Review: Continuous Manufacturing of Small Molecule Solid Oral Dosage Forms

Abstract

Continuous manufacturing (CM) is defined as a process in which the input material(s) are continuously fed into and transformed, and the processed output materials are continuously removed from the system. CM can be considered as matching the FDA's so-called 'Desired State' of pharmaceutical manufacturing in the twenty-first century as discussed in their 2004 publication on 'Innovation and Continuous Improvement in Pharmaceutical Manufacturing'. Yet, focused attention on CM did not really start until 2014, and the first product manufactured by CM was only approved in 2015. This review describes some of the benefits and challenges of introducing a CM process with a particular focus on small molecule solid oral dosage forms. The review is a useful introduction for individuals wishing to learn more about CM.

Keywords: continuous manufacturing; control strategy; drug products; modelling; process analytical testing; process validation and verification; real-time release testing; residence time distribution; traceability.

Figure 1

Schematic of a continuous manufacturing end-to-end (E2E) process compared to a traditional batch process. Adapted from [3], J. Pharm. Innov. 2015. Note: API manufacturing has traditionally occurred at a primary manufacturing site typically separate from the drug product site and often in a different (low-tax) country.

Figure 2

Schematic of continuous manufacturing process development. Adapted from [68], Pharmaceutics 2021. DoEs = Design of Experiments. Schematic assumes scale-up is achieved by running CM process for longer periods and technology transfer is avoided by using same equipment throughout development and into commercialisation.