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- Herausgeber: John Wiley & Sons
- Kategorie: Wissenschaft und neue Technologien
- Sprache: Englisch
A comprehensive introduction for scientists engaged in new drug development, analysis, and approvals Each year the pharmaceutical industry worldwide recruits thousands of recent science graduates--especially chemistry, analytical chemistry, pharmacy, and pharmaceutical majors--into its ranks. However, because of their limited background in pharmaceutical analysis most of those new recruits find making the transition from academia to industry very difficult. Designed to assist both recent graduates, as well as experienced chemists or scientists with limited regulatory, compendial or pharmaceutical analysis background, make that transition, Pharmaceutical Analysis for Small Molecules is a concise, yet comprehensive introduction to the drug development process and analysis of chemically synthesized, small molecule drugs. It features contributions by distinguished experts in the field, including editor and author, Dr. Behnam Davani, an analytical chemist with decades of technical management and teaching experience in compendial, regulatory, and industry. This book provides an introduction to pharmaceutical analysis for small molecules (non-biologics) using commonly used techniques for drug characterization and performance tests. The driving force for industry to perform pharmaceutical analyses is submission of such data and supporting documents to regulatory bodies for drug approval in order to market their products. In addition, related required supporting studies including good laboratory/documentation practices including analytical instrument qualification are highlighted in this book. Topics covered include: * Drug Approval Process and Regulatory Requirements (private standards) * Pharmacopeias and Compendial Approval Process (public standards) * Common methods in pharmaceutical analysis (typically compendial) * Common Calculations for assays and impurities and other specific tests * Analytical Method Validation, Verification, Transfer * Specifications including how to handle out of specification (OOS) and out of trend (OOT) * Impurities including organic, inorganic, residual solvents and elemental impurities * Good Documentation Practices for regulatory environment * Management of Analytical Laboratories * Analytical Instrument Qualifications including IQ, OQ, PQ and VQ Due to global nature of pharmaceutical industry, other topics on both regulatory (ICH) and Compendial harmonization are also highlighted. Pharmaceutical Analysis for Small Molecules is a valuable working resource for scientists directly or indirectly involved with the drug development process, including analytical chemists, pharmaceutical scientists, pharmacists, and quality control/quality assurance professionals. It also is an excellent text/reference for graduate students in analytical chemistry, pharmacy, pharmaceutical and regulatory sciences.
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Table of Contents
Cover
Title Page
Copyright
Dedication
About the Editor
List of Contributors
Preface
Acknowledgment
Chapter 1: Drug Approval Process and Regulatory Requirements
1.1 Introduction
1.2 The Regulatory Process for New Drug Entity
1.3 Good Laboratory Practice for Nonclinical Laboratory Studies
1.4 Validation of Analytical Procedures: Methodology
1.5 FDA Role in the Discovery and Development of New Drug Entities
1.6 FDA Inspectors’ Role in Analytics Relative to Products in the Marketplace
1.7 Conclusions
References
Chapter 2: Pharmacopeias and Compendial Approval Process
2.1 Introduction
2.2 USP History
2.3 Evolution of the Mission of the USP
2.4 The USP Organization
2.5 The USP-NF Revision Process
2.6 Publications of USP
2.7 Relationship between USP and FDA
2.8 USP and the Pharmacopoeias of Europe and Japan
2.9 Harmonization of Pharmacopeial Monographs and General Chapters
2.10 Comparisons between the PDG Process and the ICH Process in Harmonization
2.11 The Special Case of Pharmacopeial Harmonization of Excipients
2.12 Retrospective versus Forward Pharmacopeial Harmonization
2.13 Conclusions and Recommendations
2.14 Final Thoughts
References
Chapter 3: Common Methods in Pharmaceutical Analysis
3.1 Scope
3.2 Analytical Methods
3.3 Spectroscopy Methods
3.4 Other Spectroscopy Methods
3.5 Wet Chemistry Methods
3.6 Performance Methods (Contributed by Oscar Liu)
3.7 Microbiological Methods (Contributed by Roger Dabbah)
3.8 Critical Factors Involved in Microbial Limit Tests and in Sterility Tests
3.9 Harmonization of Pharmacopeial Procedures and Requirement
3.10 Bacterial Endotoxins Test
3.11 Summary
References
Chapter 4: Common Calculations
4.1 Scope
4.2 Calculations (Quantitative Analysis)
4.3 Calculations (System Suitability Parameters)
4.4 Summary
References
Chapter 5: Analytical Method Validation, Verification, and Transfer
5.1 Introduction
5.2 Scope
5.3 Typical Validation Characteristics
5.4 Definition and Determination of Analytical Characteristics
5.5 Types of Analytical Procedures
5.6 Typical Validation Requirement
5.7 Revalidation
5.8 System Suitability
5.9 Forced Degradation (Stressed) Studies
5.10 Analytical Method Verification
5.11 Analytical Method Transfer
5.12 Summary and Conclusion
References
Chapter 6: Specifications
6.1 Scope
6.2 Introduction
6.7 Release Specifications
6.8 Relationship between Release and Shelf-Life Specifications
6.9 Using a Control Chart for Trend Analysis
6.10 Life Cycle Management of Specifications
6.11 Summary
Acknowledgments
References
Chapter 7: Impurities
7.1 Scope
7.2 Definitions
7.3 Classification of Impurities
7.4 Qualification of Impurities
7.5 Other Specific Types of Impurities
7.6 Non-Drug-Related Impurities
7.7 Other Sources of Impurities
7.8 Degradation/Stability Studies
7.9 Summary
References
Chapter 8: Good Documentation Practices
8.1 Scope
8.2 Definition, Purpose, and Importance
8.3 General Rules and Principles of GDocP
8.4 General Tips for Laboratory Notebook Documentation
8.5 Electronic Documents and Electronic Signatures (21 CFR, Part 11)
8.6 US Pharmacopeia General Chapter <1029>
8.7 Rules Governing Medicinal Products in the European Union (Vol. 4: Documentation)
8.8 GDocP Enforcement
8.9 Summary
References
Chapter 9: The Management of Analytical Laboratories
9.1 Introduction
9.2 Principles of Management Applicable to the Laboratory Function
9.3 Management of Analytical Scientists
9.4 Conclusions and Recommendations
References
Chapter 10: Analytical Instrument Qualification
10.1 Introduction
10.2 Definitions
10.3 Qualification: General Flow
10.4 Qualification Strategy: V Model
10.5 Qualification
10.6 Qualification Phases
10.7 Qualification Issues
10.8 Combined Qualification Approach/Commissioning
10.9 Risk-Based Approach
10.10 Calibration/Verification
10.11 Track Performance Verification/Calibration Due Date
10.12 Warning Letters Related to Laboratory Equipment
10.13 Equipment Qualification/Validation and Its Importance
10.14 Examples
10.15 Qualification Status of Existing Equipment/Instrument
10.16 Summary
Acknowledgments
References
List of Abbreviations
Index
End User License Agreement
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Guide
Cover
Table of Contents
Preface
Begin Reading
List of Illustrations
Chapter 1: Drug Approval Process and Regulatory Requirements
Figure 1.1 Schematic high-level representation of the overall FDA review process [1].
Figure 1.2 Generalized NDA review process from Dabbah [1], which was adapted from Mathieu [2].
Chapter 4: Common Calculations
Figure 4.1 A chromatogram of two peaks with a resolution (
R
s
) of 1.8.
Figure 4.2 A diagram showing the calculation of peak asymmetry (
A
s
) and tailing factor (
T
f
) from peak width at 5% height (
W
0.05
) according to the USP. Inset diagrams show fronting and tailing peaks.
Chapter 6: Specifications
Figure 6.1 Normal (bell-shaped) data distribution curve.
Figure 6.2 Stability trend line for the first 12 months of a 60-month stability program.
Figure 6.3 Stability trend line for a 60-month stability program.
Figure 6.4 Process capability.
Figure 6.5 Relationship between release and shelf-life specifications for an assay determination.
Figure 6.6 Graphical representation of the uncertainties to consider between shelf life and release for an assay determination.
Figure 6.7 Control chart.
Chapter 8: Good Documentation Practices
Figure 8.1 Schematic representation of examples for “Information” and “Media.”
Figure 8.2 Schematic representation of examples for “Record”.
Figure 8.3 Attributes of records based on GDocP regulations.
Figure 8.4 Schematic representation of a hardcover lab notebook.
Chapter 10: Analytical Instrument Qualification
Figure 10.1 General concept of qualification activity.
Figure 10.2 V model for the execution of qualification activity including flow of documentation.
List of Tables
Chapter 5: Analytical Method Validation, Verification, and Transfer
Table 5.1 Accuracy data for assay using spike recovery method.
Table 5.2 Precision data for assay (repeatability and intermediate).
Table 5.3 Detection and quantitation limits for impurities.
Table 5.4 Linearity data for impurities.
Table 5.5 Validation characteristics for different types of analytical procedures.
Table 5.6 System suitability parameters and typical criteria.
Table 5.7 Stress parameters and typical conditions for drug substance.
Table 5.8 Stress parameters and typical conditions for drug product.
Chapter 6: Specifications
Table 6.1 Example of specifications for universal tests for a drug substance.
Table 6.2 Common spectroscopic and chromatographic tests used for identification testing.
Table 6.3 Typical specific tests commonly included in drug substance specifications.
Table 6.4 Specific test for drug products.
Table 6.5 Illustration of rounding numerical values for comparison with numerical acceptance criteria.
Table 6.6 Comparison of statistical estimation methods.
Chapter 7: Impurities
Table 7.1 Thresholds for impurities in drug substances [1].
Table 7.2 Example of reporting, identification, qualification of impurities.
Table 7.3 Reporting thresholds for impurities and degradation products in drug products.
Table 7.5 Qualification thresholds for impurities and degradation products in drug products.
Table 7.6 Example of reporting, identification, qualification for impurities.
Chapter 8: Good Documentation Practices
Table 8.1 List of some of the regulatory bodies around the world and their relative countries.
Chapter 10: Analytical Instrument Qualification
Table 10.1 Recommended group based on complexity of instrument.
Table 10.2 Protein content result by changing the volume to verify the accuracy level.
Table 10.3 Injector precision of two different HPLC brands.
Table 10.4 Parameters to be considered for HPLC during qualification and its importance [1–5].
Table 10.5 Parameters to be considered for UV/visible spectrophotometer during qualification and its importance [6–9].
Table 10.6 Parameters to be considered for autotitrator during qualification and its importance [7, 10].
Table 10.7 Parameters of Karl Fischer titrators to be considered during qualification and its importance.
Table 10.8 Parameters of weighting balance to be considered during qualification and its importance [7, 11].
Table 10.9 Parameters of auto pipettes to be considered during qualification and its importance [12, 13].
Table 10.10 Parameters of gas chromatography to be considered during qualification and its importance [14].
Table 10.11 Parameters of analytical column to be considered during qualification and its importance [15].
Table 10.12 Parameters of melting point apparatus to be considered during qualification and its important [16, 17].
Table 10.13 Overall status of the analytical instrument used for the testing of various samples in the laboratory.
Pharmaceutical Analysis for Small Molecules
Edited by
Behnam Davani
Principal Scientific Liaison, General Chapters, Science Division, U. S. Pharmacopeia
This edition first published 2017
© 2017 John Wiley & Sons, Inc.
All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronic, mechanical, photocopying, recording or otherwise, except as permitted by law. Advice on how to obtain permission to reuse material from this title is available at http://www.wiley.com/go/permissions.
The right of Behnam Davani to be identified as the editor of the editorial material in this work has been asserted in accordance with law.
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In view of ongoing research, equipment modifications, changes in governmental regulations, and the constant flow of information relating to the use of experimental reagents, equipment, and devices, the reader is urged to review and evaluate the information provided in the package insert or instructions for each chemical, piece of equipment, reagent, or device for, among other things, any changes in the instructions or indication of usage and for added warnings and precautions. While the publisher and authors have used their best efforts in preparing this work, they make no representations or warranties with respect to the accuracy or completeness of the contents of this work and specifically disclaim all warranties, including without limitation any implied warranties of merchantability or fitness for a particular purpose. No warranty may be created or extended by sales representatives, written sales materials or promotional statements for this work. The fact that an organization, website, or product is referred to in this work as a citation and/or potential source of further information does not mean that the publisher and authors endorse the information or services the organization, website, or product may provide or recommendations it may make. This work is sold with the understanding that the publisher is not engaged in rendering professional services. The advice and strategies contained herein may not be suitable for your situation. You should consult with a specialist where appropriate. Further, readers should be aware that websites listed in this work may have changed or disappeared between when this work was written and when it is read. Neither the publisher nor authors shall be liable for any loss of profit or any other commercial damages, including but not limited to special, incidental, consequential, or other damages.
Library of Congress Cataloging-in-Publication Data:
Names: Davani, Behnam, editor.
Title: Pharmaceutical analysis for small molecules / edited by Behnam Davani.
Description: First edition. | Hoboken, NJ : Wiley, 2017. | Includes bibliographical references and index. |
Identifiers: LCCN 2017029445 (print) | LCCN 2017030630 (ebook) | ISBN 9781119425038 (pdf) | ISBN 9781119425014 (epub) | ISBN 9781119121114 (cloth)
Subjects: | MESH: Pharmaceutical Preparations-analysis | Drug Design | Drug Approval | Chemistry, Pharmaceutical-methods | Small Molecule Libraries-pharmacology
Classification: LCC RS420 (ebook) | LCC RS420 (print) | NLM QV 25 | DDC 615.1/9-dc23
LC record available at https://lccn.loc.gov/2017029445
Cover image: (Pills) © Daryl Solomon/Gettyimages;
(Texture) © aleksandarvelasevic/Gettyimages
Cover design by Wiley
This book is dedicated to my brother Behzad Davani.
About the Editor
Behnam Davani, PhD, has more than 25 years of experience in analytical chemistry, compendial science, QC/QA, and project management. He is currently Principal Scientific Liaison in the General Chapter Group, Science Division of the United States Pharmacopeia (USP). In this role, he coordinates the identification and scientific development of compendial (USP) courses for stakeholders worldwide. He is also active faculty for several compendial courses including method validation/verification/transfer, impurities in drug substances and products, compendial HPLC, residual solvents, stability studies for drug substances and products, spectroscopy, and others. He has taught these courses domestically and internationally, including in Canada, Europe, China, India, Russia, Korea, Latin America, Middle East, and North Africa. Prior to this position, he was Director of the Chemical Medicines Department. He provided scientific leadership and training to a team of international (India, China, and Brazil) and US-based scientific liaisons (PhD levels) responsible for the development and modernization of USP monographs and related general chapters for small-molecule drug substances and products.
Prior to this position, he was Senior Scientific Liaison in the Chemical Medicines Department (2003–2013). In this capacity, he worked with the USP Expert Committee, global pharmaceutical industry, and FDA for the development and revision of public standards for small-molecular-weight drug substances and drug products for human use. He was the Scientific Program Manager for the USP Industry Outreach Program (1999–2002). In this capacity, he managed the outreach program to enhance collaboration and communication with the major pharmaceutical companies and contract research organizations.
Prior to joining USP in 1999, he worked in various technical management positions in the industry for 12 years. He was Project Manager at Sigma-Aldrich for analytical method validation, stability studies, and method transfer in GMP Group/Pharmaceutical Division (1994–1999). He also managed the chromatography section in the Analytical Services Department, Research Division (1990–1994). Prior to that, he had management and research positions at HK Environmental Services (1988–1990) and Midwest Research Institute (1987–1988). He also held the postdoctoral research fellow position for 1 year at the US Department of Energy (1986–1987).
Dr Davani has authored numerous technical publications and reports in the areas of compendial science, pharmaceutical analysis, and trace organic analysis with emphasis on chromatography and mass spectrometry techniques.
He holds a PhD in Analytical Chemistry from New Mexico State University and MS degrees in Physical and Analytical Chemistry from Cal Poly University, Pomona, and University of Iowa, Iowa City, respectively. He also has an MBA degree from Webster University in St. Louis, Missouri. He is a member of the American Chemical Society and the American Association of Pharmaceutical Scientists.
List of Contributors
Dr Motamed-Khorasani is a medical and scientific affairs expert and a senior scientist with a strong background in biomedical science and clinical trial/research. She obtained her PhD and MS in molecular biology from University of Toronto and British Columbia, Canada, respectively, and did her Postdoctoral Fellowship at Microbix Biosystems Inc., Mississauga, Canada. She has a tenured and diverse range of experience in medical affairs, basic and industrial clinical research and development, clinical trials, medical and regulatory writing, and intellectual property. Dr Motamed-Khorasani has served as an independent consultant, director of medical affairs, senior medical sciences liaison, senior scientist, and senior medical analyst at Merck, Johnson & Johnson, United States Pharmacopeia (USP) Convention, Amgen, Baxter International, Covidien (eV3), Radiant Pharmaceuticals, AMDL Diagnostics, Microbix Biosystems, Neometrix Consulting, Samuel Lunenfeld Research Institute at Mount Sinai Hospital, Princess Margaret Hospital, and Vancouver General Hospital.
She has more than 20 years of experience and many national and international certificates in GLP, GMP, ICH-GCP, and FDA regulatory compliance for clinical trials and is a member of professional associations that include the Endocrine Society, American Association of Cancer Research (AACR), American Medical Writers Association (AMWA), Regulatory Affairs Professional Society (RAPS), American Society of Quality (ASQ), and Intellectual Property Institute of Canada (IPIC). Dr Motamed-Khorasani's research has focused on high-throughput approaches in the context of cancer informatics with a particular interest in the use of comparative analysis for the mining of integrated oncology datasets that include protein–protein interaction and gene expression profiling. She has published and presented more than 50 papers, abstracts, and articles in highly regarded scientific journals and high-profile conferences and scientific meetings.
Roger Dabbah, PhD, MBA, is the Principal Consultant at Tri-Intersect Solutions, which provides consulting, training in R&D and QA in the pharmaceutical, biotechnology, and medical device industries with specialization in microbiology testing, sterilization systems, and sterility assurance and management of laboratories. He also serves as an Adjunct Associate Professor at the University of Maryland University College, teaching courses in technology management including project management and risk management in projects, and at Johns Hopkins University, Whiting School of Engineering.
Prior to his current positions, he served as Director of the Complex Actives Division of the Drug Standards Department at the US Pharmacopeia. Before joining the USP, he was a Corporate Director of the Division of Microbiology, Sterilization, and Immunology for Baxter Healthcare, Manager of R&D Administration for the Nutritional Division of Abbott Laboratories, and Manager of the Biological and Information Sciences in technical services.
Dr Dabbah has extensively published papers and articles on microbiology, biotech, and management and collaborated in a number of technical books by contributing a number of chapters. He is also the author of two books: one on project management and the other on R&D management in the pharmaceutical industry. He is also on the Editorial Board of Pharmaceutical Technology and BioProcess International and on the Board of Directors of the PDA Foundation for Pharmaceutical Sciences.
Ernest Parente, PhD, is currently a Principal Scientist in the Chemistry, Manufacturing, and Control Regulatory Sciences group at Cardinal Health in Overland Park, Kansas. Formerly, he was a Sr Principal Analytical Chemist at Mallinckrodt Pharmaceuticals in St. Louis and the Head of Analytical Science and the Director of Quality Control at Sanofi-Aventis in Kansas City. In addition to his experience in Quality, Dr Parente has more than 18 years of experience in research and development and was the analytical chemistry team leader for the development of several currently marketed products. Before joining Sanofi-Aventis in 1989, he held positions in analytical and pharmaceutical R&D at Wyeth Laboratories, Warner-Lambert, and Hoffmann-La Roche. He has served at the USP for over 17 years and is currently a member of the USP Council of Experts. Dr Parente holds a PhD in analytical chemistry from the University of Delaware. He is an Adjunct Assistant Professor in the Graduate School of Pharmacy at the University of Missouri-Kansas City and is an active member of the ACS, Sigma Xi, AAAS, and AAPS. He is the author of scientific papers on chemical separations and protein analysis and has presented numerous US and International lectures on topics related to pharmaceutical analysis and the pharmaceutical industry.
Oscar Liu, PhD, is currently Director at Insys Therapeutics, Inc., leading pharmaceutical research and development including formulation. Prior to that, he has had several technical management responsibilities as Director and Senior Principal Scientist at Merck, Schering-Plough, Pfizer, and Par Pharmaceutical. In this role, he led Analytical Formulation/Product, Respiratory Product Development projects for more than 15 years. Dr Liu holds PhD degree in chemistry from Duke University. He has been board member of EAS since 2005 and was EAS president in 2014.
Dr Shaligram Rane has over 23 years in quality assurance/GMP/quality control and 2 years in academics with focus on streamlining and managing operations with proactive planning, changing existing or old concepts, and introducing new concepts for top-notch companies with consistent contribution to increased performance.
He completed his PhD in applied chemistry, MSc, and MEd. He has expertise in the quality and GMP department at various renowned organizations. Currently, he is heading the Quality (QC and QA) Department of Lupin Pharmaceuticals Ltd. (Biotech Division), Pune, India. Prior to Lupin, he associated with organizations such as Intas Pharma, Dishman Pharma, Cadila Pharma, Glenmark Pharma, Sun Pharma, Aarti Drugs and with Govt. Polytechnic College. His major areas of expertise are quality system, GMP activities, SAP-ERP system, designing of quality system according to regulatory guidelines. He has successfully handled more than 200 different types of inspection, for example, regulatory, customer, business partners, organization, and conducted more than 100 inspections at various pharma industries/laboratories. He has delivered talk on GMP topics at various workshops and conferences.
Dr Rustom Mody, Sr Vice President and Head of R&D (Biotechnology Division, Lupin Ltd.).
He has 19 years of experience in the Indian biopharmaceutical industry. He was the key person behind the development and commercialization of six biosimilars in the Indian market and two biosimilars in the US and EU markets. Dr Mody is currently developing four biosimilar products targeted for regulated markets such as the United States, Japan, Europe, and Australia. He is pioneer in the development and commercial-scale manufacturing of recombinant Hepatitis B vaccine.
Dr Mody has numerous patents filed, published, and approved and has 34 publications in peer-reviewed international journals. He was Ex-Chair of the Council of Experts for Biotherapeutics for United States Pharmacopoeia (Medicines Compendium) and Ex-Advisor to Indian Pharmacopoeia.
Preface
Pharmaceutical analysis is an important and integral part for the determination of quality including identity, purity, and strength of the drugs. In addition, related studies and programs are needed to assure the performance of the drug products. It requires analysts to acquire a solid understanding of analytical chemistry and also a thorough appreciation of pharmaceutical requirements to address these challenges.
The pharmaceutical industry is a major employer of science graduates, especially analytical chemistry majors. However, such students graduate with limited background in pharmaceutical analysis or related programs and are not prepared for employment in this industry. They find the transition from academics to this type of industry difficult due to lack of formal training in most of academic institutions. Therefore, this training/mentoring program is often performed by the pharmaceutical industry formally or informally to make these individuals productive employees as soon as possible. This type of training is also conducted as part of company’s regulatory and quality programs. As a result, they found that there is a lack of introductory materials as they struggle to transition fast to new regulatory and more complex work environment.
This book is intended to be an introductory book for pharmaceutical scientists who are directly or indirectly involved with drug development process. It covers all major topics in pharmaceutical analysis, including related regulatory requirements. The book is useful for both new and experienced scientists, including analytical chemists, pharmaceutical scientists, quality control/quality assurance personnel, and pharmacists. It is also beneficial for students at undergraduate or graduate universities, schools of pharmacy in the United States and abroad for the pharmaceutical analysis course or online programs for regulatory science or quality control programs.
There are few other books/references in the area of pharmaceutical analysis. However, my goal is to deliver a concise and at the same time comprehensive book in this area. One way to achieve this is to focus only on the smaller-molecular-weight pharmaceuticals (drug substances and products). The biological/biotechnological field and related analyses are beyond the scope of this introductory book and thus not covered.
The quality of pharmaceutical products must meet the required regulatory specifications, related guidelines, and good manufacturing and laboratory practices before being allowed to be marketed. Therefore, the book starts with the roles of FDA and ICH in setting such regulations and guidelines for drug approval process and submission (Chapter 1). Once specifications are approved, these become private standards enforced by FDA or other regulatory bodies. Chapter 2 extends this discussion to pharmacopeias and compendial approval process. This process leads to establishing public standards for pharmaceutical analysis by all stakeholders. Chapter 3 includes common methods for such analyses. The emphasis of this chapter is on more specific, stability-indicating, and instrumental techniques rather than classical nonspecific wet chemistry methods. Wet chemistry procedures are still used for routine analysis. However, the trend is toward automated instrumental tests for more sensitivity and specificity due to more stringer requirements for drug safety and toxicity concerns. This has also resulted in more efficiency and better characterization of the products, especially the determination of impurities at increasingly lower levels. The other focus of this chapter is on routine tests for the release and stability (QC lab) rather than more sophisticated instrumentation employed at the early stage in the research and development laboratory. The calculations associated with these analyses for both drug substances and products are included in Chapter 4.
The methods for pharmaceutical analysis have to be validated or verified if it is a compendial test. There is also a need to effectively transfer the noncompendial methods within the company or outsourced to qualified labs if needed. These topics are discussed in Chapter 5. Setting meaningful specifications and investigations in cases where these requirements are not met are discussed in Chapter 6. Due to the importance and more challenge to the analysis of impurities at trace or lower levels, a separate chapter is devoted to this topic (Chapter 7).
The remaining three chapters are related to GMP/GLP topics needed in a pharmaceutical regulatory environment. These include good documentation practices (Chapter 8), the management of analytical laboratories (Chapter 9), and analytical instrument qualifications (Chapter 10). These three chapters are placed at the end of the book. However, these are overarching chapters required during the entire life cycle of analytical procedures including development, validation, and performance verification. In addition, the list of abbreviations is included in both chapters and a separate appendix for the user’s convenience.
I believe the order of the chapters flows logically for the pharmaceutical analysis. However, each chapter is written in such a way that is rather independent and can be referenced or studied separately. I hope that you will find reading of this book both useful and enjoyable. Comments and feedback to my email address [email protected] are encouraged and appreciated.
February 2017 Behnam Davani
Acknowledgment
I would like to thank Professor Gary Eiceman, my PhD advisor at New Mexico State University, for the technical review of Chapters 3–5 and 7. His support and mentorship for many years during my career have been instrumental in my professional success.
I want to acknowledge the review of Chapter 3 and helpful suggestions by Dr Oscar Liu, who also contributed to a performance test section in the same chapter. I express my appreciation to my colleagues, Dr Horacio Pappa and Dr Andrzej Wilk, who supported this project as well as for many useful discussions we have had on various compendial topics during the last several years. I also want to express my gratitude to Dr V. Srini Srinivasan, former USP Chief Science Officer, for his support and encouragement as well as recommending contributors for the analytical instrument qualification chapter.
I am indebted to my late father, Hesam Davani, who planted the first seeds of my interest in learning, love of books, and critical thinking. I am grateful to my wife Ella Davani and my daughter Kimya Davani (Gheba) for their support and patience while making this long journey. This work could not have been completed without their constant encouragement.
Chapter 1Drug Approval Process and Regulatory Requirements
Roger Dabbah
1.1 Introduction
The role of the Food and Drugs Administration (FDA) in the review and approval of pharmaceutical products is divided into two broad categories. Each of the categories has its own set of regulations and issues, but regardless, they are designed to protect patients against harm and ensure the effectiveness of the medical products. These medical products include drugs from animals, plants, or human origin and products obtained via synthetic pathways, medical devices, and combination products
The two categories are as follows:
1.
Analytics in the discovery process (R&D) of pharmaceutical products
2.
Analytics in the compliance of products to their standards in the marketplace
Broadly speaking, the first category is a proactive approach while the second category is reactive. The first category ensures the safety and effectiveness of the products via the requirements for new drug applications (NDAs) and biologic license application (BLA) and occurs in the R&D phase of development of products, while the second category ensures that the manufacture of these products follows the NDA/BLA when they reach patients. The quality, safety, and effectiveness of pharmaceutical products are indicated via analysis of products that act as surrogates for these characteristics.
The nature of pharmaceutical products is their uniqueness that creates problems, issues, as well as challenges. A validated analytical procedure that works for one product might not provide for validation of the method for other products. The concept of validation must be applied in a flexible way to allow for changes due to the nature of a product, its chemical pathway, its origin and the nature of the APIs and inert ingredients (excipients) used for its manufacture. These issues will occur in both categories, and attempts to provide guidelines should include a more flexible approach that is not used presently.
The increase in regulatory requirements, often as a reaction to some perceived, potential, or real problems has increased the cost of development and compliance of pharmaceutical products. This is compounded by an adversary relationship among the regulatory agencies and pharmaceutical/biotech industry. In a perfect world, they should work in tandem in a win–win approach on scientific requirements and methodologies since they both have the same purpose, to ensure safety and effectiveness of pharmaceutical products.
However, before reviewing the role of FDA in the analytic areas, it would be of interest to briefly describe the FDA role by which a new drug entity is developed and approved.
In this chapter, we review in more detail the role of analytics required by FDA to approved products, to approve changes in products and to ensure through compliance that manufacture done according to NDAs will yield a quality product that is safe and effective. However, it is also important to discuss in some detail the good laboratory practices (GLPs) in 21CFR 58.
1.2 The Regulatory Process for New Drug Entity
A simplified schematic description of the overall FDA process [1] is shown in Figure 1.1.
Figure 1.1 Schematic high-level representation of the overall FDA review process [1].
1.2.1 Preclinical Studies
The organization will perform animal- or cell-based tests to determine if the drug is preliminarily safe and could become a candidate for human clinical trial. General guidance for these studies is provided by FDA, but must be adapted to the nature of the tested product. This is followed by one or more meetings with FDA, which reviews the data and, if necessary, requests additional data or clarifications. You can obtain guidances through the FDA website or through the Government Printing Office website.
1.2.2 Investigational New Drug Application (INDA)
The next step is to complete an INDA (21 CFR 312). Various “guidance for industry,” some based on ICH, are available from the FDA website. Following review by FDA of the INDA and approval, clinical trials are conducted in Phase 1, Phase 2, and Phase 3
1.2.2.1 Phase 1 Clinical
Initial introduction of the investigational drug to 20–30 patients or normal volunteers to determine safety, pharmacologic actions, side effects associated with increased doses, and mechanism of action.
1.2.2.2 Phase 2 Clinical
Controlled clinical study to evaluate effectiveness and risks using hundreds of patients.
1.2.2.3 Phase 3 Clinical
Expanded trials to show effectiveness in several thousand patients.
1.2.3 New Drug Application (NDA)
1.2.3.1 NDA Review by FDA
For NDA with a high urgent priority, the review of the application will take about 6 months on average. For other NDAs, the target is to complete the review in 22 months.
1.2.3.2 NDA Review Process
See in Figure 1.2, a generalized NDA review process that was adapted by Dabbah [1] based on Mathieu [2].
Figure 1.2 Generalized NDA review process from Dabbah [1], which was adapted from Mathieu [2].
1.3 Good Laboratory Practice for Nonclinical Laboratory Studies
The intent of this section is not to reproduce the 21CFR-58 that one can obtain easily through the Internet, on the FDA website. The intent is to extract items that relate directly or indirectly to the analysis of pharmaceutical products, that would be applicable to products in development as well as to products that are on the marketplace. The scope of the regulation is large, but we will confine our discussion to human and animal drugs, medical devices for human use, and biological products. We will not discuss the animal facilities or the electronic products used [3].
The term of analytics applies to analysis of products using methods and procedures that have been validated for each of the products in question, and these tests are conducted according to protocols also called standard operating procedure (SOP) that would allow a consistent analysis of products. The results of analysis should ensure that the quality of the products fulfills the requirements of the NDAs for these products. If a test procedure has been validated, but the application of the test to the products is not done under a strict protocol, the credibility of the results will be in question, and the release of products to the marketplace will be harmful to patients and will also be illegal. The SOPs will include the environment of the laboratory where testing is being done. It goes without saying that an analysis must be performed by trained and skilled personnel under the supervision of the testing facility management or its delegate.
A requirement of GLPs is that there is a Quality Assurance Unit in the organization that will approve developed protocols designed to ensure the credibility of the results of analysis. Deviations in protocols must be approved by the Quality Assurance Unit before they are implemented.
Perhaps, one of the most important factors in assessing the credibility of analysis is the calibration of equipment for the purpose intended [4]. A credible analysis starts with the choice of a test article that should be representative of the tested system or the production batch. For example, in microbiological testing, microorganisms are not homogeneously distributed, thus representative sampling is a must. The use of control articles or reference standards is indicated in protocols to ensure that the tested article has the appropriate quality, strength, identity, purity, and composition to ensure the efficacy of the products.
The reporting of results of analysis must be based on the actual analysis of a product that is documented, archived, and retrievable.
1.4 Validation of Analytical Procedures: Methodology
Every analytical procedure must be validated. Guidance and recommendation are shown in Guidance for Industry: Q2B Validation of Analytical Procedures: Methodology, which was developed by the International Congress on Harmonization (ICH) and adopted by FDA in November 1996 [5]. Since these are guidelines, other approaches to validation may be acceptable.
The main objective of validation of an analytical procedure is to demonstrate that the test is suitable for its intended purpose. In general, one wants to determine the capability of the procedure in terms of specificity, linearity, range, accuracy, precision, detection, and quantitation limits. In Chapter 5, there is an extensive discussion of these characteristics applicable to most analytical procedures but might require some modifications due to the nature of the procedure and its applicability.
In the Guidelines for Industry on Validation of Analytical Procedures [6] (ICH-Q2A, which was also adopted by FDA (March 1995)), there is a general discussion of the seven characteristics shown earlier It also adds a section on the revalidation of the validation of analytical procedures. It should occur when there are changes in the synthesis of the drug substance, changes in the composition of the finished product, and changes in the analytical procedure.
The US Pharmacopeia information on the validation of analytical procedures should be consulted, inasmuch as that they are cited and applicable for products that are approved by FDA. These US Pharmacopeia (USP) chapters are <1223> Validation of Alternative Microbiological Methods [7]; <1225> Validation of Compendial Procedures [8]; <1227> Validation of Microbial Recovery from Pharmacopeial Articles [9] and <85> Bacterial Endotoxins Test [10].
1.5 FDA Role in the Discovery and Development of New Drug Entities
Each new drug, device, or biological is unique; thus, a single regulatory process that ensures safety and effectiveness is not desirable. Thus, the manufacturer of new entities must provide data on analytical procedures that include validation of analytical methods as well as adherence to GLPs as indicted earlier. If the FDA reviewer is not satisfied with the analytical data presented or the interpretations of these results, he/she might require additional data. It is a fact of practice that the manufacturer will not present all analytical data available, but only those that are required as a minimum. The approval process will go faster if manufacturers would provide to FDA all data that are available, even negative data. Small organizations as well as start-up organization that do not have too much experience dealing with FDA will tend to use the guidelines for industry to the verbatim, even when the nature of the new products is such that it does not require following these guidelines to the verbatim.
1.5.1 INDA Analytical Requirements
In this section, we look at the requirements for the development of analytical data. Before a drug entity is to be used for clinical trial, that is, administered to humans, the process includes an investigational new drug application (INDA). The INDA gives a general idea of pharmacological effectiveness and safety. The tests performed include screening via in vitro methodologies; pharmacodynamic testing via qualitative and quantitative pharmaceutical profile such as dose response, mechanisms of action, and interaction with other drugs; pharmacokinetics through bioavailability, accumulation, and clearance of the product and species to species differences. The assurance of safety is much more complicated and includes toxicological testing, via acute toxicity, subacute and chronic toxicity, carcinogenicity, reproductive toxicity, genotoxicity, and toxicokinetics testing. Each of the areas listed will yield credible and useful data if the procedures used are completely validated and follow the requirement of GLPs. Of more direct interest in this section in the INDA is the section on chemistry, manufacturing, and control (CMC). The chemical, physical, and biological characteristics of the drug are provided along with the validated analytical procedures that will be used to determine the identity, purity, potency, and, quality of the drug substance [11]. The information that is required depends on the phase of the investigation, risks, novelty of the drug, previous studies, route of administration, and the patient population targeted. At the INDA level, especially in Phase 1, there is a requirement for brief description of analytical procedures to be used. In the subsequent phases, there should be a list of tests performed, such as for the identification of impurities that should be qualified and quantified. If USP analytical procedures are used, they should be described in general terms. However, if non-USP analytical procedures are used, there is a need for a complete description including validation data [11]. The clinical investigation can start 30 days after the FDA receives the INDA application, unless FDA decides not to allow the start of the clinical phase. The reason for a hold on clinical investigation can be that FDA needs additional technical data, such as appropriate validation of the analytical procedures to be used or perhaps that the risk to patients is too high.
1.5.2 NDA Analytical Requirements
NDA requirements are covered in detail under 21 CFR Part 314. From an analytical point of view, there should be a description of analytical methods, their rationale for use, and appropriate statistical analysis. The CMC section includes references to the USP analytical methods as well as to non-USP analytical procedures with appropriate validation data. It is understood that both for INDA and NDA data presented to FDA have been obtained under GLP guidelines.
1.5.3 Biotechnology-Derived Products – Small Molecules
In 1999, ICH developed a Q6B guidance that was adopted by FDA as guidance for industry. It is titled Q6B Specifications: Test Procedures and Acceptance Criteria for Biotechnological/Biological Products [12]. The objective was to provide guidance on general principles for the setting and justification of a uniform set of specifications for these products. Specifications, according to the guidance, are defined as a list of tests, reference to analytical procedures, and acceptance criteria. Conformance to specifications means that, when tested, using the analytical procedures indicated, these products will meet the acceptance criteria.
The analytical methods for biotechnology-derived products are very complex and mainly apply to large molecules. On the other hand, biotechnological processes can also lead to the development of small molecules, which will follow the requirements of drugs modified by the nature of the process and its process- or product-related impurities.
1.6 FDA Inspectors’ Role in Analytics Relative to Products in the Marketplace
Drug manufacturing inspections are part of the overall involvement of FDA in ensuring the effectiveness and safety of products on the marketplace. The FDA has issued a number of guidance documents in its compliance program. We will review the general guidance for compliance, the guides for inspection of quality control laboratories, the biotechnology inspection guide, and the guide for inspection of microbiological quality control labs as they related to test procedures used, which constitute the overall area of analytics. The comprehensive regulatory coverage of all aspects of production and distribution of drugs that meet the requirements of the 501(a)(2)(B) becomes consistent across the pharmaceutical industry, thus reducing variations in compliance inspections.
1.6.1 FDA Compliance Program Guidance Manual (Implemented on 09/11/2015 with a Completion Date of 09/11/2016 – Program 7356.002)
The guidance manual [13] evaluates through manufacturer’s inspections such as the collection and analysis of samples, the conditions and practices under which drugs and drug products are manufactured, packed, tested, and stored. Inspections are conducted every 2 years and zero in on compliance to current good manufacturing practices (cGMP)s. In this section, we deal with laboratory control systems. These include the availability of approved procedures and their documentations. The laboratory can have written approved procedures, but the role of the FDA inspector is to determine if the written procedures are used in the performance of analytical procedures. As the inspection proceeds, results might require a more in-depth investigation. For example, are the personnel qualified and trained to accomplish the various analytical procedures? Is
