AAPS Advances in the Pharmaceutical Sciences Series – serie

This edition includes both updates and new uses and issues concerning CTS, along with case studies of how clinical trial simulations are being applied in various therapeutic and application areas. Importantly, the book expands on the utility of CTS for informing decisions during drug development and regulatory review. Each chapter author was selected on the basis of demonstrated expertise in state-of-the-art application of CTS. The target audience for this volume includes researchers and scientists who wish to consider use of simulations in the design, analysis, or regulatory review and guidance of clinical trials. This book does not embrace all aspects of trial design, nor is it intended as a complete recipe for using computers to design trials. Rather, it is an information source that enables the reader to gain understanding of essential background and knowledge for practical applications of simulation for clinical trial design and analysis. It is assumed that the reader has a working understanding of pharmacokinetics and pharmacodynamics, modeling, pharmacometric analyses, and/or the drug development and regulatory processes.

This comprehensive volume discusses approaches for a systematic selection of delivery systems for various classes of therapeutic agents including small molecule, protein, and nucleic acid drugs.  Specific topics covered in this book include:Solution, suspension, gel, nanoparticle, microparticle, and implant dosage formsRefillable and microneedle devicesIntravitreal, suprachoroidal, intrascleral, transscleral, systemic, and topical routes of deliveryPhysical methods including iontophoresis for drug deliveryRational selection of routes of administration and delivery systemsNoninvasive and continuous drug monitoring Regulatory path to drug product developmentClinical endpoints for drug product developmentEmerging and existing drugs and drug targets  Drug Product Development for the Back of the Eye is authored by renowned ocular drug delivery experts, representing academic, clinical, and industrial organizations and serves as indispensable resource for ophthalmic researchers, drug formulation scientists, drug delivery and drug disposition scientists, as well as clinicians involved in designing and developing novel therapeutics for the back of the eye diseases. This book is also relevant for students in various disciplines including ophthalmology, pharmaceutical sciences, drug delivery, and biomedical engineering. Refillable and microneedle devicesIntravitreal, suprachoroidal, intrascleral, transscleral, systemic, and topical routes of deliveryPhysical methods including iontophoresis for drug deliveryRational selection of routesof administration and delivery systemsNoninvasive and continuous drug monitoring Regulatory path to drug product developmentClinical endpoints for drug product developmentEmerging and existing drugs and drug targets  Drug Product Development for the Back of the Eye is authored by renowned ocular drug delivery experts, representing academic, clinical, and industrial organizations and serves as indispensable resource for ophthalmic researchers, drug formulation scientists, drug delivery and drug disposition scientists, as well as clinicians involved in designing and developing novel therapeutics for the back of the eye diseases. This book is also relevant for students in various disciplines including ophthalmology, pharmaceutical sciences, drug delivery, and biomedical engineering. Refillable and microneedle devicesIntravitreal, suprachoroidal, intrascleral, transscleral, systemic, and topical routes of deliveryPhysical methods including iontophoresis for drug deliveryRational selection of routes of administration and delivery systemsNoninvasive and continuous drug monitoring Regulatory path to drug product developmentClinical endpoints for drug product developmentEmerging and existing drugs and drug targets  Drug Product Development for the Back of the Eye is authored by renowned ocular drug delivery experts, representing academic, clinical, and industrial organizations and serves as indispensable resource for ophthalmic researchers, drug formulation scientists, drug delivery and drug disposition scientists, as well as clinicians involved in designing and developing novel therapeutics for the back of theeye diseases. This book is also relevant for students in various disciplines including ophthalmology, pharmaceutical sciences, drug delivery, and biomedical engineering.

This volume is intended to provide the reader with a breadth of understanding regarding the many challenges faced with the formulation of poorly water-soluble drugs as well as in-depth knowledge in the critical areas of development with these compounds. Further, this book is designed to provide practical guidance for overcoming formulation challenges toward the end goal of improving drug therapies with poorly water-soluble drugs. Enhancing solubility via formulation intervention is a unique opportunity in which formulation scientists can enable drug therapies by creating viable medicines from seemingly undeliverable molecules. With the ever increasing number of poorly water-soluble compounds entering development, the role of the formulation scientist is growing in importance. Also, knowledge of the advanced analytical, formulation, and process technologies as well as specific regulatory considerations related to the formulation of these compounds is increasing in value. Ideally, this book will serve as a useful tool in the education of current and future generations of scientists, and in this context contribute toward providing patients with new and better medicines.

This edition includes both updates and new uses and issues concerning CTS, along with case studies of how clinical trial simulations are being applied in various therapeutic and application areas. Importantly, the book expands on the utility of CTS for informing decisions during drug development and regulatory review. Each chapter author was selected on the basis of demonstrated expertise in state-of-the-art application of CTS. The target audience for this volume includes researchers and scientists who wish to consider use of simulations in the design, analysis, or regulatory review and guidance of clinical trials. This book does not embrace all aspects of trial design, nor is it intended as a complete recipe for using computers to design trials. Rather, it is an information source that enables the reader to gain understanding of essential background and knowledge for practical applications of simulation for clinical trial design and analysis. It is assumed that the reader has a working understanding of pharmacokinetics and pharmacodynamics, modeling, pharmacometric analyses, and/or the drug development and regulatory processes.

This comprehensive volume discusses approaches for a systematic selection of delivery systems for various classes of therapeutic agents including small molecule, protein, and nucleic acid drugs.  Specific topics covered in this book include:Solution, suspension, gel, nanoparticle, microparticle, and implant dosage formsRefillable and microneedle devicesIntravitreal, suprachoroidal, intrascleral, transscleral, systemic, and topical routes of deliveryPhysical methods including iontophoresis for drug deliveryRational selection of routes of administration and delivery systemsNoninvasive and continuous drug monitoring Regulatory path to drug product developmentClinical endpoints for drug product developmentEmerging and existing drugs and drug targets  Drug Product Development for the Back of the Eye is authored by renowned ocular drug delivery experts, representing academic, clinical, and industrial organizations and serves as indispensable resource for ophthalmic researchers, drug formulation scientists, drug delivery and drug disposition scientists, as well as clinicians involved in designing and developing novel therapeutics for the back of the eye diseases. This book is also relevant for students in various disciplines including ophthalmology, pharmaceutical sciences, drug delivery, and biomedical engineering. Refillable and microneedle devicesIntravitreal, suprachoroidal, intrascleral, transscleral, systemic, and topical routes of deliveryPhysical methods including iontophoresis for drug deliveryRational selection of routesof administration and delivery systemsNoninvasive and continuous drug monitoring Regulatory path to drug product developmentClinical endpoints for drug product developmentEmerging and existing drugs and drug targets  Drug Product Development for the Back of the Eye is authored by renowned ocular drug delivery experts, representing academic, clinical, and industrial organizations and serves as indispensable resource for ophthalmic researchers, drug formulation scientists, drug delivery and drug disposition scientists, as well as clinicians involved in designing and developing novel therapeutics for the back of the eye diseases. This book is also relevant for students in various disciplines including ophthalmology, pharmaceutical sciences, drug delivery, and biomedical engineering. Refillable and microneedle devicesIntravitreal, suprachoroidal, intrascleral, transscleral, systemic, and topical routes of deliveryPhysical methods including iontophoresis for drug deliveryRational selection of routes of administration and delivery systemsNoninvasive and continuous drug monitoring Regulatory path to drug product developmentClinical endpoints for drug product developmentEmerging and existing drugs and drug targets  Drug Product Development for the Back of the Eye is authored by renowned ocular drug delivery experts, representing academic, clinical, and industrial organizations and serves as indispensable resource for ophthalmic researchers, drug formulation scientists, drug delivery and drug disposition scientists, as well as clinicians involved in designing and developing novel therapeutics for the back of theeye diseases. This book is also relevant for students in various disciplines including ophthalmology, pharmaceutical sciences, drug delivery, and biomedical engineering.

A vast number of diagnostic and therapeutic decisions are based on measuring blood concentrations of molecules, yet most biochemical and pharmacological events actually take place in the tissues. Microdialysis is a key semi-invasive sampling technique to measure in vivo drug penetration to the target site in humans, the method being feasible in virtually every organ. Authored by international experts in this cutting edge field, this book will provide a comprehensive overview of microdialysis and its application for measuring drug distribution in drug development.

This volume will consider one of ICH’s major categories, Safety i.e. topics relating to in vitro and in vivo pre-clinical studies (Carcinogenicity Testing, Genotoxicity Testing, etc.). Since the start of the ICH process, many guidelines have been written, but even after ICH6 no explanations have been given during a formal Congress about the background of the ICH Guidance documents. Even more important than what has been written, might have been those thoughts of the experts that are not included in the Guidance documents. Why has the guideline been written as it is written, and why have some aspects been deleted. These and other related questions are the contents of this book, written by experts who were involved in the ICH process. Furthermore, the chapters will contain discussions on the “lessons learnt” and “future developments”.

This comprehensive book encompasses various facets of sterile product development. Key concepts relevant to the successful development of sterile products are illustrated through case studies and are covered under three sections in this book:• Formulation approaches that discuss a variety of dosage forms including protein therapeutics, lipid-based controlled delivery systems, PEGylated biotherapeutics, nasal dosage form, and vaccines• Process, container closure and delivery considerations including freeze-thaw process challenges, best practices for technology transfer to enable commercial product development, innovations and advancement in aseptic fill-finish operations, approaches to manufacturing lyophilized parenteral products, pen / auto-injector delivery devices, and associated container closure integrity testing hurdles for sterile product closures• Regulatory and quality aspects in the areas of particulate matter and appearance evaluation, sterile filtration, admixture compatibility considerations, sterilization process considerations, microbial contamination investigations and validation of rapid microbiological methods, and dry and moist heat sterilizersThis book is a useful resource to scientists and researchers in both industry and academia, and it gives process and product development engineers insight into current industry practices and evolving regulatory expectations for sterile product development.

Transporters in Drug Development examines how membrane transporters can be dealt with in academic–industrial drug discovery and pharmaceutical development as well as from a regulatory perspective. The book describes methods and examples of in vitro characterization of single transporters in the intestines, liver and kidneys as well as characterization of substrate overlap between various transporters. Furthermore, probes and biomarkers are suggested for studies of the transporters’ impact on the pharmacokinetics of drug substrates/candidates interacting on transporters. The challenges of translating in vitro observed interaction of transporters into in vivo relevance are explored, and the book highlights perspectives of applying targeted proteomics and mechanistic modeling in this process.

The volume aim to be a comprehensive overview of the drug and biologic development process that is often called “the valley of death” (pre-IND through approval) where high costs of studies and high rates of product failure are part of the drug development landscape. Imaging tools can serve in this period by adding high value data, the images and the kinetic information they can provide, and cost-effective development alternative tools which potentially improve pivotal study designs. Imaging may identify safety issues early such as unwanted organ or tissue distributions, and then can serve advanced development with added certainty of a drug or biologic’s success to senior corporate management and investors. There are numerous textbooks, reference texts and treatises on medical imaging technologies, teaching tools on medical cases and physics books on the science of detector and computer interface systems. Rarely, in each of these are examples of medical imaging protocols and animal models of disease i.e. a text on methodology in drug development is currently unavailable.

This volume provides readers with the basic principles and fundamentals of extrusion technology and a detailed description of the practical applications of a variety of extrusion processes, including various pharma grade extruders. In addition, the downstream production of films, pellets and tablets, for example, for oral and other delivery routes, are presented and discussed utilizing melt extrusion. This book is the first of its kind that discusses extensively the well-developed science of extrusion technology as applied to pharmaceutical drug product development and manufacturing. By covering a wide range of relevant topics, the text brings together all technical information necessary to develop and market pharmaceutical dosage forms that meet current quality and regulatory requirements. As extrusion technology continues to be refined further, usage of extruder systems and the array of applications will continue to expand, but the core technologies will remain the same.

This volume is intended to provide the reader with a breadth of understanding regarding the many challenges faced with the formulation of poorly water-soluble drugs as well as in-depth knowledge in the critical areas of development with these compounds. Further, this book is designed to provide practical guidance for overcoming formulation challenges toward the end goal of improving drug therapies with poorly water-soluble drugs. Enhancing solubility via formulation intervention is a unique opportunity in which formulation scientists can enable drug therapies by creating viable medicines from seemingly undeliverable molecules. With the ever increasing number of poorly water-soluble compounds entering development, the role of the formulation scientist is growing in importance. Also, knowledge of the advanced analytical, formulation, and process technologies as well as specific regulatory considerations related to the formulation of these compounds is increasing in value. Ideally, this book will serve as a useful tool in the education of current and future generations of scientists, and in this context contribute toward providing patients with new and better medicines.

This volume will consider one of ICH’s major categories, Safety i.e. topics relating to in vitro and in vivo pre-clinical studies (Carcinogenicity Testing, Genotoxicity Testing, etc.). Since the start of the ICH process, many guidelines have been written, but even after ICH6 no explanations have been given during a formal Congress about the background of the ICH Guidance documents. Even more important than what has been written, might have been those thoughts of the experts that are not included in the Guidance documents. Why has the guideline been written as it is written, and why have some aspects been deleted. These and other related questions are the contents of this book, written by experts who were involved in the ICH process. Furthermore, the chapters will contain discussions on the “lessons learnt” and “future developments”.

A vast number of diagnostic and therapeutic decisions are based on measuring blood concentrations of molecules, yet most biochemical and pharmacological events actually take place in the tissues. Microdialysis is a key semi-invasive sampling technique to measure in vivo drug penetration to the target site in humans, the method being feasible in virtually every organ. Authored by international experts in this cutting edge field, this book will provide a comprehensive overview of microdialysis and its application for measuring drug distribution in drug development.

This comprehensive reference provides an in-depth discussion on state-of-the-art regulatory science in bioequivalence. In sixteen chapters, the volume explores a broad range of topics pertaining to bioequivalence, including its origin and principles, statistical considerations, food effect studies, conditions for waivers of bioequivalence studies, Biopharmaceutics Classification Systems, Biopharmaceutics Drug Disposition Classification System, bioequivalence modeling/simulation and best practices in bioanalysis. It also discusses bioequivalence studies with pharmacodynamic and clinical endpoints as well as bioequivalence approaches for highly variable drugs, narrow therapeutic index drugs, liposomes, locally acting gastrointestinal drug products, topical products and nasal and inhalation products.FDA Bioequivalence Standards is written by FDA regulatory scientists who develop regulatory policies and conduct regulatory assessment of bioequivalence. As such, both practical case studies and fundamental science are highlighted in these chapters. The book is a valuable resource for scientists who work in the pharmaceutical industry, regulatory agencies and academia as well as undergraduate and graduate students looking to expand their knowledge about bioequivalence standards.

This comprehensive volume provides an update on the current state of pharmacometrics in drug development. It consists of nineteen chapters all written by leading scientists from the pharmaceutical industry, regulatory agencies and academia. After an introduction of the basic pharmacokinetic and pharmacodynamic concepts of pharmacometrics in drug development, the book presents numerous examples of specific applications that utilize pharmacometrics with modeling and simulations over a variety of therapeutic areas, including pediatrics, diabetes, obesity, infections, psychiatrics, Alzheimer’s disease, and dermatology, among others. The examples illustrate how results from all phases of drug development can be integrated in a more timely and cost-effective process.Applying pharmacometric decision tools during drug development can allow objective, data-based decision making. At the same time, the process can identify redundant or unnecessary experiments as well as some costly clinical trials that can be avoided. In addition to cost saving by expedited development of successful drug candidates, pharmacometrics has an important economic impact in drug product selection.  Unsuccessful drug candidates can be identified early and discontinued without expending efforts required for additional studies and allocating limited resources. Hence, pharmacometric modeling and simulation has become a powerful tool to bring new and better medications to the patient at a faster pace and with greater probability of success.

This authoritative volume provides a contemporary view on the latest research in molecules with optimal drug-like properties. It is a valuable source to access current best practices as well as new research techniques and strategies. Written by leading scientists in their fields, the text consists of fourteen chapters with an underlying theme of early collaborative opportunities between pharmaceutical and discovery sciences. The book explores the practical realities of performing physical pharmaceutical and biopharmaceutical research in the context of drug discovery with short timelines and low compound availability. Chapters cover strategies and tactics to enable discovery as well as predictive approaches to establish, understand and communicate risks in early development. It also examines the detection, characterization, and assessment of risks on the solid state properties of advanced discovery and early development candidates, highlighting the link between solid state propertiesand critical development parameters such as solubility and stability. Final chapters center on techniques to improve molecular solubilization and prevent precipitation, with particularly emphasis on linking physiochemical properties of molecules to formulation selection in preclinical and clinical settings.

This detailed volume addresses key issues and subtle nuances involved in developing hydrophilic matrix tablets as an approach to oral controlled release. It brings together information from more than five decades of research and development on hydrophilic matrix tablets and provides perspective on contemporary issues. Twelve comprehensive chapters explore a variety of topics including polymers (hypromellose, natural polysaccharides and polyethylene oxide) and their utilization in hydrophilic matrices, critical interactions impacting tablet performance, in vitro physical and imaging techniques, and microenvironmental pH control and mixed polymer approaches, among others. In one collective volume, Hydrophilic Matrix Tablets for Oral Controlled Release provides a single source of current knowledge, including sections of previously unpublished data. It is an important resource for industrial and academic scientists investigating and developing these oral controlled release formulations.

This volume explores the application of Quality by Design (QbD) to biopharmaceutical drug product development. Twenty-eight comprehensive chapters cover dosage forms, liquid and lyophilized drug products. The introductory chapters of this book define key elements of QbD and examine how these elements are integrated into drug product development. These chapters also discuss lessons learned from the FDA Office of Biotechnology Products pilot program. Following chapters demonstrate how QbD is used for formulation development ranging from screening of formulations to developability assessment to development of lyophilized and liquid formats. The next few chapters study the use of small-scale and surrogate models as well as QbD application to drug product processes such as drug substance freezing and thawing, mixing, sterile filtration, filling, lyophilization, inspection and shipping and handling.Later chapters describe more specialized applications of QbD in the drug product realm. This includes the use of QbD in primary containers, devices and combination product development. The volume also explores QbD applied to vaccine development, automation, mathematical modeling and monitoring, and controlling processes and defining control strategies. It concludes with a discussion on the application of QbD to drug product technology transfer as well as overall regulatory considerations and lifecycle management. Quality by Design for Biopharmaceutical Drug Product Development is an authoritative resource for scientists and researchers interested in expanding their knowledge on QbD principles and uses in creating better drugs.

“Biobetters: Protein Engineering to Approach the Curative” discusses the optimization of protein therapeutic products for treatment of human diseases. It is based on the fact that though numerous important therapeutic protein products have been developed for life threatening and chronic diseases that possess acceptable safety and efficacy profiles, these products have generally not been reexamined and modified for an improved clinical performance, with enhancements both to safety and efficacy profiles. Advances in protein engineering, coupled with greatly enhanced understanding of critical product quality attributes for efficacy and safety, make it possible to optimize predecessor products for clinical performance, thereby enhancing patient quality of life and with the potential for great savings in health care costs. Yet despite such knowledge, there is little movement towards such modifications. This book examines engineering protein therapeutic products such that they exhibit an optimal, not just an adequate, clinical performance profile. Two product classes, therapeutic enzymes for lysosomal storage diseases (enzyme replacement therapies, ERT) and monoclonal antibodies (mAbs), are used as examples of what modifications to such proteins could be made to enhance clinical performance, “closer to a cure” as it were. For ERT, the key to optimizing clinical performance is to ensure the ERT is endowed with moieties that target the protein to the relevant target tissue. Thus, for Gaucher Disease, our best example of how to optimize an ERT to address a disease that manifests in specific target tissues (macrophages and monocytes), the enzyme has been extensively modified to target macrophages. For diseases such as Pompe Disease, largely a disorder of muscle, optimal performance of ERT will depend on endowing the enzyme with the ability to be taken up via the Mannose 6 Phosphate Receptor, and so one of the chapters in the book will discuss such approaches.Moreover, a major failure of biotechnology based products is to gain access to the CNS, a key target tissue in numerous diseases. Thus, a chapter has been devoted to strategies to access the CNS. Additionally, immune responses to therapeutic proteins can be highly problematic, eliminating the efficacy of life saving or highly effective protein therapeutics. This is especially poignant in the case of Pompe Disease wherein great improvement in muscle strength and functionality is lost following development of an immune response to the ERT with consequent patient deterioration and death. Thus, a chapter regarding protein engineering, as well as other non-clinical approaches to diminishing immunogenicity is a valuable part of the book. Monoclonal antibodies (mAbs) can be engineered to bind targets relevant to a wide variety of diseases; binding affinity, however, is only part of the equation and one of the chapters will present a molecular assessment approach that balances affinity with pharmacokinetics and manufacturability. As with other proteins immunogenicity can be problematic, being responsible for loss of efficacy of anti-TNF mAbs, often after prolonged successful treatment. The authors will also share their perspective on the consequences of physico-chemical modifications occurring to mAbs once they reach the circulation or their target, a research area open to further development from a protein engineering as well as analytical perspective. This book will also discuss novel platforms for protein therapeutics, technologies that exceed mAbs with respect to potency, and hence, potentially efficacy. These platforms consist largely of repeat domain proteins with very high affinity for their target ligands, but while potentially more efficacious, immunogenicity may be a major problem limiting use. The economics surrounding the issue of biobetters is another high-profile issue - this final chapter will explore the incentives and disincentives for developingbiobetters and consider incentives that might make their pursuit more rewarding.

This comprehensive volume provides an update on the current state of pharmacometrics in drug development. It consists of nineteen chapters all written by leading scientists from the pharmaceutical industry, regulatory agencies and academia. After an introduction of the basic pharmacokinetic and pharmacodynamic concepts of pharmacometrics in drug development, the book presents numerous examples of specific applications that utilize pharmacometrics with modeling and simulations over a variety of therapeutic areas, including pediatrics, diabetes, obesity, infections, psychiatrics, Alzheimer’s disease, and dermatology, among others. The examples illustrate how results from all phases of drug development can be integrated in a more timely and cost-effective process.Applying pharmacometric decision tools during drug development can allow objective, data-based decision making. At the same time, the process can identify redundant or unnecessary experiments as well as some costly clinical trials that can be avoided. In addition to cost saving by expedited development of successful drug candidates, pharmacometrics has an important economic impact in drug product selection.  Unsuccessful drug candidates can be identified early and discontinued without expending efforts required for additional studies and allocating limited resources. Hence, pharmacometric modeling and simulation has become a powerful tool to bring new and better medications to the patient at a faster pace and with greater probability of success.

This detailed volume addresses key issues and subtle nuances involved in developing hydrophilic matrix tablets as an approach to oral controlled release. It brings together information from more than five decades of research and development on hydrophilic matrix tablets and provides perspective on contemporary issues. Twelve comprehensive chapters explore a variety of topics including polymers (hypromellose, natural polysaccharides and polyethylene oxide) and their utilization in hydrophilic matrices, critical interactions impacting tablet performance, in vitro physical and imaging techniques, and microenvironmental pH control and mixed polymer approaches, among others. In one collective volume, Hydrophilic Matrix Tablets for Oral Controlled Release provides a single source of current knowledge, including sections of previously unpublished data. It is an important resource for industrial and academic scientists investigating and developing these oral controlled release formulations.

This authoritative volume provides a contemporary view on the latest research in molecules with optimal drug-like properties. It is a valuable source to access current best practices as well as new research techniques and strategies. Written by leading scientists in their fields, the text consists of fourteen chapters with an underlying theme of early collaborative opportunities between pharmaceutical and discovery sciences. The book explores the practical realities of performing physical pharmaceutical and biopharmaceutical research in the context of drug discovery with short timelines and low compound availability. Chapters cover strategies and tactics to enable discovery as well as predictive approaches to establish, understand and communicate risks in early development. It also examines the detection, characterization, and assessment of risks on the solid state properties of advanced discovery and early development candidates, highlighting the link between solid state propertiesand critical development parameters such as solubility and stability. Final chapters center on techniques to improve molecular solubilization and prevent precipitation, with particularly emphasis on linking physiochemical properties of molecules to formulation selection in preclinical and clinical settings.

“Biobetters: Protein Engineering to Approach the Curative” discusses the optimization of protein therapeutic products for treatment of human diseases. It is based on the fact that though numerous important therapeutic protein products have been developed for life threatening and chronic diseases that possess acceptable safety and efficacy profiles, these products have generally not been reexamined and modified for an improved clinical performance, with enhancements both to safety and efficacy profiles. Advances in protein engineering, coupled with greatly enhanced understanding of critical product quality attributes for efficacy and safety, make it possible to optimize predecessor products for clinical performance, thereby enhancing patient quality of life and with the potential for great savings in health care costs. Yet despite such knowledge, there is little movement towards such modifications. This book examines engineering protein therapeutic products such that they exhibit an optimal, not just an adequate, clinical performance profile. Two product classes, therapeutic enzymes for lysosomal storage diseases (enzyme replacement therapies, ERT) and monoclonal antibodies (mAbs), are used as examples of what modifications to such proteins could be made to enhance clinical performance, “closer to a cure” as it were. For ERT, the key to optimizing clinical performance is to ensure the ERT is endowed with moieties that target the protein to the relevant target tissue. Thus, for Gaucher Disease, our best example of how to optimize an ERT to address a disease that manifests in specific target tissues (macrophages and monocytes), the enzyme has been extensively modified to target macrophages. For diseases such as Pompe Disease, largely a disorder of muscle, optimal performance of ERT will depend on endowing the enzyme with the ability to be taken up via the Mannose 6 Phosphate Receptor, and so one of the chapters in the book will discuss such approaches.Moreover, a major failure of biotechnology based products is to gain access to the CNS, a key target tissue in numerous diseases. Thus, a chapter has been devoted to strategies to access the CNS. Additionally, immune responses to therapeutic proteins can be highly problematic, eliminating the efficacy of life saving or highly effective protein therapeutics. This is especially poignant in the case of Pompe Disease wherein great improvement in muscle strength and functionality is lost following development of an immune response to the ERT with consequent patient deterioration and death. Thus, a chapter regarding protein engineering, as well as other non-clinical approaches to diminishing immunogenicity is a valuable part of the book. Monoclonal antibodies (mAbs) can be engineered to bind targets relevant to a wide variety of diseases; binding affinity, however, is only part of the equation and one of the chapters will present a molecular assessment approach that balances affinity with pharmacokinetics and manufacturability. As with other proteins immunogenicity can be problematic, being responsible for loss of efficacy of anti-TNF mAbs, often after prolonged successful treatment. The authors will also share their perspective on the consequences of physico-chemical modifications occurring to mAbs once they reach the circulation or their target, a research area open to further development from a protein engineering as well as analytical perspective. This book will also discuss novel platforms for protein therapeutics, technologies that exceed mAbs with respect to potency, and hence, potentially efficacy. These platforms consist largely of repeat domain proteins with very high affinity for their target ligands, but while potentially more efficacious, immunogenicity may be a major problem limiting use. The economics surrounding the issue of biobetters is another high-profile issue - this final chapter will explore the incentives and disincentives for developingbiobetters and consider incentives that might make their pursuit more rewarding.

This volume explores the application of Quality by Design (QbD) to biopharmaceutical drug product development. Twenty-eight comprehensive chapters cover dosage forms, liquid and lyophilized drug products. The introductory chapters of this book define key elements of QbD and examine how these elements are integrated into drug product development. These chapters also discuss lessons learned from the FDA Office of Biotechnology Products pilot program. Following chapters demonstrate how QbD is used for formulation development ranging from screening of formulations to developability assessment to development of lyophilized and liquid formats. The next few chapters study the use of small-scale and surrogate models as well as QbD application to drug product processes such as drug substance freezing and thawing, mixing, sterile filtration, filling, lyophilization, inspection and shipping and handling.Later chapters describe more specialized applications of QbD in the drug product realm. This includes the use of QbD in primary containers, devices and combination product development. The volume also explores QbD applied to vaccine development, automation, mathematical modeling and monitoring, and controlling processes and defining control strategies. It concludes with a discussion on the application of QbD to drug product technology transfer as well as overall regulatory considerations and lifecycle management. Quality by Design for Biopharmaceutical Drug Product Development is an authoritative resource for scientists and researchers interested in expanding their knowledge on QbD principles and uses in creating better drugs.

The volume aim to be a comprehensive overview of the drug and biologic development process that is often called “the valley of death” (pre-IND through approval) where high costs of studies and high rates of product failure are part of the drug development landscape. Imaging tools can serve in this period by adding high value data, the images and the kinetic information they can provide, and cost-effective development alternative tools which potentially improve pivotal study designs. Imaging may identify safety issues early such as unwanted organ or tissue distributions, and then can serve advanced development with added certainty of a drug or biologic’s success to senior corporate management and investors. There are numerous textbooks, reference texts and treatises on medical imaging technologies, teaching tools on medical cases and physics books on the science of detector and computer interface systems. Rarely, in each of these are examples of medical imaging protocols and animal models of disease i.e. a text on methodology in drug development is currently unavailable.

This volume provides readers with the basic principles and fundamentals of extrusion technology and a detailed description of the practical applications of a variety of extrusion processes, including various pharma grade extruders. In addition, the downstream production of films, pellets and tablets, for example, for oral and other delivery routes, are presented and discussed utilizing melt extrusion. This book is the first of its kind that discusses extensively the well-developed science of extrusion technology as applied to pharmaceutical drug product development and manufacturing. By covering a wide range of relevant topics, the text brings together all technical information necessary to develop and market pharmaceutical dosage forms that meet current quality and regulatory requirements. As extrusion technology continues to be refined further, usage of extruder systems and the array of applications will continue to expand, but the core technologies will remain the same.

This comprehensive book encompasses various facets of sterile product development. Key concepts relevant to the successful development of sterile products are illustrated through case studies and are covered under three sections in this book:• Formulation approaches that discuss a variety of dosage forms including protein therapeutics, lipid-based controlled delivery systems, PEGylated biotherapeutics, nasal dosage form, and vaccines• Process, container closure and delivery considerations including freeze-thaw process challenges, best practices for technology transfer to enable commercial product development, innovations and advancement in aseptic fill-finish operations, approaches to manufacturing lyophilized parenteral products, pen / auto-injector delivery devices, and associated container closure integrity testing hurdles for sterile product closures• Regulatory and quality aspects in the areas of particulate matter and appearance evaluation, sterile filtration, admixture compatibility considerations, sterilization process considerations, microbial contamination investigations and validation of rapid microbiological methods, and dry and moist heat sterilizersThis book is a useful resource to scientists and researchers in both industry and academia, and it gives process and product development engineers insight into current industry practices and evolving regulatory expectations for sterile product development.

Transporters in Drug Development examines how membrane transporters can be dealt with in academic–industrial drug discovery and pharmaceutical development as well as from a regulatory perspective. The book describes methods and examples of in vitro characterization of single transporters in the intestines, liver and kidneys as well as characterization of substrate overlap between various transporters. Furthermore, probes and biomarkers are suggested for studies of the transporters’ impact on the pharmacokinetics of drug substrates/candidates interacting on transporters. The challenges of translating in vitro observed interaction of transporters into in vivo relevance are explored, and the book highlights perspectives of applying targeted proteomics and mechanistic modeling in this process.