Formulation and Analytical Development for Low-Dose Oral Drug Products

1 - FORMULATION AND ANALYTICAL DEVELOPMENT FOR LOW-DOSE ORAL DRUG PRODUCTS [Seite 3]
1.1 - CONTENTS [Seite 9]
1.2 - PREFACE [Seite 17]
1.3 - FOREWORD [Seite 21]
1.4 - CONTRIBUTORS [Seite 23]
1.5 - 1 AN OVERVIEW [Seite 27]
1.5.1 - 1.1 The Drug Discovery and Development Process [Seite 28]
1.5.2 - 1.2 Challenges and Strategies in Development of Low-Dose Drug Products [Seite 36]
1.5.3 - 1.3 Summary [Seite 46]
1.5.4 - Acknowledgments [Seite 46]
1.5.5 - References [Seite 46]
1.6 - I CHALLENGES AND STRATEGIES IN FORMULATION DEVELOPMENT OF ORAL LOW-DOSE DRUG PRODUCTS [Seite 49]
1.6.1 - 2 CHALLENGES AND STRATEGIES IN FORMULATION DEVELOPMENT OF ORAL SOLID LOW-DOSE DRUG PRODUCTS [Seite 51]
1.6.1.1 - 2.1 Introduction [Seite 51]
1.6.1.2 - 2.2 Current Regulatory Environment and its Impact on New Drug Product Development [Seite 54]
1.6.1.3 - 2.3 Challenges in Developing Low-Dose Formulations [Seite 57]
1.6.1.4 - 2.4 Manufacturing Platforms for Low-Dose Drug Products [Seite 64]
1.6.1.5 - 2.5 Use of Experimental Design in Formulation and Process Development [Seite 68]
1.6.1.6 - 2.6 Containments [Seite 70]
1.6.1.7 - 2.7 Summary [Seite 71]
1.6.1.8 - Acknowledgments [Seite 72]
1.6.1.9 - References [Seite 72]
1.6.2 - 3 PARTICLE SIZE OF DRUG SUBSTANCE AND PRODUCT CONTENT UNIFORMITY-THEORETICAL CONSIDERATIONS [Seite 75]
1.6.2.1 - 3.1 Introduction [Seite 75]
1.6.2.2 - 3.2 Concept of Ideal Mixing [Seite 76]
1.6.2.3 - 3.3 Ideal Mixing Model Comparison with the Yalkowsky and Bolton Approach [Seite 82]
1.6.2.4 - 3.4 Experimental Support of Model Assumptions [Seite 85]
1.6.2.5 - 3.5 Analytical and Practical Considerations [Seite 87]
1.6.2.6 - References [Seite 88]
1.6.3 - 4 DEVELOPMENT OF LOW-DOSE FORMULATIONS USING FLUIDIZED BED GRANULATION [Seite 89]
1.6.3.1 - 4.1 Introduction [Seite 89]
1.6.3.2 - 4.2 Granulation Fundamentals [Seite 92]
1.6.3.3 - 4.3 Theory of Fluidization [Seite 94]
1.6.3.4 - 4.4 Formulation Development [Seite 98]
1.6.3.5 - 4.5 Process Development [Seite 103]
1.6.3.6 - 4.6 Summary [Seite 112]
1.6.3.7 - References [Seite 112]
1.6.4 - 5 DEVELOPMENT OF LOW-DOSE SOLID ORAL FORMULATIONS USING WET GRANULATION [Seite 115]
1.6.4.1 - 5.1 Introduction [Seite 115]
1.6.4.2 - 5.2 Granulation Mechanisms [Seite 117]
1.6.4.3 - 5.3 General Considerations on Wet Granulation [Seite 119]
1.6.4.4 - 5.4 Advantages and Disadvantages of Wet Granulation [Seite 126]
1.6.4.5 - 5.5 Use of Wet Granulation for Low-Dose Formulations [Seite 127]
1.6.4.6 - 5.6 Process-Induced Form Changes in Wet Granulation [Seite 135]
1.6.4.7 - 5.7 Concluding Remarks [Seite 137]
1.6.4.8 - References [Seite 138]
1.6.5 - 6 CHALLENGES IN DEVELOPMENT AND SCALE-UP OF LOW-DOSE DRUG PRODUCTS BY DRY GRANULATION: A CASE STUDY [Seite 143]
1.6.5.1 - 6.1 Introduction [Seite 143]
1.6.5.2 - 6.2 Dry Granulation Process-Pros and Cons [Seite 144]
1.6.5.3 - 6.3 Overview of Dry Granulation Processes and Equipment Design [Seite 145]
1.6.5.4 - 6.4 Challenges for Low-Dose Product Development and their Assessment Methods [Seite 151]
1.6.5.5 - 6.5 Case Study: Formulation Challenges for Low-Dose Products [Seite 154]
1.6.5.6 - 6.6 Process Challenges During Dry Granulation Optimization for Low-Dose Products [Seite 166]
1.6.5.7 - 6.7 Conclusions [Seite 180]
1.6.5.8 - Acknowledgments [Seite 181]
1.6.5.9 - References [Seite 181]
1.6.6 - 7 DEVELOPMENT OF LOW-DOSE SOLID ORAL TABLETS USING DIRECT COMPRESSION [Seite 185]
1.6.6.1 - 7.1 Introduction [Seite 185]
1.6.6.2 - 7.2 Advantages of Direct Compression [Seite 186]
1.6.6.3 - 7.3 Challenges in Low-Dose Tablet Development Using Direct Compression [Seite 188]
1.6.6.4 - 7.4 Formulation Development for Low-Dose Drug Products Using Direct Compression [Seite 195]
1.6.6.5 - 7.5 Manufacturing Process Development for Low-Dose Drug Products [Seite 213]
1.6.6.6 - 7.6 Scale-Up for Blending Operation [Seite 222]
1.6.6.7 - 7.7 Formulation Examples for Direct Compression [Seite 223]
1.6.6.8 - 7.8 Conclusions [Seite 225]
1.6.6.9 - Acknowledgments [Seite 225]
1.6.6.10 - References [Seite 226]
1.6.7 - 8 REDUCTION OF PARTICLE SIZE OF DRUG SUBSTANCE FOR LOW-DOSE DRUG PRODUCTS [Seite 231]
1.6.7.1 - 8.1 Introduction [Seite 231]
1.6.7.2 - 8.2 Reduction of Particle Size of Drug Substance by Milling Technologies [Seite 233]
1.6.7.3 - 8.3 Reduction of Particle Size of Drug Substance Using Crystallization Technologies [Seite 242]
1.6.7.4 - 8.4 Scale-Up Considerations [Seite 244]
1.6.7.5 - 8.5 Emerging Technologies and Future Directions [Seite 245]
1.6.7.6 - Acknowledgments [Seite 245]
1.6.7.7 - References [Seite 245]
1.6.8 - 9 FUNCTION, QUALITY, AND REGULATIONS OF PHARMACEUTICAL EXCIPIENTS FOR ORAL SOLID DOSAGE FORMS [Seite 249]
1.6.8.1 - 9.1 Introduction [Seite 249]
1.6.8.2 - 9.2 Classification of Pharmaceutical Excipients in Solid Dosage Forms [Seite 250]
1.6.8.3 - 9.3 Physicochemical Attributes of Pharmaceutical Excipients [Seite 251]
1.6.8.4 - 9.4 Regulatory Status and Excipient Quality [Seite 254]
1.6.8.5 - 9.5 Summary [Seite 261]
1.6.8.6 - Acknowledgments [Seite 261]
1.6.8.7 - References [Seite 262]
1.7 - II CHALLENGES IN ANALYTICAL METHOD DEVELOPMENT FOR ORAL LOW-DOSE DRUG PRODUCTS [Seite 265]
1.7.1 - 10 ANALYTICAL METHOD DEVELOPMENT: CHALLENGES AND SOLUTIONS FOR LOW-DOSE ORAL DOSAGE FORMS [Seite 267]
1.7.1.1 - 10.1 Introduction [Seite 267]
1.7.1.2 - 10.2 Case Study 1: Drug Adsorption to Surfaces [Seite 268]
1.7.1.3 - 10.3 Case Study 2: Challenges Due to Nondrug-Related Impurities [Seite 271]
1.7.1.4 - 10.4 Case Study 3: HPLC Purity Method Development Challenges for a Fixed Combination Product Containing a Low-Dose Active Ingredient and a High-Dose Active Ingredient [Seite 276]
1.7.1.5 - 10.5 Case Study 4: Small Volume Dissolution Testing [Seite 281]
1.7.1.6 - 10.6 Summary [Seite 287]
1.7.1.7 - Acknowledgments [Seite 287]
1.7.1.8 - References [Seite 287]
1.7.2 - 11 IN VITRO DISSOLUTION TESTING AND METHOD DEVELOPMENT [Seite 291]
1.7.2.1 - 11.1 Introduction [Seite 291]
1.7.2.2 - 11.2 Overview of Dissolution Testing [Seite 291]
1.7.2.3 - 11.3 Dissolution Method Development [Seite 297]
1.7.2.4 - 11.4 Dissolution Method Development for Low-Dose Oral Drug Products [Seite 301]
1.7.2.5 - 11.5 Summary [Seite 305]
1.7.2.6 - References [Seite 306]
1.7.3 - 12 ANALYSIS OF PHYSICAL TRANSFORMATION OF API DURING MANUFACTURE AND STORAGE [Seite 309]
1.7.3.1 - 12.1 Introduction [Seite 309]
1.7.3.2 - 12.2 Discussion of Solid-State Forms [Seite 310]
1.7.3.3 - 12.3 Monitoring Processing Steps [Seite 311]
1.7.3.4 - 12.4 Measuring Transitions and Solid-Form Transformations in the Low-Dose Tablet [Seite 313]
1.7.3.5 - 12.5 Common Methods Used for Examination of Solid Forms [Seite 315]
1.7.3.6 - 12.6 Conclusions [Seite 331]
1.7.3.7 - References [Seite 332]
1.7.4 - 13 PHYSICAL CHARACTERIZATION TESTS FOR DRUG SUBSTANCES USED IN LOW-DOSE FORMULATIONS [Seite 335]
1.7.4.1 - 13.1 General Issues in the Physical Characterization of Micronized Powders Used in Low-Dose Formulations [Seite 335]
1.7.4.2 - 13.2 Particle Size Analysis [Seite 335]
1.7.4.3 - 13.3 Specific Surface Area Analysis [Seite 346]
1.7.4.4 - 13.4 Summary [Seite 349]
1.7.4.5 - References [Seite 349]
1.7.5 - 14 AN EXCIPIENT LIBRARY APPROACH TO ANALYTICAL DEVELOPMENT FOR LOW-DOSE, SOLID ORAL DOSAGE FORM DRUG PRODUCTS [Seite 353]
1.7.5.1 - 14.1 Introduction [Seite 353]
1.7.5.2 - 14.2 Importance of Excipient Absorbance Background to Low-Dose Impurity Analysis [Seite 354]
1.7.5.3 - 14.3 Factors Affecting Excipient Absorbance Background [Seite 358]
1.7.5.4 - 14.4 Use of Excipient Library [Seite 365]
1.7.5.5 - 14.5 Conclusions [Seite 367]
1.7.5.6 - Acknowledgments [Seite 367]
1.7.5.7 - References [Seite 368]
1.7.6 - 15 CLEANING VERIFICATION FOR HIGHLY POTENT COMPOUNDS [Seite 371]
1.7.6.1 - 15.1 Introduction [Seite 371]
1.7.6.2 - 15.2 Cleaning Validation vs Cleaning Verification [Seite 372]
1.7.6.3 - 15.3 Acceptance Limit Calculations [Seite 373]
1.7.6.4 - 15.4 Analytical Method Validation [Seite 378]
1.7.6.5 - 15.5 General Analytical Techniques [Seite 387]
1.7.6.6 - 15.6 Analytical Techniques for Low-Dose Compounds [Seite 390]
1.7.6.7 - 15.7 Conclusions [Seite 402]
1.7.6.8 - Acknowledgments [Seite 403]
1.7.6.9 - References [Seite 403]
1.8 - III CONTAINMENT TECHNIQUES FOR HIGHLY POTENT PHARMACEUTICAL COMPOUNDS [Seite 407]
1.8.1 - 16 CONTAINMENT CHALLENGES AND STRATEGIES FOR POTENT COMPOUNDS IN THE PHARMACEUTICAL INDUSTRY [Seite 409]
1.8.1.1 - 16.1 Introduction [Seite 409]
1.8.1.2 - 16.2 Safe Exposure Control Levels-Bands, Limits, and Handling Guidance [Seite 410]
1.8.1.3 - 16.3 The Hierarchy of Workplace Controls [Seite 415]
1.8.1.4 - 16.4 Case Studies [Seite 423]
1.8.1.5 - 16.5 Summary [Seite 429]
1.8.1.6 - Acknowledgments [Seite 429]
1.8.1.7 - References [Seite 429]
1.8.2 - 17 SAMPLE HANDLING AND CONTAINMENT IN ANALYTICAL TESTING LABORATORIES [Seite 431]
1.8.2.1 - 17.1 Introduction [Seite 431]
1.8.2.2 - 17.2 Sample Handling Considerations [Seite 432]
1.8.2.3 - 17.3 Handling Potent Compounds in Standard Analytical Laboratories [Seite 433]
1.8.2.4 - 17.4 Handling Potent Compounds in a Containment Laboratory [Seite 437]
1.8.2.5 - 17.5 Additional Considerations for Handling Potent Materials [Seite 452]
1.8.2.6 - 17.6 Summary [Seite 453]
1.8.2.7 - Acknowledgments [Seite 454]
1.8.2.8 - References [Seite 454]
1.9 - IV REGULATORY CONSIDERATIONS IN THE DEVELOPMENT OF LOW-DOSE DRUG PRODUCTS [Seite 455]
1.9.1 - 18 REGULATORY CONSIDERATIONS IN THE DEVELOPMENT OF LOW-DOSE SOLID ORAL DRUG PRODUCTS [Seite 457]
1.9.1.1 - 18.1 Introduction and Overview [Seite 457]
1.9.1.2 - 18.2 Three-Pronged Approach to Low-Dose Formulations [Seite 459]
1.9.1.3 - 18.3 Pharmaceutical Development Report [Seite 460]
1.9.1.4 - 18.4 Facility Controls for Highly Potent Drugs [Seite 477]
1.9.1.5 - 18.5 Conclusion [Seite 478]
1.9.1.6 - References [Seite 479]
1.10 - INDEX [Seite 481]