Therapeutic Peptides Control Strategy: Perspective on Current Industry Practices

Abstract

There is currently a lack of harmonization from health agencies on the control strategies that should be implemented for the manufacture of synthetic peptide active pharmaceutical ingredients throughout clinical development and commercialization. In this Perspective, we use the term “peptide” to refer to an α-amino acid polymer with a specific defined sequence without regard to the total number of amino acids that it contains. In the U.S., the FDA currently defines “proteins” that are subject to biological product licensure as follows: “A protein is any alpha amino acid polymer with a specific, defined sequence that is greater than 40 amino acids in size. When two or more amino acid chains in an amino acid polymer are associated with each other in a manner that occurs in nature, the size of the amino acid polymer for purposes of this paragraph (h)(6) will be based on the total number of amino acids in those chains, and will not be limited to the number of amino acids in a contiguous sequence” [21 CFR 600.3(h)(6)]. In contrast, other regulatory authorities apply requirements based on the method of manufacture, resulting in regulatory risks of disparate requirements depending on the jurisdiction. To provide visibility into current industry practices on the control strategies applied to synthetic peptides, a benchmark survey of member companies of the IQ Consortium was conducted. This work provides a comprehensive analysis of the survey results. The compiled responses from 10 companies reveal that while most follow similar control strategies for identification, purity, and assay testing, none of the survey questions received a unanimous response. Interestingly, the number and type of analytical techniques utilized for each test differed when comparing the phase of development, the number of amino acids in the peptide, and whether it was for the drug substance or drug product. Additionally, the limits set for impurity reporting, identification, and qualification thresholds throughout development varied widely. The knowledge acquired from the survey in combination with previously published literature and individual company experiences enables the IQ Consortium to put forth appropriate recommendations to achieve harmonization of control strategies for synthetic peptides with regard to assay, identity, impurity reporting and identification thresholds, bioassay, and comparability assessments.