Scale-up of API crystallization using Raman and FBRM Process Analytical Technology (PAT) to ensure Quality by Design (QbD)

scale-up-active-pharmaceutical-ingredients-api-american-pharmaceutical-reviewIn this recent paper published in American Pharmaceutical Review (Nov/Dec 2009) , the authors describe a comprehensive approach to QbD throughout the development and scale-up of a final crystallization step for an active pharmaceutical ingredient.

“The use of the QbD approach throughout the life-cycle of a drug product is an efficient tool for faster and more focused process development”

The paper describes the use of various tools, including:

  • Phase diagrams for a complete understanding of system thermodynamics, and determination of operating conditions to ensure production of the desired anhydrous form
  • The use of factorial design of experiments to map the operating design space, understand the effect of process variations and ensure robust operation
  • Real-time monitoring of the crystal product with FBRM (focused beam reflectance measurement) to monitor crystal nucleation and growth for optimization of seeding protocol and detection of undesirable events upon scale-up
  • In-line Raman to detect the presence of a metastable undesirable solvated form of the API, and to confirm its complete conversion to the desired stable form

Citation: or New Developments in Scale-Up and QbD to Ensure Control Over Product Quality, by Martin Bohlin Ph.D., Helen Jones Ph.D., & Simon Black Ph.D. Global Process R&D, AstraZeneca, American Pharmaceutical Review, Volume 12, Issue 7, November/December 2009.