Hidden Cost Drivers in Oligonucleotide Manufacturing

In oligonucleotide manufacturing, discussions of capital cost often center on process equipment and cleanroom space. In practice, process chemistry often establishes the hazard profile that drives major facility systems, including HVAC, fire protection, containment, electrical classification, and bulk solvent infrastructure. Solid-phase oligonucleotide synthesis (SPOS), combined with downstream purification, drives solvent consumption to a level that shapes many aspects of facility design and operation.^1-6

At commercial scale, this can shift facility designs away from a typical bioprocess paradigm toward something closer to a chemical plant operating within a GMP environment.^2,4-6 Once solvent volumes reach scale, they influence not only utilities and storage, but also code classification, safety systems, and site infrastructure. The sections below highlight the less visible drivers that can materially affect both capital investment and long-term operating cost.^7-10

Solvent Inventory Becomes a Core Design Basis

SPOS relies on repetitive chemical cycles, typically detritylation or deprotection, coupling, capping, and oxidation or sulfurization, repeated sequentially to build the desired nucleotide sequence on a solid support resin. Each step requires reagent delivery, solvent washing, and waste removal; common SPOS solvents include toluene, acetonitrile, and other organic solvents.^1,2,5,11

At scale, the result is a high-throughput movement of flammable liquids through synthesis, purification, and waste systems; recent oligonucleotide manufacturing literature reports solvent demand on the order of 1,500 kg of solvent per 1 kg of product, with a 20 kg batch requiring approximately 30,000 kg of solvent.^2,4 Facility design is therefore driven not only by process equipment footprint but also by the peak solvent inventory, which influences hazardous-material quantities, control-area strategy, occupancy classification, containment requirements, ventilation needs, and process room locations. That distinction is crucial because maximum allowable quantities (MAQ) and control-area concepts determine whether hazardous material quantities remain within ordinary occupancy limits or trigger high-hazard design requirements.^4,6-8,12

Hazard Classification Drives Architectural Design

As facilities scale, solvent quantities can exceed code-defined control-area limits and trigger high-hazard occupancy classifications tied to the use, processing, handling, or storage of hazardous materials above maximum allowable quantities. That transition is one of the most important cost inflection points in solvent-intensive oligonucleotide manufacturing.^6-7,12

High-hazard occupancy classification and hazardous-material provisions can affect fire-area strategy, rated separations, egress, construction features, and building interfaces. These requirements are deeply coupled to layout. Even relatively minor changes, such as adding a synthesis train or increasing solvent day-tank capacity, can change room inventories and force reassessment of walls, exits, fire-rated assemblies, and adjacent systems.^6-8,12

Electrical Classification Expands Across Systems

These classification requirements also extend into electrical systems. Where flammable vapors or liquids can be present and conditions capable of creating ignitable atmospheres, electrical equipment and wiring must be suitable for the classified location, and each room or area must be considered individually.^13,14

This can impact both upfront capital and facility design. Classified electrical design can affect not only process equipment but also lighting, instrumentation, power distribution, control wiring practices, and documentation. Routing philosophy may also change where sealing, classified equipment selection, or vapor-migration controls are needed to support the area-classification strategy.^6,13-14

HVAC Becomes an Important Safety Layer

HVAC design becomes one of the most important safety layers of the facility. Solvent-intensive suites must balance GMP cleanroom expectations with vapor control, dilution, exhaust, and prevention of flammable vapor accumulation. The IFC identifies the core hazard of flammable and combustible liquids as vapors that, when mixed with air in the flammable range, can burn or explode near normal working temperatures.⁸

Emergency exhaust, gas detection, and standby power may become design considerations depending on the material, quantity, operation, adopted code, and AHJ interpretation. Depending upon the process, negative pressure solvent-handling zones often coexist with positive-pressure clean corridors and airlocks, making early pressure-cascade and containment decisions essential to avoid late mechanical rework.^6,8,15

Fire Protection, Drainage, and Containment

Beyond HVAC, fire protection introduces another layer of system complexity. Fire protection for flammable and combustible liquids is not only sprinkler density; it can include detection, suppression, segregation, drainage control, spill control, secondary containment, and other safeguards selected for the specific liquid class, quantity, storage/use mode, and design basis.^8,9,15-17

Containment requirements can add another layer of cost. For example, IFC Section 5703.4 links Class I, II, and IIIA liquid storage, use, dispensing, mixing, or handling areas to spill control and secondary containment where the maximum allowable quantity per control area is exceeded and where Section 5004.2 applies. IFC Section 5004.2.1 requires spill control for certain hazardous-material liquid storage arrangements and describes acceptable methods such as sloped or recessed liquid-tight floors, raised or recessed sills or dikes, sumps and collection systems, or other approved engineered systems.^16,17

Solvent Logistics and Waste Infrastructure

As solvent volumes increase, infrastructure requirements extend beyond process areas themselves.^2,4-6 At laboratory scale, solvents may be handled in glass bottles or drums; as manufacturing scale increases, facilities frequently transition from container-based solvent handling toward centralized storage, distribution, waste collection, and sometimes solvent recovery systems, creating an infrastructure layer that extends well beyond production equipment. Because solvent can be a dominant process-mass and cost contributor, these systems should be sized and evaluated as core manufacturing infrastructure rather than secondary support utilities.^4-6,8-10,18

This infrastructure may include bulk storage tanks, transfer systems, solvent distribution piping, dedicated waste systems, secondary containment, inerting systems, delivery access, and controls integration.^6,8-10 Bulk flammable-liquid handling also commonly utilizes vapor-space inerting for tanks, vessels, and connected vapor systems where flammable vapor-air mixtures could credibly occur. NFPA 69 provides a recognized basis for explosion-prevention systems, including inerting approaches used to control oxidant concentration in enclosures containing flammable vapors. These requirements can increase nitrogen demand and may drive larger bulk inert-gas storage, vaporization, distribution, monitoring, control, and interlock infrastructure.^8,9,19

Purification and Solvent Recovery: An Often-Underestimated Driver

Further downstream, purification adds another dimension to solvent intensity. Synthesis consumes substantial solvent, but chromatographic purification can also generate high solvent use and waste at manufacturing scale. Industry literature on oligonucleotide API purification identifies high solvent consumption and waste generation, particularly during purification, as a key scale-up challenge.^2,3

Solvent recovery systems, including acetonitrile recovery and recycling, are increasingly investigated to reduce waste, operating costs, and exposure to constrained solvent supply chains. However, recovery may introduce additional capital equipment, utilities, quality controls, traceability expectations, and integration complexity. The decision to recover versus dispose should therefore be treated as an early design variable rather than a late optimization.^4,5,18

Case Vignette: When a Suite Crosses into High-Hazard Occupancy

The following simplified example illustrates how incremental process decisions can drive disproportionate facility impacts.

A hypothetical facility initially limits the solvent inventory per control zone to less than the MAQ. Then, as facility demands increase, a slight change in the in-room quantities may push the inventory to be greater than the MAQ.^6,7,12

At that point, the suite may cross into high-hazard occupancy or require additional hazardous-material protection features, and the impact is not necessarily incremental. Fire-rated separations, egress strategy, HVAC capacity, bulk solvent infrastructure, spill control, secondary containment, electrical area classification extensions, and environmental or waste systems may need to be reassessed. This step change demonstrates how modest process decisions can create disproportionate downstream cost and complexity.^{6-8,12-14,16,17}

Raw Material Inherent Costs and Supply

Beyond facility systems, solvent intensity also shapes the broader economic model. High solvent consumption increases utility and infrastructure demand and creates sustained dependence on commodity solvents such as acetonitrile and methanol at manufacturing scale; for high-demand oligonucleotide products, published manufacturing analyses indicate that acetonitrile requirements can become material relative to global market capacity.^2-5,18

This introduces price-volatility and supply-risk exposure, particularly for acetonitrile. The 2008-2009 acetonitrile shortage is a documented example: Chemical & Engineering News reported in November 2008 that acetonitrile was scarce because it is a byproduct of acrylonitrile production, while LCGC reported in June 2009 that the worldwide shortage began in early fall 2008 and affected laboratories and preparative/process-scale LC users.^20,21

As facilities scale and solvent demand becomes more continuous, organizations must design not only for safe handling but for supply assurance. Practical responses can include increased storage capacity, qualified alternate suppliers, procurement commitments, solvent minimization, or recovery strategies, all of which can increase capital, working capital, quality concerns, and operational complexity.^{2,4,5,18,20,21}

Aligning Cost, Risk, and Scalability from the Outset

Solvent-driven process intensity frequently governs the facility infrastructure required to support commercial oligonucleotide manufacturing.^2,4-6 While process equipment establishes production capability, solvent inventory often determines the scale and complexity of HVAC systems, hazardous-material controls, fire protection, containment, electrical classification, and bulk handling infrastructure.^5-10,13

As a result, relatively small increases in synthesis capacity can sometimes create disproportionately large increases in facility cost when they alter the underlying hazardous-material design basis.^{4,7,8,12-14,16,17}

Many facility cost decisions are effectively shaped once key process assumptions are set. Decisions around synthesis configuration, purification strategy, solvent recovery, and scale-out philosophy define the hazard envelope and, as a result, the required building systems and capital scope.^2-6,18 Treating these variables as early-stage design inputs, rather than downstream engineering consequences, allows organizations to align cost, risk, and scalability from the outset.^5-10

In a market in which speed to commercial readiness is crucial, organizations that recognize and plan for this connection between chemistry and capital are better positioned to deliver more predictable, efficient, and adaptive manufacturing assets.

References

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4. MacLeod C. Oligonucleotide Manufacturing Scaling Challenges for Undruggable Targets. Pharmaceutical Engineering. November/December 2025. View source

5. CRB Group. Best practices in oligonucleotide manufacturing. View source

6. CRB Group. Large-scale oligo synthesis: Scaling-up requirements. View source

7. International Code Council. 2024 International Building Code, Section 307.1, High-hazard Group H. View source

8. International Code Council. 2024 International Fire Code, Chapter 57, Flammable and Combustible Liquids. View source

9. National Fire Protection Association. NFPA 30: Flammable and Combustible Liquids Code. 2024 edition. View source

10. International Society for Pharmaceutical Engineering. ISPE Baseline Guide: Volume 1-Active Pharmaceutical Ingredients. Second Edition. Published June 1, 2007. View source

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12. Tubbs B. Code Corner: 2024 International Fire Code Tables 5003.1.1(1) and 5003.1.1(2): Maximum Allowable Quantities. International Code Council Building Safety Journal. Published February 12, 2025. View source

13. Occupational Safety and Health Administration. 29 CFR 1910.307, Hazardous (classified) locations. View source

14. National Fire Protection Association. NFPA 497: Recommended Practice for the Classification of Flammable Liquids, Gases, or Vapors and of Hazardous (Classified) Locations for Electrical Installations in Chemical Process Areas. Current edition information. View source

15. International Code Council. 2024 International Fire Code, Chapter 9, Fire Protection and Life Safety Systems. View source

16. International Code Council. 2024 International Fire Code, Section 5703.4, Spill control and secondary containment. View source

17. International Code Council. 2024 International Fire Code, Section 5004.2.1, Spill control for hazardous material liquids. View source

18. Novartis AG. Acetonitrile recovery process. WO2023170657A1. Published September 14, 2023. View source

19. National Fire Protection Association. NFPA 69: Standard on Explosion Prevention Systems. 2024 edition. View source

20. Tullo AH. A Solvent Dries Up. Chemical & Engineering News. Published November 24, 2008. View source

21. Majors RE. The Continuing Acetonitrile Shortage: How to Combat it or Live with It. LCGC North America. Published June 1, 2009. View source