CASE STUDYUNITED
WITH
EFFECTIVENESS &EFFICIENCY

The criticality of API CDMO selection:
insights from a client
The global value of the oncology drug market isestimated to reach nearly $180 billion by 2025,
making it a targeted area of opportunity formany pharmaceutical companies.1 Yet, despite
its promise, the complexity of cancer and thedrugs used to treat it present several risks whenit comes to the cost of development and thethreat of failure.
Small and emerging companies entering this space already facesignificant challenges related to limited funding and resources,such as technical expertise and capacity, making it imperative theyfind a competent partner to support them. This requires not justa Contract Development & Manufacturing Organization (CDMO)
that can fill these gaps but also one that values the relationshipenough to maintain clear and open lines of communication at
every stage of a project. Doing so helps avoid common pitfalls
that can result from a lack of transparency, especially for acompany taking on the exciting but challenging field of oncology.
Finding this type of partner as it began its journey was top ofmind for 4SC AG, a clinical-stage biopharmaceutical company
focusing on the development of small molecule drugs targetingkey indications in cancer with high unmet medical needs. With lessthan 50 people in its company, 4SC sought a CDMO that could

provide the know-how and mutual trust necessary for the smallcompany to successfully develop its lead asset, resminostat. It
found this partnership with Thermo Fisher Scientific Pharma
Services, where an experienced team helped 4SC overcome
active pharmaceutical ingredient (API) manufacturing hurdles,
leading to a path toward commercial success.

The power of effective project management
Resminostat is an orally administered histone deacetylase
inhibitor that could potentially be used for a wide range of oncology
indications, both in monotherapy and in combination with otheranti-cancer drugs.2 Dr. Rolf Krauss, Director CMC at 4SC, says
they ultimately selected Pharma Services based on positive
interactions with the project management team. “Some factors
we use to evaluate the capabilities of a potential partner, such as
experience and cost, are fairly simple to measure. However, whatis most important is how effective and empowered its project
management team is, which can be determined by how openly
and honestly they communicated from the start,” he explains.
“With Pharma Services, we were given direct communication withthe account manager, and his expertise gave us the confidence
we could consult him and his team on any issue and they would
be able to help.”

As with most project management teams in drug development,
Pharma Services’ consists of a project leader working on-site withthe experts and a business manager overseeing the commercial
side of the project. What makes the structure of Pharma Services’teams unique, though, is that the project leader and business
manager positions are filled by chemists and project engineers
with several years of experience in lab and production settings. “Itis imperative that the technical experts can communicate directlywith their counterparts while keeping the project leader on bothsides in the loop,” explains Dr. Hanno Wertal, Senior ProjectManager, Thermo Fisher Scientific. “That way, information is not
lost in translation, and the project leader can rely on his strong
technical background to steer discussions in the most productivedirection.”
Pharma Services’ project teams are small, including only aquality specialist, analytical chemist, chemist, process engineer
and manager, so core members can communicate directly. This
leads to faster response times, something smaller companies
are often used to. If necessary, the composition of the teams
can be adjusted to better fit the level of knowledge required forthe project. “It is important to have a mix of young chemists whoquestion things and have a certain drive and experienced experts
who have a better overview and can draw from previous projects,”
says Wertal. “It is a key task for the project leader to ‘feel’ whichapproach best suits the customer.”
He says the relationship should begin with a face-to-face
discussion, where all team members from the customer’s sideand Pharma Services’ internal team get to know each other andcontacts can be established. Dr. Krauss agrees this is a vital partof CDMO/customer relationship. “Having direct communication
with the people who will play a critical role in the project, such as
developing the synthesis, is essential to breaking down the silosthat so often exist in our industry,” he explains. “If those people
have expertise and experience with that task, they can understandour concerns and address them in real time.” As challenges wereencountered later in the project, this aspect of their partnership
became a key factor in maintaining the timely delivery of 4SC’s
clinical materials.

Readying for the reality of API development
Drug development is an inherently costly and risky undertaking
that will undoubtedly have setbacks and surprises along the way.
Fundamental to the long-term success of a molecule, though,is the development and validation of the API manufacturing
process. Working with a CDMO with the resources to seamlesslyalign the development and manufacture of an API and finisheddrug product will help speed a molecule through development
and prepare a company for commercial success faster. This,
combined with open lines of communication, can provide thetools necessary to overcome challenges that often find their way
into the drug development process.

For example, due to tightened, process-immanent raw material
specifications, an additional step had to be added at the beginningof the five-step synthesis for resminostat shortly before scheduled
production. In addition, a challenging impurity control strategy
required longer analytical and experimental development times
on nearly all of the steps. Resminostat is an anti-cancer agent
and a high-potency compound; thus, very high safety standards
had to be applied. New results from API physicochemical
characterization and drug product formulation made a nearreal-time update of the accompanying GMP-documentationnecessary. Specifically, over 500 pages of documentation had
to be quickly but accurately revised, reviewed, and approved byboth parties before validation could begin. This required not only
fast action from Pharma Services but also seamless collaboration
between both parties, facilitated by weekly teleconferences andseveral face-to-face meetings.
Although the issue could have caused serious and costly delays,
the teams worked together and overcame the challenge, leading
to a successful validation campaign with a substantial amountof material produced and ready for commercial use. “In ourentire communication with Pharma Services, we always felt they
possessed the capabilities and forward-thinking necessary to
deeply understand our process, determine what we needed, andhelp us through any challenges,” says Dr. Krauss. “Almost more
importantly, we felt we were being given the same amount ofattention as they would give a bigger company and that it meant
just as much to them as it did to us that this project finishedsuccessfully.”
Today, resminostat has shown to be well-tolerated in several
clinical trials and is currently being investigated in a pivotal study
in cutaneous T-cell lymphoma (CTCL) by 4SC.4 Looking forward,
4SC is eager to pursue the development of another candidate
in its pipeline, domatinostat. This is another orally administeredsmall molecule treatment for cancer, which is currently being
tested in clinical trials. Once these trials are complete, 4SC plansto advance domatinostat into a pivotal case study, where it will
look to Pharma Services for its API development. Dr. Krauss
explains, “The relationship we developed with Pharma Services
during the development of resminostat gives us confidence that
we can entrust our company’s future with their team, and they willoffer us the expertise, effective problems olving, and attention weneed to bring our drugs to the market safely, efficiently, and withthe highest level of quality.”References
1. Big Market Research. (March 14, 2019). Oncology Drugs Market Growth Outlook
Shows 7.6% CAGR To Hit $176,509 Million by 2025. Retrieved from https://www.globenewswire.com/news-release/2019/03/14/1753284/0/en/
Oncology-Drugs-Market-Growth-Outlook-Shows-7-6-CAGR-to-Hit-176-509Million-by-2025.html
2. 4SC Resminostat summary. Retrieved from https://www.4sc.com/
product-pipeline/resminostat/
3. 4SC. (January 28, 2019). 4SC’s pivotal RESMAIN study of Resminostat in CTCL
receives second positive safety review. Retrieved from https://www.4sc.com/
news/4scs-pivotal-resmain-study-of-resminostat-in-ctclreceives-secondpositive-safety-review/
4. U.S. National Library of Medicine. Resminostat for Maintenance Treatment of Patients
With Advanced Stage Mycosis Fungoides (MF) or Sézary Syndrome (SS) (RESMAIN).
Retrieved from https://clinicaltrials.gov/ct2/show/NCT02953301+1 919 226 3200 • thermofisher.com/patheon • pharmaservices@thermofisher.com© 2021 Thermo Fisher Scientific Inc. All rights reserved.
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