CASE STUDY: A JOURNEY TO REVOLUTIONIZE DRUG
MANUFACTURING
IN AN INDUSTRY CHARGED WITH HELPING THE WORLD’S POPULATION
BE WELL, GREEN CHEMISTRY IS A CRITICAL TOOL
WHAT
WHERE
WHEN
WHO
Green Chemistry
Global
2007–Present
Biocatalysis team at Merck
LOCAL STRATEGY REDUCES WASTE,
SUPPORTS MERCK’S ENVIRONMENTAL
SUSTAINABILITY GOALS
WHAT IS GREEN CHEMISTRY?
Green Chemistry is about designing chemical processes that
reduce or eliminate the use and generation of hazardous
substances. Less hazardous waste means a healthier
environment. The benefits of green chemistry are realized
across the life cycle of a chemical product, including its design,
manufacture and use. Specifically, these innovations are driving
production methods that are:
• More efficient: Fewer reaction steps, fewer resources required,
less waste
• Simpler to use: Operate at normal temperatures and pressures
• Environmentally friendlier: Lower-impact solvents, less
hazardous waste
CHALLENGE
In 2007, Merck chemists had to find a way to support the
growing demand for JANUVIA® (sitagliptin), the company’s
treatment for type 2 diabetes, and make the manufacturing
process of the active ingredient, sitagliptin, more efficient and
have less impact on the environment. The manufacturing
process for sitagliptin at that point was energy intensive and
required a rare metal, rhodium, as a catalyst that had to be
removed at the end of the process. A new process needed to be
developed that would be scalable, sustainable, deliver significant
cost savings and have less impact on the environment.
SOLUTION
Matt Truppo, a Director in Merck’s Process Chemistry
Biocatalysis group, was part of the team that discovered the
solution while partnering with Codexis, Inc., a company
specialized in directed evolution technology. Directed evolution
technology offers the ability to generate customized enzymes,
which can be used in place of traditional chemistries. Merck had
been working on a class of enzymes known as transaminase,
believing that transaminases could revolutionize the industrial
synthesis of complex pharmaceutical compounds. Merck just
needed an opportunity to test that theory.
That opportunity was sitagliptin. But there was one challenge.
“At the time,” says Rich Tillyer, then Senior Vice President of
Preclinical Development at Merck, “most synthetic chemists had
limited to no experience using enzymes, and the experience they
did have was usually based on decades-old enzyme technology.”
Merck was intent on proving that the new technology would
work. As Matt described it, “Enzymes are the ultimate green
catalysts – they are renewable, biodegradable and are generally
believed to provide a more sustainable means of synthesis than
more traditional chemistry approaches.”
It took 10 months to produce an industrially ready enzyme, and
another five months to deliver enough enzyme for the Merck
team to include in the remaining process steps.
Enzymes enable Merck’s chemists to use simpler equipment and
processes. And unlike chemical catalysis, which often use rare
earth metals that are mined and then purified in energy- and
waste-intensive processes, enzymes can be grown in a tank
– fermented in a process similar to making beer.
By November 2008, the team had successfully developed a
second-generation green synthesis of sitagliptin. This enzymatic
process demonstrated potential to improve productivity by 56
percent, increase yield by 10 –13 percent and reduce overall
waste generation by 19 percent. Merck scaled-up the new
process in 2009 in its pilot plant.
Directed evolution technology by 2007 had advanced to the point
where it was possible to develop enzymes in months rather than
years, which was critical for manufacturing.
“There was a lot of excitement within the group to push green
chemistry because we recognized how powerful it could be early
on,” remembers Matt. “Codexis had this great technology and
we had a lot of ideas at Merck about how to apply it.”
“Green chemistry, done correctly, is about
more than just preventing waste. It’s about
increasing efficiency, reducing cost and
operating in a more sustainable way. As a
global healthcare company, we have an
obligation to bring our products to the
patients who need them in the most costeffective and environmentally responsible
way. It’s good for Merck, and it’s good for
the patients we serve. The advances we’ve
made over the last few years show that
these notions are not mutually exclusive.”
Matt Truppo, Director, Process Chemistry
“We were confident that our technology could deliver solid
results, including creating a custom enzyme, or biocatalyst, that
would allow for commercial-scale manufacturing of sitagliptin,”
recalls Peter Seufer-Wasserthal, Senior Vice President, Codexis.
After a few months of work, the team developed a prototype
enzyme and then fine-tuned the conditions under which the
enzyme would operate. Matt recalls, “Constant feedback from
teams at Merck about the process needs was provided to
Codexis to develop better versions of the enzyme we needed.”
The results did not go unnoticed. In 2010, the new process won
the Presidential Green Chemistry Award, which is presented
annually by the U.S. Environmental
Protection Agency. The Award
recognizes new technologies that
help prevent pollution by reducing
or eliminating hazardous waste in
industrial production. The process
was also described in a 2010 paper published in Science.
Five years from the start of the work, Merck received FDA
approval in April 2012 to apply the new enzymatic catalysis step
for the manufacture of sitagliptin.
Getting this innovative, first-ever green chemistry approach to
work in a reliable and repeatable manner in a full-scale
manufacturing environment was the work of Merck’s
Manufacturing Division, which worked hand-in-hand with the
research scientists who developed the process. “Developing this
enzyme and getting the process to work in the lab was amazing.
But then it needed to be shown that the process could work and
deliver the benefits at manufacturing scale, running all day, every
day,” said Mike Thien, Senior Vice President of Merck
Manufacturing’s Global Science Technology and
Commercialization area.
There were significant technical challenges on the engineering
and analytical fronts that needed to be addressed before the
patient and the environment could benefit from this new process.
“The collaboration between Merck’s research and manufacturing
teams and our partner Codexis was impressive. Numerous
functions from both companies worked seamlessly to develop
the process, scale it up and demonstrate it at full scale at Merck’s
Barceloneta, Puerto Rico, manufacturing facility. These same
people worked with Merck’s Regulatory group to prepare global
submissions for the new process, allowing us to realize not only
environmental improvements, but also reduced manufacturing
costs,” said Steve Poehlein, Vice President of Technical
Operations, whose team worked to make this a reality.
biocatalysts developed by this collaboration will continue to
pay dividends to the environment, drug development and
synthetic chemistry in the years ahead not just for Merck but
for the entire industry.”
In May 2012, Codexis and Merck announced a three-year
extension of their collaboration, allowing Merck to continue to use
the proprietary enzyme products developed by Codexis to
develop more cost- and resource-efficient manufacturing
processes for the company’s pipeline of therapeutic candidates.
Merck Chairman and CEO Ken Frazier and members of Merck’s Green Chemistry
team accepting the 2012 Chairman’s Award for their efforts to revolutionize the
manufacturing process for Januvia.
In June 2012, Merck Chairman and CEO Ken Frazier presented
the Chairman’s Award to Merck’s Green Chemistry team. The
Award recognizes Merck employees who demonstrate
Environmental, Health and Safety (EHS) excellence through an
initiative that has significant, positive impact across the company
and sets a benchmark for world-class EHS practices within Merck
and beyond.
“We continue to change how we manufacture our products, and
green chemistry is a catalyst for this change,” said Matt. “We’re
just scratching the surface of what will be possible in the next
decade. Our job now is to continue to inspire a culture throughout
the company in which green chemistry and engineering is a
guiding philosophy in research and active pharmaceutical
ingredient manufacturing.”
To read more about Merck’s environmental sustainability
journey, including how green chemistry is helping the
company achieve its 2020 goals, go to
www.merckresponsibility.com
In his remarks, Mr. Frazier said:
“The issues of environment, safety and health are important
to any organization or business. But for a global healthcare
leader like Merck, these issues are absolutely central to what
we do and how we do it…We are on a path to reinvent Merck,
and you are helping us make best use of our finite corporate
resources as well as the earth’s finite natural resources. Your
attention to increasing efficiency and reducing costs frees up
valuable company resources, and at the same time, it
contributes to environmental sustainability…You are helping
us deliver on our mission and invest in profitable global
growth opportunities.”
THE NEXT CHAPTER
“The worldwide demand for lower-priced drugs with proven
benefits to human health poses an increasing challenge to
process chemists to develop manufacturing routes that not only
deliver maximum value, but also minimize waste generation,”
says Rich. “It is imperative that we push the frontiers of science,
technology and innovation to meet these demands. The
Copyright © 2012 Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. All rights reserved.