Suzanne Shelley is contibuting editor to 

Suzanne Shelley

Drug manufacturers involved in the production and dissemination of time- and temperature-sensitive specialty biologic medications, cell and gene therapies (CGT), and other personalized medicines have a lot on their minds, as they ponder factors that could disrupt their various supply chains at any given moment. Considerable effort is required to understand, avoid, and quickly ameliorate diverse factors that threaten both the upstream supply chain connecting them with their own vendors and supply partners, and the downstream supply chain that feeding their distributors, wholesalers, clinical trial settings, physician offices, and ultimately, patients.

Consider the strong growth in CGTs, just one sector of the overall biologics market. As of early 2023, 27 CGT products have been approved for use in the United States, according to FDA, and a handful more have been approved already in early 2023 (1). CVS Health (2) projects 15 new CGT products will be approved in 2023 (including the first expected gene therapy for sickle cell disease), and 17 more in 2024 (including therapies for Duchenne muscular dystrophy, DMD).

Robust, resilient supply chains are important not only to support commercial-scale production, but far earlier during the clinical-development process, as well. Today there are more than 1500 clinical trials for CGTs registered within ClinicalTrials.gov—across many disease categories including oncology, rare diseases, regenerative medicine, and more. This signals great potential for patients—and growing complexity of the sophisticated supply chain infrastructure. “Strong, swift growth in this sector is also creating increased, parallel demand on upstream suppliers, which may lead to longer lead times for delivery,” says Alexander Aust, principal/owner of pharmaceutical consultancy, Aust Business Solutions. “This must be factored in by drug sponsors.”

“Manufacturers are always concerned about large orders of hundreds or thousands of kilos of critical ingredients at a time, but shortages or delays in lower-volume materials that are key to the manufacture of lifesaving biologics can still shut down an entire plant and create disruption,” notes Jim Luchsinger, vice president, business development and international distribution for Spectrum Chemical Manufacturing Corp.

“The most pressing source of risk in the timely production of biologics is manufacturing readiness including material readiness,” says Sigma Mostafa, PhD, senior site head, KBI Biopharma, a global contract development and manufacturing organization (CDMO) and manufacturer of APIs. “To address the risks our clients face and allow them to be able to take drugs to the clinic as quickly as possible, it is of the utmost importance that we maintain our own manufacturing schedule.”

During the pandemic, lead times for many standard materials went from less than a month to over 12 months, says Mostafa. Such uncertainty “created considerable upheaval to our own manufacturing schedule and forced us to slow down the cadence of runs for a short period and pivot to finding and cultivating as many alternate vendors as possible for a given product.”

To hedge risk, she says that the company ended up placing orders with multiple suppliers at a time. “In some cases, we identified smaller manufacturers further upstream (that had been suppliers to our original suppliers), and we even started to switch to raw materials and processes in favor of those that were more widely available during the process-development phase,” Mostafa continues.

“Setting up a robust material requirement planning (MRP) process is one important way for suppliers to meet their pharma customers’ drug-development and manufacturing needs and help to reduce risk,” says Mostafa. For a CDMO with a large early-phase pipeline and a considerable number of complex molecules, determining the full bill of material (BOM) a year ahead can be challenging. “Nonetheless, during the pandemic, we took action to strengthen our MRP process and our tech-transfer workflow to be able to complete 95% of the BOM well ahead of time.”

Similarly, by considerably improving material demand planning and safety stock determination process—while consolidating its own global materials demand database to allow for quicker identification of available inventory within our own network—Mostafa continues, “We have been able to transition to a leaner inventory while still retaining our agility to respond to client needs.”

The reliable supply of APIs, excipients, and critical components (e.g., vials, stoppers, tubing, filters, aseptic bags, specialized temperature-controlled packaging) is subject to disruption at any moment because of workforce shortages, weather events, geopolitical tensions, mechanical failures, fire or flooding, cyberattacks, quality or regulatory issues, transportation issues, and other risk factors that may impact suppliers. To manage risk, producers of biologics (and their third-party CDMO partners) must be imaginative during strategic planning exercises and contracting efforts with suppliers—running many ‘what if’ scenarios to develop an accurate assessment of both obvious and non-obvious sources of risk.

A regular review of best practices that are emerging among competitors, along with increased use of state-of-the-art modeling that can support improved demand forecasting, should be part of any winning risk-reduction strategy. “Biopharmaceutical companies rarely have the luxury of extra time,” says Aust. “Supply chain interruptions create costly and painful consequences for drug manufacturers that are not prepared. Long lead times could delay or interrupt clinical trials, threaten the regulatory filing, and lead to shortages in commercial therapies.”

“One of the challenges many manufacturers have is that they don’t always get transparency from upstream suppliers in terms of where their chemicals are coming from,” says Luchsinger. “A lack of transparency can compound risk because many materials come through multiple layers of the supply chain.”

How many suppliers is enough? While intuitively there is often benefit to be gained from simplifying and streamlining any complex supply chain to reduce the number of players, many experts agree that reliance on a single vendor for mission-critical supplies or components is never wise.

While supplier redundancy certainly makes sense, “many biologics manufacturers are still making the mistake of having one company designated as primary and all others as secondary,” says Luchsinger. “A better practice is to designate two primary suppliers. That way, if there is an issue arises with one supplier, the other can hopefully jump in to make up the temporary shortfall in supply with little to no lag time in the event of two scenarios—either a surge in demand on the part of the drug sponsor, or a supply interruption from one of the suppliers.” Increased use of domestic suppliers can also help to streamline the rigorous documentation that is required by various regulatory bodies worldwide when suppliers have many different countries of origin.

However, adding a secondary source brings its own challenges. “With materials that have unique traits, there may be only one type of supplier approved,” Luchsinger continues. “Approving a second source of supply within the realm of biologics is certainly more challenging compared to basic chemicals, which tend to have a relatively straightforward set of specifications.” Given the complexity, the objective for drug makers should be to identify and qualify new sources of supply and straighten out all of the non-disclosure and other agreements as early as possible, he adds.

Meanwhile, vertical integration is another way that some CDMOs are working to increase overall visibility and reduce the potential for supply chain surprises. For instance, in recent years, science and technology innovator Danaher has acquired both Pall Corp. (a maker of specialized filtration, separation, and purification systems), and Cepheid (a molecular testing and diagnostics company). Danaher also acquired Integrated DNA Technologies (which develops, manufactures, and markets DNA products to support the life sciences industry), and Cytiva (which offers products and solutions that allow for the development and scaling of biomanufacturing operations), and many more, with a goal of keeping under one roof critical suppliers that support steriledrug development.

“When planning for safety stock inventories, drug sponsors must take into account total lead time required, so that items can be replenished in an efficient manner without creating potential disruptions in production,” says Aust. “Since supply planning is a function of demand planning, the need for visibility up and down the supply chain is essential.” He notes that electronic quality management systems (eQMS) from competing vendors can help drug sponsors keep track the status of all raw materials and integrate product demand signals, but also be alerted to audits, deviations, and status updates and more from suppliers and other vendors.

When it comes to kicking the tires with critical suppliers and third-party CDMOs, biologics manufacturers should carry out regular audits and inspections. “The goal is to verify their quality systems, to be sure they have their own contingency planning in place, and to ensure that all quality systems are robust,” says Aust. Importantly, when partnering with key suppliers or a CDMO, Aust recommends drug sponsors establish three critical documents—a Business Continuity Plan (which specifies the supplier’s own business-interruption plans), a master service agreement (which specifies all agreed-upon terms and conditions), and a quality agreement (which is a legal document that outlines when the
supplier or contractor must report a certain deviation, how long that company have to deliver a batch, and how often the drug company can go onsite to carry out its own GMP qualification and quality testing).

When it comes to CGTs, the downstream supply chain that connects these highly personalized therapies with patients is fraught with peril and calls for the right mix of high-tech and high-touch support considerations. For instance, there is zero tolerance for failure in any one of the discrete, yet tightly intertwined steps required to produce autologous (“vein-to-vein”) CGT products that are customized for a single patient using blood or tissue extracted from them as the first step of the process.

Each step requires tight coordination and handoffs among parties, all the while working to ensure proper temperature-controlled packaging and swift transportation to reduce delays and temperature excursions that could spoil the high-value product.

When it comes to allogeneic (“off-the-shelf”) CGT products, even greater logistical planning is required. This involves scheduling the collection of the starting materials from the designated donor, delivery to the manufacturing site and then interim storage and distribution to multiple, geographically disparate patients—each of whom must also be scheduled to receive their therapy infusions in different clinical settings. Each step involves specialized packaging and shipping requirements, with robust chain-of-custody and chain-of-identity documentation. With allogenic CGTs, there is also a need to plan for multiple interim temperature-controlled storage, time- and temperature-sensitive transit legs to reach each of the multiple, geographically diverse recipients.

Advanced monitoring and tracking systems that track individual shipments to the individual vial and individual patient and provide user-friendly dashboards to all stakeholders en route help to increase real-time visibility into location, temperature, time in transit, and more. Today’s state-of-the-art data-analytics capabilities help stakeholders to coax actionable insights from the real-time data and identify weak links and potential vulnerabilities with enough time to act upon them.

Just as important is the rise in the use of outsourcing of critical functions. The right third-party partners bring to bear their own specialized expertise and infrastructure to provide end-to-end coordination of services for every dose and every patient. This option is especially useful for smaller companies that lack the financial resources and managerial and tactical bandwidth to manage all of the complexity on their own.

“Working with a specialized service provider to deliver dedicated case-management services for complex supply chains—to take advantage of their scale and scope, as well as established relationships with multiple premium couriers so sponsors don’t have to navigate this—can reduce strain on the pharma company’s limited internal resources, and enables greater program scalability, as the number of indications, patients, and clinical settings continues to add complexity to the overall picture,” says Trish Demko, director of case management services for Catalent Clinical Development and Supply.

When the service provider takes responsibility for the downstream supply chain for CGT products, “we will have already identified multiple backup plans ahead of time and have the infrastructure in place that enables a quick pivot when any situation arises.” She continues, “We’re doing the heavy lifting—managing all steps from scheduling of starting material collection to delivery of the finished therapy for infusion—so pharma and biotech companies don’t have to navigate this on their own and can instead continue to focus on the science and ongoing innovation while still knowing that the product is in good hands at all times.”

By leveraging this specialized service, customers retain complete visibility at all times, knowing that a dedicated case manager is always on call 24/7 for emergency response and issue resolution. “This service is critical because many pharma and biotech companies may not have sufficient resources, experience or long-term relationships with courier services to confidently manage these complex logistics on their own—and may not be comfortable managing these shipments given the potential impact on the patient if the therapy is not received in time,” says Demko.

“Outsourcing supply chain management to an experienced service provider can provide peace of mind,” Demko adds. The goal is to expect the unexpected and then plan accordingly.

FDA. Approved Cellular and Gene Therapy Products. 

CVS Health, White Paper, Gene Therapy Pipeline 3Q 2022–1Q 2027: Projected Treatments and Approval Timelines.

Suzanne Shelley is a contributing editor to 

When referring to this article, please cite it as Shelley, S. Reducing Vulnerabilities in Upstream and Downstream Supply Chains. 

Articles

Makers of specialty biologics, gene therapies, and other personalized medicines are working to identify and reduce potential supply chain risks both upstream and downstream.

Reducing Vulnerabilities in Upstream and Downstream Supply Chains

Pharmaceutical manufacturers maintain complex, global supply chains with both upstream suppliers and downstream distributors and customers. With so many factors shaping the landscape—ranging from the pandemic, volatility in raw materials, finished products and labor, to delays created by shortages and bottlenecks in the transportation infrastructure, to the unavoidable disruption that can arise from weather events, inflation, trade wars, and geopolitical unrest—it’s something of a miracle that pharma-related raw materials and finished products ever reach their destination on time and on budget.

“The pharma industry is in better shape today than it was at the height of the [COVID-19 pandemic],” says Anne Marie O’Halloran, managing director, global supply chain/IX.O life sciences for Accenture. “The level of collaboration across partners and public and private sectors helped the world overcome a once-in-a-century pandemic.” Nonetheless, she notes that “the past few years have also brought to the forefront the need to build improved supply chain and business resilience.”

“I think that we’ve gotten through the worst of it together as an industry, but I have more concern today than I did a year ago about the various types of risks that threaten to create supply chain disruptions for pharma stakeholders,” adds Tommy Pourmahram, vice president, multi-source products and analytics for McKesson.

Rising costs. “For pharmaceutical manufacturers, the rising costs of raw materials is a really big deal,” says Anshul Agarwal, principal at ZS Associates. “In recent years, API costs have almost doubled while the costs of excipients have tripled in some cases. The impact becomes even more of a pressing concern for generics manufacturers, as the slender profit margin can threaten to shut down production.”

Drug shortages. At the end of 2022, 160 drugs were in active shortage in the United States—the highest number since 2014 (48% of them injectables), according to the University of Utah Drug Information Service (UUDIS), which tracks such data (1).These shortages include antimicrobials, central nervous system drugs, fluids/electrolytes, ophthalmology medications, and hormones. According to UUDIS, the main factors to blame included manufacturing or business decisions, regulatory issues, raw material issues, and supply/demand imbalance.

“The number of shortages is currently higher than it was during the height of the COVID-19 pandemic in 2020 and given the pricing pressure on generic manufacturers and the limited number of reliable API suppliers, this number of shortages will continue to grow,” notes John Bermudez, vice president of product marketing at TraceLink.

“I’m highly concerned about generic injectables right now,” says Pourmahram, who notes that unfavorable pricing dynamics and increased competition impact all manufacturers of generic medicines, because simply raising prices to account for rising costs isn’t really an option. “Facing tight margins, a manufacturing line that can switch between making Product A or Product B may cause the manufacturer to simply exit one market altogether and that can create shortages,” Pourmahram explains.

Regulatory uncertainty. Regulatory scrutiny creates another source of supply chain risk, and many sense a Sword of Damocles hanging over the head of the industry right now. Pourmahram says: “It is interesting to note that the pace of site inspections from the [FDA] has been falling, due to both the pandemic and other factors, and there’s been a huge drop in inspections of foreign facilities.” For instance, across all regulated products, the number of domestic inspections dropped from 14,725 in Fiscal Year 2017 to about 4500 so far in FY 2022, and the number of foreign inspections dropped from, 3166 in FY 2017 to 135 thus far in FY 2022, according to FDA’s Inspections Data Dashboard (2).

“FDA is beginning to pick up the pace, having conducted 97 foreign inspections in the first two weeks of January 2023, so this year may be the first since 2019 when we see a thousand or more inspections in a year, and this is bound to be another factor impacting supply chain volatility,” says Pourmahram. “As a whole, the industry is bracing for what they are going to find when more inspections are carried out and inevitably lead to the discovery of sterility issues, cross-contamination, and compliance breaches that may lead to shutdowns.”

Any shutdown creates a ripple effect, particularly if the manufacturer produces significant market share of a given product. “There is often not a surplus supply just sitting around—rather, it can take three to six months for another facility to ramp up production to meet a sudden shortfall,” notes Pourmahram.

“As a distributor, we maintain strong relationships with multiple manufacturers and multiple transportation companies and parallel distribution centers, and we work closely with our downstream customers to ensure that our inventory matches their needs, and that there is enough inventory to reallocate, as needed, to ensure the most equitable distribution when shortages do arise,” says Ammie McAsey, senior vice president, customer distribution experience, US pharmaceutical, for McKesson.

“However, it just doesn’t make good business sense to build up a ton of inventory to meet a potential shortfall that may or may not come,” McAsey continues. “Rather, it’s also important to continuously identify new sources for products, and to develop relationships with as many vendors as possible and build good working relationships.”

For instance, McAsey says, “with the right data signals and inventory
planning, when we see a flu outbreak starting in the western part of the US, we can quickly redirect inventory to push it out to field distribution
on the west coast and get the inventory on trucks or planes in a matter of hours.” And when related data flows back to the manufacturers, they are able to quickly respond to such
demand spikes, too, helping to reduce the likelihood of a shortage.

“The focus on building increased resiliency into the supply chain aims to give stakeholders the ability to both minimize day-to-day risk and absorb, adapt to, and recover from catastrophic disruption whenever and wherever it strikes,” adds O’Halloran of Accenture. “This requires managing and adapting to unknowns across the spectrum of risk—operational, tactical, and strategic.” Proven tactics include scenario planning, modeling, simulation, and risk/opportunity analysis.

Blind spots in digital connectivity. “Fortunately, many stakeholders throughout the pharma landscape are more prepared (both mentally and systematically) than they were during the worst of the pandemic, so there’s less need for triage,” Agarwal says. Some of this improved preparation, he notes, has been the result of enhanced data collection, and investment in the use of artificial intelligence and machine learning modalities to enhance prediction of shortages and enhance inventory planning.

“The competitive advantage in connecting the data end-to-end is the ability to then build predictive and prescriptive modeling capabilities onto that foundation, and all of the relevant supply and demand data can be accessed from a central place,” Agarwal continues. “The ‘Amazons of the world’ are doing it, and the pharma industry needs to catch up.”

Geopolitical risk. “Today, an estimated 80% of drug [APIs] come from two countries—China and India,” says Bermudez. “Shipping disruptions, trade wars, another pandemic, and other factors that disproportionately impact these two countries could have a devastating impact on the ability of Western pharma companies to reliably produce lifesaving medications.” Compounding the risk, he adds that too many pharma companies are also sole sourced from specific suppliers in these regions.

“Today there is additional pressure (and government incentives) to encourage manufacturers to bring manufacturing of certain essential raw materials and finished products back into the US,” adds Agarwal. “However, while this is [a] positive, stabilizing trend, we anticipate this may create short-term shortages in terms of labor, raw materials, and other limited resources. This could create additional costs and temporary shortages.”

Labor shortages. “When you think about talent and labor shortages, especially in supply chains that require highly skilled people, not having the right people to react decreases your ability to mitigate risk,” says Bermudez. “If you are short on personnel, you can only respond to so many disruptions—or perhaps you can’t respond at all.”

Through a collaboration, Accenture and Massachusetts Institute of Technology (MIT) co-developed a supply chain resilience stress test, which enables organizations to assess operational and financial risks created by significant market disruptions, disasters, or other catastrophic events and use the findings to identify appropriate mitigation strategies. “We have found that leading supply chain organizations build resilience through visibility across two dimensions—structural and dynamic,” explains O’Halloran. “Together they help companies to see where they might be vulnerable to disruption and prepare for or bounce back quickly from a crisis.”

Using structural visibility, companies can see a snapshot of their operations at a point in time or over a certain period. “This helps them to uncover hidden issues and better understand such factors as supplier location, points of manufacturing, logistic routes and more, and monitor and respond to events in real time with dynamic visibility,” O’Halloran continues. This can help improve data-driven decision making and help prioritize ongoing investments.

“What we have found is that while structural visibility may be relatively mature, dynamic visibility capabilities could be better for many companies,” O’Halloran continues. “Most of the executives we talked to reported they are strong in the first two stages—monitoring and predicting, but only about 40% said they use data prescriptively, and almost all companies are unable to
execute autonomously.”

Additional best practices have begun to emerge to bolster supply chain continuity.

Build improved visibility through increased monitoring and data integration. “Increasing visibility through monitoring, data integration, and collaboration is the number one way to reduce risk in the supply chain and improve supply,” says Bermudez.

“While investment has been increasing in enhanced digitization, and that’s a good thing, much of the data still remains siloed,” Agarwal continues. “When it comes to true end-to-end connectivity, the industry is making progress but there is so much more work to be done to improve connectivity and enable true visibility. The good news is that many companies that have been talking about this for years are now moving it to the front burner.”

Balance the need to be lean with the need to stockpile inventory. “Unlike some other industry sectors, the pharma industry has not pushed hard on lean or just-in-time inventory management because ensuring patient access to medications is too important,” says Agarwal of ZS Consulting. “But now that raw materials have become more expensive, so companies must be more strategic about how to optimize the amount of inventory they maintain, in the most strategic amounts and locations, to reduce risk.”

“Ultimately, many companies are stuck in the old way of doing things, thinking that if you have two years of inventory, everything will work. But in a pandemic, two years of inventory can run out in two weeks, so that’s not the answer,” adds Bermudez. “The answer is that while you can’t predict what will run out quickly, you must do what it takes to build a more agile supply chain that is able to react more quickly.”

“I’m feeling optimistic—the healthcare supply chain is stronger than it ever was,” says McAsey of McKesson. “Many factors are out of our control, but all of the work that has been done over the past few years (upstream, downstream, and laterally), and the fact that more than ever, competitors are willing and able to work together as needed to take care of the patient, has helped us to bridge a lot of gaps.”

“We’ve bridged a lot of gaps, and Healthcare Distribution Alliance (the trade association that represents pharmaceutical distributors) has really helped us come together as an industry,” she adds. “After [COVID-19], distributors and manufacturers understand the importance of collaborating to do whatever is necessary to deliver vital products to patients.”

American Society of Health-System Pharmacists. Drug Shortage Statistics. 

Eglovitch, J.S. Experts Say FDA Enforcement Focus Unchanged, Use of Alternative Tools to Grow, 

Regulatory Focus, a Regulatory Affairs Professionals


Vol. 47, No. 3
March 2023
Pages: 45–47

When referring to this article, please cite it as Shelley, S. Taking Steps Toward Supply Chain Continuity. 

Editor's note: This article was updated on March 21, 2023 to clarify a comment from Ammie McAsey of McKesson. 

Stockpiling excess inventory is no longer enough to respond to supply chain volatility. 

Taking Steps Toward Supply Chain Continuity

The coordinated steps required to safeguard biologic medications, vaccines, and personalized cell and gene therapies (CGTs) from the moment they begin the journey from origin to destination are notoriously complex. Many best practices and lessons learned have emerged in recent years as pharma/life sciences companies, along with their third-party logistics partners and vendors that supply specialized packaging and monitoring solutions, have all weathered the COVID-19 pandemic together and continued to support ongoing growth in the pipeline of therapeutic products that must be continuously maintained at refrigerated, frozen, or ultra-frozen temperatures.

There is no room for failure if any of these high-value—and increasingly one-of-a-kind—therapy options are allowed to experience temperature excursions. “Especially when it comes to autologous CGT products, the need to track the shipment from the donor patient to the processing center (laboratory or manufacturing location) and back to the patient is of paramount importance,” says John Bermudez, vice president, product marketing, TraceLink.

“What really complicates CGT shipping in particular is that these high-stakes shipments must be customized for smaller-sized, highly individualized parcels,” notes Shea Vincent, senior marketing director of BioLife Solutions. “With some of today’s gene therapies priced at $1, $2, or even $3 million, failure is not an option during distribution.”

While the industry has learned a lot during the steep and fast learning curve imposed by the pandemic, and many of the lessons learned are now routinely being applied to optimize the shipment of both larger-volume biologic products and vaccines and smaller-volume CGTs, “the reality is that the tactical implementation of these specialized supply chains for CGT products has yet to be fully established on an industry-wide scale,” says Vivian Berni, director of product management and strategic marketing for Sonoco ThermoSafe. “This leaves a significant burden on manufacturers of today’s cell-based products to distribute their products reliably. Unknowns cause doubt, uncertainty, and risk—and these are not friendly ingredients in a discipline that strives for repetition and predictability.”

“There are already a lot of capabilities in place—experienced cold-chain couriers, state-of-the-art insulated containers, the ability to track and monitor with reliable, cost-effective sensors—so it’s more about pulling the right mix of the elements together in the most strategic and effective way to maximize visibility and minimize the risk,” says Bermudez.

Cold chain planning and execution “… continues to be impacted by not only the pandemic but by other factors, such as air cargo capacity being down, instability related to inflation, the Russia/Ukraine conflict, and more, but despite it all, you still have patients depending on what you’re delivering,” notes Rob Coyle, senior vice president, healthcare strategy, Kuehne+Nagel. As such, he says that stakeholders handling high-end CGT products “need to be really honest about the risks and plan for them ahead of time. Developing a robust backup plan (and having all parties agree to it) ahead of time allows for seamless pivot and rapid response should any delay arise en route.”

For many routes, it makes sense to use passive shipping containers, as they require no power infrastructure, have a more favorable carbon footprint, and can often provide a lower-cost option if appropriate. “With careful planning, we’re often able to replace active shippers with passive units by leveraging existing infrastructure, ongoing advances in insulation materials, phase-change materials (PCM), and container designs, using advanced GPS and other monitoring devices to ensure continuous access to real-time location, temperature, and other data,” adds Scott Ohanesian, senior vice president, commercial operations, QuickStat, a Kuehne+Nagel company.

“Those handling temperature-sensitive pharma products and biologics have experienced a lot of frustration over the past few years due to strategic shortages and supply-chain issues related to dry ice, liquid nitrogen, and the types of specialized packaging that is needed,” says Vincent. “Fortunately, newer materials such as advanced insulation materials and PCMs that continue to come to market are setting up the industry for a better, more reliable future.”

PCMs are engineered materials—based on paraffins, fatty acids, alcohols, hydrated salts, and more—that are conditioned to the refrigerated or frozen setpoint temperature at the outset and placed inside the specialized transportation container. They are able to store and release energy (undergoing a change in phase as they are warmed and cooled) as needed to maintain the critical setpoint temperatures inside the passive thermal containers throughout the trip. Meanwhile, to ensure dock-to-dock shipping integrity, Vincent says it’s important “to develop a backup plan and to ensure that all stops on the trip have sufficient ultra-low-temperature (ULT) storage capacity, or the ability to access more dry ice or recondition the PCM.” She notes that the planning gets more complicated when the customer will be shipping product by the pallet but then dividing the pallet to repackage smaller volumes to ultimately reach many different destinations.

“The Holy Grail for the pharma cold chain is ‘how do I get perfect service at a more economical price?’” says Dan Gagnon, vice president of global strategy for UPS Healthcare. Economies of scale and tighter overall integration can help to coax out some unnecessary expenditures.

A particular challenge is that the end-to-end distribution of biologics often requires handoffs among multiple partners using disparate systems, and this creates unnecessary complexity. “Today, existing tools can be used to reliably track individual shipments, but the challenge is that it has to be coordinated with actual patients and the labs that process the cells,” notes Bermudez. “The ability to closely coordinate all handoffs improves visibility and gives timely alerts when a shipment has gone out of temperature range or needs intervention.”

In other cases, pharma/life sciences stakeholders producing biologics and CGT products enlist multiple vendors and partners to create complex end-to-end distribution routes. “Stakeholders should choose partners who take a consultative approach,” says Amy DuRoss, president, cell and gene therapies, CSafe Global. “They can help to identify the challenges ahead of time and address them effectively when they do arise.”

In recent years, UPS Healthcare “has made its mission to streamline and integrate the pharma cold chain as much as possible, bringing as much of the end-to-end capabilities—in terms of storage capacity, ocean, ground, and airline networks—in house as possible to maximize quality and visibility,” says Gagnon. “Any time you can remove a handoff between two parties it dramatically reduces the risk of excursion, and our singular, unified system uses the same systems and similar training for all personnel, which provides a complete end-to-end cold chain under one roof.”

In November, UPS Healthcare acquired global healthcare logistics provider Bomi Group, helping to expand its footprint across Europe and Latin America. UPS Healthcare customers now have access to 216 facilities with 17 million square feet of current good manufacturing practice and good distribution practice-compliant healthcare distribution space in 37 countries and territories.

“Scientific advances are always ahead of the regulatory frameworks, so logistics providers need to work closely with regulatory authorities when it comes to CGT distribution,” notes Ohanesian. For example, delays in Customs vary from country to country and can chip away at the limited window for which packages transporting biologics and CGT products is guaranteed to remain at its setpoint temperature. “Customers often make a packaging choice and get locked in, so they don’t really consider qualifying newer packaging options—we see that a lot,” adds Coyle.

For instance, Ohanesian says, “If your quality team has already qualified a particular technology that can ensure the setpoint temperature is maintained for three days, but there exists an option that can maintain it for eight days, you need to consider making the switch.”

“One of the challenges associated with competing technology options is that you need to keep investing in new technology, but you can’t just get distracted by every shiny new technology solution,” adds Gagnon. “You have to critically evaluate which technology advances will bring significant value to customers and focus on which offerings are likely to still be around in the years to come.”

Despite ongoing innovation in supply chain traceability, real-time tracking, and enhanced visibility, DuRoss says, “we urgently need solutions that simplify and standardize CGT operations so that this field can scale. High complexity often translates to higher-than-necessary costs, which results in fewer patients being treated.” To achieve mass adoption within the CGT space, “we need to both industrialize and personalize in parallel,” she continues.

 “Having a comprehensive commitment to quality is a winning strategy and putting the systems in place now can save you a lot of headaches later,” says Gagnon. Meanwhile, in all partnerships, specific elements (such as hardware, software, service, and more) must go through consistent qualification and validation processes and be demonstrated as suitable for use in the regulated environment, notes Emanuel Schäpper, head of global business management for ELPRO. Coyle adds, “If you don’t have detailed standard operating procedures (SOP) and quality systems in place, and enforce that each of your partners implement them, too, it will open you up to human and process error.”

 “Not all technology, tracking devices, and packaging options work across all networks, locations, or applications,” adds Berni. “Understanding the constraints of each option helps all parties to manage expectations and set things up for success.”

 “In response to the COVID pandemic, we developed a passive parcel ULT shipper that can transport and store mRNA [messenger RNA] vaccines at a range of -60 °C to -90 °C for up to 30 days, and it has been used to reliably ship COVID-19 vaccines to 180 countries,” says DuRoss of CSafe Global. “We must leverage all of the global COVID-19 learnings and solutions to enable scaleup in CGT.”

When it comes to container designs, insulation, and PCM materials, monitoring, and control systems and versatile cloud-based solutions to enable greater visibility, stakeholders should keep up with ongoing advances and be willing to embrace best-in-class solutions, rather than becoming locked into a particular solution. “The entire chain is only as strong as its weakest link,” says Schäpper.

Choose monitoring and tracking devices carefully.

 “From the perspective of a suitable monitoring solution, care must be taken to ensure that the operability of monitoring devices [is] user-friendly and easy to understand, especially in the case of extensive, global distribution networks,” says Schäpper. “The operating elements must be clear, and the display must provide unambiguous information about the status of the product or the measurement parameters.”

Engage logistics partners and vendors as early as possible

“The more we can get critical information earlier in the product lifecycle, the better we can design systems to optimize each of the steps. This has been one of the biggest learnings in recent years,” says Coyle. Similarly, Berni adds, “Involving packaging providers and logistics partners in the discussions early on enables a more cohesive overall strategy. I cannot emphasize this enough; start the conversation early with all of your partners—don’t wait.”

 “You can’t adequately support CGT patients worldwide when you have cold chain service centers in just a few locations—for instance, you can’t support and service the distributed global CGT infrastructure if you operate just a few locations in North America and Europe,” says DuRoss.

“More than ever, these two teams—which formerly functioned largely independently of one another—are working hand-in-glove from the earliest phases of drug development, and that’s the way it should be,” says Coyle. “We’re still in the infancy of the era of high-end biopharma and personalized medicine, and while we’re already learned so much, there’s still so much more room for ongoing improvement to minimize the risk of product damage and ensure patient access to these high-value, lifesaving therapies,” says Coyle. As the pharma/life sciences pipeline of biologic therapies, vaccines, state-of-the-art CGTs, and other gene therapies continues to grow, so does the need to push for ongoing innovation in the technologies and practices needed to safeguard them during shipping and storage.


Vol. 47, No.2
February 2023
Pages 20–21, 28

When referring to this article, please cite it as Shelley, S. Safeguarding Biologics—Blending Engineering Ingenuity and Managerial Excellence. 

Efforts to optimize the delivery of sensitive biotherapeutics continue to evolve.

Safeguarding Biologics—Blending Engineering Ingenuity and Managerial Excellence

It has become painfully clear in recent years that potential supply chain disruptions across all industries have become more the rule than the exception. Such disruptions arise when manufacturers experience short-term or prolonged shortages in raw materials, packaging materials, and/or critical components and are then unable to produce a reliable output of finished products or deliver them on time to their own downstream customers.

For pharma manufacturers, such issues increase business risk, create unnecessary costs and product losses, and increase the likelihood of drug shortages. Today, a range of parallel efforts are underway to address them. These include the expanded use of affordable monitoring solutions, increased overall digital connectivity among a larger number of players up and down a given supply chain, and advanced modeling capabilities to make sense of the real-time data. Such efforts aim to analyze and model large data sets using machine learning and artificial intelligence (AI) techniques and other modeling modalities.

“The goal is to develop advanced insights and predictions under changing scenarios to enable earlier, data-driven interventions that can help to avoid supply chain interruptions—before they occur,” says Emanuel Schapper, term leader, key account management, Elpro Global.

“The effort to improve supply chain visibility is essentially an inventory
-management strategy that involves using advanced techniques to improve the allocation and orchestration of products and shipments to achieve better outcomes,” says Vivian Berni, director of product management and strategic marketing, Sonoco ThermoSafe. “Improved visibility allows you to see what inventory is with your suppliers in your distribution center and in your warehouse at any moment—and understand what’s going on with your suppliers and your customers—so you can take the necessary steps to accelerate order fulfillment and exceed customer expectations while keeping operating costs low,” she adds.

“The idea of transparency carries more weight than it did years ago,” Berni continues, adding that such efforts are especially important in the pharma industry, as pharmaceutical companies routinely outsource key segments of the process—such as packaging, logistics, distribution, and more—to third-party partners, amplifying the potential risk of disruption.

“It is essential to map the supply chain both upstream and downstream and to perform a proper risk assessment,” says Ben VanderPlas, director of engineering and R&D, Sonoco ThermoSafe. Meanwhile, VanderPlas notes that establishing regular audits, quality agreements, and standard operating procedures with all suppliers is also essential to reduce risk and eliminate supply chain blind spots.

“As audits uncover issues, each finding should be categorized according to risk (major, minor, recommendation) and an action plan must be developed with the supplier to address each concern,” VanderPlas adds.

“We have all these islands of information and all these people working in the supply chain, but we just don’t share the right information as effectively as we could,” says John Bermudez, vice president, product marketing, TraceLink. “Increased visibility among all upstream and downstream supply chain helps pharma manufacturers detect issues sooner, inform decision making, and enable data-driven interventions to prevent more costly and disruptive problems.”

“[During the COVID-19 pandemic,] the pharma industry got a very rude awakening that the way that companies run their supply chains was not very good,” Bermudez continues. “Historically, many pharma companies used a very basic approach, saying, ‘If we maintain two years of inventory, we’ll always be able to ship on time.’ But during the early months of the COVID pandemic, products for which they had held a two-year inventory ran out in two months. That’s not a very agile supply chain.”

“As the level of global interconnectivity continues to grow among supply chain partners, technical and compliance challenges must also be addressed to ensure data integrity and enable traceability and audit trails,” says Schapper. “More work needs to be done to figure out how we can validate distributed systems, software, and databases, as well as critical supply routes, and whether the current regulations and guidance are still applicable for the possible digitized systems of the future.”

Similarly, increasing end-to-end visibility within a supply chain “[i]s an ever-changing process because new technologies and opportunities are
introduced every day to improve operations and results,” says Berni. “This is not an area of business where you can simply integrate solutions and consider it done.”

“As a packaging manufacturer and service provider that takes possession of critical pharma products while en route, our role is to reduce [the] risk for our pharma customers as time- and temperature-sensitive pharma products are moving through city streets, interstate highways, and international airspace,” Berni continues, adding that today’s innovative packaging options are designed to both secure pharma deliveries and support improved supply chain visibility. The options range from lightweight insulated recyclable shippers to plug-and-play rental services to high-tech air freight containers and containers for bulk transportation.

Real-time monitoring capabilities integrated into cold chain packaging yield insights into what’s potentially going on right now along the route.

“Intervention can be further enhanced by being able to predict the performance over a given route or shipping lane using existing data sets, ultimately mitigating the risk of potential product spoilage,” says Alyssa Roberts, director of global product management, CSafe Global.

State-of-the-art containers are equipped with an integrated telemetry system to provide critical real-time, cloud-based data on both payload and ambient temperature and key environmental factors, precisely synchronized with GPS location while maintaining the payload at the required refrigerated or frozen temperatures, adds Berni.

Increased digitalization helps to connect the dots

Increased investment in supply chain digitalization is essential and can yield many dividends, according to Bermudez. These include improvements in:

Transparency. Improving product availability, change management, and the handling of recalls.

Traceability. Supporting anti-counterfeiting and product diversion effort.

Visibility. Reducing upstream material shortages and downstream shipping delays and help capture key performance trends for ongoing process improvement.

Collaboration. Integrating suppliers more effectively and enable greater operational flexibility.

Sustainability. Safeguarding the business and clinical objectives of both pharma manufacturers and patients over time.

“If—despite precautionary measures being taken—shipping delays still occur, the ultimate consequences will depend on how much data is available to demonstrate relevant product quality,” says Schapper. “For instance, when shipping temperature-sensitive pharma products, access to [real-time] monitoring data related to the temperature, humidity, duration of travel, open-door events, and other factors that could imperil product integrity can help stakeholders to prove that despite the delays, the product stability and quality were not corrupted, which allows the products to still be released for patient use.”

Prewave, a company that specializes in supply chain visibility, has pioneered a data-gathering process to yield timely alerts for stakeholders.

“We analyze the direct suppliers of our clients and map out their supply chain down to the raw material. The data allows us to screen suppliers and generate a risk score,” says Miriam Jonas, industry specialist for pharmaceuticals, Prewave. Specifically, the company’s monitoring system gathers publicly available information about the client’s suppliers, which may range from posts on social media about human rights issues to local newspaper reporting to a regional risk of COVID infection due to a supplier’s particular location.

“We generate risk alerts for these events, which are displayed in the Prewave system,” Jonas continues. “Our customers can then track the types of factors impacting their suppliers and get alerts in real-time to factors that could interrupt upstream supplies—many of which have not been announced by the company.”

“If pharma manufacturers are not aware of, say, multiple fires at a given raw material supplier’s site, the impact on the availability for that commodity could impact the entire supply capacity, and even if the news eventually ripples through the supply chain, having more time to react to it—and pivot to an alternative source for that strategic material—can provide a significant advantage in the long run,” says Jonas.

“We’ve been working with a consortium of pharma companies, and one thing they’ve consistently asked for is the improved capability to use TraceLink data to predict shortages,” says Bermudez.

Toward that end, TraceLink has developed AI-based “collective intelligence capabilities” to analyze just the shipments from pharma companies and the receipts of drug dispensers.

“We’re looking at the mismatch using machine learning capabilities to predict shortages even more accurately to allow for preventive measures to be taken before the crisis,” says Bermudez.

Bermudez emphasizes that, no matter how effective the technology-based elements are, the human element cannot be overlooked.

“The system must alert the right people when things change so [that] they can collaborate with their peers to make decisions that cannot be made with data alone,” says Bermudez.

Consider, for example, the prolonged shipping bottlenecks that occurred in 2021 in the Ports of Los Angeles and Long Beach in California, which created weeks of delays when cargo ships piled up without the resources needed to unload and reload them or the prolonged cargo shipping crisis that resulted after a 2021 shipping accident jammed up the Suez Canal.

“This past spring, supply chain professionals continued to send cargo through these pinch points despite the known extended delays we were all experiencing,” says Bermudez. “We know it can only take 30 to 40 days for a cargo ship from China to reach the US; so, it made no sense to put cargo on ships headed to ports with a 40-70 day backup… Either they didn’t have the required visibility, or they didn’t understand the implications.”

By contrast, freight forwarders with the right visibility could have
redirected many cargo ships that normally go through the Port of Long Beach to Jacksonville, Savannah, Charleston or Oakland, Bermudez adds, which would help to reduce the glut in that port and preventing losses (in terms of missed sales and spoiled products) that resulted when shipments ended up being 40 to 70 days late. But companies can’t be that nimble if they don’t have full insight into what’s going on up and down the supply chain.

Initially introduced to reduce drug counterfeiting and improve track-and-trace capabilities, serialization also plays a growing role in expanding supply chain visibility today, says Bermudez, helping pharma companies to:

Verify product identity and products as they move through supply channels

Develop and deploy rules-based serialized product identity profiles based on business and market needs

Track and manage products across internal packaging and other external partners

Create a single source of truth for critical product, copay, and partner master data across the supply chain

Manage serialized inventory, events, and operational workflows to connect the physical supply chain with the digital network.

“Ongoing barriers are not really related to the available system or technological capabilities,” says Bermudez. “Such systems are coming along, and we are already able to connect tens of thousands of entities to improve overall supply chain visibility.” Instead, Bermudez says that greater commitment is needed across the entire industry.

“One of the biggest barriers to better supply chain visibility is that the industry as a whole has not yet invested the time, resources, or effort that is needed to move to the next level in terms of predictive modeling,” adds Roberts. “Interaction and integration with all the stakeholders in the supply chain are key to be able to use real-time data to inform efforts to avoid disruption and increase overall supply chain integrity and reliability.” 

Suzanne Shelley is a contributing editor at 


Vol. 46, No. 9
September 2022
Pages: 30-33

When referring to this article, please cite it as S. Shelley, “Reducing Blind Spots in the Pharma Supply Chain,” 

Expanded use of data analytics can help to avoid disruptions, but the possibilities cannot be realized without sufficient investment and direct human involvement.

Reducing Blind Spots in the Pharma Supply Chain

Vaccines have been in the news and on the minds of people everywhere in recent years, thanks to the aggressive effort and timetable that was required to discover, develop, and disseminate the COVID-19 vaccines. Meanwhile, developers of other types of pediatric and adult vaccines have continued to advance the manufacturing, drug-administration, and packaging options that are used to support their products.

Vaccines are traditionally packaged and distributed in vials that contain either single or multiple doses. This approach requires the healthcare professional to prepare the vaccine for injection, withdrawing the precise dosage from the vial using a syringe, administering it into the patient, and safeguarding the remaining doses until the vial is empty.

Prescribers and patients alike appreciate safe and easy vaccine administration. Today, of the 900 or so vaccine-development programs that are reported to be in development in Informa’s PharmaProjects database with known route of administration, one quarter are being evaluated in non-injectable formats, including oral, inhaled, and nasal routes, notes Cornell Stamoran, PhD, vice-president of corporate strategy and government affairs for Catalent, and about one third of these non-injectable programs are already in the clinical phases.

“There are also examples of promising R&D activities involving microneedle patches (which deliver the vaccine subcutaneously via a reservoir or coating on the needles), and, potentially, certain vaccines could be dried and stabilized in the microneedles to overcome issues related to logistics and ultracold storage conditions,” notes Vincenza Pironti, PhD, senior staff scientist, research and development, pharma services for Thermo Fisher Scientific. However, Pironti continues, “the regulatory landscape is still unclear about the acceptance criteria of these newer forms, as methods for release are still unclear, but these new modalities can represent potential solutions in the future.”

“Initial theoretical work and early R&D efforts suggest that the transdermal route may work, but more study and clinical trials are required to establish the safety and efficacy profiles and demonstrate benefits of this alternative approach, and then move toward the manufacturing considerations to allow these novel products to reach the market,” adds Stamoran.

In June 2022, Catalent announced it is carrying out a feasibility study with Israeli biopharmaceutical company MigVax, to investigate the possibility of delivering the COVID-19 vaccine to the oral mucosae (for absorption through the mouth and intestines) using Catalent’s proprietary Zydis Bio orally disintegrating tablet (ODT) technology, which creates a freeze-dried tablet that disperses in the mouth without water (1).

MigVax’s lead oral vaccine program for COVID-19, MigVax-101, which would be transported using the Zydis Bio ODT in unrefrigerated vehicles and stored in standard warehouses, “has shown positive results in preclinical tests,” said the companies at the time of the announcement. MigVax is also working with the Coalition for Epidemic Preparedness Innovations (CEPI) to develop oral tablet vaccines that are broadly protective against both SARS-CoV-2 variants and other coronaviruses, such as severe acute respiratory syndrome and Middle East respiratory syndrome.

Early work is also underway to pursue intranasal vaccines for COVID-19. Today, several dozen companies are at work, exploring not just aerosolized sprays but also nasally administered drops, powder, and gels (2).

Catalent, “Catalent and MigVax Sign Agreement to Develop an Orally Disintegrating Freeze-Dried Tablet Vaccine Against COVID-19,” Press Release, June 7, 2022.

A newer alternative—prefilled syringes (PFS)—has continued to gain favor among vaccine manufacturers and healthcare providers, thanks to several demonstrable advantages. During manufacturing, PFS are prefilled with a single dose representing one vaccination, in accordance with good manufacturing practices (GMPs).

“Today there is very strong preference among physicians and patients that if a therapy or vaccine can be supplied via PFS, it should, and the tangible results the PFS brings—where applicable—can create strategic marketing opportunities for drug makers,” says Cornell Stamoran, PhD, vice-president of corporate strategy and government affairs for Catalent. He is also a co-founder and co-chair of Catalent’s Applied Drug Delivery Institute, a research and advocacy arm founded in 2012 that explores how advanced drug delivery options can improve patient outcomes.

“Globally, PFS currently account for approximately half of the total market for prescription-based vaccine volume in the Americas and Europe, according to IQVIA’s MIDAS database,” notes Stamoran. (Note: The MIDAS database reflects vaccine doses that are dispensed with a prescription in retail or hospital settings, so the COVID-19 vaccines and other public-health-administered vaccines are not fully reflected in that data set.) Stamoran adds, “However, across the rest of the world, vial-based vaccines still make up the majority of the volume dispensed.”Thus, there is plenty of room for growth for this newer administration device.

The use of PFS has been shown to streamline and simplify vaccine administration, reduce dosing errors and wasted product, and minimize the potential for microbial cross-contamination and pathogen transmission, which can happen when multiple doses are withdrawn from a single vial. As a result, PFS are now widely used for annual flu shots, heparin injections, and a growing list of injectable therapies across multiple disease states.

“When vaccine is filled in a PFS, no further manipulation is required to safely administer it to the patient,” notes Vincenza Pironti, PhD, senior staff scientist, research and development, pharma services for Thermo Fisher Scientific. “For this reason, the risk of dose failure or injuries during manipulation is reduced to almost zero.”

Similarly, the use of PFS can help to streamline mass-vaccination efforts, especially in situations where the availability of trained staff may be limited. By not having to prepare traditional syringe-and-vial vaccines for injection at the point of care, frontline workers do not need the same level of training. This, along with the inherent sterility of vaccines in PFS form, is a key differentiating factor supporting broader use of PFS in developing nations and remote regions where the number of skilled medical professionals may be limited.

According to a 2021 article authored by Guillaume Lehée, R&D Innovation Leader for BD Medical—Pharmaceutical Systems, the use of PFS to vaccinate 300 million individuals in the United States in the event of a future pandemic could save more than three million hours of healthcare practitioners’ time (1).

Traditional vaccines (including the flu vaccines) that are based on proteins must be maintained at 2–8 °C (refrigerated conditions). “One potential downside to PFS is that in some retail or hospital pharmacies, vaccines stored in PFS take up more refrigerator shelf space (compared to traditional vials), so this may limit uptake by smaller pharmacies or smaller physician offices,” notes Stamoran of Catalent. “Similarly, if you’re trying to vaccinate in a developing country, having multi-dose vials may make more sense due to limited shipping capacity and refrigerator space; in more developed regions, those limitations may not exist.”

PFS provide advantages for vaccine manufacturers, as well. “There is no need to overfill the single-dose syringes,” Pironti says. “This increases the overall yield of the manufacturing process and preserves valuable vaccines and drug substances from losses.” By comparison, multidose vials are routinely overfilled and excess vaccine material is left behind when the multi-dose glass vials are discarded.

Meanwhile, “if the vaccine manufacturer is considering converting its product from a traditional vial-delivery system to a PFS, it may need to revise the formulation and carry out additional testing (and in some cases seek additional regulatory approval),” notes Stamoran, adding: “The developer will also need to explore other sources for packaging and materials, and all of this must be factored into the commercialization timeline and supply chain planning.”

Frozen and ultrafrozen vaccines—not candidates for PFS (yet)

Despite their advantages, PFS are not suitable for all vaccine types. Notably, the COVID-19 vaccines that are based on the messenger RNA (mRNA) technology platform (from Pfizer/BioNTech and Moderna) require frozen and ultrafrozen temperatures. They cannot, therefore at this time, be packaged and delivered in single-dose PFS form. “Generally speaking, today’s PFS are not yet proven to be compatible with ultrafrozen temperatures as the existing glass materials and other components may not stand up to the extremely low required temperatures,” explains Stamoran.

When PFS technology is able to advance sufficiently to support frozen and ultrafrozen vaccines, the breakthrough will be met with open arms, as the pursuit of more mRNA-based vaccines is already underway.

Every year, the seasonal results in roughly five million cases of severe illness and 290,000 to up to 650,000 deaths worldwide, according to the World Health Organization (2). And the currently available seasonal flu vaccines prevent just 40–60% of the disease in the best-matched seasons, according to the US Centers for Disease Control and Prevention (CDC) (3). In September 2021, Pfizer launched a Phase I study to evaluate a single-dose quadrivalent mRNA vaccine against influenza (4). Unlike conventional seasonal flu vaccines that are based on inactivated virus, the investigational process of designing vaccines based on mRNA “requires only the genetic sequences of the viruses, enabling more flexible, rapid manufacturing and the potential opportunities to improve upon the efficacy of current flu vaccines,” said the company at the time of the announcement. Hoping to capitalize on the “immense scientific opportunity of mRNA,” Beyond the seasonal flu vaccine, Pfizer is also exploring mRNA-based vaccines targeting other viral diseases, including HIV, Zika, and rabies, and is pursuing mRNA-based therapies in oncology and other genetic diseases.

Moderna is also pursuing flu vaccines based on mRNA, as well as mRNA-based vaccines against the mosquito-borne viral disease chikungunya, malaria, respiratory syncytial virus (RSV), endemic human coronavirus, Zika, Epstein-Barr virus, HIV, and others (5).Sanofi is also developing mRNA-based flu vaccines, while GSK is partnering with CureVac on both flu and second-generation COVID-19 mRNA vaccines.

With the advent of the ultrafrozen COVID-19 vaccines, “rubber materials and glass were challenged to demonstrate that the sterility barrier will be preserved even when ultra-frozen conditions are required,” says Pironti. “Potential mechanical solutions have been introduced and are in a preliminary phase, such as design alterations that allow the plunger to be rod blocked in order to avoid any unwanted movement, and customized combinations of plungers and syringes that could prevent vaccine degradation at extremely low temperatures.”

Stakeholders are also working to address this limitation by evaluating alternative materials, such as plastics or resins and glass-coated resin syringes that remain stable at extreme temperatures. “Ongoing studies and efforts to develop new materials are underway to address this challenge, with the hope of expanding the use of PFS for frozen and ultrafrozen vaccines in the next few years,” says Stamoran.

Becton, Dickinson and Co. (BD) completed a study in 2021 to assess the stability of drugs contained in glass PFS at frozen and deep-frozen temperatures (-20 °C to -40°C), and to evaluate how the syringes themselves cope at these extremely low temperatures (6). The company’s analysis involved syringes with different glass barrel coatings, different volumes, and other characteristics that could influence the response to deep cold storage. Tests were conducted on several combinations of glass barrel coatings, different formats (from 0.5 mL to 3 mL), different tip and flange designs, and multiple elastomeric closures with various state-of-the-art methods. “We’re encouraged by these results and look forward to partnering with pharmaceutical companies to further advance PFS in deep cold conditions,” said Bruno Baney, vice president of R&D for Pharmaceutical Systems at BD, at the time of the September 2021 announcement.

In December 2020, BD announced plans to invest roughly $1.2 billion over a four-year period to expand and upgrade manufacturing capacity and technology for PFS and other advanced drug-delivery systems across its six global manufacturing sites, and the company is adding a new manufacturing facility in Europe (to be online by late 2023) (7).

Meanwhile, in May 2022, BD and Mitsubishi Gas Chemical (MGC) signed a letter of intent to explore a partnership agreement to explore new ways to advance biologic drug development. The companies will investigate ongoing development of OXYCAPT—an innovation from MGC that “integrates the best of plastic and glass for plastic syringes”—to support the next generation of PFS for advanced biological pharmaceuticals. OXYCAPT is a multilayer structure applied on silicon-free plastic syringe barrels, to provide high breakage resistance, oxygen and vapor barrier, lower protein adsorption, very low extractables, high UV barrier, and pH stability, according to the company (8).

CDC, “Vaccine Effectiveness: How Well Do Flu Vaccines Work?” 

Pfizer, “Pfizer Starts Study of mRNA-Based Next Generation Flu Vaccine Program,” Press Release, Sept. 27, 2021.

A. Extance, “mRNA Vaccines: Hope Beneath the Hype,” 

b3cnewswire, “BD Completes Study Investigating Performance of Glass Prefillable Syringes (PFS) in Deep Cold Storage,” 

BP, “BP to Invest $1.2 Billion in Pre-Fillable Syringe Manufacturing Capacity Over Next Four Years,” Press Release, Dec. 2, 2020.

BD, Our Response Plan on COVID-19 (Coronavirus), 


Vol. 46, No. 8
August 2022
Pages: 28–30

When referring to this article, please cite it as S. Shelley, “Vaccine Administration: The Growing Role of Prefilled Syringes,” 

The option of using prefilled syringes for vaccinations is not (yet) available for all types of vaccines. Stakeholders are working to expand that option while also pursuing other non-traditional routes of administration.

Vaccine Administration: The Growing Role of Prefilled Syringes

Where applicable, therapy options that are available in a topical format are often preferable for patients, compared to alternatives that may involve injection or oral dosing (especially as oral alternatives often involve higher doses, because the drug must first be metabolized by the liver). This preference is an attributable factor to the growth in the topical pharmaceuticals market, which is projected to reach US$150 billion by 2028, expanding at a compounded annual growth rate of 6.4% between 2021 and 2028, according to market research (1).

When it comes to manufacturing successful topical formulations, a lot of pressure rests on the shoulders of the drug developer and its contract manufacturing partners. Fundamentally, two things are required for developing any successful topical drug—establishing the optimal formulation and then developing a robust and reliable manufacturing, monitoring, and quality control process.

Semi-solid topical therapies (e.g., creams, ointments, lotions, hydrogels, and foams) must deliver the required clinical attributes while providing the desired mix of physical properties that will make the product appealing to the patient. Otherwise, product uptake will be hindered. For instance, patients managing acne may reject creams or lotions that feel greasy or clog the pores, while those being treated for eczema are more likely to abandon a medication that irritates the skin. Other patients may avoid their disease-specific creams, lotions, or gels—whether they are prescribed or over-the-counter (OTC) products—because they feel sticky, have an unpleasant odor, or stain their clothing. When patients reject specific topical therapies, it creates both clinical and commercial implications—undermining adherence to therapy (and hence, reducing desired clinical outcomes) and undercutting revenue and market share for brand teams.

“Human skin is a complex organ, and each of the distinct layers (epidermis, dermis, and hypodermis) differ in functionality, so formulating the right dosage form that can produce the required therapeutic effect can be challenging,” notes Chetan Chure, senior manager, Formulation Development at CPL, a contract development and manufacturing organization (CDMO) based in Mississauga, Ontario. Once the optimal blend of excipients and APIs has been identified, all steps in the manufacturing process—from mixing of ingredients to blending in APIs and excipients to homogenization/emulsion to heating, cooling, and filling packaging and more—and related monitoring systems must be designed and operated.

“The number of excipients required by a topical formulation can be significantly higher compared to a solid oral dose or injectable, thereby compounding the opportunities to create potential incompatibilities between excipients, API, packaging, and the manufacturing process,” says Lynn Allen, vice president of Business Development for MedPharm, a CDMO. “Changing anything from the grade of excipient to a process parameter during manufacturing can significantly impact the stability and performance of the product.” Once the target formulation has been identified, a reproducible and replicable manufacturing process must be established to ensure that the desired API payload will be delivered with every dose.

Today, a broad range of excipients are available to help manufacturers achieve desired therapeutic outcomes and improve the quality and shelf life of the product, noted Daryl Bassett, product owner, Bora Pharmaceutical CDMO, in a published article (2). These excipients include:

Polymers to control viscosity; these may be fermented (such as Xanthan gum) or synthetic (such as hydroxypropyl methylcellulose or hydroxypropyl cellulose).

Surface active agents, to help solubilize APIs in the formulation.

Preservatives to extend shelf life and control microbiological activity.

Ongoing advances in technology and modeling techniques are helping to align all the objectives of both drug manufacturers and patients.