PEPTIDES & PROTEINS tt
,,------------------------------..: Larger non-crystalline fragments j---
-- '-------------
,,-----------------
Small crystalline fragments rr
AA Conventional solution chemistry
Figure 2- Cambrex s LPPS approach
Peptide API( full length)
8 ~ 14mer GMP intermediates
3 ~ 5mer Currently justified as GMP starting materials
Peptide API( full length)
8 ~ 14mer Justifiable as GMP
Larger fragments starting materials under ICH Q11
- ·.........________________ rr SPPS ' '
----- rr Z-Flow( automation)
: '
-
Tag-AA AA Tag-AA
' Resin: Tag = C8-12 aliphatic ester
•••• •••••••••• •••••••., I
--
AA
'------------ ··------ ··' \ ______________________________ _ progressively less efficient due to resin compression and mass-transfer limitations. As a result, SPPS reactors larger than a few thousand litres are uncommon, imposing a hard ceiling on batch size.
Third, cycle times for long peptides are substantial. Manufacturing campaigns for peptides exceeding 40 amino acids often extend beyond one month and any deviation or failure during the multi-step process can result in complete batch loss.
The platform nature of SPPS further limits its portability across manufacturing networks, contributing to constrained global capacity. These challenges have been directly reflected in recent supply shortages for high-volume GLP-1 receptor agonists.
Resurgence of LPPS
Until the early 2000s, peptides were rarely considered to be viable blockbuster drugs, due to their short half-lives and the requirement for parenteral administration. Consequently, there was little incentive to revisit LPPS as an alternative manufacturing platform.
One notable exception was enfuvirtide( Fuzeon), a 36-mer HIV fusion inhibitor developed by Roche. To overcome the scalability limitations of SPPS, Roche implemented a hybrid strategy in which peptide fragments were prepared by SPPS and subsequently assembled using liquid-phase chemistry. This convergent approach
enabled commercial production, although the drug ultimately failed to achieve blockbuster status due to competition from oral antiretrovirals.
The strategic value of hybrid and fully liquid-phase approaches has become far more evident with the emergence of GLP-1-based therapies. Drugs like semaglutide and tirzepatide rely on extensive chemical modifications, including fatty-acid conjugation and non-coded amino acids, to achieve prolonged half-life and enhanced potency.
These features are incompatible with recombinant expression and place significant pressure on SPPS-based manufacturing. Public disclosures and patent literature suggest that fragment-based LPPS strategies now underpin the commercial-scale manufacture of several GLP-1 drugs.
These offer several compelling advantages. Fragment coupling can be conducted in conventional stirred-tank reactors, enabling direct leverage of existing small-molecule cGMP infrastructure. Parallel manufacture of fragments reduces overall cycle time and allows tight quality control at intermediate stages, simplifying final API purification. In addition, fragments can be sourced flexibly, stockpiled or transitioned from SPPS to LPPS over time, enhancing supply-chain resilience.
Tag-assisted LPPS
Early efforts to generalise LPPS focused on tag-assisted strategies,
in which a hydrophobic solubilising tag maintains the growing peptide in an organic phase, while impurities are removed via aqueous washes or precipitation.
First-generation tag technologies, developed in the early 2010s, demonstrated conceptual feasibility but proved difficult to implement for long peptides. Proprietary tags were often large( on the order of 1,000 Da), expensive on a molar basis, operationally cumbersome and constrained by IP considerations. These factors limited adoption beyond niche applications.
Subsequent work demonstrated that such large tags were unnecessary for many peptide fragments. Cambrex scientists showed that small, non-proprietary aliphatic ester tags( typically C 8 or
C 12
) are sufficient to solubilise peptide fragments up to approximately 15 amino acids in length. These fragment sizes align well with convergent manufacturing strategies already validated at commercial scale. Because these tags are inexpensive and non-patented, they offer a clear path to broad industrial adoption. Using this second-generation tag strategy, LPPS can function as a drop-in replacement for SPPS in fragment synthesis while delivering dramatic sustainability benefits. Solvent consumption, particularly DMF, can be reduced by 90-95 % relative to SPPS, with concomitant reductions in waste generation and environmental footprint.
MAR / APR 2026 SPECCHEMONLINE. COM
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