STEVEN MCINTYRE*, CRAIG JOHNSTON, RUTH BELL, KATARZYNA KALTENBERG-ZIOLKOWSKA
*Corresponding author
Almac, Seagoe Industrial Estate, Craigavon, United Kingdom

Abstract

The regulations controlling the use of synthetic peptides as therapeutics has changed significantly over the last number of years with peptides now being viewed as closer to small molecules in terms of process control, structural characterisation and individual impurity limits.  This can become challenging as peptides move through clinical development, and further complicated if a new manufacturer is tasked with preparing material that is of a higher quality than previously produced, with little information as to how the peptides were manufactured previously.  In parallel to the increased regulatory requirements, advances in analytical technologies have led to an increased scrutiny of therapeutic peptides, brightening the spotlight on the control of individual impurities.    Furthermore, if an analytical method is subsequently modified to meet tighter regulatory controls, this can result in previously co-eluting impurities being resolved and a change in the control strategy being required at a late stage of clinical development.

REGULATORY REQUIREMENTS FOR SYNTHETIC PEPTIDES

The FDA issued and later withdrew guidance on synthetic peptides, before a guidance on Abbreviated New Drug Application (ANDA) for peptides produced synthetically was introduced (1).  In Europe, the expectation for control of individual impurities in peptides is based on the information in the European Pharmacopeia (EP) (2), as summarised in Table 1.

In general terms, control of impurities should increase through clinical development.  Specifically, individual impurities should not exceed their values as qualified in the Tox batch, or be greater than 1.0%, whichever is higher.  However, these limits apply to a specified analytical method and as method development is performed, this can result in changes to the levels of impurities previously thought to be qualified.

ANALYTICAL DEVELOPMENT AND IMPURITY DETECTION

In recent years there has been a huge increase in the development of technologies for the analysis ...