Achieving Continuous Manufacturing for Final Dosage Formation: Challenges and How to Meet Them May 20–21 2014 Continuous Manufacturing Symposium

doi:10.1002/jps.24247

Journal of Pharmaceutical Sciences

Volume 104, Issue 3, March 2015, Pages 792-802

https://doi.org/10.1002/jps.24247 Get rights and content

ABSTRACT:

We describe the key issues and possibilities for continuous final dosage formation, otherwise known as downstream processing or drug product manufacturing. A distinction is made between heterogeneous processing and homogeneous processing, the latter of which is expected to add more value to continuous manufacturing. We also give the key motivations for moving to continuous manufacturing, some of the exciting new technologies, and the barriers to implementation of continuous manufacturing. Continuous processing of heterogeneous blends is the natural first step in converting existing batch processes to continuous. In heterogeneous processing, there are discrete particles that can segregate, versus in homogeneous processing, components are blended and homogenized such that they do not segregate. Heterogeneous processing can incorporate technologies that are closer to existing technologies, where homogeneous processing necessitates the development and incorporation of new technologies. Homogeneous processing has the greatest potential for reaping the full rewards of continuous manufacturing, but it takes long-term vision and a more significant change in process development than heterogeneous processing. Heterogeneous processing has the detriment that, as the technologies are adopted rather than developed, there is a strong tendency to incorporate correction steps, what we call below “The Rube Goldberg Problem.” Thus, although heterogeneous processing will likely play a major role in the near-term transformation of heterogeneous to continuous processing, it is expected that homogeneous processing is the next step that will follow.

Specific action items for industry leaders are:

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Form precompetitive partnerships, including industry (pharmaceutical companies and equipment manufacturers), government, and universities. These precompetitive partnerships would develop case studies of continuous manufacturing and ideally perform jointtechnology development, including development of small-scale equipment and processes.
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Develop ways to invest internally in continuous manufacturing. How best to do this will depend on the specifics of a given organization, in particular the current development projects. Upper managers will need to energize their process developers to incorporate continuous manufacturing in at least part of their processes to gain experience and demonstrate directly the benefits.
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Training of continuous manufacturing technologies, organizational approaches, and regulatory approaches is a key area that industrial leaders should pursue together. © 2015 Wiley Periodicals, Inc. and the American Pharmacists Association.

Section snippets

INTRODUCTION TO CONTINUOUS MANUFACTURING FOR FINAL DOSAGE FORMATION

As discussed in the Introduction of this volume, “continuous manufacturing” means integration, a systems approach, and a model-based control within a flow process. Thus, as a continuous process is designed as a whole, the distinction between upstream and downstream, or drug substance and drug product, as currently used, can be, potentially, eliminated. The disappearance of these terms corresponds to a change in mindset, which itself would lead to the adoption of new terms., There is, however,

HOW THE VISION OF CONTINUOUS PHARMACEUTICAL MANUFACTURING WILL CHANGE FINAL DOSAGE FORM OPERATIONS

Given that continuous manufacturing encompasses integration, a systems approach, flow, and model-based control, future continuous facilities will be set up quite differently than existing facilities. Below, we discuss the trade-offs involved in dedicated final dosage form process trains versus multi-use process trains. We do envision minimizing, if not eliminating, powders handling, at least within the process itself—there will, most likely, still be the need for powder dosage into the process.

CHALLENGES AND BARRIERS

Why, given the tremendous benefits of continuous manufacturing, has it not become the industry standard? The main reason is a “business as usual” approach embraced by a highly conservative industry. Specifically, it has been seen that new manufacturing approaches must be proven both technologically and financially superior, and tied to a product before widespread adoption will take place. This leads to the “chicken and egg” conundrum that technologies must be already adopted for the industry to

Overview

The true benefits of continuous manufacturing can be harvested when new technologies are implemented. This means designing a continuous process with the mindset of continuous processing. This mindset is difficult to acquire given the inertia of batch processing between both process designers and managers. Thus, in many companies there is likely to be a transitional period during which batch approaches are converted to continuous. This will result in lower perceived risk and lower up-front

What Each Company Should Do

Given the projected advantages of continuous manufacturing, the industry should initiate continuous manufacturing efforts immediately. Each company should go through its product (development and in-line) portfolio and choose one or more products for some degree of continuous manufacturing. This could be a life-cycle management product, but the real value is in a new product, chosen as early in the development phase as possible, for example at proof of concept in the clinic. Of course, a new

ACKNOWLEDGMENTS

We would like to thank our Frank Roche and Sonja Sharp for valuable comments to improve this paper, in addition to all of those who made helpful comments online or at the symposium. This white paper was updated based on their suggestions.

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CommentaryAchieving Continuous Manufacturing for Final Dosage Formation: Challenges and How to Meet Them May 20–21 2014 Continuous Manufacturing Symposium