Foreword

When I joined the pharmaceutical industry many years ago, I was initially involved in formulation
development. Having come from a different industry and having understood that the pharmaceutical
industry is highly regulated, I was still surprised to learn that since it would take months to know
whether a formulation was stable enough by using the ICH or ICH-like stability testing methods,
the formulators would need to develop two alternative formulations, just in case the first failed. Sim-
ilarly, for packaging selection, the prevailing methodology was to set up many parallel trials with a
variety of packaging options on a months-long ICH or ICH-like stability testing regimen. There
was a widespread belief that highly accelerated methods for determining drug product shelf-life do
not work, especially for solids. This meant that not only was drug product development slow because
of the time involved waiting for the real-time stability results, but also that it had poor efficiency since
parallel tracks were necessary to have something successful in the event the primary options failed.
Decisions were made largely on an empirical, not scientific, basis. The need for a fast, reliable, scien-
tific method for accelerated determination of product stability prompted the work that ultimately has
led to the revolutionary Accelerated Predictive Stability (APS) methods described in this book.
The development of APS methods has advanced over the last fifteen years, gradually enveloping an
ever-greater share of the pharmaceutical and aligned industries, including generics, OTCs, and nutra-
ceuticals. While APS methods have had a significant impact in clinical development stages, partly be-
cause of relatively less regulatory risk of using a science and risk-based approaches during clinical
development, the overall industry value is now distributed across development and commercial phases.
Besides the enhanced scientific understanding of product stability and reduced development timelines,
there has been encouraging developments in the acceptance of APS methods by regulatory agencies of
many major pharmaceutical markets. As more companies adopt APS methods, new opportunities for
reducing risk, shortening timelines, increasing efficiency, and cutting costs emerge. In addition, there is
a gradual trend toward using APS methods in more stages of regulatory filings, including registrations
and postapproval changes. In addition, companies have begun using these methods to justify a product
change as minor by bridging traditional ICH stability data before the change with APS evaluation after
the change.
The success of APS methods has naturally increased the desire to use these scientific concepts more
broadly. This has resulted in active development in my labs and others, investigating and developing
new APS methods in many areas. These include expanding APS methods into large-molecule (biolog-
ical) drugs, drug devices, in-use stability and justification of acceptance for product storage or shipping
temperature excursions. Scientific work has also expanded APS methods to include oxygen sensitivity,
amorphous crystallization, accelerated extractables/leachables determinations, and other aspects of
physical stability. Work has continued on developing better statistical methodologies. The field con-
tinues to expand as APS methods are applied more widely and as the basic research continues. This
book should therefore be viewed as an effort to capture the best thinking and applications at this time,
which will hopefully inspire advancements into the future.
The editors of this book, Drs. Fenghe Qiu and Garry Scrivens, are two scientists I have known for
many years. Both have been influential in their own companies and outside in making APS methods a
reality. Putting together this book was a major undertaking requiring years of work and is a great

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service to the pharmaceutical industry. These two have assembled an amazing team of scientists and
statisticians from a range of companies as contributors. The list of subjects covered in this book in-
cludes science, statistics, the regulatory interface, and real-world applications. All are discussed in
a balanced way that should provide a tremendous resource not only for the scientist looking to under-
stand and apply APS methods, but also for those already using these techniques.
As the scientific success of APS methods has gained wider industry acceptance, there is a
relatively slow and uneven movement toward acceptance with regulatory authorities. This book thus
also provides the substrate for a broader discussion between industry scientists and regulatory
authorities about different ways of adopting scientific methodologies for meeting the responsibility
of assuring product safety and quality throughout the product shelf life.

Kenneth C. Waterman