Peptide therapeutics are being developed for many applications beyond treatment of cardiometabolic diseases and weight loss, including as antimicrobial therapies, anticancer treatments, and vaccines.
Peptides are readily degraded in the body and typically have low oral bioavailability and poor membrane permeability.
Advances in peptide synthesis techniques are enabling the most cost-effective and sustainable production of peptides with improved stability, solubility, and permeability, enabling their wider use as therapeutics.
CDMOs are investing in expanded peptide capacities and capabilities to meet growing demand for their specialized expertise as more and more complex peptide therapeutics advance through the clinic.
Growing Therapeutic Peptide Demand
Peptide therapeutics comprise a rapidly expanding class of drugs owing to a number of attractive properties. They are medium-sized molecules that fall in between small and large molecule drugs.1 In addition to their significant growth in the treatment of cardiometabolic diseases and for weight loss, peptides are being developed as antimicrobial therapies, anticancer treatments, and vaccines.2,3 The rapid growth of the market can be attributed to advances in peptide design; chemical and biological synthesis, including cell-free and enzymatic; synthesis and modification methods; and analytics.
Approximately 100 peptide drugs have been approved worldwide, with an additional 200 in preclinical development and about another 170 being investigated in clinical trials.4 Market research firms estimate the value of the global peptide synthesis market to be expanding at a compound annual growth rate (CAGR) between 6.7% and 11.7%, reaching approximately $1.4 billion by 2029–2031.5,6 In addition to the greater demand for peptides, their growing complexity and increasing regulatory requirements are driving greater outsourcing to contract development and manufacturing organizations (CDMOs) with specialized skills, technologies, and capabilities in peptide therapeutics development and prodiuction.7
Challenges to Peptides as Therapeutics
As short chains of amino acids, peptides are simpler than proteins, yet their structural diversity allows them to be designed with greater target specificity than small molecules and tailored for personalized therapeutic applications. They also participate in many physiological processes and provide the opportunity to address targets previously thought to be undruggable. Furthermore, unlike most biologics, they can be formulated for oral administration as well as injection and typically have lower immunogenicity.
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However, peptides are highly susceptible to proteolytic degradation and thus often have short half-lives under physiological conditions.2 As such, they must be administered repeatedly or be formulated using specialized delivery systems designed to protect them from enzymatic attack. Low oral bioavailability presents additional challenges, as does poor membrane permeability, which makes reaching intracellular targets difficult. Drug developers are pursuing various strategies to overcome these issues, including incorporation of non-natural amino acids, side chain modification, conjugation with various molecules, such as cell-penetrating peptides, and formulation as nanoparticles.
Issues with Traditional Solid-Phase Peptide Synthesis
Most peptides are produced using solid-phase peptide synthesis (SPPS), a technique established in the 1960s. Functional groups on amino acids are protected or modified to enable their coupling (with the initial amino acid tethered to a solid resin support) and impart desired properties to the resultant peptide, such as improved metabolic stability, greater resistance to enzymatic degradation, and highly specific interactions with the drug target.2 Typical processes leverage either acid-labile tert-butyloxycarbonyl (Boc) or the base-sensitive 9-fluorenylmethoxycarbonyl (Fmoc) coupling chemistry. Modification includes terminal functionalization, side-chain derivatization, and cyclization. Incorporation of non-canonical amino acids is also increasingly used.
Unfortunately, traditional SPPS processes require the use of excess quantities of reagents to ensure coupling of amino acids, large volumes of solvents, and non-degradable solid supports, making peptide synthesis in this manner unsustainable.9,10 Raw materials (e.g., specialized amino acids and coupling reagents) are also expensive, accounting for approximately two-thirds of the cost of goods and often presenting supply chain challenges. Purification of SPPS-produced peptides is complex and time-consuming, and production of peptides longer than 30 amino acids can be quite difficult.5 Finally, in-process analytics typically used for chemical synthesis are generally not applicable, and testing is only achieved once the peptide has been release from the resin support.8 Consequently, there is an urgent need for more efficient, cost-effective, water-based peptide synthesis methods that allow for in-process monitoring, provide high yields, and have dramatically reduced environment impacts.1
In addition to poor water solubility of amino acids and peptides, another issue is the significant difference in the conditions used for peptide synthesis compared with physiological conditions.11 During SPPS, the peptide chain is anchored and thus has less flexibility to fold. The protecting groups on many of the amino acids used to make proteins alter their steric, electronic, and structural properties. The use of nonpolar organic solvents and polymeric supports, such as polystyrene or polyethylene glycol (PEG), inhibits natural folding compared with what would be observed in an aqueous environment but often induces undesired formation of β-sheet structures that can lead to truncations and deletions, making synthesis of the desired peptide difficult. Research has shown that C-terminal amino acids are the greatest contributors to aggregation, which is exacerbated by β-branched amino acids.
Advances in Solid-Phase Peptide Synthesis
Despite these limitations, SPPS accounted for nearly three quarters of the peptide synthesis market in 2025 because of the maturity of the technology and is expected to expand at a CAGR of 5.71% through 2031.5 That growth can in part be attributed to investments in new technologies that support more efficient SPPS processes with reduced solvent volumes and higher yields, even for peptides comprising up to 200 residues.
Advances in SPPS technology include not only better coupling reagents and solvents but automation, microwave-assisted processes, and water-based approaches. Incorporating the non-canonical amino acid pseudoproline at serine, threonine, and cysteine positions has been shown to reduce aggregation during peptide synthesis and provide higher yields.2 Eliminating the washing step between coupling and Fmoc deprotection has, meanwhile, been demonstrated to reduce solvent use without affecting peptide yield.4 A wider selection of solid supports is enabling more efficient synthesis of longer peptides, even in more environmentally friendly solvents.2 Automated, microwave-assisted SPPS proceeds more quickly with higher yields, while automated systems support better scalability through parallel synthesis arrays and enable use of real-time monitoring.
Soluble PEG supports are also enabling liquid-phase peptide synthesis (LPPS), which is better suited for large-scale production.2 One research group has reported the development of a water-soluble activating agent that enables water-based SPPS using a hydrophilic and biodegradable poly-ε-lysine-based solid support.10 Another has developed a one-pot, metal-free approach for the removal of more environmentally friendly allyloxycarbonyl (Alloc) protecting groups using iodine/water in PolarClean (PC)/ethyl acetate (EtOAc) without racemization.12 The reaction is compatible with long peptides and replaces the existing challenging method that uses air-sensitive Pd(0) complexes in hazardous solvents.
With these advances, chemical synthesis is typically viewed as the most efficient and cost-effective approach to the production of short-chain peptides.8 It is limited, however, with respect to the ability to incorporate posttranslational modifications (PTMs; e.g., glycosylation) that are readily achieved via biological synthesis.
Biological Peptide Production
Manufacturing peptides using microbial systems offers some advantages over chemical synthesis, including the ability to achieve PTMs, generate more complex and longer peptides, and use more environmentally friendly process conditions.8 These systems are also more scalable. However, the engineering of yeast and bacterial cells is time-consuming, batch-to-batch variability can be an issue, misfolding is often a problem (requiring refolding), downstream purification can be challenging owing to host-cell protein and endotoxin impurities, and only natural amino acids can be used.2
Work is being done to address these limitations, including the development of synthetic promoters and improvement of the transcription process.2 The use of engineered solubility tags (vs. traditional fusion tags) can improve soluble peptide yields when using microbes that generate inclusion bodies.
Cell-Free and Enzymatic Synthesis
While SPPS is the most established method for peptide synthesis, cell-free and enzymatic synthesis techniques are being adopted at a more rapid pace.5 These methods are more environmentally friendly and scalable than chemical methods while also avoiding issues associated with fermentation processes. Furthermore, enzyme-catalyzed peptide synthesis proceeds with high stereoselectivity and chemoselectivity, yielding purer products with reduced by-product formation, making downstream purification simpler. Non-canonical amino acids can also be used in cell-free and enzymatic processes, allowing for the production of novel peptides.2
Downsides are the need to use expensive cofactors, such as adenosine triphosphate for ligases, the cost- and time-intensive nature of enzyme engineering, and variable enzyme activity from batch to batch.2
Continuous Flow, Automation, and More
Advances in technology supporting continuous flow peptide synthesis are being applied to commercial SPPS and LPPS. Using continuous-flow synthesizers enables production of much larger peptides (200 amino acids and greater) more rapidly and at the kilogram scale.1 Some SPPS systems being investigated at commercial scale have exhibited high volumetric productivity, with nearly solvent-recovery rates approaching 80%.5 For instance, in August 2025, UK-based Vapourtec Ltd introduced its benchtop Peptide-Builder instrument, which leverages the company’s Variable Bed Flow Reactor technology. With automated sequence design software, real-time reaction monitoring, and optimized coupling protocols, the system enables high-throughput, accurate peptide production across small to larger scales.13
Ready-to-Go Novel Amino Acids
One of the challenges to peptide synthesis is the high cost of non-canonical amino acids used to impart improved properties beyond what is possible with natural amino acids. Researchers at the University of California, Santa Barbara, have developed a synthetic method that generates non-natural amino acids that can be directly used for peptide synthesis without any modification requirements.14 In the process, a gold catalyst stereoselectively combines inexpensive raw materials to generate amino acids with active acid groups. The amino acids are generated in the presence of a resin scaffold upon which the peptide chain is grown in a controlled sequence.15
Leveraging Computational Models for Peptide Design and Synthesis
Peptide synthesis is not only benefiting from advances in various synthetic methods. Applications of artificial intelligence (AI) and machine learning (ML) are also facilitating more rapid design of high-performing peptides and enabling real-time process optimization and implementation of autonomous synthesis platforms.16 As more high-quality data become available, researchers are building predictive models that take into account the impacts of different amino acids on overall peptide behaviors.17 In one example, scientists developed ML algorithms and natural language models to predict peptide aggregation and trained the system using analytical data collected during the operation of an automated fast-flow peptide synthesizer.11
CDMO Investments
Given the growing interest in peptide therapeutics and the challenges involved in developing robust, cost-effective, sustainable, and commercially scalable processes, it is not surprising that many pharma companies are relying on outsourcing partners with expertise in peptide design and production. CDMOs have also been making notable investments in peptide capacities and capabilities to meet the rising demand for their services.
Recent examples include:
WuXi AppTec: In January 2024, WuXi AppTec commissioned two new peptide manufacturing plants in China, increasing its SPPS capacity to 32,000 liters.18 The investment supports expanding interest in the company’s WuXi TIDES CRDMO platform that provides integrated services for oligonucleotides, peptides, and conjugates.
CordenPharma: In March 2025, CordenPharma reported that it is investing >500 million over the next three years to expand peptide manufacturing capabilities across Europe and the United States, including a greenfield facility for small- to large-scale development and production in Switzerland and expansion of its Colorado site with upgrades to existing and new large-scale peptide production capacity.19
BioDuro: In January 2025, BioDuro opened a fully automated SPPS scale-up laboratory in Shanghai capable of producing peptides and peptide–drug conjugates at the kilogram scale.20
SK pharmteco: SK announced a $6.1 million investment in in a new lab and a CGMP kilo-scale SPPS facility in California. Both are expected to be online in 2025.21
Syngene International: Syngene announced also investment in a dedicated peptide laboratory in India for production of linear and cyclic peptides and peptide–drug conjugates up to the 800 mmol scale in October 2025.22 The lab will include six automated peptide synthesizers with robotic arms operating in parallel and integrated with high-performance liquid chromatography and liquid-phase purification. It will work in conjunction with existing quality control labs at the site.
Lifecore and PolyPeptide: The two companies announced a collaboration enabling the provision of integrated, end-to-end development and manufacturing of peptide therapeutics with a seamless transition between drug substance and drug product support, also in October 2025.23
CPC Scientific: Plans first announced in 2022 for the construction of a peptide manufacturing facility in California were updated in November 2025, with the company indicating the site should be operational in 2026.24 Currently, its global network supports production of more than 1,000 kg of peptide drug substances annually in 20–25 kg batches.
Ambiopharm: In March 2026, Ambiopharm announced a significant expansion of its South Carolina peptide facility to support “full upstream commercial synthesis, flexible SPPS, LPPS and hybrid synthesis, and large-scale, complex peptide programs,” focusing on late-stage and commercial projects.25
Cambrex: In September 2024, Cambrex launched a new, more environmentally friendly and cost-effective LPPS technology that is performed in traditional batch reactors in continuous flow mode that use much less solvent and avoids the need for excess reagents.26 The process can be used to produce peptides comprising up to 12 amino acids, which can then be coupled in the liquid phase to produce larger peptides.
12. Pawlas, Jan, and Andreas Lindgren. “Expanding the Reach of Sustainable Solid-Phase Peptide Synthesis: One-Pot, Metal-Free Alloc Removal–Peptide Coupling.” Organic Letters. 27: 2891–2896 (2025). h
