Leachables and Extractables Handbook E-Book

• Herausgeber: John Wiley & Sons
• Kategorie: Wissenschaft und neue Technologien
• Sprache: Englisch

Seitenzahl: 1082

Veröffentlichungsjahr: 2012

Beschreibung

A practical and science-based approach for addressing toxicological concerns related to leachables and extractables associated with inhalation drug products

Packaging and device components of Orally Inhaled and Nasal Drug Products (OINDP)—such as metered dose inhalers, dry powder inhalers, and nasal sprays—pose potential safety risks from leachables and extractables, chemicals that can be released or migrate from these components into the drug product. Addressing the concepts, background, historical use, and development of safety thresholds and their utility for qualifying leachables and extractables in OINDP, the Leachables and Extractables Handbook takes a practical approach to familiarize readers with the recent recommendations for safety and risk assessment established through a joint effort of scientists from the FDA, academia, and industry. Coverage includes best practices for the chemical evaluation and management of leachables and extractables throughout the pharmaceutical product life cycle, as well as:

• Guidance for pharmaceutical professionals to qualify and risk-assess container closure system leachables and extractables in drug products

• Principles for defining toxicological safety thresholds that are applicable to OINDP and potentially applicable to other drug products

• Regulatory perspectives, along with an appendix of key terms and definitions, case studies, and sample protocols

Analytical chemists, packaging and device engineers, formulation development scientists, component suppliers, regulatory affairs specialists, and toxicologists will all benefit from the wealth of information offered in this important text.

Leseprobe

Table of Contents

Cover

Title page

Copyright page

ROBERT KROES: IN MEMORIAM

PREFACE

ACKNOWLEDGMENTS

CONTRIBUTORS

PART I: DEVELOPMENT OF SAFETY THRESHOLDS, SAFETY EVALUATION, AND QUALIFICATION OF EXTRACTABLES AND LEACHABLES IN ORALLY INHALED AND NASAL DRUG PRODUCTS

CHAPTER 1 OVERVIEW OF LEACHABLES AND EXTRACTABLES IN ORALLY INHALED AND NASAL DRUG PRODUCTS

1.1 INTRODUCTION

1.2 LEACHABLES IN OINDP: THE ISSUE IN DETAIL

1.3 REGULATORY BACKGROUND

1.4 WHY DO WE NEED SAFETY THRESHOLDS?

1.5 SAFETY THRESHOLDS AND THEIR APPLICATION TO LEACHABLES IN OINDP

1.6 SUMMARY

CHAPTER 2 A GENERAL OVERVIEW OF THE SUITABILITY FOR INTENDED USE REQUIREMENTS FOR MATERIALS USED IN PHARMACEUTICAL SYSTEMS

2.1 INTRODUCTION

2.2 AN OVERVIEW OF THE ISSUE OF SUITABILITY FOR INTENDED USE

2.3 ADDITIVE INTERACTIONS

2.4 UTILIZATION OF RUBBER AND PLASTIC MATERIALS IN PHARMACEUTICAL SYSTEMS: OPPORTUNITIES AND ISSUES

CHAPTER 3 CONCEPT AND APPLICATION OF SAFETY THRESHOLDS IN DRUG DEVELOPMENT

3.1 INTRODUCTION

3.2 THRESHOLDS AND RISK ASSESSMENT

3.3 THRESHOLDS AND DRUG DEVELOPMENT

3.4 THRESHOLDS AND GENOTOXIC EFFECTS

3.5 CONCLUSION

CHAPTER 4 THE DEVELOPMENT OF SAFETY THRESHOLDS FOR LEACHABLES IN ORALLY INHALED AND NASAL DRUG PRODUCTS

4.1 INTRODUCTION

4.2 DERIVATION OF THE SCT

4.3 DERIVATION OF THE QT

4.4 CONCLUSION

CHAPTER 5 THE ANALYTICAL EVALUATION THRESHOLD (AET) AND ITS RELATIONSHIP TO SAFETY THRESHOLDS

5.1 INTRODUCTION

5.2 LEACHABLES/EXTRACTABLES CHARACTERIZATION AND PROFILING

5.3 DETERMINATION OF THE AET

5.4 ANALYTICAL SENSITIVITY AND THE AET: WHAT IS MODERN ANALYTICAL CHEMISTRY CAPABLE OF?

5.5 SPECIAL CASE COMPOUNDS

5.6 SUMMARY AND CONCLUSIONS

CHAPTER 6 SAFETY THRESHOLDS IN THE PHARMACEUTICAL DEVELOPMENT PROCESS FOR OINDP: AN INDUSTRY PERSPECTIVE

6.1 INTRODUCTION

6.2 USE OF SAFETY THRESHOLDS IN OINDP: HISTORY AND BACKGROUND

6.3 QUALIFICATION OF LEACHABLES

6.4 USE OF THRESHOLDS FOR QUALIFICATION: DECISION TREE

6.5 CONCLUSION

CHAPTER 7 THE CHEMISTRY AND TOXICOLOGY PARTNERSHIP: EXTRACTABLES AND LEACHABLES INFORMATION SHARING AMONG THE CHEMISTS AND TOXICOLOGISTS

7.1 INTRODUCTION

7.2 INFORMATION EXCHANGE AMONG CHEMISTS AND TOXICOLOGISTS

7.3 CASE STUDIES

7.4 CONCLUSION

CHAPTER 8 USE OF SAFETY THRESHOLDS IN THE PHARMACEUTICAL DEVELOPMENT PROCESS FOR OINDP: U.S. REGULATORY PERSPECTIVES

8.1 REGULATORY HISTORY RELATED TO CONTROL OF LEACHABLES AND EXTRACTABLES IN ORALLY INHALED AND NASAL DRUG PRODUCTS

8.2 HISTORICAL PERSPECTIVE OF THE USE OF SAFETY THRESHOLDS FOR OINDP BY THE FDA

8.3 IDENTIFICATION OF A SAFETY THRESHOLD BASED ON POTENTIAL FOR SYSTEMIC TOXICITY

8.4 IDENTIFICATION OF A SAFETY THRESHOLD BASED ON THE POTENTIAL FOR RESPIRATORY TOXICITY

8.5 IDENTIFICATION OF A SAFETY THRESHOLD BASED ON THE POTENTIAL FOR MUTAGENIC/CARCINOGENIC POTENTIAL

8.6 COMPARISON OF FDA/DPARP PRACTICES WITH THE PQRI RECOMMENDATIONS IN RELATION TO THE SAFETY QUALIFICATION OF LEACHABLES AND EXTRACTABLES

8.7 ILLUSTRATIVE CASE EXAMPLES

8.8 CONCLUSIONS

CHAPTER 9 THE APPLICATION OF THE SAFETY THRESHOLDS TO QUALIFY LEACHABLES FROM PLASTIC CONTAINER CLOSURE SYSTEMS INTENDED FOR PHARMACEUTICAL PRODUCTS: A REGULATORY PERSPECTIVE

9.1 INTRODUCTION

9.2 A TOXICANT AND ITS ASSOCIATED RISK

9.3 THE PLASTIC USE FOR MEDICAL PACKAGING

9.4 GENERAL REGULATORY CONSIDERATIONS TO QUALIFY AN IMPURITY

9.5 THE QUALIFICATION PROCESS PROPOSED BY THE PRODUCT QUALITY RESEARCH INSTITUTE (PQRI) LEACHABLES AND EXTRACTABLES WORKING GROUP IN COMPARISON TO THAT PROPOSED BY THE EMEA

9.6 FINAL THOUGHTS

ACKNOWLEDGMENTS

PART II: BEST PRACTICES FOR EVALUATION AND MANAGEMENT OF EXTRACTABLES AND LEACHABLES IN ORALLY INHALED AND NASAL DRUG PRODUCTS

CHAPTER 10 ANALYTICAL BEST PRACTICES FOR THE EVALUATION AND MANAGEMENT OF EXTRACTABLES AND LEACHABLES IN ORALLY INHALED AND NASAL DRUG PRODUCTS

10.1 INTRODUCTION

10.2 REGULATORY ENVIRONMENT FOR EXTRACTABLES AND LEACHABLES

10.3 KEY TERMINOLOGY AND DEFINITIONS

10.4 BEST PRACTICE RECOMMENDATIONS

10.5 THE FUTURE: RESPONDING TO CURRENT TRENDS

CHAPTER 11 CHEMICAL AND PHYSICAL ATTRIBUTES OF PLASTICS AND ELASTOMERS: IMPACT ON THE EXTRACTABLES PROFILE OF CONTAINER CLOSURE SYSTEMS

11.1 INTRODUCTION

11.2 POLYMER CHEMISTRY

11.3 MATERIAL PROPERTIES

11.4 EXTRACTABLES PROFILE FOR PLASTIC AND RUBBER COMPONENTS OF CONTAINER CLOSURE SYSTEMS

11.5 ADDITIVES ANALYSIS IN POLYMERS

11.6 SUMMARY

CHAPTER 12 PHARMACEUTICAL CONTAINER CLOSURE SYSTEMS: SELECTION AND QUALIFICATION OF MATERIALS

12.1 SELECTION, CHARACTERIZATION, AND APPROPRIATE ANALYTICAL TESTING OF MATERIALS FOR THE CONTAINER CLOSURE SYSTEM (CCS): THE DEVELOPMENT CHEMISTRY AND ENGINEERING PERSPECTIVE

12.2 ANALYTICAL DATA REQUIREMENTS FOR A TOXICOLOGICAL ASSESSMENT

12.3 THE RISK ASSESSMENT OF EXTRACTABLES AND LEACHABLES: THE TOXICOLOGIST’S PERSPECTIVE

12.4 CASE STUDY: SELECTION OF A SUITABLE DRUG PRODUCT CONTAINER MATERIAL FOR A DRY POWDER INHALER

12.5 CONCLUSION

CHAPTER 13 ANALYTICAL TECHNIQUES FOR IDENTIFICATION AND QUANTITATION OF EXTRACTABLES AND LEACHABLES

13.1 INTRODUCTION

13.2 TOA

13.3 IDENTIFICATION OF EXTRACTABLES/LEACHABLES

13.4 QUANTITATIVE ANALYSIS OF EXTRACTABLES/LEACHABLES

13.5 CONCLUDING SUMMARY

CHAPTER 14 EXTRACTABLES: THE CONTROLLED EXTRACTION STUDY

14.1 INTRODUCTION AND OVERVIEW

14.2 EXTRACT GENERATION

14.3 ANALYSIS OF EXTRACT

14.4 INTERPRETATION OF THE CES

14.5 “SPECIAL CASE” COMPOUNDS

14.6 SUMMARY OF RECOMMENDED BEST PRACTICES FOR CESS

14.7 CONCLUSIONS

CHAPTER 15 EXTRACTABLES: CASE STUDY OF A SULFUR-CURED ELASTOMER

15.1 INTRODUCTION

15.2 EXTRACTABLES PROFILING (QUALITATIVE CES)

15.3 RESULTS FROM EXTRACTABLES PROFILING BY LC/MS

15.4 OPTIMIZATION OF A SELECTED GC/MS EXTRACTABLE PROFILING METHOD

15.5 SIMULATED LEACHABLES STUDY (QUALITATIVE EXTRACTABLES/LEACHABLES CORRELATION)

15.6 CONCLUSIONS AND RECOMMENDATIONS

APPENDIX: CASE STUDY 15.1: DEVELOPMENT AND EVALUATION OF A ROUTINE EXTRACTABLES TEST METHOD FOR A SULFUR-CURED ELASTOMER

APPENDIX: CASE STUDY 15.2: ANALYSIS OF 2-MERCAPTOBENZOTHIAZOLE (2-MBT) FROM SULFUR-CURED RUBBER BY LIQUID CHROMATOGRAPHY–TANDEM MASS SPECTROMETRY (LC/MS/MS) METHOD

CHAPTER 16 CASE STUDY OF A POLYPROPYLENE: EXTRACTABLES CHARACTERIZATION, QUANTITATION, AND CONTROL

16.1 INTRODUCTION

16.2 CONTROLLED EXTRACTION STUDY

16.3 DEVELOPMENT OF ANALYTICAL METHOD FOR ROUTINE CONTROL OF EXTRACTABLES

16.4 METHOD VALIDATION FOR EXTRACTABLES CONTROL IN PP MATERIAL

16.5 SUMMARY AND CONCLUSIONS

CHAPTER 17 ANALYTICAL LEACHABLES STUDIES

17.1 INTRODUCTION

17.2 ANALYTICAL METHODS

17.3 ANALYTICAL METHODS FOR SPECIAL CASE LEACHABLES

17.4 SETTING UP LEACHABLES STUDIES

17.5 ASSESSMENT OF LEACHABLES DATA

17.6 SPECIFICATION SETTING

17.7 LEACHABLES CONTROL STRATEGY

17.8 VALIDATION OF LEACHABLES METHODS

17.9 LEACHABLES ARISING FROM MATERIAL CONTACT DURING MANUFACTURING

17.10 THE FUTURE: NOVEL APPROACHES FOR LEACHABLES TESTING IN MDIS

17.11 CONCLUSION

ACKNOWLEDGMENTS

CHAPTER 18 DEVELOPMENT, OPTIMIZATION, AND VALIDATION OF METHODS FOR ROUTINE TESTING

18.1 INTRODUCTION

18.2 PURPOSES OF ROUTINE METHODS

18.3 A RISK-BASED APPROACH TO THE ROUTINE CONTROL DECISION

18.4 ROUTINE METHOD REQUIREMENTS

18.5 DEVELOPMENT AND OPTIMIZATION CONSIDERATIONS FOR ROUTINE METHODS

18.6 ASSESSMENT AND VALIDATION OF ROUTINE METHODS

18.7 PQRI RECOMMENDED BEST PRACTICES FOR ROUTINE TESTING

18.8 CONCLUSION

ACKNOWLEDGMENTS

APPENDIX: CASE STUDY 18.1: DEVELOPMENT OF A LIQUID CHROMATOGRAPHY/MASS SPECTROMETRY (LC/MS) METHOD TO DETERMINE LEACHABLES FROM PLASTIC VALVE COMPONENTS

APPENDIX: CASE STUDY 18.2: DEVELOPMENT OF A HIGH-PERFORMANCE LIQUID CHROMATOGRAPHY/ULTRAVIOLET (HPLC/UV) METHOD FOR THE DETERMINATION OF EXTRACTABLES IN POLYPROPYLENE COMPONENTS

CHAPTER 19 CRITICAL COMPONENT QUALITY CONTROL AND SPECIFICATION STRATEGIES

19.1 OVERVIEW

19.2 QUALITY BY DESIGN (QbD)

19.3 SPECIFICATION SETTING STRATEGIES

19.4 CURRENT GOOD MANUFACTURING PRACTICES (cGMP) AND COMPLIANCE

19.5 ESTABLISHING CONTROLS

19.6 CONCLUSION

CHAPTER 20 INORGANIC LEACHABLES

20.1 INTRODUCTION

20.2 SOURCES OF INORGANIC LEACHABLES

20.3 METHODS FOR EXTRACTION AND ANALYSIS OF INORGANIC COMPOUNDS

20.4 CONSIDERATIONS FOR INORGANIC LEACHABLES AND CASE STUDIES

20.5 CONCLUSION

ACKNOWLEDGMENTS

CHAPTER 21 FOREIGN PARTICULATE MATTER: CHARACTERIZATION AND CONTROL IN A QUALITY-BY-DESIGN ENVIRONMENT

21.1 INTRODUCTION: FROM QUALITY BY TESTING (QbT) TO QUALITY BY DESIGN (QbD)

21.2 INTERNATIONAL PHARMACEUTICAL AEROSOL CONSORTIUM FOR REGULATION AND SCIENCE (IPAC-RS) OINDP “BUILDING QUALITY IN” APPROACH

21.3 WHAT IS A FOREIGN PARTICLE?

21.4 PARTICLE SIZE

21.5 ALLOWABLE LIMITS

21.6 PARTICLE SIZING TECHNIQUES

21.7 PARTICLE COMPOSITION ANALYSIS

21.8 HOW TO ANALYZE OINDPS FOR FPMS

21.9 METHOD VALIDATION

21.10 CURRENTLY AVAILABLE TECHNOLOGY FOR FPM ANALYSIS

21.11 SUGGESTED STRATEGIES FOR IMPLEMENTING QbD PRINCIPLES INTO FOREIGN PM CONTROL

21.12 CONCLUSION

APPENDIXES

APPENDIX 1 EXPERIMENTAL PROTOCOL FOR CONTROLLED EXTRACTION STUDIES ON ELASTOMERIC TEST ARTICLES

A1.1 INTRODUCTION

A1.2 PURPOSE AND SCOPE OF WORK

A1.3 REGULATORY STATUS

A1.4 SAFETY AND ENVIRONMENTAL IMPACT

A1.5 TEST ARTICLES

A1.6 CHEMICALS AND EQUIPMENT

A1.7 EXTRACTION PROCEDURES

A1.8 ANALYTICAL METHODS

A1.9 ANALYTICAL PROCEDURES

A1.10 DATA EVALUATION AND REPORTING

A1.11 GLOSSARY

APPENDIX 2 EXPERIMENTAL PROTOCOL FOR CONTROLLED EXTRACTION STUDIES ON PLASTIC TEST ARTICLES

A2.1 INTRODUCTION

A2.2 PURPOSE AND SCOPE OF WORK

A2.3 REGULATORY STATUS

A2.4 SAFETY AND ENVIRONMENTAL IMPACT

A2.5 TEST ARTICLES

A2.6 CHEMICALS AND EQUIPMENT

A2.7 EXTRACTION PROCEDURES

A2.8 ANALYTICAL METHODS

A2.9 ANALYTICAL PROCEDURES

A2.10 DATA EVALUATION AND REPORTING

A2.11 GLOSSARY

APPENDIX 3 PROTOCOL ADDITION, PHASE 2 STUDIES: QUANTITATIVE CONTROLLED EXTRACTION STUDIES ON THE SULFUR-CURED ELASTOMER

A3.1 INTRODUCTION AND BACKGROUND

A3.2 TEST ARTICLE

A3.3 METHOD DEVELOPMENT

A3.4 VALIDATION PARAMETERS AND ACCEPTANCE CRITERIA

A3.5 PURPOSE

A3.6 APPARATUS

A3.7 REAGENTS AND STANDARDS

A3.8 PREPARATION OF STANDARDS AND CALIBRATION SOLUTIONS

A3.9 SAMPLE PREPARATION

A3.10 GC CONDITIONS

A3.11 INJECTION SEQUENCE

A3.12 SYSTEM SUITABILITY

A3.13 CALCULATION OF ANALYTE LEVELS IN THE ELASTOMER SAMPLE

APPENDIX 4 PROTOCOL ADDITION, PHASE 2 STUDIES: QUANTITATIVE EXTRACTABLES STUDIES ON SULFUR-CURED ELASTOMER AND POLYPROPYLENE

A4.1 INTRODUCTION AND BACKGROUND

A4.2 METHOD DEVELOPMENT

A4.3 VALIDATION PARAMETERS AND ACCEPTANCE CRITERIA

A4.4 PURPOSE

A4.5 REFERENCE STANDARDS, SOLVENTS, AND SAMPLES

A4.6 INSTRUMENTATION

A4.7 EXTRACTION PROCEDURE

A4.8 STANDARD AND SAMPLE PREPARATION

A4.9 ANALYTICAL METHODS

A4.10 QUANTITATION

A4.11 FURTHER READING

A4.12 INTRODUCTION AND BACKGROUND

A4.13 METHOD DEVELOPMENT

A4.14 VALIDATION PARAMETERS AND ACCEPTANCE CRITERIA

A4.15 INTRODUCTION AND BACKGROUND

A4.16 APPARATUS AND EQUIPMENT

A4.17 CHEMICALS/REAGENTS

A4.18 PREPARATION OF INTERNAL-STANDARD-SPIKED EXTRACTION SOLUTION

A4.19 PRE-EXTRACTION OF CELLULOSE THIMBLES

A4.20 PREPARATION AND EXTRACTION OF RUBBER SAMPLE

A4.21 SAMPLE COLLECTION

A4.22 GC WITH MSD OR FID

A4.23 CALCULATIONS (FOR DATA COLLECTED BY MS)

Index

Cover photograph taken by George Axford of Novartis Pharmaceuticals Corporation.

Copyright © 2012 by John Wiley & Sons, Inc. All rights reserved

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Published simultaneously in Canada

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Library of Congress Cataloging-in-Publication Data:

Leachables and extractables handbook : safety evaluation, qualification, and best practices applied to inhalation drug products / edited by Douglas J.

Ball . . . [et al.].

p. ; cm.

 Includes bibliographical references.

ISBN 978-0-470-17365-7 (hardback)

ISBN 978-1-118-14768-9 (epub)

ISBN 978-1-118-14769-6 (mobi)

ISBN 978-1-118-14770-2 (epdf)

 I. Ball, Douglas J.

 [DNLM: 1. Drug Delivery Systems–standards. 2. Nebulizers and Vaporizers–standards. 3. Drug Contamination–prevention & control. 4. Drug Packaging–standards. 5. Pharmaceutical Preparations–administration & dosage. 6. Risk Assessment–standards. QV 785]

 LC classification not assigned

 615'.6–dc23

2011026193

ROBERT KROES: IN MEMORIAM

This book is dedicated to the memory of Professor Robert Kroes whose scientific contributions played a vital role in developing the concept of the threshold of toxicological concern and the application of that concept to important societal issues including the safety evaluation of inhalable pharmaceutical products.

Robert Kroes, known as Bobby to his friends and colleagues around the world, was a native of The Netherlands. He received his Doctor of Veterinary Medicine in 1964. His training in Veterinary Medicine provided him with a solid scientific basis for a career grounded in comparative medicine, toxicology, and risk assessment, with a focus on the promotion of human health. In 1964, he was appointed Research Scientist at the National Institute of Public Health, which later became the National Institute of Public Health and Environment (known by the Dutch acronym, RIVM) in Bilthoven, The Netherlands. In 1970, he received a PhD in experimental pathology. He became a certified toxicologist in 1988 and a certified laboratory animal pathologist in 1989.

In 1972, he became Head of the Department of Oncology in the National Institute of Public Health. During this time in his career, he made important scientific contributions to understanding carcinogenicity. Moreover, he soon became a key contributor to major scientific committees within The Netherlands and on the international scene including the Benelux, the European Community, the Food and Agricultural Organization of the United Nations, and the World Health Organization. He was a member and, ultimately, Chair of the Dutch Scientific Council on Cancer Research of The Netherlands Academy of Science. He was a key contributor in the development of the first cancer research policy plan (1980–1984) of the Dutch Organization for Cancer Research.

In 1977, he was appointed Deputy Director of the Central Institute for Food and Nutrition Research (CIVO-TNO). In that position, he provided critical leadership for stimulating research in carcinogenesis, toxicology, biochemistry, and nutrition. In 1980, he became Director of the CIVO-TNO Institute for Toxicology and Nutrition. In 1983, he was appointed as a Director of RIVM with responsibility for managing the Institute’s toxicology and pharmacology programs. He was also responsible for guiding the institute’s advisory mission to the government with respect to the safety of chemicals. In 1988, he developed the Center for Epidemiology, further broadening the scope of RIVM’s activities. In 1988, he began a part-time association as a Professor of Biological Toxicology in the Research Institute for Toxicology of the University of Utrecht. In 1989, he became Deputy Director-General of RIVM. In 1995, he retired from his leadership roles at RIVM. In that year, he became the Scientific Director of the Institute for Risk Assessment Sciences (IRAS) of the University of Utrecht. He retired from IRAS in 2005.

The use of the word “retired” certainly did not apply to Bobby’s scientific activities. He continued to play a prominent role in many scientific advisory groups in The Netherlands and on the international scene. He had a key role in the National Institute of Toxicology. Of special note are the key roles he played in the International Life Sciences Institute (ILSI) and the related ILSI Risk Science Institute, as well as the International Union of Toxicology. He served the latter organization in multiple roles including service as president-elect and was scheduled to assume the position of president in 2007. Unfortunately, Bobby lost a courageous battle with cancer and died on December 28, 2006.

During his scientific career spanning over four decades, Bobby’s many important scientific contributions to the fields of oncology, toxicology, comparative medicine, and risk assessment are well documented in some 200 publications he authored or coauthored. As noteworthy as those contributions are, his most significant contributions came from his ability to rise above the scientific details and understand how to synthesize and integrate science and relate it to important societal health issues. He took a pragmatic view and focused on concepts and solutions to resolving complex issues. He was truly a problem solver.

This pragmatic, science-based approach was exemplified by Professor Kroes championing the use of the concept of “threshold of toxicological concern” (TTC) and its application to the safety of food and pharmaceuticals. The TTC concept refers to the establishment of a generic human exposure threshold for groups of chemicals below which there would be no appreciable risk to human health. He recognized that such a value could be identified for many chemicals, including those of unknown toxicity, by considering their chemical structure and drawing analogies from the known toxicity and modes of action of many chemicals that have been extensively studied. In December 2005, the Product Quality Research Institute organized a workshop to address the use of the TTC concept in evaluating the safety of inhalable pharmaceuticals. The organizers were unanimous in deciding that Professor Kroes should be invited to give an opening presentation to set the stage for the workshop. He gave a marvelous review of the developing field. His presentation served to energize activities that culminated in preparation of this volume. Therefore, it is indeed fitting that this volume be dedicated to the memory of Professor Robert Kroes. In using the science-based concepts championed by Professor Kroes, we celebrate the value of his contributions as a scientist and, for many of us, also have the opportunity to recall a wonderful friend who lived life to its fullest.

Roger O. McClellan, DVM, DSc (Honorary), DABVT, DABT, FATS

PREFACE

The establishment of data-based safety thresholds for leachables and extractables in orally inhaled and nasal drug products (OINDPs) is an important scientific advancement that helps OINDP manufacturers make knowledge-based safety and risk assessments for extractables and leachables and ensure the safety of their products for patient use. This book describes the development and application of these safety thresholds for OINDP and best practices for the chemical evaluation and management of extractables and leachables throughout the pharmaceutical product life cycle. Although the book addresses OINDP-specific thresholds and best practices, many of the general concepts presented can be applied to extractables and leachables assessments for other drug product types and dosage forms. The purpose of this book is to provide the reader with practical knowledge regarding how and why the thresholds were developed and how they can be applied, as well as practical approaches to management of extractables and leachables. This book is useful to analytical chemists, packaging and device engineers, formulation development scientists, component suppliers, regulatory affairs specialists, and toxicologists, all of whom must work together in the pharmaceutical development process to identify, qualify, and manage extractables and leachables.

Management of extractables and leachables in OINDP is a critical part of the OINDP life cycle. By “management” we mean a thorough understanding of (1) potential and actual extractables from a given container closure system or device material for the purposes of eliminating or limiting the levels of leachables from such materials and (2) potential safety concerns associated with these extractables and/or leachables. These issues highlight the key regulatory and industrial concern regarding leachables in OINDPs as well as other drug products—that of patient safety. Regulatory guidance identifies patient exposure to leachables via OINDPs as an area of high importance in risk assessments for these products. Over the last 30 years, scientific and regulatory thought has evolved on the best ways to approach both chemical and safety assessments of extractables and leachables in the OINDP pharmaceutical development process. A vexing challenge in these assessments has been knowing “how low to go” in determining what concentrations of extractables and leachables should be evaluated for safety assessments; that is, is there a threshold of safety that can be established for the majority of compounds that could be found as leachables or extractables in OINDPs, such that compounds existing at levels below the threshold need not undergo safety evaluation? This question has become increasingly important with the continuous advancement of chemical analysis techniques, which have been, for the past four decades, able to detect chemical compounds at picogram levels and below.

In 2006, the Product Quality Research Institute’s (PQRI) Leachables and Extractables Working Group, consisting of scientists from the United States Food and Drug Administration (FDA), academia, and industry, answered this question by developing data-based safety and analytical thresholds for OINDP extractables and leachables, and corresponding best practices for analytical evaluation of these compounds. This book is based on the information contained in the Working Group’s recommendations (publicly available through PQRI); but it provides further, more in-depth context and background, case studies, and specific regulatory perspectives and extends the concepts to practices that may be implemented across the industry.

Douglas J. Ball

Daniel L. Norwood

Cheryl L.M. Stults

Lee M. Nagao

ACKNOWLEDGMENTS

We thank the Product Quality Research Institute (PQRI) for supporting the development of this book, and the members of the PQRI Leachables and Extractables (L&E) Working Group, whose efforts formed the basis for this volume. We also thank the International Pharmaceutical Aerosol Consortium on Regulation and Science (IPAC-RS) for initiating the process to develop safety thresholds for inhalation and nasal drug products, for providing the impetus to form the PQRI L&E Working Group, and for giving its ongoing support of collaborative efforts addressing the most challenging aspects of leachables and extractables in inhalation and nasal drug products.

Mr. Ball and Dr. Norwood thank Pfizer, Inc. and Boehringer Ingelheim Pharmaceuticals, Inc., respectively, for supporting their efforts in the PQRI L&E Working Group and in the development of this book. Dr. Stults thanks Novartis Pharmaceuticals Corporation for supporting her efforts in the development of this book and thanks colleagues across the industry for their support in the preparation of this book. We extend a very large thank you to Mr. Duane Van Bergen and Ms. Kara Young of Drinker Biddle & Reath LLP, who worked extremely hard to format, harmonize, and help edit the chapters of this book. Also from Drinker Biddle & Reath LLP, we thank Ms. Mary Devlin Capizzi, Esq. for invaluable guidance on contracts and agreements; Dr. Svetlana Lyapustina and Ms. Melinda Munos for assistance in managing the work of the PQRI L&E Working Group; and Ms. Dede Godstrey and Ms. Kim Rouse for their invaluable assistance in managing and planning the meetings, teleconferences, and administrative details critical in the completion of this book. We thank Mr. Gordon Hansen, Dr. Terrence Tougas, and Ms. Devlin Capizzi for helping to guide the development of this book through the PQRI process. Finally, we thank Dr. Roger McClellan for sharing with us his inhalation toxicology expertise and for helping to facilitate the creation of the PQRI Group’s seminar on safety thresholds at the 2007 Society of Toxicology meeting, which lead to the publication of this book.

D.J.B.

D.L.N.

C.L.M.S.

L.M.N.

CONTRIBUTORS

David Alexander, DA Nonclinical Safety Ltd., Cambridgeshire, United Kingdom

Douglas J. Ball, Drug Safety Research & Development, Pfizer Global Research & Development, Groton, CT

William P. Beierschmitt, Drug Safety Research and Development, Pfizer Global Research and Development, Groton, CT

James Blanchard, Preclinical Development, Aradigm Corp, Hayward, CA

James R. Coleman, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT

Jason M. Creasey, GlaxoSmithKline, Ware, Hertfordshire, United Kingdom

Tianjing Deng, PPD, Inc., Middleton, WI

Xiaoya Ding, PPD, Inc., Middleton, WI

Barbara Falco, Barbara Falco Pharma Consult, LLC, Bethlehem, PA

Andrew D. Feilden, Smithers Rapra, Shawbury, Shropshire, United Kingdom

Thomas N. Feinberg, Catalent Pharma Solutions, LLC, Research Triangle Park, NC

Cornelia B. Field, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT

Alice T. Granger, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT

John Hand, Sr., New Rochelle High School, New Rochelle, NY

Alan D. Hendricker, Catalent Pharma Solutions, Morrisville, NC

David Jacobson-Kram, Office of New Drugs, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD

Dennis Jenke, Baxter Healthcare Corporation, Round Lake, IL

Song Klapoetke, PPD, Inc., Middleton, WI

Shuang Li, PPD, Inc., Middleton, WI

Ernest L. Lippert, American Glass Research, Maumee, OH

Timothy J. McGovern, SciLucent, LLC, Herndon, VA

Keith McKellop, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT

Kimberly Miller, West Pharmaceutical Services, Lionville, PA

Brian D. Mitchell, American Glass Research, Maumee, OH

James O. Mullis, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT

Melinda K. Munos, Drinker Biddle & Reath LLP, Washington, DC

Lee M. Nagao, Drinker Biddle & Reath LLP, Washington, DC

Kumudini Nicholas, Bureau of Pharmaceutical Sciences, Health Canada, Ottawa, Ontario, Canada

Daniel L. Norwood, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT

David Olenski, Intertek, Whitehouse, NJ

Diane Paskiet, West Pharmaceutical Services, Lionville, PA

Scott J. Pennino, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT

Fenghe Qiu, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT

Michelle Raikes, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT

Andy Rignall, Analytical Chemistry, AstraZeneca, Loughborough, United Kingdom

Suzette Roan, Pfizer Global Research & Development, Groton, CT

John A. Robson, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT

Michael A. Ruberto, Material Needs Consulting, LLC, Montvale, NJ

Arthur J. Shaw, Pfizer Analytical Research and Development, Groton, CT

John A. Smoliga, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT

Ronald D. Snyder, Schering-Plough Research Institute, Summit, NJ

Laura Stubbs, West Pharmaceutical Services, Lionville, PA

Cheryl L.M. Stults, Novartis Pharmaceuticals Corporation, San Carlos, CA

Terrence Tougas, Boehringer Ingelheim, Ridgefield, CT

W. Mark Vogel, Drug Safety Research & Development, Pfizer Global Research & Development, Chesterfield, MO

Ronald Wolff, Preclinical Safety Assessment, Novartis Institutes for Biomedical Research, Emeryville, CA

Derek Wood, PPD, Inc., Middleton, WI

Xiaochun Yu, PPD, Inc., Middleton, WI

Diego Zurbriggen, West Analytical Services, Lionville, PA

PART I: DEVELOPMENT OF SAFETY THRESHOLDS, SAFETY EVALUATION, AND QUALIFICATION OF EXTRACTABLES AND LEACHABLES IN ORALLY INHALED AND NASAL DRUG PRODUCTS

CHAPTER 1

OVERVIEW OF LEACHABLES AND EXTRACTABLES IN ORALLY INHALED AND NASAL DRUG PRODUCTS

Douglas J. Ball, Daniel L. Norwood, and Lee M. Nagao

1.1 INTRODUCTION

The purpose of this book is to provide a historical perspective on the development and application of safety thresholds in pharmaceutical development, and to discuss the development and implementation of safety thresholds for the qualification of organic leachables, a particular class of drug product impurity, in orally inhaled and nasal drug products (OINDPs). The book will also describe and consider the United States Food and Drug Administration (FDA) and international regulatory perspectives concerning the qualification of organic leachables in OINDP. Although the book is written specifically for OINDP, the principles used in defining safety thresholds could be applied to organic leachables in other drug product types.

Since the environmental movement of the 1970s, analytical chemistry and analytical techniques have become increasingly sophisticated and sensitive, capable of detecting, identifying, and quantifying both organic and inorganic chemical entities at ultratrace (i.e., parts per trillion) levels.1 However, it is generally accepted that there are levels of many chemicals below which the risks to human health are so negligible as to be of no consequence. This rationale has been a strong impetus for development of safety thresholds for regulating chemicals to which humans are exposed, most notably in the federal regulations for food packaging.2,3 Safety thresholds have also been developed for application to pharmaceuticals, including organic impurities in drug substances4 (process and drug related), drug products,5 and residual solvents in drug substances and drug products.6 Note that the international regulatory guidance for drug product impurities specifically excludes from consideration “impurities … leached from the container closure system.”5

OINDPs are developed for delivery of active pharmaceutical ingredient (API or drug substance) directly to the respiratory or nasal tract, to treat either a respiratory or nasal condition, or a systemic disease. Examples of OINDP include metered dose inhalers (MDIs), dry powder inhalers (DPIs), solutions/suspensions for nebulization, and nasal sprays (see Figs. 1.1 and 1.2). These drug product types incorporate complex delivery devices and container closure systems whose function and performance are critical to the safety and efficacy of the drug product. Components of OINDP delivery systems can be composed of polymers, elastomers, and other materials from which minute quantities of chemicals can migrate (i.e., leach) into the drug product formulation and be delivered to the sensitive surfaces of the respiratory and/or nasal tract along with the therapeutic agent. FDA guidance considers these drug product types high risk for containing leachables, which are delivered to the patient, because of the route of administration and because of the direct interaction of packaging and/or device components with drug formulation. While every effort is usually taken to reduce the levels of leachables, complete removal is neither practical nor desirable as many of these chemical entities perform important functions in container closure system components. Since leachables are non-drug-related impurities, there is an increased concern regarding the human risk associated with inhaling them on a daily basis, often for many years or decades. Historically, acceptable levels of leachables in OINDP have been set by negotiation with regulatory authorities on a case-by-case basis with no standard guidelines available. Recently, however, safety thresholds for risk assessment of organic leachables have been developed through a joint effort of scientists from the FDA, academia, and industry. This book will address the concepts, background, historical use, and development of safety thresholds and their utility in qualifying organic leachables in OINDP.