Clinical relevance of dissolution testing in quality by design

Abstract

Quality by design (QbD) has recently been introduced in pharmaceutical product development in a regulatory context and the process of implementing such concepts in the drug approval process is presently on-going. This has the potential to allow for a more flexible regulatory approach based on understanding and optimisation of how design of a product and its manufacturing process may affect product quality. Thus, adding restrictions to manufacturing beyond what can be motivated by clinical quality brings no benefits but only additional costs. This leads to a challenge for biopharmaceutical scientists to link clinical product performance to critical manufacturing attributes. In vitro dissolution testing is clearly a key tool for this purpose and the present bioequivalence guidelines and biopharmaceutical classification system (BCS) provides a platform for regulatory applications of in vitro dissolution as a marker for consistency in clinical outcomes. However, the application of these concepts might need to be further developed in the context of QbD to take advantage of the higher level of understanding that is implied and displayed in regulatory documentation utilising QbD concepts. Aspects that should be considered include identification of rate limiting steps in the absorption process that can be linked to pharmacokinetic variables and used for prediction of bioavailability variables, in vivo relevance of in vitro dissolution test conditions and performance/interpretation of specific bioavailability studies on critical formulation/process variables. This article will give some examples and suggestions how clinical relevance of dissolution testing can be achieved in the context of QbD derived from a specific case study for a BCS II compound.

Fig. 1

Different steps to be considered in relating manufacturing variables to clinical

Fig. 2

Evidenced required to demonstrate clinical quality according to BCS class of compound

Fig. 3

Initial risk assessment of product and process variables that could affect clinical quality through dissolution

Fig. 4

Mean (n = 6) tablet dissolution in various media. a pH 1.2 b pH 4.5 c pH 6.8 d water with surfactant providing solubilisation

Fig. 5

Geometric mean and individual plasma drug concentrations from tablet variants (n = 10 for tablets a and b, n = 11 for tablet c and n = 9 for tablet d) versus an oral solution (n = 15) after dosing to healthy volunteers

Fig. 6

The role of BCS in defining the approach to ascertaining clinical performance by dissolution testing within QbD

Fig. 7

The role of drug BCS class in defining the approach to setting dissolution specifications

Fig. 8

Changes in C_max and AUC for Safe Space and IVIVC establishment