Pharmaceutical Inhalation Aerosol Technology

747 Pages·2019·32.986 MB·English

by  Anthony J. Hickey, Sandro R. P. da Rocha

Pharmaceutical Inhalation
Aerosol Technology
DRUGS AND THE PHARMACEUTICAL SCIENCES
A Series of Textbooks and Monographs
Series Executive Editor
James Swarbrick
Pharmaceutech, Inc.
Pinehurst, North Carolina
Recent Titles in Series
Good Manufacturing Practices for Pharmaceuticals, Seventh Edition, Graham P. Bunn
Pharmaceutical Extrusion Technology, Second Edition, Isaac Ghebre-Sellassie,
Charles E. Martin, Feng Zhang, and James Dinunzio
Biosimilar Drug Product Development, Laszlo Endrenyi, Paul Declerck, and
Shein-Chung Chow
High Throughput Screening in Drug Discovery, Amancio Carnero
Generic Drug Product Development: International Regulatory Requirements for
Bioequivalence, Second Edition, Isadore Kanfer and Leon Shargel
Aqueous Polymeric Coatings for Pharmaceutical Dosage Forms,
Fourth  Edition,  Linda A. Felton
Good Design Practices for GMP Pharmaceutical Facilities, Second Edition,
Terry Jacobs and Andrew A. Signore
Handbook of Bioequivalence Testing, Second Edition, Sarfaraz K. Niazi
Generic Drug Product Development: Solid Oral Dosage Forms, Second Edition,
edited by Leon Shargel and Isadore Kanfer
Drug Stereochemistry: Analytical Methods and Pharmacology, Third Edition,
edited by Krzysztof Jozwiak, W. J. Lough, and Irving W. Wainer
Pharmaceutical Powder Compaction Technology, Second Edition, edited by Metin Çelik
Pharmaceutical Stress Testing: Predicting Drug Degradation, Second Edition,
edited by Steven W. Baertschi, Karen M. Alsante, and Robert A. Reed
Pharmaceutical Process Scale-Up, Third Edition, edited by Michael Levin
Sterile Drug Products: Formulation, Packaging, Manufacturing, and Quality,
Michael J. Akers
Pharmaceutical Inhalation
Aerosol Technology
Third Edition
Edited by
Anthony J. Hickey
Sandro R.P. da Rocha
CRC Press
Taylor & Francis Group
6000 Broken Sound Parkway NW, Suite 300
Boca Raton, FL 33487-2742
© 2019 by Taylor & Francis Group, LLC
CRC Press is an imprint of Taylor & Francis Group, an Informa business
No claim to original U.S. Government works
Printed on acid-free paper
International Standard Book Number-13: 978-1-1380-6307-5 (Hardback)
This book contains information obtained from authentic and highly regarded sources. Reasonable efforts have been made
to publish reliable data and information, but the author and publisher cannot assume responsibility for the validity of all
materials or the consequences of their use. The authors and publishers have attempted to trace the copyright holders of all
material reproduced in this publication and apologize to copyright holders if permission to publish in this form has not been
obtained. If any copyright material has not been acknowledged please write and let us know so we may rectify in any future
reprint.
Except as permitted under U.S. Copyright Law, no part of this book may be reprinted, reproduced, transmitted, or utilized
in any form by any electronic, mechanical, or other means, now known or hereafter invented, including photocopying,
microfilming, and recording, or in any information storage or retrieval system, without written permission from the
publishers.
For permission to photocopy or use material electronically from this work, please access www.copyright.com (http://www.
copyright.com/) or contact the Copyright Clearance Center, Inc. (CCC), 222 Rosewood Drive, Danvers, MA 01923, 978-750-8400.
CCC is a not-for-profit organization that provides licenses and registration for a variety of users. For organizations that have been
granted a photocopy license by the CCC, a separate system of payment has been arranged.
Trademark Notice: Product or corporate names may be trademarks or registered trademarks, and are used only for
identification and explanation without intent to infringe.
Library of Congress Cataloging‑in‑Publication Data
Names: Hickey, Anthony J., 1955- editor.
Title: Pharmaceutical inhalation aerosol technology
/ [edited by] Anthony J. Hickey, Sandro R.P. da Rocha.
implementing game mechanics, art, design and programming / Penny de Byl.
Description: Third edition. | Boca Raton, Florida : CRC Press, [2019] |
Drugs and the pharmaceutical sciences |
Includes bibliographical references and
index
Identifiers: 2018044344| ISBN 9781138063075 (hardback : alk.paper)
ISBN 9780429055201 (ebook)
Subjects: LCSH: Aerosol therapy.
Classification: LCC RM161 .P55 2019 | DDC 615/.6--dc23
LC record available at https://lccn.loc.gov/2018044344
Visit the Taylor & Francis Web site at
http://www.taylorandfrancis.com
and the CRC Press Web site at
http://www.crcpress.com
Contents
Preface ......................................................................................................................................................ix
Editors .......................................................................................................................................................xi
Contributors ............................................................................................................................................xiii
1. Introduction ......................................................................................................................................1
Anthony J. Hickey and Sandro R.P. da Rocha
Section I Discovery
2. Physiology of the Airways ................................................................................................................5
Anthony J. Hickey and David C. Thompson
3. Drug Targeting to the Lung: Chemical and Biochemical Considerations ...............................29
Peter A. Crooks, Narsimha R. Penthala, and Abeer M. Al-Ghananeem
Section II Aerosol Critical Attributes
4. Aerosol Physics and Lung Deposition Modeling .........................................................................81
Warren H. Finlay
5. Practical Aspects of Imaging Techniques Employed to Study Aerosol Deposition and
Clearance ........................................................................................................................................93
Myrna B. Dolovich
6. Pharmacokinetics and Pharmacodynamics of Drugs Delivered to the Lung .........................131
Stefanie K. Drescher, Mong-Jen Chen, Jürgen B. Bulitta, and Günther Hochhaus
Section III Active Pharmaceutical Ingredient/Drug
Product Manufacturing
7. Small Molecules: Process Intensification and Continuous Synthesis ......................................181
Thomas D. Roper
8. Biologic Drug Substance and Drug Product Manufacture ......................................................205
Ajit S. Narang, Mary E. Krause, Shelly Pizarro, and Joon Chong Yee
9. Scale-Up Considerations for Orally Inhaled Drug Products ..................................................233
Jeremy Clarke and S. van den Ban
10. Quality by Control .......................................................................................................................249
Helen N. Strickland and Beth Morgan
v
vi Contents
Section IV Particle Engineering/Processing
11. Milling and Blending: Producing the Right Particles and Blend Characteristics for
Dry Powder Inhalation ................................................................................................................273
Bernice Mei Jin Tan, Lai Wah Chan, and Paul Wan Sia Heng
12. Engineering Stable Spray-Dried Biologic Powder for Inhalation ............................................291
Nicholas Carrigy and Reinhard Vehring
13. Supercritical Fluid Manufacture ................................................................................................327
Ana Aguiar-Ricardo and Eunice Costa
14. Particle Engineering Technology for Inhaled Therapies .........................................................349
David Lechuga-Ballesteros, Susan Hoe, and Benjamin W. Maynor
Section V Drug Product Formulation
15. Emerging Pulmonary Delivery Strategies in Gene Therapy: State of the Art and
Future Considerations .................................................................................................................365
Gabriella Costabile and Olivia M. Merkel
16. Genome Editing for Genetic Lung Diseases ..............................................................................389
Ying Zhang and Hao Yin
17. Inhalation Drug Products Containing Nanomaterials .............................................................403
Sandro R.P. da Rocha, Rodrigo S. Heyder, Elizabeth R. Bielski, Ailin Guo,
Martina Steinmaurer, and Joshua J. Reineke
Section VI Devices
18. Pressurized Metered-Dose Inhalers ...........................................................................................427
Sandro R.P. da Rocha, Balaji Bharatwaj, Rodrigo S. Heyder, and Lin Yang
19. Dry Powder Inhalation .................................................................................................................455
Anne H. de Boer and Floris Grasmeijer
20. Nebulizers ......................................................................................................................................473
John N. Pritchard, Dirk von Hollen, and Ross H.M. Hatley
21. Soft Mist Inhalers .........................................................................................................................493
Stefan Leiner, David Cipolla, Joachim Eicher, Wilbur de Kruijf, and Herbert Wachtel
Section VII Drug Product Testing
22. Quality by Design Considerations ...............................................................................................511
William Craig Stagner and Anthony J. Hickey
Contents vii
23. Solid State Testing of Inhaled Formulations .............................................................................523
Philip Chi Lip Kwok and Hak-Kim Chan
24. Aerodynamic Particle Size Testing ..............................................................................................541
Jolyon Mitchell
Section VIII Regulatory Considerations
25. Scanning the Intricate Regulatory Landscape and Trying to Peek Over the Horizon .........591
Stephen T. Horhota, Stefan Leiner, and Allen Horhota
26. Pharmacopeial and Regulatory Guidances on Product Quality and Performance ..............601
Anthony J. Hickey
27. The European Union Regulatory Scene ......................................................................................611
Steven C. Nichols and Dennis Sandell
Section IX Preclinical Testing
28. Reconstituted 2D Cell and Tissue Models .................................................................................627
Nicole Schneider-Daum, Patrick Carius, Justus C. Horstmann, and Claus-Michael Lehr
29. 3D In Vitro/Ex Vivo Systems ........................................................................................................653
Bethany M. Young, Alexandria Ritchie, Laleh Golshahi, and Rebecca L. Heise
30. Preclinical Models for Pulmonary Drug Delivery ....................................................................669
Jibriil P. Ibrahim, Robert J. Bischof, and Michelle P. McIntosh
Section X Clinical Testing
31. Bioequivalence of Orally Inhaled Drug Products: Challenges and Opportunities ...............687
Jayne E. Hastedt and Elise Burmeister Getz
32. General Conclusions .....................................................................................................................719
Anthony J. Hickey and Sandro R.P. da Rocha
Index .......................................................................................................................................................721

Preface
Two previous editions of the book Pharmaceutical Inhalation Aerosol Technology (PhIAT) were pub-
lished in 1993 and 2004. The first edition appeared at a time when few books on aerosol technology were
available, notably those of WC Hinds (Aerosol Technology, Wiley) and PC Reist (Introduction to Aerosol
Science) that had only been available for a decade. There were few general texts on medical aerosols, and
those were in specialized areas, notably several volumes by Stephen Newman. With this background, the
original PhIAT book was intended to broadly cover all aspects of the field from lung biology (pharmacol-
ogy, physiology, and anatomy) to drug product manufacturing, performance, and clinical applications. In
the intervening decades many new volumes have appeared and much more has been published on aerosol
physics, formulation and device development, and therapeutic strategies, supported by the commercial-
ization of many new drug products.
This edition of PhIAT not only provides an update on many topics addressed in the 2nd edition, but
also expands the “technology” focus of the original volumes to address the title more directly. Since the
major purpose of any book should be its utility to the reader, it is logical to look at the topic from the
perspective of clear unmet needs. The new text covers all aspects of product development and manu-
facturing encompassing the important areas of preformulation, formulation, device selection, and drug
product evaluation. In order to expand the scope to consider previously unaddressed aspects of phar-
maceutical inhalation aerosol technology, considerations of the patient interface have been restricted to
those aspects of aerosol delivery, lung deposition, and clearance that are used as measures of effective
dose delivery.
The introduction of Dr. Sandro da Rocha as co-editor of the new edition reflects the intention to bring
engineering principles to bear on this important topic and to stress the importance of pharmaceutical
engineering as a foundational element of all inhaler products and their application to pulmonary drug
delivery.
We are grateful to the publishing staff, in particular, Hilary LaFoe and Jessica Poile for their assis-
tance in navigating the manuscript through the process.
This book is dedicated in memory of Professor Paul Myrdal, outstanding scientist, educator, family
man, and friend. He is missed by all.
Anthony J. Hickey
Chapel Hill, NC
Sandro R.P. da Rocha
Richmond, VA
September 2018
ix