How Eli Lilly's Making Peptides Faster And More Reliably
A conversation with Matt Foster, Darragh McDonagh, and Kevin Seibert, Eli Lilly and Company
Eli Lilly and Company’s approach to high-throughput peptide manufacturing has caught the industry’s attention for its ingenuity and layers of complexity.
Amid an unprecedented push to build out production capacity for GLP-1 drugs, Lilly developed a platform that uses continuous manufacturing processes to produce more synthetic peptides and do it more reliably, the company said, at its existing facility in Kinsale, Ireland.
The International Society for Pharmaceutical Engineering will recognize Lilly at the 2024 Facility of the Year Awards (FOYA) Banquet and Awards Celebration at the 2024 ISPE Annual Meeting & Expo in Orlando later this year. The project, called IE2b, won the FOYA in the innovation category.
Three Lilly leaders — former Kinsale plant manager and current Research Triangle site head Matt Foster, Senior Director of Engineering Darragh McDonagh, and Vice President of Engineering Kevin Seibert — fielded our questions about what makes IE2b special and some of the challenges they encountered along the way.
What makes the peptide production platform at IE2b unique compared to the status quo?
The technology used to produce synthetic peptides was first proposed in 1959 – in fact, it won a Nobel Prize in 1984. That same platform technology has been used ever since with little advancement in technology or innovation to improve the manufacturing processes. To meet the need of an exciting new Lilly portfolio of peptide medicines, a team of Lilly subject matter experts started working on a new innovative peptide manufacturing platform incorporating novel manufacturing technology and digital innovations. Rather than go with the status quo, our team’s objective was to design an industry-leading, high-throughput facility capable of reliably manufacturing peptide medicines efficiently, safely, sustainably, and with a high degree of control to meet patient needs all over the world.
The team started by evaluating various technologies and approaches available for peptide synthesis. Efficient, sustainable, compliant, safe, and reliable operations were high-priority goals for us.
With these goals in mind and building on previous experience with innovative continuous processing technology, the team developed a hybrid manufacturing platform, liquid phase peptide synthesis/solid phase peptide synthesis (LPPS/SPPS), which combines the traditional approaches to synthetic peptide production using SPPS to manufacture high-purity pre-assembled peptide fragments combined with coupling the fragments via LPPS using novel continuous processing technology.
In addition to the hybrid approach, we wanted to layer in other technology such as integrated process analytical technology (PAT) control enabling exquisite stoichiometric control and conversion of reagents, especially expensive reagents like peptide fragments. Also, peptides are notoriously amorphous in nature, which makes isolation very complicated because they’re not crystalline, so we incorporated another technology that allows us to avoid isolating intermediates and carry our chemistry straight through to the next step via a nanofiltration operation. This first-of-its-kind ceramic nanofiltration system is resistant to a lot of the chemicals used in peptide manufacture.
All of these layered technologies resulted in a platform that not only met the team’s goals but is a first in the pharmaceutical industry and delivers far higher operational efficiency benefits than traditional peptide manufacturing platforms.
Can you talk about some of the material tracking bottlenecks and how IE2b solved them?
Developing systems for material tracking in continuous manufacturing was a challenge – especially at a large commercial manufacturing scale. In order to track materials within this new platform, we had to develop a new digital solution that is an industry first.
In continuous manufacturing, we need to ensure a continuous supply of makeup reagents without needing or causing the process to shut down. PAT tools allow us to control the stoichiometry of reagents with the simple adjustment of a pump so we can seamlessly change or bring in fresh materials and then adjust the process accordingly to get the maximum yield and purity attainable from those raw materials. The quality of material is very high and very consistent with this platform, making for a significant step change from a normal batch operation. Online HPLC (high-performance liquid chromatography) further enhances real-time monitoring and control of the process streams.
At the outset of the IE2b project, we set out to achieve an innovative digital mandate that would enable operational efficiency and enhanced control of the new peptide manufacturing platform. With digital solutions comes a lot of data, which we analyze with a multivariate data analysis tool, Simca-Online. It gives us a real-time multivariate process monitoring picture that helps detect in real time any variability that's trending out of expected target ranges, and it provides a simplified view for operators to be able to respond and adjust in a proactive manner to any variances from normal process trends.
Fitting IE2b into the existing Kinsale complex required some clever engineering and construction, including integrating with existing site infrastructure. Describe some of the challenges to making this fit and your solutions for them.
Our novel platform required entirely new equipment that hadn’t been used in the pharmaceutical industry before. So, while this was a complex project, it was also incredibly important to deliver it on schedule given the promising pipeline of peptide medicines that were in approval stage.
IE2b was built on an existing site – and a busy one at that. IE2b is a stand-alone facility (circa 92,000 sq. ft.) on the existing Lilly manufacturing campus in Kinsale, Ireland. Another challenge was the neighboring facilities were not to be disturbed or interrupted during construction as they were manufacturing critical medicines 24/7. To maximize the time available and to ensure we would be able to accelerate getting medicine to patients we designed the peptide production platform in parallel with designing the facility.
To enable this strategy, we designed as many equipment sets as skids in off-site fabrication shops as possible. This allowed us to make equipment changes quickly and efficiently to incorporate process changes if needed as the process was concurrently being finalized by our research and development team.
Fabricating as much of the equipment sets off-site also reduced the number of people working on-site as teams could work away in their own off-site fabrication facilities. Subsequently, when the building shell was built and the multitude of pre-assembled skids were brought to site it was like building a Lego set, fitting the various pieces together.
Overall, the approach enabled an accelerated delivery schedule for the facility and ensured a much safer work environment compared to needing all those people on-site working in the same space at the same time. This was particularly important for this project as it was delivered through the COVID-19pandemic. The project was one of a few that was deemed essential (by the Irish government) to continue through the pandemic, and we are proud that we were able to continue with the project, hold to the original project schedule, and provide a safe working environment for all workers on-site throughout the pandemic.
Designing a new platform, with new technology and digital applications, is disruptive innovation – it’s the first of its kind – which is why it was so important for us to engage with regulatory agencies early in the design. By involving them early and often in this project, we were able to take onboard any feedback and ensure our engineering and control strategies were clear and concise, which subsequently helped to streamline our product submission and enable a successful pre-approval inspection.
Even with all these challenges, IE2b was designed and constructed in under 33 months, an impressive engineering feat involving a phenomenal team effort.
Describe the industry's shift in priorities from large batch manufacturing to smaller-scale continuous manufacturing.
The shift toward continuous manufacturing across the industry makes sense for certain processes where process steps can be telescoped together, and the process can be run 24/7 over long periods of time. Once set up and operational, continuous processing steps produce very high yields and conversion compared to batch processing. With traditional batch processing, you must set up, manufacture, clean up, and repeat. With continuous manufacturing, multiple steps can be connected together. The number of setups and cleanups is significantly reduced, providing significantly more uptime to manufacture medicine on an annual basis.
The equipment we used is designed to last for long periods of time — the membranes and other components are meant to run for 12 months or more. This also reduces time wasted on switching out or repairing unit components. There’s also minimal human interruption in the digital and automated processes, resulting in less human error and enhanced safety and quality compliance performance.
We’ve been operating for over a year now, and the benefits are significantly positive. The level of variability control of the process is highly capable, and it’s been demonstrated consistently. With high-frequency monitoring, you also get a high frequency of data, resulting in digital batch records. With this, we’ve been able to control and release batches at a much faster rate that wouldn’t be possible if it were a classic batch paper process.
The ultimate outcome is for patients. We make medicines 24 hours a day, seven days a week — we do not stop. With continuous manufacturing, we can ensure a reliable supply of high-quality medicine gets to the patients who need it most. And we’ve already started to think about the next generation of this in this synthesis itself. How can we make fragments in a greener fashion? How can we reduce the solvent consumption for those fragments to avoid solid-phase peptide synthesis altogether? These are the questions we’re asking.
This project really energized an entire group of scientists and engineers in R&D to think not just about how to make a molecule but how to make a molecule in a manner that's green, environmentally friendly, efficient, and without toxic reagents.
Above all, IE2b was a reminder for us – and for the broader industry – of our responsibility to keep pushing the envelope. We will be the ones to help usher in this new era of medicine, but we need to continually improve the technology and our processes to make that happen. The future is bright and we’re excited.
Editor’s note: Life Science Connect and ISPE are collaborating to explore the winning strategies behind select 2024 FOYA winners. Learn more about the awards.
About The Experts:
Matt Foster is the site head at Eli Lilly and Company’s Research Triangle campus in North Carolina. Previously, he was the plant manager at Eli Lilly Kinsale in Ireland. Foster began working for Eli Lilly in 2004 as a plant engineer and took on additional management and technical responsibilities. He received a Bachelor of Engineering degree from the Georgia Institute of Technology.
Darragh McDonagh is a senior director of engineering for Eli Lilly. He has worked for Eli Lilly since 2008. Previously, he was an operations engineer for Pfizer. He received a M.Eng. degree at Swansea University, an M.Sc. degree in risk management and safety engineering at the University of Aberdeen, and an MBA at Open University UK.
Kevin Seibert is a vice president of engineering overseeing synthetic molecule design and development at Eli Lilly and Company in Indianapolis, Indiana, where he has worked since 2004. Previously, he was a research fellow for Merck. He received his M.Eng. and Ph.D. in chemical engineering from the University of Michigan.