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Advanced Manufacturing Technologies Shift Outside the Box

Mish Boyka

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Advanced Manufacturing Technologies Shift Outside the Box

At the request of the 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 a new urgency to reduce dependence on bulk active ingredients and generic drugs sourced from India and China (3). Sanofi and Sequins, for example, are putting a new focus on European API manufacturing (see Sidebar).

Making chemical APIs

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, co-founder, 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 the 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 the 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 a 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 the 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 the 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.

Continuous path for OSD drugs

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 the 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.

End-to-end manufacturing

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, Continuous Pharmaceuticals. Continuous 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 Continuous, 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. “Continuous 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, Continuous 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.

Small-scale end-to-end systems

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 a rapid turnaround time of approximately two hours for the changeover from the 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.

Challenges for novel processes

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.

References

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.

About the author

Jennifer Markarian is a manufacturing editor at Pharmaceutical Technology.

Article details

Pharmaceutical Technology
Vol. 45, No. 4
April 2021
Pages: 16–19

Citation

When referring to this article, please cite it as J. Markarian, “Advanced Manufacturing Technologies Shift Outside the Box,” Pharmaceutical Technology 45 (4) 2021.

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Vermont Health Connect had 10 data breaches last winter

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Vermont Health Connect had 10 data breaches last winter
Vermont Health Connect has set up a special enrollment period in response to the coronavirus outbreak. VHC photo

In mid-December, a Vermont Health Connect user was logging in when the names of two strangers popped up in the newly created account.

The individual, who was trying to sign up for health insurance, deleted the information that had suddenly appeared.

“It was super unsettling to think that someone is filing in my account with my information,” the person, whose name is redacted in records, wrote in a complaint to the Department of Vermont Health Access. “Just seems like the whole thing needs a big overhaul.”

It was one of 10 instances between November and February when Vermont Health Connect users reported logging to find someone else’s information on their account.

The data breaches included names of other applicants and, in some cases, their children’s names, birth dates, citizenship information, annual income, health care plans, and once, the last four digits of a Social Security number, according to nearly 900 pages of public records obtained by VTDigger. On Dec. 22, the department’s staff shut down the site to try to diagnose the problem.

While officials say the glitches have been resolved, it’s the most recent mishap for a system that has historically been plagued by security and technical issues. The breaches could be even more widespread: Administrators of Vermont Health Connect can’t tell if other, similar breaches went unreported.

“We don’t know what we don’t know,” said Jon Rajewski, a managing director at the cybersecurity response company Stroz Friedberg. Regardless of whether there are legal ramifications for the incidents, they should be taken “very seriously,” he said.

“If my data was being stored on a website that was personal, — maybe it contains names or my Social Security number, like my status of insurance… — I would expect that website to secure it and keep it safe,” he said.

“I wouldn’t want someone else to access my personal information.”

Andrea De La Bruere, executive director of the Agency of Human Services, called the data breaches “unfortunate.” But she downplayed the severity of the issues. Between November and December, 75,000 people visited the Vermont Health Connect website for a total of 330,000 page views, she said. The 10 incidents? “It’s a very uncommon thing to have happen,” she said.

De La Bruere said the issue was fixed on Feb. 17, and users had reported no similar problems since. The information that was shared was not protected health information, she added, and the breaches didn’t violate the Health Insurance Portability and Accountability Act, or HIPAA.

“No matter what the law says technically, whether it’s HIPAA-related or just one’s personal information, it’s really concerning,” said Health Care Advocate Mike Fisher.

The timing of the issue is less than ideal, he added. Thousands of Vermonters will be logging into Vermont Health Connect in the coming weeks to take advantage of discounts granted by the American Rescue Plan. “It’s super important that people can access the system, and that it’s safe and secure,” Fisher said.

A ‘major issue

The issues first arose on Nov, 12, when at least two Vermonters logged in and found information about another user, according to records obtained by VTDigger.

Department of Vermont Health Access workers flagged it as a “major issue” for their boss, Kristine Fortier, a business application support specialist for the department.

Similar incidents also occurred on Nov. 17 and 18, and later on multiple days in December.

Department of Vermont Health Access staff members appeared alarmed at the issues, and IT staff escalated the tickets to “URGENT.”

“YIKES,” wrote a staff member Brittney Richardson. While the people affected were notified, the data breaches were never made public.

State workers pressed OptumInsights, a national health care tech company that hosts and manages Vermont Health Connect, for answers. The state has contracted with the company since 2014. It has paid about $11 million a year for the past four years for maintenance and operations, with more added in “discretionary funds.”

Optum appeared unable to figure out the glitch. “It is hard to find root cause of issue,” wrote Yogi Singh, service delivery manager for Optum on Dec. 10. Optum representatives referred comments on the issues to the state.

By Dec. 14, Grant Steffens, IT manager for the department, raised the alarm. “I’m concerned on the growing number of these reports,” he wrote in an email to Optum.

The company halted the creation of new accounts on Dec, 14, and shut down the site entirely on Dec, 22 to install a temporary fix. “It’s a very complex interplay of many many pieces of software on the back end,” said Darin Prail, agency director of digital services. The complexity made it challenging to identify the problem, and to fix it without introducing any new issues, he said.

In spite of the fixes, a caller reported a similar incident on Jan. 13.

On Feb. 8, a mother logged in to find that she could see her daughter’s information. When she logged into her daughter’s account, the insurance information had been replaced by her own.

“Very weird,” the mother wrote in an emailed complaint.

Optum completed a permanent fix on Feb. 17, according to Prail. Vermont Health Connect has not had a problem since, he said.

Prail said the state had reported the issues to the Centers for Medicaid and Medicare Services as required, and had undergone a regular audit in February that had no findings. The state “persistently pressured Optum to determine the root cause and correct the issue expeditiously but at the same time, cautiously, so as to not introduce additional issues/problems,” he wrote in an email to VTDigger.

“We take reported issues like this very seriously,” he said.

A history of glitches

The state’s health exchange has been replete with problems, including significant security issues and privacy violations, since it was built in 2012 at a cost of $200 million.

The state fired its first contractor, CGI Technology Systems, in 2014. A subcontractor, Exeter, went out of business in 2015. Optum took over for CGI, and continued to provide maintenance and tech support for the system.

Don Turner
Don Turner, right, then the House minority leader, speaks in 2016 about the need to fix the state’s glitch-ridden Vermont Health Connect website. With him are Phil Scott, left, then the lieutenant governor, and Sen. Joe Benning. Photo by Erin Mansfield/VTDigger

In 2018, when Vermont Health Connect was less than 6 years old, a report dubbed the exchange outdated and “obsolete.”

Officials reported similar privacy breaches in 2013, when Vermonters saw other people’s information.

An auditor’s report in 2016 found a slew of cybersecurity flaws, and officials raised concerns again during a  2018 email breach.

It wasn’t the first time that Vermont Health Connect users had been able to view other people’s personal information. Three times since October 2019, individuals had logged in to see another individual’s insurance documents. Prail attributed those incidents to human error, not to system glitch; a staff member uploaded documents to the wrong site, he said.

In spite of the issues, Prail said he and other state officials have been happy with Optum. After years of technical challenges with Vermont Health Connect, “Optum has really picked up the ball and improved it and been running it pretty well,” he said.

Glitches are inevitable, he added, and Optum has addressed them quickly. “They took a really difficult-to-manage site and made it work pretty well,” he said. “Optum is generally quite responsive to any issues we have.”

“I find any privacy breach to be concerning,” said Scott Carbee, chief information security officer for the state. He noted that the state uses “hundreds of software systems.” “While the scope of the breaches can be mitigated, true prevention is a difficult task,” he wrote in an email to VTDigger.

Optum spokesperson Gwen Moore Holliday referred comments to the state, but said the company was “honored” to work with Vermont Health Connect “to support the health care needs of Vermont residents.”

Prail said the Agency of Human Services had no plans to halt its contract with the company. “I don’t have a complaint about Optum,” he said. “They took a really difficult-to-manage site and made it work pretty well.”

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Health Care

Tags: data breaches, Optum, Vermont Health Connect

Katie Jickling

About Katie

Katie Jickling covers health care for VTDigger. She previously reported on Burlington city politics for Seven Days. She has freelanced and interned for half a dozen news organizations, including Vermont Public Radio, the Valley News, Northern Woodlands, Eating Well magazine and the Herald of Randolph. She is a graduate of Hamilton College and a native of Brookfield.