Guest Editorial by Dr. Andrew Kennedy, Ambiopharm
- Your synthesis strategy choice at Phase 2/3 has direct implications for cost of goods, supply reliability, and commercial timelines
- SPPS alone carries escalating risk at commercial scale: declining yield, high solvent consumption, and batch failure exposure
- LPPS improves purity and efficiency for shorter fragments, but cannot handle long or complex peptides as a standalone approach
- Hybrid synthesis combines both methods and is increasingly the strategy of choice for complex peptides at late-stage and commercial scale
As peptide therapeutics advance toward late-stage development and commercialization, manufacturing strategies play an important role in the overall program success. What works in early development does not always translate for peptide therapies that are in later stages of development.
For late-stage programs, priorities shift to scalability, yield, timelines, cost, and purity; therefore, selecting the right synthesis approach is no longer a technical decision, but a strategic one.
Three primary approaches dominate peptide manufacturing today: solid-phase peptide synthesis (SPPS), liquid-phase peptide synthesis (LPPS), and hybrid synthesis. Each offers distinct advantages and limitations.
The Three Approaches: A Decision-Maker’s Summary
Solid-Phase Peptide Synthesis (SPPS)
SPPS remains the most widely used approach for peptide fragments, valued for its speed, reliability, and compatibility with automation. For early-stage and shorter peptides, it is often the default choice.
At commercial scale, however, the limitations become commercially significant:
- Cumulative coupling inefficiencies increase as chain length grows, reducing crude yield and purity
- Solvent and reagent volumes scale substantially, increasing process mass intensity (PMI) and cost
- Longer peptides carry risk of full batch failure
- These factors compound in terms of cost, sustainability commitments, and supply reliability at launch
Liquid-Phase Peptide Synthesis (LPPS)
LPPS offers a cleaner alternative for shorter fragments, with lower reagent stoichiometry, reduced solvent use, and the ability to isolate and characterize intermediates — which reduces risk at each synthesis step and produces better crude impurity profiles.
The constraint is specificity: LPPS is not viable for long peptides or complex sequences, and requires molecule-by-molecule process development. For many programs, it cannot serve as a standalone commercial strategy.
Hybrid Synthesis
Hybrid synthesis uses SPPS to build individual peptide fragments, then LPPS to assemble those fragments — combining the strengths of each approach while offsetting their respective limitations.
For late-stage and commercial programs, the practical advantages include:
- Improved crude purity and yield by reducing cumulative coupling inefficiencies
- Reduced solvent use compared to SPPS alone, supporting sustainability and PMI targets
- Opportunity to incorporate greener solvents at the assembly stage
- Fragment-level isolation enables tighter quality control and containment of synthesis challenges
- Parallel fragment synthesis can compress manufacturing timelines
- Greater flexibility to optimize process design as the molecule’s complexity is better understood
What This Means When Evaluating a CDMO
For buyers assessing a CDMO’s peptide capabilities, synthesis strategy is one of the clearest indicators of whether a partner is positioned for commercial-scale success — or has simply optimized for clinical batch production.
Questions worth asking include: At what chain length does the CDMO transition from SPPS to a hybrid approach? What is their track record on PMI reduction for complex peptides? Can they demonstrate fragment-level quality data for comparable molecules?
The peptide therapeutic space is growing faster than manufacturing capacity in many regions. Choosing a CDMO with a flexible, molecule-appropriate synthesis strategy — rather than a one-size-fits-all platform — directly affects cost of goods, batch reliability, and time to first commercial supply.
Andrew Kennedy, PhD is Sales Manager – Europe at Ambiopharm, a CDMO specializing in peptide synthesis from clinical through commercial scale.
