Chemistry Reference
In-Depth Information
To date, our organization has developed and commercialized amorphous disper-
sions twice with drugs for treating cystic
fibrosis and hepatitis C infection requiring the
navigation of global marketing approval paths for amorphous materials through agencies
such as the FDA and EMA as well as the regulatory authorities of Canada and Australia.
In both cases, the TDD process led us to use an alternate material form to maximize the
clinical value of a promising compound. Below, we describe the TDD process in general.
In later sections, we discuss in greater detail the steps we take to develop amorphous
dispersions
first commercialized drug, telaprevir (Incivek
), as a
—
with references to our
case study.
7.1.2 How TDD Works
Our organization has implemented Development 3.0 by tasking a single department
—
the
Materials Discovery and Characterization (MDC) department
—
with collaborating with
the other pharmaceutical development
line functions
—
analytical, formulation, and
chemical development
as well as discovery research and our commercial pharmaceu-
tical operations unit, to support translation throughout the entire development process.
The bene
—
t of an integrated department like this one primarily accrues over time. As
translational experience grows, a substantial body of knowledge is produced that perhaps
could, eventually, allow development groups to predict the physical properties of a
molecule able to bind a speci
c target.
s personnel are involved in projects from lead optimization, through
preclinical and clinical development, into commercial manufacture and ultimately line
extension, the group is necessarily interdisciplinary. It includes physical chemists, such
as specialists in thermodynamics, crystallography, and spectroscopy; analytical chem-
ists; materials scientists and engineers; protein biochemists; and biopharmaceutics
experts. Although the department
Because MDC
'
'
is disciplinary base is broad, its name, Materials
Discovery and Characterization, re
ects a common focus. The group considers the
whole drug product to be a single unit of analysis
the API, in a given crystalline or
amorphous form, with all its excipients. As a material, it has certain properties, for
instance, solubility, chemical stability, physical stability (i.e., polymorphic and amor-
phous-to-crystalline interconversion), ease of manufacture, and disposition in the body.
The department's mission is to understand these properties as rigorously and as early in
development as possible and, thereby, support other line functions in their objectives as
needed.
This orientation evokes the
—
approach described by Gardner
et al. [15]. However, it differs in two respects. First, as this chapter will demonstrate,
personnel involved in TDD are integrated into each stage of discovery and development,
serving as regular members of working groups, projects teams, and major steering
committees. Second, as described below, the basic tool of these TDD personnel is
rational, structure-based drug design, rather than a high-throughput approach.
In practice, the department begins its involvement at the lead optimization stage of
discovery, when a disease area management team de
“
drugs as materials
”
nes what is known as a target
product pro
le (TPP). A TPP includes the pathophysiology of the disease and the clinical
