Good Cascade Impactor Practices, AIM and EDA for Orally Inhaled Products

443 Pages·2013·14.04 MB·English

by  Terrence P. Tougas

Terrence P. Tougas
Jolyon P. Mitchell
Svetlana A. Lyapustina Editors
Good Cascade
Impactor Practices,
AIM and EDA
for Orally Inhaled
Products
Good Cascade Impactor Practices, AIM and EDA
for Orally Inhaled Products

Terrence P. Tougas (cid:129) Jolyon P. Mitchell

Svetlana A. Lyapustina
Editors
Good Cascade
Impactor Practices,
AIM and EDA
for Orally Inhaled
Products
Editors
Terrence P. Tougas Jolyon P. Mitchell
Analytical Development Trudell Medical International
Boehringer Ingelheim Pharmaceuticals Inc. London , ON, Canada
Ridgefi eld , CT, USA
Svetlana A. Lyapustina
Drinker Biddle & Reath LLP
Washington, DC, USA
ISBN 978-1-4614-6295-8 ISBN 978-1-4614-6296-5 (eBook)
DOI 10.1007/978-1-4614-6296-5
Springer New York Heidelberg Dordrecht London
Library of Congress Control Number: 2013932873
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Preface
The measurement of the aerodynamic size properties of aerosols from orally inhaled
products has been a long-standing topic of interest to stakeholders because of the
need to provide measurements that can ultimately be related to the likely deposition
in the human respiratory tract and therefore to subsequent clinical response to the
active pharmaceutical ingredient(s). The challenge has been the limited choice of
measurement equipment available that meets all of the requirements demanded of
it. Historically, the full-resolution multistage cascade impactor has been the work-
horse in the laboratory undertaking inhaler performance testing, but its successful
operation requires a high degree of operator skill and know-how, and the measure-
ment process is both laborious and time consuming.
This book has been the outcome of several years work within two cross-industry
organizations: the Cascade Impaction Working Group of the International
Pharmaceutical Consortium on Regulation and Science (IPAC-RS) and the Cascade
Impactor Sub-Team of the European Pharmaceutical Aerosol Group (EPAG). The
abbreviated impactor measurement (AIM) concept was developed in the middle of
2000 out of the realization that there is a need to offer users of the cascade impaction
technique, the opportunity to make measurements of the important aerodynamic
size-based metrics, without the need to determine the aerodynamic particle size dis-
tribution. From these developments came the realization that in the product quality
environment, the minimum number of metrics that is needed relating to the sum and
ratio of the large and small particle fractions, are all that is needed to defi ne the
APSD. If the boundary dividing them was chosen appropriately, could result in
better decision-making than the currently accepted practice in the USA of accumu-
lating the mass of active pharmaceutical ingredient collected on each stage of a
full-resolution impactor into groupings that broadly refl ected coarse, fi ne, and extra-
fi ne particulates. This new approach was termed effi cient data analysis (EDA) and
is the companion concept to AIM, although EDA may be applied to data from either
full or abbreviated impactor measurements.
As this volume was in the process of early development, it became evident that
in order to describe the AIM and EDA concepts meaningfully, it would be necessary
to place these approaches into the context of the existing apparatuses that are defi ned
v
vi Preface
in the pharmacopeial literature. This material is currently in disparate locations and
is therefore not always easy to fi nd quickly. A chapter has therefore been devoted to
the description of the underlying theory, including key descriptive information con-
cerning the compendia apparatuses. This chapter also addresses the potential impact
that assumptions concerning the properties of the collection effi ciency profi les of
cascade impactor stages may have both on measurements by full and abbreviated
systems, to provide assurance to the reader that such fundamental concerns have
been addressed.
In addition to a chapter that reviews in detail and updates the so-called good
cascade impactor practice (GCIP) concept developed in February 2002 through the
US-based Product Quality Research Institute, this book also contains information
on how AIM and EDA could be applied at various stages in the orally inhaled drug
product life cycle. There are also several case studies that illustrate how these concepts
have already been applied to the assessment of currently marketed products. The
intriguing question ‘When could AIM fail…?’ has also been addressed through
scenarios in which the underlying physical processes that infl uence the size distri-
bution of inhaler aerosols are considered as well as by failure modes analyses related
to the cases of pressurized metered dose inhaler and dry-powder-inhaler categories
of drug products.
An extensive chapter contains a compilation of the large number of experimental
validations of the AIM concept that have been undertaken since 2008. Its purpose is
again to provide confi dence in the robustness of the concept and, at the same time,
to highlight the precautions that should be considered when beginning the process
of implementing an AIM-based regimen with or without EDA.
A chapter is included that addresses the regulatory and compendia pathways that
will likely need to be followed before either or both concepts become fully accepted
as routine approaches by all stakeholders involved in the process of inhaler perfor-
mance evaluation.
Towards the end of this book, a chapter has been included that considers how the
AIM concept might be adapted in the future to explore the possibilities for greater
correlation than has been possible hitherto, between impactor-generated measures
of particle size and likely particle deposition in the human respiratory tract. This is
a highly active topic of current research as the development of robust in vitro–
in vivo relationships for the class of orally inhaled products as a whole continues to
pose severe challenges.
This volume concludes with a chapter that attempts to look forward and present
ideas to encourage further research into the application of both AIM and EDA
concepts.
This compilation of knowledge concerning the cascade impaction technique will
be of interest to all those who are involved with the day-to-day management of
orally inhaled product quality testing, as well as to the researcher seeking to know
how AIM and EDA might be applied in novel ways. The authors have provided new
insights that will help both the novice and experienced user of the impaction method
come to grips with either concept.
Preface vii
At the same time, the authors and editors acknowledge that this fi eld is evolving
rapidly, and no single published work could capture all of the possible angles.
This book is but a stepstone on the way towards much deeper understanding of
the various aspects of cascade impactor testing, and particle sizing in general, of the
pharmaceutical aerosols. Future investigations and publications will undoubtedly
elaborate on concepts presented here as well as introduce new data and consider-
ations. One of the goals Good Cascade Impactor Practices, AIM and EDA for
Orally Inhaled Products could serve, therefore, is to provide a helpful backdrop
and to strengthen a foundation for further work in this important and actively
debated area.
The editors pay tribute to the effort that has gone into development of each
contributed chapter, making it both information rich and authoritative and therefore
a valuable resource.
Ridgefi eld, CT, USA Terrence P. Tougas
London, ON, Canada Jolyon P. Mitchell
Washington, DC, USA Svetlana A. Lyapustina

Acknowledgments
The coeditors wish to acknowledge the input from many organizations and individual
contributors who are not identifi ed as coauthors of chapters for this book. In this con-
text, they acknowledge the support of the Cascade Impaction Working Group of
IPAC-RS and the Impactor Sub-Team of EPAG. The following individuals are also
acknowledged:
William Doub, FDA, USA
Prasad Peri, FDA, USA
Marjolein Weda, RIVM, Netherlands
Anthony J. Hickey, University of North Carolina at Chapel Hill and Chair of Aerosol
Expert Sub-committee of the USP General Chapters Dosage Forms Committee,
USA
Paul Curry, Abbott Laboratories and Member of Aerosol Expert Sub-committee of
the USP General Chapters Dosage Forms Committee, USA
Mike Smurthwaite, Westech Instrument Services, UK
Frank Chambers, Covance, UK
David A. Lewis, Vectura, UK
Adam Watkins, Vectura, UK
Andrew D. Cooper, Mylan, UK, formerly Pfi zer, UK
Dave Russell-Graham, Mylan, UK, formerly Pfi zer, UK
Geoffrey E. Daniels, GSK, UK
Melanie Hamilton, GSK, UK
Fabienne Després-Gnis, Aptar Pharma, France
Gerallt Williams, Aptar Pharma, France
Philippe G.A. Rogueda, Watson Pharmaceuticals, UK, formerly Novartis Pharma,
UK
Gracie Sheng, MAP Pharmaceuticals, USA
Elna Berg, Emmace Consulting AB, Sweden, formerly AstraZeneca, Sweden
Yvonne Sizer, Melbourn Scientifi c, UK
Teresa Russell, Melbourn Scientifi c, UK
Mark W. Nagel, Trudell Medical International, Canada
ix