Quality by Design Drug Substance Correlating CQA's to Synthesis Steps made easy

Drug Substance Quality by Design (QbD) is straight forward early in the risk assessment process. Quality Risk Management of the drug substance development follows a definite pattern with respect to correlating API Critical Quality Attributes (CQA’s) to individual synthesis steps. Correlating the synthesis steps to the API CQA’s) follows directly after defining the CQA’s themselves. Discussion on defining the drug substance CQA’s is found in my article, Quality by Design: Drug Substance Critical Quality Attributes made easy. This article discusses the approach for defining the individual synthesis steps and their potential to impact a CQA.
The process starts with the Starting Materials and goes to the final drug substance including any particle size adjustments done at the end of the process. It does not include the packaging operation since that is not an API specific process design consideration. The packaging process is defined and controlled within the Quality Management System (QMS). The best time to initiate CQA correlation of the risk assessment process is when the final synthesis route is locked. It makes no sense to begin earlier because major changes in the synthetic route means the synthesis proceeds through a different set of intermediates and can have a different impurity profile. Once locked, the synthesis has a defined chemistry and a defined set of intermediates. Each synthesis step is defined by a given isolated intermediate. More than one chemical transformation can occur per synthesis step. The process ranges are probably not defined at this stage and critical parameters are not identified. Characterization and optimization work are still ongoing. It is still possible to change isolated intermediates with some steps being combined while others may be split.
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