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

On the Internet, dual-level authentication delivers more secure transactions. A similar multi-level strategy is needed to ensure the pharmaceutical product being dispensed to the consumer is the same one that left the factory.

The enhanced protection is needed because the COVID-19 pandemic and other forces are spurring growth in counterfeiting and gray market diversion. “Changing tariffs and Brexit also encourage counterfeiters,” reports Mark Manning, chief executive officer at iTRACE Technologies, a supplier of product authentication technology and partner with Global Automation and Identification Group, a specialist in anti-counterfeiting programs.

“Securing the supply chain must be part of the manufacturing process,” says Manning. Meeting the requirements of the Drug Supply Chain Security Act (DSCSA) in the United States and the European Union’s Falsified Medicines Directive (FMD) won’t completely solve the problem of counterfeiting. Loopholes in the laws mean “the supply chain isn’t as secure as we want it to be. Additional security steps will be needed,” explains Manning.

He advises starting at the beginning of the supply chain to secure the factory and production. He says, “Security needs to start before the product is made. Brand owners need to be able to validate the factory is secure. Starting with the ingredients enables a secure product all down the line to the patient.” Authentication from the beginning of the supply chain serves as the foundation of trust and depends on data. Then security must be maintained at each level of the supply chain, and each level has to work together.

Manning suggests that blockchain-based systems provide a solution. “Blockchain provides irrefutable proof of the existence of the product and tracks and traces it at every step so you know the product at the bedside is the same one that left the factory,” he explains. “That level of visibility is not something that can be done with a barcode or Datamatrix code. Barcodes and Datamatrix codes are open-source technologies and easily replicated and read by anyone. If I’m a counterfeiter, I can create my own barcode, based on the structure stipulated by the FMD or DSCSA.”

Unfortunately, says Michael Cizek, managing director and founder of Global Automation and Identification Group, “If the carrier for data can’t be trusted, then the data can’t be trusted.”

A multi-level strategy is needed. The iTRACE 2DMI technology is a hybrid technology relying on closed-source, proprietary software and an open hardware platform so the code is readable by virtually any reader, including smartphones. An iTRACE 2DMI code can be printed or laser etched by virtually any system, including desktop printers. Options include reproduction in very small (near-nano) spaces and with ultraviolet ink if covert coding is desired. When read, if the data generated by the iTRACE code matches the serialization, barcode, or Datamatrix code on the package, the product is authentic.

Another recent development in authentication technology, Covectra’s next-generation StellaGuard smart label and mobile authentication system, works in conjunction with its AuthentiTrack track-and-trace system. A free app allows consumers, field inspectors, and customs officials to scan a product barcode with their smartphone and verify authenticity in seconds (1).

The StellaGuard smart label combines a serialized QR barcode with a three-dimensional image of holographic “stars” embedded in a random, non-repeatable pattern at various levels and positioned inside a patented film. On the packaging line, cameras capture the star pattern on each product label and store it in the AuthentiTrack Cloud. When it’s time to authenticate the product, a smartphone scan of the label is compared to the scan captured on the packaging line (1).

1. Covectra, “Covectra Introduces Next Generation StellaGuard Smart Label and Mobile Authentication Solution to Combat Counterfeiting of Products,” Press Release, Feb. 22, 2021.

Drug product security requires anti-counterfeiting techniques such as authentication throughout the supply chain.

Package Authentication Depends on Multi-Level Tactics

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.

Equipment and Processing Report 04-21-2021

Evaluating Cold-Temperature Packaging Closure Systems

Package Authentication Depends on Multi-Level Tactics

Tracking Technologies Safeguard Vaccine Cold Chain