Theodore W. Randolph - Bayer HealthCare Pharmaceuticals

Engineering Challenges of Protein
Formulations
Protein therapeutics offer remarkable potential benefits to human health.
Indeed, they form the fastest-growing new class of drugs. But because the
mechanism of their action depends on their three-dimensional molecular
conformation, this proper conformation must be preserved not only through
production, but also through the drug’s shelf life and eventual delivery to
patients. Thus, the engineer must deliver a purification process that yields a
chemically and conformationally pure product, and also a set of conditions
(temperature, pH, solution additives, container materials, etc., collectively
called the formulation) that maintains these purities.
In this talk, two examples of formulation engineering will be discussed.
The first will explore the thermodynamic effects of formulation solutes on
the kinetics of protein aggregation. Protein aggregation kinetics typically are
modeled using the modified Lumry-Eyring framework, which assumes that
the compact native protein exists in an equilibrium with reactive partially
unfolded species that form the transition state for aggregation. These
partially unfolded intermediates react through collisions with themselves
(or existing aggregates) to form aggregates (or larger aggregates). Under
favorable solution conditions described by the Wyman linkage relationship the
equilibrium between the native state and the transition state intermediates
can be shifted to favor the native state, reducing the concentration of reactive
intermediates and, consequently, the rate of aggregation.
The second example explores kinetic control of protein degradation
reactions. Lyophilization can be used to create formulations of proteins
contained in glassy matrices. Within these glassy matrices, some (but not
all) undesirable degradation may be significantly inhibited. Rational design
of lyophilization processes and the resulting glassy state formulations offer
promise of ultra-stable protein therapeutics and vaccines; the particular
example of development of a botulism vaccine will be discussed.
Theodore W. Randolph
Theodore W. “Ted” Randolph received
his Ph.D. in chemical engineering
at the University of California, Berkeley,
in 1987. He worked as a post-doctoral fellow
at the École Polytechnique Fédérale de
Lausanne and then joined the Department
of Chemical Engineering at Yale University
as an assistant professor. After promotion
to associate professor, he was named to
Yale’s first John J. Lee Junior Professorship
in Chemical Engineering.
In 1993, Dr. Randolph accepted the
Patton Associate Professorship in the
Department of Chemical Engineering
at the University of Colorado at Boulder. He currently serves as the Gillespie
Professor of Bioengineering, co-director of the University of Colorado’s Center for
Pharmaceutical Biotechnology, and Director of the NIH Leadership Training in
Pharmaceutical Biotechnology Program.
Dr. Randolph is a National Science Foundation Presidential Young
Investigator, and he has received the AIChE Professional Progress Award
and the American Pharmacist’s Ebert Prize. His research interests include
biopharmaceutical formulation, lyophilization of proteins, protein-solvent
interactions in non-aqueous environments, and protein refolding.
Dr. Randolph is an inventor on numerous patents, some of which form the
basis for two companies that he has founded: RxKinetix (now owned by Endo
Pharmaceuticals), a company formed to commercialize new extended-release
drug delivery technologies; and BaroFold, a company that uses high-pressure
protein refolding technology to develop and produce new protein therapeutics.