR BANKS 113 CHAPTER 6 PRODUCTION: EXPANSION OF THE RECOMBINANT ORGANISM AND EXPRESSION OF THE BIOPHARMACEUTICAL 1. GOALS: IDENTITY, CAPACITY AND CONSISTENCY 115 1.1. TWO MAJOR CMC REGULATORY CONCERNS FOR PRODUCTION 116 1.2. NEED FOR HIGH AND CONSISTENT EXPRESSION OF THE BIOPHARMACEUTICAL 116 1.3. WHAT IS A 'PRODUCTION PROCESS'? 117 1.3.1. TYPES OF BIOREACTORS FOR CELL-BASED PRODUCTION 118 1.3.2. HARVESTING PROCEDURES FOR BIOPHARMACEUTICALS 119 1.4. PRODUCTION PROCESSES FAMILIAR TO THE FDA 119 2. ADEQUATE DESCRIPTION OF THE PRODUCTION PROCESS 122 2.1. DURING CLINICAL DEVELOPMENT 122 2.1.1. PHASE 1 IND SUBMISSION 122 2.1.2. PHASE 2 IND SUBMISSION 124 2.1.3. PHASE 3 IND SUBMISSION 124 2.2. PREPARING THE BLA/NDA SUBMISSION 125 3. VALIDATION OF A CELL-BASED PRODUCTION PROCESS 128 3.1. WHEN SHOULD VALIDATION OF THE PRODUCTION PROCESS OCCUR? 129 3.2. FIVE MAJOR AREAS INVOLVED IN VALIDATION OF THE PRODUCTION PROCESS 130 3.2.1. THE PRODUCTION FACILITY, UTILITIES AND PROCESS EQUIPMENT 130 3.2.2. MONITORING OF GROWTH PARAMETERS 132 3.2.3. IN-PROCESS CONTROLS 133 3.2.4. GENETIC STABILITY 136 3.2.5. CLEANING VALIDATION 137 3.3. FINAL COMMENTS ON PROCESS VALIDATION 140 4. ADDITIONAL PRODUCTION CONTROLS AND CONCERNS 140 4.1. CELL-BASED PRODUCTION PROCESSES 140 4.1.1. CELL CULTURE MEDIA ACCEPTANCE CRITERIA 141 4.1.2. AVOIDANCE OF ANIMAL- AND HUMAN-DERIVED RAW MATERIALS 141 4.1.3. CONTAINMENT OF THE RECOMBINANT ORGANISM 144 4.1.4. CONTAMINATION CONTROL FOR ASEPTIC PROCESSING OPERATIONS 144 4.2. GENE THERAPY PRODUCTION PROCESSES 146 4.2.1. CONTROL OF THE CELLS 146 CONTENTS XIII 4.2.2. RAC REVIEW AND APPROVAL OF THE PRODUCTION PROCESS 148 4.3. TRANSGENIC ANIMAL PRODUCTION PROCESSES 149 4.3.1. PRODUCTION-CONTROLS 149 4.3.2. PROTECTING THE GENE POOL 151 4.4. TRANSGENIC PLANT PRODUCTION PROCESSES 151 4.4.1. 'PHARMING' CONTROLS 152 4.4.2. USDA/APHIS PROTECTING THE GENE POOL 155 5. WHAT CAN GO WRONG 157 6. STRATEGIC CMC TIPS FOR PRODUCTION 158 CHAPTER 7 PURIFICATION OF THE BIOPHARMACEUTICAL 1. GOALS: PURITY, RECOVERY AND CONSISTENCY 161 1.1. TWO MAJOR CMC REGULATORY CONCERNS FOR PURIFICATION 162 1.2. NEED FOR HIGH RECOVERY OF A PURE PRODUCT 162 1.3. WHAT IS A 'PURIFICATION PROCESS'? 163 1.3.1. PHYSICAL SEPARATIONS METHODS FOR BIOPHARMACEUTICALS 164 1.3.2. CHROMATOGRAPHIC PURIFICATION METHODS FOR BIOPHARMACEUTICALS 165 1.4. PURIFICATION PROCESSES FAMILIAR TO THE FDA 167 2. ADEQUATE DESCRIPTION OF THE PURIFICATION PROCESS 169 2.1. DURING CLINICAL DEVELOPMENT 170 2.1.1. PHASE 1 IND SUBMISSION 170 2.1.2. PHASE 2 IND SUBMISSION 171 2.1.3. PHASE 3 IND SUBMISSION 172 2.2. PREPARING THE BLA/NDA SUBMISSION 172 3. FACILITY AND UTILITY CONCERNS 174 3.1. DESIGN AND OPERATION 175 3.2. ENVIRONMENTAL MONITORING 176 4. PURIFICATION PROCESS VALIDATION 177 4.1. WHEN SHOULD PURIFICATION VALIDATION OCCUR? 177 4.2. PROCESS VALIDATION CONCERNS FOR A CHROMATOGRAPHIC STEP 178 4.3. PROCESS VALIDATION CONCERNS FOR A FILTRATION STEP 182 5. IN-PROCESS CONTROLS 1 83 6. PROCESS-RELATED IMPURITY PROFILE 185 7. VIRAL SAFETY EVALUATION 188 7.1. GENERAL STUDY DESIGN 189 7.2. JUSTIFICATION OF THE CHOICE OF VIRUSES 191 7.3. CALCULATION OF VIRUS REDUCTION FACTORS 193 7.4. VIRUS SAFETY CALCULATION 195 7.5. WORTH ALL THE TROUBLE AND COST? 196 7.6. WHEN SHOULD THE VIRAL CLEARANCE STUDIES BE PERFORMED? 196 8. PURIFICATION CONTROLS FOR GENE THERAPY PROCESSES 197 9. WHAT CAN GO WRONG 197 XIV CONTENTS 10. STRATEGIC CMC TIPS FOR PURIFICATION 199 CHAPTER 8 BIOPHARMACEUTICAL DRUG PRODUCT MANUFACTURING 1. THREE BASIC CMC REGULATORY CONCERNS 201 2. FORMULATION OF A BIOPHARMACEUTICAL 20 3 2.2. FORMULATIONS FAMILIAR TO FDA 203 2.3. CHEMCIAL MODIFICATION OF API PRIOR TO FORMULATION 205 3. BIOPHARMACEUTIAL MANUFACTURING PROCESSES 206 4. ADEQUATE DESCRIPTION OF THE MANUFACTURING PROCESS 208 4.1. DURING CLINICAL DEVELOPMENT 209 4.1.1. PHASE 1 IND SUBMISSION 209 4.1.2. PHASE 2 IND SUBMISSION 210 4.1.3. PHASE 3 IND SUBMISSION 211 4.2. BLA/NDA SUBMISSION 212 5. ADEQUATE CONTROL OVER THE MANUFACTURING PROCESS 213 5.1. REGULATORY REQUIREMENTS FOR MARKET APPROVED PRODUCTS 214 5.2. REGULATORY EXPECTATIONS DURING CLINICAL DEVELOPMENT 216 6. WHAT CAN GO WRONG 217 7. STRATEGIC CMC TIPS FOR DRUG PRODUCT MANUFACTURING 218 CHAPTER 9 PHYSICOCHEMICAL/BIOLOGICAL ANALYSIS OF THE BIOPHARMACEUTICAL PRODUCT 1. A CHALLENGING ANALYSIS 222 1.1. GOALS: CONSISTENT, SAFE, POTENT AND PURE PRODUCT 222 1.2. RELATIONSHIP BETWEEN PRODUCT CHARACTERIZATION AND QC TESTING 223 2. UNRAVELING THE MOLECULAR PROPERTIES 224 2.1. MOLECULAR VARIANTS FOR DNA 224 2.2. MOLECULAR VARIANTS FOR PROTEINS 224 2.3. PLETHORA OF ANALYTICAL METHODS AVAILABLE FOR PROTEINS 226 3. CHARACTERIZATION OF BIOPHARMACEUTICALS 229 3.1. REGULATORY EXPECTATIONS DURING CLINICAL DEVELOPMENT 229 3.1.1. PHASE 1 IND SUBMISSION 229 3.1.2. PHASE 2 IND SUBMISSION 230 3.1.3. PHASE 3 IND SUBMISSION 230 3.2 REGULATORY EXPECTATIONS FOR THE BLA/NDA SUBMISSION 231 3.3. FULL CHARACTERIZATION OF RECOMBINANT PROTEINS AND MONOCLONAL ANTIBODIES .232 CONTENTS XV 3.3.1. WHAT IS 'FULL' CHARACTERIZATION? 232 3.3.2. HOST-DEPENDENT GLYCOSYLATION 236 3.3.3. HOST-DEPENDENT IMPURITIES 237 3.3.4. IMPACT OF MOLECULAR VARIANTS ON BIOLOGICAL ACTIVITY 238 3.4. CHARACTERIZATION OF A GENE THERAPY BIOPHARMACEUTICAL 239 3.5. APPLYING THE MINIMUM CMC CONTINUUM TO CHARACTERIZATION 240 4. RELEASE TESTING AND SPECIFICATIONS 241 4.1. REGULATORY EXPECTATIONS DURING CLINICAL DEVELOPMENT 241 4.1.1. PHASE 1 IND SUBMISSION 241 4.1.2. PHASE 2 IND SUBMISSION 242 4.1.3. PHASE 3 IND SUBMISSION 242 4.2. REGULATORY EXPECTATIONS FOR THE BLA/NDA SUBMISSION 243 4.3. APPROPRIATE RELEASE TEST METHODS 244 4.3.1. NOT ALL RELEASE TESTING IS AT API OR DRUG PRODUCT STAGE 244 4.3.2. ELIMINATION OF RELEASE TESTING BY PROCESS VALIDATION 245 4.3.3. TEST METHOD PARAMETERS REQUIRED FOR RELEASE: PROTEINS 246 4.3.4. TEST METHOD PARAMETERS REQUIRED FOR RELEASE: DNA VECTORS 250 4.4. THE BIOASSAY - ABSOLUTE REQUIREMENT FOR A BIOPHARMACEUTICAL 252 4.5. TEST METHOD VALIDATION - HOW MUCH AND WHEN? 253 4.5.1. REGULATORY EXPECTATIONS FOR TEST METHOD VALIDATION 254 4.5.2. ASSAY QUALIFICATION DURING CLINICAL DEVELOPMENT 256 4.5.3. APPLYING THE MINIMUM CMC CONTINUUM TO TEST METHOD VALIDATION 257 4.6. THE ART OF SETTING A SPECIFICATION 258 4.6.1. DEVELOPMENT OF A SPECIFICATION 258 4.6.2. RELEASE VERSUS SHELF-LIFE SPECIFICATIONS 261 4.6.3. ARE THERE REQUIRED PURITY/IMPURITY LIMITS? 261 4.6.4. STRATEGIC CMC TIPS FOR SETTING SPECIFICATIONS 263 5. BIOPHARMACEUTICAL STABILITY AND EXPIRATION DATING 266 5.1. REGULATORY EXPECTATIONS DURING CLINICAL DEVELOPMENT 267 5.1.1. PHASE 1 IND SUBMISSION 267 5.1.2. PHASE 2 IND SUBMISSION 267 5.1.3. PHASE 3 IND SUBMISSION 268 5.2. REGULATORY EXPECTATIONS FOR THE BLA/NDA SUBMISSION 270 5.3. STABILITY-INDICATING TEST METHODS 272 5.4. SETTING AN EXPIRATION DATE 274 5.5. HOW MUCH CHANGE IS ACCEPTABLE? 277 5.6. APPLYING THE MINIMUM CMC CONTINUUM TO STABILITY 278 6. WHAT CAN GO WRONG 279 6.1. INCOMPLETE RELEASE/STABILITY TESTING REQUIREMENTS IN BLA/NDA FILING 280 6.2. FDA 483 INSPECTIONAL OBSERVATIONS 281 6.3. BIOPHARMACEUTICAL PRODUCT RECALLS 282 6.4. MISUSE IN THE CLINIC 284 7. STRATEGIC CMC TIPS FOR BIOPHARMACEUTICAL ANALYSIS 285 XVI CONTENTS CHAPTER 10 MANAGING PROCESS CHANGES - DEMONSTRATING PRODUCT COMPARABILITY 1. NOT AS EASY AS IT SEEMS! 287 2. REGULATORY MANAGEMENT OF PROCESS CHANGES 28 8 2.1. PRE-IND STAGE 289 2.2. IND CLINICAL DEVELOPMENT STAGES 289 2.3. BLA/NDA FILING STAGE 290 2.4. POST-APPROVAL MARKET STAGE 291 3. DEMONSTRATING PRODUCT COMPARABILITY 296 3.1 GUIDANCE DOCUMENTS ON PRODUCT COMPARABILITY 297 3.2. A THREE-TIERED TESTING HIERARCHY 297 3.3. DESIGNING THE COMPARABILITY STUDY - FOUR MAJOR FACTORS 300 3.3.1. FACTOR 1: CLINICAL DEVELOPMENT STAGE FOR THE CHANGE 301 3.3.2. FACTOR 2: WHERE IN THE PROCESS THE CHANGE IS INTRODUCED 301 3.3.3. FACTOR 3: QUALITY CRITERIA CONSIDERATIONS 302 3.3.4. FACTOR 4: SUITABILITY OF AVAILABLE ANALYTICAL METHODS 302 3.4. REGULATORY AGENCIES HAVE FINAL APPROVAL 302 3.5 IF IN DOUBT, ASK! 303 4. COMPARABILITY PROTOCOLS 304 5. CASE EXAMPLES OF BIOPHARMACEUTICAL COMPARABILITY 305 5.1. COMPARABILITY SUCCESS STORIES 306 5.2. COMPARABILITY SURPRISES 308 5.3. NOT COMPARABLE 309 CHAPTER 11 BIOPHARMACEUTICAL CMC OUTSOURCING 1. REGULATORY EXPECTATIONS FOR CONTRACTED WORK 311 1.1. WHY OUTSOURCE? 311 1.2. WRITTEN QUALITY AGREEMENTS REQUIRED 312 1.3. REGULATORY REQUIREMENTS DURING CLINICAL DEVELOPMENT 313 1.4. REGULATORY REQUIREMENTS FOR THE BLA/NDA SUBMISSION 313 1.5. REGULATORY REQUIREMENTS POST-MARKET APPROVAL 314 2. DEVELOPING THE INTERCOMPANY QUALITY AGREEMENT 315 2.1. TWO VIEWPOINTS 315 2.1.1. THE BIOPHARMACEUTICAL COMPANY SEEKING TO OUTSOURCE 315 2.1.2. THE CONTACT MANUFACTURER OFFERING OUTSOURCING 316 2.1.3. MAXIMUM LEVERAGE 316 2.2. CONTENTS OF AN IQA 316 3. STRATEGIC CMC TIPS FOR OUTSOURCING 319 CONTENTS XVII CHAPTER 12 CONCLUDING THOUGHTS ON BIOPHARMACEUTICAL CMC REGULATORY COMPLIANCE 1. MOST HELPFUL WEBSITES FOR BIOPHARMACEUTICALS 322 2. WEBSITE RESOURCES FROM FDA 323 3. RESOURCES FROM EMEA 329 4. RESOURCES FROM PROFESSIONAL ASSOCIATIONS 330 5. CONCLUSION 330 REFERENCES 331
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spelling	Geigert, John Verfasser aut The challenge of CMC regulatory compliance for biopharmaceuticals John Geigert New York, NY Kluwer Academic / Plenum Publishers 2004 XXII, 350 S. txt rdacontent n rdamedia nc rdacarrier Includes bibliographical references and index GBV Datenaustausch application/pdf http://bvbr.bib-bvb.de:8991/F?func=service&doc_library=BVB01&local_base=BVB01&doc_number=014680279&sequence=000001&line_number=0001&func_code=DB_RECORDS&service_type=MEDIA Inhaltsverzeichnis
spellingShingle	Geigert, John The challenge of CMC regulatory compliance for biopharmaceuticals
title	The challenge of CMC regulatory compliance for biopharmaceuticals
title_auth	The challenge of CMC regulatory compliance for biopharmaceuticals
title_exact_search	The challenge of CMC regulatory compliance for biopharmaceuticals
title_exact_search_txtP	The challenge of CMC regulatory compliance for biopharmaceuticals
title_full	The challenge of CMC regulatory compliance for biopharmaceuticals John Geigert
title_fullStr	The challenge of CMC regulatory compliance for biopharmaceuticals John Geigert
title_full_unstemmed	The challenge of CMC regulatory compliance for biopharmaceuticals John Geigert
title_short	The challenge of CMC regulatory compliance for biopharmaceuticals
title_sort	the challenge of cmc regulatory compliance for biopharmaceuticals
url	http://bvbr.bib-bvb.de:8991/F?func=service&doc_library=BVB01&local_base=BVB01&doc_number=014680279&sequence=000001&line_number=0001&func_code=DB_RECORDS&service_type=MEDIA
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