Preface

The concept of “getting long-term stability predictions based on a short-term stability study” is appeal-
ing to the pharmaceutical industry because there is an ever-increasing pressure to reduce the cost and
time of drug development. However, this goal cannot be realized by simply shortening the duration of
stability testing using severe environmental conditions, such as stress testing, as defined in the ICH
Q1A(R2) guidelines, because this type of conventional stress testing is only qualitative in nature.
On the other hand, a well-controlled and well-designed short-term stability study coupled with
in silico modeling has been demonstrated recently to be a viable approach to provide a quantitative
determination of the impacts of environmental conditions and a prediction of the long-term stability
behavior of the drug. Indeed, it can be argued that these new accelerated stability approaches coupled
with computational modeling are simply a transition from qualitative to quantitative assessments of
stability data as the pharmaceutical industry increasingly adopts in silico and computational
approaches to drug development. In this book, the editors termed this emerging science and risk-based
approach of “getting long-term stability predictions based on a short-term stability study and in silico
modeling” as Accelerated Predictive Stability (APS) to differentiate it from the terminologies used in
the ICH paradigm and to cover all the similar approaches in this space. At this time, at least two APS
models, the Accelerated Stability Assessment Program (ASAP) and Accelerated Stability Modeling
(ASM), have been adopted by many pharmaceutical companies. Both of these APS models are based
on the foundational physical chemistry concept of the Arrhenius relationship for modeling the effect of
temperature and further modified to account for the effects of humidity. Thus, these models are intu-
itively plausible given that both temperature and humidity are known to be the two most important
environmental conditions affecting the rate of degradation of pharmaceuticals.
Despite the concepts of Arrhenius relationship not being explicitly mentioned in the ICH stability
guidelines, they underpin many of their general principles. For example, ICHQ1A(R2) makes
reference to mean kinetic temperature (MKT), which is based on an assumption of Arrhenius temper-
ature dependence, and the recommended durations for the accelerated conditions (e.g., 6 months at 40°
C/75%RH) are consistent with the Arrhenius relationship. Similarly, the regulatory guidelines do not
necessitate in silico modeling of stability data; however, ICH Q1A(R2) states: “the purpose of stability
testing is to provide evidence on how the quality of a drug substance or drug product varies with time
under the influence of a variety of environmental factors such as temperature, humidity and light…”
The APS approach is entirely consistent with this aim since model development, which is at the core of
the APS approach, is a numerical method for making sense of stability data and is synonymous with
gaining an (quantitative) understanding of the effects of environmental factors.
Since this is the first book on APS, the book is constructed with both general chapters and appli-
cation chapters. The general chapters are designed to cover the general and fundamental aspects of the
APS approach to help the readers understand the science and risk associated with this approach, such as
when and where APS can be applied in various drug development phases (Chapter 1), regulatory basis
and opportunities of the APS approach (Chapter 2), fundamental theories of the two APS models
(Chapter 3), practical considerations in designing an APS study (Chapter 4), modeling of packaged
product (Chapter 5), statistical considerations (Chapter 6), strategies to improve accuracy of predic-
tions (Chapter 7), role of APS in formulation development (Chapter 8), current regulatory experiences

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in submitting APS data in regulatory filings and regulatory feedbacks (Chapter 9), and finally strategies
of implementing the APS approach within a pharmaceutical company (Chapters 10 and 11). The
application chapters are balanced with both ASAP application chapters (Chapters 12–18) and ASM
application chapters (Chapters 19–22) and are intended to demonstrate the actual utilities of the
APS approaches in predicting both chemical and physical stability (e.g., disintegration (Chapter 19)
and dissolution (Chapters 17 and 18)) during the full drug development life cycle through various
representative real-world case studies, including solid oral, liquid, and lyophilized products.
Currently APS studies are typically used as a facilitator of rapid product development: they provide
a good basis for making decisions when waiting for the long-term data is inconvenient, costly, or could
even jeopardize the commercial viability of a product. Although APS studies are not intended to
replace traditional stability testing for registration, the feasibility of using APS data to substantiate
the first retest period/use period or assessing changes in early clinical development has been demon-
strated by many companies. As the science progresses and our experience increases, faith in the
reliability of APS approaches will inevitably grow and may increasingly be used in lieu of traditional
stability testing in more areas. It is our hope that this book will be a useful and practical resource for
scientists in the pharmaceutical industry who are interested in furthering the science and applications of
the APS approaches.

Fenghe Qiu, Garry Scrivens