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Leveraging Integrated Continuous Manufacturing to Address Critical Issues in the U.S. Military

Introduction

The manufacturing of pharmaceuticals has lagged behind the research and development of new therapeutics. The same batch processes that were used over a century ago are still being used today, while other industries have moved forward with automated and continuous operations (eg, fine chemical, oil, gas, and food industries). Current pharmaceutical manufacturing methodology consists of carrying out individual reactions in large batches (eg, vessels), and then running analytical tests on the end product to determine if it meets specifications. It is important to note that the large process volumes of these reactions require increased safety procedures/precautions, especially with raw materials or intermediates that are unstable or explosive in nature. The products of these reactions are often transported to other sites, where they undergo additional reactions and further processing to form the final active pharmaceutical ingredient (API). The API itself is then shipped to another facility, where it is formulated and finally transformed into a tablet, pill, or other final dosage form. The end result is a fragmented process with a very long lead time and very large plant footprint. It is not unusual for the production of a pharmaceutical product to take 200 to 300 days, from start to finish. In addition to being time-intensive, pharmaceutical production is also cost-inefficient ($65 B/year is wasted in inefficient pharmaceutical operations). Quality is also a problem, as product recalls continue to plague the industry—over the last year (November 19, 2017 to November, 18, 2018) over 70 drugs were recalled, three blood pressure medications alone within a 2-week period. This last fact is largely because the U.S. Food and Drug Administration (FDA) has been enforcing its regulations to improve quality standards during pharmaceutical production, and current manufacturers are finding it difficult to meet these standards. With all of these limitations associated with batch processes, it is clear that the pharmaceutical industry needs more advanced and reliable manufacturing capabilities. Furthermore, from a strategic perspective, rival countries of the United States have advanced their manufacturing capabilities, narrowing significantly the technological gap. A recent publication from the National Defense Strategy Commission, “Providing for the Common Defense,” detailed this trend, including how China’s investments in technology and manufacturing have resulted in considerable growth of their innovation and manufacturing sectors. This expansion has not been mirrored by U.S. industry, resulting in a comparative disadvantage. Indeed, with the risk of trade wars escalating from mounting tensions among global superpowers, the United States is not well prepared, with its current manufacturing infrastructure, to ensure that all U.S. citizens will immediately receive the medications they need in the event of a major conflict. For example, close to 80% of the active and bulk pharmaceutical ingredients consumed by U.S. citizens is imported. This overwhelming dependence on foreign suppliers that implement an outdated and substandard quality manufacturing method for life-saving products is particularly concerning. The current batch manufacturing paradigm is long, fragmented, and uncoordinated. Objective The authors believe that the United States should invest in drug manufacturing infrastructure to develop a “critical mass” of capability and capacity. This would ensure our ability to rapidly respond to potential crises that could affect our drug supply chain. In addition, this manufacturing base could address current issues, such as drug shortages that are affecting patient care. A recent survey of over 200 oncologists revealed that over 80% of them had to change the way they prescribe chemotherapy during the previous 6 months because of a shortage. Thus, this is an issue that negatively impacts many U.S. citizens. Furthermore, the drugs in shortage are mainly small molecules (ie, structurally simple drugs that are chemically synthesized) that are off patent, low-margin, and often produced abroad by only a few and sometimes just a single manufacturer. From a military perspective, the proposed manufacturing capability will provide several key strategic advantages. First, continuous processes are much smaller than their corresponding batch units. This will enable continuous manufacturing lines to be located closer to, or perhaps within military bases, providing soldiers better access to life-saving drugs. Second, because lead times with continuous processes are much shorter than with batch processes, the United States will be able to respond more rapidly and effectively to a biological, chemical, or nuclear attack that requires immediate medical care, both at home and abroad. Finally, the ability to produce medications within the United States will lessen its reliance on potentially rival nations, eliminating leverage they may have to compromise political, economical, and military options. The proposed manufacturing facilities should be different from the stereotypical pharmaceutical plant. They should be automated to the extent possible. As U.S. wage rates are greater than those of competitor countries, it would be economically infeasible to implement a labor-intensive manufacturing line. They should be environmentally friendly. U.S. citizens do not want plants that discharge toxic solvents and wastes on U.S. soil. Furthermore, there are strict regulations that are enforced by agencies such as the Environmental Protection Agency. They should produce high-quality products. Regulators are demanding that manufacturers adhere to the high-quality standards set forth in the guidelines and regulations regarding drug production. Finally, they should be cost-effective. With the untenable growing cost of health care, the U.S. economy cannot support more expensive drugs. As described below, there is an opportunity to reduce the costs of these drugs. This article will describe how innovative continuous manufacturing systems can help the United States achieve the aforementioned objectives. The authors will then provide a detailed example that highlights specific technical advantages when a strategically important drug is manufactured continuously.

Abstract

There is a tremendous opportunity to modernize the pharmaceutical manufacturing industry—relinquishing outdated machines that have been used for decades, and replacing them with state-of-the-art equipment that reflect contemporary advanced technologies. The implementation of continuous manufacturing, can positively impact our health care sector. Important benefits include the creation of manufacturing jobs in the United States, the establishment of capabilities and capacity to quickly produce drugs critical to U.S. citizens, the reduction of health care costs through efficient manufacturing, and access to better quality drugs through more sophisticated and reliable processes. The application of continuous manufacturing will enable the U.S. Government, in partnership with pharmaceutical companies, to address issues such as drug shortages, national emergencies, the Strategic National Stockpile, and the delivery of critical drugs to distant geographies. The article provides a detailed example of a critical aspect of continuous manufacturing: the ability to overcome technical challenges encountered by batch technologies.

 

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