The International Conference on Harmonization Q8 (R2) includes a requirement that “Critical formulation attributes and process parameters are generally identified through an assessment of the extent to which their variation can impact the quality of the drug product,” that is, the need to assess the robustness of a formulation. In this article, a quality-by-design–based definition of a “robust formulation” for a biopharmaceutical product is proposed and illustrated with a case study. A multivariate formulation robustness study was performed for a selected formulation of a monoclonal antibody to demonstrate acceptable quality at the target composition as well as at the edges of the allowable composition ranges and fulfillment of the end-of-shelf-life stability requirements of 36 months at the intended storage temperature (2°C-8°C). Extrapolation of 24 months’ formulation robustness data to end of shelf life showed that the MAb formulation was robust within the claimed formulation composition ranges. Based on this case study, we propose that a formulation can be claimed as “robust” if all drug substance and drug product critical quality attributes remain within their respective end-of-shelf-life critical quality attribute–acceptance criteria throughout the entire claimed formulation composition range.

Keywords: biotechnology; formulation; HPLC; multivariate analysis; oxidation; factorial design; protein aggregation; protein formulation; proteins; stability