(T1230-09-51) FDA Perspective on Dissolution Testing for Development of High-Risk Oral Drug Products Containing Amorphous Solid Dispersions

Purpose: Amorphous solid dispersions (ASDs) have emerged as a promising formulation technique for poorly water-soluble drugs. ASD allows the dispersion of amorphous active pharmaceutical ingredient (API) within the excipient polymer matrix at a molecular level, offering advantages such as enhanced apparent solubility, increased dissolution rate, and improved bioavailability (BA). However, the lack of thermodynamic stability in ASDs may lead to the formation of the crystalline form, posing significant concerns on BA and clinical performance. The recent ICH M13A Draft Guidance describes ASD-containing drug products as high-risk, emphasizing that their in-vivo performance may be impacted by varying gastrointestinal (GI) conditions between fasted and fed states. It follows that a single bioequivalence (BE) study may not be able to detect the performance differences related to different formulation and/or different manufacturing process. This research was to investigate the relationships between formulation, process attributes, and dissolution, and in vivo performance on the FDA-approved drug products containing ASD. A profound understanding of these aspects is crucial in the development of BE approaches and to support formulation and manufacturing process changes.

Methods: We collected information and data of solubility, dissolution, ASD formulation compositions and manufacturing techniques for 45 drug substances in 53 FDA-approved ASD-containing products from new drug applications as of December 31, 2023. Their corresponding dissolution acceptance criteria, method discriminating ability, and clinical relevance information were also researched and collected.

Results: Among 53 FDA-approved ASD-containing products, 32 products were classified as novel drugs, 13 classified as new dosage forms, 6 classified as new formulations, 1 classified as new combination and 1 was classified as new molecular entity/new combination. Among these drug products, the dissolution methods used in 31 products demonstrated discriminating ability against API particle size, critical formulation attributes (e.g., ratio of drug and polymer), critical process attributes (e.g., tablet compression force), or levels of crystalline API. For seven products with adequate dissolution method discriminating ability, dissolution methods were developed based on the solubility and dissolution profile data of ASD intermediate. It is noted that both dissolution method and acceptance criterion/criteria were considered when the discriminating ability of a proposed dissolution test was evaluated. Among 53 FDA-approved products with ASD, 10 utilized biorelevant two-stage dissolution testing to develop an in vitro in vivo correlation (IVIVC; 5 products) or physiologically based biopharmaceutic modeling (PBBM; 5 products). However, none of the submitted IVIVC or PBBM were considered acceptable by the FDA to support a dissolution “safe space” for a waiver of BA/BE studies due to incomplete dissolution/pharmacokinetic information and data or inadequate model development, verification, or validation.

Conclusion: When developing a dissolution test for ASD-based drug products, discriminating ability of the dissolution method towards critical bioavailability attributes, including critical material attributes (e.g., crystalline content), critical formulation variables (e.g., levels and/or grade of polymer, surfactant, disintegrant), and critical process parameters (e.g., ASD particle size, compression force/hardness), that could potentially impact the dissolution and BA should be evaluated. Since precipitation impacts absorption time and BA, it is also important to utilize biorelevant two-stage, acid-to-neutral pH dissolution testing that simulate the GI pH shift for assessing the extent of supersaturation in order to establish a meaningful correlation between in vitro dissolution and in vivo absorption for drug products containing ASD. This research consolidates information on formulation attributes, dissolution, and their impact on clinical performance in FDA-approved ASD-containing products. There is potential for in vitro dissolution methods to assess and predict in vivo performance, guiding formulation development throughout different stages of drug product development. This approach could potentially reduce the reliance on clinical BE studies in generic drug development.

Acknowledgements: Dr. Gang Zhao is supported in part by an appointment to the Research Participation Program at the U.S. Food and Drug Administration administered by the Oak Ridge Institute for Science and Education through an interagency agreement between the U.S. Department of Energy and the U.S. Food and Drug Administration.