Defining Oligonucleotide Scale-Up: Why Manufacturing Advantage Begins at the Phosphoramidite and Wider Building Block Level

As therapeutic oligonucleotide programs mature and advance toward late-stage clinical trials, industry conversations have developed over the last 20+ years. The focus is no longer solely on the target molecule itself, but on the complex manufacturing capabilities required to produce it reliably, at scale, lower COGs and to exacting quality standards.

Discovery programs also require the same raw materials, including new entities, to enable high-quality research.

At Sapala and Cohance Lifesciences, this prompted us to reinforce how the quality of the foundational building blocks of synthesis and how their roles are evolving in a maturing landscape. Take one building block: phosphoramidites however this applies to all the structural components which can be GalNAc, linkers, lipids and more.

From Sourcing Commodity to Critical Quality Driver

As oligonucleotide architectures grow more complex—incorporating novel modifications, GalNAc conjugates, and longer sequences – whether synthesized in full or ligated – phosphoramidites are critical determinants of synthesis performance, yield, and final drug substance quality.

In solid-phase oligonucleotide synthesis, quality is cumulative. An impurity in even a single amidite building block can carry through the entire synthesis cycle, generating closely related side-products that are difficult to purify downstream.

For therapeutic applications, phosphoramidite quality requires:

• Stringent Purity & Impurity Control: Ensuring high coupling efficiency at every single step to minimize n-, n+ and isobaric products.
• Rigorous Characterization: Deep profiling and control of impurity profiles across batches.
• Traceable Quality Systems: Comprehensive testing and regulatory documentation to satisfy global compliance standards.
• Scalable Production: Seamlessly transitioning phosphoramidite synthesis from discovery to commercial-scale supply without batch-to-batch variation.
• Back integrated supply chain: Control of quality begins from the nucleoside and ultimate origin.

Ultimately, phosphoramidite quality is an integral manufacturing consideration, not merely a procurement item.

The CDMO Equation

Contract Development and Manufacturing Organizations (CDMOs) working with oligonucleotide pipelines require fundamental technical capabilities. They must offer:

1. Deep Chemical Expertise: A granular understanding of phosphoramidite reactivity, degradation pathways, and long-term stability.
2. Batch-to-Batch Consistency: Process robustness that guarantees identical performance across multi-kilogram lots.
3. Advanced Analytical Controls: High-resolution methods to identify trace impurities.
4. End-to-End Scalability: Dedicated infrastructure to scale custom and complex oligonucleotide chemistries in line with clinical progress.

Securing the Building Blocks of Oligonucleotide Success

At Sapala and Cohance Lifesciences, this reality has driven deeper investment in our internal amidite capabilities, giving us greater control over the core chemistry that underpins oligonucleotide manufacturing and supporting our innovator and CDMO customers.

Sapala, as per the last 20+ years, is dedicated to the discovery and early phase market to generate the next generation of candidates and Cohance, as per the last 30+ years, to taking materials through to commercial supply.

Through our R&D center of excellence at Sapala Organics, Hyderabad, and scale up teams at Cohance Nacharam, Hyderabad, we bring specialized expertise in custom amidites and complex nucleic acid chemistry. From early-stage route development to commercial scale-up, we help partners mitigate supply chain risks and ensure quality from the ground up.

As the oligonucleotide field expands, long-term competitive advantage won’t just come from having raw manufacturing capacity; it will belong to those who understand and control the critical building blocks that feed that capacity.

Interested in learning how integrated phosphoramidite expertise can de-risk your oligonucleotide pipeline? Connect with our team at Sapala and Cohance Lifesciences to discuss your custom synthesis needs.

And visit www.cohance.com and www.sapalaorganics.com to learn more.