Wet Milling Impact on Particle Size

This presentation details the development, understanding, and scale-up of an aseptic crystallization, which utilizes a novel wet milling during anti-solvent addition approach, that consistently delivers desired physical properties that result in an acceptable uniformity of the final drug product formulation.

The drug substance described is formulated as a sterile powder blend in a vial in combination with other sterile powder drug substances, and needs to fit into the existing formulation process and equipment. The use of an aseptic blending operation requires that the final crystallization of the drug substance be performed in an aseptic environment as well. Due to the nature of the sterile processing environment, sampling of the powder blend during processing to verify blend uniformity is not possible, and sampling of the crystal slurry during processing to ensure suitable physical properties is not feasible, so process adjustments based on in-process testing cannot be done. 

Presentation Overview

• Active Pharmaceutical Ingredient (API) and Process Background
  • What crystallization strategies have been explored?
  • Why was wet milling chosen?
• Wet Milling Process Characterization
  • Initial Assessment
  • Nucleation
  • Milling after nucleation
  • What actual controls particle size?
  • Further Studies: Understanding Mill Nucleation Mechanism
    • What role is the mill playing exactly when it comes to nucleation and generating more particles?
    • Experiment idea: only send fluid through the mill, filter out particles using a particle size analyzer
  • Scale-up Results, Acknowledgement and Questions