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Why We Need Continuous Pharmaceutical Manufacturing and How to Make It Happen

Authors
Clive Badman, Charles L. Cooney, Alastair Florence, Konstantin Konstantinov, Markus Krumme, , Moheb M. Nasr, Bernhardt L. Trout

Introduction

Most industries as they evolve to meet market needs have embraced continuous manufacturing, a combination of continuous movement of components, a systems approach to designing processes and automated model-based control. Such an approach has led to tremendous increases in efficiency and quality. Among major industries, the exception is the pharmaceutical and biotech industry. Despite a long time acknowledgment of the benefits of continuous manufacturing in this industry, adoption has been slow and piecemeal. In 2007, after many years discussing continuous manufacturing in industry and academics, Dr. Janet Woodcock, CDER Director, USFDA, at the inauguration of the Novartis-MIT Center for Continuous Manufacturing challenged the industry to accelerate its adoption. In 2011, the first end-to-end continuous pharmaceutical process with automated, model-based control was run at MIT (bench scale). Thereafter, followed 3 International Symposia on Continuous Manufacturing of Pharmaceuticals in 2014, 2016, and 2018, held in the US and UK. The outputs have included highly cited white papers in this journal on continuous pharmaceutical technology, supply chain, and regulatory approaches. There are now 6 drugs, all small-molecule pharmaceuticals, that incorporate continuous manufacturing, but only partially and with incorporation of basic technologies. Vertex’s Orkambi and Symdeko, Johnson & Johnson’s Prezista, Eli Lilly’s Verzenio, and Pfizer’s Daurismo have been approved in the US; Vertex’s Orkambi and Symkevi, Johnson & Johnson’s Prezista, and Eli Lilly’s Verzenio in the EU; and Johnson & Johnson’s Tramacet and Eli Lilly’s Verzenio in Japan. Although the progress is acknowledged by the pharmaceutical community, for 12 years of development, it is hardly admirable. The situation with biomanufacturing is similar. Although continuous bioprocessing has been successfully implemented commercially for upstream (perfusion cell culture) for more than 25 years, integration of the downstream operation (chromatography and filtration) has not yet been demonstrated commercially. The irony is that none of the approved continuous processes had any major regulatory challenges related to the technologies, including control, and regulators keep encouraging development of new innovative processes, but still progress is slow. The rate of progress was particularly evident at the 2018 International Symposium on Continuous Manufacturing of Pharmaceuticals, where there was continued enthusiasm for continuous manufacturing among the technical and quality community, but acknowledgment that the pace of implementation is slower than anticipated. The irony is that among this same community, there is industrywide agreement that continuous pharmaceutical manufacturing would provide tremendous benefits, including substantial cost benefits, and regulators do not see scientific barriers per se and find the successes to date encouraging. However, the industry, such as a car with its wheels stuck in mud, seems unable to get out of its rut. If only we could get on the road of continuous manufacturing, we would be cruising ahead, but as for now, we are spinning our wheels, inching forward. After the 2018 symposium, over a decade after Dr. Woodcock’s historic speech, we intended to provide a summary of the progress in continuous manufacturing. However, because it is evident that progress is slow, we decided to act more directly to try to pull the continuous manufacturing vehicle out of the mud. Here we provide a summary of the reasons why we believe the industry is stuck and how to get it unstuck. It has become evident that major policy initiatives are needed.

Abstract

We make the case for why continuous pharmaceutical manufacturing is essential, what the barriers are, and how to overcome them. To overcome them, government action is needed in terms of tax incentives or regulatory incentives that affect time.

Abstract Image

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