SMALL MOLECULE DRUG DEVELOPMENT
reactions that process chemists try to avoid,
because they allow a new molecule to be accessed quickly. These might be organolithium
bases that must be used at very low temperatures, perhaps, or a reaction that gives a complex mix of products that require separation
using solvent-heavy column chromatography.
This is the first point along the development pathway for a small molecule drug
that a contract manufacturing organization (CMO) is likely to get involved. Scale
up and route optimization is an art in itself,
and if in-house expertise is not available,
the skills of the CMO can be invaluable. The
CMO can be a complement to a Big Pharma company’s own process development
team and, in the case of a biotech company
with no in-house capabilities, can offer the
means to design an appropriate large-scale synthesis.
It is also important to get a good synthetic route early
on in the development cycle. It is rarely altered past phase
IIa, but where the demands for API increase throughout
the clinical stages, and then further into commercial
manufacturing, the synthetic route is scrutinized, and
process chemists and engineers look to adapt it.
Route evaluation is common for CMOs once the market has been established for a drug, as late as a number
of years after launch. Although there are regulatory costs
involved in changing the route post launch, there are occasions when it can be worthwhile. This is particularly the
case if the new route is very much faster or very much
cheaper, and may even help to reduce the impact of generic competition once patent expiry occurs.
EARLY STAGE SUPPORT
The following two case studies illustrate support provided
for API manufacturing demand across the drug development spectrum.
Case Study No. 1: Early process development and rapid
progression to first GMP bulk manufacture. A client
had developed a 13-step route for a new molecule and initially required sub-kilogram quantities to be manufactured
under non-GMP conditions, followed by a scale up to 5kg
batches that would be manufactured in accordance with cGMP.
Cambrex was able to design a new route to replace that original medicinal chemistry route, and at the same time increase the
overall reaction yield significantly from 2% to 18%. In addition,
downstream development was completed in parallel with plant
production of the API to minimize the timeline for the process.
Two steps were shaved off the route, bringing the total number down to 11. Furthermore, a hazardous diazotization step was
evaluated and risk-mitigated, and solubility and final form issues
were resolved to provide the desired polymorph.
Case Study No. 2: Process development and process valida-
tion studies. In some cases, full time equivalent (FTE)-based
R&D is a more appropriate way to approach a problem. In this
example, Cambrex provided FTE-based R&D to support a cli-
ent’s medicinal chemistry/structure-activity-relationship stud-
ies. The result was a second-generation process that was de-
veloped in collaboration with the client, and sufficient API was
delivered to satisfy an early toxicity study program. This was
quickly followed up by the first kilogram-scale GMP batch of
API to meet the demands of clinical trials.
During the development process, an issue with water sensi-
tivity was identified. To meet the stringent purity requirements,
refinements to the process were made, in collaboration with
the client, to ensure its robustness at scale. Further process im-
provements resulted in an efficient and streamlined route that
also dramatically reduced the cost of the API. Full analytical and
FIGURE 1. It costs more than a billion U.S. dollars to bring a drug from the discovery stage to commercialization and
only about 1 in 5,000 new drug candidates make it through the whole process to become a marketable product.
However, the reward is worth the risk.
FIGURE 2. Although the number of new drug approvals per year fluctuates, there is a constant
supply of new products to the market.