process validation was successfully completed, enabling the API
to be manufactured at a 40kg batch scale.
SUPPORTING API DEMAND AT LATE
CLINICAL PHASE AND COMMERCIAL LAUNCH
Late-stage development requires specific skills that a CMO may be
better placed to provide than a company’s in-house team. Biotech companies are unlikely to be able to do these tasks themselves, and therefore will look for a CMO with extensive experience in supporting API
manufacturing for late-stage development and commercial launch.
Case Study No. 3. Internal development and transfer. A customer synthesis project for a generic API project was originated
by Cambrex at the company’s R&D site in Tallinn, Estonia, and
a number of scouting runs performed to establish the synthetic
route and initial development procedures. The development and
technical transfer teams from the company’s Charles City site became involved early on in the project to help direct development,
which included design of experiment (DoE) studies.
The process transfer was undertaken in Estonia, so the U.S.
staff were able to see the process being implemented and discuss progress with the Estonian development team. This early
involvement resulted in very little process development being
required after the campaign was transferred back to Cambrex
Charles City for full-scale commercial manufacture.
Case Study No. 4: Process development. A client approached
Cambrex with an 8-step process that required further development
and CMO support for production and commercial launch of an API.
A previous CMO had made 50kg of the API with an overall yield
of 9%. By understanding and optimizing two key reaction steps,
Cambrex was able to develop a process that gave a substantially improved overall yield of 49%. DoE being used to determine a proven
acceptable range (PAR) for each critical process parameters (CPP),
and fate/purge of impurities. Analytical method development and
validation included chiral chromatography and UPLC-MS.
Case Study No. 5: Technology transfer. A U.S. client that had
developed a complex 4-step process was looking for a domestic
supplier of the product. Cambrex had considerable knowledge
of the client’s process, having previously manufactured it at pilot
scale, and developed a suite of analytical methods that enabled
the chemical process to be monitored.
Cambrex committed to building and qualifying a new large-scale manufacturing facility for the process in Charles City. This
was achieved in less than one year, and only one laboratory-scale run was required before the process was transferred to the
pilot plant. Furthermore, just two validation pilot runs were required prior to the scale up of the process to 15,000-litre equipment. The application of Six Sigma techniques has allowed an
increase in production year-on-year, and more than 60 tons of
this API have now been manufactured by Cambrex over the
past four years.
WHAT MAKES A GOOD SMALL MOLECULE CMO?
For a partnership with a CMO to succeed, there are multiple
factors that will be important. The CMO should have extensive
expertise in process chemistry and engineering, with a reputation for quality and reliability in its manufacturing operations. As well as a strong safety record, it should offer advanced
chemical manufacturing technology, and flexibility that allows it
to manufacture small molecules from milligram through to ton
scales, and be able to adapt as the molecule moves through the
Perhaps the most critically important factor, however, is that
the CMO should offer dedicated support throughout the whole
route through development, from compound selection to commercial launch and beyond. Speed is of the essence, and any
delay in the development process will shave weeks, months or
even years off the time a drug will have on the market before it
is subject to generic competition on patent expiry. A good CMO
will play a key role in getting the drug to the market in a timely
fashion, so it can start to recoup those huge development costs. CP
ABOUT THE AUTHORS: Dr. Dan Bowles is senior director of chemical development at Cambrex High Point, North Carolina. Dr. Michael Tracey is principal scientist
for new product development at Cambrex Charles City, Iowa.