Table 2 Unique issues for large versus small molecules

• Applicability of Arrhenius equation for large molecules

• Perceived need to start with first principles

• Variability for biologics may make it more difficult to precisely model

• Fundamental model selection for biologics

• Lack of trust of non-linear models

• Temperature and/or Humidity is too high thus modeling is not predictive.

• Physical changes/polymorph changes–modeling in solids

• Modeling is difficult for proteins in solution–reversible step vs irreversible steps

• Label condition for Biologic drug substances is -20C – > what is accelerated?

• Extrapolation can be risky