APPLYING LOW FREQUENCY RAMAN TO QBD IN PHARMACEUTICAL DEVELOPMENT

Presented by ohn Wasylyk, Senior Principal Scientist at Bristol-Myers Squibb Company and James Carriere, Product Line Manager for Coherent’s THz-Raman product line.
Low frequency Raman spectroscopy has been used to study various polymorphs and can be applied to the design of crystallization control strategy. Extending the low frequency spectral region to include the fingerprint region provides access to collective vibrations of molecules in the amorphous and crystalline states and yields valuable insight when differentiation of various forms is quintessential. Whether during process development or production, low-frequency Raman bands provide greater sensitivity for detecting the onset of crystallization and has allowed differentiation of crystal types when multiple forms are possible. Applying this to Quality by Design (QbD) studies brings an increase in process understanding leading to developing an optimal control strategy and avoiding the many pitfalls that can occur when scaled up to the production environment. Recent applications of in-line crystallization processes provided insight into establishing the ideal crystallization control parameters. The parameters evaluated include temperature, mixing rate, seed levels and solvent variable. In-line and off-line QbD studies demonstrated both ideal and non-ideal conditions, ultimately yielding critical process knowledge. As a result of our studies, low frequency Raman has proven to be a valuable tool for at-line and on-line monitoring of active pharmaceutical ingredient crystallization and paves the way for robust production in a large scale facility.