Strategies for Managing Solid Form Transformation Risk in Drug Product.

The International Conference of Harmonization (ICH) Q6A document provides guidance on setting specifications for new drug substances and drug products. In this paper we focus on decision trees 4 (#1) to (#3) in the guidance related to solid-state form transformation. Form transformation could occur from use of high energy forms to overcome solubility challenges or stresses from manufacturing processes. The decision trees provide guidance on when and how polymorphic form changes should be monitored and controlled. However, guidance is high level and does not capture aspects related to assessments needed to understand if there is a risk of transformation or tools that can be integrated to understand the severity of bioavailability impact at different stages of development. The objective of this paper is therefore to provide comprehensive chemistry manufacturing and controls (CMC) and regulatory strategies to manage the risk of form transformation. This includes practical workflows for form transformation risk assessment, analytical tools to detect and quantify the transformation including their shortcomings, biopharmaceutical tools to understand the severity of transformation risk and if needed justify the limits based on clinical relevance. Finally, a few case studies are discussed that capture how the workflow can be used to manage transformation risk.