Analytical Techniques for Clinical Chemistry E-Book
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- Herausgeber: John Wiley & Sons
- Kategorie: Wissenschaft und neue Technologien
- Sprache: Englisch
Discover how analytical chemistry supports the latest clinical research This book details the role played by analytical chemistry in fostering clinical research. Readers will discover how a broad range of analytical techniques support all phases of clinical research, from early stages to the implementation of practical applications. Moreover, the contributing authors' careful step-by-step guidance enables readers to better understand standardized techniques and steer clear of everyday problems that can arise in the lab. Analytical Techniques for Clinical Chemistry opens with an overview of the legal and regulatory framework governing clinical lab analysis. Next, it details the latest progress in instrumentation and applications in such fields as biomonitoring, diagnostics, food quality, biomarkers, pharmaceuticals, and forensics. Comprised of twenty-five chapters divided into three sections exploring Fundamentals, Selected Applications, and Future Trends, the book covers such critical topics as: * Uncertainty in clinical chemistry measurements * Metal toxicology in clinical, forensic, and chemical pathology * Role of analytical chemistry in the safety of drug therapy * Atomic spectrometric techniques for the analysis of clinical samples * Biosensors for drug analysis * Use of X-ray techniques in medical research Each chapter is written by one or more leading pioneers and experts in analytical chemistry. Contributions are based on a thorough review and analysis of the current literature as well as the authors' own firsthand experiences in the lab. References at the end of each chapter serve as a gateway to the literature, enabling readers to explore individual topics in greater depth. Presenting the latest achievements and challenges in the field, Analytical Techniques for Clinical Chemistry sets the foundation for future advances in laboratory research techniques.
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Contents
Cover
Title Page
Copyright
Dedication
Foreword
Preface
Contributors
Part I: Exploring Fundamentals
Chapter 1: Good Clinical Practice Principles: Legal Background and Applicability
Summary
1.1. Introduction
1.2. Good Clinical Practice
1.3. Good Clinical Practice: Legal Background in the European Union
1.4. Good Clinical Practice: Applicability in the European Union
1.5. Good Clinical Practice And Bioequivalence Trials: GCP Inspections and Laboratories
1.6. Good Clinical Practice for Clinical Trials With Advanced Therapy Medicinal Product
1.7. Good Clinical Practice and Clinical Trials in Developing Countries
References
Chapter 2: Clinical Chemistry and the Quest for Quality
Summary
2.1. Introduction
2.2. Quality Today
2.3. Conclusions
References
Chapter 3: Uncertainty in Clinical Chemistry Measurements Including Preanalytical Variables
Summary
3.1. Introduction
3.2. Analytical Uncertainty in Laboratory Results
3.3. Trueness and Traceability
3.4. Proficiency Testing
3.5. Biological Variations and Quality Goals
3.6. Reference Intervals
3.7. Estimating Preanalytical Uncertainty
3.8. Conclusions
References
Chapter 4: The Role and Significance of Reference Values in the Identification and Evaluation of Trace Elements from Diet
Summary
4.1. Reference Values
4.2. Reference Values in Specific Groups of Population: The Children Case
4.3. Trace Elements and Diet
4.4. Arsenic
4.5. Mercury
4.6. Lead
4.7. Chromium
4.8. Cadmium
4.9. Conclusions
References
Chapter 5: Sample Collection, Storage, and Pretreatment in Clinical Chemistry
Summary
5.1. Introduction
5.2. Collection Procedures
5.3. Storage
5.4. Pretreatment
5.5. Conclusions
References
Chapter 6: Metal Toxicology in Clinical, Forensic, and Chemical Pathology
Summary
6.1. Introduction
6.2. Biological Markers
6.3. Methodology For Trace Metal Ion Analysis in Clinical, Forensic, and Chemical Pathology
6.4. Case Studies of Relevance to Research and Diagnosis on Clinical Chemistry, Forensic Toxicology, and Chemical Pathology
Disclaimer
References
Part II: Selected Applications
Chapter 7: Elemental Speciation in Clinical Sciences
Summary
7.1. Introduction
7.2. Selected Elements
7.3. Conclusions
References
Chapter 8: The Role of Analytical Chemistry in the Safety of Drug Therapy
Summary
8.1. Drug Quality and Analysis: Their Role in Drug Safety
8.2. Methodological Aspects
8.3. The Role of Analytical Chemistry in Drug Research, Development, and Production
8.4. Future Trends
References
Chapter 9: Analytical Techniques and Quality Control of Pharmaceuticals
Summary
9.1. Introduction
9.2. Sources of Impurities in Medicines
9.3. Validation of Analytical Methods
9.4. Analytical Approaches
9.5. Conclusions
References
Chapter 10: Detection of Drugs in Biological Fluids for Antidoping Control
Summary
10.1. Introduction
10.2. Doping Control and Analytical Requirements
10.3. Confirmation Techniques
10.4. Conclusions
References
Chapter 11: The Applicability of Plasma-Based Techniques to Biological Monitoring
Summary
11.1. Introduction
11.2. ICP As A Spectrochemical Source
11.3. Element Analysis in Environmental and Biological Materials
11.4. Conclusions
References
Chapter 12: Atomic Spectrometric Techniques for the Analysis of Clinical Samples
Summary
12.1. Introduction
12.2. Analytical Techniques
12.3. Sample Preparation
12.4. Speciation Analysis
12.5. Quality Control in Trace Element Determination
12.6. Conclusions
References
Chapter 13: Applications of ICP-MS in Human Biomonitoring Studies
Summary
13.1. Introduction
13.2. Advantages and Limitations of Inductively Coupled Plasma Mass Spectrometry
13.3. Sample Collection and Storage
13.4. Sample Preparation
13.5. Human Biomonitoring by Inductively Coupled Plasma Mass Spectrometry
13.6. Trace Element Speciation and Metallomics
13.7. Determination of Stable Isotopes
13.8. Method Validation and Quality Assurance
13.9. Conclusions
References
Chapter 14: Molybdenum in Biological Samples and Clinical Significance of Serum Molybdenum
Summary
14.1. Introduction
14.2. Analysis of Molybdenum in Biological Samples by Inductively Coupled Plasma Mass Spectrometry
14.3. Molybdenum in Food
14.4. Molybdenum in Human Samples
14.5. Clinical Significance of Serum and Plasma Mo
14.6. Conclusions
References
Chapter 15: Application of Organometallic Speciation in Clinical Studies
Summary
15.1. Introduction
15.2. Arsenic
15.3. Mercury
15.4. Tin
15.5. Conclusions
References
Chapter 16: Biosensors for Drug Analysis
Summary
16.1. Introduction
16.2. Basic Concepts
16.3. Electrochemical Biosensors
16.4. Surface Plasmon Resonance
16.5. Biosensors for Drugs Analysis
16.6. Conclusions
References
Chapter 17: Bioimaging of Metals and Proteomic Studies of Clinical Samples by Laser Ablation Inductively Coupled Plasma Mass Spectrometry (LA-ICP-MS)
Summary
17.1. Introduction
17.2. Analytical approaches
17.3. Experimental Aspects of Imaging Laser Ablation Inductively Coupled Plasma Mass Spectrometry
17.4. Conclusions
Acknowledgment
References
Chapter 18: Applications of LC-MS/MS in Clinical Laboratory Diagnostics
Summary
18.1. Introduction
18.2. Current Applications and Future Perspectives
18.3. Liquid Chromatography-Tandem Mass Spectrometry Applications in Clinical Laboratories
18.4. Conclusions
References
Chapter 19: Metabolomics Using UPLC/HPLC-Tandem Mass Spectrometry in Diagnosis and Research of Inherited Metabolic Diseases
Summary
19.1. Introduction
19.2. Acylcarnitines
19.3. Acyl-Coenzyme A Thioesters
19.4. Amino acids
19.5. Organic Acids
19.6. Purines and Pyrimidines
19.7. Bile Acids
19.8. Lipidomics
19.9. Carbohydrates
19.10. Neurotransmitters
19.11. Conclusions
Further Reading
References
Chapter 20: Biomarkers of Oxidative Stress in Plasma and Urine
Summary
20.1. Introduction
20.2. Antioxidant Mechanisms and Assays
20.3. Concluding Remarks and Perspectives
References
Chapter 21: The Use of X-Ray Techniques in Medical Research
Summary
21.1. Introduction
21.2. Physical Basis of XRF Analytical Methods
21.3. Basic Equipment and Setup for X-ray Fluorescence Analysis
21.4. Quantification Approaches
21.5. Sample Preparation Techniques
21.6. Applications
21.7. Conclusions
References
Part III: Future Trends
Chapter 22: A New Tool Based on the Use of Stable Isotopes and Isotope Pattern Deconvolution (IPD)-ICP-MS for Nutritional and Clinical Studies
Summary
22.1. Introduction
22.2. Milk as Source of Trace Elements
22.3. Stable Isotopes and Trace Elements Metabolism
22.4. Isotope Pattern Deconvolution
22.5. Selenium Metabolism in Lactating Rats by Means of Stable Isotopes and Isotope Pattern Deconvolution
22.6. Determination of Selenium in Urine, Faeces, Serum, and Erythrocytes by Isotope Pattern Deconvolution Inductively Coupled Plasma Mass Spectrometry
22.7. Quantitative Speciation of Selenium In Urine, Serum, and Erythrocytes by High Performance Isotope Pattern Deconvolution Inductively Coupled Plasma Mass Spectrometry
22.8. An Application of Isotope Pattern Deconvolution to Clinical Studies
22.9. Conclusions
References
Chapter 23: Breath Analysis: Analytical Methodologies and Clinical Applications
Summary
23.1. Introduction
23.2. Sampling Methods
23.3. Analytical Techniques
23.4. application of Breath Analysis
23.5. Exposure Assessment
23.6. Exhaled Breath Condensate
23.7. Conclusions
References
Chapter 24: Proteo-Metabolomic Strategies in the Future of Drug Development
Summary
24.1. Introduction
24.2. The Principles of Molecular Marker Development
24.3. Technologies for Molecular Marker Development
24.4. Molecular Markers in Drug Development and Clinical Monitoring
24.5. Current Challenges
References
Chapter 25: Basics in Laboratory Medicine: Past, Present, and Future
Summary
25.1. Introduction
25.2. Informatics
25.3. Global Standardization
25.4. Focus on the Individual
25.5. A Look into the Future
References
Index
Copyright © 2012 by John Wiley & Sons, Inc. All rights reserved
Published by John Wiley & Sons, Inc., Hoboken, NJ
Published simultaneously in Canada
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Library of Congress Cataloging-in-Publication Data:
Analytical techniques for clinical chemistry: methods and applications / edited by Sergio Caroli, Gyula Záray.
p. cm.
Includes index.
ISBN 978-0-470-44527-3 (cloth)
1. Clinical chemistry–Analysis. I. Caroli, Sergio, 1943- II. Záray, Gyula.
RB40.A53 2012
616.07′9–dc23
2011043320
ISBN: 9780470445273
In memory of Károly Zimmer, our beloved friend Karcsi, who always stimulated us to do well what we had to do, taught us that work can be a source of real fun, and lives forever in our hearts.
Sergio Caroli and Gyula Záray
Foreword
The quality and reliability of data generated during the conduct of clinical trials represent a very critical aspect in the development of pharmaceutical products. The latter must meet all the regulatory and legislative requirements established at an international level in order to protect the health and well being of the patients exposed to these new drugs. Analytical techniques represent a very important aspect in producing the supporting data required by clinical research protocols. In this context, analytical work performed in research and control laboratories must comply with current legislation and guidelines, especially with the requirements of the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use. This fact represents a real challenge in the conduct of clinical investigations and, in particular, the development of appropriate analytical techniques, due to the fact that the actors in this field are faced with ever-changing regulations that attempt (but do not always succeed) to keep pace with the rapid technological advancements in developing instrumentation for use in research and control laboratories.
This multiauthored book aims at underlining the role played by analytical techniques in supporting and promoting research and control in the various fields of clinical activity, starting from the very early stages of clinical research to the attainment of marketing authorizations as well as in practical applications. The book also elicits the progress made in developing instrumentation that is fit-for-purpose as well as to identify outstanding problems that deserve further investigation, investment, and improvement in both research and routine laboratories.
The 25 chapters of this book have been written by prominent scientists and cover primary issues which include three main parts Fundamentals, Selected Applications, and Future Trends. The first area provides a survey of the current legal framework (in particular the EC Directive 2005/28 of April 2005 on the principles of Good Laboratory Practice), the major challenges of clinical investigations and the availability of analytical techniques for research and routine work. In this section the reader will encounter topics such as uncertainty in clinical chemistry measurements, the role and significance of reference values in the identification of trace elements from diet, sample collection, storage and pretreatment in clinical chemistry, metal toxicology in clinical, forensic and chemical pathology, elemental speciation in clinical sciences, and detection of drugs in biological fluids for antidoping control, which are discussed in detail. The book then goes on to illustrate the applicability of the most popular and successful analytical techniques as well as the relevant quality systems and their implementation. Here the reader can find information such as the applicability of plasma-based techniques to biological monitoring, atomic spectrometry, organometallic speciation, the clinical meaning of molybdenum, bioimaging of metals and proteomic studies of clinical samples by laser ablation inductively coupled plasma mass spectrometry, application of liquid chromatography combined with tandem mass spectrometry in clinical laboratory diagnostics, metabolomics using high-performance liquid chromatography-tandem mass spectrometry, biomarkers of stress in plasma and urine, X-ray techniques in medical research, and analytical examination of drugs in the forensic science laboratory. The third part gives the reader a look at promising innovative approaches and their possible exploitation, e.g., for breath analysis, development of proteo-metabolic strategies and optimization of laboratory medicine.
This book greatly benefits from the enthusiastic participation and support of all authors who greatly collaborated with the editors and to whom the editors express their sincere gratitude.
Valentine Anthony Sforza
Preface
The first idea of a multiauthored book devoted to the role played by analytical chemistry in fostering clinical research was conceived by the Editors some four years ago during a lively conversation had in the aftermath of the publication by Wiley of another book of ours.1 It was perhaps the enthusiasm sparked by the fact that this work was well received by the readers, or perhaps the exciting atmosphere of the Hungarian tavern where we were dining (not to speak of a bottle of excellent red wine which made us rather loquacious), or perhaps—and most likely—the synergistic action of these factors altogether, that fertilized our minds and led us to plan a new book in the belief that it would meet the needs of the scientific community. Greatly inspired by optimism and self-confidence (never out of place under such circumstances), the more we debated this issue, the more the project became a fascinating challenge. Deliberately minimizing all the difficulties that we knew by personal experience would thwart the progress of the work and make our professional lives uneasy for quite a long period of time, a list of key topics was promptly drafted and a tentative list of potential contributors was jotted down. A new adventure was starting. . .
Now that the book has finally reached completion in spite of an endless number of technical problems, delays, withdrawal of manuscripts, and all kinds of unexpected events, we wish to express our sincere gratitude to all contributing authors for their valuable competence, their willingness to cooperate at all stages of preparation of their chapters, and their infinite patience in tackling all our often complex, always time-consuming, and certainly tedious requests. Needless to say, we do hope that they will be happy with the outcome of their unremitting efforts.
The sponsorship of PerkinElmer, Inc. to the making of this book is gratefully acknowledged. Without their generosity, constant support, and firm trust in our project, it would never be possible for us to accomplish it. If the result of our commitment pleases them, this will also significantly add to our satisfaction.
Sergio Caroli Gyula Záray
Note
1. Sergio Caroli (Editor), The Determination of Chemical Elements in Food—Applications for Atomic and Mass Spectrometry, John Wiley & Sons, Inc., Hoboken, NJ, USA, 2007.
Contributors
María del Carmen Barciela Alonso, Trace Elements, Spectroscopy and Speciation Group, Department of Analytical Chemistry, Nutrition and Bromatology, Faculty of Chemistry, University of Santiago de Compostela, Spain
Pietro Apostoli, Department of Experimental and Applied Medicine, Section of Occupational Health and Industrial Hygiene, University of Brescia, Brescia, Italy
Pilar Bermejo Barrera, Trace Elements, Spectroscopy and Speciation Group, Department of Analytical Chemistry, Nutrition and Bromatology, Faculty of Chemistry, University of Santiago de Compostela, Spain
J. Sabine Becker, Central Division of Analytical Chemistry, Forschungszentrum Jülich, Jülich, Germany
J. Susanne Becker, Aeropharm, Francois-Mitterrand-Allee 1, Rudolstadt, Germany
Bjrn J. Bolann, Laboratory of Clinical Biochemistry, Haukeland University Hospital, Helse Bergen HF, Bergen, Norway; and Institute of Medicine, University of Bergen, Bergen, Norway
Sergio Caroli, National Institute of Health (Istituto Superiore di Sanità), Rome, Italy
Alessio Ceccarini, Department of Chemistry and Industrial Chemistry, University of Pisa, Pisa, Italy
Uta Ceglarek, University Hospital Leipzig, Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, Leipzig, Germany
José A. Centeno, Biophysical Toxicology, The Joint Pathology Center, 606 Sitter Stephen Ave., Silver Spring, MD, USA
Marcello Chiarotti, Institute of Forensic Medicine, Catholic University of the Sacred Heart, Rome, Italy
Uwe Christians, iC42 Clinical Research & Development, Department of Anesthesiology, University of Colorado Denver, Bioscience East, Aurora, CO, USA
Loránd A. Debreczeni, Department of Laboratory Medicine, St. Imre Hospital of Budapest Metropolis, Budapest, Hungary
Daniela Deriu, Department of Chemistry and Drug Technologies, La Sapienza University, Piazzale Aldo Moro Roma, Italy
Fabio Di Francesco, Department of Chemistry and Industrial Chemistry, University of Pisa, Pisa, Italy
Angela Del Vecchio, Italian Medicine Agency (Agenzia Italiana del Farmaco, AIFA), Rome, Italy
Maria Luisa Fernández-Sánchez, Department of Physical and Analytical Chemistry, University of Oviedo, Oviedo, Spain
Georg Martin Fiedler, Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University Hospital Leipzig, Leipzig, Germany
Umberto Filibeck, Italian Medicine Agency (Agenzia Italiana del Farmaco, AIFA), Rome, Italy
Rossella Fioravanti, Department of Chemistry and Drug Technologies, Faculty of Pharmacy, La Sapienza University, Rome, Italy
Roger Fuoco, Department of Chemistry and Industrial Chemistry, University of Pisa, Pisa, Italy
Fabrizio Galliccia, Italian Medicine Agency (Agenzia Italiana del Farmaco, AIFA), Rome, Italy
Silvia Ghimenti, Department of Chemistry and Industrial Chemistry, University of Pisa, Pisa, Italy
Sándor Görög, Gedeon Richter Plc., Budapest, Hungary
Bin He, State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing, P.R. China
Peter Heitland, Medical Laboratory Bremen, Bremen, Germany
Héctor González Iglesias, Department of Physical and Analytical Chemistry, University of Oviedo, Oviedo, Spain
Guibin Jiang, State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing, P.R. China
Jelena Klawitter, iC42 Clinical Research & Development, Department of Anesthesiology, University of Colorado Denver, Bioscience East, Aurora, CO, USA
Jost Klawitter, iC42 Clinical Research & Development, Department of Anesthesiology, University of Colorado Denver, Bioscience East, Aurora, CO, USA
Anna Kovácsay, Department of Laboratory Medicine, St. Imre Hospital of Budapest Metropolis, Budapest, Hungary
Helmut D. Köster, Medical Laboratory Bremen, Bremen, Germany
Willem Kulik, Academic Medical Center, University of Amsterdam, Laboratory of Genetic Metabolic Diseases, Department of Clinical Chemistry, Amsterdam, The Netherlands
Fedele Manna, Department of Chemistry and Drug Technologies, Faculty of Pharmacy, La Sapienza University, Rome, Italy
Franco Mazzei, La Sapienza University, Department of Chemistry and Drug Technologies, Roma, Italy
Florabel G. Mullick, Biophysical Toxicology, The Joint Pathology Center, 606 Sitter Stephen Ave., Silver Spring, MD, USA
Sandor Nagy, Monash Medical Centre, Southern Cross Pathology Australia, Biochemistry Clayton, Victoria, Australia
Massimo Onor, Institute of Chemistry of Organometallic Compounds, UOS Pisa, CNR, Pisa, Italy
Antonio Moreda Piñeiro, Trace Elements, Spectroscopy and Speciation Group, Department of Analytical Chemistry, Nutrition and Bromatology, Faculty of Chemistry, University of Santiago de Compostela, Spain
Maria Cristina Ricossa, Department of Experimental and Applied Medicine, Section of Occupational Health and Industrial Hygiene, University of Brescia, Brescia, Italy
Francesca Rossi, Department of Chemistry and Drug Technologies, Faculty of Pharmacy, La Sapienza University, Rome, Italy
Sabina Strano Rossi, Institute of Forensic Medicine, Catholic University of the Sacred Heart, Rome, Italy
Alfredo Sanz-Medel, Department of Physical and Analytical Chemistry, University of Oviedo, Oviedo, Spain
Volker Schmitz, iC42 Clinical Research & Development, Department of Anesthesiology, University of Colorado Denver, Aurora, CO, USA
Valentine Anthony Sforza, Quality Management Associates, Valentine A. Sforza & C. S.a.s., Via Volturno, 69-00042 Anzio, Rome, Italy
Ilse Steffan, Department of Analytical and Food Chemistry, University of Vienna, Vienna, Austria
Papasani V. Subbaiah, Department of Medicine, University of Illinois at Chicago, Chicago, IL, USA
Jing Sun, State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing, P.R. China
Marit Sverresdotter Sylte, Laboratory of Clinical Biochemistry, Haukeland University Hospital, Helse Bergen HF, Bergen, Norway
Imre Szalóki, Institute of Nuclear Techniques, Budapest University of Technology and Economics, Budapest, Hungary
Norbert Szoboszlai, Department of Analytical Chemistry, Eötvös Loránd University, Budapest, Hungary
Sara Tabucchi, Department of Chemistry and Industrial Chemistry, University of Pisa, Pisa, Italy
Andrew Taylor, Department of Clinical Biochemistry, Royal Surrey County Hospital, Guildford, UK; and Faculty of Health and Medical Sciences, University of Surrey, Guildford, UK
Maria Giovanna Trivella, Institute of Clinical Physiology, CNR, Pisa, Italy
Douglas M. Templeton, University of Toronto, Department of Laboratory Medicine and Pathobiology, 1 Kings College Circle, Toronto, ON, Canada
Joachim Thiery, University Hospital Leipzig, Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, Leipzig, Germany
Todor I. Todorov, Crustal Geophysics and Geochemistry Science Center, US Geological Survey, Denver, CO, USA
Gijsbert B. van der Voet, Gezondheidsraad Parnassusplein 5 - 2511 VX Den Haag, The Netherlands
André B. P. van Kuilenburg, Academic Medical Center, Laboratory of Genetic Metabolic Diseases, Department of Clinical Chemistry, University of Amsterdam, Amsterdam, The Netherlands
Goran Vujicic, Institute for Testing of Materials (IWM), Glattbrugg, Switzerland
Tore Wentzel-Larsen, Centre for Clinical Research, Haukeland University Hospital, Bergen, Norway
Munehiro Yoshida, Department of Life Science and Biotechnology, Faculty of Chemistry, Materials and Bioengineering, Kansai University, Osaka, Japan
Chungang Yuan, State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing, P.R. China; and School of Environmental Science & Engineering, North China Electric Power University, Hebei, P.R. China
Gyula Záray, Department of Analytical Chemistry, Eötvös Loránd University, Budapest, Hungary; Cooperative Research Centre of Environmental Sciences, Eötvös Loránd University, Budapest, Hungary; and Hungarian Satellite Centre of Trace Element for UNESCO, Budapest, Hungary
Part I
Exploring Fundamentals
Chapter 1
Good Clinical Practice Principles: Legal Background and Applicability
Umberto Filibeck, Angela Del Vecchio, and Fabrizio Galliccia
Summary
Since 1991 the European Medicines Agency (EMA, formerly EMEA) adopted the Guidelines of the International Conference on Harmonization (ICH) on Good Clinical Practice (GCP). In this regard, one European Union (EU) Guideline and three EU Directives are in force at present, that is, the E6/CPMP/ICH/135/95 GCP Guideline, Directive 2001/83/EC (Community Codex on Pharmaceuticals), Directive 2001/20/EC (GCP and Clinical Trials, CTs), and Directive 2005/28/EC (Detailed Guidance on GCP).
European Directive 2001/20 on GCP and CTs has been widely criticized by a large portion of the scientific community more directly involved in the promotion and management of noncommercial academic CTs. Since 2003 several scientists from academia highlighted through the international scientific literature the difficulties inherent in the new EU regulation, in particular as regards GCP compliance and quality monitoring problems. Such difficulties have also been acknowledged by Directive 2005/28 where, among others, it is stated that for academic CTs the application of certain GCP aspects may be unnecessary or guaranteed by other means.
None of these documents oblige CTs to be in compliance with the GCP ICH Guideline (GCP-ICH) full text and details. Rather, they prescribe that CTs be in compliance only with GCP principles and with GCP Guidelines laid down in Directive 2005/28 EC, this being less binding when compared to the GCP-ICH Guideline. At the national level, EU Member States (MS) adopted different legislation to implement the GCP obligations. MS GCP Inspectorates generally act as if all GCP aspects were mandatory to verify the reliability of data reported by the CTs audited.
At the international level, in particular in developing countries, where several bioequivalence (BE) studies are conducted and the number of CTs is increasing, often neither specific aspects nor the principles of GCP are complied with. In the case of data submitted to EU MS Regulatory Authorities (RAs) for a Marketing Authorization (MA) of a medicinal product, the CTs of which were performed outside the EU, Directive 2001/83 allows the MA to be granted only if the CTs are in compliance with the ethical principles of GCP, although in practice only a few RAs assess that this actually has been done.
Specific examples are given to illustrate the above issues and a number of key aspects related to laboratory activities are reported and discussed in the frame of different international normative and guidelines on GCP.
1.1. Introduction
Since 1991 the European Medicines Agency (EMA, formerly EMEA)1 adopted the Guidelines of the International Conference on Harmonization (ICH) on Good Clinical Practice (GCP). In this regard, one European Union (EU) Guideline and three EU Directives are in force at present, that is, the E6/CPMP/ICH/135/95 GCP Guideline [1], Directive 2001/83/EC (Community Codex on Pharmaceuticals) [2], Directive 2001/20/EC (GCP and Clinical Trials, CTs) [3], and Directive 2005/28/EC (Detailed Guidance on GCP) [4].
The introduction of GCP in EU is linked with Good Manufacturing Practice (GMP), particularly Annex 1, 13, and 16 (The rules governing medicinal products in the European Union, EudraLex, Vol. 4) [5] regarding directly or indirectly the production of Investigational Medicinal Product (IMP) and Directive 2003/94/EC on GMP for Medicinal Products and IMP [6]. At global level, besides ICH-GCP, WHO has also issued WHO GCP.
The GCP legal background and applicability are discussed hereafter along with the description of related documents and implementation problems. This legal framework is of paramount importance to attach credibility to the experimental information obtained when carrying out clinical investigations, thus substantially contributing to preserving and improving human health.
1.2. Good Clinical Practice
1.2.1. ICH E6: Guidelines for Good Clinical Practice
ICH Guidelines for GCP [1] have been prepared by the ICH of Technical Requirements for Registration of Pharmaceuticals for Human Use, which is composed by the Medicine Regulatory Agencies and members of the pharmaceutical industry of the EU, Japan, and the USA. The WHO, Canada, and European Parliamentary Technology Assessment (EPTA) have observer status. Since its creation in 1990, the ICH has issued 58 Tripartite Guidelines on issues related to its four main areas of work, namely quality, safety, efficacy, and multidisciplinary topics. The process to reach harmonization of technical requirements resulting from scientific progress goes along with the process of keeping up-to-date the current guidelines, in order to ensure that the harmonization process, so far achieved, is not lost. Guidelines are adopted by the Steering Committee and signed by the three regulatory parties to ICH. However, guidelines become binding only when the regulatory bodies in the three regions implement them. The objective of this guidance is to provide “international ethical and scientific quality standards for designing, conducting, recording and reporting trials that involve the participation of human subjects. Compliance with this standard provides public assurance that the rights, safety and well-being of trial subjects are protected, consistent with the principles that have their origin in the Declaration of Helsinki, and that the clinical trial data are credible.”
ICH E6 GCP Guideline is designed to set a unified standard for the ICH countries in order to facilitate the mutual acceptance of clinical data by RAs in these jurisdictions and speed up registration for market authorization of medicines. Topics covered include the composition of Ethics Committees/review boards, the responsibilities of investigators and sponsors, provisions regarding trial protocols and protocol amendments, including treatment of data, informed consent, payment of subjects, insurance in case of harm. This guideline has been adopted by the EU in 1995 (updated version) [1] and largely transposed into their legislation by the United States [7] and Japan in 1997.
ICH Good Clinical Practice Principles
The ICH-GCP Principles can be divided into three different categories:
GCP Details in the Field of the Quality
ICH-GCP Guidelines describe in detail how the principles can be implemented. Principles related to the quality of the CT are crucial for all clinical investigations. Many paragraphs of GCP are related to quality principles. Among others, the following should be noted.
The investigator/institution should maintain the trial documents as specified in “Essential Documents for the Conduct of a Clinical Trial” and as required by the applicable regulatory requirement(s). The investigator/institution should take measures to prevent accidental or premature destruction of these documents (par. 4.9.4).The sponsor is responsible for implementing and maintaining Quality Assurance (QA) and Quality Control (QC) systems with written Standard Operating Procedures (SOPs) to ensure that trials are conducted and data are generated, documented (recorded), and reported in compliance with the protocol, GCP, and the applicable regulatory requirement(s) (par. 5.1.1).QC should be applied to each stage of data handling to ensure that all data are reliable and have been processed correctly (par. 5.1.3).If significant formulation changes are made in the investigational or comparator product(s) during the course of clinical development, the results of any additional studies of the formulated product(s) (e.g., stability, dissolution rate, bioavailability) needed to assess whether these changes would significantly alter the pharmacokinetic profile of the product should be available prior to the use of the new formulation in clinical trials (par. 5.13.5).The sponsor should1.2.2. WHO Guidelines for Good Clinical Practice for Trials on Pharmaceutical Products
These guidelines [8] have been prepared by the WHO, in consultation with National Drug Regulatory Agencies in developed countries. It is intended to set globally accepted and applicable standards for the conduct of trials with human subjects by bringing together standards already in use in developed countries. Their aim is to provide mutual recognition of data among interested countries and contribute to the process of harmonization of provisions. It is interesting to note that while the guidelines do not challenge or replace national guidelines, they aim at being a model for standard setting in those countries where no regulation exists.
The guidelines are designed to be applicable to all stages of drug development, but they can be applied to biomedical research as a whole, including evaluation of scientific and ethical integrity of manuscripts submitted to editors for publication.
Principles and detail of WHO GCP are similar to those of ICH-GCP.
1.2.3. WHO Handbook for Good Clinical Research Practice Guidance for Implementation
This document [9] is an adjunct to WHO's Guidelines for GCP for trials on pharmaceutical products (1995) [8]. The handbook aims at assisting national RAs, sponsors, investigators, and Ethics Committees in implementing GCP for industry-sponsored, government-sponsored, institution-sponsored, or investigator-initiated clinical research.
1.2.4. WHO Good Clinical Laboratory Practice
This guidance [10] identifies systems required and procedures to be followed within an organization conducting analysis of samples from clinical trials in compliance with the requirements of GCP. It thus provides sponsors, laboratory management, project managers, Clinical Research Associates (CRAs), and QA personnel with the framework for a quality system in analysis of clinical trial samples, ensuring GCP thorough compliance processes and results.
The Special Program for Research and Training in Tropical Diseases (TDR) Diagnostics Evaluation Expert Panel (DEEP) has recommended GCLP as the standard for clinical laboratories involved in the evaluation of diagnostics for infectious diseases.
This document is intended to provide a framework for the analysis of samples from clinical trials on the facilities, systems, and procedures that should be present to assure the reliability, quality, and integrity of the work and results generated by their contribution to a clinical trial.
It is recommended that the framework outlined in this document be adopted by any organization that analyzes samples generated by a clinical trial.
The principles defined in this framework are intended to be applied equally to the analysis of a blood sample for routine safety screening of volunteers (hematology/biochemistry) as to pharmacokinetics or even the process for the analysis of ECG traces.
The types of facilities undertaking analyses of clinical samples may include pharmaceutical company laboratories, Contract Research Organisations (CROs), central laboratories, pharmacogenetic laboratories, hospital laboratories, clinics, investigator sites, and specialized analytical services.
GCLP applies those Principles established under GLP for data generation used in regulatory submissions relevant to the analysis of samples from a clinical trial. At the same time it ensures that the objectives of the GCP Principles are achieved. This ensures the reliability and integrity of data generated by analytical laboratories.
This guidance provides details, among others, on the following issues: personnel responsibilities; facilities; equipment, materials, and reagents; SOPs; trial materials; conduct of the work; QC; quality audit.
1.3. Good Clinical Practice: Legal Background in the European Union
In the EU, ICH-GCP Guidelines have been adopted by the Committee for Proprietary Medicinal Products (CPMP) of the EMA in 1991 and at a later stage as the updated version of 1996 [1].
The EMA Guidelines are not mandatory, but many aspects of GCP have been introduced in EU Directives, namely Directive 2001/20/EC of the European Parliament and of the Council of April 4, 2001: On the approximation of the laws, regulations and administrative provisions of the Member States relating to the implementation of good clinical practice in the conduct of clinical trials on medicinal products for human use [3] and Commission Directive 2005/28/EC. Laying down principles and detailed guidelines for good clinical practice as regards investigational medicinal products for human use, as well as the requirements for authorisation of the manufacturing or importation of such products [4].
The main provision of these two Directives is that all CTs, including bioavailability (BA) and bioequivalence (BE) studies, shall be designed, conducted, and reported in accordance with the principles of GCP. Other targets of CT Directives are as follows:
simplification and harmonization of CTs across the EU;better protection of subjects who take part in CTs;enforcement by law of the principles of GCP and GMP.The scope of the CT Directives is wide. It covers all commercial and academic CTs of IMPs and marketed medicines.
The types of IMPs specified in the Directive 2005/28/EC (5) are the following:
chemical entities;biotechnology products;cell therapy products;gene therapy products;plasma-derived products;other extractive products;immunological products, such as vaccines, allergens, and immune sera;herbal products;homeopathic products;radiopharmaceutical products.Also a placebo, or a marketed product used or assembled in a way other than the approved form, is an IMP when used as a comparator.
The impact of the CTs Directive on trials is as follows:
the already mentioned obligation is to be in compliance with the ICH-GCP principles;trials of IMPs in healthy subjects and in patients are regulated in all EU Member States (MSs) according to CT Directives;sponsors must apply to and receive approval from the national RA for a Clinical Trial Authorization (CTA) and for substantial protocol amendments;investigators must apply to and receive approval from Ethics Committee for the protocol and substantial amendments.According to this legislation Ethics Committee foreseen in ICH-GCP are in charge of supervising CTs. Ethics Committee is an independent body in a MS whose responsibility it is to protect the rights, safety and well being of human subjects involved in a trial and to provide public assurance of that protection, by, among other things, expressing an opinion on the trial protocol, and on the methods and documents to be used to inform trial subjects and obtain their informed consent (article 2 (k) of Directive 2001/20/EC [3]).
The Ethics Committee approval is necessary before the commencement of a clinical trail. The Ethics Committee shall consider, among other things, also aspects regarding quality of the trial such as
To verify compliance with the provisions on GCP, EU MS appoint inspectors to inspect the sites concerned by any CT conducted, particularly the trial site, the sponsors, premises, and Ethics Committee as well.
The inspections shall be conducted on behalf of the EU and the results shall be accepted by all EU MSs.
1.4. Good Clinical Practice: Applicability in the European Union
1.4.1. EU 2007 Conference on the Implementation and Applicability in the European Union of Legislation on Clinical Trials of Medical Products
At the request of the European Commission (EC), the EMA organized on October 30, 2007 a conference on the implementation and applicability in the EU of legislation on CTs of medicinal products and on GCP-related Guidelines.
It was recognized by conference participants that the legislation on CTs has introduced a common legal framework and a legal basis for compliance with GCP and has improved the protection of individuals through procedures for ethical approval of CTs in the EU.
Participants stressed the importance of maintaining the general principles of protecting patients, facilitating high-quality research, and promoting a favorable research environment in the EU.
It was acknowledged that, in some cases, problems that have been encountered appeared to be a consequence of different interpretations and different implementation in the national legislation of the MS, whereas other aspects would need to be addressed through proposed changes to the legislation.
The main areas in which efforts should be focused are multinational CTs, safety reporting and monitoring, noncommercial sponsorships/trials, CTA dossier and process, IMP-related issues, and the application of ethical principles and GCP standards in developing countries.
The key issues arising from the conference presentations are summarized below.
Based on data from the European data base on Clinical Trial (EudraCT), 80% of CTs conducted in the EU since 2004 have been by commercial sponsors and 20% by noncommercial sponsors.
Most of the trials are performed in multiple sites and multiple countries. The challenge in the EU is therefore to optimize the regulatory environment to
ensure protection of subjects participating in CTs (EU and third countries);ensure a framework for high-quality research in the EU and its acceptability worldwide (product development, product authorization);promote a favorable research environment (clear, efficient, and effective administrative and scientific procedures).The Directives have set out a legal basis for GCP compliance in the conduct of CTs. As a result, increased awareness of the requirements for the conduct of CTs, including GCP, has led to improvements in the available infrastructure for clinical-trial management and improved GCP compliance.
The GCP Inspectors Working Group (WG) recommended that there be a harmonized reference to ICH-GCP as the EU standard in the EU legislation.
It was noted that, while requirements for CTs of medicinal products are well regulated and relatively well harmonized, requirements for other biomedical research on human subjects are poorly implemented. It was recommended that both the GCP standards and harmonized administrative requirements should apply not only to CTs with investigational medicinal products but also to other types of trials, including those for in vitro diagnostics, medicinal devices, and so on.
As far as commercial and noncommercial trials and sponsors are concerned, consensus was reached on the fact that there should be one set of GCP standards for all trials, and not different standards for commercial trials and for noncommercial trials. Noncommercial investigators, in the authors' view, did not realize that this approach could require in the future the compliance to the full text of GCP provisions, rather than only to principles as it is now. In fact, rather than a distinction between commercial and noncommercial trials, the idea of a differential application of the legislation, using a risk-based approach, was proposed. This approach should be based on the risk involved in the trial and on the extent of knowledge of the product (e.g., novel product, marketed product, marketed product used within its Summary of Product Characteristics (SPC), and so on), thus avoiding the development of double standards in terms of GCP compliance and quality and credibility of data. This approach would prevent the perception that there be two levels of quality in the present legislation and in its implementation. It would lead to a general improvement in the quality and cost effectiveness of trials (e.g., better prioritization of monitoring and of other QC activities).
Proposals to improve the cost-effectiveness of noncommercial trials without reducing compliance with GCP included adapting record-keeping and monitoring requirements (e.g., by web-based trial master files/investigator site files and by developing models of monitoring and auditing tailored to the structures or their organizations and the risk of the trials).
1.4.2. Directives 2001/20/EC, 2005/28/EC, and Good Clinical Practice in Case of Noncommercial Clinical Trials
Aspects of Directives 2001/20 and 2005/28 regarding GCP and noncommercial clinical trial misunderstood by some noncommercial investigators.
European Directive 2001/20 EC on GCP and CTs has been widely criticized by an important part of the scientific community more directly involved in the promotion and management of noncommercial or academic CT. Since 2003 several academic experimentalists stressed on scientific international literature difficulties derived from new EU Regulation specifically as far as it concerns: (i) GCP compliance; (ii) GCP monitoring; (iii) sponsorship; (iv) IMP; (v) contents of authorization dossier; and (vi) notification of adverse event/reactions [11–15].
In the authors' view [16], as regards the first four aspects, provisions of Directive 2001/20/EC read in conjunction with Directive 2005/28/EC and with Directive 2005/28/EC do not hinder noncommercial/academic clinical trails for the following reasons:
Aspect of the Directive 2001/20/EC that could be modified regarding GCP and noncommercial trials.
In the authors' view, the aspects of CT Directives that should be modified to obtain the complete compliance to GCP are as follows:
that CTs the results of which are used for regulatory purposes have to be in compliance both with ICH-GCP Principles and full text details while academic CTs have to be in compliance with GCP-ICH Principles to be either achieved by GCP-ICH details or guaranteed by other means;that only CTs in compliance with ICH-GCP Principles and details shall be considered for regulatory purposes while other CTs can be used only as a support, but not as a replacement, of the documentation required for the MA.Moreover, art. 9.8 of Directive 2001/20 provides that the EC shall draw up and publish the detailed Guidance on the contents of the request for CT authorization, without taking into account the specificity of academic CTs. The EC published this detailed Guidance that has been judged as red tape (i.e., too prescriptive, redundant, and bureaucratic) by academic experimentalists.
In case of revision of Directive 2001/20, it might be necessary to foresee, for academic CTs, simplified Guidelines as far as it concerns CT authorization.
Finally, art. 18 of Directive 2001/20 prescribes that the EC shall draw up and publish the detailed Guidance on the collection, verification, and presentation of adverse event/reaction report, without taking into account the specificity of academic CT. The EC published this detailed Guidance; also in this case this guidance has been judged red tape by academic experimentalists.
In case of revision of Directive 2001/20 it might be necessary to foresee for academic CTs simplified Guidelines as far as it concerns the notification of adverse event/reactions.
1.5. Good Clinical Practice And Bioequivalence Trials: GCP Inspections and Laboratories
1.5.1. General Aspects
BE trials are comprised of several parts:
a clinical part, where the test and the reference products are administered to the trial subjects and where biological samples (generally plasma or serum, possibly blood, urine, or any other suitable fluid) are collected from the subjects;a bioanalytical part, where the concentration of the active moiety and/or its biotransformation product(s) in the said biological samples is measured;the pharmacokinetic analysis, where pharmacokinetic parameters derived from these concentrations are calculated;the statistical comparison of the pharmacokinetic parameters obtained for the test and the reference products.As already pointed out, EU Directive 2001/20 foresees that all CTs, BE included, have to be designed, conducted, and reported according to the GCP Principles.
For this purpose, the EMA has worked out a specific Guideline on the Investigation of Bioequivalence, still under evaluation at the time of writing, which replaces the previous one issued in 1998 [17].
1.5.2. EMA Guidelines on Bioequivalence Studies
The Guideline [17] sets forth requirements for the design, conduct, and evaluation of BE studies. These requirements are technical and by the same token implement the GCP Principles. A few examples on standardization and chemical analyses are given below to better illustrate these concepts.
Standardization
The test conditions should be standardized in order to minimize the variability of all factors involved except that of the products being tested. Therefore, it is recommended to standardize diet, fluid intake, and exercise.
The time of day for ingestion should be specified. As fluid intake may influence gastric passage for oral administration forms, the test and reference products should be administered with a standardized volume of fluid (at least 150 mL). All meals and fluids taken after the treatment should also be standardized in regard to composition and time of administration during the sampling period. As the bioavailability of an active moiety from a dosage form could be dependent upon gastrointestinal transit times and regional blood flows, posture and physical activity may need to be standardized.
The subjects should abstain from food and drinks, which may interact with circulatory, gastrointestinal, hepatic or renal function (e.g., alcoholic or xanthine-containing beverages or grapefruit juice) during a suitable period before and during the study.
Subjects should not take any other concomitant medication (including herbal remedies) for an appropriate interval before as well as during the study. In case concomitant medication is unavoidable and a subject is administered other drugs, for instance to treat adverse events like headache, the use must be reported (dose and time of administration) and possible effects on the study outcome must be addressed.
Chemical Analysis
The bioanalytical part of bioequivalence trials should be conducted according to the Principles of Good Laboratory Practice (GLP). However, as such studies fall outside the formal scope of GLP, the sites conducting the studies are not required to be certified as part of the GLP compliance certification scheme.
The bioanalytical methods used must be well characterized, fully validated and documented to yield reliable results that can be satisfactorily interpreted. The main objective of method validation is to demonstrate the reliability of a particular method for the quantitative determination of an analyte(s) concentration in a specific biological matrix.
The validation of a bioanalytical method should comprise two distinct phases: (1) the pre-study phase in which the compliance of the assay with the characteristics listed above is verified and (2) the study phase itself in which the validated bioanalytical method is applied to the actual analysis of samples from the bioequivalence study in order to confirm the validity of the determinations.
Pre-study Phase
As validation involves documenting that the performance of characteristics of the method are suitable and reliable for the intended analytical application, commercial kits need to be re-validated for their use in bioequivalence studies. Similarly, demonstration of stability based on literature data only is not acceptable.
Study Phase
A calibration curve should be generated for each analyte in each analytical run and it should be used to calculate the concentration of the analyte in the unknown samples in the run. A sufficient number of separately prepared QC samples should be analyzed with processed test samples at intervals based on the total number of samples. In addition, it is necessary to validate the method of processing and handling the biological samples.
All activities should be performed according to pre-established SOPs. All relevant procedures and formulae used to validate the bioanalytical method should be submitted and discussed. Any modification of the bioanalytical method before and during analysis of study specimens may require adequate revalidation; all modifications should be reported and the scope/validation justified.
1.5.3. EMA Reflection Paper for Applicants Who Want to Submit Bioequivalence Performed Outside the European Union
The necessity of assuring technical and quality requirements in BE (and other) CTs, has induced the GCP inspectors WG of EMA to adopt a specific Reflection Paper [18] to warn the applicants who want to submit BE conducted in countries where the GCP Principles are not mandatory. The document is addressed to sponsors, CROs, and applicants, specifically in the field of generics, because
According to the guidance, for evaluation of quality the following aspects are of importance:
type of organization and its activities, previous inspection experience, etc.qualification of the facilities where the studies are performed;availability of audit certificates, etc.Further aspects that should be taken into account are
type of products, e.g., stability, pharmacokinetic and pharmacodynamic profiles, and analytical methods;production site, e.g., location, GMP license/inspection, Qualified Person (QP) activities;traceability;conditions of administration of the product;provision of in vitro dissolution data for both test and reference products.Labeling, traceability, storage, and transport conditions of the biological samples before their analysis should be considered.
Location and regulatory environment (EU/European Economic Area, third countries) of the clinical and laboratory sites, should be considered together with Ethics Committee and Competent Authority (e.g., applicable local regulations and guidelines, national, international, trial type, specific local guidance).
At the time of contracting a study to a CRO or developing an application dossier, the sponsor and the applicant should consider the following (as well as other) activities, which fall under their responsibility
quality and completeness of the protocol;validation of analytical methods;validation of clinical activities;quality system (including performance of monitoring and auditing) implemented by the CRO and the sponsor,verification of report, data listings, statistics and protocol;performance of audits by sponsor (post-study); evaluation of audit results and improvement cycles;verification that the sponsor/CRO had adequate control of the quality of the study (performance and outcome of sponsor audits, evaluation of the activities of the sponsor);audit of the clinical and bioanalytical sites;in relation to IMP production, verification of GMP certification, inspection status (and site authorization where applicable) and audit.A quality system approach to the sponsoring, contracting, purchase of a dossier/product, or applying for a marketing authorization will give a good basis through which verification of a number of the above issues can be implemented. This approach will ensure that the chances for problematic quality in BA/BE study dossiers used in generic applications are lessened.
1.5.4. Good Clinical Practice Bioequivalence Inspections
In a complementary way the EMA GCP Inspection WG has adopted (12 March 2008) the Procedure for conducting GCP inspections requested by the EMEA: bioanalytical part, pharmacokinetic and statistical analyses of bioequivalence trials [19].
This annex describes specific items that may be verified during the GCP inspection of the bioanalytical part and of the pharmacokinetic and statistical analyses of BE trials.
According to this procedure the documents and data relating to the following topics are generally reviewed during the GCP inspection:
storage of the biological samples;validation of the bioanalytical method;performance of the assays;if requested, pharmacokinetic and statistical analyses of the trial data.Some of the major points to be taken into account during the GCP inspection reported in the document are
nature of the activities carried out at the laboratory;share of BE trials in this activity;command of the analytical methods used, particularly for complex methods;QA system in place at the laboratory;existence, availability, accessibility, and validity of SOPs.The suitability of the facilities and equipment available and their appropriateness for the activity of the laboratory and for the BE trial inspected should be checked during the inspection.
Some of the main points to be considered during the inspection regarding reference substances are
availability and contents of the certificates of analysis;expiry dates;storage conditions;conditions for access to reference substances.The key points to be considered regarding calibration and control samples are
dates and conditions of preparation of the stock and working solutions and of the calibration and control samples, and the number of aliquots prepared for each sample;accuracy of the calculation of nominal concentrations;conditions and duration of storage of the stock solutions, working solutions, and calibration and control samples, compared to their stability, as described in the validation report;matrix used, including the anticoagulant, if any.The crucial points to be considered during GCP inspections as regards the calibration for each run are
number of calibration samples;response function used, including weighing, if any;acceptance criteria for the calibration curve;exclusion criteria of calibration samples.Some of the major points to be considered as regards method validation are
validation protocol;completeness of the validation report, when compared to the various experiments performed.General aspects on sample handling at the facility may be inspected, including the following:
responsibilities for receipt and handling of biological samples;organization of the receipt system, including outside workdays/hours;sample registration;controls performed on receipt.As pointed out in this document a number of aspects should be checked for the storage of the samples collected for the inspected trial, including the following:
storage conditions of the trial samples;temperature records of the freezer;calibration of the thermometer and its traceability to national/international standards;alarms and other surveillance measures;consistency of the validation report with the source documents;chromatogram integrations;stability of the stock solutions and of the sample.The document also lists the main points to be assessed during GCP inspections regarding assays such as
completeness of the analytical report;assessment of the risk of sample mix-ups;assessment of the risk of sample cross-contamination;chromatogram integrations;calculation of the concentrations.1.5.5. Good Clinical Practice Clinical Laboratory Inspections
The EMA GCP inspectors WG has also adopted (September 5, 2007) the Procedure for conducting GCP inspection requested by the EMEA on clinical laboratories [20].
This procedure is merely presenting a general outline of the elements that have to be taken into account when inspecting laboratories involved in clinical trials, e.g., analytical chemistry, clinical biochemistry, hematology, microbiology, histopathology, cytology, genetics.
As prescribed by this document a number of key issues should be checked during a GCP inspection, namely:
quality system formally adopted by the laboratory (e.g., GLP, GMP, ISO, EN);fulfillment of national requirements of accreditation;relevance of accreditation in the context of clinical trial(s);systems for QA and QC, including programs for internal audits;SOP system (distribution, availability, audit-trail, clinical trials, archiving, etc.);suitability and adequacy of premises (e.g., adequate degree of separation of work areas to avoid mix-ups, contamination and interference);environmental conditions, e.g., temperature, airflow and air pressure, microbiological contamination;records of operation, maintenance and calibration;records of the validation for the methods used for the measuring equipment and apparatus (including computerized systems);log books;documentation of receipt (date and time), identification, condition, re-labeling, and storage of samples by an identifiable person;aliquoting and distribution for examination;handling of non-conformance, repeat analysis, and results within critical/alert ranges;material and methods according to the specification stated in the protocol/contract and/or required according to the European Pharmacopoeia;validation status of the methods, appropriately setting of limits of detection and quantification, precision/accuracy, known inferences, and specific control measures;participation in external quality programs, if applicable;systems for alerting results that are unexpected and/or significant deviations from pre-specified limits;integrity of data reported by internal QA/QC and/or sponsor's QA/QC personnel, audit certificate.1.5.6. Good Clinical Practice Inspections on Phase I Units
Last but not least, it is not out of place to recall that the EMA GCP Inspectors WG has also adopted (July 23, 2008) the Procedure for conducting GCP Inspections Requested by the EMEA on Phase 1 Units [21].
Without repeating what already stated above, some of the major points to be considered during a GCP inspection of interest to laboratories involved in Phase I studies are as follows:
