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)
Batch manufacturing is the tried, tested, and trusted approach for manufacturing pharmaceutical products. In addition, pharmaceutical companies have approval from regulators for their products based on them being produced using batch manufacturing techniques.
Batch manufacturing involves manufacturing pharmaceutical products in multiple steps. At the end of each step, production stops before the process moves to the next step. Hold times like this can vary depending on the next stage of the process.
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 another final dosage form.
While there are benefits to batch manufacturing, there are downsides too. The length of time it takes to produce a product using batch manufacturing is one of those downsides. Hold times also increase the risk of material degradation, while scaling production can be a challenge. For example, in some situations, materials are shipped to a different location between steps. It is not unusual for the production of a pharmaceutical product to take 200 to 300 days, from start
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.
To scale up production in a batch manufacturing process, you typically need to scale up your equipment. This requires time, money, and additional space. There is an increasing push, however, for the industry to switch to continuous manufacturing.
Continuous manufacturing involves a pharmaceutical product being produced nonstop in one continuous manufacturing process. The entire process takes place in one facility, start to finish, without hold times.
The benefits of continuous manufacturing include Reduced manufacturing costs, particularly over the long term. It leads to Shorter production times – reducing manufacturing times from weeks to days is not unusual. It also reduces the risk of human error and improves quality. Monitoring is more efficient as continuous manufacturing processes typically use automated monitoring techniques and predictive maintenance
In addition, continuous manufacturing is a more agile technique, making scaling production much easier. Scaling up, for example, simply means running the continuous manufacturing process for longer.
In other words, matching supply to demand is much easier with continuous manufacturing than it is with batch manufacturing
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.
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.
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
End-to-End Integrated Continuous Systems
There are two end-to-end technologies that were recently developed at the Massachusetts Institute of Technology (MIT). The first was funded by the Defense Advanced Research Projects Agency (DARPA), and has been commonly referred to as the “Pharmacy on Demand.” Through this project, a very small-scale, end-to-end manufacturing process for small molecule drugs was created.
This system consists of an upstream unit, where the reaction(s) take place, and a downstream unit, where the reaction products are crystallized, filtered, dried, and dissolved in a solution that can then be dosed to patients. Each unit is approximately the size of a household refrigerator, and modules within these 2 units can be interchanged and reconfigured to produce different drugs.
Because these units are much smaller than conventional batch units, more extreme processing conditions can be used to achieve increased efficiencies. The throughput capacity of this
system is considerable—thousands of doses can be produced each day. On-Demand Pharmaceuticals is currently advancing this platform technology toward commercialization.
The second end-to-end continuous manufacturing platform for small-molecule drugs developed at MIT was sponsored by a pharmaceutical partner, Novartis. The collaboration was extremely successful, and led to the development of the first manufacturing prototype to produce finished drug tablets from raw chemical ingredients through a fully integrated, non-stop, end-to-end continuous process. This platform, called ICM, was built on the concepts of continuous flow, endto-end integration, systems approach, and integrated control strategy. More specifically, this process proceeds from start to finish with no intermediate products that require isolation, storage, or shipping to another location (these steps are necessary with batch manufacturing). As a result, a commercial batch process that normally takes 200 days was reduced to just 2 days with ICM. The entire manufacturing train, which has approximately one-tenth the footprint of an
equivalent batch line, was able to be located in a single room. CONTINUUS Pharmaceuticals is currently advancing this platform technology toward commercialization
On Jan. 15, 2021, the Department of Defense (DoD), in coordination with the Department of Health and Human Services (HHS), awarded a $69.3 million contract to CONTINUUS Pharmaceuticals Inc. to develop a domestic production capability for critical active pharmaceutical ingredients (APIs) and final dosage form medicines using their proprietary integrated continuous manufacturing (ICM) technology. ICM enables rapid, on-demand production of medicines from API to final dosage form without interruption in a fully-automated, small-footprint facility.
CONTINUUS’ proprietary technology will also enable the establishment of a new manufacturing logistics capability, allowing more efficient delivery of medical countermeasures in future healthcare crises.
DARPA selects Continuity Pharma, funds continuous manufacturing technology
DARPA has established a competitive review process, awarding grant funding to companies presenting advanced manufacturing technologies.
Continuity Pharma’s mission is to apply novel continuous manufacturing capabilities to reshore generic drug products to the U.S., with specific focus on drugs in short supply.
Grant specifics include development funding over the next 24 months, with additional funding for commercialisation in the subsequent 12 months. Focus areas include capabilities for multiple API manufacturing in the Integrated Continuous Manufacturing System (ICMS), with demonstrated efficiencies for rapid changeover and manufacturing efficiencies.
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