AAPS Workshop on the Role of Dissolution in QbD and Drug Product Life Cycle: A Commentary

This is a summary report of the “AAPS Workshop on the Role of Dissolution in QbD and Drug Product Life Cycle” organized by the AAPS In Vitro Release and Dissolution Testing (IVDRT) Focus Group. Representatives from the pharmaceutical industry, regulatory authorities, and academia in the U.S. and Europe attended this workshop to discuss the role of dissolution in a Quality by Design (QbD) setting and its relevance in drug product development. Other areas of discussion included IVIVC/R and hot topics like alcohol dose-dumping. Numerous case studies were presented, and issues relevant to the dissolution scientist and areas needing further research were highlighted at this workshop. Views expressed in this paper are those of the participants from the industry and the agency and do not necessarily represent those of the FDA and USP. INTRODUCTION This paper summarizes the panel discussions of the “AAPS Workshop on the Role of Dissolution in QbD and Drug Product Life Cycle” held on April 28–30, 2008 in Crystal City, Va., and jointly sponsored by the American Association of Pharmaceutical Scientists (AAPS) and the U.S. Food and Drug Administration (FDA) (1). The workshop was a follow-up to a previous meeting (2) organized by the AAPS In Vitro Release and Dissolution Testing (IVDRT) Focus Group, and highlights have been published (3). This two-and-a-half-day workshop provided a forum for participants and experts from the pharmaceutical industry, the regulatory authorities, and academia in the United States and Europe to share current thinking on the role of dissolution testing in the following areas: • Role of Dissolution in QbD and Product Development Continuum (Session 1) • Role of Dissolution in QbD (Session 2) • Relevance of Dissolution in Drug Development (Session 3) • IVIVC/R (Session 4) • Dissolution: Hot Topics (Session 5) Each session consisted of a series of presentations followed by a Q&A session. A panel discussion was conducted at the end of each session. This summary paper is based on the panel discussions and is divided into five sections, one for each session. SESSION 1: ROLE OF DISSOLUTION IN QBD AND PRODUCT DEVELOPMENT CONTINUUM The panel discussion centered around three points. The first topic was the importance of having the in vitro test reflect bioequivalence and further the understanding of the release mechanism. In such cases, the BCS classification should be taken into account so that product quality can be related to clinical relevance. In some cases, as with BCS Class 1, in vitro studies could be more appropriate than in vivo testing in terms of total cost and may actually better assess the performance of the product. It is necessary for the formulator to be more critical of the formulation and to understand the release mechanisms, especially when there is high in vivo and in vitro variability. The intrinsic variability can be high when there is a firstpass effect combined with low solubility and when the pKa is close to the gastric pH. Sometimes the in vivo result can be inaccurate, showing that the BCS class needs to be considered when relating quality to clinical relevance. Another point of discussion centered on the difficulty in applying QbD principles to in vitro testing given the limited time available for development. This point was challenged, especially with regard to generic products where prior knowledge of the formulation may be available. An understanding of the release mechanism of the generic formulation is important since in many cases there are different excipients that can pose comparable change in the release mechanism. All agreed that the safety of the product should always prevail. There was discussion regarding use of the peak vessel, since it is not favored by the FDA but has been used in a few approved *Corresponding author. diss-17-04-08.indd 41 11/19/2010 9:05:05 AM dx.doi.org/10.14227/DT170410P41