Biowaiver Applications in Support of a Polymorph During Late-Stage Clinical Development of Verubecestat-Current Challenges and Future Opportunities for Global Regulatory Alignment.

Dissolution experiments to support an active pharmaceutical ingredient (API) form change in Verubecestat immediate release tablets were performed following current regulatory guidance published by health authorities in Canada, Australia, Japan, the EU, and the USA. Verubecestat API meets the requirements of a Biopharmaceutics Classification System class 1 compound and tablets are very  rapidly dissolving in aqueous dissolution media. While the in vitro data were reviewed favorably by these agencies, the divergence in regulatory requirements led to unnecessary work and highlights several issues companies operating globally face to justify product changes that have very little impact on quality. The data presented in this manuscript provide a compelling case for adjustments to the current draft ICH M9 guidance which provides recommendations for biowaiver applications. Specifically, this manuscript contains recommendations with respect to API attributes, selection of dissolution media and apparatus, and methods to assess dissolution similarity if needed, which should be considered for inclusion in a science- and risk-based global guidance document to benefit patients, regulators, and the pharmaceutical industry.

Dissolution Testing in Drug Product Development: Workshop Summary Report.

This publication summarizes the proceedings and key outcomes of the first day ("Day 1") of the 3-day workshop on "Dissolution and Translational Modeling Strategies Enabling Patient-Centric Product Development." The overall aims of the workshop were to foster a productive dialog between industry and regulatory agencies and to discuss current strategies toward the development and implementation of clinically relevant dissolution specifications as an integral part of enhanced drug product understanding and effective drug product life-cycle management. The Day 1 podium presentations covered existing challenges and concerns for implementing highly valuable, yet often unique and novel experimental dissolution setups as quality control tools. In addition, several podium presentations highlighted opportunities to replace conventional dissolution testing with surrogate test methods to enable robust drug product and process understanding within the context of quality by design (QbD), new manufacturing technologies, and real-time release testing (RTRT). The topics covered on Day 1 laid the foundation for subsequent discussions which focused on the challenges related to establishing an in vitro-in vivo link and approaches for establishing clinically relevant drug product specifications which are becoming an expectation in regulatory submissions. Clarification of dissolution-related terminology used inconsistently among the scientific community, and the purpose of various testing approaches were key discussion topics of the Day 1 breakout sessions. The outcome of these discussions along with creative ways to overcome challenges related to bridging "exploratory dissolution approaches" with methods suitable for end-product control testing are captured within this report.