Chapter 21: Rational Design of a Freeze-Drying Process for Protein Products

  • Feroz JameelEmail author
  • Tong Zhu
  • Ehab M. Moussa
  • Brittney J. Mills
Part of the AAPS Advances in the Pharmaceutical Sciences Series book series (AAPS, volume 35)


Freeze-drying is a commonly used manufacturing operation for biopharmaceuticals to enhance the storage stability. The stability of the product during freeze-drying and upon storage depends on the design of the formulation and the freeze-drying process. The robustness of the freeze-drying process is dictated by the formulation composition and the nature of the excipients. In this chapter, the underlying principles and concepts involved in the design of the formulation and the process are discussed and illustrated with a case study. In addition, a novel approach using predictive modeling for the initial guesses of the input parameters of the process is discussed.


Lyophilization Freeze-drying Freezing Primary drying Scale-up Manufacturing 



Chamber pressure


Sublimation front pressure


Reference pressure


Shelf temperature


Average shelf surface temperature


Shelf heating fluid inlet temperature

Tbot (or Tb, Tpr)

Product bottom temperature


Eutectic melting temperature


Collapse temperature


Reference temperature


Critical product temperature

Tsh, crit

Critical shelf temperature


Glass transition temperature of the dry powder


Glass transition temperature of the maximum freeze-concentrated solution


Residual unfrozen water content at the Tg′ temperature

\( {\dot{Q}}_{\mathrm{cond}} \)

Heat conduction rate in the frozen product

\( {\dot{Q}}_{\mathrm{tot}} \)

Total heat transfer rate to the vial

\( {\dot{Q}}_{\mathrm{sub}} \)

Heat transfer rate at the sublimation front


Vial heat transfer coefficient in general

Kv, surf

Vial heat transfer coefficient between the shelf surface and the vial bottom

Kv, inlet

Total/apparent heat transfer coefficient between the shelf fluid inlet and the vial bottom


Radiative heat transfer coefficient to the vial from the surroundings


Gas conductive heat transfer coefficient between the vial bottom and the shelf/tray


Pressure independent part of heat transfer coefficient between the vial and the shelf/tray


Constant parameter expressing the pressure dependence of heat transfer coefficient


Pressure dependence of heat transfer coefficient specific to a vial geometry


Area-normalized product resistance


Maximum area-normalized product resistance for a given product


Solid concentration of the formulation (w/v)


Universal gas constant


Latent heat of ice sublimation


Bottom area of the frozen product


Outer area of the vial cross section


Effective gap distance between the vial bottom and the shelf/tray

lpr, 0

Initial frozen product thickness


Dried cake thickness


Fill volume


Heat conductivity of the frozen product


Stefan-Boltzmann constant


Heat conductivity of the water vapor at a given pressure


Energy accommodation coefficient for water vapor


Primary drying time


Porosity of the dried cake


Tortuosity of the dried cake


Average radius of the pores in the dried cake


Fast design space


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Copyright information

© American Association of Pharmaceutical Scientists 2020

Authors and Affiliations

  • Feroz Jameel
    • 1
    Email author
  • Tong Zhu
    • 1
  • Ehab M. Moussa
    • 1
  • Brittney J. Mills
    • 1
  1. 1.Formulation Development, New Biological Entities, AbbVie (United States)North ChicagoUSA

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