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Keywords:

  • Comparability studies;
  • Forced degradation (stress testing);
  • Analysis;
  • Deamidation;
  • Oxidation;
  • Protein aggregation;
  • Protein formulation;
  • Protein structure;
  • Proteins Stability

Abstract

The scope of this paper is to review approaches used for forced degradation (synonym, stress testing) of therapeutic proteins. Forced degradation studies play a central role in the development of therapeutic proteins, for example, for candidate selection, molecule characterization, formulation development, assay development, and comparability studies. Typical stress methods are addressed within this review, such as exposure to elevated temperatures, freeze–thawing, mechanical stress, oxidation, light, as well as various materials and devices used in the clinics during final administration. Stability testing is briefly described as far as relevant to the discussion of forced degradation studies. Whereas stability-testing requirements are defined in regulatory guidelines, standard procedures for forced degradation of therapeutic proteins are largely unavailable, except for photostability. Possible selection criteria to identify appropriate stress conditions and recommendations for setting up forced degradation studies for the different phases of development of therapeutic proteins are presented. © 2011 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 101:895–913, 2012