Review: Continuous Manufacturing of Small Molecule Solid Oral Dosage Forms

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. Continuous manufacturing 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 continuous manufacturing 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.

Introduction

This review on the Continuous Manufacturing (CM) of small molecule solid oral dosage forms provides a basic introduction to the key elements of a CM process, gives the references to some of the key publications on the subject and mentions some of the recent developments and future opportunities. For a more in depth understanding of the subject, see Kleinebudde et al.

Continuous manufacturing has been defined to ‘be a process in which the input material(s) are continuously fed into and transformed within the process, and the processed output materials are continuously removed from the system’, where ‘system’ is defined as an integrated process that consists of two- or more-unit operations

CM may be applied both to the drug substance manufacture and to the drug product. Developing a drug substance CM process is more complicated than a drug product one. The linkage between the two CM processes is described as end-to-end or E2E manufacturing (Section 5.2) (Figure 1).

Figure 1. Schematic of a continuous manufacturing end-to-end (E2E) process compared to a traditional batch process.
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.

The first regulatory approval of a drug product made by CM was in 2015. Since then, take-up by industry has been quite slow despite encouragement from the regulatory agencies. To date, there have been seven approvals. Some of these products use a combination of CM and batch manufacturing.

A research report put the market size for continuous manufacturing at 2.3B USD in 2018 with the potential to grow at a CAGR (Compound Annual Growth Rate) of 8.8%, reaching 3.8B USD in 2024

This paper will discuss the manufacture of tablets by direct compression (DC), dry granulation (roller compaction) and wet granulation (WG). These processes are listed in increasing levels of complexity. Some of the unit operations making up the processes are inherently continuous (i.e., tablet compression), while others are quite difficult to make continuous (e.g., tablet coating). CM may consist of a few unit operations linked together up to a fully integrated drug product system and on to an E2E system (of which few details have been published).

Regulatory authorities (EMA, MHRA, FDA and PDMA) have all been strong advocates of CM in particular for its benefits to improve the quality and control of drug products and to produce a more flexible supply chain. The industry has been slow to adopt the approach mainly due to its conservatism, the cost implications and the potential difficulty of registering CM products. Regulators have suggested that CM is suited to NCEs requiring new facilities or to established products with expanding markets. Most investment in CM has been made by Big Pharma working with some academic and not-for-profit centres. There is limited information on CDMO (Contract Development and Manufacturing Organisations) involvement in CM, although Patheon (Thermo Fisher Scientific), Catalent and Aesica have been mentioned as having CM capabilities. The drivers for generic companies to be involved are different to those of pharma companies, and the initial investment and technical requirements for data handling, etc. make their involvement less likely. A model where there are hubs between academic centres and CDMOs to develop CM processes may be the way forward. Continue reading the review on continuous manufacturing

or download the full article as pdf here: Continuous Manufacturing of Small Molecule Solid Oral Dosage Forms

Wahlich, J. Review: Continuous Manufacturing of Small Molecule Solid Oral Dosage Forms. Pharmaceutics 2021, 13, 1311. https://doi.org/10.3390/pharmaceutics13081311

Tags: formulation