(605a) Scaleup Considerations for Solid-Phase Peptide Synthesis in Highly Dynamic Packed Beds.

Macrocyclic peptides are a growing and promising asset class within the development pipeline at Merck & Co., Inc. (Rahway, NJ). While batch automated solid-phase peptide synthesis (SPPS) is the foundational technology for accessing milligrams of peptide, it does not align with Merck’s Green and Sustainable Science guidelines for larger-scale production due to the need for high solvent volumes and stoichiometric excesses of non-canonical amino acids. These considerations suggest that scaleup efforts be directed toward developing a packed-bed reactor configuration which may offer improvements to volumetric productivity and process mass intensity. However, the resin comprising the solid phase tends to undergo dramatic and peptide-specific swelling and contraction over the course of each coupling, which necessitates careful consideration of scaling parameters, as well as development of novel control methods that are challenging to integrate with existing piloting and manufacturing process equipment.

To address these issues, Merck has identified key scaling parameters and developed dynamic axial compression variable bed reactors with closed-loop bed height control to provide line-of-site for more environmentally sustainable scaleup of SPPS to support kilo- and multi-kilo-scale deliveries of macrocyclic peptide APIs.