Peptide and oligonucleotide manufacturing relies heavily on solvent- and reagent-intensive synthesis, making green chemistry increasingly important for scalable production.
Solid-phase peptide synthesis (SPPS) and solid-phase oligonucleotide synthesis (SPOS) create sustainability challenges because repeated reaction, washing, deprotection and purification steps can drive high process mass intensity (PMI).
Greener peptide synthesis will require more than replacing DMF; solvent alternatives must also support resin swelling, coupling efficiency, impurity control and downstream purification.
Oligonucleotide manufacturing faces similar environmental pressure, but green chemistry strategies must be adapted to its distinct reaction chemistry, impurity profiles and purification requirements.
CDMOs can play a central role in greener peptide and oligonucleotide manufacturing by integrating process development, solvent-handling infrastructure, purification expertise and scalable manufacturing platforms.
The Sustainability Challenge Behind Peptide and Oligonucleotide Growth
Peptide and oligonucleotide therapeutics occupy an increasingly important space in drug development, offering unique ways to address biological targets and disease mechanisms that are not always accessible to traditional small molecules or larger biologics. As these modalities advance, their manufacturing requirements are receiving greater scrutiny. Therapeutic peptides and oligonucleotides are closely linked by their reliance on iterative synthetic methods, complex purification needs, and process chemistries that can generate substantial solvent and reagent demand. Their continued growth therefore raises a practical question for the industry: how can these high-value modalities be produced at the scale needed for broader clinical and commercial use without carrying forward an unsustainable manufacturing footprint?
Green chemistry provides a useful lens for addressing that challenge because it focuses on reducing or eliminating hazardous substances through the design of chemical products and processes. In this framing, sustainability is not limited to treating waste, managing emissions, or improving disposal practices after manufacturing is complete. It begins earlier, with choices about solvents, reagents, reaction conditions, purification strategies and process architecture. The most effective green manufacturing strategy is therefore often source reduction: preventing unnecessary solvent and reagent use before those materials enter the process at all.
For peptide and oligonucleotide manufacturing, that shift matters because greener production will depend on more than replacing one problematic solvent with a marginally better alternative. Reducing process mass intensity, improving solvent recovery and reuse, redesigning purification workflows and adopting more efficient synthesis platforms will all be part of making production more sustainable. The central issue is not whether peptides and oligonucleotides can continue to advance therapeutically but whether the manufacturing systems supporting them can evolve quickly enough to meet clinical, commercial and environmental expectations at the same time.
Solvent Use and PMI: Making the Footprint Visible
Solvent use sits at the center of the sustainability challenge in peptide and oligonucleotide manufacturing because these processes often depend on repeated cycles of reaction, washing, deprotection and purification. In solid-phase peptide synthesis (SPPS), that cycle-based structure is part of what has made the approach so powerful and widely adopted in both academic research and pharmaceutical development. It allows peptides to be assembled stepwise on a solid support, with each coupling and deprotection step followed by washing to remove excess reagents and byproducts. The same basic logic that supports efficient sequence assembly, however, also creates substantial solvent demand. As a result, SPPS is associated with significant use of hazardous solvents and a negative environmental footprint.1
The issue becomes especially visible in peptide active pharmaceutical ingredient (API) manufacturing, where solvent use can represent a major share of total waste. Common process solventsn such as N,N-dimethylformamide (DMF), dichloromethane (DCM), and N-methyl-2-pyrrolidone (NMP) are useful because they support swelling, solubility, coupling efficiency, and process performance, but they also raise environmental, health and safety concerns. That tension explains why greener peptide manufacturing cannot be treated as a simple matter of choosing a preferred “green” solvent from a list. The replacement solvent must support the chemistry, preserve product quality and work across sequences that may differ substantially in length, hydrophobicity, aggregation behavior, and impurity profile.1
Oligonucleotide manufacturing faces a parallel challenge. Solid-phase oligonucleotide synthesis (SPOS) also relies on repeated synthetic cycles, and industrial SPPS and SPOS both depend on large quantities of solvents and reagents. For both modalities, the environmental burden is tied less to a single waste stream than to the cumulative material intensity of the entire process. Process mass intensity (PMI) makes that burden visible by measuring how much material is required to generate a given amount of API. Reported examples include a mean of 8,400 kg of waste per kg of API for a 50-amino-acid peptide and approximately 4,300 kg of waste per kg of API for a 20-mer oligonucleotide. A broader analysis of peptides and oligonucleotides with average molecular masses between 1,000 and 7,000 Da placed PMI in the range of 2,000–7,000 kg of material per kg of API, excluding the contribution from nucleotide starting-material synthesis for oligonucleotides. These figures should be read as reported examples rather than universal benchmarks, but they show why solvent- and reagent-intensive production has become such a central concern for both modalities.2
PMI also helps explain why incremental improvements can matter. In a multistep, cycle-based process, even modest reductions in solvent volume, washing frequency, reagent excess, or purification burden can multiply across the full sequence. Conversely, a process change that improves one step but increases downstream impurity formation or purification demand may not improve the overall footprint. Greener manufacturing therefore requires attention to the full process, not only to the apparent sustainability profile of a single solvent or reagent.
Solvent Replacement in Peptide Synthesis: Progress, But Not a Simple Swap
Because solvent use is so central to the footprint of SPPS, solvent substitution has become one of the most visible green chemistry strategies in peptide manufacturing. The appeal is clear: if a hazardous or high-burden solvent can be replaced without compromising synthesis performance, the process can become safer and more sustainable while preserving the familiar architecture of SPPS. Solvent substitution, reduction, and recycling are therefore active areas of work in efforts to improve the sustainability profile of SPPS.1
The challenge is that peptide synthesis solvents do more than carry reagents. They influence resin swelling, reagent diffusion, coupling efficiency, solubility, aggregation, impurity formation, and the ease with which intermediates and byproducts can be washed away. DMF has remained difficult to displace precisely because it performs well across many of these parameters. A greener replacement must therefore be evaluated not only by its safety or environmental profile but also by whether it can support the physical and chemical conditions required for efficient synthesis.
One promising approach is to move away from the idea that a single neat solvent must replicate DMF in every relevant respect. Instead, binary solvent mixtures can be designed to approximate the performance characteristics needed for SPPS. In this context, polarity and viscosity have been identified as key parameters for evaluating potential replacements. Mixtures of dimethyl sulfoxide (DMSO) with either 1,3-dioxolane or 2-methyltetrahydrofuran were found to resemble DMF in relevant properties and were tested as potential greener alternatives. Those systems were used in the synthesis of challenging model peptides and therapeutically relevant peptides, supporting the feasibility of binary solvent mixtures as a practical route for reducing dependence on DMF.1
This strategy also points to a more nuanced understanding of solvent selection. Different sequences present different synthetic challenges, including aggregation-prone regions and side reactions that can vary depending on the amino acid composition and step conditions. Binary mixtures create an additional lever for process development because the solvent ratio can be adjusted to influence synthesis performance. In one example, varying binary solvent composition helped mitigate side reactions, such as Arg-lactamisation and aspartimide formation, demonstrating that solvent design can affect not only sustainability metrics but also impurity control.3
For manufacturers, greener solvent adoption will have to be molecule-specific and data-driven. A solvent system that performs well for one sequence may not be optimal for another, and changes in solvent composition may influence yield, purity, resin handling, impurity formation, and downstream purification needs. The practical path forward is likely to involve a toolbox of solvent systems and process-development strategies rather than a single universal replacement for DMF.
Oligonucleotide Manufacturing: Similar Pressure, Different Chemistry
Oligonucleotide manufacturing faces many of the same sustainability pressures as peptide production, but the solutions cannot be copied directly from one modality to the other. Like peptide synthesis, oligonucleotide production relies heavily on iterative synthetic chemistry and uses substantial quantities of solvents and reagents. It also requires demanding purification and isolation workflows that contribute further to material use and energy consumption. These features have made greener oligonucleotide API manufacturing a recognized priority, with greener processes for oligonucleotide APIs identified as a critical unmet need by the American Chemical Society Green Chemistry Institute Pharmaceutical Roundtable in 2016.4
The comparison with peptide manufacturing is useful because both modalities depend on repeated synthetic cycles, high reagent inputs, and solvent-intensive operations. That shared structure creates opportunities for cross-learning. Lessons from greener SPPS, including solvent substitution, reduced solvent use, recovery and reuse, and closer attention to PMI, can help frame sustainability efforts in SPOS. The broader point is that peptide and oligonucleotide manufacturing faces a common material-efficiency problem: the value of the final API is high, but the mass of solvents, reagents and ancillary materials needed to produce it can also be high.2
At the same time, oligonucleotide chemistry has its own constraints. Process changes must account for the specific reaction chemistry, impurity profile, protecting-group strategy, purification requirements, and product-quality attributes associated with oligonucleotides. A greener solvent or process adjustment that is feasible in SPPS may not perform the same way in SPOS, and the downstream consequences may differ. Green innovations in peptide synthesis can inform oligonucleotide manufacturing, but they must be adapted rather than transferred wholesale.2
Beyond Substitution: Recovery, Redesign, and Downstream Integration
Solvent replacement is important, but it is only one part of a greener manufacturing strategy for peptides and oligonucleotides. If the overall process still depends on high solvent volumes, repeated washes, large reagent excesses, and intensive purification, replacing one solvent with another may reduce certain hazards without fundamentally changing the material burden. In both SPPS and SPOS, PMI can be reduced through two broad strategies: lowering solvent and reagent volumes or recovering and reusing materials when reduction is not feasible.2
Oligonucleotide manufacturing illustrates why this broader view matters. Commercial facilities must handle large solvent volumes moving to synthesizers and remove spent solvent as hazardous waste. As demand increases, waste generation and solvent consumption become more significant operational considerations, not just environmental ones. Solvent recycling may help reduce waste and raw-material costs, but it also introduces practical questions around facility design, solvent segregation, impurity control, recovery efficiency, and quality expectations for reused materials.5
Downstream processing adds another layer to the sustainability challenge. For oligonucleotides in particular, purification and isolation are often regarded as bottlenecks in therapeutic production. Relevant downstream operations include purification, preparative chromatography, continuous chromatography, ultrafiltration, and freeze-drying, each of which can influence yield, purity, solvent use, water use, energy demand, cycle time, and facility throughput. A synthesis route that appears more efficient upstream may still create a difficult sustainability profile if it generates impurities that require more intensive purification, lower-yield recovery, additional solvent use, or energy-demanding isolation steps.6
For manufacturers, the key is to treat upstream synthesis and downstream purification as connected design spaces. Reducing solvent use may involve optimizing wash volumes, improving reaction efficiency, selecting more efficient purification methods, recovering high-volume solvents, or redesigning the route so that fewer material-intensive steps are needed. Those decisions must be made with attention to yield, purity, safety, equipment compatibility, and regulatory expectations. A greener process that cannot be scaled, validated, or operated reliably will not solve the industrial problem.
Alternative Platforms and the CDMO Role
Improving the sustainability of peptide manufacturing will not depend only on making SPPS cleaner. SPPS will remain important, but the scale and complexity of emerging peptide pipelines are encouraging broader interest in alternative or complementary manufacturing platforms. These approaches are not universal replacements for established methods, and their value will depend on the specific peptide, route, impurity profile, scale, and quality requirements. Even so, they point to a wider shift in how greener peptide production is being framed: not simply as solvent substitution within an existing process but as a reconsideration of the process architecture itself.
Liquid-phase peptide synthesis (LPPS), enzymatic peptide synthesis, and continuous-flow peptide synthesis have all been described as part of an integrated platform for greener and scalable peptide supply. LPPS is particularly relevant to the solvent discussion because it can avoid the repetitive washing steps associated with solid supports and thereby reduce solvent consumption at industrial scale. That does not mean LPPS is automatically preferable for every peptide. Rather, it gives process developers another option when the chemistry, scale and purification strategy support it.7
Enzymatic and continuous-flow approaches fit within the same platform logic. Their promise lies less in replacing current peptide manufacturing outright than in expanding the set of tools available for greener process development. For the purposes of a manufacturing strategy, the key question is not whether any one platform is inherently greener in all cases, but whether it improves the full process when synthesis efficiency, solvent use, impurity formation, purification burden, scalability, and operational reliability are evaluated together.7
This is where contract development and manufacturing organizations (CDMOs) become especially relevant. As peptide and oligonucleotide programs advance, developers will need more than additional production capacity. They will need partners that can help make solvent-intensive processes more efficient, safer, and more scalable while still meeting expectations for quality, yield, purity, and regulatory control. Addressing sustainability challenges in oligonucleotide production will require collaboration among academia, contract research, development, and manufacturing organizations and pharmaceutical companies because the barriers span chemistry, analytics, equipment, facility design, purification, waste handling, and commercial operations.4
For CDMOs, the operational burden is particularly important. Commercial oligonucleotide production requires facility planning around large solvent volumes, hazardous and flammable materials, containment, equipment compatibility, and hazardous waste removal. These considerations affect how a facility is designed, how materials move through the plant, how risks are controlled, and how efficiently production can scale. A manufacturing partner with appropriate infrastructure and solvent-handling expertise may therefore influence not only whether a process can be run, but whether it can be run safely, reproducibly, and sustainably at larger scale.5
Regulatory and Safety Pressure: DMF as a Signal of Broader Change
Green chemistry is often discussed in environmental terms, but its relevance to peptide and oligonucleotide manufacturing is also tied to worker safety, facility design, regulatory expectations, and supply resilience. The same principles that support lower waste and lower solvent burden also emphasize safer solvents and reaction conditions, energy efficiency, avoiding unnecessary derivatives, catalysis, real-time analysis, and accident prevention. For peptide and oligonucleotide manufacturing, those priorities align closely with the practical realities of handling large volumes of hazardous or flammable materials in development and commercial production environments.8
DMF illustrates how this pressure is evolving. DMF has long been important in SPPS because of its process performance, but its reproductive health concerns have made it a focus of regulatory restriction in Europe. The European restriction that began applying in December 2023, with longer transition periods for some uses, has increased the urgency of identifying and qualifying solvent alternatives. That shift does not mean DMF can be eliminated from every process immediately, but it does signal that solvent selection is becoming a strategic issue rather than a routine process choice.9
The same logic applies beyond peptide synthesis. Commercial oligonucleotide manufacturing must account for flammable and hazardous solvents, containment, electrical classification, spill management, and removal of spent solvent as hazardous waste. These are not peripheral engineering details. They influence facility design, capital planning, operational safety, environmental controls, and the economics of scaling oligonucleotide production. As solvent volumes rise, the burden extends across procurement, storage, transfer, waste handling, and compliance.5
For programs moving from early development into larger-scale clinical or commercial supply, solvent choices that are manageable at small scale may become more difficult when volumes, batch frequency, and waste streams increase. Building green chemistry principles into development can help avoid late-stage process changes that are technically disruptive, expensive, and difficult to validate. DMF is therefore less an isolated case than a warning signal: solvent-intensive manufacturing platforms will face increasing pressure to justify not only whether they work, but whether they can be operated safely, responsibly, and reliably at scale.
Conclusion: Green Chemistry as Industrial Strategy
For peptides and oligonucleotides, green chemistry is no longer a peripheral sustainability exercise. It is becoming part of the industrial strategy needed to make solvent-intensive modalities more scalable, resilient and commercially viable. As programs expand, the manufacturing burden associated with repeated synthetic cycles, high solvent volumes, hazardous reagents, and demanding purification workflows will become harder to treat as an acceptable cost of doing business. The question is not only how to make these molecules but how to make them in ways that can support broader clinical and commercial use without carrying forward unnecessary material intensity.
The practical path forward will require a molecule-specific mindset. Solvent substitution can reduce reliance on high-concern materials, such as DMF, but greener manufacturing will also depend on reducing solvent and reagent volumes, recovering and reusing materials where feasible, improving impurity control, and redesigning purification and isolation workflows. For peptides, this may mean selective use of SPPS, LPPS, enzymatic methods, flow approaches, or hybrid strategies, depending on the molecule. For oligonucleotides, it means adapting green chemistry principles to the specific demands of SPOS, downstream purification, and commercial facility operations. For developers and CDMOs, the opportunity is to treat sustainability as a manufacturing-quality and process-efficiency discipline, designing processes that use fewer materials, manage them more intelligently and align the chemistry with the realities of scalable production.
