Green Chemistry Challenge: 2017 Greener Reaction Conditions Award
Green Process for Commercial Manufacture of Etelcalcetide Enabled by Improved Technology for Solid Phase Peptide Synthesis
Amgen Inc., Cambridge, Massachusetts, in partnership with Bachem, Switzerland, is being recognized for improving the process used to manufacture the active ingredient in ParsabivTM, a drug for the treatment of secondary hyperparathyroidism in adult patients with chronic kidney disease. This improved peptide manufacturing process reduces chemical solvent use by 71%, manufacturing operating time by 56%, and manufacturing cost by 76%. These innovations could increase profits and eliminate 1,440 cubic meters of waste or more, including over 750 cubic meters of aqueous waste annually.
Summary of Technology:
Peptides have gained increased interest as therapeutics over the last three decades, largely due to their advantageous properties including high specificity and affinity, as well as superior safety and tolerance. These properties make peptide drugs more desirable than small molecule drugs in certain diseases, such as cancer, enzyme deficiency disorders, protein-dysfunction disorders, genetic and degenerative diseases, and infectious diseases. Currently, there are over 60 FDA approved peptide drugs on the market and over 600 either in clinical trials or pre-clinical development. Peptide-based pharmaceuticals are an important class of therapeutic agents with the potential to replace many existing small molecule-based pharmaceuticals in the near future.
Compared to the manufacturing process of small molecule drugs, the environmental impact of this technology has not garnered much attention, in part because the high potency of peptide drugs has rendered supply needs significantly lower than traditional small molecule drugs. Recent investigations have revealed that, on average, producing 1 kg of peptide requires over 5 metric tons of solvent, significantly higher than most other types of synthetic small molecules.
Etelcalcetide was manufactured using a standard solid phase peptide synthesis manufacturing platform up to the phase 3 trial stage, but the expected high demand for the product made full scale commercial production problematic given the amount of materials needed and the waste generated. Amgen and Bachem redesigned the manufacturing process to eliminate one of five stages and optimize the remaining four. This improved process resulted in a 5-fold increase in manufacturing capacity and a 56% decrease in manufacturing time, mitigating risks to drug supply. In addition, the new process reduced the amount of solvent, completely eliminated an ion-exchange column process requiring over three liters of water for every gram of drug, and reduced the number of energy intense lyophilization cycles from 13 per batch to one.
This new commercial manufacturing process was implemented and validated prior to drug approval. These innovations will result in the annual elimination of more than 1440 cubic meters of waste, including over 750 cubic meters of aqueous waste. Additionally, the broad and general applicability of this improved peptide manufacturing platform has been demonstrated for other peptide drug candidates.