CO2_2016 - page 25

Chimica Oggi - Chemistry Today
- vol. 34(2) March/April 2016
KEYWORDS: Supercritical fluid chromatography SFC, chiral drugs, preparative chromatography, batch chromatography.
Strategy during early drug development requires attention to the profiling and de-risking of the drug
candidate and to planning for supply as the preclinical and clinical programs progress. Supplying chiral
drug candidates as single stereoisomers adds a layer of complexity. Chiral resolution by chromatography is considered an expensive
alternative for large scale production, but in preclinical development it may not be cost effective to invest in a later stage production
process. In this article, we discuss ways to improve the cost equation in favor of chromatography – to ensure that near term program
needs are met and to reduce the costs of large scale or commercial production.
Relative cost-effectiveness modeling
to understand the value of preparative chiral
separations in pharmaceutical R&D
Drug development is an increasingly long and expensive
process. While much of the cost comes from risk
management, much comes from efforts to develop and
use the best scientific knowledge when intending to give
a new therapy to humans. One way this is done is to focus
on specificity of action, reducing dosage and off-target
toxicity concerns. Chirality – stereoisomerism, or right- and
left-handedness - is a property of many molecules that
can be taken advantage of to enhance specificity of drug
action (1). Because of this powerful strategy, new drug
products are overwhelmingly chiral molecules developed
as single enantiomers – 76% in 2001 compared with 21%
in 1991 (2). Regulatory guidance charges sponsors with
investigating efficacy, bioavailability, toxicity, and stability
of all isomers of a new molecule. Risk management
played a role in the change – thalidomide is a good
example of a racemic drug with one effective and an
opposite toxic enantiomer – but market value played
a bigger role, as developers motivated by differential
isomeric activity moved fast to develop target-specific
single enantiomer drugs.
Developing a chiral molecule requires an ever-increasing
supply of (at first) both enantiomers, followed by a well-
characterized supply of the desired or active enantiomer.
These supplies don’t come easily or cheaply. Often
the first pure stereoisomers come from separations
work that starts with the racemic mixture; later a large
scale synthesis of enantiopure compound or a classical
resolution(3) may be developed.
Therefore an “economics” problem develops quickly in a
progressing drug development program: When does your
developing chiral drug candidate justify the effort and spend
to develop a commercial scale process? At the 10 gram
scale? 100 grams? Kilo? Clinical supply? Asymmetric synthesis
or classical resolution processes are costly to develop, and
chromatographic resolution – easiest at small scale - is costly
for production scale. Conventional wisdom says it’s best to
eliminate chromatography from production process, but no
rule tells you when.
Chromatographic chiral resolution is usually favored at
the early stages of development because it’s simple and
somewhat scalable. Generally chromatography is an
available “bird in the hand” approach as compound needs
escalate. But as you go up in scale, chromatography is
expensive and hard to manage.
The thesis of this article is that it’s impossible to quantify
accurately the relative costs of chromatography against the
investment in a production scale resolution because a) there
are too many unknowns about the investment in synthetic or
crystallization processes, and b) it’s often possible to improve
the efficiency of chromatographic resolutions. By focusing
on the balance between the estimated effort in a) and the
potential advantages in b), we employ what we term a
“relative cost” model and attempt to balance the return of
the chromatographic “bird in the hand” against the synthetic
“two in the bush”.
The factors that should be considered in the balancing of this
equation are often called “soft costs”.
Averica Discovery Services Inc.
260 Cedar Hill Street, Marlborough, MA 01752, USA
Jeffrey P. Kiplinger
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