(622f) A Scale Down Approach to Liquid Phase Peptide Synthesis

Over the next ten years, the demand for peptide therapeutics is projected to triple due to recent unprecedented therapeutic successes in high volume areas such as weight loss and diabetes. Traditional solid phase peptide synthesis approaches to produce peptide are both extremely expensive and wasteful and can have an E-factor of 10,000-30,000, meaning that to produce 1 kg peptide, up to 30,000 kg of waste are generated. This technique also struggles to achieve high purity for longer length peptides, requires the use of specialized equipment, and employs cumbersome unit operations associated with loading and unloading particles in GMP manufacturing facilities. Overall, meeting the forecasted demand for peptide therapeutics using solid phase synthesis technology will require overcoming a tremendous number of challenges.

We believe that liquid phase peptide synthesis (LPPS) offers a solution to the many manufacturing challenges presented by SPPS. A key premise of LPPS technology is the use of phase selective tags, which enables the peptide fragment to reside in an organic phase during aqueous-organic purifications to remove waste byproducts. Following completion of the synthesis, the tag can be cleaved to enable isolation of the peptide fragment in high purity. LPPS technology under development at Snapdragon uses new, atom efficient tags as well as an amine protecting group that can be cleaved via hydrogenation. Both of these improvements to existing LPPS technologies have resulted in significant reductions to E-factor while also allowing peptide synthesis to be run in standard batch reactors while leveraging existing capacity.

Due to the complexity of the manufacturing process, traditional process optimization approaches are labor intensive and slow. To address this, we have built a scale-down, fully automated liquid phase peptide synthesizer that employs black box optimization approaches to improve critical parameters such as yield, purity, and productivity. These new tools are being leveraged to drastically accelerate process understanding and timelines while providing critical data for eventual commercial scale peptide manufacture.