Peptides and oligonucleotides: Production route
Solid-phase, liquid-phase or brewed: four ways to build peptides
What this tab covers How it is made: the main production routes or, for product families, the main product types and technologies, compared on share of supply, inputs per tonne, plant scale, yield, co-products and unit cost.Four routes make peptides: solid-phase peptide synthesis (SPPS), liquid-phase synthesis (LPPS), hybrid fragment assembly, and recombinant expression in yeast or bacteria followed by chemical modification. Oligonucleotides are made almost entirely by solid-phase phosphoramidite chemistry, with enzymatic ligation emerging. Solvent volume, purification yield and reactor size set cost. Recombinant routes suit long, unmodified backbones; chemical routes suit modified or short chains.
Routes compared
| Route | Share of supply | Inputs per tonne | Typical scale | Yield | Co-products | Unit cost |
|---|---|---|---|---|---|---|
| Solid-phase peptide synthesis (SPPS) | most synthetic peptide APIs (indicative) | PMI about 13,000 t per t API (Kekessie et al. 2024); a 50-residue peptide averaged 8,400 kg waste per kg API (Pharma's Almanac) | reactors up to several thousand litres; output kg to tonnes per year | overall often 10-40% after purification (indicative) | spent DMF, DCM, piperidine, TFA, acetonitrile | not published; GLP-1 API thought to cost hundreds to thousands of $/g at launch, falling with scale (indicative) |
| Liquid-phase and hybrid synthesis (LPPS) | growing (indicative) | lower PMI than SPPS (not published) | large batch reactors | not published | fewer washes | lower at scale (indicative) |
| Recombinant expression plus semi-synthesis | originator semaglutide and liraglutide (indicative) | not published | large fermenters | not published | biomass | low at scale (indicative) |
| Solid-phase oligonucleotide synthesis | almost all oligonucleotide APIs | PMI about 4,300 kg per kg for a 20-mer; 2,000-7,000 kg/kg range for peptides and oligos of 1,000-7,000 Da | synthesisers at mole scale; output kg to tonnes | not published | acetonitrile, dichloroacetic acid in toluene or DCM, pyridine | not published |
How each route works
Solid-phase peptide synthesis (SPPS)The peptide grows on a polymer resin. Each cycle removes the Fmoc protecting group, washes, couples the next amino acid and washes again, mostly in DMF or NMP. The finished chain is cleaved with TFA and purified by chromatography.
flexible and fast to develop; very solvent-heavy
Pharma's Almanac (2025); Kekessie et al. 2024 (indicative) Liquid-phase and hybrid synthesis (LPPS)Fragments are made in solution or on resin and joined in solution, with intermediate isolation. Used for tirzepatide and some semaglutide generics to cut solvent use.
scalable; longer development
Liu et al., ACS GCI The Nexus (2026) via Pharma's Almanac Recombinant expression plus semi-synthesisYeast or E. coli express the peptide backbone in fermenters; it is purified and chemically modified (for semaglutide, an acylated fatty side chain is attached).
efficient for long chains; limited to natural amino acids before modification
qualitative Solid-phase oligonucleotide synthesisPhosphoramidite monomers are coupled on a solid support in a four-step cycle (detritylation, coupling, oxidation or sulphurisation, capping), then cleaved, deprotected and purified by chromatography.
mature chemistry; acetonitrile-heavy
Pharma's Almanac (2025) Unit economics are indicative ranges from the sources named; costs move with feedstock and energy prices, plant size and region.