As peptide therapies move toward the market, efficient and cost effective large scale production becomes essential. Liquid Phase Peptide Synthesis (LPPS) is increasingly adopted for peptide API manufacturing thanks to its scalability and more sustainable profile, with reduced solvent use. At FIS, we support the transition from clinical development to commercial supply with robust LPPS capabilities, designed for projects where purity, cost control, and scale matter.
Discover how we do it through the voices of our experts.
Peptide therapies are advancing rapidly. Manufacturing must keep pace.
As products move toward commercialization, manufacturers face increasing pressure to deliver:
- scale
- cost efficiency
- sostenibilita
Traditional approaches often rely heavily on end-stage purification, creating a significant manufacturing bottleneck.
This is one of the reasons why Liquid Phase Peptide Synthesis is gaining attention as a scalable and efficient route to peptide API manufacturing.
In this video, our colleagues Roberto Profeta and Deepshikha Angrish share why it matters.
How does FIS approach LPPS?
At FIS, LPPS starts with process chemistry. Our convergent strategies are designed to generate key peptide fragments with high purity, helping simplify downstream processing and support industrial scale-up. From clinical supply to commercial manufacturing, FIS combines:
- process chemistry expertise
- large-scale manufacturing capabilities
- a strong focus on purity and cost control.
Hear from Roberto Profeta and Deepshikha Angrish in this new video.
Innovation in LPPS requires the right enabling technologies. That’s why FIS developed FISTag™, our proprietary tagging platform designed to strengthen peptide manufacturing processes.
FISTag™ helps:
- support purity through controlled precipitation and crystallization
- improve solubility
- enable more efficient processing.
It also supports a more sustainable manufacturing approach, as the tag can be recovered and recycled at the end of synthesis.
In this video, Roberto Profeta and Deepshikha Angrish explain how FISTag™ enhances the FIS approach to peptide manufacturing.
Whitepaper
Beyond Solubility: How Crystallisation-Driven Fragment Purification with FISTag™ Improves Final Peptide Yield and Quality
The therapeutic peptide market has been transformed in less than a decade. Semaglutide, Tirzepatide, and a deep pipeline of follow-on dual and triple agonists have moved peptides from a specialist niche into one of the highest-volume small-molecule-adjacent manufacturing challenges in the industry.
The question is no longer whether a peptide can be made — it is whether it can be made reproducibly, at scale, at a cost of goods that supports commercial pricing, and at a quality that satisfies the impurity control expectations set out by regulatory agencies.
Where the established routes struggle
Solid-phase peptide synthesis (SPPS) remains the workhorse of clinical-stage peptide development, but at commercial scale it presents well-documented economic and environmental challenges: high resin and solvent consumption, unacceptable PMIs, and limited productivity.
As chain length increases, the statistical accumulation of deletion and modification impurities means the crude SPPS product entering final purification carries a complex similarity-impurity profile. These critical similarity impurities (CSIs) are not removed by scale — they are concentrated by it. As batch sizes grow into the multi-kilogram and tonne range required for blockbuster peptides, chromatographic recovery yields fall, solvent consumption climbs disproportionately, and meaningful quantities of qualified API are discarded in side fractions to meet purity specifications.
Current tag-assisted LPPS platforms have addressed several of these limitations by enabling convergent assembly, but they have been designed around a single optimisation target: maximising solubility. Fragment intermediates isolated by massive precipitation typically reach <90% purity by HPLC area — leaving the deletion, diastereomeric, and modification variants that become overlapping peaks, challenging to remove later.
This is the central commercial problem. Achieving a final API specification of NMT 0.10–0.15% for any single specified impurity requires aggressive heart-cutting, with main-fraction recoveries that can fall below 50% on a mass basis. The lever with the greatest financial impact is not improving the resolution of the final column — it is removing the CSIs before they get there.
FISTag™: a different question
FIS approached the design question from a different direction. We asked: what tag architecture, attached to a growing protected peptide fragment, would template a reproducible, well-ordered and easily filtrable crystalline solid — across a range of fragment sequences and lengths?
The FISTag™ tag combines three functional elements: a peptide attachment handle for stable, orthogonal linkage compatible with standard Fmoc and Boc based LPPS couplings; a crystallisation-directing scaffold that biases the tagged fragment toward accessible, thermodynamically stable crystal forms; and a solubility-modulating region tuned so that controlled crystallisation can be triggered reproducibly when needed.
By placing the crystallisation-directing functionality in the tag rather than relying only on the peptide sequence, the solid form behaviour is dominated by tag-tag interactions and is less sequence-dependent. The consequence: accessible, reproducible solid forms within weeks rather than months of solid-state development for new fragments.
Results
A series of 4-6mer GLP relevant fragments were prepared with consistent 99+% purity — clean compounds eligible as new Regulatory Starting Materials (RSMs) for convergent synthesis of more complex APIs. More advanced 8-12mer intermediates were also prepared at Kilo lab scale, reaching consistently 97%+ purities and good yield, with a consistent control strategy. The advanced clean protected fragments, condensed into the final crude API, reached >90% purity prior to chromatography.
The bottom line
FISTag™ reframes the design objective of tag-assisted LPPS: by engineering the tag for crystallisation rather than solubility alone, FIS has built a fragment synthesis platform that purges critical similarity impurities at the point in the route where they are still simple to remove — through a unit operation that is mature, scalable, regulator-friendly, and economically efficient.
The downstream consequence is materially improved final peptide yield, lower cost of goods, and a more defensible impurity control strategy. For peptide programmes approaching late-stage clinical or commercial supply — particularly high-volume GLP-1 and related long-peptide programmes — FISTag™ offers a route to commercial viability that conventional SPPS and current solubility-focused tag-assisted LPPS approaches struggle to match.
About FIS
FIS is a global “small molecule” CDMO with decades of experience designing and optimising commercial API manufacturing routes. Building the most efficient, cost-effective synthetic pathway to a high-purity active ingredient is our core discipline, one that demands rigorous process chemistry, deep understanding of impurity fate and purge, and a relentless focus on cost of goods. FISTag™ is the product of applying that same discipline to peptide synthesis: a tag-assisted LPPS platform engineered to bring small molecule production efficiencies to the manufacture of complex peptides.
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