Demand for nucleic acid therapeutics (NATs) is expanding as mRNA and oligonucleotide therapeutics advance beyond rare diseases into high-prevalence indications, particularly cardiometabolic conditions such as hypertension and dyslipidemia. For example, zilebesiran is an RNA interference (RNAi) therapeutic in late-stage clinical development for hypertension [1]. Its development highlights the potential of nucleic acid-based medicines to address widespread chronic diseases, creating new demands for scalable drug substance manufacturing.
This shift is reflected in the growth of the global NAT CDMO market, valued at USD 13.53 billion in 2023 and projected to reach USD 33.86 billion by 2030 [2]. As clinical pipelines advance and target populations expand, manufacturers face increasing pressure to deliver reliable, high-volume supply. However, a multi-vendor supply chain, in which critical manufacturing activities are distributed across separate suppliers, can introduce coordination challenges and complicate the transition to commercial production. By contrast, vertical integration brings key manufacturing capabilities and quality systems under coordinated management, reducing reliance on external handoffs and helping to improve supply chain reliability and streamline the path to commercial scale.
1. Challenges of a Multi-Vendor Supply Chain
In conventional NAT manufacturing, production activities are often distributed across multiple suppliers, each responsible for specific operations, such as raw material supply, oligonucleotide drug substance (DS) and drug product (DP) manufacturing, fill-finish, and analytical testing. Although this model provides access to specialized expertise, each transfer of materials, documentation, and technical responsibility introduces potential delays and coordination risks.
When manufacturing data, batch records, and quality decisions are managed by different organizations, investigating deviations and implementing corrective and preventive actions (CAPAs) can become more complex and time-consuming. Smaller developers may also face capacity constraints or longer lead times when suppliers prioritize larger customers. These challenges can disrupt development timelines, increase operational costs, and make it more difficult to establish a reliable commercial supply chain.
2. How Vertical Integration Strengthens NAT Manufacturing
A vertically integrated supply model brings key manufacturing activities, from starting material production through cGMP manufacturing and fill-finish, under a unified operational and quality management framework.
By coordinating critical manufacturing activities within a single organization, a CDMO can reduce external handoffs, streamline material and information flows, and strengthen oversight across production stages. Standardized quality procedures, documentation practices, and batch record management also facilitate technology transfer, deviation investigations, and process continuity.
Rather than eliminating all supply chain risks, vertical integration provides greater control over critical manufacturing interfaces and reduces the operational complexity associated with coordinating multiple suppliers.
3. Enabling Flexible and Continuous Manufacturing Across NAT Modalities
Different NAT modalities require distinct raw materials, manufacturing processes, and quality controls. A vertically integrated model can align these requirements across the supply chain, helping maintain material consistency, improve production coordination, and minimize potential delays.
(1) Oligonucleotide Therapeutics. Key starting materials include phosphoramidites, nucleoside-loaded solid supports, and other specialized reagents. These materials involve complex synthesis processes and stringent quality requirements. Their downstream conversion into oligonucleotide DS and DP requires tightly controlled chemical processes to minimize process-related impurities and ensure consistent product quality.
For programs using chemoenzymatic ligation, additional specialized inputs, including ligase enzymes, are required, together with expertise in enzymatic processing and associated regulatory controls. By developing in-house capabilities for producing critical starting materials and ligases, Hongene aims to strengthen supply security and support the large-scale manufacturing of oligonucleotide therapeutics.
(2) mRNA Therapeutics. Key inputs include modified nucleoside triphosphates (NTPs), enzymes, cap analogs, and plasmid DNA templates. Coordinating the supply and quality of these materials with downstream processes—including mRNA synthesis, purification, lipid nanoparticle (LNP) formulation, and fill-finish—helps maintain manufacturing continuity.
(3) Gene-editing Therapeutics. Gene-editing therapeutics can involve multiple interdependent components, such as chemically synthesized single-guide RNA (sgRNA), mRNA encoding Cas nucleases, and LNP delivery components. When these components are manufactured and supplied by separate vendors, coordinating their production schedules, quality requirements, and release processes can increase the risk of delays and inconsistencies. An integrated manufacturing model helps streamline these interfaces and improve overall process coordination.
4. What to Look for in an End-to-End CDMO Partner
Selecting an end-to-end CDMO requires more than evaluating individual manufacturing capabilities. Developers should assess whether a partner can maintain operational and quality continuity from early development through scale-up, cGMP production, and fill-finish. Four factors are particularly important:
(1) Scalable Infrastructure and Development Continuity
A CDMO that supports early-stage development but lacks sufficient scale-up infrastructure may require technology transfers at critical stages, adding time and introducing comparability challenges. Conversely, a provider focused exclusively on commercial-scale production may lack the flexibility and responsiveness needed during early development. An ideal partner should support both development and manufacturing scale-up within a coordinated framework.
(2) Cross-Functional Expertise
NAT manufacturing requires collaboration across chemistry, molecular biology, process development, analytical development, formulation, and quality assurance. An integrated team of subject matter experts can facilitate technical communication, accelerate problem-solving, and support coordinated decision-making across the manufacturing workflow.
(3) Regulatory-Ready Quality Systems
The CDMO should operate cGMP-compliant facilities supported by a robust quality management system capable of meeting applicable regulatory requirements across major markets. Comprehensive material traceability, controlled documentation, and complete batch records are essential for quality investigations, regulatory submissions, and inspections.
(4) Operational Flexibility
NAT programs evolve as clinical data, analytical findings, and regulatory requirements emerge. A suitable CDMO should be able to adapt manufacturing schedules, process parameters, and documentation requirements while maintaining quality oversight and clear accountability.
(5) Building a Reliable and Scalable Supply Chain Through Vertical Integration
The global NAT CDMO market continues to expand, driven by a growing clinical pipeline and the development of new therapeutic applications, including cardiometabolic diseases that may require large-volume manufacturing [3][4]. As these programs progress toward commercialization, selecting the right CDMO partner becomes increasingly important.
A vertically integrated manufacturing model offers a strategic approach to managing supply chain complexity by strengthening control over critical materials, manufacturing processes, and quality systems. For drug developers, partnering with a CDMO that combines scalable infrastructure, cross-functional expertise, and regulatory-ready operations can help mitigate manufacturing and supply chain risks while supporting a more reliable transition from clinical development to commercial supply.
To learn more about how Hongene's vertically integrated manufacturing model addresses supply chain complexity and supports the development of nucleic acid therapeutics, read our full white paper.
Explore or download the Scaling Nucleic Acid Therapeutics brochure to learn more about our capabilities.
References
- Verma, S.; Pradhan, A.; Thandi, P. Zilebesiran: An RNA Interference Agent—Its Need and Potential to Transform Hypertension Treatment. Egypt. Heart J. 78.1 (2026): 12. https://doi.org/10.1186/s43044-026-00724-9.
- Nucleic Acid Therapeutics CDMO Industry Outlook 2024–2030. GlobeNewswire. October 10, 2024. https://www.globenewswire.com/news-release/2024/10/10/2961563/28124/en/Nucleic-Acid-Therapeutics-CDMO-Industry-Outlook-2024-2030.html
- Youssef, M., Hitti, C., et al. “Enabling mRNA Therapeutics: Current Landscape and Challenges in Manufacturing.” Biomolecules. 13.10 (2023): 1497.
- Ingle, R. G., & Fang, W. J. “An Overview of the Stability and Delivery Challenges of Commercial Nucleic Acid Therapeutics.” Pharmaceutics. 15.4 (2023): 1158.