Seqens eBook - 11
Synthetic Route Selection for APIs:
It Pays to Get it Right the First Time
Ed Price, CEO, Seqens CDMO North America
The pressures to reduce costs while meeting more complex regulatory
leading up to commercial production can be difficult to predict. Serious
mandates, create a difficult challenge: how to develop a commercial process
issues with the process may not come to light until the process is taken
for a drug candidate more efficiently and within a much shorter timeframe?
to pilot plant scale.
Because of these challenges, it pays to carefully plan synthetic route
Understand how the synthetic route changes as development
selection in API development so that you can shorten the time from
progresses. As the life cycle of drug development unfolds, the demands
synthesis to regulatory approval.
on the synthetic process will change. In early development, the emphasis is
Planning a synthetic route for a compound is the job of a process chemist.
The chemist typically first looks at the required compound, and works
backwards through a logical sequence of reactions until the suitable
very much on timely delivery of bulk supplies of the API using a safe process.
Thus, most of the SELECT criteria can usually be satisfied when preparing
the first few kilograms of the API or New Chemical entity (NCE) in bulk.
starting materials can be found. During this process, there may be many
In the early clinical trial stages, the most frequent issue encountered
intermediate compounds that have to be separated and purified from
involves patient safety. However, we are also focusing our efforts on
the other compounds. These are the necessary steps and the key process
attaining the highest yield, the lowest number of impurities, the easiest
during drug development.
purification process, the least amount of pressure and most moderate
The Complexity of Synthetic Route Selection
temperature. In other words - the most efficient process.
Although drug candidates range from relatively simple structures to
available, little can be done to progress these clinical and toxicology
highly complex ones, nearly all drug candidates present significant
challenges to the process chemist. Every API requires new chemistry
never before attempted, with all the pitfalls that it entails.
Prepare for Scale-Up. Until the first few kilograms of API are made
studies. Given the complexity of the processes involved in scale-up,
a key best practice is to include at least three kilo scale-up trials of the
process while still in the lab, before heading into a far more costly cGMP
Initially, as the chemistry is developed, you may be working on a small scale
manufacturing facility for commercial processing.
and everything seems easy - or so you think. Although the hypothesis being
Developing Sound Synthetic Route Processes
tested in a clinical trial may seem straightforward, the complexity resulting
from the large number of variables involved creates a high-risk business
with the highest failure rate for new product candidates of any industry.
So how do you ensure you get it right the first time when it comes to
While there are many things to consider and multiple steps to undertake
in selecting a synthetic process for your drug candidate, best practices
CMOs focus on the following five key factors:
*
Chemical yield
*
Cycle time
much attention to yields as long as the conversion is relatively decent.
*
Number of chemical steps and convergence
Additionally, before you start doing experiments, focus first on things
*
Use of higher molecular weight protecting group and reagents
*
Number of energy-consuming operations
synthetic route selection?
Choose the route to greatest efficiency. You should not pay too
like which reagents to use and how to make the process as efficient as
possible. The more efficient the chemistry, the easier to purify and to meet
ICH guidelines.
Implementing this approach is key to reducing API development time as
Take the starting point: The medicinal route. The starting point for
complexity grows and budgets shrink. As with any risk management plan,
most process development programs is the medicinal chemistry route.
This route is typically designed to be divergent to allow access to a variety
the goal is to be proactive in finding and mitigating sources of risk. This is
accomplished by removing unwanted variability in each stage of a process.
of targets. But it is only a starting point. The medicinal chemistry route
When a drug enters clinical trials, the key is to identify, reduce, and monitor
is not usually designed for further scale-up into a commercial process.
risks to patient safety, data integrity, regulatory and protocol compliance,
Consequently it is likely that the process chemist will need to change
and project scope. Paying close attention to the five key factors outlined
the synthetic route at least once during the course of the development
above, not only ensure the most advantageous synthetic route, but safe,
program. And the performance of a process on an even larger scale
effective drugs for patients. While manufacturing Active Pharmaceutical
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Seqens eBook
Table of Contents for the Digital Edition of Seqens eBook
Contents
Seqens eBook - 1
Seqens eBook - Contents
Seqens eBook - 3
Seqens eBook - 4
Seqens eBook - 5
Seqens eBook - 6
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