What Transfers, What Doesn’t

Leveraging small-molecule proficiency to advance peptide and oligonucleotide manufacturing

What capabilities transfer best from small molecules to TIDES?

Most people would point first to technology: enzyme engineering, flow chemistry, and advanced analytics. Those matter, but in my opinion, the capabilities that create the greatest advantage — talent, and a quality system transfer best.

Small-molecule chemists already understand reaction design, process optimization, and scale-up — they aren’t starting from scratch in TIDES. However, modality-specific expertise still takes six months to a year to build, while demand for experienced TIDES talents continues to exceed supply. The solution is to combine strategic recruitment with talent development.

The same is true for quality. Decades of commercial manufacturing have established the principles that matter most: robust process design, clear specifications, operational disciplines, and the ability to demonstrate quality control to health authorities. While chemistries differ across modalities, the fundamentals of quality do not.

What’s the real lesson behind industrializing GLP-1 peptide manufacturing?

If a product can be made in ten steps instead of twenty, costs fall dramatically. In small molecules, route redesign has repeatedly reduced cost of goods by 30−40% while improving sustainability.

The industry’s immediate response to GLP-1 demand has been to add capacity. Capacity is necessary, but it does not address the underlying economics. Solid-phase peptide synthesis remains robust and reliable, yet at scale, solvent consumption and waste become significant challenges.

Small molecules faced similar constraints before. During COVID-19, we converted a cryogenic process to continuous process and produced 480 metric tons of an intermediate over six months, solving both a capacity and energy challenges that batch processing couldn’t address efficiently. Experiences like this reinforce our view that continuous manufacturing is not merely a capacity tool but a way to improve process economics.
Today, the most practical solution is often a hybrid approach, combining solid-phase and liquid-phase syntheses. We manufacture dipeptide and tripeptide intermediates using immobilized enzymes in continuous mode, achieving routinely titers above 60 g/L within an hour. Capacity is essential, but chemistry ultimately defines economics.

How is chemoenzymatic technology changing the game for oligonucleotides?

The challenge with traditional solid-phase oligonucleotide synthesis is straightforward: as sequences become longer, maintaining yield and purity become increasingly difficult because impurities accumulate throughout the process.

Chemoenzymatic manufacturing changes the assembly strategy. Instead of constructing a long sequence nucleotide by nucleotide, shorter high-purity fragments are synthesized and then assembled under enzymatic conditions. Historically, selecting ligation sites required extensive trial and error. Today, our AI-assisted platform can identify optimal ligation sites with greater than 95% success, making the process far more predictable.

The impact can be substantial. In a recent siRNA program, the process achieved 99% conversion, more than 90% crude purity without chromatography, and 98% purity after a single purification step. Process mass intensity was reduced by more than 70% compared with a conventional solid-phase synthesis. The platform has also been validated at hundred-gram scale and applied to modalities including divalent siRNA and sgRNA.

By changing how oligonucleotides are assembled, chemoenzymatic manufacturing makes longer and more complex sequences increasingly practical to produce.

Why does integrated expertise across modalities matter to drug developers?

The greatest value is often not within a single modality but at the interfaces between them. Next-generation therapeutics increasingly combine peptide, oligonucleotides, and small-molecules. In these programs, risk frequently arises from handoffs rather than chemistry itself. A common technical and quality framework enables faster information flow, quicker decision-making, and lower technology-transfer risk.

On a recent dual-target peptide program, Pre-Approval Inspection (PAI) readiness was achieved within six months, regulatory questions were addressed in 18 days, approval was obtained approximately one month ahead of schedule, and the first commercial API batch was released within six weeks of approval. As therapeutics grow more complex, the interfaces matter just as much as the technologies themselves.

Looking ahead, which bottlenecks will small-molecule experience help solve — and which demand entirely new science?

Some capabilities transfer directly: process understanding, analytical control, CMC discipline, and commercial execution. As TIDES molecules become more complex, these strengths become increasingly valuable.

Other challenges require new science. Enzymatic oligonucleotide synthesis beyond phosphoramidite chemistry is still emerging.
Characterizing very long, heavily modified sequences continues to push analytical limits. Delivery beyond the liver remains challenging and is ultimately a biology problem rather than a chemistry problem.

The third bottleneck lies in operations. Scientific advances can happen in weeks, while documentation and technology transfer may take months. Unlike many scientific challenges, this can be addressed today through better systems, automation, and digital tools.

The next decade of TIDES manufacturing will be shaped by two forces: applying proven industrial discipline more effectively and developing the new science needed for novel therapeutics.

Dr. Cheng-Yi Chen is Chief Technology Officer at Asymchem, leading development and manufacturing across small molecules, peptides, oligonucleotides, and ADCs. He joined Asymchem in 2024 after three decades in process chemistry, including two decades at Merck and senior roles at Janssen, Mirati Therapeutics, and Bristol Myers Squibb. At Mirati, he resolved the supply constraint on KRAS G12C inhibitor adagrasib and validated its commercial launch. His work spans marketed medicines including efavirenz, losartan, and esketamine. He holds 120+ publications and patents, received a PhD from The Ohio State University.