Freezing of Biologicals Revisited: Scale, Stability, Excipients, and Degradation Stresses

Freezing is a common unit operation in the production of biopharmaceuticals

Jean-Rene Authelin; Miguel A. Rodrigues; Serguei Tchessalov; Satish K. Singh; Timothy McCoy; Stuart Wang; Evgenyi Shalaev

2019

Scholarcy highlights

  • Freezing is a common unit operation in the production of biopharmaceuticals
  • Many biotech products are successfully stored in the frozen state, there are confirmed cases of freeze-induced instability
  • In most cases reported in the literature, frozen state degradation has been linked to crystallization of a cryoprotector
  • 2 additional freezing-related destabilization pathways are introduced in the paper, that is, air bubbles formed on the ice crystallization front, and local pressure and mechanical stresses due to volume expansion during water-toice transformation
  • Air bubbles could destabilize proteins by exposing them to additional air/solution interface, whereas the freezing-induced mechanical stresses could result in unfolding of proteins because of either hydrostatic presser or shear stress effects
  • Water-to-ice transformation results in approx. 9% increase in the volume, and such volumetric expansion can result in significant shear stress and elevated local pressure
  • Stability during freeze-storage could depend on the sample size, via relationships between sample volume and the kinetics of freezing
  • For biological drug product, ready-to-use solution is the preferred dosage form, depending on the stability of the active pharmaceutical ingredient and the stage of development, freeze-dried and occasionally frozen solution forms could be a valuable option

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