Ten years of the manufacturing classification system: a review of literature applications and an extension of the framework to continuous manufacture.

The MCS initiative was first introduced in 2013. Since then, two MCS papers have been published: the first proposing a structured approach to consider the impact of drug substance physical properties on manufacturability and the second outlining real world examples of MCS principles. By 2023, both publications had been extensively cited by over 240 publications. This article firstly reviews this citing work and considers how the MCS concepts have been received and are being applied. Secondly, we will extend the MCS framework to continuous manufacture. The review structure follows the flow of drug product development focussing first on optimisation of API properties. The exploitation of links between API particle properties and manufacturability using large datasets seems particularly promising. Subsequently, applications of the MCS for formulation design include a detailed look at the impact of percolation threshold, the role of excipients and how other classification systems can be of assistance. The final review section focusses on manufacturing process development, covering the impact of strain rate sensitivity and modelling applications. The second part of the paper focuses on continuous processing proposing a parallel MCS framework alongside the existing batch manufacturing guidance. Specifically, we propose that continuous direct compression can accommodate a wider range of API properties compared to its batch equivalent.

Trends in oral small-molecule drug discovery and product development based on product launches before and after the Rule of Five.

In 1997, the 'Rule of Five' (Ro5) suggested physicochemical limitations for orally administered drugs, based on the analysis of chemical libraries from the early 1990s. In this review, we report on the trends in oral drug product development by analyzing products launched between 1994 and 1997 and between 2013 and 2019. Our analysis confirmed that most new oral drugs are within the Ro5 descriptors; however, the number of new drug products of drugs with molecular weight (MW) and calculated partition coefficient (clogP) beyond the Ro5 has slightly increased. Analysis revealed that there is no single scientific or technological reason for this trend, but that it likely results from incremental advances are being made in molecular biology, target diversity, drug design, medicinal chemistry, predictive modeling, drug metabolism and pharmacokinetics, and drug delivery.