Abstract
The quality of a peptide drug mainly depends on its impurity profile, with the emphasis on the related impurities. These impurities may be biomedically active, alter the desired efficacy or induce unwanted toxicity, an aspect which is termed the “functional quality” of the peptide drug. Therefore, regulatory authorities have set up guidances or have legally established specification limits to assure a consistent purity of these peptide drugs. For the active pharmaceutical ingredients (APIs), the pharmacopoeial monographs are legally binding. Additional information can be found in regional and international guidelines. For the finished pharmaceutical drug products (FDPs) containing peptide active ingredients, only general guidelines are available. The construction of a complete related-impurity profile is very challenging due to the wide availability of different protecting groups, coupling agents and additives that may be used during peptide synthesis. In addition, chemical degradation, occurring during synthesis, formulation or at storage, may occur as well, including not only so-called pure chemical degradation but interaction with excipients as well. This review provides an update of the regulatory and scientific rationales behind the related impurities in peptide drugs.
Highlights
Peptides are becoming key players in the pharmaceutical industry, gaining more and more attention as possible diagnostics or therapeutics
Because solid-phase is the standard method to synthesize peptides, the different synthesis steps consists of subsequent protecting, coupling and cleavage from the resin
Additional reagents are added, which may remain present in the final product
Summary
Peptides are becoming key players in the pharmaceutical industry, gaining more and more attention as possible diagnostics or therapeutics. The extent of diketopiperazine formation (Figure 5) can be reduced because the N-amino function is protonated and less prone to attack the benzyl ester bond after the deprotection reaction in tBoc SPPS compared to the situation in Fmoc based SPPS [70] Another side reaction consists of the aspartimide formation in peptides containing the Asp-Gly, Asp-Ala or Asp-Ser sequences. Anisole or p-cresol react with the acylium ion formed from the dehydration of the side chains of Asp in strong acidic medium, thereby yielding stable ketone impurities [84] These scavengers may reduce the occurrence of possible side-chain reactions, they may not be completely removed and remain present as an impurity.
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
