Tirzepatide is a novel 39 amino acid residue GIP (gastric inhibitory polypeptide) and GLP-1 (glucagon-like peptide-1) dual receptor agonist targeted as a treatment for diabetes, obesity, and other indications. A hybrid solid-phase peptide synthesis (SPPS) / liquid-phase peptide synthesis (LPPS) manufacturing process has been developed to produce drug substance of high purity, while minimizing manufacturing risk and providing high yield. The tirzepatide SPPS manufacture strategy incorporates four shorter peptide fragments (each ≤14 amino acid residues) in high purity as well-characterized precipitated intermediates. These fragments are subsequently coupled in liquid phase to form the crude drug substance. High resolution analytical chromatography methods were established specific to each fragment to provide quantitation of key process impurities and degradation products. Reversed-phase UHPLC-UV analysis was used as the foundational method for individual and total impurities reporting, while UHPLC-MS methods were developed for quantitation of impurities co-eluting with the main peak or with other impurities in the UV chromatogram. The UHPLC-MS methods were fully validated according to ICH Q2 expectations to support impurities quantitation using external standards across the range of 0.1% to 1.0% w/w. The UHPLC-MS and UHPLC-UV purity methods combine to support the fragment release specifications. Together with starting material specifications and downstream process controls, the fragment impurity control strategy ensures that all fragment impurities are below the specification criteria in the final tirzepatide drug substance.
Who should participate:
- QA Manager
- QA Staff
- QC Chemist
- QC Manager
The live version of this recording took place on during the USP Workshop on Therapeutic Peptides and Oligonucleotides:
Regulations and Quality Standards on March 4, 2022
Access to this course expires 60 days from the date of registration or until you mark the course ‘Complete’ – whichever occurs first.
Mark Strege, M.S.
Principal Research Scientist
Eli Lilly & Company