APPLICATION OF QbD PRINCIPLES TO BIOLOGICS PRODUCT: FORMULATION AND PROCESS DEVELOPMENT

TheinherentcomplexityofbiologicspresentsachallengeintheapplicationofQbDanddesign space concepts. The link between product/molecule attribute and clinicalperformance is not always well understood. The heterogeneity of the product makesit difficult to precisely measure all the attributes of the molecule. It can be difficult todefine the quality attributes (QAs) that are truly critical to safety and efficacy.Consequently,thefocusshiftstowardusingclinicalexperienceandmaintainingprocessconsistency. Similarly, the functional relationship between process parameters andquality attributes may not be readily defined.The development of a stable formulation for a biologic therefore involves account-ing for the inherently complex structure of the protein and the multiple degradationpathways it may undergo. A compromise among competing degradation pathways mayberequiredtodevelopanoptimizedformulation(e.g.,acidhydrolysisanddeamidation).A large body of knowledge has been generated that can aid the formulation scientist inthistask,andanumberofsummariesandreviewshavebeenpublished(see,forexample,Refs [1–3]). For biologics, heterogeneity of the bulk drug substance is the rulerather than exception, and the upstream and downstream processes are a major source