Clinical Relevance of Dissolution Testing in Quality by Design

Abstract

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.

Simulation of In Vitro Dissolution Behavior Using DDDPlus™

“…In the early drug development stage, dissolution test helps researchers to find the best formulation to tailor the in vitro behavior of oral dosage form to the desired profile (1,(6)(7)(8)10). Later, dissolution profiles can be used to establish an in vitro/in vivo correlation (IVIVC) which can reduce the need for costly bioequivalence studies (6,11).…”

Summary Workshop Report: Facilitating Oral Product Development and Reducing Regulatory Burden Through Novel Approaches to Assess Bioavailability/Bioequivalence

“…He proposed a five-step approach to develop a dissolution method, similar to one previously described (15), with an emphasis on optimal dissolution power and adequate discrimination. He highlighted three possible outcomes:…”

Meeting Report: International Workshop on Implementation of Biowaivers Based on the Biopharmaceutics Classification System (BCS)

“…Prof. Dr. Bertil Abrahamson presented some experimental examples and suggestions of how clinical relevance of dissolution testing can be achieved in the context of Quality by Design (QbD), emphasizing that in vitro dissolution testing together with BCS considerations could provide a key link between manufacturing/product design variables and clinical safety/efficacy in QbD. Also, Prof. Dr. Abrahamson pointed out that IVIVR and physiologically based pharmacokinetic models (PBPK) can be useful tools to build "safe spaces" aiming to achieve regulatory flexibility, which in turn, may facilitate continuous improvement of both drug product and manufacturing process (6). Prof. Pablo Quiroga used the equation for calculating risk priority number (RPN) in Failure Mode and Effects Analysis (FMEA), first suggested by Kubinga and coworkers (7) as a useful tool for supporting biowaivers to assess the risks of extending BCS-based biowaiver decisions to BCS Class 2 drugs.…”