Main Conference Day 3Thursday, 13 November 2025 - CET (Central European Time, GMT+01:00)

The talk will share the cross-industry perspective developed within the Synthetic Peptide Working Group of the International Consortium for Innovation and Quality in Pharmaceutical Development (IQ Consortium) on selection of Regulatory starting materials for synthetic peptides. The established approach when using solid phase peptide synthesis leads to all protected amino acids and dipeptides being designed regulatory starting materials (RSMs). As the industry strives to reduce carbon footprint and costs related to drug substance manufacturing, newer alternative manufacture strategies (such as fragment-based approaches) could lead to opportunities for enhanced RSM positions. This talk will give an outline on alternative options, include theoretical case studies.

The global deprotection step is the final stage in the upstream process of peptide synthesis. When peptide elongation is performed via solid-phase peptide synthesis (SPPS), this step coincides with resin cleavage. Traditionally, polyfluoroalkyl substances (PFAS), particularly trifluoroacetic acid (TFA), have been the reagents of choice. However, increasing regulatory scrutiny and anticipated usage restrictions necessitate the development of alternative strategies. Here, we present ongoing efforts in our laboratory to identify and implement viable substitutes for TFA.

Peptide therapeutics have experienced a rapid increase in popularity and demand over recent years, necessitating research into advanced monitoring and manufacturing methods. Within Solid-Phase Peptide Synthesis (SPPS) methods, large amounts of solvent and time are required in sequential and repetitive cycles to manufacture peptide therapeutics. By aligning with the FDA directive for Process Analytical Technology (PAT), Raman spectroscopy shows great promise as an on-line and real-time method for improving the efficiency of SPPS across all major steps of the synthesis. Specifically, Raman spectroscopy can be used to monitor residual piperidine concentration during the de-Fmoc wash step, leading to significant solvent and time savings when used in conjunction with novel continuous wash methods. Additionally, Raman spectroscopy can be used to monitor the concentration of Fmoc-Amino Acid in the reaction solution, which may be useful in developing a greater understanding of the kinetics of the amino acid coupling reactions. The work described herein will outline efforts towards greener, cleaner, and more efficient SPPS methods that can be applied on a commercial scale.

Discovery and production of synthetic peptides has significantly progressed in the last years resulting in the fact that rather complex peptides like GLP-1 analogues, e.g., Semaglutide and similar sequences, are produced in large quantities for commercial consumption. Length, challenging sequences, and modifications require extended efforts to develop a robust process.

We are demonstrating how different tags placed on different positions on a sequence can help to manufacture difficult peptides in high yield and how such tags can be removed in a traceless manner. This approach includes replacing conventional solid support (resin) on the C-terminus with innovative linkers or a small molecule tag leading to tag-assisted liquid-phase peptide synthesis (LPPS) methodology. Each technology has benefits and drawbacks which will be highlighted, to help the process chemist developing an efficient process, keeping also an eye on material efficiency, sustainability and green aspects in general.

Our unique liquid-phase synthesis technology, utilizing anchor compounds, has been refined for processes like GLP-1 suitable for large-scale production. This method allows post-reaction treatment with simple aqueous washing and uses environmentally friendly solvents. It suppresses side reactions, achieving high purity and yield in long sequence and complex peptide synthesis. We will present examples showing reductions in purification load and PMI.

Health authorities are increasingly emphasizing the need for rigorous risk assessments focusing on the formation and presence of nitrosamine impurities in peptide Active Pharmaceutical Ingredients (APIs) produced via synthetic methods. While clear assessment protocols, informed by structure-activity relationship-based methods have been defined for small molecule drug substances, equivalent guidance for synthetic peptides is lacking. This gap in guidance presents significant challenges, including control strategy justification and analytical testing expectations. In this presentation, we will explore relevant literature evidence regarding the formation potential and stability of nitroso-impurities in the context of amino acids, peptides, and proteins. Our study focuses on potential vulnerable nitrogens found in synthetic peptide APIs, such as primary and secondary amides and indoles amongst others. We aim to provide critical insights and general conclusions that inform nitrosamine risk assessments for synthetic peptide API manufacturing processes. Attendees will benefit from a deeper understanding of the formation and stability of nitroso-impurities, enabling them to develop more robust assessment and mitigation strategies.

Exploring novel technologies in solid-phase peptide synthesis designed to improve CMC outcomes—enhancing crude purity, reducing solvent use, and enabling precise temperature control. These innovations support robust process development and tech transfer, offering practical solutions for cost-efficient and scalable peptide manufacturing.

Tag-Assisted Peptide Synthesis (TAPS) is a solution-phase synthetic approach that offers several advantages to the established Solid-Phase Peptide Synthesis (SPPS), for example by reducing the environmental footprint of peptide synthesis through significantly lower solvent use. TAPS has to date mainly been employed for linear synthesis of short peptides and peptide fragments with subsequent convergent assembly, but herein we disclose for the first time the development and application of a TAPS platform to produce full-length, complex peptide active pharmaceutical ingredients in a linear manner, on manufacturing scale.