This presentation explores lifestyle medicine as a growing market, focusing on challenges in large-scale biopharmaceutical manufacturing and cost reduction strategies. It highlights advances in peptide bioprocessing and beyond, examining whether these innovations can meet rising market demands for anti-aging biopharmaceuticals. Emphasis is placed on optimising production efficiency and scalability to align with consumer expectations for effective, accessible lifestyle, and anti-aging therapies

The environmental challenges with solid- and liquid-phase peptide synthesis are many, particularly with EU legislation moving to ban crucial solvents such as DMF and forever chemicals like TFA. Origin Peptides has discovered and developed a novel method of peptide synthesis which is completely aqueous, solid-phase free, and uses standard amino acids, in a one-pot reaction with high fidelity, reproducibility, and a broad range of applicability.

Recombinant peptide production in E. coli offers a sustainable alternative to chemical synthesis. Challenges in producing high-yield disulfide-bonded peptides include: degradation by host peptidases, the need for translocation into the periplasm, and the requirement for individualised manufacturing processes. We have developed the CASPON technology, a generic fusion tag-based platform that enables high-titre soluble expression, efficient affinity purification, and tag removal—particularly important for biopharmaceutical applications.

Efficient manufacturing of disulfide-bonded peptides remains challenging due to proteolytic degradation, complex downstream processing, and the need for peptide-specific process development. CASPON technology offers a platform solution, enabling high-titre soluble expression in E. coli, affinity purification, and precise tag removal. By combining CASPON with outer membrane engineering, we achieved peptide release into the medium, simplifying DSP. This approach accelerates process development and ensures high-quality peptide production for biopharmaceutical applications.

A versatile and highly efficient bioproduction platform to generate various forms of disulfide-constrained peptides (DCPs) has been developed as an environmentally sustainable alternative to SPPS. This platform can be used to generate: (1) multivalent DCPs with different geometries, (2) DCPs with functional chemical groups such as biotin, (3) DCPs with unnatural amino acids through amber codon suppression, and (4) isotope-labeled DCPs.

The pipeline of oligonucleotide therapeutics promises to deliver treatments for increasingly large patient populations and oligonucleotide manufacturing needs to respond to this shift in demand. Significant effort has been put into technologies to improve the scalability, sustainability, and cost of oligonucleotide manufacturing, all of which have their advantages and challenges. The potential introduction of these technologies and the interactions between them present a complex yet tantalising opportunity for future supply.

Recombinant manufacturing of oligonucleotides has the potential of overcoming the severe concerns of poor scalability and yield, as well as, the huge waste generation associated with solid-phase synthesis. The development of perfusion cell cultures and multicolumn countercurrent chromatographic purification of oligonucleotides are presented herein as a way of reaching consistent product quality and improved process mass intensity compared to traditional operations. A dynamic process control strategy is presented to reduce the sensitivity of chromatographic yield and purity towards fluctuations of operating parameters like temperature, buffer composition and loading, with the anticipation of streamlining process integration.

Therapeutic oligonucleotides represent a rapidly expanding class of drugs, including antisense oligonucleotides, siRNAs, and aptamers. Supporting quality of these products begins with the control of starting materials, particularly phosphoramidites. Key considerations include impurity classification, process-dependent impurity impact, selection of analytical methods for impurity detection and characterisation, and use of reference standards. This presentation will focus on strategies and USP resources to support risk-based quality assessment of phosphoramidite starting materials.

Ensuring quality in oligonucleotide therapeutics requires robust controls for both legacy nucleoside phosphoramidites and newer starting materials such as GalNAc ligands and linkers used in conjugates. These inputs present different challenges, ranging from well-established specifications to the added complexity of novel chemistries. This presentation will discuss phase-appropriate control strategies, analytical method development, and how regulatory expectations differ for established versus emerging inputs.

Oligonucleotide synthesis is performed using a highly automated synthesiser, without in-process controls until the full-length oligonucleotide is cleaved from the solid support. Already a 20-base-long sequence requires 80 reaction steps. To ensure high quality and high yields every reaction step needs to be done almost quantitatively. Today's oligonucleotides are highly modified resulting in unique manufacturing challenges and regulatory hurdles. Latest manufacturing technologies including enzymatic ligation will be discussed.