Proposal for New General USP Chapter on Quality Attributes of Starting Materials for the Chemical Synthesis of Therapeutic Peptides

In the Pharmacopeial Forum, PF 48(1), a proposal for a new general chapter <1504> Quality Attributes of Starting Materials for the Chemical Synthesis of Therapeutic Peptides was published. The draft of the new chapter is available on PF Online. (Please note: a one-time registration is required to access the Pharmacopeial Forum.) The deadline for submitting comments is March 31, 2022.

Structure of the New Chapter

The new chapter is divided into the following sections:

• Scope
• Introduction
• Supplier qualification and evaluation of synthetic route
• Amino acid derivatives (AAD)-related impurities originating from amino acids
• AAD-related impurities originating from the AAD manufacturing process
• Non-AAD impurities
• Conclusion and recommendations for AAD specifications

Content

According to the Expert Committee, the scope of the new chapter is to provide an overview of the minimum quality attributes required for starting materials used in the manufacture of synthetic therapeutic peptides. The discussion in the new chapter focuses on the most commonly used protected amino acid derivatives (AAD). However, the general concepts and guidance described can be applied to all peptide starting materials.

For the manufacture of peptides by chemical synthesis, the starting materials are amino acids, protected amino acid derivatives, and fragments. As these starting materials have the potential to directly impact the quality of the drug substance, special attention must be paid to the quality attributes.

The synthetic route for the amino acid derivative potentially could result in different impurities, which can be classified into three main categories (AAD-related impurities originating from the amino acids; AAD-related impurities originating from the AAD manufacturing process; Non-AAD-related impurities), whereby the first two types are considered to be critical.

According to the new chapter, the most common quality attributes to be used for protected amino acid derivative starting materials are:

• Appearance
• Identification
• Related impurities
• Other impurities (not related)
• Assay by titration
• Other components