Pharma Manufacturing - June 2024

IT’S TIME FOR THE U.S. TO SIFT

THROUGH DOMESTIC

MANUFACTURIN

EFFORT

Richmond’s pharma hub

Can CAPA live up to its name?

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Ensuring CAPA lives up to its name

The Richmond-Petersburg region has rebounded from its tobacco breakup 24 quality & compliance

How pharma can use CAPA as a tool to support continuous process improvement 28 automation & control Pushing the boundaries of health

Technological advancements are setting new standards for what’s possible 32

EDITORIAL TEAM

karen langhauser Chief Content Director klanghauser@endeavorb2b.com

andrea corona Senior Editor acorona@endeavorb2b.com

EDITORIAL ADVISORY BOARD

BiKaSh chatterJee, Pharmatech Associates

emiL ciurcZaK, Doramaxx Consulting roBert Dream, HDR Company

BarrY hoLtZ, Phylloceuticals eric Langer, BioPlan Associates iVan Lugo, INDUNIV, Puerto Rico

giriSh maLhotra, Epcot International rich mYer, Tergus Pharma garY ritchie, GER Compliance

michaeL touSeY, Solid Dose Technology

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Removing the gold-colored glasses

What will it take to make pharma reshoring more than a glint in the pan?

Karen Langhauser Chief Content Director

In January of 1848, a carpenter by the name of James Marshall was busy building a water-powered sawmill in the American River at the foothills of the Sierra Nevada Mountains when he noticed flakes of gold in the water. He and his boss, John Sutter, did a spectacularly bad job of keeping the news under wraps, because before long, a storekeeper was running through the streets of San Francisco screaming about gold, and major news outlets had gotten wind of the situation.

In the year that followed, hundreds of thousands of people began hitching their wagons to dreams of prosperity and heading west.

While the promise of frontier life had been ingrained in American culture for decades, the timing of Marshall’s striking discovery proved pivotal.

The 1840s saw Americans crawling out from under a depression that had been ignited by financial panic during the previous decade. Much of the country’s middle class held factory jobs, where the working conditions and morale were poor. Unemployment had risen, wages had dropped. Land prices were surging, making land ownership for many Americans impossible — a problem that was especially difficult to swallow at a time when ‘independence’ was closely linked to possessing property.

When the gold rush hit, people flocked to California in hopes that gold would be the answer to all their problems. (Spoiler: While a handful of prospectors did end up rich; far more ended up dead.) In short, Americans found themselves in a bad place and were offered a shiny solution — and they dug in.

In a similar way, the stage was set for pharma’s westward return when the global pandemic laid bare the country’s worrisome overreliance on China for medical supplies. In the background, the industry continued to struggle with drug shortages and quality issues. Cue the calls to ‘bring manufacturing home.’ Add to that favorable legislation and billions of dollars in government incentives…and you have yourself a reshoring rush.

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Sparked by the pandemic, the U.S. government’s investments into generic drugs and ingredients have created an air of excitement surrounding repatriation. Now, with the urgency of the pandemic behind us, the U.S. has the chance to candidly assess pharma’s reshoring progress — and create a more structured plan for supply chain resilience. While there have been numerous articles justifying the need to repatriate the pharma supply chain, this month’s cover story focuses on how we can make domestic manufacturing sustainable for the long haul.

It has become clear that reshoring isn’t a cure-all for pharma’s supply chain problems. But if the groundswell of government support can be properly channeled and upheld, a stronger domestic manufacturing base offers a golden opportunity to better position the country in the event of future supply chain shocks.

And for the pharma supply chain, true wealth will not come in the mass movement west, but rather in the government’s commitment to keep mining until a valuable solution pans out. 

Andrea Corona Senior Editor

Interphex 2024: Pharma embraces obstacles

Drugmakers are tackling modern therapies, and equipment providers are eager to help

This year, Interphex brought over 9,000 attendees to New York City. The Pharma Manufacturing team was among them and got an up-close look at the industry’s newest innovations and future plans.

One theme resonated clearly throughout the exhibition hall — enthusiasm. After enduring the pandemic and a period of cautious optimism, pharma is poised and ready to embrace future challenges.

“People are excited to be here and learn the best ways to tackle the issues brought by the drugs of the future,” said Michael Mühlegger, senior director of marketing & inside sales at Single Use Support.

This year, Interphex showcased the industry’s proactive embrace of innovative technologies and strategies to accelerate drug manufacturing and enhance operational efficiency, emphasizing the sector’s readiness to meet future health care challenges.

Show floor trends

Speed-to-market

Drugmakers are under pressure to create quality products faster and more efficiently. Processing equipment can help facilitate this by offering

flexible design, quick changeover and smaller footprints.

On the plant floor, the goal is to maximize machine uptime — because each minute spent on changeover represents a loss in overall equipment effectiveness. Fred Murray, CEO, KORSCH America, described it as taking a “pit-crew mentality” to equipment changeovers.

Murray also noted a shift towards equipment containment rather than suiting workers. “The industry is moving towards containing the process instead of containing the people,” said Murray.

Speed is also a factor when it comes to facility construction. According to Grant Merrill, chief commercial officer, AES Clean Technology, a slowdown in funding in the biopharma space means the timelines for building infrastructure are increasingly compressed — and for equipment and facility providers like AES, this makes for a challenging landscape where speed is vital.

Equipment makers must ensure seamless integration and not stand in the way of getting a drugmaker’s product to market, says Merrill. “The magic is in our clients’ science; we protect that science.” To that end, AES launched its new CleanLock Module at Interphex

— a next-gen airlock solution that enhances cleanliness, speed and efficiency in cleanroom project execution.

In a similar vein, Single Use Support showcased its RoSS.PADL platform, which enables multiple cooling/heating and kneading mechanisms to be placed side by side to scale up with one control system.

“Our end goal here was to offer aliquoting and cooling at the same time,” said Mühlegger. Combining these steps reduces complexity, enhances safety and ensures the stability of sensitive materials used in cell and gene therapies.

Digital solutions

As pharma companies strive to deliver new treatments to patients, digital technologies are transforming cumbersome traditional processes. Biosafety testing is one area particularly poised for innovation through these solutions. Because CHO cells are naturally unstable, the FDA requires multiple kinds of tests to make sure the cells’ genes are stable, which is historically expensive and time-consuming. But Millipore’s new Aptegra platform, launched at Interphex, transforms biosafety testing with a digital solution using next-generation sequencing.

The technology platform replaces five different assays and four different technologies with one assay, reducing testing time by 66% and costs by 43%, according to Millipore.

ConSynSys Technologies’ ProCaaSo platform — which was declared the Interphex efficiency champion — offers a modern approach to manufacturing process control. The platform facilitates Pharma 4.0 by utilizing Python programming and modern industrial edge computers, rather than traditional PLC technology.

According to ConsynSys, the cloud-managed process-control-as-aservice (ProCaaS) enhances operational efficiency and accelerates the time to revenue as it functions as a comprehensive platform rather than a singular application, streamlining aspects such as security, networking,

communications, scheduling and process control, making decentralized manufacturing and control feasible.

Single-use aseptic processing

The halls of the Javits echoed with emphasis on single-use aseptic processing tools and services, as exhibitors looked to expand capabilities amid exploding demands for sterile drugs. Discussions about the scramble for sterile fill-finish manufacturing capacity continued, with the industry still buzzing about Novo Holdings $16.5 billion acquisition of CDMO giant Catalent announced back in February.

On the show floor, many CDMOs highlighted their sterile fill-finish manufacturing capacity. Alcami, for example, touted its recent addition of a new sterile fill-finish line with an isolator and two lyophilizers at its existing

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New products

The event also showcased an array of innovative products, keeping its promise to introduce cutting-edge technology. Winners of the 2024 Interphex Exhibitor Awards included:

• Best in show: AST Inc. | GENiSYS C

• Best new product/service: IMA Group | KryoAir

• Editor’s choice: KORSCH America | X 5 Tablet Press

• Best technologies innovation: AustinPX, Pharmaceutics and Manufacturing | Kinetisol

• Efficiency champion: ConSynSys Technologies | ProCaaSo Platform

• Biotech innovation award: IDEX MPT | MP350 Microlyser Processor 

Stevanato Group

Alessandro Morandotti Director, Product Management

Daniel Martinez Head of Product Management

The importance of robust drug containment and inspection solutions cannot be overstated. These processes are essential for maintaining the integrity and safety of drug products throughout their life cycle, from development to delivery to patients.

As drugs evolve, so too do their containment and inspection needs. Fortunately, as technology advances, the methods and equipment used in these processes are continuously evolving, providing enhanced accuracy and safety.

To better understand the issue, Pharma Manufacturing recently sat down with Alessandro Morandotti, Daniel Martinez and Federico Scattolin from Stevanato Group to discuss the latest advancements in containment and inspection technologies.

Q: What are the recent growth trends in pharma?

Alessandro Morandotti: We’re seeing significant growth in biologics and biosimilars, the fastest-growing segments in the industry. Additionally, there’s substantial growth in vaccinations, which are now expanding their technology from Europe and the United States to emerging countries. Prefillable syringes are increasingly important for delivering new drugs and therapies.

In biologics, three areas are particularly noteworthy: GLP-1 treatments for weight management, biologics, and mRNA treatments, which have surged since the pandemic. These are

Federico Scattolin System Owner

Advancing drug containment & inspection

How new technologies can help drugmakers keep pace with modern therapies

all driving growth in the biopharma market and creating specific requirements for drug-containing solutions.

Q: How are GLP-1 formulation advancements influencing container design and production?

Daniel Martinez: GLP-1s aren’t new. Recently, we’ve seen advancements in formulations for weight management, where they’re used in devices like cartridges for type 2 diabetes treatment. The design and production of these containers must ensure compatibility and performance when integrated into devices. GLP-1s, being smaller and less complex than biologics, are less sensitive, yet they demand high-volume production — hundreds of millions of containers. This requires high-capacity, high-speed processing not just for the containers but for the machines handling them.

Developers of GLP-1s target various suppliers, requiring different containers. It’s crucial to handle fill and finish capacities efficiently to maximize production and distribution. To minimize breakages, line issues, or high rejection rates during inspection, a high-quality container is necessary. For Stevanato Group, this means using Nexa syringes or cartridges, which provide mechanical robustness and cosmetic quality to reduce false rejects during inspection.

AM: I see similarities between GLP-1s and vaccines, particularly in terms of

volume and the need for flexibility in container solutions. Globally, vaccines are delivered using diverse drug containment methods. We’re witnessing a trend toward pre-fillable syringes and a significant role for vials.

Specifically, there’s growing interest in ready-to-fill vials, which offer the pharma industry more flexibility and finishing options. For us, both bulk and ready-to-fill vials remain crucial, especially as the latter allow vaccine manufacturers to utilize contract manufacturers for these containers.

Q: What specific container challenges do biologics face?

DM: Biologics are sensitive to substances like silicone, tungsten oxide residues, and even the glass of the container itself. This necessitates a distinct approach to container design, including mechanical resistance and additional measures to ensure stability before application.

These containers must meet high cosmetic standards to prevent rejects, but also accommodate lower batch sizes typical of new monoclonal antibodies, usually between 3 to 6 million units, unlike the larger batches of blockbuster biologics. This smaller scale necessitates greater flexibility and careful inspection of each container. For example, in our Alba syringes, we use a cross-linked silicone coating to prevent silicone from interacting with and destabilizing the drug. We also work to minimize

tungsten residues in syringes to reduce harmful interactions.

Q: How have vaccine container trends evolved after the pandemic?

DM: For mRNA vaccines, the primary concern during the pandemic was managing the extremely cold storage conditions required for dry ice shipments at -80 degrees Celsius. Our containers are robust enough to manage these conditions, ensuring no loss of container closure integrity. The shift has been towards using syringes for mRNA, reflecting a broader trend in vaccine delivery.

them. For instance our Mavis inspection platform, which exemplifies this nicely. Another significant aspect of flexibility is the ability to handle products in a human-like manner, which we’ve achieved with our VRU unit.

Q: How do higher drug concentrations and viscosities impact visual inspection?

FS: Managing this issue often involves controlling how the product is spun and the speed of the spin. We have multiple techniques at our disposal for this. Additionally, in our product port-

The challenge of false rejections commonly associated with automatic visual inspections is significant — employing a robotic unit alongside the vision inspection machine can add value for the end customer.

The major challenge for mRNA stability, aside from storage temperature, is its sensitivity to silicone particulates from standard silicone oil used in syringes, which can destabilize the drug during freeze-thaw cycles. Our Alba syringes effectively reduce the release of particulates, enhancing the stability of the drug product through several freeze-thaw cycles.

Q: How can inspection processes be enhanced?

Federico Scattolin: A key aspect of flexibility is having a robust set of inspection stations, so you can utilize various lighting options, cameras and viewpoints, potentially integrating

folio, we have machines like the VRU, which I mentioned earlier, that offer more flexibility. Other machines like the CVT and Mavis also facilitate this by allowing the product to be spun in various ways, preparing it for the final inspection. Dealing with this is a daily occurrence for us.

AM: Another key point to discuss is the ability to perform human-like inspections on drug containment solutions — especially when dealing with very expensive products. The challenge of false rejections commonly associated with automatic visual inspections is significant. In this context, employing a robotic unit or an alternative inspection unit alongside the vision

inspection machine can add value for the end customer.

Q: How can AI be leveraged to improve visual inspection systems?

AM: Integrating a robotic unit or artificial intelligence around the vision inspection machine can enhance inspection quality, increase productivity, and minimize the waste of expensive drugs.

FS: At Stevanato Group, we’ve integrated AI into our operations for over five years. Our machines are equipped with AI, using neural networks to improve defect detection and ensure more accurate defect classification. This enhances process understanding and helps eliminate errors like bubbles or protein agglomerates that shouldn’t cause rejections.

We utilize pre-trained networks to reduce the need for sample quantities, boosting efficiency. Additionally, our inspection digital twin technology supports the offline development and testing of inspection recipes, allowing uninterrupted production. This process includes collecting images, developing, testing and validating the inspection recipe while production continues.

Q: Does Stevanato offer solutions tailored to these market needs?

DM: Our response to the market for GLP-1s involves our Nexa platform, which includes syringes and cartridges known for their robustness and ability to be processed at high speeds. For biologics, we offer the Alba and Nexa platforms, known for drug compatibility, high cosmetic quality, and mechanical robustness suitable for auto-injectors. For mRNA, we provide the Alba cross-linked silicone layer and the Nexa Flex, a polymer syringe. 

Karen Langhauser Chief Content Director

IT’S TIME FOR THE U.S. TO SIFT THROUGH DOMESTIC DRUG MANUFACTURING EFFORTS

When the pandemic hit and Americans found themselves looking to China for critical medical supplies, the idea of reshoring — a concept that had drifted along the currents of the manufacturing sector for over a decade — embedded itself into pharma discourse with renewed luster.

Reshoring found some of its most fervent supporters inside the halls of Congress, with leaders touting the idea as a catch-all cure to pharma’s longstanding supply chain ills and putting forth a rush of legislation. The solution also had a champion in the White House, with President Trump, just months into the pandemic, issuing a controversial ‘Buy American’ executive order mandating that essential drugs and medical supplies purchased by the federal government be manufactured domestically.

The country’s reshoring fever has persisted into the Biden administration, with the president invoking the Defense Production Act, a Truman-era policy, to unlock government investment in the domestic manufacturing of essential medicines, countermeasures and critical inputs last November.

As Mark Twain once said, “During the gold rush it’s a good time to be in the pick and shovel business.” And for the handful of pharma stakeholders willing to get on board with the reshoring effort, the government — through the Department of Health and Human Services’ (HHS) Administration for Strategic Preparedness and Response (ASPR) — has offered lucrative incentives. ASPR’s Biomedical Advanced Research and Development Authority (BARDA) has awarded contracts totaling more than $2.1 billion to expand domestic production of pharma

ingredients and related supplies for pandemic response and build future capacity. ASPR’s newly created Office of Industrial Base Management and Supply Chain (IBMSC) has invested over $17 billion across 87 contracts to expand the U.S. industrial base for key materials and products.1

“There’s certainly a lot of activity in this space right now and a tremendous amount of money that’s being thrown at it. And you’re seeing bits and pieces of it take hold,” says Bikash Chatterjee, president and chief science officer at Pharmatech Associates, a USP company.

The government’s investments into generic drugs and APIs have created an air of excitement surrounding the westward migration of manufacturing. But health care economists, such as Marta Wosińska, who currently serves as a senior fellow at the Brookings Institution Center on Health Policy, are worried about what comes next.

“If I were a manufacturer and the government were to offer me a bunch of money to build a facility, I would be asking a lot of questions about whether that’s going to be enough for me to be competitive in the market after,” says Wosińska.

While many of the companies who received these contracts have managed to deliver on their initial promises, they are now faced with the daunting task of remaining self-sustaining as the dollars dry up.

Now comes arguably the most vital phase of U.S. domestic manufacturing efforts — figuring out where to get the most lasting bang for our reshoring bucks.

“There’s an opportunity for the U.S. government to be much more strategic about this. Think about which supply chains, which players, and how to think holistically about not only infrastructure but also follow-on,” says Wosińska. “If it’s not systematic, the government can very easily end up spending a bunch of money and accomplishing very little.”

With the pandemic finally in our rearview, the U.S. has what many industry insiders see as a golden opportunity to candidly assess pharma’s reshoring progress — and create a more formal plan for supply chain resilience.

Panning the lists

Given the sheer enormity of the pharma market, it’s easy to imagine how quickly spending on domestic manufacturing will escalate if left unchecked.

“There are around 2,800 generic API molecules on the U.S. market. There’s tens of thousands of drugs on file with

Phlow’s Virginia-based manufacturing infrastructure is strategically designed to support R&D and manufacturing scale up for small and large commercial volumes.

the FDA. So where do you start?” asks Kevin Webb, chief operating officer at the API Innovation Center (APIIC), a St. Louis-based nonprofit formed in 2021 to help lead U.S. efforts to reshore APIs. “Initially it was just ‘throw a lot of money at it, fix the problem.’ But now the position that the administration and Congress is taking is that we need to be more tailored in our approach.”

Among the supply chain issues currently in need of resolution, no problem has garnered more widespread attention than drug shortages — which has made shortage lists an attractive starting point for reshoring efforts. Currently, the FDA is tracking over 120 drug shortages (reported at the molecular entity level).2

According to the American Society of Health-System Pharmacists (ASHP), ongoing and active shortages have reached a record high in the U.S.3 Per ASHP’s list, which reports shortages

at the drug preparation level, there were 323 active shortages during the first three months of 2024 — largely involving the same molecules that FDA is tracking.

Because the lists include vital drugs such as chemotherapies, antibiotics and emergency medicines used on hospital crash carts, finding a fix has resulted in a flood of Congressional hearings, reports and proposed policy solutions. But the idea of reshoring has been a consistent part of these discussions, and in some ways, constantly pushing domestic manufacturing as the remedy for all that ails the pharma supply chain has diluted the movement’s mission.

“When I testified with Senate Finance Committee, we were talking about shortages of generic sterile injectables, which are largely made in the U.S. and in Europe. But senators make their statements and it seemed

like their solution often was ‘we should onshore’ as if that alone would solve the problem,” says Wosińska.

Wosińska, who served as economic advisor to the U.S. Senate Finance Committee and has spent over a decade doing policy work on drug shortages and supply chain resilience through positions at the FDA and HHS, is among those trying to help the government prioritize its supply chain spending. And for Wosińska, using reshoring as the primary means to trim the drug shortages list doesn’t add up. According to Wosińska, current persistent shortages are caused by a race-to-the-bottom in pricing, not geopolitical risk, which makes reshoring a mismatched solution.

The countless drug shortage reports that have been released by various organizations and sectors of the government have reached similar conclusions: Factors that cause drug shortages are multifaceted and thus, solutions need to reflect the nature of each of those factors.

Because it stands at the intersection of so many supply chain issues, reshoring continuously runs the risk of losing focus, which makes the need to create a refined, targeted list crucial to the movement’s momentum.

“We need to be strategic about which supply chains to prioritize for government support. Let’s assess which products, if lacking, would have the largest consequences for our health care system,” says Wosińska.

Efforts to do that have been underway. Currently there are a multitude of lists attempting to define ‘essential’ medicines. FDA’s list, posted in October 2020, includes 227 drug and biological products deemed essential medicines, medical countermeasures and critical inputs. ASPR, in response to an executive order from President Biden, solicited input from various stakeholders to down select FDA’s list to create a prioritized list of medicines that the government could target for domes-

If I were a manufacturer and the government were to offer me a bunch of money to build a facility, I would be asking a lot of questions about whether that’s going to be enough for me to be competitive in the market after.

— Marta Wosińska

tic manufacturing. The list, published in a resilience assessment report in May 2022, included 86 medicines.4 At the time the report was created, half of those medicines were on a drug shortage list, highlighting the persistent and alarming overlap between shortages and essential medicines.

Those closest to the problem are calling for further refinement of reshoring targets, which would establish a ‘vulnerable’ medicines list. This list would look at the already established essential medicines lists overlaid with all possible supply chain vulnerabilities, creating a continually updated ‘super list’ of the most essential medicines facing the highest risk of shortage.

“You have to talk about vulnerable generics such as those that have been on the ASHP or FDA drug shortage list or a combination thereof and then further classify those drugs for which there is no American manufacturer and there is no

clinical alternative,” says Eric Edwards, co-founder and CEO at Phlow Corp.

Shortly after its inception in 2020, Phlow, a certified B Corp pharma manufacturer, made national headlines when it was awarded a $354 million contract from BARDA to procure medication for the Strategic National Stockpile (SNS) as well as build domestic infrastructure for advanced manufacturing of essential medicines.

“We need a global supply chain for resiliency, but we have lost our pharmaceutical sovereignty for these medicines, and we need to make them here again as a matter of national public health security,” says Edwards.

Upstream and down

With efforts underway to narrow the reshoring list, experts stress the need to simultaneously broaden its scope.

“If you onshore APIs, but your starting ingredients still come from China, then what problem did you solve?” probes Wosińska. “When you are thinking about domestic manufacturing, it’s a more complex system.”

Currently, much of federal policy focus has been on repatriating generic drugs and APIs, but stakeholders have realized that in order to achieve true sovereignty, reshoring efforts must reach further into the supply chain — both upstream and down.

Phlow’s government-backed program initially focused on surge response to the pandemic. The company procured 2 million doses of medications from various manufacturers in shortage for patients hospitalized with COVID-19 and delivered them to the SNS. But in doing so, Phlow recognized that the SNS was not set up to facilitate the rapid production of essential medicines because it was lacking starting materials and ingredients.

Working alongside BARDA and ASPR, Phlow built a Strategic API

Reserve (SAPIR) to store and supply critical starting materials and active ingredients that can be rapidly converted to finished essential medicine if needed. Phlow also built two new facilities, a kilo-scale facility and a metric-ton scale facility, that are both capable of manufacturing necessary components to make drugs: key starting materials (KSMs), intermediates and APIs.

Biden’s use of the Defense Production Act last November specifically acknowledged the importance of these KSMs, a crucial component of APIs, in supply chain security by including a $35 million investment in their domestic production.

Also vital to the drug supply chain are excipients, which are included alongside the APIs in formulations and are necessary to enhance stability and bioavailability of the finished drug products.

A deep dive into pharma supply chains for the purpose of repatriating its various constituents requires visibility into said supply chains — historically a stumbling point in the U.S. According to Edwards, while the country has made progress towards comprehending the API supply chain, that’s where visibility ends. “We have a long way to go to truly understanding where the key starting materials and some of these constituent components are being manufactured.”

Phlow has been working for years on mapping the extended supply chain for essential medicines, leveraging a variety of publicly available databases as well as private information from market research firms, manufacturers, distributors and others.

While the Federal Food, Drug and Cosmetic Act requires all API manufacturing facilities serving the U.S. market to register their locations with the FDA, the agency has lacked data on

the actual volume of APIs that facilities are producing and how much is entering the U.S. market. When the Coronavirus Aid, Relief and Economic Security (CARES) Act was signed into law in March 2020, the $2.2 trillion economic stimulus bill included a provision that requires all manufacturers of drugs and APIs to report drug volume details to the FDA via a dedicated portal.

Taking that idea a step further, last year, legislators introduced a bipartisan bill — Mapping America’s Pharmaceutical Supply (MAPS) Act — that would require HHS to update its essential medicines list, creating a federal database to map the origin of each drug, the location of the facilities involved in the production of the KSMs and excipients needed to produce the APIs and finished dosage forms, as well associated inspections and recall alerts.

For the top 100 generic medicines consumed by U.S. citizens, 83% have no U.S.-based source and another 11% have only one U.S.-based source.

— Cortellis Generics Intelligence, Clarivate

“We’ve done a lot of work, but we still need to do more, especially as you start trying to go upstream and downstream across this opaque essential medicine supply chain,” says Edwards. “It’s a critical task because to find an effective cure, you have to have an accurate diagnosis.”

All that glitters

When it comes to building domestic manufacturing infrastructure, Uncle Sam has dug deep, trying to mitigate the supply disruptions caused by the pandemic while also investing in future capacity. But as with any government-backed model, there are concerns about long-term sustainability once the initial funding is drained.

Among those worries is the concern that if the government stands up facilities and then thrusts them into the open market, the companies will eventually fall victim to the same systemic economic issues that drove them offshore to begin with. In short, are we pouring money into a broken system?

“The mistake is thinking that if we build a new manufacturing plant, it’s going to solve everything. It won’t. Those companies that the government has funded or put money into, they risk falling into the same trap that everyone else has fallen,” says Webb.

No one knows this better than the companies that are living this reality.

“Having the government step in and finance the build-out of advanced manufacturing facilities in the U.S. is an essential part of reshoring. But it’s not everything,” says Salvatore Mascia, founder and CEO of CONTINUUS Pharmaceuticals. “Once you build a facility, unless you have a take-off contract providing financial incentives to make these generic medications, then it’s not going to be enough to resolve these problems.”

In January 2021, the Department of Defense awarded CONTINUUS a $69.3 million contract to develop domestic production capabilities for critical APIs and final

Reshoring Legislation and directives

CORONAVIRUS AID, RELIEF AND ECONOMIC SECURITY ACT

MARCH 2020

The CARES Act included several provisions regarding the supply chain: Additional drug/API shortage and sales volume reporting requirements, a mandate to develop redundancy risk management plans for each drug/API establishment, and a study by the National Academies of Sciences, Engineering and Medicine on the national security and public health threats related to the pharma supply chain.

ENSURING ESSENTIAL MEDICINES, MEDICAL COUNTERMEASURES AND CRITICAL INPUTS ARE MADE IN THE U.S.

AUGUST 2020

The ‘Buy American’ executive order directed federal agencies to identify vulnerabilities in the supply chain, support domestic production through various investments, and prioritize the procurement of essential medicines, countermeasures and critical inputs from U.S. manufacturers. It also directed the FDA to identify a list of essential medicines that are medically necessary to have available at all times.

AMERICA’S SUPPLY CHAINS

FEBRUARY 2021

The executive order initiated a government 100-day review of the supply chains that underlie the U.S. industrial base, among them pharmaceuticals and APIs. The order directed HHS to create a one-year report on the public health supply chain and industrial base outlining successes and strategies.

ADVANCING BIOTECH AND BIOMANUFACTURING INNOVATION FOR A SUSTAINABLE, SAFE AND SECURE

AMERICAN BIOECONOMY

SEPTEMBER 2022

The executive order laid out a vision for a whole-of-government approach to advance biotech and biomanufacturing. It launched a National Biotechnology and Biomanufacturing Initiative to ensure that the U.S. had the domestic capacity to make biobased products. Included was also a $40 million investment to expand the role of biomanufacturing for APIs, antibiotics and relevant key starting materials needed for essential medications and pandemics.

dosage generics using the company’s proprietary integrated continuous manufacturing (ICM) technology. CONTINUUS, which was spun out of the Novartis-MIT Center for Continuous Manufacturing in 2012, had earmarked a portion of the money to build a first-of-its-kind GMP facility for critical generic sterile injectables — but things didn’t go as planned.

The company ran into permitting issues linked to FEMA regulations, which triggered a 12-month delay and the decision to change the location of the expansion to a more expensive site. As the project budget increased, CONTINUUS struggled to attract interest from outside investors, eventually running out of money to build the plant, voiding a portion of the contract.

While all was not lost — CONTINUUS was able to use its ICM technology and develop the key synthetic manufacturing routes of some pandemic drugs that were in shortage in its lab and deliver these synthetic routes to the U.S. government, providing proof of concept for the company’s platform — the situation highlights that federal infrastructure investments alone may not be enough to create a thriving domestic manufacturing sector.

Mascia says the economic realities of producing low-revenue generic drugs make for a difficult pitch to outside investors. The company has since pivoted away from generic drugs and is instead working with large pharma/ innovators on new products.

“When we were working with U.S. government, our goal was to be a generic company — we wanted to build a GMP facility and commercialize generic products,” says Mascia. “What we are focusing on right now involves working with pharma companies on new molecular entities that are not facing all this financial constraint.”

Phlow, which represents both the greatest reshoring success story and the government’s largest individual investment, has a government contract can be extended for up to a total of $812 million over 10 years to help maintain the company’s system and supplies. However, the company’s objective is to establish a sustainable commercial business.

To that end, in early 2022, Phlow launched a CDMO business to serve government entities as well as commercial pharma customers. With the U.S. government already a committed customer, Phlow has generated some commercial interest, delivering CDMO services in its lab and supporting customers with programs for both generic and innovator products.

But despite Phlow’s laudable achievements, Edwards acknowledges the need for ongoing government support and says that certain incentives “would be huge” as the company continues to navigate the market.

“Government subsidies for us are just a starting point to help catalyze reshoring efforts for the essential medicines industrial base. But the government also must provide incentives to domestic manufacturers who are focused on going back to high quality manufacturing,” says Edwards.

Those incentives could include things like tax breaks or loans to companies willing to repatriate the manufacturing of FDA approved medications. They also don’t necessarily have to be in the form of cash. In its “Blueprint for Enhancing the Security of the U.S. Pharmaceutical Supply Chain,” the Association for Accessible Medicines suggests that the FDA could create regulatory efficiencies by forming an internal, intra-agency working group focused on helping to expedite reviews and approvals to onshore

pharma manufacturing.5 Another option would be for the FDA to create regulatory vehicles that help reward domestic-made drugs. Creating a ‘first generic that uses U.S. components’ designation that comes with an exclusivity period could go a long way for companies in the highly competitive generics market.

Restoring luster to AMTs

Success in the reshoring movement hinges on the industry’s ability to not only build back its capabilities when it comes to the generic drug supply chain, but also (to borrow the phrase) build back better.

“When you look at why companies moved overseas in the first place — lower labor rates, lax environmental regulations and heavy government subsidies — we can’t compete against that, nor should we,” says Webb. “In order to bring that back to the U.S., we need better technology and improved efficiencies. We have to be cost competitive.”

To that end, no discussion of reshoring is complete without the mention of advanced manufacturing technologies, with the most popular tool being continuous manufacturing. Much like reshoring, continuous manufacturing is commonly offered up as a fix for pharma supply chain issues. The FDA in particular, through its Emerging Technologies Program as well as its newly created Advanced Manufacturing Technologies Designation Program, has supported the idea that continuous manufacturing, over time, could help prevent drug shortages caused by product quality and manufacturing problems.6

“Thinking about onshoring the old way doesn’t make sense. You still have all the process segmented and the underlying problems of batch manufacturing,” says Mascia. “If you are

going to onshore, you need to onshore in a new way.”

But the idea of replacing outdated batch processing methods has existed in the pharma industry with marginal uptake for over two decades. While there have been a handful of innovator drugs approved using continuous methods, the generics industry has been a tougher sell.

On the innovator side, the robust ROI on branded drugs has enabled capex investments into different advanced development and manufacturing approaches. Yet for the highly competitive, low-margin generics industry, continuous might seem like an economic mismatch. “The generics industry, they don’t touch that. There’s been no incentives to invest in advanced technologies, so they’ve remained antiquated,” says Edwards.

Last year, the Brookings Institute convened a group of experts from academia, industry, government and nonprofits to explore technology options for improving the resilience of generic drug manufacturing. During the workshop, generic drug leaders voiced concerns that the cost efficiencies captured by continuous manufacturing still fall short when compared with current models for generic drug production, including sourcing from foreign producers.7

But continuous manufacturing proponents, Chatterjee among them, insist that with technology costs coming down and regulatory uncertainty surrounding those technologies lessened, there is a role for continuous to play in generic drug manufacturing.

“There’s more than a wealth of generic drugs out there that could benefit from continuous, but it’s just that activation energy to get management to realize that the upside far outweighs the downside,” says Chatterjee.

Reshoring

Legislation and directives

CONSOLIDATED APPROPRIATIONS ACT

DECEMBER 2022

The omnibus appropriations bill included $1.7 trillion in fiscal year 2023 discretionary government funding, as well as a number of other health care provisions. The bill contained important reforms relevant to the FDA, including FDORA, which directed the agency to establish advanced manufacturing centers of excellence and an advanced manufacturing technologies designation program.

BOLD GOALS AND PRIORITIES TO ADVANCE AMERICAN BIOTECHNOLOGY AND BIOMANUFACTURING

MARCH 2023

In response to the executive order issued in September 2022, this initiative set ambitious national targets for the next two decades to help establish R&D priorities. Specifically for pharma, it aimed to deploy broad synthetic biology and biomanufacturing capabilities in the U.S. within five years to produce 25% of all APIs for small molecule drugs.

ACTIONS TO STRENGTHEN AMERICA’S SUPPLY CHAINS

NOVEMBER 2023

During the inaugural meeting of the White House Council on Supply Chain Resilience, 30 actions designed to strengthen supply chains across multiple industries were unveiled. Among them, the use of the Defense Production Act to make more essential medicines in the U.S. and mitigate drug shortages. This included $35 million for investments in domestic production of KSMs for sterile injectable medicines and the designation of a new Supply Chain Resilience and Shortage Coordinator.

“The government is trying to incentivize folks to push in that direction to overcome their fears.”

It’s here that the reshoring movement has given continuous manufacturing new luster.

The infusion of government funds associated with reshoring has enabled companies like Phlow to de-risk that leap for generics. Phlow’s goal, according to Edwards, is to take the best of what’s happening with innovator drugs and apply it to generics, where the chemistry hasn’t been looked at for decades.

And the results have been encouraging. Using continuous-flow processes and other green chemistry approaches, Phlow has been able to cut costs and waste, improve quality and yield, and offer a more environmentally friendly alternative to batch manufacturing for several different generic compounds.

“New chemistry, new process, new catalysts, new solvents and putting it into a manufacturing environment that requires less manual steps to take out some of that expensive labor. Now you’re starting to become more cost competitive,” says Edwards.

CONTINUUS has developed its own form of advanced manufacturing that the company calls integrated continuous manufacturing (ICM). Rather than just making the finished drug using a continuous process, ICM offers a single continuous end-to-end chain — from KSM to API to final dosage. The process is designed to increase quality and efficiency while reducing manufacturing costs and the exposure of supply chain components to geopoltical risks.

Those efficiencies alone, however, have not been enough to attract investment from the generics space. According to Mascia, CONTINUUS was able to develop a full end-to-end process for metformin, a key generic drug, through which the company demonstrated numerous operational benefits, including better speed and quality. But the client wasn’t willing to invest in building a facility for continuous production of metformin, given the low profitability of the drug.

“That’s where the hang-up is — capex activation energy,” says Mascia. “And that’s why it’s important to have the government invest in this, because unless the government steps in and makes that investment, private investors will not do it for a low-profitability product.”

Buying in

While the recent pitch for domestic manufacturing has hooked a diverse group of players — equipment suppliers, government, academic institutions, nonprofits, specialty

manufacturers — global pharma companies have conspicuously kept their distance.

When the FDA solicited public commentary from stakeholders regarding the essential medicines list the agency had been directed to create through President Trump’s ‘Buy American’ order, the industry wasted no time making it clear that forcing a domestic supply chain (in a pandemic no less) would likely just worsen problems.

“Use of overly broad and blunt instruments, such as the executive order, to encourage domestic manufacturing does not account for the realities, challenges, and nuances of pharmaceutical supply chains, or the actual risks of supply shortages. Such actions may actually result in market disruptions and product shortages,” said Sarah Lieber, Sanofi’s North America head of global regulatory affairs, in a written commentary.

While timing a domestic manufacturing mandate with a global pandemic that wreaked havoc on supply chains certainly didn’t encourage the pharma industry to embrace the reshoring movement, the pandemic did provide a unique opportunity to reintroduce the idea of repatriating the drug supply. According to Chatterjee, the pandemic also allowed the U.S. government to demonstrate that it could catalyze the pharma industry if the government was a customer.

“Now that the subsidies are gone for vaccines, for example, the attractiveness around that sector is definitely far less. So there’s going to have to be some component of government support that’s going to drive the industry to get real traction,” says Chatterjee.

At Phlow, Edwards is quick to point out that building a domestic supply chain is “not a call towards removing diversity in our supply chain” and to

clarify what ‘buy in’ from the pharma industry might look like.

“The role large global pharma companies can play in this movement is to come alongside Phlow and help the U.S. government understand the problems and contributors to these supply chain challenges and align on the right incentives that need to be in place to secure a resilient supply of these critical essential medicines,” says Edwards.

Even without a ringing endorsement from big pharma, APIIC’s Webb feels that the government’s efforts over the past four years to identify stakeholders and “hardwire a domestic network” was money well spent towards navigating future supply chain shocks.

“Are we doing this better than we were a couple years ago? Yes — because now people are asking the right questions.” 

References

1 Bolstering biopharma manufacturing in the U.S. is essential to health preparedness. BARDA. (Feb. 22, 2024)

2 FDA Drug Shortages. U.S. Food and Drug Administration. (accessed: May 20, 2024).

3 Drug Shortages Statistics. American Society of Health-System Pharmacists. (accessed: April 11, 2024).

4 Essential Medicines Supply Chain and Manufacturing Resilience Assessment. ASPR and Nexight Group. (May 2022).

5 A Blueprint for Enhancing the Security of the U.S. Pharmaceutical Supply Chain. AAM. (Oct. 2021).

6 FDA is Advancing New Efforts to Address Drug Shortages. Gottlieb, Scott. (Nov. 19, 2018).

7 Workshop summary: Technology solutions for improving the resilience of generic prescription drug manufacturing. Wosińska, M., Conti, R. and Reynolds, E. (Jan. 11, 2024).

Arijit Chatterjee Senior Director, Pharma Solutions Leader, Capgemini Engineering

Building the next generation of future-ready labs

To achieve lab transformation, leaders must confront challenges in data, technology, people and processes

In the pharma industry, there is a growing pressure to combat global health challenges with greater speed, accuracy and impact.

As a result, many pharma organizations are looking to create futureready ‘next-gen’ labs to drive medical breakthroughs. This will involve rethinking their entire approach to lab structure and operation, increasing emphasis on digitalization, AI, workforce skills and culture.

While many are keen to capitalize on the benefits offered by nextgen labs, transformation is not a swift process. Our recent survey of pharma execs found that nearly half of organizations anticipate that they will require two to five years to transform labs.

While most enterprises are still in the early stages of transformation, leaders must prepare to confront challenges in data, technology, people and processes to achieve longterm success.

Enabling next-gen labs

As the market shifts towards advanced drug production, there are several essential elements to consider.

Firstly, to enable next-gen labs, organizations must have the correct architecture and systems integration in place. This includes enabling the necessary systems, instruments, data protocols and physical and digital architecture. What’s further, leaders should evaluate both cutting-edge and sustainable design options, which

lower carbon footprint and increase energy efficiency.

Intelligent data capture and reporting is also essential. Data and analytics can be leveraged in labs to terminate poor drug candidates early and reduce late-stage failures. By implementing new technologies that make data collection more intelligent and analytical in nature, organizations can achieve faster and more accurate reporting.

With architecture and data capture capabilities in place, the next step is to simplify and digitize workflows. In many existing lab ecosystems, personnel are utilizing analog methods of communication, resulting in lost data, transcription errors, translation mistakes and misinformation. By optimizing workflows in digital systems, communication becomes more seamless, resulting in less human error and a more agile workforce.

Discovery acceleration is the final piece of the puzzle. This involves applying innovative technologies, such as AI and ML, to speed up data capture.

Gearing up for transformation

Once an organization has put the pieces in place to enable transformation, there are several guidelines for success:

• Build for adoption: From an early stage, involve end users, scientists and lab technicians.

• Develop incrementally: Starting with pilot projects builds momentum. Leaders should create an agile project management strategy to divide

the program into smaller projects, meeting milestones incrementally while sharing achievements with stakeholders.

• Deploy changes with agility: Adopting a ‘fail-fast’ momentum will help encourage adoption from scientists and technicians. Engaging personnel with minimal disruption to day-today activities will require agility from project managers.

• Safeguard investments: Regardless of how a transformation evolves, it’s crucial for labs to protect the investments that have been made, improving ROI across their line of operations.

• Infuse scientific talent into IT projects: Integrating lab practitioners into data science, system integrations, and other transformation initiatives will enhance lab transformation.

Leveraging innovative technology is also important. For example, adapting generative AI and large language models in R&D can streamline structure elucidation, toxicity testing and experiment design, while AI and natural language processing models can be used for CMC documentation, product quality reports, and lab experiment analysis. Leaders who do not prepare their businesses to take on this level of change will inevitably fail. Next-gen labs are the key to unlocking the full potential of scientific exploration and drug discovery. But without the correct tools, technologies and culture in place, the benefits offered by these labs can never fully be realized. 

Sanner

Adrian Possumato President Chris Gilmor Director of Sales

Streamlining packaging design

By integrating a QbD approach with moisture management solutions, manufacturers can quickly design robust packaging to optimize product stability

Drugmakers are continuously seeking ways to enhance efficiency, and packaging plays a crucial role. Traditionally, the packaging development process involves extensive stability testing to ensure medications remain effective throughout their shelf life, but the process can be time-consuming and costly.

By integrating a Quality by Design (QbD) approach, developers can design robust packaging from the outset, drastically reducing development time and costs. Understanding how moisture affects a product is key, allowing developers to use industry-accepted and validated models to predict and address potential stability issues early in the design phase, thereby reducing the need for prolonged probe stability testing and potential reformulations or packaging redesign.

To understand more about the issues at hand, Pharma Manufacturing recently spoke with Adrian Possumato, president and Chris Gilmor, director of sales, at Sanner of America.

Q: How are current trends in pharma manufacturing impacting the design and production of oral dose packaging?

Adrian Possumato: There is a move towards sustainability across the board in the pharmaceutical industry, including both prescription and OTC products. This involves material selection and regionalization of supply as customers aim to minimize their

carbon footprint and de-risk the supply chain. This shift is partly due to concerns exposed during the COVID19 pandemic.

While the current major drugs are small-volume, high-value biologics in parenteral form, small molecule oral solid dose (OSD) formulations still represent about 38% of the drugs in phase 3 clinical trials. From 2017 to 2022, 182 of the 293 (close to 62% ) of the new chemical entities approved by the FDA were small molecule drugs. Formulators are now focusing on using small molecule drug substances

therapeutic effects rather than injecting biologically active proteins.

AP: Because biologically active materials like peptides and proteins can’t be delivered orally as they’re destroyed by the gastrointestinal system, pharma companies are using small molecules to synthesize therapeutic proteins in the body. This maintains the relevance of small molecule drugs. We see many requests for packaging presentations that stabilize these drugs for a twoyear shelf life.

While the current major drugs are smallvolume, high-value biologics in parenteral form, small molecule OSD formulations still represent about 38% of the drugs in phase 3 clinical trials.

to directly bind to proteins in the body to produce a therapeutic effect, rather than injecting a prepared biologically active protein therapy. Essentially, they aim to get the small molecule drug substance to synthesize therapeutic proteins in the body.

Chris Gilmor: Small molecules still hold significant potential. Formulators are using them innovatively, like binding to proteins in the body for

Q: What are some critical components as well as challenges for OSD packaging?

AP: OSD remains a focus for the pharmaceutical industry. Stability challenges, both physical and chemical, persist. Consequently, passive and active packaging continues to be necessary. There’s no avoiding the use of HDPE or PVC and related desiccants in packaging presentations.

CG: Because ensuring the physical and chemical stability of drugs is challenging, mathematical models can help streamline these processes.

Q: How has the industry adopted QbD in drug packaging, and what are the main advantages?

AP: Twenty years ago, there was little QbD applied at this development level. Now, QbD is used increasingly to quickly select successful packaging during phase 2B clinical trials. Historically, probe stability studies were used, but now empirical modeling models like ASAPprime (FreeThink Technologies, Inc.) predicts outcomes, saving 6-12 months of development time and $225,000 per stability test. The first to market gains significant advantages, especially in the generic industry, where exclusivity can yield 60% of profits in the first six months.

Industry scientists have advanced predictive stability modeling programs that operate across a comprehensive range of ICH stability conditions, utilizing a QbD approach.

These programs determine moisture management outcomes by integrating empirical measurements, such as moisture adsorption/desorption isotherms, on the drug product, the moisture vapor transmission rate (MVTR) of the primary packaging, and

desiccant isotherms. By collaborating closely with formulation chemists, these moisture management outcomes can accurately predict stability results for the drug product within the modeled packaging presentation.

CG: Using QbD, Sanner’s ‘advance with agility’ proposition determines stability outcomes quickly, designs optimal packaging, and ensures proper use in commercial operations. This comprehensive approach involves all key stakeholders, improving efficiency and reducing costs.

Q: What are the typical cost savings with QbD for OSD packaging?

AP: Our QbD-based approach saves time and money by eliminating probe stability testing and optimizing packaging. This saves 6-12 months of development time, allowing earlier market access and improving cash flow. The design and designate steps reduce package design time and related stability testing, again leading to earlier market access and better cash flow. In the dispense step, we optimize the use of materials, reducing quality costs, packaging waste, and improving operational efficiencies.

CG: Involving all stakeholders ensures that needs are addressed, enhancing

the overall efficiency and effectiveness of the process.

Q: What technological innovations does Sanner employ for moisture control in OSD packaging?

AP: We offer standard desiccants, both moderate and aggressive, moisture regulators, and odor/volatile absorbers. These are used in:

• Drop-in solutions for conventional bottle and pouch packaging presentations

• Built-in solutions, which are integrated into Sanner’s stock or custom-designed rigid packaging presentations with child-resistant closures

CG: Built-in solutions prevent desiccants from being mistaken for drugs and simplify packaging processes. This approach is increasingly favored by pharmaceutical companies for its efficiency and safety.

AP: Built-in solutions also streamline commercial packaging operations and are identifiable with a brand. We’re seeing more custom built-in packaging used even at the prescription level for chronic use drugs, preserving stability and efficacy without needing additional pill carriers. 

Karen Langhauser Chief Content Director

Virginia is for pharma lovers

Richmond has rebounded from its tobacco breakup and is courting a serious relationship with advanced manufacturing

First debuted in 1969, the now-iconic marketing slogan was purposeful in its ambiguity. “Virginia is for lovers” invites people to personalize the tagline with whatever they love about the state — be it the rich history, beautiful beaches or breathtaking mountains.

But far before it was for lovers, Virginia, specifically the capital city of Richmond, was for tobacco. From the inception of Virginia as a colony, tobacco was essential to the area’s economy. Philip Morris began making cigarettes in Richmond in 1929, opening a 1.6-million-square-foot manufacturing center in 1973 that soon was churning out half the cigarettes sold in the U.S. Heading into the 1990s, Philip Morris was the area’s largest private employer, providing jobs for more than 10,000 workers.

But as the number of smokers declined, and the tobacco industry squared off against stricter regulations and large class action lawsuits, many of Virginia’s tobacco farms began to

technology

disappear. Philip Morris began laying off workers. Richmond’s Model Tobacco factory, a prominent six-story art deco building, sat dormant for decades after closing its doors in the mid-80s. Tobacco Row, once a vibrant collection of tobacco warehouses and cigarette factories along Richmond’s James River, was converted into trendy loft apartments and retail spaces.

Faced with a fizzling tobacco business, Richmond was a city in need of a new identity — and it has found one in the pharma space. Today, the Richmond-Petersburg region, through its collaborative ecosystem and focus on advanced technology, is rebuilding itself as a global hub for pharma manufacturing.

The Virginia Bio+Tech Park in downtown Richmond is a 34-acre life sciences and emerging technologies community.

Finding the spark

The rapid chain of events that sparked the Richmond-Petersburg pharma manufacturing cluster was fueled by a focused mission — improving access to quality medicines.

It started with a Bill & Melinda Gates Foundation-funded project at Virginia Commonwealth University’s (VCU) College of Engineering, focused on using advanced technologies to develop a more cost-effective way to manufacture the HIV/AIDS therapy, nevirapine. In 2017, additional funding from the Gates Foundation allowed for the university to officially establish the Medicines for All Institute (M4ALL) and apply its optimized active pharmaceutical ingredient (API) development platform to a broader array of lifesaving vaccines and treatments.

At the helm of M4ALL was pharma industry veteran and VCU professor, Frank Gupton. In 2019, Gupton teamed up with long-time friend and pharma entrepreneur Eric Edwards, to apply continuous processes and flow chemistry to the development and manufacturing of critical drugs in shortage, with a focus on pediatric medicines. In early 2020, they officially launched Phlow, a public benefit corporation based in the Virginia Bio+Tech Park in downtown Richmond.

Then, the pandemic hit and Gupton and Edwards quickly realized that many of the drugs that would be needed to treat COVID were also on the drug shortage list, which lead them to respond to a request for proposals issued by the Biomedical Advanced Research and Development Authority (BARDA).

In May 2020, Phlow was awarded a $354 million contract from BARDA to procure medication for the Strategic National Stockpile as well as build domestic infrastructure for advanced manufacturing of essential medicines,

including drugs for pandemic response. Executing the contract involved Phlow — which at the time did not have a manufacturing facility — collaborating with strategic partners M4ALL, Ampac Fine Chemicals (now SK pharmteco) and Civica Rx.

From there, the partners began investing in advanced manufacturing infrastructure in nearby Petersburg and the area’s pharma ecosystem began to flourish. Ampac, a leading manufacturer of essential medicine key starting materials (KSMs) and APIs, spent $25 million to expand its existing facility. Right next door, Phlow built a 19,200-square-foot kilo-scale facility capable of manufacturing KSMs, intermediates and APIs, as well as a (soon-to-be-operational) 18,000-square-foot facility for production on a metric-ton scale. Phlow and U.S. Pharmacopeia also built adjoining lab space in the Bio+Tech Park to facilitate the development of guidelines, best practices and resources to assist in the adoption of advanced manufacturing technologies.

Down the street, Utah-based nonprofit generic drug company, Civica, invested $140 million to build a 140,000-square-foot highly automated sterile injectables facility. Now operational, the facility has three different filling lines — one each for vials, syringes and insulin pen cartridges.

Collectively, the companies offer an end-to-end process for domestic drug manufacturing and serve as a foundation for the region’s rapidly growing pharma manufacturing cluster.

Virginia is ranked number 2 for business and number 1 for education — CNBC’s Top States for Business in 2023

Making it official with advanced tech

Amid this collaboration, Frank Gupton had recognized the powerful role that flow chemistry and continuous processing could play in the future of drug production. In 2020, he and Edwards assembled pharma-minded stakeholders in the Richmond-Petersburg region — among them, M4ALL, Phlow, Ampac and Civica — and made their relationship official, forming the Alliance for Building Better Medicine.

The group, convened by Richmond-based innovation ecosystem development organization Activation Capital, has since amassed over $53 million in federal funding through the U.S. Department of Commerce’s Economic Development Administration’s (EDA) Build Back Better Regional Challenge. The funding has gone towards the scaling of the region’s advanced pharma manufacturing (APM) cluster, with an end goal of expanding the domestic supply chain for essential medicines and critical APIs.

The alliance’s efforts have been paying off, too — last fall, the Biden-Harris administration designated the Richmond-Petersburg region as an ‘APM Technology and Innovation Hub,’ setting the coalition up to apply for additional funding through the EDA.

Spreading the love

The region’s advanced technology successes have not been confined solely to pharma manufacturers. Virginia-grown equipment innovator, Grenova, has

The Medicines for All institute is redesigning processes to facilitate more sustainable manufacturing.

developed solutions that enable labs to wash contaminated plastic consumables, such as pipette tips and microwell plates, so that they can be safely reused. The company’s fully automated pipette tip washer, known as the TipNovus, enables labs to wash and reuse pipette tips an average of 10-25 times.

In 2021, Grenova invested $10.6 million to relocate its operations a few miles north of its original location to a larger facility in Richmond. The company worked with the Virginia Economic Development Partnership (VEDP) to choose the location, which made it eligible to receive grants from the state.

VEDP also provided assistance to support Grenova’s recruitment and training through its Virginia Jobs Investment Program. The discretionary program provides funding to companies creating new jobs or retraining workers due to a technology change. In addition to direct funding, VEDP also offers free human resource consultations to qualified companies.

Startups are not being left out of the action in the Richmond-Petersburg region either. Richmond’s VA Bio+Tech Park, opened in 1995, is now a thriving 34-acre life sciences and emerging technologies community that has been instrumental in launching entrepreneurs and helping existing companies flourish. The park, which sits adjacent to the VCU medical campus, is home to nearly 70 companies, research institutes and state/ federal labs.

Last year, Activation Capital announced plans to develop a new Innovation Center within the Bio+Tech

Park that they are hoping will become a world class hub for startups, entrepreneurs and scientific breakthroughs. The center is currently searching for its lead tenant to occupy the location’s premier lab and office spaces. The remainder of the center will be dedicated to an incubator and will include much-needed labs and private offices. The first floor will offer community training and gathering spaces as well as a street level café.

People: The heart of the cluster

Cultivating a pharma ecosystem, especially one built around advanced technology, requires a steady stream of skilled workers.

Virginia’s education system — ranked number one in the nation by CNBC — places a strong emphasis on manufacturing technology-related skills. Development of the talent pipeline starts as early as middle school, with Virginia’s ‘Go Tec’ initiatives. These hands-on programs enable students to learn to use actual equipment applicable to various fields, such as precision machining, robotics, automation or mechatronics (electronics plus mechanical engineering). Richmond-Petersburg high schools continue the technology instruction, offering mechatronics training inside their career and technical education center.

At the college level, VCU’s School of Engineering is home to the first Ph.D. pharma engineering program in the nation. The two community colleges that serve the region, Brightpoint and Reynolds, offer a pharmaceutical manufacturing technician certificate. The program teaches students appropriate gowning procedures, manufacturing procedures and documentation requirements, working directly with local pharma companies. For those interested in equipment operation, Brightpoint offers an associate degree and certificate programs in mechatronics.

Virginia’s 27 military bases offer a second source of skilled talent. The Richmond-Petersburg area has the most concentrated population of military service people, with roughly 10,000 exiting the military each year and seeking employment. Because the military’s focus on discipline and SOPs translates well to the regulated pharma industry, the transition has proven to be a natural fit.

As an incentive for job creation, Virginia offers assistance to companies who are either new to the state or undergoing significant expansion. VEDP’s Virginia Talent Accelerator Program, which works in partnership with a network of community

colleges, offers no-cost job-specific training and recruitment services customized to a company’s unique operations, equipment and culture.

The talent accelerator program has a proven track record of success and has contributed to the R&D renaissance in the region. When GSK and Pfizer merged their consumer health care businesses, forming Haleon, company leadership began an evaluation of R&D facilities across both businesses, ultimately earmarking Pfizer’s global R&D headquarters in Richmond for expansion. In 2019, Haleon announced plans to invest $16.7 million to expand the R&D center, adding 150 new jobs. Haleon worked with the talent accelerator program on a successful recruitment campaign, with an emphasis on enticing scientists from other Haleon locations to relocate to Richmond.

Thermo Fisher also utilized the program in 2022, in conjunction with a $97 million expansion of clinical research operations that added 500 new jobs in the Richmond area.

Building a lasting relationship

While the sweet smell of tobacco no longer lingers in the Richmond air, motorists traveling down I-95 from downtown can still see the monument-sized cigarette looming tall in front of the Philip Morris manufacturing site. In a way, it stands as a reminder of a city that flourished around manufacturing, with workers utilizing some of the most advanced production methods and processing equipment in the industry.

Today’s Richmond-Petersburg region has been completely reimagined, offering a mix of modern happenings and rich cultural history. Centuries-old cobblestone streets lead to host of award-winning restaurants

and breweries. The region boasts a reliable public transportation system and an abundance of green space, all against the backdrop of the scenic James River.

Through close collaboration of the region’s pharma ecosystem and a business-friendly environment backed by federal and state investments, Richmond-Petersburg is rising from the ashes of its tobacco past — this time in a quest to use advanced technologies to improve access to essential medicines. 

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Ensuring CAPA lives up to its name

How pharma can use CAPA as a tool to support continuous process

improvement

Corrective and Preventive Action (CAPA) is not a new quality record by any means — it has been a critical component of pharma quality management systems (QMS) for a very long time. In fact, an organization does not have a QMS without one, even if it is paper-based.

That said, CAPA was not intended to be a QMS compliance tool only; its intent is in fact defined by its name. It is a system or process for analyzing, correcting and preventing issues. CAPA applies to products and processes alike and it is meant to support continuous improvement. Ultimately, CAPA’s target isn’t compliance, although that is one of its roles; it is improving patient outcomes.

Pharma organizations, along with all life sciences companies, need to be sure their CAPA process has not become a checkbox item in their QMS and is instead being used as a tool to support continuous process improvement. However, CAPA can’t be used to support continuous improvement if it is not analyzing causality to prevent reoccurrence. Additionally, if CAPA actions are not being prioritized based on risk, CAPA will become a compliance burden rather than an improvement tool with bottom line impact for the business. If it has become a rote process, mechanical in its execution, chances are improvement is not being achieved.

CAPA effectiveness must be measured individually and over time. So how does an organization make sure its CAPA process supports continuous improvement and lives up to its name and intent?

Assessing risk

Let’s start with risk. To support continuous improvement organizations must prioritize CAPAs by focusing on the issues that have the most impact on patients, product quality and the organization overall. This means focusing on the highest risk issues first. There are varying schools of thought on how to measure the risk

CAPA

of a CAPA. To measure risk, organizations must know what could happen or what did happen.

Formal tools for defining the ‘what’ and performing risk assessments include but are not limited to:

• failure mode and effects analysis (FMEA)

• fault tree analysis

• hazard analysis and critical control points (HACCP)

• hazard operability analysis (HAZOP)

• preliminary hazard analysis (PHA)

• risk ranking

Informal risk assessment methods include:

• brainstorming

• impact assessments

• statistical tools

FMEA, which is the most often used to identify, analyze and prioritize risk, is resource intensive and requires skill and experience with the technique itself. For this reason, it’s a method that is used less frequently in pharma, however there is progress being made towards applying it more.

When conducting a FMEA, the risk assessment output is known as the risk priority number (RPN). It is calculated as follows: RPN = severity (S) x occurrence (O) x detection(D). The RPN

is the risk score for each failure mode. There is some debate in the industry regarding the use of the RPN. There are those that believe risk should be viewed as a continuum and therefore one cannot assign nor calculate risk numerically. Some also disagree with the utilization of ‘detection’ in the calculation, as it can put focus on issues with much lower severity that are difficult to detect.

That said, FMEA and RPN (with or without detection) is a way to systematically evaluate risk. It is consistent and it removes subjectivity as much as possible. It is also widely accepted by regulatory bodies.

HACCP in pharmaceuticals is traditionally used to identify, assess and control safety hazards and pinpoint where they might occur in the drug manufacturing process. This preemptive action is taken to prevent hazards from occurring. By monitoring and controlling each step in the process, the risk of the hazard occurring is minimized.

HAZOP is also focused on using a systematic approach to identifying potential problems and assessing the safety of designs, processes and operations. A structured method for risk management, a HAZOP study is one of the leading techniques used to identify potential standard and compound technology failures in the production process and to eliminate or reduce the probability of occurrence. HAZOP is a critical tool in pharma manufacturing as failures in manufacturing process controls can lead to contamination, potency issues, and a litany of other product problems — not to mention the harm it can cause to manufacturing personnel.

Collectively, all of these techniques are quality risk management tools that define not only what could or did happen (the problem) but also the risk involved with the potential or actual failures for a product or process. Understanding the problem is the first step in the continuous improvement process. You cannot improve what you don’t understand and correcting what isn’t a problem compounds the risk that new issues will be introduced while the original issue remains.

Determining root cause

The CAPA process also involves assessing the cause — you cannot correct an issue or prevent (eliminate) a problem’s occurrence if the root cause of the issue can’t be determined. For this reason, once we understand

Without appropriate measurable effectiveness reviews, organizations could find themselves doing the same things over and over again, making little or no headway in correcting issues, much less achieving continuous improvement of the process.

what has gone wrong, it is important to understand why an issue or issues occurred. It is equally important to determine if there is more than one root cause for the issue(s). Additionally, it is critical that organizations ensure that the investigation they are performing is properly scoped.

Determining root cause involves performing a solid root cause analysis. Root cause analysis tools may include but are not limited to:

• 5 whys

• fishbone

• scatter plot diagrams

• histograms

• Pareto charts

• brainstorming

From the above list, 5 whys is the most widely used tool across industries, pharma included. It is the process of asking why repeatedly to ensure that companies move beyond the obvious symptoms to discover the root cause. The key is that an iterative interrogation is completed to determine cause and effect for a problem.

The fishbone diagram, a process also known as the Ishikawa diagram; has the same goal: to look at cause and effect to determine root cause. It is a more structured process than 5 whys because it looks at several contributing factors for the problem — personnel, materials, measurements, machines, methods and environment.

Choosing which root cause process is deployed within a company is dependent on the company’s products and organizational preferences.

Investigations into what went wrong along with its risk and root cause cannot come only from predefined spreadsheets. Understanding the problem (what), the risk (seriousness) and the cause can only be achieved through thorough analysis. It is important to reiterate that CAPA can only be used to support continuous improvement if it is analyzing causality. If the CAPA investigation is not getting to the root cause(s), the wrong problem is being addressed and therefore continuous improvement is not possible.

Effectiveness review

Corrective actions must correct and prevent recurrence. To accomplish this, companies must address the true root cause or causes, rather than higher-level causes that are too generic. In addition to that, organizations must guard against having only cookie cutter actions predefined for issues. Doing so will only lead to the same result and same effectiveness.

Therefore, the final step to ensuring that CAPA supports continuous improvement is to include an effectiveness review. During an effectiveness review, an action plan will lay out the steps or tasks needed to measure and determine whether the CAPA has or has or hasn’t eliminated the issue.

The action plan tasks should be clear, detailed and contain no ambiguity. To ensure action innovation, be sure that CAPA doesn’t become a task assigned

exclusively to the quality assurance team. Making the process inclusive ensures that ideas from other disciplines within the organization can be considered and that everyone is aware of changes to be made.

However, simply checking if the actions taken are effective over a certain period of time is not enough. Instead there needs to be a plan in place to identify what determines effectiveness, including qualitative and quantitative measures to determine effectiveness. Meaning that the criteria for acceptance and the tasks associated with determining acceptance are well defined. There needs to be appropriate justification for the verification of effectiveness and the sampling plan as well.

Without appropriate measurable effectiveness reviews, organizations could find themselves doing the same things over and over again, making little or no headway in correcting their issues, much less achieving continuous improvement of the process.

Keeping CAPA fresh

Pharma organizations need to be sure their CAPA processes haven’t become checkbox items in their QMS. CAPA is a process that can get stale if an organization is not paying attention. Assessing trends in CAPA effectiveness, monitoring root cause depth and accuracy, and assessing risk over time is key to achieving continuous improvement through the CAPA process.

It’s important to note that the FDA calls out ineffective CAPA procedures and investigations often. While CAPA is a regulatory requirement, it’s intended to correct and prevent. CAPA’s real value lies in its ability to support continuous process improvement, enhancing product efficacy while optimizing organizational impact.

To achieve continuous improvement as an industry and move CAPA beyond compliance, we must embrace discovery and discard cookie cutter approaches that serve only to get the CAPA completed on time. While CAPA can strengthen an organization’s performance, more importantly, it improves the efficacy, safety and efficiency of pharma products, ultimately improving patient lives. 

Andrea Sardella Technical Sales Support Inspection

Daniel Martinez Product Management DCS & Analytical Services

Pushing the boundaries of health

Technological advancements are setting new standards for what’s possible

Stevanato Group

The pharma industry has always been complex, so technological advances that can enhance workflow efficiencies and promote new breakthroughs are always welcomed. Consequently, the industry faces a state of flux where technology is pushing the traditional boundaries of drug development, manufacturing and regulation to new limits — but mostly for the better.

Artificial intelligence (AI) signifies the arrival of the technological revolution. Through the deployment of sophisticated machine learning and deep learning techniques, algorithms and extensive datasets are enhancing success rates to boost efficiencies across a range of processes. Advances in automation and robotics mean that intelligent machinery now automates previously manual jobs, with analytics utilizing the cloud to provide real-time data to ensure optimal performance and avoid unwanted deviation from manufacturing protocols.

These technologies are resulting in a series of significant pharmaceutical innovations to provide hope for unmet clinical needs through personalized treatment plans. Furthermore, this has stirred a demand for innovations such as injectable biologics, which are utilizing new drug technologies for patient convenience.

With many complexities still existing across the pharma supply chain — from manufacturing to post-market surveillance — new technologies are presenting additional opportunities to address and improve upon these challenges.

From drug containment solutions to modern manufacturing technologies, the latest technological advancements are not just changing the industry but also setting new standards for what’s possible in health care.

Drug containment solutions

Drug containment systems continue to play a vital role in the delivery of lifesaving drugs to patients.

Whilst the development of new drugs often exhibits complex analytical and processing challenges, safely storing and delivering sensitive biologics to patients presents another. As such, packaging manufacturers are focusing on providing innovative solutions to address this challenge, while demonstrating additional time-saving and cost-cutting benefits.

Using advanced processing technologies, specialist manufacturers are offering ready-to-use pre-sterilized primary containment units — such as syringes, vials or cartridge

formats — that only require filling by the manufacturer.

In an era where the demand for pharmaceutical products can fluctuate in response to market needs, readyto-use drug containment solutions offer flexibility and versatility in batch size, but without the compromise of quality or efficiency.

Whereas production volumes should be flexible, patient quality and safety should not. The innovative designs of these drug containment solutions ensure that all containers are separated through the use of secondary packaging, minimizing the risk of contamination while maintaining the integrity of the pre-sterilized containers during transportation and handling. With a streamlined production process, the increased efficiency results in a shorter time period between production and distribution, ensuring pharma manufacturers can deliver drugs to patients faster than ever before.

Although the above points are clearly beneficial, cost is usually the most important consideration. These customizable drug containment solutions typically result in significant cost savings through the elimination of in-house processes such as washing, depyrogenation and sterilization, and associated labor and equipment requirements.

AI and machine learning

The pharmaceutical landscape is undergoing a seismic shift, thanks to the integration of artificial intelligence, machine learning (ML) and deep learning (DL). These technologies are no longer buzzwords but practical applications that mimic human intelligence in tasks such as data analysis, decision making and problem solving — often doing so faster, more accurately and with greater cost effectiveness.

For instance, the use of computational technologies in the drug discovery process is facilitating the identification of potential genes or proteins as targets for new drugs. Through the analysis of extensive biological datasets and the prediction of molecular interactions, the time taken to screen potential drug candidates is significantly reduced during the initial phases of drug development.

In both preclinical and clinical research phases, AI is improving efficiency and safety by forecasting the toxicity of compounds, reducing the reliance on animal testing while enhancing safety measures.

In addition, the patient recruitment process for clinical trials is being optimized. Through the analysis of intricate data, AI enables the simulation of trial scenarios and the fine-tuning of factors (such as dosage and treatment length) to ensure the selection of the most appropriate participants for trials.

The same technology is also helping to transform pharma manufacturing processes.

Visual inspection technologies have emerged as pivotal tools in improving manufacturing precision via the integration of AI visual inspection units across the production line.

Historically, pharma products have presented significant challenges to visual inspection systems that usually lead to erroneous interpretations

A fully integrated pre-sterilized containment solution facilitates an easy, flexible and streamlined production process.

of presumed defects. Conventional methods may inaccurately categorize harmless attributes like cosmetic flaws or air bubbles — particularly in suspension or lyophilized cake form — as contaminating particles, resulting in the need for reinspections and a time and cost expense.

However, the integration of cloud-based AI platforms utilizing ML and DL models provides a range of additional benefits:

• Enhanced inspection performance: Detects product cosmetic defects and particle inspections with increasing accuracy, whilst concurrently minimizing the number of false rejections

• Cost efficiency: Cuts costs by obviating the need for reinspecting gray items and significantly reducing the time spent on optimizing and parameterizing machines

• Cloud-based ownership: The cloud-based nature eradicates disk space limitations and high maintenance costs, while still taking advantage of secure data protection, encryption and traceability of data

Enhancing inspection accuracy increases defect detection and reduces incorrect rejection rates, thereby improving overall quality. It also reduces costs for high-value, small-scale batch production, as well as for high-volume and lower-value drugs. Through the coupling of existing manufacturing processes with AI and robotics, it is possible to fully automate batch production and improve the output of manufacturing lines.

Another application promising to unlock new opportunities is digital twin technology. The software tool can simulate the analysis and outcomes of various inspection stations installed into the machine, offering the same interface and the same potential as the machine vision system. The technology processes images captured by the machine (during testing or production phases) and enables the refinement of existing recipes or the creation of new ones. It also facilitates the reprocessing of images from an entire batch to monitor waste trends as parameters are adjusted — all without halting production.

Container traceability tools

Container traceability plays an important role in ensuring the integrity and safety of products across the supply chain. Through the implementation of quick response (QR) codes and radio-frequency identification (RFID) technology on pharmaceutical glassware, increased levels of traceability and control can be achieved.

QR codes and RFID tags act as digital fingerprints for each container to store essential data such as origin, batch number and expiration date, and offer real-time tracking throughout internal manufacturing processes.

This integration of container traceability technology with other technologies opens new avenues for innovation and efficiency. For instance, combining insights from visual inspection tools with container traceability can provide insights into specific manufacturing failures. Or when combined with AI-driven analytics, data collected can be analyzed to predict and prevent disruptions prior to manufacturing.

Looking ahead, additional integration with blockchain technology could offer an immutable ledger of a container’s journey, ensuring transparency and compliance with regulatory standards.

Data-driven decision-making will enable optimized drug development and manufacturing processes to enhance overall efficiency.

Data-driven decision-making

These technological innovations outline just some of the ways that the pharma industry is shifting from reactive to proactive strategies. The result: Enhanced, patient-centered solutions that elevate the standard of care and overall patient well-being.

AI’s predictive analytics will lead to more personalized medicine through the tailoring of treatments aligned to individual genetic profiles, combined with AI’s self-learning capabilities providing insights into improvements and efficiencies across supply chains.

Innovative drug containment solutions will allow manufacturers to provide patients with drug delivery systems that are more convenient for the user, while simplifying the manufacturing process for pharma companies and contract manufacturers. By combining drug containment systems with new traceability technologies, manufacturers will have greater confidence in the overall quality of their products, while providing additional safety reassurance to end users.

A commonality between the success of all of the technologies discussed in this article will rely on data. Data-driven decision-making will enable optimized drug development and manufacturing processes to enhance overall efficiency. However, harnessing this data deluge necessitates robust data management and analytics capabilities to ensure that drugs meet the highest quality standards.

Sustainable manufacturing practices are also coming to the fore, driven by both regulatory pressures and a societal push towards eco-friendly practices. New

technologies are actively aiding sustainability through efficiency and further using data to uncover new opportunities for improvements.

Future outlook

With the pharma industry being on the cusp of a technological revolution, innovations will transform the industry into one that is more patient-centric, data-driven and sustainable.

However, the path forward is not straightforward. Regulatory hurdles are a significant concern, as the industry must navigate a complex set of standards that vary across different markets. Ensuring compliance while fostering innovation requires a delicate balance and a proactive approach to regulatory engagement.

Data privacy and security are also critical. As health care becomes increasingly digitized, protecting sensitive patient information against breaches and unauthorized access is paramount, with a necessity for robust cybersecurity measures and a continuous reassessment of data protection strategies.

Despite these challenges, the outlook for technology in the pharma industry is positive. These technologies are not just incremental improvements but are fundamental drivers of change and are poised to bring about a new era of innovation across all aspects of the pharma industry.

The successful integration of these technologies relies on collaboration among all stakeholders. Pharma companies, tech firms, regulatory bodies and health care providers must prioritize the challenge of working together for the sake of all parties involved.

If these challenges can be met, the future of the pharma industry looks not only promising but revolutionary, with technology driving progress and patient care to new heights. 

Heidi Vanheerswynghels Global Commercial Manager, Pharma, Videojet Technologies

Keeping pace with pharma packaging

Pharma manufacturers need modern printing, marking and coding solutions to ensure compliance and stay ahead of trends

Packaging, coding and labeling technologies play a vital role in protecting pharmaceutical product and brand integrity. As pharma manufacturers and OEM partners face growing complexity in packaging products for health care and consumer markets, they need solutions that can support regulatory compliance while keeping pace with evolving trends.

The pharma industry is utilizing more environmentally friendly packaging materials to support sustainability strategies, while governmental regulations continue to raise the bar on packaging coding requirements to improve traceability and mitigate rampant global counterfeiting. At the same time, manufacturers are striving to achieve greater customization to meet the needs of health care distributors, pharmacists, medical providers and patients.

Today’s pharma manufacturers need modern printing, marking and coding solutions not only to assure compliance but enable them to stay ahead of trends and thrive.

Driver #1: Sustainability

Global manufacturers are leading the charge to incorporate more eco-friendly packaging, printing and other consumable materials in the pharma supply chain as the regulatory climate grows increasingly complex. Government and industry initiatives regarding packaging reduction, recycling and material requirements are widely recognized as more than guidelines; they signal a significant pivot toward a future where sustainability and transparency are integral and expected. Leaders in the packaging sector are navigating these regulations as catalysts for change and innovation.

Regulations such as the EU Packaging and Packaging Waste Directive specifically target packaging recycling and restrict the use of nonrecyclable materials. Additionally, U.S. Food Contact Materials Regulations and EU’s REACH restricts the use of harmful chemicals in packaging materials. In the EU, Canada and, increasingly, the U.S., Extended Producer Responsibility (EPR) holds producers of packaging products responsible for managing packaging waste throughout its life cycle. Meeting these and other environmental requirements requires organizations to have the right solutions and processes in place.

The sustainability push has sparked growing interest in everything from plant-based materials and compostable fiber-based substrates to recyclable plastics and rigid paper packaging. Although implementation of new substrates — requiring extensive testing and validation first — always lags behind interest, companies need to keep an eye on the horizon for innovative substrates and anticipate stricter regulations promoting circularity and waste reduction.

Sustainability demands a level of commitment by pharma companies and their partners to holistically assess products and packaging, from raw materials throughout the full life cycle of the product.

Driver #2: Traceability

The trade of counterfeit and illicit drugs represents a serious worldwide public health issue, costing millions of dollars annually and threatening patient safety. Over 6,000 pharma crime incidents involving counterfeiting, illegal diversion and theft were reported globally in 2022, representing an increase of over 50% (4,344 incidents reports) since 2020.1

Due to the increasing number of counterfeit medicines and unauthorized supply chains, most countries — both industrialized and in emerging markets — have implemented serialization regulations for drugs and medical devices to protect patient safety. In the U.S., the Drug Supply Chain Security Act (DSCSA) underscores the need to ramp up serialization compliance sooner rather than later. Enforcement is due to begin on November 27, 2024, at which time pharma companies need to be ready for full interoperable electronic unit-level traceability for all stakeholders.

As governing bodies enact stringent serialization and traceability legislation and guidelines, manufacturers are reacting and changing the way they code products and packaging to meet requirements.

In the context of the pharma supply chain, serialization is typically achieved by assigning a unique serial number to each saleable unit and conferring it with a distinctive identity that enables chain-of-custody tracking back to the manufacturer at virtually any point during its life cycle. Many companies are implementing aggregation to track individual products through the distribution chain. Aggregation refers to

the grouping of individually serialized packaging into larger units such as bundles, cases or pallets. These units bear a code containing information correlated directly to the serialized products contained within the package. This approach requires a coder that can communicate with machine vision solutions and packing equipment. For code legibility, measures must be taken to protect against condensation, light exposure and other environmental influences that may cause an ink code to smudge or fade. Consideration is given to each package and code’s exposure to damaging elements and conditions over the life cycle of the product. In the selection of coding technology, finding the optimal coding and marking solution combined with line speed, installation requirements, consumables and substrate is key to achieving legible and fully compliant codes. Thorough testing of a coded product or packaging can determine a code’s durability and help prevent traceability problems.

For medical devices sold in the U.S., the FDA’s UDI (unique device identification) standardized identification system was established to set rules for the consistent, unambiguous and globally harmonized tracking of medical devices during distribution and use. This UDI system facilitates the device’s traceability, significantly increasing the effectiveness of recalls and enabling better surveillance by authorities.2 Similar UDI regulations are being adopted and phased in by the EU and other countries, requiring that the device itself and all higher levels of packaging be marked with a unique code in machine-readable (barcode) and human-readable format.

Driver #3: Customization

Personalized, tailored medicine is gaining traction among consumers

TIJ, CIJ and lasers are all suited to applying codes in the small areas available on blister packs.

and health care providers, resulting in a higher number of smaller batches being produced. Lower volume manufacturing in any industry needs flexibility and efficiency while being cost effective, and modern packaging and coding solutions can help achieve this.

Fully integrated companies that manufacture and market a range of pharmaceutical preparations in various dosage forms must be able to customize for diverse therapeutic categories, across various geographies. Rather than opting for fully preprinted packaging materials and labels, many companies are printing on demand. On-demand, variable-data package coding technologies support smaller production batches and enable drug tailoring while reducing packaging inventories. Performed on the production or packaging line, these agile technologies provide greater flexibility for customization while managing critical, complex coding to adhere to regulatory and traceability requirements.

Packaging materials and production processes must align with global regulations and support an efficient, cost-effective supply chain while addressing sustainability, traceability and customization trends.

Exploring packaging substrates

Packaging materials and production processes must align with global regulations and support an efficient, cost-effective supply chain while addressing sustainability, traceability and customization trends. But not all coding and marking solutions are the same, and the ideal system must be carefully matched to the packaging substrate.

For example, folding cartons are one of the most widely used packaging materials for drugs and medical devices because of their versatility in form and function. Unit-level, variable-data printing and marking technologies like thermal inkjet (TIJ), continuous inkjet (CIJ) and laser marking systems perform well on most carton types.

Flexible packaging such as pouches and stick packs are handy, user-friendly options for many pharmaceutical and medical device manufacturers. Pouches, often made of Tyvek, medical paper, metal foil and plastic, can be coded with thermal transfer overprinters (TTO), CIJ printers, and even laser marking systems.

White HDPE (high-density polyethylene) bottles are a very common choice for pharmaceutical products, especially in North America. Until recently, it has been a challenge to deliver the high resolution, high contrast codes required for machine readability on these bottles. Now, innovations in laser marking technologies leverage UV wavelengths to create crisp, indelible black marks including serial numbers and 2D bar codes on HDPE. Laser marking can also achieve high-resolution codes on the side, bottom, shoulder or cap of HDPE bottles.

Supporting patient safety and security by protecting drugs from contaminants, blister packs are another leading packaging format. TIJ, CIJ and lasers are all suited

to applying codes in the small areas available on blister packs while meeting line speed requirements.

Vials, syringes and ampules are inherently challenging for coding, given the small size and radius of the packaging. Integrating a coding solution into OEM equipment can provide improved product control, leading to high quality human- and machine-readable codes.

Vial coding has unique challenges due to internal processes like bright stocking, sterilization and refrigerated storage. Vials can be directly coded with CIJ printing, while vial caps can be marked with both lasers and CIJ printers. Covert coding is achievable with special invisible UV CIJ inks that are readable when illuminated with UV light. Fast illumination response times allow these codes to be read and captured on high-speed production lines.

Proven coding solutions

The need for high resolution printing and serialization has fueled the continued development of coding equipment and technologies. As a result, packaging specifiers and pharma manufacturers now have a choice of solutions to choose from to meet their needs:

Thermal inkjet

Offering high-resolution coding at high line speeds, TIJ is generally used to print traceability information on pharmaceutical packaging such as cartons, labels, blister packs, pouches, bottles and barrier materials.

Developments in TIJ printers and inks have unlocked the ability to code nonporous and semi-porous packaging such as films, foils, plastics and coated stocks. Some solutions provide complex data handling and high-resolution printing of linear bar codes, text, logos, GS1, DataMatrix and QR codes.

Boasting excellent adhesion and contrast, TIJ is an ideal fit for applications where traceability, high quality printing and ease of use are essential. It has been selected by pharma companies for years due to its ability to deliver consistent, high resolution codes at industry standard line speeds; simple and clean cartridge changes; no-wear parts for reliable production; and flexible configurations for integration into complex machinery.

Continuous inkjet

Highly versatile CIJ printers allow for the printing of dates and codes on both flat and curved surfaces and almost any substrate in any shape. CIJ offers fluids-based, non-contact printing of alphanumeric text, linear bar codes, and 2D bar codes on cartons, bottles, labels, vials and ampules, tubes, blister foils, pouches, barrier materials and stick packs.

Laser marking

Laser marking systems are designed to mark sharp, complex codes at high speeds. Depending on the substrate, UV, fiber and CO2 laser marking can produce permanent codes that are resistant to abrasives, chemicals and sterilization processes. Lasers can produce variable text, human-readable codes, and machine-readable linear and 2D bar codes on cartons, blister packs, bottles, HDPE bottles, labels, tubes, syringes, pouches, stick packs, and a variety of Tyvek materials.

High-contrast, permanent codes help to enable lifetime track and trace security for pharma products. Additionally, laser marking meets pharma’s demand for marking more data on products and packaging while requiring no consumables — aside from fume extractor filters — to align with sustainability initiatives.

Thermal transfer overprinting (TTO)

TTO printing is a digital technology used to print high-resolution, variable-content codes on thin, flexible packaging such as plastic film, pouches and labels. TTO systems, available in a range of speeds and with printheads of varying widths, can also provide excellent sensitivity and compatibility with porous substrates such as medical grade paper and Tyvek.

Technologies for serialization

Both laser and TIJ technologies can operate in continuous and intermittent (stop-and-go) packaging applications. An advantage of laser marking is its ability to print on either moving or stationary packaging. By comparison, a TIJ printhead requires the substrate to traverse across the front of the printhead to apply a code. Alternatively, a TIJ printhead can be physically traversed across a stationary substrate, but this adds some mechanical integration to the packaging line.

Both laser marking and TIJ printing provide the high-resolution detail required for multi-line printing and linear bar codes, as well as DataMatrix codes — the standard code carrier for serialization in many regions. Laser markers use a focused beam of light to inscribe or physically alter the top layer of a substrate. In contrast, TIJ printers fire tiny ink drops onto a package as it passes by the printhead.

Substrate, speed, installation considerations and capital costs are factors to evaluate when selecting a packaging technology. A coding and marking specialist with knowledge of the available technologies can provide a customized cost comparison of suitable printing solutions, taking into consideration the unique requirements of a given application and making application-optimal recommendations.

GAMP compliance

Good automated manufacturing practice (GAMP) is a set of guidelines and principles for manufacturers of automated systems in the pharma industry developed by the International Society for Pharmaceutical Engineering. The guidance aims to safeguard patient safety, product quality and data integrity when using GxP computerized systems.

Experienced coding solutions providers can help pharma manufacturers comply with GAMP by commenting on and supporting the draft of the technical reference document needed for the purchase of capital equipment, known as user requirement specification (URS), and providing installation and operational qualification (IQ/OQ) documentation. Providers can also modify standard printer configurations to satisfy the URS.

An integral role

Ultimately, coding and serialization solutions for pharma packaging protect patients, manufacturers, supply chains and brand integrity. Optimal coding solutions are part of a sound approach to pharma manufacturing, with the printer or laser playing a deceptively small but integral role in addressing industry regulations, trends and safety.

In navigating the complex landscape of packaging regulations, companies must strive to stay informed and proactive in addressing regulatory challenges and industry trends to better seize opportunities for growth in global markets. 

References

1 Incident Trends. Pharmaceutical Security Institute. (2023).

2 Benefits of a UDI System. FDA. (October 20, 2023).

Matt Lowe Chief Strategy Officer, MasterControl

Shoring up supply chains

Aging populations are straining pharma production — here’s what the industry should do

Here’s one pathway to a nationwide drug shortage: Start with a rapidly aging population, add increasing costs from new technologies and advancing health care, toss in supply chain chaos thanks to a global pandemic or geopolitical fallout and you’ve arrived.

Japan is dealing with this exact situation right now, and, in the U.S., we aren’t too far behind. Unraveling this frightening issue is a top priority in both countries. Japan’s government has approached drugmakers and insisted they increase throughput, but has yet to offer solutions or subsidies to help.

Here in the U.S. we have a similar approach, with some members of Congress insisting we hold the pharma industry accountable for shortages. But most pharma companies are doing everything they can and the FDA is already stretched too thin.

We desperately need more productive discussion about how the industry can safely and reasonably increase throughput and reliable yield. Here are important steps U.S. pharma manufacturers can take now.

Lean on technology

Right now, the big tech question pharma companies are asking is: How do we leverage AI? Fortunately, there are many positive use cases.

Pharma manufacturers rely on people pouring through quality and manufacturing data to figure out the parameters that will lead to the maximum yield with the minimum amount of waste and errors. Searching for this

so-called ‘golden batch’ typically takes an army of people weeks or months.

Using AI, companies can process clean, digitized data in near-real time, identifying processing improvements, finding problems before they occur and sorting issues into actionable insights. This requires only a handful of skilled technicians, freeing up personnel for more critical tasks.

Leveraging technology is increasingly critical for pharma manufacturers as they seek to increase potential throughput. Using modern tools to help build a bigger pipeline is the first step in alleviating the looming shortage problems.

Maintain consistent quality

Of course, it doesn’t matter the size of the pipeline if companies can’t deliver consistent quality to the end user. Creating yields as high as possible comes from building quality into manufacturing, which should be table stakes for pharma. Failed batches and product recalls can be incredibly costly, in every possible way.

As tech tools become more ubiquitous and important, our focus on quality needs to extend to how they are used. Right now, the industry struggles from a lack of standardized data models. In order to gain the full benefit of nextgen technology, we need an industry consortium or a standards body to help create and provide those models.

Making data more universal would allow for greater understanding across the industry and give manufacturers powerful tools to control quality. It

would also allow companies to share critical safety information without having to reinvent the wheel every time.

Collaborate across the chain

Speaking of sharing through technology, opening collaboration across companies will play a major role in helping avoid dangerous shortages.

The pandemic showed us the weak spots in our supply chains. Many pharma companies were unable to produce at any volume because shipments from other countries — where the raw materials were produced — suddenly stopped.

Ensuring the robustness of your supply chain all the way from the raw materials to packaged products has become a critical conversation. Many are proposing challenging and politically charged solutions, including repatriating the supply chain.

Whatever comes of those efforts, it’s clear that when companies within the chain can work together, they see better outcomes. Creating that level of collaboration is a tall task, as companies generally operate on different systems and can be adversarial due to competitive situations. But we must cultivate a spirit of partnership and a willingness to share necessary data.

Increasing throughput while maintaining quality at the same or lesser cost is where pharma companies need to focus on in the next few years. Embracing technology, cementing the principles of safety within the process and fostering collaboration are steps that will help get us there. 

Nick Armstrong Senior Director of Digital Enablement, CAI

Pharma manufacturing in the (virtual) clouds

Digital twins are a valuable tool for bringing the pharma industry into the future

The management and upkeep of a pharma manufacturing facility is a challenging task. Complicated machinery must interact seamlessly, and errors in the process must be immediately flagged to ensure patient safety. Add to that the fact that many drugs for the U.S. market are being produced in India and China, creating a barrier of visibility into plant construction and ongoing operations. Drug shortages in the U.S. have reached an all-time high, and many of these shortages can be attributed to manufacturing issues. Now more than ever, increased collaboration and visibility on a global scale are critical to support optimal facility operations and speed the safe development and delivery of lifesaving treatments.

Fortunately, technological advancements allow the industry to keep up with this challenging landscape. One such groundbreaking technology is digital twinning, which creates virtual counterparts of manufacturing facilities that are fed data in real time from the facility, enabling monitoring, auditing, forecasting and simulation.

Visit facilities from anywhere

Digital twinning is the virtual representation of a physical location. These digital twins can be configured to include real-time data to perfectly sync with the physical space. This allows users to explore the facility space from their computer screen. For example, digital twins can be used in industrial real estate. By creating a virtual replica of the space, potential

pharma manufacturing plants can be mapped out in advance to ensure the space will meet the production needs and optimize the factory layout.

However, most of the benefits of creating digital twins are seen in facilities that are already operational. Digital twins allow experts across the organization, from engineers to data analysts, to collaborate on a single platform, regardless of geography.

their issues through the twin, giving a precise location and full context. This significantly streamlines efforts to address an issue by ensuring that repair personnel have all the pertinent information while automatically generating a record of factory events.

Digital twins can also be designed to incorporate AI and machine learning tools for data analysis. The real-time data generated by monitoring the

The FDA has indicated that digital twins would be a welcome supplementary technology for auditing facilities, particularly for those outside the U.S.

Access to a digital twin will benefit those outside the company as well. For CDMOs, the creation of a digital twin provides customers the ability to monitor the progress of their projects. The FDA has also indicated that digital twins would be a welcome supplementary technology for auditing facilities, particularly for those outside the U.S. According to FDA Commissioner Robert Califf, digital tools have recently allowed the FDA to check in on facilities in between inspections, minimizing chances of errors and subsequent delays.

Benefits beyond remote access

The benefits of digital twins are not exclusive to remote work. When issues or concerns appear on the factory floor, digital twins enable workers to escalate

factory in a virtual space can provide valuable input for optimizing a given process. Using the real-time data collected by the virtual twin, processes can be accurately characterized and fed to machine learning algorithms to uncover methods for making the system more efficient.

A future-facing tool

Digital twins are an exciting advancement in pharma manufacturing that benefits a company’s employees, customers and auditors. They foster collaboration on a global scale, while simultaneously streamlining communication and optimizing key processes. When properly implemented, digital twins can be a valuable tool for bringing pharma manufacturing into the future. 