Choosing the Right Peptide Synthesis Strategy for Late-Stage Development and Manufacturing

By: Andrew Kennedy, PhD

Your synthesis strategy directly impacts commercialization success, which includes cost, timelines and supply reliability
SPPS alone may introduce risk at scale, with declining yield, higher solvent use and potential batch failure
LPPS improves efficiency and purity, but is limited in handling longer or more complex peptides
Hybrid synthesis provides flexibility, allowing you to optimize each step based on molecule complexity

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.

Solid Phase Peptide Synthesis (SPPS):

SPPS is one of the most common approaches for long peptide fragments. SPPS is valued for its reliability, speed and compatibility with automation. However, as peptide length increases, there are several challenges that emerge:

As the peptide chain grows, coupling issues can lead to declining quality and yield of the crude
Large volumes of reagents and solvents required
Risk of full batch failure
High process mass intensity (PMI)

For late-stage and commercial production, these factors can significantly impact cost, sustainability and reliability.

Liquid Phase Peptide Synthesis (LPPS):

LPPS offers an alternative for shorter fragments. Key advantages include:

Lower reagent stoichiometry and reduced solvent usage
Cleaner crude impurity profiles
Ability to isolate intermediates, reducing risk at each step

However, LPPS is not universally applicable:

Not suitable for long peptides or long fragments
Fragment length limitations restrict flexibility
Requires molecule-specific optimization

These constraints can limit its use as a standalone solution for more complex or longer peptides.

Hybrid Synthesis

Rather than choosing between SPPS and LPPS, hybrid synthesis combines the strengths of SPPS and LPPS in order to optimize purity, yield and cost.

In this approach:

SPPS is used to generate peptide fragments
LPPS is used to assemble the fragments

This enables:

Improved crude purity and yield by reducing cumulative coupling inefficiencies
Reduced solvent usage compared to SPPS alone
Opportunity to use greener, sustainable solvents during synthesis
The ability to isolate and manage synthesis challenges at the fragment level
Greater flexibility in process design based on molecule complexity
Reduces timeline when doing parallel fragment synthesis

For late-stage programs, hybrid synthesis offers a balanced option that supports manufacturing needs and lifecycle optimization.

Why Hybrid is the Best Fit for Late-Stage Programs

As programs move toward commercialization, a more flexible approach becomes increasingly important. Rather than relying on a single synthesis platform, using a more flexible approach that uses the strengths of SPPS and LPPS might be a better option. Hybrid synthesis is able to offset the challenges with LPPS and SPPS, which will improve efficiency, yield, cost and scalability.

For pharmaceutical companies navigating these decisions, understanding the differences between the strategies can help identify the right path forward, and ultimately help bring important therapies to patients faster and more reliably.