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- Herausgeber: John Wiley & Sons
- Kategorie: Wissenschaft und neue Technologien
- Sprache: Englisch
Provides practical guidance on pharmaceutical analysis, written by leading experts with extensive industry experience
Analytical Testing for the Pharmaceutical GMP Laboratory presents a thorough overview of the pharmaceutical regulations, working processes, and drug development best practices used to maintain the quality and integrity of medicines. With a focus on smaller molecular weight drug substances and products, the book provides the knowledge necessary for establishing the pharmaceutical laboratory to support Quality Systems while maintaining compliance with Good Manufacturing Practices (GMP) regulations.
Concise yet comprehensive chapters contain up-to-date coverage of drug regulations, pharmaceutical analysis methodologies, control strategies, testing development and validation, method transfer, electronic data documentation, and more. Each chapter includes a table of contents, definitions of acronyms, a reference list, and ample tables and figures. Addressing the principal activities and regulatory challenges of analytical testing in the development and manufacturing of pharmaceutical drug products, this authoritative resource:
- Describes the structure, roles, core guidelines, and GMP regulations of the FDA and ICH.
- Covers the common analytical technologies used in pharmaceutical laboratories, including examples of analytical techniques used for the release and stability testing of drugs.
- Examines control strategies established from quality systems supported by real-world case studies.
- Explains the use of dissolution testing for products such as extended-release capsules, aerosols, and inhalers.
- Discusses good documentation and data reporting practices, stability programs, and the Laboratory Information Management System (LIMS) to maintain compliance.
- Includes calculations, application examples, and illustrations to assist readers in day-to-day laboratory operations.
- Contains practical information and templates to structure internal processes or common Standard Operating Procedures (SOPs).
Analytical Testing for the Pharmaceutical GMP Laboratory is a must-have reference for both early-career and experienced pharmaceutical scientists, analytical chemists, pharmacists, and quality control professionals. It is also both a resource for GMP laboratory training programs and an excellent textbook for undergraduate and graduate courses of analytical chemistry in pharmaceutical sciences or regulatory compliance programs.
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Table of Contents
Cover
Title Page
Copyright Page
Dedication Page
Einstein Quotation
Preface
About the Editor
Biographies of Contributing Authors
Editorial Notes
Acknowledgments
1 Drug Regulations and the Pharmaceutical Laboratories
1.1 Introduction
1.2 Food and Drug Administration: Roles and Its Regulations
1.3 International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) and Its Role
1.4 Pharmaceutical Analysis
1.5 Summary
List of Abbreviations
References
2 Good Manufacturing Practices (GMPs) and the Quality Systems
2.1 Introduction to Good Manufacturing Practices
2.2 Objectives of GMPs
2.3 Personnel Qualification and Responsibilities – Subpart B
2.4 Equ ipment – Subpart D
2.5 Laboratory Controls
2.6 Records and Reports
2.7 Pharmaceutical Quality
List of Abbreviations
References
3 Analytical Techniques Used in the GMP Laboratory
3.1 Introduction
3.2 Definitions
3.3 Basic Laboratory Procedures
3.4 Chromatography
3.5 Spectroscopic Sciences
3.6 Uniformity of Dosage Units
3.7 Elemental Analysis
3.8 Appearance
3.9 Visual Inspection
3.10 Microbiological Testing
3.11 Summary
List of Abbreviations
References
4 Control Strategies for Pharmaceutical Development
4.1 Introduction
4.2 Quality‐by‐Design Concept
4.3 Risk Management
4.4 Establishing Specifications
4.5 Design of Experiments
4.6 Common Statistical Analysis
4.7 Summary
List of Abbreviations
References
5 Development and Validation of Analytical Procedures
5.1 Introduction
5.2 Method Development
5.3 Qualification, Validation, and Verification
5.4 Validation Parameters
5.5 Validation for Physical, Chemical, Biotechnological, and Microbiological Procedures
5.6 Validation of In‐process, Environmental, Release, and Stability Procedures
5.7 Other Procedures
5.8 Validation of Procedures in Continuous and Batch Manufacturing
5.9 Summary
List of Abbreviations
References
6 Transfer of Analytical Procedures
6.1 Introduction
6.2 Purpose of Method Transfer
6.3 Transfer Options
6.4 Method Transfer Process
6.5 Transfer Protocol
6.6 Method Transfer Report
6.7 Related Documents
6.8 Handling Transfer Failures
6.9 Transfer to a Contract Lab
6.10 Transfer to an International Site
6.11 Summary
List of Abbreviations
References
7 Dissolution Testing in the Pharmaceutical Laboratory
7.1 Introduction
7.2 Regulatory and Compendial Role in Dissolution Testing
7.3 Theory
7.4 Equipment Operation and Sources of Error
7.5 Common Errors of Dissolution Apparatus
7.6 Dissolution Method Considerations
7.7 Method Development
7.8 Poorly Soluble Drugs
7.9 Setting Specifications
7.10 Harmonization
7.11 Method Validation
7.12 Validation of Product Performance Parameters
7.13 Validation of the Analytical Finish
7.14 Method Transfer Considerations
7.15 Good Manufacturing Practices (GMP) in the Dissolution Testing Laboratory
7.16 Summary
Acknowledgment
List of Abbreviations
References
Bibliography of Important Books Related to Dissolution Testing
8 Analytical Data and the Documentation System
8.1 Introduction
8.2 GMP for Records and Reports–Subpart J
8.3 Keeping Good Records
8.4 Raw Data Documentation
8.5 Samples, Reagents, Standards, Reference Standards
8.6 Drug Substance Analysis
8.7 Drug Product Analysis
8.8 Batch Release
8.9 Establishment of Specifications
8.10 Out‐of‐Specification (OOS) Results
8.11 Compendial Testing
8.12 Standard Operating Procedures
8.13 Analytical Documents
8.14 Quality Assurance
8.15 Summary
List of Abbreviations
References
9 Stability Program Supporting Pharmaceutical Products
9.1 Introduction
9.2 Regulatory Requirements for Stability Testing
9.3 Types of Stability Studies
9.4 Stability Program
9.5 Stability Chambers
9.6 Stability Sample Management
9.7 Stability Protocol
9.8 Stability Report
9.9 Annual Product Review (APR)
9.10 Summary
List of Abbreviations
References
10 Laboratory Information Management System (LIMS) and Electronic Data
10.1 Introduction
10.2 Analytical and Quality Data Management
10.3 Quality System
10.4 Process Control in Quality Management
10.5 Material Management
10.6 Product Release
10.7 Stability Studies
10.8 Cleaning Validation – Contamination Control
10.9 Equipment Management (Metrology)
10.10 Laboratory Operations
10.11 Automation of Risk Management
10.12 Automated Training Management
10.13 SOPs and Document Management
10.14 Audit Management and Compliance
10.15 Corrective and Preventive Actions (CAPAs)
10.16 Change Management
10.17 Computer Systems Validation
10.18 Evolution in the Data Integrity Regulation
10.19 Data Integrity
10.20 Quality Data
10.21 Benefits of Computerized Systems
10.22 Big Data
List of Abbreviations
References
Index
End User License Agreement
List of Tables
Chapter 1
Table 1.1 Organizations involved in the ICH process.
Table 1.2 The regional harmonization groups.
Table 1.3 ICH membership.
Table 1.4 Categories of the ICH guidelines.
Table 1.5 ICH quality guidelines.
Table 1.6 ICH safety guidelines.
Table 1.7 ICH efficacy guidelines.
Table 1.8 ICH multidisciplinary guidelines.
Chapter 3
Table 3.1 List of the typical sources of errors in pH measurements.
Table 3.2 Summary of different modes of HPLC.
Table 3.3 Parameters to be included in system suitability tests.
Table 3.4 List of examples of injection sequences showing system suitabilit...
Table 3.5 Qualification parameters.
Table 3.6 Wavelengths regions.
Chapter 4
Table 4.1 Typical CQA of an immediate release oral solid dosage form (table...
Table 4.2 Example of an FMEA analysis.
Table 4.3 Initial FMEA analysis on blending.
Table 4.4 Final FMEA analysis on blending.
Table 4.5 Example of risk assessment on drug substance attributes.
Table 4.6 Factors to be studied for the blending step.
Table 4.7 The DoE study design of factors from Table 4.6.
Table 4.8 Mean, standard deviation, and relative standard deviation calcula...
Table 4.9 Table of t‐values.
Table 4.10 Assay results from the uncoated and coated tablets.
Table 4.11 Q value.
Chapter 5
Table 5.1 Phases of analytical instrument qualification.
Table 5.2 ICH Reporting thresholds for drug substance (API) and finished dru...
Table 5.3 Four most common analytical procedures and specific tests for dru...
Table 5.4 Types of in‐process tests.
Chapter 6
Table 6.1 Typical number of replicates recommended for different analytical...
Table 6.2 Suggested acceptance criteria used for accuracy.
Table 6.3 Suggested acceptance criteria used for precision.
Chapter 7
Table 7.1 Biopharmaceutics classification system (BCS) classifications.
Chapter 8
Table 8.1 Typical purposes of documentation.
Table 8.2 Examples of records vs reports.
Table 8.3 21 CFR 211 Subpart J – general requirements.
Table 8.4 21 CFR 211 Subpart J – 211.180(e) and (f) general requirements.
Table 8.5 21 CFR 211 Subpart J – equipment cleaning and use log.
Table 8.6 21 CFR 211 Subpart J – component, drug product container, closure,...
Table 8.7 21 CFR 211 Subpart J – master production and control records.
Table 8.8 21 CFR 211 Subpart J – batch production and control records.
Table 8.9 21 CFR 211 Subpart J – 211.192 production record review.
Table 8.10 21 CFR 211 Subpart J – 211.194 laboratory records.
Table 8.11 Typical decimal places and significant figures in specification d...
Table 8.12 Limit of impurity results.
Table 8.13 Examples of different options to report impurity results.
Table 8.14 Typical release tests for new drug substance and drug product.
Table 8.15 Typical disposition categories for materials.
Table 8.16 Data used in the evaluation of specifications.
Table 8.17 Example of a tablet specification.
Table 8.18 Example of dissolution specifications.
Table 8.19 Responsibilities of analyst and supervisor.
Table 8.20 Example of a checklist for HPLC method validation of a solid form...
Table 8.21 Comparison between a procedural SOP and metrology SOP.
Table 8.22 Quality assurance checklist.
Table 8.23 Planning for a method validation.
Table 8.24 Checklist to evaluate and prepare for chromatographic method vali...
Table 8.25 Quality program to be reviewed in a laboratory audit.
Table 8.26 Example of a checklist to audit a pharmaceutical laboratory.
Chapter 9
Table 9.1 ICH time points for stability protocols.
Table 9.2 ICH storage conditions for stability studies.
Table 9.3 Definitions of significant changes in data stored at accelerated c...
Table 9.4 Typical conditions for semipermeable container.
Table 9.5 Example of stability protocol to monitor clinical supplies.
Table 9.6 Example of stability protocol for API/drug substance.
Table 9.7 Example of stability protocol for drug product.
Table 9.8 Example of a simple bracketing design.
Table 9.9 Example of a two‐thirds factorial matrixing design.
Chapter 10
Table 10.1 List of quality metrics to be evaluated for LIMS and QMS.
List of Illustrations
Chapter 1
Figure 1.1 FDA offices that interact closely with the pharmaceutical industr...
Figure 1.2 FDA offices overseeing the development of policies and guidelines...
Figure 1.3 The ICH organization.
Figure 1.4 The ICH steering committee.
Figure 1.5 Development of a typical drug product.
Figure 1.6 Collaboration of analytical development department with other fun...
Figure 1.7 Regulatory requirements considered during product development....
Figure 1.8 The drug development process.
Figure 1.9 FDA Form 1571 – investigational new drug (IND) application.
Chapter 2
Figure 2.1 Example of a personnel training record.
Figure 2.2 Example of an employee training record for continued GMP training...
Figure 2.3 Example of a form used for a pH meter in the analytical lab.
Figure 2.4 Example of a form used for an analytical balance.
Chapter 4
Figure 4.1 Quality‐by‐design (QbD) concept.
Figure 4.2 Basic elements of the risk management process.
Figure 4.3 Example Ishikawa diagram of tablet manufacturing process.
Figure 4.4 Relationship between knowledge space, design space, and control s...
Chapter 5
Figure 5.1 Target true value.
Figure 5.2 High and low precision illustration.
Figure 5.3 Accuracy and precision examples.
Figure 5.4 Monitoring compounds at various wavelengths.
Figure 5.5 Separation of impurities A, B, and C from the peak of interest (P...
Figure 5.6 HPLC chromatograms of samples of fluoxetine hydrochloride from fo...
Figure 5.7 The linearity of standard solutions in chromatographic analysis....
Figure 5.8 Nonlinearity of standard solutions in chromatographic analysis....
Chapter 6
Figure 6.1 Summary of transfer options of analytical procedure.
Figure 6.2 Decision tree for transfer options.
Figure 6.3 Example of an analytical method transfer plan.
Figure 6.4 Example of a transfer gap analysis checklist.
Figure 6.5 Example of an analytical qualification protocol.
Chapter 7
Figure 7.1 Example of modern dissolution test equipment.
Figure 7.2 USP Apparatus 1: basket.
Figure 7.3 USP Apparatus 2: paddle.
Figure 7.4 USP Apparatus 3: reciprocating cylinder.
Figure 7.5 USP Apparatus 4: flow‐through cell.
Figure 7.6 USP Apparatus 5: paddle over a disk with “Sandwich or Watch Glass...
Figure 7.7 USP Apparatus 6: rotating cylinder.
Figure 7.8 USP Apparatus 7: five designs of reciprocating holder.
Figure 7.9 Typical dissolution curve for immediate release.
Chapter 8
Figure 8.1 Lifecycle of analytical data.
Figure 8.2 Documentation practices.
Figure 8.3 Example of a form to request for analytical testing.
Figure 8.4 Flow of laboratory testing.
Figure 8.5 Quality investigation of suspect analytical data.
Figure 8.6 Example of a Laboratory Investigation Report (LIR).
Figure 8.7 Hierarchy of analytical documentation systems.
Figure 8.8 Six quality systems.
Figure 8.9 Supporting quality systems to support overall QMS.
Figure 8.10 Managing the lifecycle of analytical procedure.
Chapter 9
Figure 9.1 Setup excursion study and long‐term stability study. (a) Cycling ...
Figure 9.2 Flow of a stability study.
Figure 9.3 Chronological order of stability activities to support a drug pro...
Figure 9.4 Example of a sample pull date deviation form.
Figure 9.5 Example of a stability test cancelation.
Figure 9.6 Example of an inventory form for a stability chamber.
Figure 9.7 Example of an inventory adjustment form.
Figure 9.8 Example of a stability protocol.
Figure 9.9 Example of a stability data record.
Chapter 10
Figure 10.1 Big data – types of analytics.
Figure 10.2 Big data 6V‐model. http://www.ngi‐summit.org/wp‐content/material...
Figure 10.3 Paper vs computerized cross contamination.
Figure 10.4 An example of the FMEA table.
Figure 10.5 Validation drivers.
Figure 10.6 GAMP categories.
Figure 10.7 GAMP validation V‐model.
Figure 10.8 Number of FDA warning letters from 2011 to 2017.
Figure 10.9 Data integrity ALCOA.
Figure 10.10 MHRA data integrity guideline. http://academy.gmp‐compliance.or...
Guide
Cover Page
Title Page
Copyright Page
Dedication Page
Einstein Quotation
Preface
About the Editor
Biographies of Contributing Authors
Editorial Notes
Acknowledgments
Table of Contents
Begin Reading
Index
Wiley End User License Agreement
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Analytical Testing for the Pharmaceutical GMP Laboratory
Edited by
Kim Huynh‐Ba
Pharmalytik LLC
Newark, DE, USA
This edition first published 2022© 2022 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 athttp://www.wiley.com/go/permissions.
The right of Kim Huynh‐Ba to be identified as the author of the editorial material in this work has been asserted in accordance with law.
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Limit of Liability/Disclaimer of WarrantyIn 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: Huynh‐Ba, Kim, author.Title: Analytical testing for the pharmaceutical GMP laboratory / Kim Huynh‐Ba, M.Sc., PMP, FAAPS, Chief Executive Officer and Managing Director, Pharmalytik LLC Newark, DE, USA.Description: First edition. | Hoboken, NJ : Wiley, 2022. | Includes index.Identifiers: LCCN 2021031990 (print) | LCCN 2021031991 (ebook) | ISBN 9781119120919 (hardback) | ISBN 9781119680468 (adobe pdf) | ISBN 9781119680437 (epub)Subjects: LCSH: Pharmaceutical industry–Quality control. | Analytical chemistry. | Drugs–Testing. | Drug development.Classification: LCC RS189 .H89 2022 (print) | LCC RS189 (ebook) | DDC 615/.19–dc23LC record available at https://lccn.loc.gov/2021031990LC ebook record available at https://lccn.loc.gov/2021031991
Cover Design: WileyCover Image: © DocsR/iStock/Getty Images
This book is dedicated to the memory of Dr. James Shea, who passed suddenly after completing the technical review of several chapters of this book.
“Education is not the learning of facts, but the training of the mind to think.”
Albert Einstein
Preface
Pharmaceutical analysis is an important and integral part of determining drug quality, including identity, purity, and stability of the active drug substance and drug product. In addition, related programs are necessary to ensure the physical and chemical performance of the medicines. With such critical functions, it requires analysts to acquire a solid understanding of analytical chemistry and a thorough appreciation of pharmaceutical requirements to address these challenges.
The pharmaceutical industry is one of the major employers of science graduates, especially analytical chemistry majors. However, many students graduate with a limited background in pharmaceutical analysis or related programs and are not prepared for employment in this industry. Those who do will find the transition from academia to this type of industry difficult due to a lack of formal training in most academic institutions. Rather, the training/mentoring program is often performed by the pharmaceutical industry, formally or informally, to develop these individuals into productive employees as soon as possible. Therefore, this type of training program is conducted as a part of the company's regulatory and quality programs.
In addition, many scientists are interested in changing their career to join the healthcare industry and they found that there is a lack of introductory materials in applying GMP regulations and connecting it with industry best practices for the pharmaceutical laboratory.
This book is intended to be an introductory book for pharmaceutical scientists, who are directly or indirectly involved with the laboratories supporting drug development and manufacturing processes. It covers the main activities for new and experienced scientists, including analytical chemists, pharmaceutical scientists, pharmacists, quality control professionals, and quality assurance specialists. This book will be useful for students in undergraduate or graduate Schools of Pharmacy in the United States. It could also benefit the pharmaceutical analysis course or online regulatory or quality programs.
There are other books that cover Good Manufacturing Practices; however, there is not a good mix of regulations, guidelines, and practical procedures in these books. My goal is to deliver a concise and comprehensive book, yet affordable, for this area that can be used in an industrial or academic environment. It focuses on the smaller molecular weight drug substances and products. The biological/biotechnological field and related bioanalytical analyses are beyond the scope of this introductory book and thus are not covered; however, you might find some similarities in GMP practices.
The quality of pharmaceutical products must meet the required regulatory specifications, related guidelines, good manufacturing, and laboratory practices prior to commercialization. Therefore, this book starts with the structure and roles of the Food and Drug Administration (FDA) and the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) in Chapter 1, Drug Regulations and the Pharmaceutical Laboratories, with core guidelines and critical regulations. Chapter 2, Good Manufacturing Practices (GMPs) and the Quality Systems, introduces the Good Manufacturing Practices (GMPs), specifically the Code of Federal Regulations (CFR) Title 20 and 21, and furthers the discussion leading to laboratory quality systems that support the pharmaceutical industry.
Chapter 3, Common Methods in Pharmaceutical Analysis, introduces the common analytical methods used in pharmaceutical laboratories. The emphasis of this chapter is more on specific and stability‐indicating, and instrument techniques rather than classical wet chemistry methods. This chapter also contains several examples of analytical techniques used in the laboratory for the release and stability testing of drug substances and drug products. Chapter 4, Control Strategies for Pharmaceutical Development, discusses control strategies established from quality systems with case studies and calculation examples.
Analytical data are important in the evaluation of the drug substance and drug product; thus, the qualification of analytical procedures is critical. Chapter 5, Development and Validation of Analytical Procedures, covers the validation of the analytical procedures, and Chapter 6, Transfer of Analytical Methods, discusses the different types of transfer strategies to ensure the procedure can be successfully transferred to another laboratory. Chapter 7, Dissolution Testing in the Pharmaceutical Laboratory, introduces dissolution testing as a performance test for pharmaceutical products, such as the extended‐release dosage forms, aerosols, or inhalers.
Chapter 8, Analytical Data and the Documentation System, discusses the product specifications and challenges of investigations. Good documentation and data reporting practices are the focus of this chapter. Specifications must be set for the release time and the shelf‐life of the drug in the market. The heavy workload in any pharmaceutical quality control laboratory is to support the stability program. Therefore, Chapter 9, Stability Program Supporting Pharmaceutical Products, covers the most critical regulations and practices necessary to set up an effective stability program. The final chapter is Chapter 10, Laboratory Information Management System (LIMS) and Electronic Data, covering the analytical data, including electronic data. This chapter emphasizes the integrity of the results and how they are used in the evaluation of pharmaceutical products.
The order of the chapters is carefully laid out to provide the reader with a logical flow of materials to explore Good Manufacturing Practices (GMPs) that apply to critical quality systems supporting the pharmaceutical laboratories. However, each chapter is written in a way that it can stand on its own for ease of reading or downloading. Therefore, each chapter contains its own table of content, a list of acronyms, a reference list, a list of tables and/or figures. The included regulations and guidances are up to date at the time of publishing. However, readers should be aware that these guidelines may change due to the dynamic of the drug development and commercialization process.
I hope you enjoy reading these chapters as much as we enjoyed writing them. It is my sincere desire that this book will help those who work in the pharmaceutical laboratories seeking to learn more about GMP regulatory compliance today and for years to come.
Kim Huynh‐Ba
About the Editor
Kim Huynh‐Ba, M.Sc., PMP, FAAPS, has almost 30 years of experience in analytical development, project management, strategic drug development, and stability sciences. She is currently the Chief Executive Officer and Managing Director of Pharmalytik LLC, where she provides consulting and training services to pharmaceutical companies, including companies operating under FDA's Consent Decree, on harmonization and optimization of analytical practices since 2003. Before Pharmalytik, Kim was the Director of Pharmacopeial Education Department at the United States Pharmacopeia (USP), where she was responsible for their onsite and online education programs worldwide. Kim has held several technical and quality positions with increased responsibilities at Astra Zeneca (formerly ICI Americas), DuPont Merck, DuPont Pharmaceuticals, Bristol Myers Squibb, and Wyeth Vaccines.
As an education advocate, Kim teaches cGMP compliance and quality topics for several global organizations such as the American Chemical Society (ACS), American Association of Pharmaceutical Scientists (AAPS), Pittsburgh Conference, and many other international training groups. She is an Adjunct Professor at Temple University School of Pharmacy, Widener University, and Illinois Institute of Technology (IIT), teaching Pharmaceutical Analysis, Good Manufacturing Practices (GMP), ICH Quality Guidelines, and Quality Audit and Inspection for their graduate programs of regulatory compliance.
Kim is a member of the Executive Committee of the Governing Board of Eastern Analytical Symposium (EAS) and was their 2013 President. She is a member of the United States Pharmacopeia (USP) Council of Experts (2015–2025), chairing the Small Molecules 4 Expert Committee, responsible for the psychiatric, psychoactive, neuromuscular, radio‐pharmaceutical and imaging products. She was the Chair of the USP Good Documentation Practices Expert Panel and a member of USP's Impurities of Drug Products Expert Panel. From 2010 to 2013, Kim also participated in the Consumer Healthcare Product Association's (CHPA) Stability and Impurities Breakout Groups as a technical advisor. Kim is a member of the AAPS Publication Committee, Chair of the Stability Focus Group, and serves on the Steering Committees of Chemistry, Manufacturing and Controls (CMC) and Pharmaceutical Impurities Focus Groups. Kim is a recipient of the 2008 Service Award of Analysis and Pharmaceutical Quality Section and the 2008 Recognition Award of Regulatory Section of AAPS. She received the 2001 DuPont Pharmaceutical Company Asian American Leadership Award. In 2020, Kim was named a Fellow of the AAPS organization. In 2021, she received the EAS Distinguished Services Award.
Kim has authored over 30 technical publications, 17 book chapters, and delivered over 400 presentations, both domestic and internationally, in the areas of compliance and quality. She is the editor of the Handbook of Stability Testing in Pharmaceutical Development: Regulations, Methodologies and Best Practices (2008), which is known as a notable reference in Stability sciences, and Pharmaceutical Stability Testing to Support Global Markets (2010).
Kim completed her graduate degree in Analytical Chemistry from Villanova University with the late Dr. Robert Lee Grob. She earned the Project Management certification from the University of Delaware. Kim has a Bachelor of Science in Chemistry and a Bachelor of Arts in Mathematics from the Millersville University of Pennsylvania.
For corresponding, contact: [email protected] or www.pharmalytik.com.
Biographies of Contributing Authors
Susan Cleary, BSc., MBA, is the Director of Product Development at Novatek International. Prior to this, Susan was the Program Manager and Lead Software Engineer for three major applications: Finished Products Analyzer, Raw Materials Management, and Environmental Monitoring software programs. Susan has more than 20 years of experience in designing, developing, implementing, validating, and managing large‐scale LIMS and Quality Management software projects, while working with both Pharmaceutical and Biotech companies to capture their requirements and provide fully validated turnkey systems. Susan specializes in Laboratory Information Management, Environmental Monitoring, and Cleaning Validation processes and works with clients to streamline their procedures and manage their data more effectively.
Parsa Famili, MSc., is the President and CEO of Novatek. He has held senior management positions in quality departments of several North American pharmaceutical companies before joining Novatek. He has participated and completed several FDA, EMEA, TGA, and Health Canada audits. Parsa was also an instructor of Chemistry and Biochemistry at Vanier College in Montreal and has shared his more than 25 years of practical experience in many published chapters and articles in various journals and books. He is an international speaker at ISPE, IVT, PDA, IPA, CBI, among others.
Vivian A. Gray, B.Sc., has spent the last 42 years involved in all aspects of dissolution testing and evaluating new dissolution technology. She enjoyed an extensive career with the United States Pharmacopeia and DuPont‐Merck Pharmaceutical Company. She has over 50 publications, including 6 book chapters. Vivian has co‐authored a book on dissolution testing called Handbook of Dissolution Testing, Third Edition, published in 2004. She served on the PhRMA Dissolution Committee from 1997 to 2001. Vivian received the American Society of Hospital Pharmacists Research and Education Foundation 1982 Research Award. In 2002, she formed V.A. Gray, Consulting, LLC to support dissolution testing and became the Managing Director of Dissolution Technologies in June 2003.
Walter Holberg, B. Sc., is the Director of Chemistry, Manufacturing, and Controls for Rockwell Medical, where he oversees and manages new product development, API and drug product manufacturing, and analytical development. Walter has worked in or managed GMP laboratories for 30 years and has extensive knowledge of current analytical methodologies, US, and international regulatory requirements, and GLPs and GMPs as they relate to analytical development and manufacturing. He currently lives near Philadelphia and spends his free time restoring a classic air‐cooled Porsche 911.
Kim Huynh‐Ba, MSc., PMP, FAAPS, is the Managing Director of Pharmalytik, LLC, where she provides consulting and training services to pharmaceutical companies since 2003. She has almost 30 years in analytical development, project management, strategic drug development and stability sciences. Kim has held several technical and quality positions at Astra Zeneca (formerly ICI Americas), DuPont Merck, DuPont Pharmaceuticals, Bristol Myers Squibb, and Wyeth Vaccines. She is an Adjunct Professor at Temple University‐School of Pharmacy, and Illinois Institute of Technology (IIT) teaching a variety of topics on GMPs and compliance audit. She serves on the Board of Eastern Analytical Symposium and the editorial board of Journal of Validation Technology. She has published over 30 publications and 17 book chapters. She was named Fellow of American Associate of Pharmaceutical Scientists in 2020.
Judy Lin, MSc., RAC., Associate Director of Regulatory Affairs – CMC, Novartis Pharmaceutical Corp. Prior to joining Novartis, she worked in the analytical development departments of Bristol‐Myers Squibb Company and Merck & Co. She has more than 20 years of experience in pharmaceutical development with numerous successful worldwide approvals of new chemical/ biologics drugs. She is an expert in CMC development strategy for projects ranging from early development to post‐approval submissions. Judy serves on the Board of Eastern Analytical Symposium and was their 2020 President.
Linda L. Ng, Ph.D., is a Senior Director, Strategic Regulatory Affairs and Quality Management with Fresenius‐Kabi. Previously she was with FDA, CDER for 25 years, serving 20 years in the CMC New Drugs Review Divisions and last 5 years in the Compliance Division. Linda was the FDA Analytical Method Expert with numerous nationally and internationally invited presentations through the years. In addition, she served for two terms on a USP Expert Committee and AOAC International Task Force and Advisory Committee.
Editorial Notes
The technical information presented, and practical recommendations, are drawn from our experience and knowledge. Review perspectives may vary depending on individual technical backgrounds, personal experiences, and discussion preferences. In addition, information may be drawn from industry practices or web links that appear to be valid at the time of publication. Great care has been taken in the individual development of each chapter to ensure accuracy as much as possible. However, we assume no responsibility nor can we endorse the material referenced in this publication.
Acknowledgments
As an educator, I have found it difficult to find a textbook that is not only to be used in the classroom, but one that an analyst can also use in his/her day‐to‐day work. Therefore, the writing and publication of this book was undertaken. After 30 years in the pharmaceutical industry, I would have thought that GMP regulations would have been outdated by now. However, I am constantly amazed with the new scientific programs developed based on fundamental GMPs to effectively manage the regulatory compliance and build the quality systems. All of this is possible because of the collaboration and transparency of the regulatory authorities and the industry practitioners.
This work cannot be accomplished without the encouragement and support from many individuals. Each chapter was reviewed by at least three individuals of various disciplinaries to provide clarity and technical applicability to the readers. I want to express my sincere thanks and appreciation to the following individuals: D.J. Doan, Yangming Lin, Oscar Liu, Karen Lucas, Greg Martin, Mariann Neverovitch, Richard Nguyen, Leonel Santos, Ani Sarkahian, James Shea (late), Thomas Rosanske, and Martin Williamson. I also want to thank Mr. Richard Nguyen and Ms. Karishma Kumar for their assistance in formatting and proofing my chapters.
Lastly and most importantly, I want to thank my family for their support: my husband, Thai Huynh‐Ba, and my sons, John Huynh‐Ba and James Huynh‐Ba. I also want to thank my parents, Mr. Cao Nguon Hong and Mrs. Bach Ngoc Kim Hoa, who have always stood by me to make sure I do not give up on what I started. To them, I am indebted with my gratitude.
Winter 2021,
Kim Huynh‐Ba
1Drug Regulations and the Pharmaceutical Laboratories
Kim Huynh‐Ba
Pharmalytik LLC, Newark, DE, USAUSA
TABLE OF CONTENTS
1.1 Introduction
1.2 Food and Drug Administration: Roles and Its Regulations
1.2.1 Code of Federation Regulations
1.2.2 FDA Guidance Documents
1.2.3 FDA Manual of Policies and Procedures
1.3 International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) and Its Role
1.3.1 ICH Background
1.3.2 ICH Structure
1.3.3 ICH Organization
1.3.3.1 Steering Committee
1.3.3.2 Global Cooperation Group
1.3.3.3 MedDRA Management Board
1.3.3.4 Working Groups
1.3.3.5 Secretariat
1.3.3.6 Coordinators
1.3.4 ICH Topics
1.3.4.1 Quality Guidelines
1.3.4.2 Safety Guidelines
1.3.4.3 Efficacy Guidelines
1.3.4.4 Multidisciplinary Guidelines
1.4 Pharmaceutical Analysis
1.4.1 Analytical Testing
1.4.2 Interaction of the Analytical Development Department and Other Functional Areas
1.4.3 Drug Development Process
1.4.3.1 Toxicological Phase
1.4.3.2 Investigational New Drug
1.4.3.3 Clinical Phase
1.4.3.4 Registration Phase
1.4.3.5 New Drug Application
1.4.3.6 Post‐Approval Phase
1.5 Summary
List of Abbreviations
References
1.1 Introduction
The pharmaceutical industry is a complex business in the global economy. As well as having to meet profit margins, issues such as safety considerations, effectiveness assurance, regulatory compliance, patent protection, labeling, and the supply chain, can significantly affect the development and commercialization of pharmaceutical products. Regulatory agencies define testing requirements, and these requirements vary from country to country where the products are marketed. This chapter explains different regulatory bodies and how they affect the testing of pharmaceutical products.
1.2 Food and Drug Administration: Roles and Its Regulations
The regulatory body in the United States (US), the Food and Drug Administration (FDA) (www.fda.gov), is within the Department of Health and Human Services (HHS). The primary responsibility of the FDA is to protect the public health, and pharmaceutical companies must maintain the quality of the drug products through their shelf life based on current regulations. The FDA consists of the Office of the Commissioner and four Directorates overseeing the core functions of the agency: Medical Products and Tobacco, Foods, Global Regulatory Operations and Policy, and Operations. Each of these offices has numerous centers and offices with the goal of protecting public health. Figure 1.1 shows a few centers that interact closely with the pharmaceutical industry.
The Center for Drug Evaluation and Research (CDER) ensures that safe and effective drugs are available to improve the health of people in the United States. This center regulates over the counter (OTC) and prescription drugs, including biological therapeutics, brand drugs, and generic drugs. The Center for Biologics Evaluation and Research (CBER) regulates biological products for human use. The Center for Devices and Radiological Health (CDRH) oversees the medical devices and radiation‐emitting products. The Center for Veterinary Medicine (CVM) regulates the manufacture and distribution of drugs, devices, and food additives that will be given to animals, including animals from which human foods are derived, as well as food additives and drugs that are given to companion animals. The Center for Food Safety and Applied Nutrition (CFSAN) provides support for safety and labeling issues relating to food and cosmetics. For additional information, visit the FDA webpage at www.fda.gov/ [1, 2].
Although residing under the same umbrella, these FDA centers may have different policies specific to the products they review, and pharmaceutical laboratories interact with the different centers based on their products. Since FDA issues regulations that are legally enforced, the agency works closely with the industry to develop various guidances and initiatives that support the development of new medicines for US consumers. For the past several years, the FDA has gone through many reforms to be more effective in providing support to the industry (Figure 1.2).
Figure 1.1 FDA offices that interact closely with the pharmaceutical industry.
Figure 1.2 FDA offices overseeing the development of policies and guidelines.
1.2.1 Code of Federation Regulations
The code of federal regulations (CFR) is the set of final regulations that are published in the federal register, which companies must comply with while distributing their products in the United States [1]. The CFR encompasses 50 broad areas subject to federal regulations. Section 21 of the CFR contains regulations pertaining to food and drug products. The federal law governing pharmaceutical labs can be found in 21 CFR Part 210 – Current Good Manufacturing Practices (CGMP) in Manufacturing Process, Packing, or Holding of Drug; General, and 21 CFR Part 211 – CGMP for Finished Pharmaceuticals [2].
Given these regulations are written into law and are legally enforceable, the FDA audits manufacturers and laboratories and conducts inspections of total quality systems. When a manufacturer fails to meet CGMP requirements, its products are considered adulterated and FDA can take legal action without proving that the product is contaminated. Any violations in CGMPs can result in observations, warning letters, consent decree, or criminal prosecution. These regulations also include the requirement that manufacturers wanting to market a prescription product in the United States submit an appropriate application to the FDA.
1.2.2 FDA Guidance Documents
In addition to the CFR, the FDA also issues guidances to introduce current views of the agencies on different subjects. FDA guidance documents provide additional guidelines for the operation of manufacturing facilities, laboratories, etc., and the format and content of the application that is not included in the CFR, helping to maintain consistency among agency reviewers or application owners. The guidance documents are not laws and thus are not enforceable; however, many find that these documents provide more specific details and better clarity than the requirements listed in the regulations. Scientific justifications are necessary if the application does not follow this guidance. The FDA typically issues these guidelines after they collaborate with other regulatory agencies, such as the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) and industry [3–5].
1.2.3 FDA Manual of Policies and Procedures
The FDA creates operating manuals listing internal policies and procedures to assist in achieving consistency in application review and operational activities. These documents are publicly available to provide transparency and a better understanding of regulatory policies and agency responsibilities.
When a pharmaceutical manufacturer develops a new drug, it must understand the regulations of quality systems supporting their processes. The manufacturer must conduct its work correctly the first time, as the cost of noncompliance can be enormous. A manufacturer can request meetings with the appropriate center to discuss various scientific and regulatory aspects of their application prior to submission to assure that their development strategy is acceptable. Since 2016, the FDA has required all regulatory submissions to be filed electronically for ease of review and communication [4, 6, 7].
1.3 International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) and Its Role
In the late 1980s, to harmonize regional regulatory requirements, many industry expert groups collaborated with regional agencies to discuss technical requirements for drug submissions. This section goes into further detail on the collaboration within the global pharmaceutical industry [6].
1.3.1 ICH Background
The fundamental purpose of a regulatory agency is to protect public health; therefore, it can deny market access to pharmaceutical products if the product’s development does not meet the agency’s requirements. These requirements usually vary from country to country and often with similar but slight, and sometimes significant, variations in registration requirements. This key factor drives up the cost of development, expands resources, and delays market access to high‐quality medicines. Recognizing this problem, in the early 1990s, regulators and industry representatives from the European Union (EU), Japan, and the United States formed a group called the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) (www.ich.org) [5, 6, 8]. On 23 October 2015, this group was reformed as a nonprofit legal entity under Swiss Law and named International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH). The objective of the ICH is to provide guidelines for harmonizing their testing requirements, application, and approval processes of a pharmaceutical product intended for human use. These three regions represent 85% of the worldwide pharmaceutical consumption. The ICH members, collectively representing 18 nations, have now harmonized over 50 guidelines to ensure the quality, safety, and efficacy of their pharmaceutical products. ICH guidelines have been widely used and adopted in several countries voluntarily, and several non‐ICH members have also adopted these guidelines [8].
The purpose of the ICH is to streamline the process of registration requirements and avoid unnecessary duplication of work. Additionally, ICH provides a forum for dialogue between health authorities and industry on the disparities concerning requirements of the United States, Europe, and Japan. This group has developed several guidelines that are acceptable for regulatory review by these regions.
1.3.2 ICH Structure
Each ICH member has two active parties, one representing the regulatory agencies and the other representing industry manufacturers. The two parties work closely together to ensure the smooth development of guidelines that address industry concerns while maintaining standards for people’s safety. The ICH members consist of the European Union (EU) and the European Federation of Pharmaceutical Industries’ Associations (EFPIA), the Ministry of Health, Labor and Welfare (MHLW), the Japan Pharmaceutical Manufacturers Association (JPMA), the US Food and Drug Administration (FDA), and Pharmaceutical Research and Manufacturers of America (PhRMA). ICH has a nonvoting member, the International Federation of Pharmaceutical Manufacturers & Associations (IFPMA), and three observers whose roles are to act as liaisons between ICH and non‐ICH countries and regions, the World Health Organization (WHO), the European Free Trade Area (EFTA), and Canada [6, 8].
1.3.3 ICH Organization
The ICH organization has six main sections as illustrated in Figure 1.3. They are described as follows.
Figure 1.3 The ICH organization.
Figure 1.4 The ICH steering committee.
Source: Based on the International Council on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use.
1.3.3.1 Steering Committee
The steering committee (SC) has two representatives from each of the six parties and one representative from each of the four observing parties. Their roles are to determine the policies and procedures, select topics for harmonization, and monitor the progress of these initiatives. Figure 1.4 illustrates the composition of the ICH steering committee and Table 1.1 provides a list of the organizations [8].
1.3.3.2 Global Cooperation Group
Representatives from eight Drug Regulatory Authorities/Department of Health (Australia, Brazil, China, Taipei, India, Republic of Korea, Russia, and Singapore) and several regional harmonization groups (Table 1.2) are invited to the ICH meetings to listen to ICH technical topics discussed and invited to nominate technical experts for the expert working groups or the implementation working groups.
1.3.3.3 MedDRA Management Board
This board is responsible for standardizing the dictionary of medical terminology and overseeing the activities of the MedDRA.
1.3.3.4 Working Groups
There are two different working groups within the ICH structure: Expert Working Groups (EWGs) and Implementation Working Groups (IWGs). The EWG is responsible for developing harmonized guidelines that meet the objectives according to the Concept Paper and Business Plan. The Steering Committee assigns each selected topic to an EWG. The EWG represents six parties, the observers, along with any interested Industry members, such as the International Generic Pharmaceutical Alliance (IGPA), World Self‐Medication Industry (WSMI), and other Pharmacopoeias. These groups are industry specialists on the topics discussed, and they participate in the timeframe in which their topic is being discussed and reviewed. Membership of an EWG can vary depending on the need. The IWGs are tasked to recommend the process to facilitate the implementation of existing guidelines.
Table 1.1 Organizations involved in the ICH process.
Source: Based on the International Council on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use.
Abbreviation
Organization
Swissmedic
Swiss agency for therapeutic products
FDA
Food and drug administration
PhRMA
Pharmaceutical research and manufacturers of America
MHLW
Ministry of health, labor, and welfare
JPMA
Japan pharmaceutical manufacturers association
EFPIA
European federation of pharmaceutical industries and associations
EU
European Union
WHO
World Health Organization
IFPMA
International federation of pharmaceutical manufacturers & associations
Table 1.2 The regional harmonization groups.
Abbreviation
Group
APEC
Asia‐Pacific Economic Cooperation
ASEAN
Association of Southeast Asian Nations
EAC
East African Community
GCC
Gulf Central Committee
PANDRH
Pan‐American Network for Drug Regulatory Harmonization
SADC
Southern African Development Community
Other than the above two Working Groups, other groups such as Informal Working Groups or Discussion Groups are formed to either develop harmonization activity or discuss scientific considerations.
1.3.3.5 Secretariat
The primary duty of the Secretariat involves the preparation of documentation for all ICH meetings. The International Federation of Pharmaceutical Manufacturers and Associations (IFPMA) provides the Secretariat in Geneva, Switzerland.
1.3.3.6 Coordinators
The coordinators are the main contact between the six‐member parties and the Secretariat, ensuring that ICH documents are distributed properly.
The SC and EWGs develop the work and process of ICH, while the Secretariat and Coordinators have administrative duties.
ICH Conferences take place every two to three years with a series of meetings taking place twice a year. The location of these meetings rotates among the three‐member regions. Table 1.3 lists the ICH members. More detailed information on the ICH structure can be found at www.ich.org.
1.3.4 ICH Topics
In the early 1990s, the ICH initiated 11 topics for harmonization. Approximately 20 years later, ICH developed close to 100 guidelines for the three regions, divided into four main categories: quality (Q), safety (S), efficacy (E), and multidisciplinary (M), as listed in Table 1.4. The following is a list of guidelines that ICH started and currently has available. New guidelines continue to be developed [8].
Table 1.3 ICH membership.
Membership type
Member organizations
Voting members
Pharmaceutical Research and Manufacturers of America (PhRMA)
Food and Drug Administration (FDA)
European Federation of Pharmaceutical Industries and Associations (EFPIA)
European Union (EU)
Ministry of Health, Labor, and Welfare (MHLW)
Japan Pharmaceutical Manufacturers Association (JPMA)
Nonvoting members
International Federation of Pharmaceutical Manufacturers and Associations (IFPMA)
Official observers
Canada,
World Health Organization (WHO)
The European Free Trade Association (EFTA)
Interested parties
Pharmacopeia(s)
International Generic Pharmaceutical Industry (IGPA)
World Self‐medication Industry (WSMI)
Table 1.4 Categories of the ICH guidelines.
Category
ICH guideline
Quality
Chemical and pharmaceutical quality assurance
Safety
In vitro
and
in vivo
preclinical studies
Efficacy
Clinical studies involving human subject(s)
Multi‐disciplinary
Cross‐cutting topics that do not fit in the above
1.3.4.1 Quality Guidelines
The quality guidelines cover various aspects, such as stability, temperature, trial duration, light sensitivity, residual solvent, impurities, etc. Table 1.5 lists the currently available quality guidelines.
Table 1.5 ICH quality guidelines.
Guidelines
Quality topics
Q1A
Stability
Q2
Analytical validation
Q3A–Q3D
Impurities
Q4–Q4B
Pharmacopeia
Q5A–Q5B
Quality of biotechnological products
Q6A–Q6B
Specifications
Q7
Good Manufacturing Practices
Q8
Pharmaceutical development
Q9
Quality risk management
Q10
Pharmaceutical quality system
Q11
Development and manufacture of drug substance
Q12
Lifecycle management
Q13
Continuous manufacturing of drug substances and drug products
Q14
Analytical procedure development
1.3.4.2 Safety Guidelines
The safety guidelines deal with scientific issues, which include carcinogenicity, genotoxicity, pharmacokinetics, and toxicokinetics (including reproductive toxicity testing), in a detailed manner. The guidelines in this section cover toxicity issues during the testing phase and preclinical safety evaluations. Table 1.6 lists the ICH safety guidelines.
1.3.4.3 Efficacy Guidelines
The efficacy guidelines address technical and administrative issues. Technical issues include the effectiveness of long‐term treatment for non–life‐threatening conditions and dose–response information. Administrative issues include clinical safety data management and standards for successful expedited reporting, maintenance of the ICH guidelines, structure, and content of clinical safety reports, and sets of ethnic factors for the acceptability of foreign clinical data. Table 1.7 lists the ICH efficacy guidelines.
1.3.4.4 Multidisciplinary Guidelines
The multidisciplinary guidelines contain topics that do not fit into one of the above three sections. Many of these sections (Table 1.8) are tools that the ICH used to help create a medical dictionary with appropriate terminology and to create a common marketing application for new pharmaceutical products.
Table 1.6 ICH safety guidelines.
Guidelines
Safety topics
S1A–S1C
Carcinogenic studies
S2
Genotoxicity studies
S3A–S3B
Toxicokinetics and pharmacokinetics
S4
Toxicity testing
S5
Reproductive toxicology
S6
Biotechnological products
S7A–S7B
Pharmacology studies
S8
Immunotoxicology study
S9
Nonclinical evaluation for anticancer pharmaceuticals
S10
Photo‐safety evaluation
S11
Nonclinical pediatric safety
S12
Nonclinical biodistribution studies for gene therapy products
Table 1.7 ICH efficacy guidelines.
Guidelines
Efficacy topics
E1
Clinical safety for drugs used in long‐term treatment
E2A–E2F
Pharmacovigilance
E3
Clinical study reports
E4
Dose–response studies
E5
Ethnic factors
E6
Good clinical practices
E7
Clinical trials in geriatric population
E8
General considerations for clinical trials
E9
Statistical principles for clinical trials
E10
Choice of control group in clinical trials
E11
Clinical trials in pediatric population
E12
Clinical evaluation by therapeutic category
E14
Clinical evaluation
E15
Definitions in pharmacogenetics/pharmacogenomics
E16
Qualification of genomic biomarkers
E17
Multiregional clinical trials
E18
Genomic sampling
E19
Safety data collection
E20
Adaptive clinical trials
1.4 Pharmaceutical Analysis
Although the quality of the manufacturing process defines a drug product, pharmaceutical analysis is crucial to verify drug product quality. CFR defines the quality of a drug product as identity, purity, and stability of the drug, whereas analytical procedures are developed to monitor physical, chemical, biological, and microbiological properties at release and throughout its shelf life. In essence, Current Good Manufacturing Practices (CGMP) are critical aspects of analytical functions that apply to pharmaceutical laboratories.
Figure 1.5 simplifies the development of a drug formulation. All formulations contain at least one active pharmaceutical ingredient (API), also known as a drug substance. Formulation studies are performed by combining this API with excipients (usually non‐active inert materials) to define the best version of the finished product. A drug product can be a solid dosage form (such as a tablet or capsule) or a liquid dosage form (such as syrup or injectable), or it can also be in the form of a transdermal patch or inhaler. The packaging system is studied for commercialization and the exact nature of which depends on the country or geographic region of interest.
Table 1.8 ICH multidisciplinary guidelines.
Guidelines
Multidisciplinary topics
M1
MedDRA terminology
M2
Electronic standards
M3
Nonclinical safety studies
M4
Common technical document
M5
Data elements and standards for drug dictionaries
M6
Gene therapy
M7
Genotoxic impurities
M8
Electronic common technical document (eCTD)
M9
Biopharmaceutics classification system‐based biowaivers
M10
Bioanalytical method validation
M11
Clinical electronic structured harmonized protocol (CeSHarP)
M12
Drug interaction studies
M13
Bioequivalence for immediate‐release solid oral dosage forms
Figure 1.5 Development of a typical drug product.
Many factors affect the quality of drug products during their shelf life. The main factor is the quality of the API at the time of manufacture and during storage. Also, the interaction between the API and excipients is critical. The selection of the dosage form and the container closure packaging system are important to maintain the quality of the drug product. Environmental storage conditions and handling of the finished products are important to maintain such that the quality of the product remains within its established criteria [3, 7, 9].
If the drug quality changes, it may put patient safety at risk. Drug products may become subpotent with time, and new or unknown impurities that have developed may be toxic.
While developing the drug product, the analytical department must establish appropriate analytical procedures to monitor the quality of the products, and operational programs are also needed to check for the performance of the drug. When the manufacturing process is not well developed and controlled, it may lead to product investigation and recalls. Therefore, a comprehensive understanding and knowledge of regulatory and analytical requirements are imperative for any pharmaceutical scientist to perform the manufacturing and analytical procedures effectively.
1.4.1 Analytical Testing
Analytical procedures are developed in pharmaceutical laboratories to verify acceptance testing of APIs, drug products, in‐process samples, raw materials, devices, packaging components, investigational samples, and equipment cleansing. In addition to the release and stability testing, analytical procedures are also used for method validation, method transfer, instrument qualification, laboratory qualification, laboratory investigation, technology transfer, process validation, and investigation. The key information section below lists the common terms used in the pharmaceutical industry for analytical analysis.
Common terms used in pharmaceutical analysis
Act: A written ordinance from the governing body. For example, federal food, drug, and cosmetic act.
Batch: A specific manufactured quantity that is intended to have uniform character and quality within specified limits. It is produced from a single manufacturing order during the same cycle of manufacture. For a continuous manufacturing process, it is a specific identified amount of material produced in a unit of time or a quantity in a manner that assures it has a uniform character and quality within specified limits.
Lot: A batch or a specifically identified portion of the batch.
A lot or batch number: A unique, distinctive combination of letters, numbers, or symbols from which the complete history of the manufacturing, packing of the batch/lot can be determined.
Theoretical yield: A calculated quantity that would be produced based upon the number of components used in the absence of any loss or error.
Percent of theoretical yield: Actual yield divided by the theoretical yield.
Representative sample: A number of units that are drawn randomly based on established criteria and intended to represent the material being sampled.
Component: Any ingredient intended for use in the manufacture of the drug product.
Drug product: Finishe d dosage form that contains an API in general, but not necessarily, in association with inactive ingredients.
Placebo: Finished dosage form that contains no API in general.
1.4.2 Interaction of the Analytical Development Department and Other Functional Areas
Developing a drug product is a concerted team effort within a pharmaceutical manufacturer. Figure 1.6 shows the six different areas within a typical pharmaceutical company, and as can be seen, there is close collaboration among these departments. The primary focus of the formulation development department is to develop the formulation of the drug product used for clinical studies. The chemical process department synthesizes the API and is responsible for scaling up the process of manufacturing the API and drug products. The packaging development department selects the appropriate container and closure for the drug product. The stability department sets up stability studies to support the storage condition and shelf life. The raw materials department is responsible for acquiring and releasing raw materials used. The quality assurance group is responsible for the compliance status of the site, while the regulatory affairs group is responsible for all regulatory submissions. Shipping and handling areas are important, too, especially for materials that require specific handling and storage conditions.
Figure 1.6 Collaboration of analytical development department with other functions.
To provide adequate controls and support to the development chain, the analytical department develops testing procedures to release and monitor raw materials and drug products at all stages. Moreover, the analytical development department can also interact with the toxicological, drug metabolism and pharmacokinetics, process development, and clinical supplies manufacturing departments.
Analysts and their managers use the analytical results to make business decisions such as setting specifications, determining the dosage forms, monitoring processes, releasing raw materials or finished products, or determining product expiration and storage conditions. Therefore, the analysts must have a broad understanding of the pharmaceutical operations such as the drug development process, handling of samples, and applications of analytical methods, so that they can apply their experience to develop appropriate methods, troubleshoot the problems if needed, and investigate analytical issues as it arises.
As well, analysts must keep up with changes in regulatory and compliance requirements. Regulations continue to change as the pharmaceutical industry goes global in its operations. Analysts must be aware of new regulations and changes in industry practices to stay current and in compliance [3, 10, 11].
