TIDES - Peptides and Oligonucleotides
TIDES - Peptides and Oligonucleotides
TIDES (Therapeutic Peptides and Oligonucleotides) are sequence-defined macromolecules that sit between traditional small-molecules drugs and large-molecule biologics. Composed of short chains of amino acids (peptides) or nucleotides (oligonucleotides), they combine the structural precision of synthetic chemistry with the high specificity typically associated with biological systems. Peptides can engage complex three‑dimensional protein surfaces that small molecules often cannot access, while oligonucleotides act directly on DNA and RNA to modulate or silence gene expression. This enables access to previously “undruggable” pathways and supports highly targeted therapeutic design. With tunable structures, consistent manufacturing, and versatile mechanisms of action, TIDES are transforming modern drug development and expanding treatment options across a wide range of diseases including cancer, genetic, neurological, and metabolic disorders.
Key Issues
TIDES manufacturing is predominantly based on solid-phase synthesis, a highly automated and reliable platform that nevertheless presents significant technical and operational challenges. These processes are resource- and solvent-intensive, resulting in very high process mass intensity (PMI) due to the extensive use of organic solvents such as dimethylformamide (DMF), N-methyl-2-pyrrolidone (NMP), dichloromethane (DCM), N,N-dimethylacetamide (DMAc), and acetonitrile.
The widespread use of excess reagents, coupling agents, and protecting groups contributes to substantial hazardous waste generation and relatively poor atom efficiency, as many process materials are discarded following each synthesis cycle. As a result, facility design must address solvent management through recovery and recycling systems, volatile organic compound (VOC) abatement technologies, hazardous-area electrical classification, and compliance with applicable environmental permitting requirements.
Manufacturing facilities must also accommodate stringent product quality requirements, including controls for aseptic processing where applicable and compliance with residual solvent limits established by global regulatory guidelines. These considerations significantly influence facility layout, process segregation strategies, utility design, and equipment selection.
Ongoing industry innovation is focused on improving the sustainability, efficiency, and scalability of TIDES production through the adoption of greener solvent alternatives, solvent reduction and recycling technologies, hybrid solid- and liquid-phase synthesis approaches, enzymatic manufacturing routes, and advanced purification platforms. Collectively, these advancements are driving the development of the next generation of TIDES manufacturing facilities, with an increased emphasis on environmental performance, operational efficiency, and lifecycle cost optimization.
How Fluor Helps
Fluor partners with TIDES manufacturers to translate complex chemistry into safe, scalable, and efficient production facilities. Leveraging deep EPCM expertise, Fluor integrates solid-phase synthesis, purification, and aseptic processing with robust solvent management, volatile organic compounds (VOCs) abatement, and high-hazard design.
By optimizing process performance and material flows, and incorporating lean principles, sustainability, and advanced emissions controls, Fluor enables reliable, high-quality production of peptide and oligonucleotide therapies at commercial scale.
Process Features
Solid phase peptide (SPPS) and oligonucleotide (SPOS) synthesis use automated, stepwise chemistry on resin, enabling precise sequence assembly. Orthogonal protecting groups ensure monomers couple in the correct sequence. Their timely deprotection (removal) minimizes side reactions. Process performance hinges on coupling efficiency, reagent quality, and tight control of critical parameters such as reaction time, temperature, and solvent composition. Crude products are purified using reverse-phase or ion-exchange chromatography to remove closely related impurities (e.g., truncated and deletion sequences). Downstream processing typically includes ultrafiltration/diafiltration for buffer exchange and impurity clearance, followed by lyophilization to isolate a stable Active Pharmaceutical Ingredient (API). Robust analytical methods (HPLC/UPLC, ion exchange) with high resolution are essential to confirm identity, purity, and impurity profiles, ensuring consistent product quality across batches.
Facility Features
TIDES facilities must integrate biopharmaceutical aseptic design with safe handling of large volumes of flammable solvents. Layouts should support flexible, scalable production with temperature-controlled storage, insulated transfer systems, and well-defined material, solvent, and waste flows. Areas handling significant solvent volumes require high-hazard classifications and enhanced hazard controls, including appropriate ventilation (often single-pass airflow) to prevent accumulation of flammable vapors, fire protection systems, ignition source controls, and classified electrical installations. Process equipment and piping should enable hygienic operation, including Clean-In-Place compatibility and effective microbial and particulate control where needed. Facility design should align cleanroom classification and air flow with process risk, ensuring proper segregation and contamination control. Automated synthesizers, chromatography systems, and digital batch records demand robust data integrity controls, ensuring reliable, traceable process data, and consistent operational performance.
Fluor Projects
Peptide Advanced Pharmaceutical Ingredient
Location: Midwest, USA
Scope: EPCM
Fluor delivered the large pharmaceutical project to date that included large-scale peptide manufacturing facilities, providing EPCM service from conceptual design through construction management for the initial site and later expansions. Work included 600-acre greenfield campus development for peptides, small molecules, and oligonucleotides with the incorporation of integrated utilities, solvent logistics, and supporting infrastructure, enabling high-containment, scalable production. Peptide buildings feature synthesis, purification, HPLC, filtration, lyophilization, and ISO8/7-class cleanrooms. Major capacity expansions included integration of new infrastructure for flexibility with new processes and evolving throughputs.
Agilent Technologies, Inc. Oligonucleotide Therapeutics Manufacturing Facility Expansion
Location: Frederick, Colorado, USA
Scope: Architectural, Engineering and Procurement
Fluor provided front-end, detailed engineering, and construction support for a new 275,000-square-foot manufacturing facility at a Frederick manufacturing site. The facility adds two production trains to double capacity for oligonucleotide APIs, including DNA and RNA therapies. Scope included utilities, tank farm, and process systems. Fluor optimized water, temperature control, and process design, and delivered architectural upgrades supporting containment, material flow, and advanced manufacturing operations.
Active Pharmaceutical Ingredient Manufacturing Facility
Location: Colorado, USA
Scope: Engineering and Construction Management
Fluor was selected to provide basic and detailed design and procurement services for the new facility that will manufacture advanced intermediates and chemically synthesized active pharmaceutical ingredients (APIs).
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