title: Robustness testing in pharmaceutical freeze-drying: inter-relation of process conditions and product quality attributes studied for a vaccine formulation.
abstract: BACKGROUND
  The recent US Food and Drug Administration (FDA) legislation has introduced the evaluation of the Design Space of critical process parameters in manufacturing processes. In freeze-drying, a "formulation" is expected to be robust when minor deviations of the product temperature do not negatively affect the final product quality attributes.
  
  
  OBJECTIVE
  To evaluate "formulation" robustness by investigating the effect of elevated product temperature on product quality using a bacterial vaccine solution.
  
  
  METHODS
  The vaccine solution was characterized by freeze-dry microscopy to determine the critical formulation temperature. A conservative cycle was developed using the SMART™ mode of a Lyostar II freeze dryer. Product temperature was elevated to imitate intermediate and aggressive cycle conditions. The final product was analyzed using X-ray powder diffraction (XRPD), scanning electron microscopy (SEM), Karl Fischer, and modulated differential scanning calorimetry (MDSC), and the life cell count (LCC) during accelerated stability testing.
  
  
  RESULTS
  The cakes processed at intermediate and aggressive conditions displayed larger pores with microcollapse of walls and stronger loss in LCC than the conservatively processed product, especially during stability testing. For all process conditions, a loss of the majority of cells was observed during storage.
  
  
  CONCLUSIONS
  For freeze-drying of life bacterial vaccine solutions, the product temperature profile during primary drying appeared to be inter-related to product quality attributes.
authors.affiliation: Division of Pharmaceutics, Freeze Drying Focus Group, University of Erlangen, Erlangen, Germany.
authors.forename: Stefan C
authors.initials: SC
authors.lastname: Schneid
authors.forename: Peter M
authors.initials: PM
authors.lastname: Stärtzel
authors.forename: Patrick
authors.initials: P
authors.lastname: Lettner
authors.forename: Henning
authors.initials: H
authors.lastname: Gieseler
mesh_terms: D001428:Bacterial Vaccines / Q000737:chemistry* / Q000592:standards; D002152:Calorimetry, Differential Scanning; D015195:Drug Design; D004355:Drug Stability; D004356:Drug Storage; D004335:Drug and Narcotic Control; D005612:Freeze Drying; D008853:Microscopy; D008855:Microscopy, Electron, Scanning; D013696:Temperature; D014481:United States; D014486:United States Food and Drug Administration; D014961:X-Ray Diffraction
chemical_list: D001428:Bacterial Vaccines