Areas For Advancement In Peptide Manufacturing
By Tyler Menichiello, contributing editor
The explosion of GLP-1 drugs (and prescriptions) in recent years has pushed aged peptide manufacturing technology and infrastructure to its capacity. As countries like the U.S. move to onshore peptide production domestically to meet this growing demand, the industry has an opportunity to reevaluate the way peptides are manufactured. How can manufacturers improve processes to achieve higher yields at lower costs? How can they make processes less resource-intensive and more environmentally friendly?
During the hour, our panelists discussed the challenges and exciting opportunities for improvement in peptide production. The conversation ranged from deciding between microbial expression and chemical synthesis to curbing solvent use, reducing costs, and making processes more environmentally friendly.
Microbial Expression Or Chemical Synthesis?
While recombinant expression may be a better fit for longer peptides, it comes at the cost of longer lead times. “The time to the clinic with a synthetic process is much faster,” Villain said. “You can be in the clinic in approximately a year from the moment you decide to launch the project.” Synthetic processes are also better suited for peptides with unnatural amino acids or side-chain modifications.
Achieving More Efficient Peptide Synthesis
For example, having a better understanding of process kinetics (e.g., coupling and deprotection kinetics) can lead to more efficient utilization of manufacturing time. Aside from understanding and characterizing the chemistry itself, optimizing reagent use is another way to reduce costs associated with peptide synthesis. “There are significant quantities of solvent used in SPPS as part of the intermediate wash steps,” Seibert explained. “So, there are efforts to reuse those washes in a way such that washes containing low levels of impurities can be used as initial washes in subsequent steps.”
It’s equally important to avoid unnecessary washing steps, said Villain. You don’t want to waste time and solvent performing washes that don’t contribute to the quality of the product.
Another way to improve process efficiency, at least in SPPS, is by using small amino acid chains (e.g., tetramers and trimers) as building blocks rather than a stepwise, linear build. “It’s a really great way to help improve the overall efficiency of SPPS,” Seibert said. This method also lends itself to a hybrid approach — i.e., combining SPPS and liquid-phase peptide synthesis (LPPS). “You can use solid-phase to generate fragments, and then in liquid-phase, assemble those fragments sequentially to form the peptide,” Seibert explained. While a linear build may be more suitable for certain peptides, the higher purities and higher yields associated with short-length peptide synthesis make this hybrid approach a reasonable choice for building complex peptides.
Resin quality can also play into manufacturing efficiency, and Villain noted the need for better characterization of resins, calling them a “black box” in terms of understanding their properties and how different batches can impact final product quality. Seibert agreed, saying, “I would love to see us invest time and effort into better characterization of the chemistry associated with synthesizing the resins themselves.” This insight would enable better predictions about how certain resins will perform once put into a manufacturing environment.
Lowering Production Costs And Environmental Impact
In the latter half of the event, our panelists deliberated on the concept of greenness — i.e., the measure of a process’s efficiency and raw material usage weighed against its environmental impact. Process mass intensity (PMI) is a generally accepted way to measure a process’s efficiency and greenness. However, assigning one PMI value to a process can be misleading, said Villain, especially when it conflates water use with chemical reagent use (as one is obviously more environmentally hazardous than the other).
Instead, he suggests evaluating a process in two parts — a PMI for upstream (synthesis) and a PMI for downstream (purification) to understand the environmental and chemical impact of each segment. Evaluating peptide synthesis in these respective parts can make it easier to measure process efficiency and determine exactly where inefficiencies can be addressed.
In an effort to curb industrial waste and improve process greenness, there is an opportunity to investigate the utilization of greener solvents — i.e., solvents that are reusable or more recoverable. Doing so can improve the environmental footprint of peptide synthesis across the board. “It’s also one of the major drivers to move away from SPPS,” Seibert said, and into more synthetic approaches (e.g., purely chemical synthesis or linker-based synthesis), “which are inherently much lower in solvent consumption.”
“I think probably our best option is to move away from solid phases as soon as we can,” Seibert said. “That, in my mind, is probably our biggest opportunity to both lower costs and improve our environmental footprint of peptide synthesis.”
For more on trends and improvements in peptide manufacturing, you can watch the whole event recording (as well as individual segments) for free thanks to the event sponsor, Federal Equipment Company. On April 16 at 11 a.m. ET, Pharmaceutical Online will host another live panel discussion, this time on facility design and validation considerations for drug manufacturers. It’s a conversation you won’t want to miss, so stay tuned to Pharmaceutical Online for more details to come!