Quality by design and process analytical technology for freeze drying

BIOT 166

Michael Pikal, pikal@uconnvm.uconn.edu, School of Pharmacy, University of Connecticut, Storrs, CT 06269
Successful applications of “Quality by Design” require at least a minimal knowledge of the basic physics of the formulation and process. Freeze drying is a unit operation for which the fundamentals are relatively well understood, and the fundamental formulation science critical for bio-stabilization has seen considerable advancement over the past decade. Thus, we argue that freeze dried dosage forms present an ideal opportunity to practice “Quality by Design”. It is our thesis that formulation development can be effectively guided by the knowledge and general rules developed over the past decade, and much (perhaps most) of the process development and robustness testing can effectively carried out by calculation, provided that key physical parameters are evaluated by the appropriate experiments. Examples of such formulation and process development/optimization will be discussed. Further, for optimal design and control, the use of Process analytical technology (PAT) offers an opportunity for improved consistency in product quality as well as significant reductions in the cost of manufacturing. Ironically, although PAT technology does exist for freeze-drying, PAT has been grossly underutilized in this important unit operation. This presentation will review current freeze drying PAT as well as discuss several new technologies: (1) mass flux and product temperature measurement via Manometric Temperature Measurement, and (2) Doppler shift Tunable Diode Laser Absorption Spectroscopy (TDLAS) measurement of mass flux and gas flow velocity in freeze dryers.