Abstract.This manuscript represents the perspective of the Dissolution Analytical Working Group of the IQ Consortium. The intent of this manuscript is to highlight the challenges of, and to provide a recommendation on, the development of clinically relevant dissolution specifications (CRS) for immediate release (IR) solid oral dosage forms. A roadmap toward the development of CRS for IR products containing active ingredients with a non-narrow therapeutic window is discussed, within the context of mechanistic dissolution understanding, supported by in-human pharmacokinetic (PK) data. Two case studies present potential outcomes of following the CRS roadmap and setting dissolution specifications. These cases reveal some benefits and challenges of pursuing CRS with additional PK data, in light of current regulatory positions, including that of the US Food and Drug Administration (FDA), who generally favor this approach, but with the understanding that both industry and regulatory agency perspectives are still evolving in this relatively new field. The CRS roadmap discussed in this manuscript also describes a way to develop clinically relevant dissolution specifications based primarily on dissolution data for batches used in pivotal clinical studies, acknowledging that not all IR product development efforts need to be supported by additional PK studies, albeit with the associated risk of potentially unnecessarily tight manufacturing controls. Recommendations are provided on what stages during the life cycle investment into in vivo studies may be valuable. Finally, the opportunities for CRS within the context of post-approval changes, Modeling and Simulation (M&S), and the application of biowaivers, are briefly discussed.KEY WORDS: BCS; biowaivers; clinically relevant dissolution specifications; PBPK modeling; SUPAC.This article was developed with the support of the International Consortium for Innovation and Quality in Pharmaceutical Development (IQ, www.iqconsortium.org). IQ is a not-for-profit organization of pharmaceutical and biotechnology companies with a mission of advancing science and technology to augment the capability of member companies to develop transformational solutions that benefit patients, regulators, and the broader research and development community. PURPOSEThe purpose of this paper is to describe a roadmap for the development and leverage of clinically relevant dissolution specifications (CRS) for immediate release oral solid dosage forms of non-narrow therapeutic window drugs. There are three objectives for presenting this roadmap: (1) to describe multiple approaches for establishing clinical relevance for dissolution methodology, (2) to outline how to leverage clinically relevant dissolution methodology and specifications for the confirmation of the final drug product quality, and (3) to suggest recommendations on supporting scale-up and post-approval changes using the established CRS.Historically, dissolution specifications have been set by controlling the formulation and process within prec...

Development of an appropriate dissolution method for quality control purposes requires consideration of many factors and a balance of different needs. The method is typically distinctive to each drug product because of the unique characteristics of the active ingredient, the formulation, and the manufacturing process. The method development and selection process remains subjective due to the potential range of profiles that could be considered acceptable. This article presents a strategy and detailed recommendations for developing a quality control dissolution method for immediate-release solid oral dosage forms for the purpose of quality control and formulation or process development. The strategy is developed based on an understanding of dissolution technology, regulatory expectations, literature, and experiences in developing various dissolution methods. A case study demonstrating this strategy with the discriminatory potential of an appropriately developed dissolution method is also described.

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