Jennifer Markarian is manufacturing reporter for Pharmaceutical Technology.

Jennifer Markarian

For biologic drug products that require frozen storage—even down to cryogenic temperatures for some cell and gene therapies—the primary packaging and closure materials and their effect on container closure integrity (CCI) risks should be considered in the system design. Evaluating CCI of the system is crucial because the system needs to maintain integrity throughout the shelf life of the product, which could be two or three years, notes Jennifer Riter, senior director of Business and Technical Operations, Services, and Solutions at West Pharmaceutical Services, which manufactures delivery systems for injectable drugs.

Specifically for low temperatures, CCI testing should evaluate any ingress or egress of gases in the headspace of a container, which could affect product quality by putting the product at risk or affect product stability. “For example, carbon dioxide ingress over time could result in product loss or degradation,” explains Riter.

 guidelines (1) and should employ quantitative, deterministic testing such as tracer gas analysis or high voltage leak detection, says Riter. She points out that older techniques, such as dye ingress, are to be used as a last resort, only if other methods are not applicable to the system. “The first step is to determine the maximum allowable leak limit (MALL) and identify the risks, such as microbial ingress, ingress of carbon dioxide or loss of headspace, which will be specific to each product and container system,” explains Riter. “The next step is to choose a test for how to examine the MALL and the associated risks. For example, laser-based headspace analysis can check for carbon dioxide ingress.

A best practice is to evaluate CCI on the complete container and closure system during development. CCI is a key part of product testing in Phase III stability studies, notes Riter. Laboratories should perform tests under the cold-storage temperature conditions. Riter says that it is even possible to do testing of systems at cryogenic temperatures, which is important for packaging of cell and gene therapies.

Material properties are another aspect to consider when designing a container system for low-temperature storage conditions. Suppliers for the elastomers used in closures, for example, have evaluated material properties at very low temperatures and can provide appropriate materials for frozen or cryogenic storage, notes Riter.

“Causes for failure could be the material itself or the way the closure is processed or sealed,” says Riter. “It is important to look at how the materials fit together (a ‘stack-up’ analysis) and to identify the appropriate compression of the stopper with the vial, and the seal quality. Different material hardnesses or coatings can affect compression and sealing.”

Modeling tools using historical or supplier data can now be used to predict appropriate compression conditions for a certain type of vial and seal. “In the past, we would seal at low, medium, and high pressures to estimate the right condition. Now, using models, we can dial in more specifically to what compression should be,” explains Riter.

 40 <1207> “Sterile Product Packaging-Integrity Evaluation” (US Pharmacopeial Convention, Rockville, MD, 2017).

Articles

Material properties play a role in container closure integrity under frozen or cryogenic storage temperatures.

Evaluating Cold-Temperature Packaging Closure Systems

Long before the COVID-19 pandemic put a spotlight on supply-chain security and drug shortages, the pharmaceutical industry was working on advanced manufacturing technologies that could address supply challenges by increasing manufacturing flexibility and efficiency. Continuous manufacturing, for example, allows drug manufacturers to more easily adapt supply to demand, incorporate more automation, and have tighter control of quality. Continuous processes with smaller footprints provide mobility, creating the potential for distributed manufacturing—even bringing drug production to the point of care. The call for reshoring manufacturing—coming perhaps most loudly from the United States but also a concern in other countries—may be answered in part by using these advanced technologies to produce APIs or to continuously manufacture drug products end-to-end, beginning with basic raw materials and ending with a finished drug form.

The US government has been concerned for several years about drug shortages and the ability to manufacture essential medicines domestically. In October 2019, Janet Woodcock, director of the Center for Drug Evaluation and Research (CDER) at FDA, reported to Congress that only 28% of API facilities were located within the US, but suggested that advanced manufacturing technologies could enable competitive US-based production that would strengthen the security and reliability of the US drug supply (1). Woodcock noted then that CDER was working with the US Biomedical Advanced Research and Development Authority (BARDA) to develop a regulatory framework and the technology for mobile manufacturing of essential drugs at or near the point of care.

At the request of FDA, a committee assembled by the US National Academies of Sciences, Engineering, and Medicine (NASEM) researched emerging technologies that have the potential to modernize pharmaceutical manufacturing in the next five to 10 years. Continuous and intensified processes, as well as mobile and distributed manufacturing, were among the innovations that could improve quality and supply security highlighted by the committee in a report published in February 2021 (2). FDA’s Emerging Technology Team, the committee noted, has been successful in facilitating process development, but regulatory review continues to be perceived by industry as a barrier to modernization.

Although “reshoring” could be more complex in Europe than in the US, the pandemic illustrated the need for supply chain security in Europe as well and perhaps created new urgency to reduce dependence on bulk active ingredients and generic drugs sourced from India and China (3). Sanofi and Seqens, for example, are putting a new focus on European API manufacturing (see 

Manufacturers in Europe and the United States have 

plans for new in-country API development and manufacturing capabilities. 

Continuous flow chemistry is one of the intensified, agile technologies showing promise, with some good manufacturing practice (GMP) lines running commercially and other novel processes in development. GlaxoSmithKline, for example, points to continuous manufacturing as a more efficient and environmentally friendly approach, with smaller operations; the company’s commercial continuous API manufacturing process in Singapore requires a facility of approximately 100 m

The CC Flow consortium in Austria includes labs at the University of Graz, the Graz University of Technology, and the Research Center Pharmaceutical Engineering (RCPE) as well as industrial partners. Researchers are developing flow chemistry for continuous API manufacturing, and recent work has looked at process analytical technology tools to enable process control (5).

Even smaller, further intensified processes are being devised, with modular approaches that can produce multiple types of drug substances by changing the process set-up. The US Department of Defense’s Defense Advanced Research Projects Agency (DARPA) has funded several continuous flow chemistry projects, promoting portable technologies that can be used to make medicines on-site in the field for the US military using a few essential raw materials.

Such technologies would also have the potential to secure the civilian US drug supply for chemical APIs. “Flexible, on-demand processes would help remove some of the brittleness in the US supply chain,” notes David Thompson, cofounder and chief scientific officer of Continuity Pharma. “Smaller footprint processes can also be designed to have greater operational efficiency in terms of energy and waste. The vision is to create more responsive systems that can produce drugs in an as-needed manner.”

Continuity Pharma, a start-up out of Purdue University, is using flow chemistry to develop a system that can continuously manufacture multiple APIs. Researchers are initially focusing on APIs that have common reaction processes to ease rapid changeover. Using $1.5 million from DARPA granted in September 2020, the researchers are building proof-of-concept equipment that can produce at least 100 g/day with a maximum six-hour turnaround time between products by the end of the first year of the project, with shorter turnaround and higher volume the aim of the project’s second year, says Thompson. The portable, refrigerator-sized units will use continuous synthesis and purification by extraction, with a final polishing step by batch crystallization.

SRI International in California had developed its SynFini platform, a fully automated, small-scale synthetic chemistry system, primarily for discovery, under an earlier DARPA program, and has developed continuous flow multistep processes for several APIs at a scale of grams per day. In August 2020, SRI was awarded a $4.3 million DARPA contract to create a process modeling scale-up tool that would speed translation of these laboratory-scale processes into commercial-scale API production. SRI is working with a team at Rutgers University on the ProSyn digital twin tool and on scaling up to a modular platform that could be configured to produce a range of small-molecule APIs commercially in a “just-in-time” capacity model.

“To compete with the cost-effectiveness of offshore API manufacturing, innovative streamlined and automated systems are needed,” notes Nathan Collins, chief strategy officer of SRI’s Biosciences Division and the principal investigator for the ProSyn project. “Speed of development and manufacturing is also critical. As was highlighted by the pandemic, we need process development translated into manufacturing within months instead of years.”

The researchers plan to have proof-of-concept modules by the end of 2021 that can demonstrate the manufacturing process. Collins notes that they are concurrently building process validation tools to enable GMP production.

Snapdragon Chemistry, a 2014 spinoff from the Massachusetts Institute of Technology (MIT) based in Waltham, Mass., has developed flow-based API manufacturing processes. In mid-2020 the process development company doubled its R&D capacity and opened a lab to produce gram to kilogram-scale APIs and demonstrate its continuous flow manufacturing technology at pilot scale. The company began construction in January 2021 of a GMP drug substance manufacturing facility, which it plans to commission in November 2021. The facility would be set up for commercial production of APIs using processes designed by Snapdragon.

In a collaboration with BARDA that began in June 2020, the company developed a synthetic continuous manufacturing route for ribonucleotide triphosphates, which are a raw material for mRNA-based COVID-19 vaccines. Snapdragon is initiating discussions with prospective users, and the materials could be produced in the new commercial facility, says Matt Bio, CEO of Snapdragon.

In a separate project launched in February 2021, Snapdragon is using a $1.5 million DARPA grant to extend its technology to enable efficient US-based production of chemicals used in pharmaceutical production. “We’ve identified a set of chemical building blocks that can be produced on the same process-equipment setup using only programming changes, and we are developing a continuous manufacturing platform with next-generation automation to accomplish this goal,” explains Bio. The platform is currently in the R&D stage, and Bio anticipates that it could be commercialized within two years.

At Virginia Commonwealth University (VCU), the Medicines for All Institute (M4ALL) has developed continuous flow processing for APIs. The institute, founded in 2017 with funding from the Bill and Melinda Gates Foundation, has focused on expanding access to medications in developing countries by developing cost-saving production methods. These methods use high-yield reactions that don’t require isolating intermediates, explains Frank Gupton, CEO of M4ALL. In May 2020, M4ALL partnered with Phlow Corporation to implement these continuous processes for US-based manufacturing of essential medicines, under a $354 million contract Phlow received from BARDA. Continuous API production processes are currently being developed in the M4ALL labs, and the processes will then be scaled up to commercial manufacturing by Phlow, says Gupton. The aim is to have a full-scale manufacturing facility running by the end of 2022. 

While FDA has approved one API made using continuous flow chemistry, continuous manufacturing—starting with API and excipients and ending with finished drug—is now being used to produce six FDA-approved oral solid-dosage (OSD) drugs, including some previously made in batch manufacturing as well as new drugs approved with continuous OSD processes. Early adopters have worked through many challenges and are continuing to optimize these systems, which offer flexibility of scale and use process analytical technology and advanced process control to improve efficiency and quality.

Similar to API manufacturing, OSD continuous manufacturing lends itself to miniaturized processes; small-scale equipment can be run for a longer time period if more volume is needed. Pfizer’s PCMM [Portable, Continuous, Miniature, and Modular] system, for example, was originally developed in 2013 in a collaboration using GEA’s OSD continuous processing equipment and G-CON’s prefabricated cleanrooms, and is being used for development as well as commercial production. The small-footprint systems are designed as skid-mounted modules, which adds flexibility. The portability of PCMM could allow rapid deployment or redeployment, which could lend itself to new ways of manufacturing and distributing drugs (6). These successes in continuous OSD manufacturing have demonstrated that a regulatory pathway is possible, which is encouraging to other companies working on continuous processes.

Fully end-to-end systems seek to encompass both API and final dosage form manufacturing in one integrated system. Technology developed at the Novartis–MIT Center for Continuous Manufacturing was demonstrated as a proof-of-concept end-to-end system in 2012. The technology is being leveraged by Novartis, which opened a facility in Basel, Switzerland in 2017, and US start-up company, Continuus Pharmaceuticals. Continuus designed and constructed a pilot plant using its Integrated Continuous Manufacturing (ICM) technology at its facility in Woburn, MA, and in January 2021, the company was awarded a $69.3 million contract from the US Department of Defense (DoD) to build a commercial ICM facility for US production of three critical APIs and their finished dosage forms. The facility is expected to be operational within two years.

Bayan Takizawa, co-founder and chief business officer of Continuus, says that the company plans to file applications to produce and market these drugs as its own products. Although there are not, as yet, any FDA-approved drugs made with a fully end-to-end line, Takizawa notes that the FDA’s Emerging Technology Team (ETT) is well informed of their advanced manufacturing platform through previous contract work the company performed for the Agency. “Continuus plans to maintain close communication with the ETT to ensure our efforts are aligned with FDA’s expectations,” he adds.

Takizawa says that ICM provides several advantages. “The process is fully automated, which eliminates human errors that often translate into quality defects and increased costs,” he explains. “We eliminate the starts and stops that normally characterize pharmaceutical manufacturing, and the entire process is located in a single facility, where manufacturing operators are all in constant communication. This is very different from the currently fragmented model, where parts of the manufacturing process are performed by different companies that are not always aligned, often resulting in rework. Also important, we leverage novel technologies that enable integration and this seamless production.”

The commercial facility will have a capacity that is several times greater than that of the pilot line, with two end-to-end lines that will have the capacity to produce multiple APIs and drug products, including both sterile injectables and OSD drugs using a “multi-suite” design. With the extra capacity beyond future US government contract requirements, the company plans to produce and market its own drugs, as well as provide contract manufacturing services.

While the commercial facility will be a conventional, fixed-location facility, Continuus envisions that the ICM platform could also be used in a Mobile Pharmaceuticals (MoP) plant, which would be housed in a prefabricated pod that could easily be transported and deployed across the globe to provide regional manufacturing and distribution.

Innovators are prototyping other mobile manufacturing facilities using continuous, end-to-end manufacturing at small scales of finished drug forms for both small- and large-molecule drugs. Funding for several of these projects is coming from DARPA. Moderna, for example, received a DARPA grant in October 2020 as part of DARPA’s Nucleic Acids on Demand World-Wide (NOW) initiative to develop a mobile, end-to-end automated, GMP-quality manufacturing platform for mRNA vaccines and therapeutics for military and local populations in remote regions (7).

At the Center for Advanced Sensor Technology at the University of Maryland, Baltimore County (UMBC), professor and director Govind Rao and his team have developed the Biological Medicines on-Demand (Bio-MOD) platform, which uses a cell-free process to translate and continuously purify proteins. Bio-MOD is a “factory on a chip” that fits in a suitcase-sized container. Rao says the device has been demonstrated to reproducibly manufacture several drugs, including His-tagged granulocyte-colony stimulating factor, and that others are in progress. The system can also make nucleic acids. The group is looking for a partner to be a first adopter and take a target molecule through FDA approval. “The vision is to broadly license the technology so that it becomes a standardized production platform,” says Rao.

On Demand Pharmaceuticals (ODP) is developing proprietary Pharmacy on Demand (PoD) technology licensed from MIT to build a miniaturized, end-to-end medicine production system. The Rockville, MD-based company was founded with the mission of producing battlefield medicines, but the company envisions its portable, refrigerator-sized PoD technology being used for any localized manufacturing. ODP received a $20 million contract award from DARPA in September 2020 to further develop its technology to produce critical APIs and final dosage forms. ODP has demonstrated that the technology can produce solid-dosage forms (diazepam, diphenhydramine hydrochloride, and ciprofloxacin hydrochloride tablets) and liquid formulations (lidocaine hydrochloride, atropine sulfate, as well as medicines used to treat critically ill COVID-19 patients requiring ventilation support). The technology can also be used to produce APIs or critical precursors as needed.

Although the units are small, they can produce significant volumes. “For some high-potency drugs, in which one dose is less than 10 mg, such as midazolam, one PoD running for 24 hours could produce as much as 2 million doses,” says Kari Stoever, chief external relations officer at ODP. The company expects, however, that its devices would make finished dosage forms of multiple drugs in a distributed manufacturing model. Stoever says that PoDs have demonstrated rapid turnaround time of approximately two hours for changeover from synthesis of one API to another.

 facility in 2020 and is completing renovations in preparations for CGMP production. Stoever says that ODP has been working closely with FDA’s Emerging Technology Team and anticipates filing its first submission to the FDA in the next year, with additional product submissions to follow shortly thereafter.

In addition to domestic production capacity and working to ensure the protection of military service members, ODP sees its technology as useful for orphan drug and precision medicine markets. “Perhaps the most compelling use case for the PoD technology resides in addressing unmet needs in the world’s poorest communities,” adds Stoever. A flexible system for local manufacturing could meet a community’s need for a broad range of essential medicines. “As the PoD technology matures, we will pursue development aid partners to work on a low-income model of the PoD,” she notes.

Although regulators have expressed support for novel technologies, some regulatory barriers do still exist. For example, current GMP regulations depend on a conventional definition of a facility with a physical address; modular and mobile manufacturing does not fit this definition. Real-time release from portable systems with innovative process controls could also be a regulatory barrier. The NASEM committee, however, concluded that mobile, end-to-end systems “are becoming mature and robust enough to push the regulatory envelope within five to 10 years,” and that FDA would need to take a proactive approach and ease the regulatory burden if such systems were to be used (2).

“In a conservative industry, getting people to change the way they do things is a big challenge. But now there are drivers to innovate, so the question is how fast change will occur,” concludes Collins. 

1. J. Woodcock, “Safeguarding Pharmaceutical Supply Chains in a Global Economy,” Congressional Testimony (Oct. 30, 2019).
2. NASEM, Innovations in Pharmaceutical Manufacturing on the Horizon: Technical Challenges, Regulatory Issues, and Recommendations (2021).
3. S. Milmo, Pharm Tech Europe 32 (6) 6-8 (2020).
4. GSK, “Less is More with Advanced Technologies in Manufacturing,” gsk.com, accessed 12 Mar. 2021.
5. P. Sagmeister et al., Angewandte Chemie online, DOI:10.1002/anie.202016007 (Jan. 12, 2021).
6. D. Blackwood, “PCMM and Beyond—Next Gen Innovation for Solid Oral Dosage Forms,” Presentation at NASEM (February 2020).
7. Moderna, “DARPA Awards Moderna up to $56 Million to Enable Small-Scale, Rapid Mobile Manufacturing,” Press Release, Oct. 8, 2020.

Jennifer Markarian is manufacturing editor at Pharmaceutical Technology.


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

When referring to this article, please cite it as J. Markarian, “Advanced Manufacturing Technologies Shift Outside the Box,” 

Intensified and distributed manufacturing approaches create flexible, local capacity.

Advanced Manufacturing Technologies Shift Outside the Box

Manufacturers in Europe and the United States have announced plans for new in-country API development and manufacturing capabilities. Citing the need to balance reliance on API sourced from other regions, in February 2020 Sanofi created a standalone company out of the combination of Sanofi’s API commercial and development activities at six of its European production sites (1). Sanofi said the spin-off company, to launch in 2022 with the name EUROAPI and headquarters in France, would allow greater agility to improve supply security (2).

Seqens, with the support of the French government, is adding flow chemistry capabilities at its R&D center and four industrial sites in France. The multi-purpose units will produce non-good manufacturing practice (GMP) intermediates in the short term, and APIs in the long term, including anesthetics, antivirals, and other small molecules (3).

In the US, Oregon-based contract development and manufacturing organization (CDMO) Cascade Chemistry began construction of five suites for Phase I and II current-GMP (CGMP) manufacturing in February 2021, and the company plans to add Phase III and commercial CGMP-scale capacity in 2022 (4).

CDMO Regis Technologies is expanding its laboratories in Illinois and installing equipment, including kilo-scale reactors, to develop APIs. The company reported a growing demand for domestic API development and manufacturing (5).

1. Sanofi, “Sanofi to Create New Industry Leading European Company to Provide Active Pharmaceutical Ingredients,” Press Release, Feb. 24, 2020.

2. Sanofi, “Sanofi Unveils EUROAPI as the Name of the New Industry Leading European API Company,” Press Release, Jan. 12, 2021.

3. Seqens, “Seqens is Committed to the Development and Production of Critical Molecules in France,” Press Release, Nov. 20, 2020.

4. Cascade Chemistry, “Cascade Chemistry Initiates $14 Million Expansion of CGMP Pharmaceutical Manufacturing Capacity,” Press Release, Feb. 18, 2021.

5. Regis Technologies, “Regis Expands Facilities to Support Rising Demand for US-Based Custom API Pharmaceutical Development and Manufacturing,” Press Release, Feb. 17, 2021.

Jennifer Markarian is manufacturing editor at 

When referring to this article, please cite it as J. Markarian, "Reshoring and Expanding API Manufacturing Capabilities,” 

Manufacturers in Europe and the United States have announced plans for new in-country API development and manufacturing capabilities. 

Reshoring and Expanding API Manufacturing Capabilities

Now that COVID-19 vaccines have received regulatory authorizations and vaccine manufacturers are providing a steady and increasing supply, the focus is on distributing doses. Vaccine manufacturers worked closely with cold-chain distribution experts to plan for maintaining and monitoring the cold chain for these crucial drug products. The vaccines must be transported and stored at temperatures ranging from refrigerated (2–8 °C) to frozen (-20 °C) or in deep-freeze, with specific requirements depending on the manufacturer and vaccine type. Pfizer and BioNTech’s COVID-19 vaccine was authorized with the most stringent requirements of the currently authorized products, with storage between -80 and -60 °C, and the vaccine is being shipped in thermal containers designed to hold dry ice for both shipping and temporary storage. The companies said in late February 2021 that they had demonstrated stability of the vaccine when stored at -25 to -15 °C and would apply for an updated label that would allow storage at these typical freezer temperatures for up to two weeks (1).

Many suppliers from all parts of the distribution chain—from makers of thermal packaging, sensors, data loggers, and supply-chain visibility systems to dry ice suppliers and airlines—stepped up to prioritize vaccine distribution, and in some cases modified existing technologies to meet the requirements (2).

“We have seen tremendous efforts across the COVID-19 vaccine distribution channel, with parties coming together to help solve a common goal for humanity,” says Gisli Herjolfssonn, CEO and cofounder of Controlant, headquartered in Iceland, which is providing monitoring and supply-chain visibility services to Pfizer for the global distribution of its COVID-19 vaccines. Herjolfsson says that collaboration throughout the supply chain is crucial. “We first learned this [lesson] in our work on H1N1 in 2009, and it continues to be Controlant’s guiding principle since we started: digitally connect the end-to-end supply chain,” he says.

Tracking technology and supply-chain visibility systems provide the ability to closely monitor shipments to ensure that temperatures are maintained and doses arrive as expected, providing real-time data so distributors can intervene if needed. Conventional technology, typically passive data loggers inside of a package, do show the receiver of the shipment that the temperature was maintained, but do not provide such real-time data.

“Pharmaceutical companies must have quick, accurate, and comprehensive capabilities in place to sense where product is as well as the condition it is in,” agrees Mahesh Veerina, CEO of Cloudleaf, whose digital visibility software is being used in the pharmaceutical cold chain by companies such as CSafe Global, which added the visibility system to its air cargo containers for vaccine distribution (2). Cold Chain Technologies, a thermal packaging provider, launched the Cold Chain Technologies Smart Solutions using Cloudleaf’s tracking systems in March 2021 (3). The digital informatics platform will track critical parameters, such as location, temperature, and vibration, along with data about weather, traffic, and flight schedules, for example. “It will not only remove blind spots in the supply chain, but flag potential issues so that they can be rectified before any product is compromised. Having real-time visibility into vaccine and drug shipments is critical in mitigating loss,” says Ranjeet Banerjee, CEO of Cold Chain Technologies.

“The need for life sciences companies to have insight into their cold chains has never been more apparent than with the COVID-19 vaccine rollout,” noted Banerjee, who reported that the company has tripled its production of temperature-sensitive parcels for vaccines in recent months (3).

 spoke with Herjolfsson and Veerina about vaccine distribution and advances in cold-chain monitoring.

 What are the biggest risks to vaccines in the cold chain, and how are visibility systems being used to mitigate these risks?

 Historically, cold-chain partners to the pharmaceutical industry have used a variety of siloed data sources to get supply-chain information, including manual methods such as hand-held bar-code scanners and passive temperature measurements from data loggers. These siloed data do not give information about when, where, and why a temperature excursion occurred. Further, when shipments needed to be located, companies relied on email and phone calls to access needed information. These methods will be insufficient for a coordinated effort of the magnitude needed for the current COVID-19 vaccine distribution.

To ensure that temperature-sensitive products don’t spoil or get damaged during transport, companies require accurate, reliable, and complete tracking information. Individual, end-to-end dosage-level tracking would drastically increase efficiency and planning accuracy in distribution, particularly to lesser developed and rural geographies where delivery routes are less formal and technologically equipped, by using remote tracking and monitoring. In recent years, the democratization of Internet of Things sensors has enabled the technology to become quite ubiquitous in the life sciences supply chain for tracking purposes. The progressive adoption of technologies like artificial intelligence and machine learning have also drastically expanded real-time knowledge of the supply chain where gaps may have previously existed. For example, if a product is out of temperature compliance, a truck driver or manufacturing plant manager can get a text telling them which product is compromised and how much time they have to fix it.

Production and distribution of COVID-19 vaccines is a complex ecosystem, with many hand-offs, but losses cannot be afforded. In addition to maintaining the cold chain, security and preventing diversion is a concern. Real-time visibility is crucial, and the industry is now rushing to put in the infrastructure for it; we’re seeing rollouts with very aggressive timelines. The entire path from the manufacturing facility to the distribution point is tracked so that suppliers can know about any deviations. In our digital visibility system, we use artificial intelligence/machine learning rules based on business inputs to predict deviations or delays. We’re also tracking the temperature and conditions to be sure product quality is maintained; containers are instrumented and the system monitors if a container door is opened or if temperature drifts, for example, and automatically sends alerts.

 There are several risk factors in the cold and ultra-cold chain of COVID-19 vaccine distribution, and really most vaccines in general. First, the vaccines must be stored at low and ultra-low temperatures, some much lower than the usual cold-chain standard of 2–8 °C. Any deviations in temperature during transport or storage can render the vaccine ineffective or even unsafe. Additionally, there are multiple hand-off points along the supply chain, and each one poses risks of temperature deviations, pallets being split, or other incidents that can compromise the products’ quality condition. Likewise, the receiving facility staff must review and understand all handling and storage instructions for each vaccine.

Most supply chains using passive loggers only receive descriptive data, showing what happened after the fact. This delay is problematic because stakeholders cannot act on the data to prevent waste and loss. Vaccine integrity has never been more crucial as millions of COVID-19 treatments have already shipped, and potentially billions over the next 12 to 24 months.

Controlant is providing monitoring and supply chain visibility services to Pfizer relating to the global distribution and delivery of its COVID-19 vaccines. Pfizer and its partners have been able to keep the excursion rate extremely low. We are also working directly with the US government to help ensure distribution continuity during hand-off, actionable communication, and visibility throughout the entire US supply-chain journey of the Pfizer COVID-19 vaccines. We are also monitoring additional COVID-19 vaccines through logistics providers during distribution in some countries.

Real-time data logger technology was designed to measure various scenarios that would require escalation, like products being delayed, pallets being split up or arriving at the wrong location, a potential security issue, or issues at borders. Our 24/7 Monitor and Response Service (MARS) team was also available in the background to facilitate corrective action if escalations occurred. In tandem, Controlant worked extensively with stakeholders and designated sites to create an onsite monitoring control tower, providing centralized services to facilitate responsiveness and corrective action, per the vaccine manufacturer’s instructions and according to specific business rules and regulations. Multiple parties involved with the distribution and onsite process are provided with pertinent information and alerts, as they happen, so that the vaccines can be protected, helping to ensure public safety, mitigate financial losses, and expedite vaccine administration.

Automation [is] another key component of successful vaccine distribution and delivery. The automated services and processes Controlant put into place can apply to other scenarios moving forward to positively impact the pharmaceutical industry, [such as] automatic triggering of events according to predefined business rules set by the customer. For example, orders are entered into the ERP [enterprise resource planning] system, and a shipment is created to the designated customer and site. When a shipment arrives, a detailed report is automatically created and emailed to designated onsite stakeholders, including the internal quality team, for sign off. Recipients know automatically if the vaccine, medicines, and other pharma products should be placed on hold pending further review or if it may be administered to patients.

Under normal circumstances, the new pharmaceutical distribution models currently in place would have taken years to accomplish, rather than only a few months. This model required a new depth of collaboration, alignment, processes, and data sharing across multiple internal and external stakeholders—such as carriers, manufacturers, governments, health systems, and others—integrating multiple control towers and implementing technology-enabling responsiveness on a level never witnessed previously. In the coming months, we will see more lessons learned from the distribution.

 How do you envision the new technologies and lessons learned during the pandemic being used in the future?

 Controlant’s view is that real-time visibility and monitoring has made previous, retrospective processes and minimal data logging irrelevant. We can answer, ‘What is happening right now?’ so parties can act on critical information, fast. Moving forward, supply chain stakeholders can leverage gathered business intelligence and data to predictively answer, ‘What will happen?’ [These] data will enable businesses to execute planning in an entirely new way. For instance, if a product is shipped using a particular lane or packaging type, during a specific time of year, prescriptive analytics can help people understand scenarios that are likely to occur. Information like this is crucial to prevent product waste and stock outages, as well as determine the best route or packaging material. Technologies such as Controlant’s include integration of multiple systems and connect the physical and digital supply chains together.

Moving ahead, we are seeing supply chains increasingly focusing on building supply-chain resilience, which includes real-time visibility, agility, and responsiveness. More businesses are interested in integrating their manufacturing, operations, and supply chains to automate processes, increase efficiency, and improve communication among internal and external stakeholders.

More broadly, healthcare supply chains are complex and have grown more so as they have incorporated many different organizations within them. They also require tech integrations with multiple systems and are working with a wide variety of stakeholders. Manufacturers need to nimbly pivot between suppliers and carriers based on market, regional, or customer demands while also operating within governmental regulations. Each variable increases the complexity, which adds risks throughout the supply chain.

Some companies have already begun [making] their supply chains [more complex] by recruiting additional suppliers. Others have started to integrate their supply chains more closely with their suppliers, logistics providers, and customers. Resilience is required to meet track and trace, monitoring, regulatory, and licensing requirements. To achieve this level of resilience, pharma companies are beginning to strategize and implement smarter solutions to deliver full digitization to every part of their supply chain operations.

 Digital visibility technology was available before, but the pandemic has accelerated implementation, and not just with the big names but with the whole ecosystem of bulk producers of materials used to make the vaccines, and the packagers and distributors. We are seeing that the crisis is driving innovation.

A secondary benefit to supply chain visibility is that companies that collect data over time can then use data analytics to proactively evaluate issues such as which routes or carriers are more prone to excursions or how routes and standard operating procedures can be optimized.

In addition, new technologies that are being evaluated and should soon be launched include inexpensive sensors that can be attached to each vial to automate tracking of vaccine doses at the point of care and incorporate these data into visibility systems. These types of systems can be used to benefit other areas in biopharmaceutical manufacturing. For example, in blood plasma manufacturing, inexpensive sensors could be put on every bottle and used to further automate. Another area is cell and gene therapies, which are very expensive and growing very rapidly. Digital visibility systems can revolutionize this space with end-to-end visibility all the way to patient care.

1. Pfizer, “Pfizer and BioNTech Submit COVID-19 Vaccine Stability Data at Standard Freezer Temperature to the US FDA,” Press Release, Feb. 19, 2021.

J. Markarian, “Accelerating Technology Adoption to Track the Cold Chain,” PharmTech.com

3. Cold Chain Technologies, “Cold Chain Technologies Partners with Cloudleaf to Provide Enhanced Real-Time Visibility for End-to-Distribution for Temperature-Sensitive Drugs and Biologics,” Press Release, March 16, 2021.

Supply-chain visibility systems are proving their worth in the distribution of COVID-19 vaccines and may see broader use in the future.

Tracking Technologies Safeguard Vaccine Cold Chain

The biopharmaceutical industry is very familiar with cold-chain distribution and has established supply chains for maintaining biologic drugs at the necessary temperature, including the refrigerated temperatures (at 2–8 °C) needed for many vaccines, down to standard freezer temperatures (-20 °C), deep-freeze using dry ice (-70 °C), and even cryogenic temperatures (-150 to -273 °C). Carefully designed and validated packaging, storage, and transportation systems, with sensors measuring temperature excursions, are all available. Distributing authorized COVID-19 vaccines urgently and at large scale, however, is a new challenge, which is being met in part by accelerating adoption of technologies such as GPS-enabled tracking and supply chain visibility systems.

This article was first published on PharmTech.com, Dec. 15, 2020.

Authorized vaccines from Pfizer and BioNTech, Moderna, and AstraZeneca are now being distributed in countries where they are authorized. These three vaccines have different cold-chain requirements.

Pfizer and BioNTech said that they would ship the frozen vaccine, BNT162b2, directly to the point of vaccination using a just-in-time distribution network by air and ground transportation to get shipments from the manufacturing site to the point of use (POU) in one or two days (1). The vaccine will be shipped in temperature-controlled shippers using dry ice to maintain a temperature of -70 °C ± 10°C for up to 10 days. The companies said that vaccine administration sites could store the vaccines in ultra-low temperature commercial freezers for six months, refill the shipping containers with dry ice to use them as temporary storage units for 15 days, or store the vaccine at 2–8 °C in a refrigerator for five days. GPS-enabled sensors on the shipping containers will track location and temperature so that Pfizer can proactively identify and prevent potential problems, such as temperature excursions. Pfizer reported that it was running pilot shipments to help refine the delivery plan (2). Test packages were shipped to Rhode Island, Texas, New Mexico, and Tennessee; the four states were chosen to demonstrate a range of immunization infrastructures that could reach individuals in urban and rural settings.

Moderna said its vaccine, mRNA-1273, should be maintained at -20 °C, which is a standard temperature for home or medical freezers, for up to six months (3). The company reported that mRNA-1273 will remain stable at standard refrigerated conditions (2–8 °C) for up to 30 days within the six-month shelf life.

AstraZeneca said its adenovirus-based vaccine will be transported and stored at 2–8 °C (4). This vaccine and others with less stringent temperature requirements would be easier to distribute globally. AstraZeneca and Moderna’s vaccines could use existing vaccine distribution infrastructure. Although Pfizer’s vaccine requires deep-freeze temperatures, the company had expressed confidence at time of authorization that its distribution systems, with shipping via its established systems of carriers such as UPS and FedEx, were ready to go.

In addition to Pfizer’s purpose-built container for its own vaccines, suppliers of commercial cold-chain containers have modified their systems to address the needs of COVID-19 vaccines.

Pelican BioThermal, for example, introduced a new -35 °C version of its Crēdo Cube container that uses a new type of phase change material (PCM). “PCM is easier to work with than dry ice, and we offer PCM coolants that can achieve -50 to -20 °C,” says Adam Tetz, director of worldwide marketing at Pelican BioThermal. The company also created a pallet-accepting shipper, the Crēdo Cargo, for dry ice. “Dry ice is the only material that can be used to achieve -80 °C. We had to separate the dry ice from the payload itself [using a physical spacer system] to avoid a cold shock that happens when dry ice contacts the payload or payload box,” explains Tetz.

The sheer scale of vaccinating the world is certainly a challenge. Availability of equipment (e.g., freezers) and materials (e.g., dry ice) is also a concern, but manufacturers are working to increase production capacity. Air transportation is another potential challenge, especially for vaccines that require deep-frozen temperatures during shipping, due to limitations on the amount of dry ice (which sublimates into carbon dioxide) that can be transported on a passenger airplane. Airlines are stepping up, however, to run chartered cargo flights, with aviation authority permission.

For all types of vaccines, although technology and equipment are prepared to maintain the cold chain, human error remains a risk. “Temperature-controlled packaging is good at eliminating temperature excursions, and our shippers are nearly error proof to condition and assemble,” says Tetz. “The most important practice is to design the cold chain—from packaging through the shipping lane—to keep the ambient temperature correct. This [design] includes standard operating procedures to ensure people take seriously how they handle the payload during shipment. Human error may cause a shipment to sit on an airport tarmac for too long, to spend too much time in a warehouse without temperature control, [or] to be opened and not properly closed at customs.”

“A vaccine shipment using dry ice needs to be completed within two days, putting added pressure on the supply chain,” adds Scott Hurley, vice-president of product marketing at Roambee. “Getting still-effective COVID-19 vaccine shipments into hard-to-reach parts of the world, such as small towns outside of large cities in less-developed countries, will be a real challenge. Without real-time monitoring, it will be all but impossible.”

Real-time monitoring using GPS-enabled and cloud-connected or cellular-enabled sensors is available, and while uptake of the technology throughout the pharmaceutical industry had been limited, primarily due to cost, the urgent need for real-time data for managing vaccine distribution is accelerating adoption.

Data loggers, which are passive sensors placed on packages, are widely used today by the pharmaceutical industry to indicate whether a container has experienced a temperature excursion. In addition, tracking technologies such as barcode scanning and radio frequency identification (RFID) tags can be used to track location at the time the tag is scanned. Active sensors with GPS c

“With COVID-19 and the supply chain complexities it introduces (including multiple hand-offs and transporters), many pharmaceutical companies are understanding that it is more important to track and monitor at the package-level in real-time as they can’t assume the carrier temperature actually translates to the package temperature,” says Hurley. “Embedded IoT sensor devices with the necessary global telecom availability can capture and communicate location and condition of shipments at a granular level along every segment of an end-to-end journey, without the need for human intervention … to validate chain of custody, chain of condition, and chain of identity; all are critical to successful COVID-19 vaccine distribution.”

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He notes that the cost of IoT sensors, which has been a barrier to wider use, is coming down, and that new communication technologies are reducing the power-consumption needs for IoT-sensor devices, which allows the devices to have a longer shelf life of over a year. Unlike data loggers that are typically designed for one-time use, Roambee’s sensor devices are designed for multiple uses, explains Hurley. The company has a fully managed service to handle the logistics of returning the sensor devices for charging and re-use.

SkyCell’s temperature-controlled air freight containers have embedded IoT communication systems using sensors that connect to SkyCell’s cloud-based software. “Wireless GPS tracking offers the best way to track the temperature and condition of vaccines in transit. The near real-time data means that problems can be mitigated en route rather than dealt with upon arrival,” says Nico Ros, CTO and cofounder at SkyCell. He notes that wireless tracking devices are restricted on flights, and so devices must be approved for specific aircraft.

CSafe Global has been implementing track-and-trace technology on its air cargo temperature-controlled containers for the past two years, and in July 2020 added a custom digital visibility platform from Cloudleaf to support digital tracking at the container level for parcel and cell and gene therapy handling (5). The system tracks data including location, temperature, humidity, pressure, shock, tilt, and door-open events. In September 2020, CSafe Global reported that it had completed pilot shipments that validated that the real-time sensor readings and alerts matched the validated data logged at the container (6), and the system was officially launched in December 2020 for its air cargo containers.

“The system is hardware-agnostic—any IoT sensor can be used,” says Mahesh Veerina, CEO of Cloudleaf. “Contextual data, including shipment details and customer business signals, are incorporated into the platform. The entire path is monitored automatically and tightly controlled; warnings are sent if anything begins to go outside of what is expected so that someone can intervene.” 

Veerina says that Cloudleaf’s visibility platform goes from shipping through to the vaccine administration point, which involves storage, thawing, administration, and disposal. Current technology tracks individual vials using QR codes that are manually scanned, and an emerging technology being tested uses inexpensive IoT sensors on vials to further automate this step. 

He says that the industry is moving quickly to implement the infrastructure for real-time visibility. “Before the pandemic, companies were using passive data loggers and manual processes primarily to achieve FDA compliance. Now, continuous monitoring of what is happening at the container level is crucial, because losses can’t be afforded,” says Veerina.

Companies typically use laboratory tests that simulate shipping conditions along with real-world pilot tests, with data collected by data loggers, to validate shipping protocols. In addition, simulation software uses artificial intelligence techniques to look for potential problems and optimize routes.

“Data loggers can be used reactively to understand if specific [shipping] lanes require additional insulation, different packaging, or a different courier partner,” says Adam Tetz, director of worldwide marketing at Pelican BioThermal. He explains that when Pelican BioThermal sets up a new customer, virtual tests are run using modeling of shipping lanes, and then real-world pilot tests are run to confirm assumptions made in the model. “This information is important to have before beginning a program that may ship thousands of valuable pharmaceutical parcels each month over the course of years,” says Tetz.

Modality Solutions’ transport simulation platform simultaneously tests the worst-case scenarios for the five key distribution hazards: temperature, vibration, shock events, pressure, and humidity, says Gary Hutchinson, president at Modality. He says that pilot shipping studies are unlikely to reach one worst-case scenario at any time during a shipment and have nearly no chance of experiencing all five worst-case risks simultaneously, and he suggests that testing vaccine quality and viability under worst-case scenarios using simulation is key. Hutchinson notes, however, that actual pilot shipping tests can be used to confirm or verify that the packaging and the multiple operators needed to deliver the vaccine have been appropriately trained, and that all the necessary monitoring and controls are in place for delivery.

Pfizer, “COVID-19 Vaccine US Distribution Fact Sheet,” Nov. 20, 2020.

Pfizer, “Pfizer Update on Our US COVID-19 Vaccine Candidate Distribution Preparedness,” Press Release, Nov. 16, 2020.

Moderna, “Moderna Announces Longer Shelf Life for its COVID-19 Vaccine Candidate at Refrigerated Temperatures,” Press Release, Nov. 16, 2020.

AstraZeneca, “Innovating Production and Manufacture to Meet the Challenge of COVID-19,” 

CSafe Global, “CSafe Global Selects Cloudleaf as Strategic Partner to Deliver a New Digital Visibility Platform,” Press Release, July 23, 2020.

CSafe Global, “CSafe Global Publishes Results of Second Pilot Test for New Shipment Visibility Capability,” Press Release, Sep. 24, 2020.

Packaging and transporting large quantities of COVID-19 vaccines pose challenges for the cold chain.

Accelerating Technology Adoption to Track the Cold Chain

The cold chain plays a crucial role in wide-scale distribution of COVID-19 vaccines. New technologies, including systems for real-time tracking using the Internet of Things (IoT), are enabling vaccine manufacturers to prevent temperature excursions and ensure that doses arrive on time. Companies throughout the supply chain have been increasing capacity and introducing products to meet needs for refrigerated and frozen storage.

Cincinnati Sub-Zero (CSZ) BioStore ultra-cold freezer rooms for large-capacity bulk storage contain individual freezer compartments with temperatures from -75 to -40°C (1). According to CSZ, freezer rooms offer benefits such as redundant, back-up cooling systems and lower costs than individual freezers.

Stirling Ultracold’s portable, ultra-low temperature freezers are capable of the storage needed for some COVID-19 vaccines (2). The freezers can be used worldwide; they plug into a 110–240V outlet and can run on 12V DC power adapter.

Telstar doubled production of its latest-generation Boreas ultra-low temperature freezers designed for vaccine storage in hospitals and in transportation (3). The freezer maintains a temperature of -80 °C with ambient temperatures up to +28 °C. 

Pelican BioThermal has expanded the temperatures available with its Crēdo Cube reusable parcel shipper and other shipping packages for deep frozen conditions; temperatures can be held at -20, -35, -50, and -80 °C using phase-change materials and dry ice systems (4).

SkyCell opened new service centers in New Jersey, Rome, and Seoul to meet increased demand for its temperature-controlled, self-charging, and IoT-tracked containers for pharmaceutical shipping (5).

Sonoco ThermoSafe’s new Pegasus unit load device (ULD) bulk temperature-controlled container received Federal Aviation Administration (FAA) approval as a ULD, which eases handling and customs processes (6). The container’s FAA-approved telemetry system provides real-time, GPS-synchronized, cloud-based data on payload, ambient temperature, and key environmental factors.

SmartSense, the IoT Solutions division of Digi International, said that its monitoring systems, which include sensors and analytics, can be used for temperature monitoring and tracking of vaccines (7).

Nordic Cold Chain Solutions’ new Pre-Tested Frozen Shippers were designed for vaccine storage and distribution. The company says its products are tested in-house at its cold chain testing facility, and that the shipper designs keep products frozen for one or two-day shipments (8).

CSZ Industrial, “CSZ Provides Bulk Cold Storage Solution for Vaccines,” Press Release, Nov. 13, 2020.

Stirling Ultracold, “Stirling Ultracold Helps Communities Around the World Prepare to Administer COVID-19 Vaccination,” Press Release, Oct. 29, 2020.

Telstar, “Telstar Doubles the Production of Boreas Ultra-low Temperature Freezers,” Press Release, Nov. 18, 2020.

Pelican BioThermal, “Pelican Biothermal Expands Deep Frozen Product Range to Meet Covid-19 Vaccine Shipping Requirements,” Press Release, Nov. 19, 2020.

SkyCell, “New SkyCell Service Centers Open as the Race for Secure Pharma Containers Intensifies,” Press Release, Nov. 5, 2020.

Thermosafe, “Sonoco ThermoSafe’s New Pegasus ULD Receives FAA Approval,” Press Release, Sept. 15, 2020.

Digi, “Nation’s Largest Retail Pharmacies to Leverage SmartSense by Digi for Government-Mandated Continuous Monitoring of Forthcoming COVID-19 Vaccine,” Press Release, Oct. 21, 2020.

Nordic Cold Chain Solutions, “Nordic Cold Chain Solutions Prepared for COVID-19 Vaccine Distribution,” Press Release, Nov. 19, 2020.

Freezers, shipping containers, and tracking systems aid distribution of COVID-19 vaccines.