Regulatory Experience with Continuous Manufacturing and Real Time Release Testing for Dissolution in New Drug Applications

Regulatory submissions involving the use of continuous manufacturing (CM)11A list of all acronyms and symbols used in this paper can be found in the section “Nomenclature”. and/or real-time release testing for dissolution (RTRT-D) to the United States Food and Drug Administration (FDA) were identified spanning several years. The submissions were for orally administered IR tablets and they were examined from a biopharmaceutics perspective to highlight commonly occurring issues which the FDA's assessment teams identified with the proposed use of CM and/or RTRT-D. The objective of this study is to provide recommendations for best practices that will help advance the field by (i) generating greater opportunities for (drug) Applicants22The term “Applicant” is used throughout this manuscript to denote an individual or organization seeking FDA's approval of a proposed drug product (DP) under a new drug application (NDA) submission or a Supplemental NDA submission for pharmaceutical sale and marketing. to benefit from the implementation of advanced manufacturing approaches, (ii) improving high quality regulatory submissions involving CM and RTRT-D, and thus (iii) lessening the regulatory review burden. This paper has identified several common deficiencies, such as inadequate strategies for stratified sampling of drug product (DP) units, inappropriate design of experiments (DoE), inability of the proposed RTRT-D model to account for dissolution variability and to predict the entire time course of dissolution, insufficient documentation, and unsuitable in vitro dissolution methods.