Handbook of Modern Pharmaceutical Analysis PDF

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HANDBOOK OF MODERN PHARMACEUTICAL ANALYSIS This Is Volume III of SEPARATION SCIENCE AND TECHNOLOGY A reference series edited by Satinder Ahuja HANDBOOK OF MODERN PHARMACEUTICAL ANALYSIS Edited by Satinder Ahuja Ahuja Consulting Calabash, North Carolina Stephen Scypinski RW Johnson Pharmaceutical Re...

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HANDBOOK OF MODERN PHARMACEUTICAL ANALYSIS

This Is Volume III of SEPARATION SCIENCE AND TECHNOLOGY A reference series edited by Satinder Ahuja

HANDBOOK OF MODERN PHARMACEUTICAL ANALYSIS Edited by

Satinder Ahuja Ahuja Consulting Calabash, North Carolina

Stephen Scypinski RW Johnson Pharmaceutical Research Institute Raritan, New Jersey

San Diego San Francisco

New York

Boston

London

Sydney Tokyo

This book is printed on acid-free paper. Copyright © 2001 by Academic Press All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopy, recording, or any information storage and retrieval system, without permission in writing from the publisher. The appearance of the code at the bottom of the first page of a chapter in this book indicates the Publisher’s consent that copies of the chapter may be made for personal or internal use of specific clients. This consent is given on the condition, however, that the copier pay the stated per-copy fee through the Copyright Clearance Center, Inc. (222 Rosewood Drive, Danvers, Massachusetts 01923), for copying beyond that permitted by Sections 107 or 108 of the U.S. Copyright Law. This consent does not extend to other kinds of copying, such as copying for general distribution, for advertising or promotional purposes, for creating new collective works, or for resale. Copy fees for pre-2001 chapters are as shown on the title pages; if no fee code appears on the title page, the copy fee is the same as for current chapters. 01 $35.00. The information provided in this handbook is compiled from reliable sources but the authors, editor, and the publisher cannot assume any responsibility whatsoever for the validity of all statements, illustrations, data, procedures, and other related materials contained herein or for the consequence of their use. ACADEMIC PRESS A Harcourt Science and Technology Company 525 B Street, Suite 1900, San Diego, CA 92101-4495, USA http://www.academicpress.com Academic Press Harcourt Place, 32 Jamestown Road, London, NW1 7BY, UK Library of Congress Catalog Number: 2001088201 International Standard Book Number: 0-12-045555-2 Printed in the United States of America 00 01 02 03 HP 9 8 7 6 5 4

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CONTENTS

CONTRIBUTORS xiii PREFACE xvii

1

Modern Pharmaceutical Analysis: An Overview SATINDER AHUJA

I. II. III. IV. V. VI. VII.

2

Identity and Purity Requirements 2 Bioavailability/Dissolution Requirements 4 Regulatory Considerations 5 Regulatory Compliance 8 International Conference on Harmonization 9 Global CMC NDA 9 Highlights of Modern Pharmaceutical Analysis 10 References 22

Combinatorial Chemistry and High-Throughput Screening in Drug Discovery and Development KEN APPELL, JOHN J. BALDWIN, AND WILLIAM J. EGAN

I. Introduction 24 II. Combinatorial Methods 25 v

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CONTENTS

III. IV. V. VI. VII. VIII. IX. X. XI. XII. XIII. XIV.

Methods for Structural Assignment 26 Diversity 28 Druglikeness 28 Designing Combinatorial Libraries with Optimal ADME Properties 28 Existing Computational Methods for ADME Properties 30 Optimization Philosophy 35 Applying Existing ADME Models to Combinatorial Library Design 37 The Future of ADME Modeling 38 High-Throughput Screening and Combinatorial Chemistry 39 Assay Plate Formats: Move to Miniaturization 40 Nonseparation or Homogeneous Assays 43 Identification of Receptor Antagonists for Chemokine Receptor and Bradykinin-1 by Screening a 150,000-Member Combinatorial Library 44 XV. Structure-based Design of Somatostatin Agonists 47 XVI. Conclusions 48 References 49

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Solid-State Analysis HARRY G. BRITTAIN

I. II. III. IV. V.

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Introduction 57 Properties Associated with the Molecular Level 58 Properties Associated with the Particulate Level 65 Properties Associated with the Bulk Level 73 Summary 81 References 81

Degradation and Impurity Analysis for Pharmaceutical Drug Candidates KAREN M. ALSANTE, ROBERT C. FRIEDMANN, TODD D. HATAJIK, LINDA L. LOHR, THOMAS R. SHARP, KIMBERLY D. SNYDER, AND EDWARD J. SZCZESNY

I. II. III. IV. V. VI. VII.

Residual Solvents and Water 86 Purposeful Degradation Studies 95 Isolation and Identification of Impurities/Degradants 119 Mass Spectrometry in Identification of Impurities 127 Role of NMR 147 Reference Standards 166 Summary 168 References 168

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CONTENTS

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Preformulation Studies EDWARD LAU (deceased)

I. II. III. IV. V.

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Introduction 173 Preformulation Studies 180 Analytical Techniques and Instruments for Preformulation Studies 214 Regulatory Requirements for Preformulation 224 Summary and Conclusions 226 Appendix 1 227 Appendix 2 229 Appendix 3 232 References 232

Solid Dosage-Form Analysis PHILIP J. PALERMO

I. Introduction 235 II. Physicochemical Characterization Techniques 241 III. Near-Infrared Analysis 252 IV. Automation 257 V. Future Directions 262 VI. Summary 263 VII.Acknowledgments 263 References 263

7

Parenteral Dosage Forms GREGORY A. BIRRER, SATYA S. MURTHY, AND JIE LIU

I. Characteristics of Parenteral Dosage Forms 270 II. Pharmaceutical Analysis During Formulation and Process Development 271 III. Analytical Testing for Finished Parenteral Products 272 IV. Packaging Components Testing 273 V. Process Development Support 274 VI. In-Process Testing 275 VII. Release Testing 276 VIII. Raw Material Testing 278 IX. Validation of Analytical Procedure 279 X. Stability-Indicating Methods 281 XI. Method Transfer 281 XII. Cleaning Method Validation 282 XIII. Admixture Studies 282 XIV. Microbiological Testing of Parenteral Formulations 283 XV. Sterility Testing 284

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CONTENTS

XVI. XVII. XVIII. XIX. XX. XXI. XXII. XXIII. XXIV. XXV. XXVI. XXVII. XXVIII.

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Bacterial Endotoxin Testing 290 Particulate Matter Testing 292 Bioburden Testing of Parenteral Product Solution 294 Introduction to Cleaning Validation 298 Swab Selection (Recovery and Compatability Studies) 298 Technician Qualification 298 Sampling 299 Acceptance Criteria 300 Methods of Analysis 301 Grouping/Matrix Approach 301 Validation Protocol 302 Validation Report 302 Summary 302 References 303

New Drug Delivery Systems DAVID C. PANG

I. II. III. IV. V. VI. VII. VIII. IX.

9

Introduction 307 Oral Drug Delivery 308 Direct Drug Delivery 310 Dermatological Delivery System 311 Tumor-Targeted Drug Delivery Systems 311 Biodegradable Drug Delivery System 313 Protein Drug Delivery System 315 Devices 319 Summary 323 References 323

Compendial Testing CHRISTINE F. RICHARDSON

I. Introduction 325 II. A Brief History of the United States Pharmacopeia 326 III. Compendial Testing for Formulated Products and Active Ingredients 327 IV. Which Compendium to Use and When to Use It 340 V. Validation 340 VI. Harmonization of Testing Methods for Multicountry Submission 342 VII. Conclusions 343 VIII. Acknowledgments 344 References 344

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CONTENTS

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Method Development HENRIK T. RASMUSSEN

I. II. III. IV. V. VI. VII. VIII. IX.

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Introduction 345 Overview of Separation Methods 346 High-Performance Liquid Chromatography 349 Thin-Layer Chromatography 374 Gas Chromatography 375 Supercritical-Fluid Chromatography 376 Capillary Electrophoresis 379 Conclusions 383 Summary 383 References 384

Setting Up Specifications IAN E. DAVIDSON

I. II. III. IV. V. VI.

12

Introduction 387 Setting Specifications at Different Stages of Drug Development 389 International Conference on Harmonization Guidelines 393 Pharmacopeias and Specifications 410 Statistical Considerations in Setting Specifications 411 Summary 412 References 412

Validation of Pharmaceutical Test Methods JONATHAN B. CROWTHER

I. II. III. IV. V. VI. VII. VIII. IX. X.

Background and Chapter Overview 415 Validation Terminology and Definitions 418 Method Development and Its Influence on Method Validation 419 Validation Requirements of The Method 428 Validation Documentation 428 Validation Experimentation 429 Method Transfer 436 Revalidation 438 Reference Standards 438 Summary 441 Acknowledgments 442 References 442

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CONTENTS

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Stability Studies JESSICA CHA, JOSEPH S. RANWEILER, PHILIP A. LANE

I. II. III. IV. V. VI.

14

Introduction 445 Operational Issues 446 Excipients 461 Drug Substance 463 Drug Product 471 Summary 480 Glossary 480 Appendix 482 References 483

Analytical Methodology Transfer STEPHEN SCYPINSKI

I. II. III. IV. V. VI. VII. VIII. IX.

15

Introduction 485 The Drug Development Process 486 Types of Method Transfer 487 Requirements and Elements of Analytical Technology Transfer Technical Transfer Time Line/Project Plan 492 Analysis of Results/Statistical Packages 493 Analyst Certification and Training 494 Transfer of Technical Ownership 494 Chapter Summary 497 References 497

489

Pharmaceutical Analysis Documentation HITESH CHOKSHI AND KATHLEEN SCHOSTACK

I. II. III. IV. V. VI. VII. VIII.

Scope 499 Introduction 500 Pharmaceutical Analysis During Product Life Cycle 500 Regulatory Documents 510 Compliance Documents 516 Research Documents 520 Summary 521 Conclusions 522 Appendix I: References for CMC Guidances 522 Appendix II: U.S. NDA Table of Contents—Analytical Documentation 525

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CONTENTS

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An Innovative Separation Platform: Electrophoretic Microchip Technology LIAN JI JIN, JEROME FERRANCE, ZHILI HUANG, AND JAMES P. LANDERS

I. II. III. IV. V. VI.

Introduction 529 Microchip Fabrication 531 Detection Techniques 535 Pharmaceutical Potential 545 Concluding Remarks 549 Summary 549 References 549

INDEX

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CONTRIBUTORS

Numbers in parentheses indicate the pages on which the authors’ contributions begin.

Satinder Ahuja (1) Ahuja Consulting, 330 Middleton Drive, Suite 803, Calabash, North Carolina 28467 Karen M. Alsante (85) Pfizer Global Research and Development Division, Analytical Research and Development, P.O. Box 4077, Pfizer Inc., Eastern Point Road, Groton, Connecticut 06340 Ken Appell (23) Pharmacopeia, Inc., P.O. Box 5350, Princeton, New Jersey 08543-5350 John J. Baldwin (23) Pharmacopeia, Inc., P.O. Box 5350, Princeton, New Jersey 08543-5350 Gregory A. Birrer (269) Baxter Anesthesia Critical Care, Baxter Healthcare Medication Delivery, 95 Spring Street, New Providence, New Jersey 07974 Harry G. Brittain (57) Center for Pharmaceutical Physics, 10 Charles Road, Milford, New Jersey 08848 Jessica Cha (445) The R. W. Johnson Pharmaceutical Research Institute, P.O. Box 300, Route 202, Raritan, New Jersey, 08869 Hitesh Chokshi (499) Hoffmann-La Roche, Inc. 340, Kingsland Street, Nutley, New Jersey 07110

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CONTRIBUTORS

Jonathan B. Crowther (415) Ortho-Clinical Diagnostics, 1001 U.S. Highway 202, Raritan, New Jersey, 08869-0606 Jan E. Davidson (387) Aventis Pharmaceuticals, P.O. Box 6800, Route 202206, Bridgewater, New Jersey 08560 William J. Eagan (23) Pharmacopeia, Inc., P.O. Box 5350, Princeton, New Jersey 08543-5350 Judy Estrada (269) Gensia-Sicor Pharmaceuticals, 19 Hughes Street, Irvine, California 92618-1902 Jerome Ferrance (ch. 16) Department of Chemistry, University of Virginia, McCormick Road, Charlottesville, Virginia 22901 Robert C. Friedmann (85) Pfizer Global Research and Development Division, Process Research and Development, P.O. Box 4077, Pfizer Inc., Eastern Point Road, Groton, Connecticut 06340 Todd D. Hatajik (85) Pfizer Global Research and Development Division, Analytical Research and Development, P.O. Box 4077, Pfizer Inc., Eastern Point Road, Groton, Connecticut 06340 Zhili Huang (529) Department of Chemistry, University of Virginia, McCormick Road, Charlottesville, Virginia 22901 Lian Ji Jin (ch. 16) Department of Chemistry, University of Virginia, McCormick Road, Charlottesville, Virginia 22901 James P. Landers (529) Department of Chemistry, University of Virginia, and Department of Pathology, University of Virginia Health Science Center, Charlottesville, Virginia 22901 Philip A. Lane (445) The R. W. Johnson Pharmaceutical Research Institute, P.O. Box 300, Route 202, Raritan, New Jersey 08869 Edward P. Lau (173) (deceased) E. L. Associates, 102 Lanark Road, Wilmington, Delaware 19807 Jie Liu (269) Baxter Anesthesia Critical Care, Baxter Healthcare Medication Delivery, 95 Spring Street, New Providence, New Jersey 07974 Linda L. Lohr (85) Pfizer Global Research and Development Division, Analytical Research and Development, P.O. Box 4077, Pfizer Inc., Eastern Point Road, Groton, Connecticut 06340 Satya S. Murthy (269) Baxter Anesthesia Critical Care, Baxter Healthcare Medication Delivery, 95 Spring Street, New Providence, New Jersey 07974 Philip J. Palermo (235) Purdue Pharma L. P., 444 Saw Mill River Road, Ardsley, New York 10502 David C. Pang (307) American Association of Pharmaceutical Scientists, 2107 Wilson Boulevard, #700, Arlington, Virginia 22201-3046 Joseph S. Ranweiler (445) The R. W. Johnson Pharmaceutical Research Institute, P.O. Box 300, Route 202, Raritan, New Jersey 08869 Henrik T. Rasmussen (345) Analytical Chemistry Research and Development, The R. W. Johnson Pharmaceutical Research Institute, 1000 Route 202, Raritan, New Jersey 08869

CONTRIBUTORS

xv

Christine F. Richardson (325) Quality Assurance, Novartis Pharmaceuticals Corporation, 25 Old Mill Road, Suffern, New York 10901 Thomas R. Sharp (85) Pfizer Global Research and Development Division, Analytical Research and Development, P.O. Box 4077, Pfizer Inc., Eastern Point Road, Groton, Connecticut 06340 Kathleen Schostack (499) Hoffmann-La Roche, Inc. 340 Kingsland Street, Nutley, New Jersey 07110 Kimberly D. Snyder (85) Pfizer Global Research and Development Division, Analytical Research and Development, P.O. Box 4077, Pfizer Inc., Eastern Point Road, Groton, Connecticut 06340 Edward J. Szczesny (85) Pfizer Global Research and Development Division, Analytical Research and Development, P.O. Box 4077, Pfizer Inc., Eastern Point Road, Groton, Connecticut 06340 Stephen Scypinski (485) Analytical Chemistry Research and Development, The R. W. Johnson Pharmaceutical Research Institute, P.O. Box 300, Route 202, Raritan, New Jersey 08869

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PREFACE

Today, modern pharmaceutical analysis entails much more than the analysis of active pharmaceutical ingredients or the formulated product. There are many reasons for this change, not the least of which is our ability to better understand physicochemical properties of pharmaceutical compounds through the use of advanced instrumental methods. Furthermore, there is a need for quality assurance of pharmaceutical products throughout their shelf life. This requires that we study interactions of the drug substance with the excipients in the presence of residual solvents, as well as other potential degradation reactions that may occur in the formulated product over a period of time under various stress conditions (these include conditions they may be subjected to during storage or shipment in the final package configuration). The pharmaceutical industry is under increased scrutiny from the government and public interest groups to contain costs and yet consistently deliver to market safe, efficacious products that fulfill unmet medical needs. As part of the crusade to hold the line on prescription drug prices, the industry has streamlined its operations with respect to drug discovery, development, and manufacturing. The drive to bring innovative products to market faster without negatively impacting quality or safety has caused every company to challenge all existing processes and to look for ways to increase capacity, shorten time lines, and “do more with less.” Coupled with this initiative is the migration of companies from functional arrangements to team-based organizational structures.

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PREFACE

Analytical chemistry has played a major role in the changes facing the pharmaceutical industry today. Traditionally viewed as a service organization, the analytical department has become a significant partner in the drug development process. Indeed, the demand for analytical data has become a critical path activity for the selection of candidate molecules for full development. Working under sample-limited conditions and in full compliance of current good manufacturing practices (cGMP), pharmaceutical analysts are called on to generate accurate and precise data—almost on demand. The science and technology utilized today, coupled with the new regulations that are now binding, have made pharmaceutical analysis much more complicated compared to what it was as little as ten years ago. This text fills the need for a handbook that is current with respect to the philosophy of analytical chemistry support for drug discovery, development, and post-market support. It is our intention to present the role of analytical research and development as a part of the overall process. For this reason, the chapters are organized in more of a process-driven manner rather than pure function or technique. In all cases, a large number of references are provided for those readers desiring a more in-depth discussion of a particular subject. The pharmaceutical analyst plays a major role in assuring identity, safety, efficacy, purity, and quality of a drug product. Safety and efficacy studies require that drug substance and drug product meet the established identity and purity as well as bioavailability/dissolution requirements (Chapter 1). The need for pharmaceutical analysis is driven largely by regulatory requirements. This stems from the fact that regulatory considerations loom large when a commercial product does not meet its purported quality. Regulatory requirements and compliance issues have been discussed thoroughly in this book. Significant discussion has also been provided regarding the International Conference on Harmonization (ICH) that has attempted to harmonize the requirements by regulatory authorities in the United States, Europe, and Japan. New drug discovery and candidate optimization processes in the pharmaceutical industry are being extensively carried out these days with combinatorial chemistry coupled with high-throughout screening (Chapter 2). Also, lately an increasing degree of attention is being given to the physical properties of the solids that can compromise a dosage form (Chapter 3). Good understanding of physicochemical behavior of pharmaceutical solids ensures a better selection of formulation. The selection process includes identification of process-related impurities and products and studying degradation mechanisms at an early stage. This allows adequate time for improvements in the drug substance synthesis and formulation to prevent the occurrence of these impurities and degradation products (Chapter 4). Preformu...