Reshoring and expanding API manufacturing capabilities
Manufacturers in Europe and the United States have announced plans for new in-country API development and manufacturing capabilities.
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Jennifer Markarian is manufacturing editor of Pharmaceutical Technology.
Intensified and distributed manufacturing approaches create flexible, local capacity.
Long before the COVID-19 pandemic put a spotlight on supply-chain security and drug shortages, the pharmaceutical industry was working on advanced manufacturing technologies that could address supply challenges by increasing manufacturing flexibility and efficiency. Continuous manufacturing, for example, allows drug manufacturers to more easily adapt supply to demand, incorporate more automation, and have tighter control of quality. Continuous processes with smaller footprints provide mobility, creating the potential for distributed manufacturing—even bringing drug production to the point of care. The call for reshoring manufacturing—coming perhaps most loudly from the United States but also a concern in other countries—may be answered in part by using these advanced technologies to produce APIs or to continuously manufacture drug products end-to-end, beginning with basic raw materials and ending with a finished drug form.
The US government has been concerned for several years about drug shortages and the ability to manufacture essential medicines domestically. In October 2019, Janet Woodcock, director of the Center for Drug Evaluation and Research (CDER) at FDA, reported to Congress that only 28% of API facilities were located within the US, but suggested that advanced manufacturing technologies could enable competitive US-based production that would strengthen the security and reliability of the US drug supply (1). Woodcock noted then that CDER was working with the US Biomedical Advanced Research and Development Authority (BARDA) to develop a regulatory framework and the technology for mobile manufacturing of essential drugs at or near the point of care.
At the request of FDA, a committee assembled by the US National Academies of Sciences, Engineering, and Medicine (NASEM) researched emerging technologies that have the potential to modernize pharmaceutical manufacturing in the next five to 10 years. Continuous and intensified processes, as well as mobile and distributed manufacturing, were among the innovations that could improve quality and supply security highlighted by the committee in a report published in February 2021 (2). FDA’s Emerging Technology Team, the committee noted, has been successful in facilitating process development, but regulatory review continues to be perceived by industry as a barrier to modernization.
Although “reshoring” could be more complex in Europe than in the US, the pandemic illustrated the need for supply chain security in Europe as well and perhaps created new urgency to reduce dependence on bulk active ingredients and generic drugs sourced from India and China (3). Sanofi and Seqens, for example, are putting a new focus on European API manufacturing (see Sidebar).
Manufacturers in Europe and the United States have announced plans for new in-country API development and manufacturing capabilities.
Continuous flow chemistry is one of the intensified, agile technologies showing promise, with some good manufacturing practice (GMP) lines running commercially and other novel processes in development. GlaxoSmithKline, for example, points to continuous manufacturing as a more efficient and environmentally friendly approach, with smaller operations; the company’s commercial continuous API manufacturing process in Singapore requires a facility of approximately 100 m2 compared to a 900-m2 facility for a batch process (4).
The CC Flow consortium in Austria includes labs at the University of Graz, the Graz University of Technology, and the Research Center Pharmaceutical Engineering (RCPE) as well as industrial partners. Researchers are developing flow chemistry for continuous API manufacturing, and recent work has looked at process analytical technology tools to enable process control (5).
Even smaller, further intensified processes are being devised, with modular approaches that can produce multiple types of drug substances by changing the process set-up. The US Department of Defense’s Defense Advanced Research Projects Agency (DARPA) has funded several continuous flow chemistry projects, promoting portable technologies that can be used to make medicines on-site in the field for the US military using a few essential raw materials.
Such technologies would also have the potential to secure the civilian US drug supply for chemical APIs. “Flexible, on-demand processes would help remove some of the brittleness in the US supply chain,” notes David Thompson, cofounder and chief scientific officer of Continuity Pharma. “Smaller footprint processes can also be designed to have greater operational efficiency in terms of energy and waste. The vision is to create more responsive systems that can produce drugs in an as-needed manner.”
Continuity Pharma, a start-up out of Purdue University, is using flow chemistry to develop a system that can continuously manufacture multiple APIs. Researchers are initially focusing on APIs that have common reaction processes to ease rapid changeover. Using $1.5 million from DARPA granted in September 2020, the researchers are building proof-of-concept equipment that can produce at least 100 g/day with a maximum six-hour turnaround time between products by the end of the first year of the project, with shorter turnaround and higher volume the aim of the project’s second year, says Thompson. The portable, refrigerator-sized units will use continuous synthesis and purification by extraction, with a final polishing step by batch crystallization.
SRI International in California had developed its SynFini platform, a fully automated, small-scale synthetic chemistry system, primarily for discovery, under an earlier DARPA program, and has developed continuous flow multistep processes for several APIs at a scale of grams per day. In August 2020, SRI was awarded a $4.3 million DARPA contract to create a process modeling scale-up tool that would speed translation of these laboratory-scale processes into commercial-scale API production. SRI is working with a team at Rutgers University on the ProSyn digital twin tool and on scaling up to a modular platform that could be configured to produce a range of small-molecule APIs commercially in a “just-in-time” capacity model.
“To compete with the cost-effectiveness of offshore API manufacturing, innovative streamlined and automated systems are needed,” notes Nathan Collins, chief strategy officer of SRI’s Biosciences Division and the principal investigator for the ProSyn project. “Speed of development and manufacturing is also critical. As was highlighted by the pandemic, we need process development translated into manufacturing within months instead of years.”
The researchers plan to have proof-of-concept modules by the end of 2021 that can demonstrate the manufacturing process. Collins notes that they are concurrently building process validation tools to enable GMP production.
Snapdragon Chemistry, a 2014 spinoff from the Massachusetts Institute of Technology (MIT) based in Waltham, Mass., has developed flow-based API manufacturing processes. In mid-2020 the process development company doubled its R&D capacity and opened a lab to produce gram to kilogram-scale APIs and demonstrate its continuous flow manufacturing technology at pilot scale. The company began construction in January 2021 of a GMP drug substance manufacturing facility, which it plans to commission in November 2021. The facility would be set up for commercial production of APIs using processes designed by Snapdragon.
In a collaboration with BARDA that began in June 2020, the company developed a synthetic continuous manufacturing route for ribonucleotide triphosphates, which are a raw material for mRNA-based COVID-19 vaccines. Snapdragon is initiating discussions with prospective users, and the materials could be produced in the new commercial facility, says Matt Bio, CEO of Snapdragon.
In a separate project launched in February 2021, Snapdragon is using a $1.5 million DARPA grant to extend its technology to enable efficient US-based production of chemicals used in pharmaceutical production. “We’ve identified a set of chemical building blocks that can be produced on the same process-equipment setup using only programming changes, and we are developing a continuous manufacturing platform with next-generation automation to accomplish this goal,” explains Bio. The platform is currently in the R&D stage, and Bio anticipates that it could be commercialized within two years.
At Virginia Commonwealth University (VCU), the Medicines for All Institute (M4ALL) has developed continuous flow processing for APIs. The institute, founded in 2017 with funding from the Bill and Melinda Gates Foundation, has focused on expanding access to medications in developing countries by developing cost-saving production methods. These methods use high-yield reactions that don’t require isolating intermediates, explains Frank Gupton, CEO of M4ALL. In May 2020, M4ALL partnered with Phlow Corporation to implement these continuous processes for US-based manufacturing of essential medicines, under a $354 million contract Phlow received from BARDA. Continuous API production processes are currently being developed in the M4ALL labs, and the processes will then be scaled up to commercial manufacturing by Phlow, says Gupton. The aim is to have a full-scale manufacturing facility running by the end of 2022.
While FDA has approved one API made using continuous flow chemistry, continuous manufacturing—starting with API and excipients and ending with finished drug—is now being used to produce six FDA-approved oral solid-dosage (OSD) drugs, including some previously made in batch manufacturing as well as new drugs approved with continuous OSD processes. Early adopters have worked through many challenges and are continuing to optimize these systems, which offer flexibility of scale and use process analytical technology and advanced process control to improve efficiency and quality.
Similar to API manufacturing, OSD continuous manufacturing lends itself to miniaturized processes; small-scale equipment can be run for a longer time period if more volume is needed. Pfizer’s PCMM [Portable, Continuous, Miniature, and Modular] system, for example, was originally developed in 2013 in a collaboration using GEA’s OSD continuous processing equipment and G-CON’s prefabricated cleanrooms, and is being used for development as well as commercial production. The small-footprint systems are designed as skid-mounted modules, which adds flexibility. The portability of PCMM could allow rapid deployment or redeployment, which could lend itself to new ways of manufacturing and distributing drugs (6). These successes in continuous OSD manufacturing have demonstrated that a regulatory pathway is possible, which is encouraging to other companies working on continuous processes.
Fully end-to-end systems seek to encompass both API and final dosage form manufacturing in one integrated system. Technology developed at the Novartis–MIT Center for Continuous Manufacturing was demonstrated as a proof-of-concept end-to-end system in 2012. The technology is being leveraged by Novartis, which opened a facility in Basel, Switzerland in 2017, and US start-up company, Continuus Pharmaceuticals. Continuus designed and constructed a pilot plant using its Integrated Continuous Manufacturing (ICM) technology at its facility in Woburn, MA, and in January 2021, the company was awarded a $69.3 million contract from the US Department of Defense (DoD) to build a commercial ICM facility for US production of three critical APIs and their finished dosage forms. The facility is expected to be operational within two years.
Bayan Takizawa, co-founder and chief business officer of Continuus, says that the company plans to file applications to produce and market these drugs as its own products. Although there are not, as yet, any FDA-approved drugs made with a fully end-to-end line, Takizawa notes that the FDA’s Emerging Technology Team (ETT) is well informed of their advanced manufacturing platform through previous contract work the company performed for the Agency. “Continuus plans to maintain close communication with the ETT to ensure our efforts are aligned with FDA’s expectations,” he adds.
Takizawa says that ICM provides several advantages. “The process is fully automated, which eliminates human errors that often translate into quality defects and increased costs,” he explains. “We eliminate the starts and stops that normally characterize pharmaceutical manufacturing, and the entire process is located in a single facility, where manufacturing operators are all in constant communication. This is very different from the currently fragmented model, where parts of the manufacturing process are performed by different companies that are not always aligned, often resulting in rework. Also important, we leverage novel technologies that enable integration and this seamless production.”
The commercial facility will have a capacity that is several times greater than that of the pilot line, with two end-to-end lines that will have the capacity to produce multiple APIs and drug products, including both sterile injectables and OSD drugs using a “multi-suite” design. With the extra capacity beyond future US government contract requirements, the company plans to produce and market its own drugs, as well as provide contract manufacturing services.
While the commercial facility will be a conventional, fixed-location facility, Continuus envisions that the ICM platform could also be used in a Mobile Pharmaceuticals (MoP) plant, which would be housed in a prefabricated pod that could easily be transported and deployed across the globe to provide regional manufacturing and distribution.
Innovators are prototyping other mobile manufacturing facilities using continuous, end-to-end manufacturing at small scales of finished drug forms for both small- and large-molecule drugs. Funding for several of these projects is coming from DARPA. Moderna, for example, received a DARPA grant in October 2020 as part of DARPA’s Nucleic Acids on Demand World-Wide (NOW) initiative to develop a mobile, end-to-end automated, GMP-quality manufacturing platform for mRNA vaccines and therapeutics for military and local populations in remote regions (7).
At the Center for Advanced Sensor Technology at the University of Maryland, Baltimore County (UMBC), professor and director Govind Rao and his team have developed the Biological Medicines on-Demand (Bio-MOD) platform, which uses a cell-free process to translate and continuously purify proteins. Bio-MOD is a “factory on a chip” that fits in a suitcase-sized container. Rao says the device has been demonstrated to reproducibly manufacture several drugs, including His-tagged granulocyte-colony stimulating factor, and that others are in progress. The system can also make nucleic acids. The group is looking for a partner to be a first adopter and take a target molecule through FDA approval. “The vision is to broadly license the technology so that it becomes a standardized production platform,” says Rao.
On Demand Pharmaceuticals (ODP) is developing proprietary Pharmacy on Demand (PoD) technology licensed from MIT to build a miniaturized, end-to-end medicine production system. The Rockville, MD-based company was founded with the mission of producing battlefield medicines, but the company envisions its portable, refrigerator-sized PoD technology being used for any localized manufacturing. ODP received a $20 million contract award from DARPA in September 2020 to further develop its technology to produce critical APIs and final dosage forms. ODP has demonstrated that the technology can produce solid-dosage forms (diazepam, diphenhydramine hydrochloride, and ciprofloxacin hydrochloride tablets) and liquid formulations (lidocaine hydrochloride, atropine sulfate, as well as medicines used to treat critically ill COVID-19 patients requiring ventilation support). The technology can also be used to produce APIs or critical precursors as needed.
Although the units are small, they can produce significant volumes. “For some high-potency drugs, in which one dose is less than 10 mg, such as midazolam, one PoD running for 24 hours could produce as much as 2 million doses,” says Kari Stoever, chief external relations officer at ODP. The company expects, however, that its devices would make finished dosage forms of multiple drugs in a distributed manufacturing model. Stoever says that PoDs have demonstrated rapid turnaround time of approximately two hours for changeover from synthesis of one API to another.
The company moved into a 44,000-ft2 facility in 2020 and is completing renovations in preparations for CGMP production. Stoever says that ODP has been working closely with FDA’s Emerging Technology Team and anticipates filing its first submission to the FDA in the next year, with additional product submissions to follow shortly thereafter.
In addition to domestic production capacity and working to ensure the protection of military service members, ODP sees its technology as useful for orphan drug and precision medicine markets. “Perhaps the most compelling use case for the PoD technology resides in addressing unmet needs in the world’s poorest communities,” adds Stoever. A flexible system for local manufacturing could meet a community’s need for a broad range of essential medicines. “As the PoD technology matures, we will pursue development aid partners to work on a low-income model of the PoD,” she notes.
Although regulators have expressed support for novel technologies, some regulatory barriers do still exist. For example, current GMP regulations depend on a conventional definition of a facility with a physical address; modular and mobile manufacturing does not fit this definition. Real-time release from portable systems with innovative process controls could also be a regulatory barrier. The NASEM committee, however, concluded that mobile, end-to-end systems “are becoming mature and robust enough to push the regulatory envelope within five to 10 years,” and that FDA would need to take a proactive approach and ease the regulatory burden if such systems were to be used (2).
“In a conservative industry, getting people to change the way they do things is a big challenge. But now there are drivers to innovate, so the question is how fast change will occur,” concludes Collins.
1. J. Woodcock, “Safeguarding Pharmaceutical Supply Chains in a Global Economy,” Congressional Testimony (Oct. 30, 2019).
2. NASEM, Innovations in Pharmaceutical Manufacturing on the Horizon: Technical Challenges, Regulatory Issues, and Recommendations (2021).
3. S. Milmo, Pharm Tech Europe 32 (6) 6-8 (2020).
4. GSK, “Less is More with Advanced Technologies in Manufacturing,” gsk.com, accessed 12 Mar. 2021.
5. P. Sagmeister et al., Angewandte Chemie online, DOI:10.1002/anie.202016007 (Jan. 12, 2021).
6. D. Blackwood, “PCMM and Beyond—Next Gen Innovation for Solid Oral Dosage Forms,” Presentation at NASEM (February 2020).
7. Moderna, “DARPA Awards Moderna up to $56 Million to Enable Small-Scale, Rapid Mobile Manufacturing,” Press Release, Oct. 8, 2020.
Jennifer Markarian is manufacturing editor at Pharmaceutical Technology.
Vol. 45, No. 4
When referring to this article, please cite it as J. Markarian, “Advanced Manufacturing Technologies Shift Outside the Box,” Pharmaceutical Technology 45 (4) 2021.