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PK Assay Development and Validation: A Comprehensive Guide
Introduction:
Are you involved in pharmaceutical development or drug discovery? Understanding pharmacokinetics (PK) is crucial, and a robust, validated PK assay is the cornerstone of your success. This comprehensive guide delves into the intricacies of PK assay development and validation, providing a step-by-step roadmap for scientists and researchers. We'll cover everything from initial assay design considerations to navigating regulatory requirements, ensuring you develop a high-quality assay that meets the highest standards. This post offers practical advice, troubleshooting tips, and best practices to help you avoid common pitfalls and ultimately accelerate your drug development pipeline. Prepare to master the art of PK assay development and validation!
1. Understanding Pharmacokinetics (PK) and its Importance in Drug Development
Before diving into assay development, a solid grasp of PK principles is essential. Pharmacokinetics describes how the body processes a drug – its absorption, distribution, metabolism, and excretion (ADME). Understanding these processes is crucial for determining:
Dosage and frequency: A well-characterized PK profile helps determine the optimal dosage and administration frequency to achieve therapeutic efficacy while minimizing adverse effects.
Drug interactions: Knowing how a drug is metabolized helps predict potential interactions with other medications.
Toxicity assessment: PK data is essential for evaluating the potential for drug-related toxicity.
Bioavailability: Understanding how much of the drug reaches the systemic circulation influences formulation design and efficacy predictions.
Regulatory approval: Comprehensive PK data is a critical component of regulatory submissions for new drug approvals.
Without a reliable PK assay, accurately assessing these parameters becomes impossible, hindering the entire drug development process.
2. Designing a Robust PK Assay: Key Considerations
Developing a robust PK assay involves meticulous planning and consideration of several factors:
Analytical method selection: Choosing the appropriate analytical method (e.g., HPLC-MS/MS, LC-MS/MS, ELISA) depends on the drug's properties, sensitivity requirements, and available resources. Factors like analyte stability, matrix effects, and the detection limit need careful evaluation.
Sample preparation: Sample preparation techniques must be efficient, reproducible, and minimize analyte loss or degradation. This often involves extraction, purification, and concentration steps, tailored to the specific biological matrix (e.g., plasma, serum, urine).
Validation parameters: Before implementation, the assay must be validated to ensure accuracy, precision, specificity, linearity, range, recovery, stability, and robustness. These parameters demonstrate the assay's reliability and suitability for its intended purpose.
Matrix effects: Biological samples contain numerous components that can interfere with the assay. Addressing matrix effects is crucial for accurate quantification and requires careful optimization of the analytical method.
Standard curves: Precisely prepared standard curves are essential for accurate quantification of the analyte in the samples. The linearity and range of the standard curve must be thoroughly validated.
3. Validation of the PK Assay: Meeting Regulatory Standards
Validation is not a single step but a comprehensive process to demonstrate the assay's suitability for its intended purpose. This involves:
Specificity: The assay must selectively measure the target analyte without interference from other components in the sample.
Sensitivity: The assay must be sensitive enough to detect the analyte at the lowest relevant concentration in the biological samples.
Linearity: The assay response must be linear across a defined concentration range.
Accuracy: The assay must provide results that are close to the true value.
Precision: The assay must provide reproducible results with minimal variation.
Recovery: The assay should recover a known amount of analyte added to the biological matrix.
Stability: The analyte's stability in various sample matrices and storage conditions must be assessed.
Robustness: The assay should be insensitive to small variations in the experimental conditions.
Meeting regulatory guidelines (e.g., FDA, EMA) is paramount. Documentation of all validation procedures, including results, is crucial for regulatory submissions.
4. Troubleshooting Common Challenges in PK Assay Development
Developing a PK assay is not always straightforward. Common challenges include:
Low analyte concentrations: Sensitivity issues can be addressed by optimizing the analytical method or using more sensitive detection techniques.
Matrix effects: Matrix effects can be mitigated by careful sample preparation techniques, such as solid-phase extraction or protein precipitation.
Lack of specificity: Improving assay specificity might involve exploring alternative chromatographic conditions or using more selective detection methods.
Poor recovery: Low recovery can stem from inefficient extraction procedures; optimizing extraction protocols is necessary.
Assay instability: Instability can be addressed by optimizing storage conditions and using appropriate stabilizers.
Addressing these challenges requires a systematic approach, often involving iterative optimization and troubleshooting.
5. Data Analysis and Reporting of PK Studies
Once the assay is validated and PK samples are analyzed, the data must be appropriately analyzed and reported. This involves:
Non-compartmental analysis (NCA): A common approach to analyzing PK data that doesn't require assumptions about the underlying physiological processes.
Compartmental modeling: More complex analysis that provides a more detailed description of the drug's distribution and elimination.
Pharmacokinetic parameters: Key parameters like AUC (area under the curve), Cmax (maximum concentration), Tmax (time to maximum concentration), and clearance are calculated and interpreted.
Report generation: A comprehensive report documenting the study design, methods, results, and conclusions is essential for regulatory submissions and internal use.
Article Outline: PK Assay Development and Validation
I. Introduction: The importance of PK assays in drug development.
II. Understanding Pharmacokinetics (PK): ADME processes and their significance.
III. Designing a Robust PK Assay: Method selection, sample preparation, validation parameters.
IV. Validation of the PK Assay: Meeting regulatory standards (Specificity, Sensitivity, Linearity, Accuracy, Precision, Recovery, Stability, Robustness).
V. Troubleshooting Common Challenges: Low concentrations, matrix effects, lack of specificity, poor recovery, assay instability.
VI. Data Analysis and Reporting: NCA, Compartmental modeling, key parameters, report generation.
VII. Conclusion: Recap of key concepts and future directions.
FAQs
1. What is the difference between PK and PD? PK focuses on what the body does to the drug, while PD focuses on what the drug does to the body.
2. Which analytical method is best for PK assay development? The optimal method depends on the drug's properties and study requirements. HPLC-MS/MS and LC-MS/MS are frequently used.
3. How long does PK assay development and validation typically take? The timeline varies depending on the complexity of the drug and the assay. It can range from several months to over a year.
4. What regulatory guidelines should be followed for PK assay validation? FDA and EMA guidelines are commonly followed.
5. What are the common pitfalls to avoid in PK assay development? Inadequate validation, improper sample handling, and neglecting matrix effects are common pitfalls.
6. How do I choose the appropriate sample type for PK analysis? The choice depends on the drug and the research question; plasma or serum are frequently used.
7. What is the role of bioanalytical method validation in PK assay development? Validation ensures the assay's accuracy, precision, and reliability.
8. How can I address matrix effects in my PK assay? Solid-phase extraction or protein precipitation can help mitigate matrix effects.
9. What software is commonly used for PK data analysis? Phoenix WinNonlin, and other specialized PK/PD software are commonly used.
Related Articles:
1. HPLC-MS/MS in Bioanalysis: A detailed explanation of this popular analytical technique for PK studies.
2. LC-MS/MS for Drug Quantification: Focuses on the application of LC-MS/MS in quantitative bioanalysis.
3. Bioanalytical Method Validation Guidelines: A review of regulatory guidelines for bioanalytical method validation.
4. Pharmacokinetic Modeling and Simulation: A discussion of various pharmacokinetic models and their applications.
5. Non-Compartmental Analysis of PK Data: A detailed explanation of NCA techniques and their applications.
6. Sample Preparation Techniques for Bioanalysis: A comprehensive overview of various sample preparation methods.
7. Matrix Effects in Bioanalysis: Causes and Mitigation Strategies: A detailed explanation of matrix effects and how to minimize their impact.
8. Bioavailability and Bioequivalence Studies: Explains the importance of these studies in drug development.
9. Regulatory Considerations for PK Studies: Focuses on regulatory requirements for PK data submission.
| pk assay development and validation: Ligand-Binding Assays Masood N. Khan, John W. A. Findlay, 2009-10-22 A consolidated and comprehensive reference on ligand-binding assays Ligand-binding assays (LBAs) stand as the cornerstone of support for definition of the pharmaco-kinetics and toxicokinetics of macromolecules, an area of burgeoning interest in the pharmaceutical industry. Yet, outside of the Crystal City Conference proceedings, little guidance has been available for LBA validation, particularly for assays used to support macromolecule drug development. Ligand-Binding Assays: Development, Validation, and Implementation in the Drug Development Arena answers that growing need, serving as a reference text discussing critical aspects of the development, validation, and implementation of ligand-binding assays in the drug development field. Ligand-Binding Assays covers essential topics related to ligand-binding assays, from pharmacokinetic studies, the development of LBAs, assay validation, statistical LBA aspects, and regulatory aspects, to software for LBAs and robotics and other emerging methodologies for LBAs. Highlights include: A general discussion of challenges and proven approaches in the development of ligand-binding assays More detailed examination of characteristics of these assays when applied to support of pharmacokinetic and toxicokinetic studies of compounds at different stages in the discovery or development timeline A concise, but detailed, discussion of validation of ligand-binding assays for macromolecules A practical approach to fit-for-purpose validation of assays for biomarkers, those molecules receiving increased attention as potentially demonstrating that the target chosen in discovery is being modulated by the candidate therapeutic, both in nonclinical and clinical studies Written by a team of world-recognized authorities in the field, Ligand-Binding Assays provides key information to a broad range of practitioners, both in the pharmaceutical and allied industries and in related contract research organizations and academic laboratories and, perhaps, even in the field of diagnostics and clinical chemistry. |
| pk assay development and validation: Statistical Methods in Biomarker and Early Clinical Development Liang Fang, Cheng Su, 2019-12-26 This contributed volume offers a much-needed overview of the statistical methods in early clinical drug and biomarker development. Chapters are written by expert statisticians with extensive experience in the pharmaceutical industry and regulatory agencies. Because of this, the data presented is often accompanied by real world case studies, which will help make examples more tangible for readers. The many applications of statistics in drug development are covered in detail, making this volume a must-have reference. Biomarker development and early clinical development are the two critical areas on which the book focuses. By having the two sections of the book dedicated to each of these topics, readers will have a more complete understanding of how applying statistical methods to early drug development can help identify the right drug for the right patient at the right dose. Also presented are exciting applications of machine learning and statistical modeling, along with innovative methods and state-of-the-art advances, making this a timely and practical resource. This volume is ideal for statisticians, researchers, and professionals interested in pharmaceutical research and development. Readers should be familiar with the fundamentals of statistics and clinical trials. |
| pk assay development and validation: Regulated Bioanalysis: Fundamentals and Practice Mario L. Rocci Jr., Stephen Lowes, 2017-04-24 The editors have engaged leading scientists in the field to participate in the development of this book, which is envisioned as a “one of a kind” contribution to the field. The book is a comprehensive text that puts fundamental bioanalytical science in context with current practice, its challenges and ongoing developments. It expands on existing texts on the subject by covering regulated bioanalysis of both small and large molecule therapeutics from both a scientific and regulatory viewpoint. The content will be useful to a wide spectrum of readers: from those new to bioanalysis; to those developing their experience in the laboratory, or working in one of the many critical supporting roles; to seasoned practitioners looking for a solid source of information on this exciting and important discipline. |
| pk assay development and validation: Development and Validation of Analytical Methods Christopher M. Riley, Thomas W. Rosanske, 1996-05-29 The need to validate an analytical or bioanalytical method is encountered by analysts in the pharmaceutical industry on an almost daily basis, because adequately validated methods are a necessity for approvable regulatory filings. What constitutes a validated method, however, is subject to analyst interpretation because there is no universally accepted industry practice for assay validation. This book is intended to serve as a guide to the analyst in terms of the issues and parameters that must be considered in the development and validation of analytical methods. In addition to the critical issues surrounding method validation, this book also deals with other related factors such as method development, data acquisition, automation, cleaning validation and regulatory considerations. The book is divided into three parts. Part One, comprising two chapters, looks at some of the basic concepts of method validation. Chapter 1 discusses the general concept of validation and its role in the process of transferring methods from laboratory to laboratory. Chapter 2 looks at some of the critical parameters included in a validation program and the various statistical treatments given to these parameters.Part Two (Chapters 3, 4 and 5) of the book focuses on the regulatory perspective of analytical validation. Chapter 3 discusses in some detail how validation is treated by various regulatory agencies around the world, including the United States, Canada, the European Community, Australia and Japan. This chapter also discusses the International Conference on Harmonization (ICH) treatment of assay validation. Chapters 4 and 5 cover the issues and various perspectives of the recent United States vs. Barr Laboratories Inc. case involving the retesting of samples. Part Three (Chapters 6 - 12) covers the development and validation of various analytical components of the pharmaceutical product development process. This part of the book contains specific chapters dedicated to bulk drug substances and finished products, dissolution studies, robotics and automated workstations, biotechnology products, biological samples, analytical methods for cleaning procedures and computer systems and computer-aided validation. Each chapter goes into some detail describing the critical development and related validation considerations for each topic.This book is not intended to be a practical description of the analytical validation process, but more of a guide to the critical parameters and considerations that must be attended to in a pharmaceutical development program. Despite the existence of numerous guidelines including the recent attempts by the ICH to be implemented in 1998, the practical part of assay validation will always remain, to a certain extent, a matter of the personal preference of the analyst or company. Nevertheless, this book brings together the perspectives of several experts having extensive experience in different capacities in the pharmaceutical industry in an attempt to bring some consistency to analytical method development and validation. |
| pk assay development and validation: Chemical Genomics Haian Fu, 2012-02-13 Advances in chemistry, biology and genomics coupled with laboratory automation and computational technologies have led to the rapid emergence of the multidisciplinary field of chemical genomics. This edited text, with contributions from experts in the field, discusses the new techniques and applications that help further the study of chemical genomics. The beginning chapters provide an overview of the basic principles of chemical biology and chemical genomics. This is followed by a technical section that describes the sources of small-molecule chemicals; the basics of high-throughput screening technologies; and various bioassays for biochemical-, cellular- and organism-based screens. The final chapters connect the chemical genomics field with personalized medicine and the druggable genome for future discovery of new therapeutics. This book will be valuable to researchers, professionals and graduate students in many fields, including biology, biomedicine and chemistry. |
| pk assay development and validation: Recent Advances in Analytical Chemistry Muharrem Ince, Olcay Kaplan Ince, 2019-04-10 This book focuses on recent and future trends in analytical methods and provides an overview of analytical chemistry. As a comprehensive analytical chemistry book, it takes a broad view of the subject and integrates a wide variety of approaches. The book provides separation approaches and method validation, as well as recent developments and applications in analytical chemistry. It is written primarily for researchers in the fields of analytical chemistry, environmental chemistry, and applied chemistry. The aim of the book is to explain the subject, clarify important studies, and compare and develop new and groundbreaking applications. Written by leading experts in their respective areas, the book is highly recommended for professionals interested in analytical chemistry because it provides specific and comprehensive examples. |
| pk assay development and validation: Nonclinical Statistics for Pharmaceutical and Biotechnology Industries Lanju Zhang, 2016-01-13 This book serves as a reference text for regulatory, industry and academic statisticians and also a handy manual for entry level Statisticians. Additionally it aims to stimulate academic interest in the field of Nonclinical Statistics and promote this as an important discipline in its own right. This text brings together for the first time in a single volume a comprehensive survey of methods important to the nonclinical science areas within the pharmaceutical and biotechnology industries. Specifically the Discovery and Translational sciences, the Safety/Toxiology sciences, and the Chemistry, Manufacturing and Controls sciences. Drug discovery and development is a long and costly process. Most decisions in the drug development process are made with incomplete information. The data is rife with uncertainties and hence risky by nature. This is therefore the purview of Statistics. As such, this book aims to introduce readers to important statistical thinking and its application in these nonclinical areas. The chapters provide as appropriate, a scientific background to the topic, relevant regulatory guidance, current statistical practice, and further research directions. |
| pk assay development and validation: Flow Cytometry in Drug Discovery and Development Virginia Litwin, Philip Marder, 2011-04-20 This book covers the unique application of flow cytometry in drug discovery and development. The first section includes two introductory chapters, one on flow cytometry and one on biomarkers, as well as a chapter on recent advances in flow cytometry. The second section focuses on the unique challenges and added benefits associated with the use of flow cytometry in the drug development process. The third section contains a single chapter presenting an in depth discussion of validation considerations and regulatory compliance issues associated with drug development. |
| pk assay development and validation: Drug Discovery and Evaluation: Safety and Pharmacokinetic Assays Franz J. Hock, Michael K. Pugsley, 2025-02 Many aspects of drug safety have become an outstanding and even persistent issue and may occur during the process of both drug discovery and development. Until 15 years ago, drug discovery and evaluation was primarily a sequential process starting with the selection of the most pharmacologically active compound from a series of newly synthesized small molecule chemical series by means of distinctive pharmacological assays. Safety aspects were addressed by evaluation of the selected compound at high doses in a series of specific studies directed at indications other than the intended indication of the new compound. These tests are then followed by pharmacokinetic studies, which are primarily conducted to confirm whether the selected compound possesses a suitable half-life for sufficient exposure and efficacy and, whether it has the desired properties specificity to the intended route of administration. Safety aspects relied predominantly on the conduct of single and repeat toxicologydose studies, which inform changes in organ structure rather than organ function. Both toxicological and pharmacokinetic studies are adapted to the progress of studies in clinical pharmacology and clinical trials. The new edition of this well and broadly accepted reference work contains several innovative and distinguished chapters. This sequential strategy has been abandoned with this new version of the book for several reasons: - Of the possible multitude of negative effects that novel drugs may impart on organ function, e.g. ventricular tachy-arrhythmia, many are detected too late in non-clinical studies to inform clinicians. On the other hand, negative findings in chronic toxicity studies in animals may turn out to be irrelevant for human beings. - New scientific approaches, e.g. high-throughput screening, human pluripotent stem cells, transgenic animals, knock-out animals, in silico models, pharmaco-genomics and pharmaco-proteomics, as well as Artificial Intelligence (AI) methods offered new possibilities. - There are several examples, that show that the druggability of compounds was considerably underestimated when the probability of success of a new project was assessed. The success rate in the pharmaceutical industry and the introduction of new chemical entities to the market per year dropped dramatically, whereas the development time for a new compound increased, sometimes exceeding the patent protection. Research and development scientists, involving the following changes, therefore adopted a change of strategy: - Parallel instead of sequential involvement of the various disciplines (multidimensional compound optimization). - The term Safety Pharmacology was coined. The International Conference on Harmonization (ICH) founded a Safety Pharmacology Working Group and the Safety Pharmacology Society (SPS) was launched. The discipline provided for evaluation, development and validation of a multitude of safety tests outlined in the 'Core Battery of Studies'. - Characterizing the exposure profile of a drug by conducting pharmacokinetic studies that evaluates the absorption, distribution, metabolism and excretion should to be investigated at an early stage of development as results contribute to the selection of a compound for further development. Advancements in Toxicology were achieved by the introduction of new methods, e.g., in silico methods, genetic toxicology, computational toxicology and AI. The book is a landmark in the continuously changing world of drug research and developments. As such, it is essential reading for many groups: not only for all students of pharmacology and toxicology but also for industry scientists and physicians, especially those involved in clinical trials of drugs, and for pharmacists who must know the safety requirements of drugs. The book is essential for scientists and managers in the pharmaceutical industry who are involved in drug discovery, drug development and decision making in the development process. In particular, the book will be of use to government institutions and committees working on official guidelines for drug evaluation worldwide. |
| pk assay development and validation: Improving and Accelerating Therapeutic Development for Nervous System Disorders Institute of Medicine, Board on Health Sciences Policy, Forum on Neuroscience and Nervous System Disorders, 2014-02-06 Improving and Accelerating Therapeutic Development for Nervous System Disorders is the summary of a workshop convened by the IOM Forum on Neuroscience and Nervous System Disorders to examine opportunities to accelerate early phases of drug development for nervous system drug discovery. Workshop participants discussed challenges in neuroscience research for enabling faster entry of potential treatments into first-in-human trials, explored how new and emerging tools and technologies may improve the efficiency of research, and considered mechanisms to facilitate a more effective and efficient development pipeline. There are several challenges to the current drug development pipeline for nervous system disorders. The fundamental etiology and pathophysiology of many nervous system disorders are unknown and the brain is inaccessible to study, making it difficult to develop accurate models. Patient heterogeneity is high, disease pathology can occur years to decades before becoming clinically apparent, and diagnostic and treatment biomarkers are lacking. In addition, the lack of validated targets, limitations related to the predictive validity of animal models - the extent to which the model predicts clinical efficacy - and regulatory barriers can also impede translation and drug development for nervous system disorders. Improving and Accelerating Therapeutic Development for Nervous System Disorders identifies avenues for moving directly from cellular models to human trials, minimizing the need for animal models to test efficacy, and discusses the potential benefits and risks of such an approach. This report is a timely discussion of opportunities to improve early drug development with a focus toward preclinical trials. |
| pk assay development and validation: Bioanalytical Aspects in Biological Therapeutics Xiaohui (Sophia) Xu, Weifeng Xu, 2022-08-23 Bioanalytical Aspects in Biological Therapeutics Deepen your understanding of how critical data are generated from bioanalysis In Bioanalytical Aspects in Biological Therapeutics, a team of renowned chemists, immunologists, and biologists delivers a timely and practical exploration of the diverse scientific and technical literature on the bioanalytical investigation of current biotherapeutics under development. The book discusses the challenges and considerations for bioanalytical support, covering a wide range of central topics in the field, including overview and basic immunology for testing of biological therapeutics, pharmacokinetic aspects, clinical immunogenicity prediction and testing, biomarker testing, biotransformation assessment for biologics, statistical aspects of bioanalytical testing, regulatory expectations, and more. Drug development and analysis professionals will learn how critical data are generated from bioanalysis and how proven tools and methods are applied to the development of biologics. Alongside coverage of topics like PK, immunogenicity, neutralizing antibody assays, and the importance of quality control for reagents, readers will benefit from: A thorough overview of the development of biotherapeutics and the role played by bioanalytical tests, as well as basic immunology for bioanalytical testing of biological therapeutics Comprehensive explorations of platform and instrument considerations in bioanalytical testing, pharmacokinetics assays, and biomarker analysis using LC-MS, LBA, and other technologies Practical discussions of immunogenicity prediction, preclinical and clinical anti-drug antibody assays, and bioanalytical schemes for anti-drug neutralizing antibody assays In-depth examinations of critical reagents in bioanalysis Regulatory expectations for bioanalytical method development, validation, and sample testing Perfect for pharmaceutical scientists in industry, Bioanalytical Aspects in Biological Therapeutics will also earn a place in the libraries of pharmaceutical regulators and other professionals working in pharmaceutical companies, as well as graduate students studying bioanalytical assays for biological therapeutics. |
| pk assay development and validation: Guideline for Submitting Samples and Analytical Data for Methods Validation , 1987 |
| pk assay development and validation: Transformation and Weighting in Regression Raymond J. Carroll, David Ruppert, 2017-10-19 This monograph provides a careful review of the major statistical techniques used to analyze regression data with nonconstant variability and skewness. The authors have developed statistical techniques--such as formal fitting methods and less formal graphical techniques-- that can be applied to many problems across a range of disciplines, including pharmacokinetics, econometrics, biochemical assays, and fisheries research. While the main focus of the book in on data transformation and weighting, it also draws upon ideas from diverse fields such as influence diagnostics, robustness, bootstrapping, nonparametric data smoothing, quasi-likelihood methods, errors-in-variables, and random coefficients. The authors discuss the computation of estimates and give numerous examples using real data. The book also includes an extensive treatment of estimating variance functions in regression. |
| pk assay development and validation: Ligand-Binding Assays Masood N. Khan, John W. A. Findlay, 2009-11-23 A consolidated and comprehensive reference on ligand-binding assays Ligand-binding assays (LBAs) stand as the cornerstone of support for definition of the pharmaco-kinetics and toxicokinetics of macromolecules, an area of burgeoning interest in the pharmaceutical industry. Yet, outside of the Crystal City Conference proceedings, little guidance has been available for LBA validation, particularly for assays used to support macromolecule drug development. Ligand-Binding Assays: Development, Validation, and Implementation in the Drug Development Arena answers that growing need, serving as a reference text discussing critical aspects of the development, validation, and implementation of ligand-binding assays in the drug development field. Ligand-Binding Assays covers essential topics related to ligand-binding assays, from pharmacokinetic studies, the development of LBAs, assay validation, statistical LBA aspects, and regulatory aspects, to software for LBAs and robotics and other emerging methodologies for LBAs. Highlights include: A general discussion of challenges and proven approaches in the development of ligand-binding assays More detailed examination of characteristics of these assays when applied to support of pharmacokinetic and toxicokinetic studies of compounds at different stages in the discovery or development timeline A concise, but detailed, discussion of validation of ligand-binding assays for macromolecules A practical approach to fit-for-purpose validation of assays for biomarkers, those molecules receiving increased attention as potentially demonstrating that the target chosen in discovery is being modulated by the candidate therapeutic, both in nonclinical and clinical studies Written by a team of world-recognized authorities in the field, Ligand-Binding Assays provides key information to a broad range of practitioners, both in the pharmaceutical and allied industries and in related contract research organizations and academic laboratories and, perhaps, even in the field of diagnostics and clinical chemistry. |
| pk assay development and validation: Drug Discovery and Evaluation: Methods in Clinical Pharmacology H.Gerhard Vogel, Jochen Maas, Alexander Gebauer, 2010-12-15 Drug Discovery and Evaluation has become a more and more difficult, expensive and time-consuming process. The effect of a new compound has to be detected by in vitro and in vivo methods of pharmacology. The activity spectrum and the potency compared to existing drugs have to be determined. As these processes can be divided up stepwise we have designed a book series Drug Discovery and Evaluation in the form of a recommendation document. The methods to detect drug targets are described in the first volume of this series Pharmacological Assays comprising classical methods as well as new technologies. Before going to man, the most suitable compound has to be selected by pharmacokinetic studies and experiments in toxicology. These preclinical methods are described in the second volume „Safety and Pharmacokinetic Assays. Only then are first studies in human beings allowed. Special rules are established for Phase I studies. Clinical pharmacokinetics are performed in parallel with human studies on tolerability and therapeutic effects. Special studies according to various populations and different therapeutic indications are necessary. These items are covered in the third volume: „Methods in Clinical Pharmacology. |
| pk assay development and validation: ICH Quality Guidelines Andrew Teasdale, David Elder, Raymond W. Nims, 2017-09-29 Examining the implications and practical implementation of multi-disciplinary International Conference on Harmonization (ICH) topics, this book gives an integrated view of how the guidelines inform drug development strategic planning and decision-making. • Addresses a consistent need for interpretation, training, and implementation examples of ICH guidelines via case studies • Offers a primary reference point for practitioners addressing the dual challenge of interpretation and practical implementation of ICH guidelines • Uses case studies to help readers understand and apply ICH guidelines • Provides valuable insights into guidelines development, with chapters by authors involved in generating or with experience implementing the guidelines • Includes coverage of stability testing, analytical method validation, impurities, biotechnology drugs and products, and good manufacturing practice (GMP) |
| pk assay development and validation: ADME and Translational Pharmacokinetics / Pharmacodynamics of Therapeutic Proteins Honghui Zhou, Frank-Peter Theil, 2015-11-23 With an emphasis on the fundamental and practical aspects of ADME for therapeutic proteins, this book helps readers strategize, plan and implement translational research for biologic drugs. • Details cutting-edge ADME (absorption, distribution, metabolism and excretion) and PKPD (pharmacokinetic / pharmacodynamics) modeling for biologic drugs • Combines theoretical with practical aspects of ADME in biologic drug discovery and development and compares innovator biologics with biosimilar biologics and small molecules with biologics, giving a lessons-learned perspective • Includes case studies about leveraging ADME to improve biologics drug development for monoclonal antibodies, fusion proteins, pegylated proteins, ADCs, bispecifics, and vaccines • Presents regulatory expectations and industry perspectives for developing biologic drugs in USA, EU, and Japan • Provides mechanistic insight into biodistribution and target-driven pharmacokinetics in important sites of action such as tumors and the brain |
| pk assay development and validation: Sample Preparation in LC-MS Bioanalysis Wenkui Li, Wenying Jian, Yunlin Fu, 2019-03-12 Revised and Expanded Handbook Provides Comprehensive Introduction and Complete Instruction for Sample Preparation in Vital Category of Bioanalysis Following in the footsteps of the previously published Handbook of LC-MS Bioanalysis, this book is a thorough and timely guide to all important sample preparation techniques used for quantitative Liquid Chromatography–Mass Spectrometry (LC-MS) bioanalysis of small and large molecules. LC-MS bioanalysis is a key element of pharmaceutical research and development, post-approval therapeutic drug monitoring, and many other studies used in human healthcare. While advances are continually being made in key aspects of LC-MS bioanalysis such as sensitivity and throughput, the value of research/study mentioned above is still heavily dependent on the availability of high-quality data, for which sample preparation plays the critical role. Thus, this text provides researchers in industry, academia, and regulatory agencies with detailed sample preparation techniques and step-by-step protocols on proper extraction of various analyte(s) of interest from biological samples for LC-MS quantification, in accordance with current health authority regulations and industry best practices. The three sections of the book with a total of 26 chapters cover topics that include: Current basic sample preparation techniques (e.g., protein precipitation, liquid-liquid extraction, solid-phase extraction, salting-out assisted liquid-liquid extraction, ultracentrifugation and ultrafiltration, microsampling, sample extraction via electromembranes) Sample preparation techniques for uncommon biological matrices (e.g., tissues, hair, skin, nails, bones, mononuclear cells, cerebrospinal fluid, aqueous humor) Crucial aspects of LC-MS bioanalytical method development (e.g., pre-analytical considerations, derivation strategies, stability, non-specific binding) in addition to sample preparation techniques for challenging molecules (e.g., lipids, peptides, proteins, oligonucleotides, antibody-drug conjugates) Sample Preparation in LC-MS Bioanalysis will prove a practical and highly valuable addition to the reference shelves of scientists and related professionals in a variety of fields, including pharmaceutical and biomedical research, mass spectrometry, and analytical chemistry, as well as practitioners in clinical pharmacology, toxicology, and therapeutic drug monitoring. |
| pk assay development and validation: Biophysical Methods for Biotherapeutics Tapan K. Das, 2014-04-28 With a focus on practical applications of biophysical techniques, this book links fundamental biophysics to the process of biopharmaceutical development. • Helps formulation and analytical scientists in pharma and biotech better understand and use biophysical methods • Chapters organized according to the sequential nature of the drug development process • Helps formulation, analytical, and bioanalytical scientists in pharma and biotech better understand and usestrengths and limitations of biophysical methods • Explains how to use biophysical methods, the information obtained, and what needs to be presented in a regulatory filing, assess impact on quality and immunogenicity • With a focus on practical applications of biophysical techniques, this book links fundamental biophysics to the process of biopharmaceutical development. |
| pk assay development and validation: Pharmacokinetics in Drug Development Peter L. Bonate, Danny R. Howard, 2005-12-05 These volumes are designed to be the most complete guide to pharmacokinetics (PK) and its role in drug development. The volumes fill a gap between the academic science and the practical application of that knowledge in drug development. Volume 1 discusses the role that PK plays in selected clinical study designs. Volume 2 details the key regulatory and development paradigms in which PK supplements decision-making during drug development. |
| pk assay development and validation: Handbook of Bioequivalence Testing Sarfaraz K. Niazi, 2014-10-29 As the generic pharmaceutical industry continues to grow and thrive, so does the need to conduct adequate, efficient bioequivalence studies. In recent years, there have been significant changes to the statistical models for evaluating bioequivalence. In addition, advances in the analytical technology used to detect drug and metabolite levels have m |
| pk assay development and validation: Variance Components Shayle R. Searle, George Casella, Charles E. McCulloch, 2009-09-25 WILEY-INTERSCIENCE PAPERBACK SERIES The Wiley-Interscience Paperback Series consists of selected books that have been made more accessible to consumers in an effort to increase global appeal and general circulation. With these new unabridged softcover volumes, Wiley hopes to extend the lives of these works by making them available to future generations of statisticians, mathematicians, and scientists. . . .Variance Components is an excellent book. It is organized and well written, and provides many references to a variety of topics. I recommend it to anyone with interest in linear models. —Journal of the American Statistical Association This book provides a broad coverage of methods for estimating variance components which appeal to students and research workers . . . The authors make an outstanding contribution to teaching and research in the field of variance component estimation. —Mathematical Reviews The authors have done an excellent job in collecting materials on a broad range of topics. Readers will indeed gain from using this book . . . I must say that the authors have done a commendable job in their scholarly presentation. —Technometrics This book focuses on summarizing the variability of statistical data known as the analysis of variance table. Penned in a readable style, it provides an up-to-date treatment of research in the area. The book begins with the history of analysis of variance and continues with discussions of balanced data, analysis of variance for unbalanced data, predictions of random variables, hierarchical models and Bayesian estimation, binary and discrete data, and the dispersion mean model. |
| pk assay development and validation: Manual of Industrial Microbiology and Biotechnology Richard H. Baltz, Arnold L. Demain, Julian E. Davies, 2010-03-25 A rich array of methods and discussions of productive microbial processes. • Reviews of the newest techniques, approaches, and options in the use of microorganisms and other cell culture systems for the manufacture of pharmaceuticals, industrial enzymes and proteins, foods and beverages, fuels and fine chemicals, and other products. • Focuses on the latest advances and findings on the current state of the art and science and features a new section on the microbial production of biofuels and fine chemicals, as well as a stronger emphasis on mammalian cell culture methods. • Covers new methods that enhance the capacity of microbes used for a wide range of purposes, from winemaking to pharmaceuticals to bioremediation, at volumes from micro- to industrial scale. |
| pk assay development and validation: Biomarker Validation Harald Seitz, Sarah Schumacher, 2015-02-23 Built on a decade of experience with novel molecular diagnostics, this practice-oriented guide shows how to cope with validation issues during all stages of biomarker development, from the first clinical studies to the eventual commercialization of a new diagnostic test. |
| pk assay development and validation: Handbook of Pharmaceutical Biotechnology Shayne Cox Gad, 2007-05-23 A practical overview of a full rangeof approaches to discovering, selecting, and producing biotechnology-derived drugs The Handbook of Pharmaceutical Biotechnology helps pharmaceutical scientists develop biotech drugs through a comprehensive framework that spans the process from discovery, development, and manufacturing through validation and registration. With chapters written by leading practitioners in their specialty areas, this reference: Provides an overview of biotechnology used in the drug development process Covers extensive applications, plus regulations and validation methods Features fifty chapters covering all the major approaches to the challenge of identifying, producing, and formulating new biologically derived therapeutics With its unparalleled breadth of topics and approaches, this handbook is a core reference for pharmaceutical scientists, including development researchers, toxicologists, biochemists, molecular biologists, cell biologists, immunologists, and formulation chemists. It is also a great resource for quality assurance/assessment/control managers, biotechnology technicians, and others in the biotech industry. |
| pk assay development and validation: Targeted Biomarker Quantitation by LC-MS Naidong Weng, Wenying Jian, 2017-07-31 The first book to offer a blueprint for overcoming the challenges to successfully quantifying biomarkers in living organisms The demand among scientists and clinicians for targeted quantitation experiments has experienced explosive growth in recent years. While there are a few books dedicated to bioanalysis and biomarkers in general, until now there were none devoted exclusively to addressing critical issues surrounding this area of intense research. Target Biomarker Quantitation by LC-MS provides a detailed blueprint for quantifying biomarkers in biological systems. It uses numerous real-world cases to exemplify key concepts, all of which were carefully selected and presented so as to allow the concepts they embody to be easily expanded to future applications, including new biomarker development. Target Biomarker Quantitation by LC-MS primarily focuses on the assay establishment for biomarker quantitation—a critical issue rarely treated in depth. It offers comprehensive coverage of three core areas of biomarker assay establishment: the relationship between the measured biomarkers and their intended usage; contemporary regulatory requirements for biomarker assays (a thorough understanding of which is essential to producing a successful and defendable submission); and the technical challenges of analyzing biomarkers produced inside a living organism or cell. Covers the theory of and applications for state-of-the-art mass spectrometry and chromatography and their applications in biomarker analysis Features real-life examples illustrating the challenges involved in target biomarker quantitation and the innovative approaches which have been used to overcome those challenges Addresses potential obstacles to obtain effective biomarker level and data interpretation, such as specificity establishment and sample collection Outlines a tiered approach and fit-for-purpose assay protocol for target biomarker quantitation Highlights the current state of the biomarker regulatory environment and protocol standards Target Biomarker Quantitation by LC-MS is a valuable resource for bioanalytical scientists, drug metabolism and pharmacokinetics scientists, clinical scientists, analytical chemists, and others for whom biomarker quantitation is an important tool of the trade. It also functions as an excellent text for graduate courses in pharmaceutical, biochemistry and chemistry. |
| pk assay development and validation: Evidence-Based Medical Monitoring Paul P. Glasziou, Les Irwig, Jeffrey K. Aronson, 2008-04-30 Monitoring is a major component of management of chronic diseases such as diabetes, cardiovascular disease, arthritis and depression. Yet poor monitoring means healthcare costs are rising. This book discusses how monitoring principles adopted in other spheres such as clinical pharmacology and evidence-based medicine can be applied to chronic disease in the global setting. With contributions from leading experts in evidence-based medicine, it is a ground-breaking text for all involved in delivery of better and more effective management of chronic illnesses. |
| pk assay development and validation: Targeted Biomarker Quantitation by LC-MS Naidong Weng, Wenying Jian, 2017-07-05 The first book to offer a blueprint for overcoming the challenges to successfully quantifying biomarkers in living organisms The demand among scientists and clinicians for targeted quantitation experiments has experienced explosive growth in recent years. While there are a few books dedicated to bioanalysis and biomarkers in general, until now there were none devoted exclusively to addressing critical issues surrounding this area of intense research. Target Biomarker Quantitation by LC-MS provides a detailed blueprint for quantifying biomarkers in biological systems. It uses numerous real-world cases to exemplify key concepts, all of which were carefully selected and presented so as to allow the concepts they embody to be easily expanded to future applications, including new biomarker development. Target Biomarker Quantitation by LC-MS primarily focuses on the assay establishment for biomarker quantitation—a critical issue rarely treated in depth. It offers comprehensive coverage of three core areas of biomarker assay establishment: the relationship between the measured biomarkers and their intended usage; contemporary regulatory requirements for biomarker assays (a thorough understanding of which is essential to producing a successful and defendable submission); and the technical challenges of analyzing biomarkers produced inside a living organism or cell. Covers the theory of and applications for state-of-the-art mass spectrometry and chromatography and their applications in biomarker analysis Features real-life examples illustrating the challenges involved in target biomarker quantitation and the innovative approaches which have been used to overcome those challenges Addresses potential obstacles to obtain effective biomarker level and data interpretation, such as specificity establishment and sample collection Outlines a tiered approach and fit-for-purpose assay protocol for target biomarker quantitation Highlights the current state of the biomarker regulatory environment and protocol standards Target Biomarker Quantitation by LC-MS is a valuable resource for bioanalytical scientists, drug metabolism and pharmacokinetics scientists, clinical scientists, analytical chemists, and others for whom biomarker quantitation is an important tool of the trade. It also functions as an excellent text for graduate courses in pharmaceutical, biochemistry and chemistry. |
| pk assay development and validation: Detection and Quantification of Antibodies to Biopharmaceuticals Michael G. Tovey, 2011-07-12 The definitive book on the neutralization of recombinant biopharmaceuticals Recombinant biopharmaceuticals are an important tool for treating a range of illnesses; however, their efficacy can be severely impaired by their immunogenicity. When introduced into the body, these pharmaceuticals can cause the immune system to produce anti-drug antibodies (ADAs) that neutralize their effects. The first and only book to cover neutralization in connection with biopharmaceuticals and the measurement and application of neutralizing antibodies in modern medicine at any real length, Detection and Quantification of Antibodies to Biopharmaceuticals: Practical and Applied Considerations offers a comprehensive and in-depth look at all the principal aspects of the detection and quantification of antibodies that are essential to understanding and responding to the challenges they present. Bringing together a large-scale review of neutralization and biopharmaceuticals and the ability to measure, detect, and apply antibodies to modern science and medicine with international regulatory perspectives, the expectations of regulatory authorities, and the strengths and weaknesses of various assays, the book describes several novel ideas for detecting ADAs. Designed to serve as a resource for biopharmaceutical drug development, the book provides biotechnology companies and pharmaceutical drug development specialists, as well as non-experts, with key insights into the design, optimization, and qualification of assays, the establishment of sampling strategies, the choice of appropriate assay end-points, and data analysis for the detection and quantification of neutralizing antibodies. |
| pk assay development and validation: Evolution of Translational Omics Institute of Medicine, Board on Health Sciences Policy, Board on Health Care Services, Committee on the Review of Omics-Based Tests for Predicting Patient Outcomes in Clinical Trials, 2012-09-13 Technologies collectively called omics enable simultaneous measurement of an enormous number of biomolecules; for example, genomics investigates thousands of DNA sequences, and proteomics examines large numbers of proteins. Scientists are using these technologies to develop innovative tests to detect disease and to predict a patient's likelihood of responding to specific drugs. Following a recent case involving premature use of omics-based tests in cancer clinical trials at Duke University, the NCI requested that the IOM establish a committee to recommend ways to strengthen omics-based test development and evaluation. This report identifies best practices to enhance development, evaluation, and translation of omics-based tests while simultaneously reinforcing steps to ensure that these tests are appropriately assessed for scientific validity before they are used to guide patient treatment in clinical trials. |
| pk assay development and validation: Handbook of LC-MS Bioanalysis Wenkui Li, Jie Zhang, Francis L. S. Tse, 2013-09-03 Consolidates the information LC-MS bioanalytical scientists need to analyze small molecules and macromolecules The field of bioanalysis has advanced rapidly, propelled by new approaches for developing bioanalytical methods, new liquid chromatographic (LC) techniques, and new mass spectrometric (MS) instruments. Moreover, there are a host of guidelines and regulations designed to ensure the quality of bioanalytical results. Presenting the best practices, experimental protocols, and the latest understanding of regulations, this book offers a comprehensive review of LC-MS bioanalysis of small molecules and macromolecules. It not only addresses the needs of bioanalytical scientists working on routine projects, but also explores advanced and emerging technologies such as high-resolution mass spectrometry and dried blood spot microsampling. Handbook of LC-MS Bioanalysis features contributions from an international team of leading bioanalytical scientists. Their contributions reflect a review of the latest findings, practices, and regulations as well as their own firsthand analytical laboratory experience. The book thoroughly examines: Fundamentals of LC-MS bioanalysis in drug discovery, drug development, and therapeutic drug monitoring The current understanding of regulations governing LC-MS bioanalysis Best practices and detailed technical instructions for LC-MS bioanalysis method development, validation, and stability assessment of analyte(s) of interest Experimental guidelines and protocols for quantitative LC-MS bioanalysis of challenging molecules, including pro-drugs, acyl glucuronides, N-oxides, reactive compounds, and photosensitive and autooxidative compounds With its focus on current bioanalytical practice, Handbook of LC-MS Bioanalysis enables bioanalytical scientists to develop and validate robust LC-MS assay methods, all in compliance with current regulations and standards. |
| pk assay development and validation: Principles of Safety Pharmacology Michael K. Pugsley, Michael J Curtis, 2015-06-19 This book illustrates, in a comprehensive manner, the most current areas of importance to Safety Pharmacology, a burgeoning unique pharmacological discipline with important ties to academia, industry and regulatory authorities. It provides readers with a definitive collection of topics containing essential information on the latest industry guidelines and overviews current and breakthrough topics in both functional and molecular pharmacology. An additional novelty of the book is that it constitutes academic, pharmaceutical and biotechnology perspectives for Safety Pharmacology issues. Each chapter is written by an expert in the area and includes not only a fundamental background regarding the topic but also detailed descriptions of currently accepted, validated models and methods as well as innovative methodologies used in drug discovery. |
| pk assay development and validation: Companion and Complementary Diagnostics Jan Trøst Jørgensen, 2019-05-08 Companion and Complementary Diagnostics: From Biomarker Discovery to Clinical Implementation provides readers with in-depth insights into the individual steps in the development of companion diagnostic assays, from the early biomarker discovery phase straight through to final regulatory approval. Further, the clinical implementation of companion diagnostic testing in the clinic is also discussed. As the development of predictive or selective biomarker assays linked to specific drugs is substantially increasing, this book offers comprehensive information on this quickly-evolving area of biomedicine. It is an essential resource for those in academic institutions, hospitals and pharma, and biotech and diagnostic commercial companies. - Covers all aspects, from biomarker discovery, to development and regulatory approval - Explains the how to aspects of companion diagnostics - Incorporates information on the entire process, allowing for easier and deeper understanding of the topic |
| pk assay development and validation: Pharmacokinetics and Pharmacodynamics of Biotech Drugs Bernd Meibohm, 2006-12-13 This first ever coverage of the pharmacokinetic and pharmacodynamic characteristics of biopharmaceuticals meets the need for a comprehensive book in this field. It spans all topics from lead identification right up to final-stage clinical trials. Following an introduction to the role of PK and PD in the development of biotech drugs, the book goes on to cover the basics, including the pharmacokinetics of peptides, monoclonal antibodies, antisense oligonucleotides, as well as viral and non-viral gene delivery vectors. The second section discusses such challenges and opportunities as pulmonary delivery of proteins and peptides, and the delivery of oligonucleotides. The final section considers the integration of PK and PD concepts into the biotech drug development plan, taking as case studies the preclinical and clinical drug development of tasidotin, as well as the examples of cetuximab and pegfilgrastim. The result is vital reading for all pharmaceutical researchers. |
| pk assay development and validation: Analytical Method Development and Validation Michael E. Swartz, Ira S. Krull, 2018-10-03 Describes analytical methods development, optimization and validation, and provides examples of successful methods development and validation in high-performance liquid chromatography (HPLC) areas. The text presents an overview of Food and Drug Administration (FDA)/International Conference on Harmonization (ICH) regulatory guidelines, compliance with validation requirements for regulatory agencies, and methods validation criteria stipulated by the US Pharmacopia, FDA and ICH. |
| pk assay development and validation: Essentials of Translational Pediatric Drug Development Elke Gasthuys, Karel Allegaert, Lien Dossche, Mark Turner, 2024-07-23 Essentials of Translational Pediatric Drug Development: From Past Needs to Future Opportunities provides integrated and up-to-date insights relevant for both translational researchers and clinicians active in the field of pediatric drug development. The book covers all key aspects from different stakeholder perspectives, providing a literature overview and careful reflection on state-of-the-art approaches. It will be an ideal guide for researchers in the field who are designing and performing high quality, innovative pediatric-adapted drug development by helping them define needs/challenges and possible solutions that advance and harmonize pediatric drug development.Despite the broad consensus that children merit the same quality of drug treatment as any other age group, children remain frequently neglected during drug research and development. Even with the adoption of multiple legislations addressing this problem, the lack of efficacy and safety data of marketed as well as newly developed drugs still remain in the pediatric population. - Covers both theoretical and practical aspects of translational pediatric drug development - Approaches the topic from different stakeholder perspectives (academics, industry, regulators, clinicians and patient/parent advocacy groups) - Offers best practices and future perspectives for the improvement of translational pediatric drug development |
| pk assay development and validation: Chromatographic Analysis of Pharmaceuticals John A. Adamovics, 2017-09-29 Updated and revised throughout. Second Edition explores the chromatographic methods used for the measurement of drugs, impurities, and excipients in pharmaceutical preparations--such as tablets, ointments, and injectables. Contains a 148-page table listing the chromatographic data of over 1300 drugs and related substances--including sample matrix analyzed, sample handling procedures, column packings, mobile phase, mode of detection, and more. |
| pk assay development and validation: Encyclopedia of Cancer Manfred Schwab, 2008-09-23 This comprehensive encyclopedic reference provides rapid access to focused information on topics of cancer research for clinicians, research scientists and advanced students. Given the overwhelming success of the first edition, which appeared in 2001, and fast development in the different fields of cancer research, it has been decided to publish a second fully revised and expanded edition. With an A-Z format of over 7,000 entries, more than 1,000 contributing authors provide a complete reference to cancer. The merging of different basic and clinical scientific disciplines towards the common goal of fighting cancer makes such a comprehensive reference source all the more timely. |
| pk assay development and validation: Comprehensive Medicinal Chemistry III , 2017-06-03 Comprehensive Medicinal Chemistry III, Eight Volume Set provides a contemporary and forward-looking critical analysis and summary of recent developments, emerging trends, and recently identified new areas where medicinal chemistry is having an impact. The discipline of medicinal chemistry continues to evolve as it adapts to new opportunities and strives to solve new challenges. These include drug targeting, biomolecular therapeutics, development of chemical biology tools, data collection and analysis, in silico models as predictors for biological properties, identification and validation of new targets, approaches to quantify target engagement, new methods for synthesis of drug candidates such as green chemistry, development of novel scaffolds for drug discovery, and the role of regulatory agencies in drug discovery. Reviews the strategies, technologies, principles, and applications of modern medicinal chemistry Provides a global and current perspective of today's drug discovery process and discusses the major therapeutic classes and targets Includes a unique collection of case studies and personal assays reviewing the discovery and development of key drugs |
| pk assay development and validation: Using Mass Spectrometry for Drug Metabolism Studies Walter A. Korfmacher, 2004-12-17 Mass spectrometry (MS) is fast becoming the premier tool for analyzing various drug metabolism samples in the early phases of drug discovery and research. Introducing the newer, more powerful MS equipment and exploring new applications for using them, this book provides a state-of-the-art look at this promising field. Using Mass Spectrometry |
