AAPS PharmSciTech

, Volume 19, Issue 7, pp 2828–2842 | Cite as

Impact of Natural Variations in Freeze-Drying Parameters on Product Temperature History: Application of Quasi Steady-State Heat and Mass Transfer and Simple Statistics

  • Michael J. Pikal
  • Paritosh Pande
  • Robin BognerEmail author
  • Pooja Sane
  • Vamsi Mudhivarthi
  • Puneet Sharma
Research Article Theme: Team Science and Education for Pharmaceuticals: the NIPTE Model
Part of the following topical collections:
  1. Theme: Team Science and Education for Pharmaceuticals: the NIPTE Model


Inter- and intra-batch variability in heat and mass transfer during the drying phase of lyophilization is well recognized. Heat transfer variability between individual vials in the same batch arise from both different positions in the vial array and from variations in the bottom contour of the vials, both effects contributing roughly equally to variations in the effective heat transfer coefficient of the vials, Kv. Both effects can be measured in the laboratory, and variations in average Kv values as a function of vial position in the array for lab and production can be calculated by use of the simple steady-state heat and mass transfer theory. Typically, in the laboratory dryer, vials on the edge of the array, “edge vials,” run 2–4°C warmer than “center vials,” but differences between laboratory and manufacturing temperatures are modest. The variability in mass transfer can be assigned to major variations in ice nucleation temperature (both intra-batch and inter-batch), including major differences between laboratory and manufacturing. The net effect of all random variations, for each class of vial, can be evaluated by a simple statistical model-propagation of error, which then allows prediction of the distribution in product temperatures and drying times, and therefore prediction of percent of vials dry and percent of vials collapsed and proximity to the edge of failure for a given process. Good agreement between theoretical and experimentally determined maximum temperatures in primary drying and percent collapsed product demonstrates the calculations have useful accuracy.


freeze-drying statistics of variability in product temperature heat and mass transfer scale-up 

Supplementary material

12249_2018_1155_MOESM1_ESM.pptx (44 kb)
ESM 1 (PPTX 43 kb)


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Copyright information

© American Association of Pharmaceutical Scientists 2018

Authors and Affiliations

  • Michael J. Pikal
    • 1
  • Paritosh Pande
    • 1
  • Robin Bogner
    • 1
    Email author
  • Pooja Sane
    • 1
    • 2
  • Vamsi Mudhivarthi
    • 1
    • 3
  • Puneet Sharma
    • 4
  1. 1.School of PharmacyUniversity of Connecticut and Institute of Materials Science, University of ConnecticutStorrsUSA
  2. 2.BioMarin PharmaceuticalsSan RafaelUSA
  3. 3.Pfizer CorporationChesterfieldUSA
  4. 4.Genentech (A Member of the Roche Group)South San FranciscoUSA

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