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Jennifer Markarian is manufacturing editor of BioPharm International.
Packaging materials, kit design, and cold-chain handling should be optimized for each study.
Contract packaging organizations for clinical trial materials are increasingly handling biologic drugs, which are typically delivered by injection and have more stringent packaging requirements than other drug forms. In addition to the shift to biologics, the trend to direct-to-patient shipping affects how materials are packaged and makes tracking even more important. Careful consideration of primary packaging materials, kit design, and distribution is crucial for optimizing packages that balance user requirements, protection of drug product quality, and efficiency.
“The shift to parenteral delivery impacts both primary and secondary packaging systems for clinical trials,” says Claudia Berrón, senior vice-president of Clinical Services at Avantor. Parenteral drugs are shipped as liquid doses that require cold-chain distribution or as lyophilized dosage forms, which require packaging for optimal reconstitution at point of care, explains Berrón. She explains that primary parenteral packaging (e.g., prefilled syringes, autoinjector pens, or vials) should be protected by the secondary packaging to prevent breakage during shipping. Packaging should also incorporate patient-friendly and child-resistant features.
When designing a kit, it is crucial to understand how it will be used by investigators, says Fiona Geiger, vice-president of client services at Yourway. “The more complete understanding that the kitting provider has about what materials will be necessary and in what order they will be used, the better the solution. Communication with sponsors and ideally the sites themselves can make a huge difference.”
“Items must be stored within the kit in a way that minimizes the risk of breakage or contamination,” adds Pieter Vercruysse, commercial director at Tjoapack. “They must also be designed in such a way that the entire product [such as a syringe or autoinjector] can be combined quickly and effectively with minimal manual input.”
Other factors to consider include package dimensions and cold-chain requirements. “Kits ultimately have to be packaged in shipping containers, and these have fixed, standard dimensions. So, when you are preparing kits that will need to end up in a 12-in. x 12-in. shipper, you have to make sure that you are sourcing ancillary supplies (e.g., syringes) with an eye on these dimensions and repackaging materials to fit into these constraints, or costs can skyrocket,” notes Geiger. She adds, “Many drug products require temperature-controlled shipping and storage, but ancillary materials do not.” If a kit’s ancillaries increase the size of a unit, it may be better to ship a separate ancillary kit that doesn’t need to be kept cold. When shipping direct to a patient’s home, convenience might be more important, however.
Decentralized clinical trials occur in a participant’s home rather than at a central clinical site. “Direct-to-patient (DTP) and direct-from-patient (DFP) services have really transformed what materials are needed for a study. We’ve seen more demand for more patient-centric kits,” says Geiger. “In trials at clinical sites, ancillary items are stocked, and drug product materials can be kept in storage for a patient for multiple visits, but for visits at the home, you need to package not just the drug product but also the means to administer it, as well as ancillary materials or medical equipment. In addition, return packages need to hold patient samples and other items such as used wearable tracking devices or completed questionnaires. DTP/DFP is new, and the packaging is specific for each unique study.”
“The trend of moving the center of clinical trials to patient homes drives requirements for primary packaging in the form of patient-friendly administration systems,” adds Berrón. “For secondary packaging, this shift increases clinical kit complexity: inserts and dividers in top-loaded cartons provide a more logical presentation for the end-users. Personalized therapies, such as CAR-T and gene therapy, will only push this trend further, increasing the requirement for user-friendly clinical kits.”
“The push in 2020 for hybrid and remote clinical trials provided fertile ground for home-based technologies,” says Berrón. She suggests that use of patient-monitoring technologies, such as barcodes that can be scanned by patients with a smart phone, will continue to increase.
In addition to barcodes used with smart phones, “smart” packaging uses digital technologies such as labels with radio frequency identification or near-field communication (NFC) tags, to track the package and how the patient uses it.
“Patient non-adherence is a prevalent concern in clinical trials and one reason why clinical trial costs are on the rise. Companies are turning to digital solutions to overcome challenges and ensure patient adherence,” notes Deepak Thassu, vice-president, R&D and regulatory submission at LGM. “Smart packages provide a means of capturing unbiased information on a patient’s dosing history. The data can be analyzed to help clinical trial teams better understand patient adherence and exposure to the drug. This dosing information can also be used in counseling patients to stay compliant with the protocol.”
“NFC technology integrated with secondary packaging can wirelessly communicate with a patient’s NFC-enabled smartphone to provide updates for the patient on when and how much of their medication to take,” adds Vercruysse.
In addition to monitoring patient adherence, smart packaging technologies help track the storage conditions of a package to ensure product safety and stability. “NFC technology can also transmit information about the package such as ‘factory sealed’ or ‘opened,’ and can contain unique identifiers for authentication and tracking,” says Vercruysse. Time-temperature indicators in labels can provide clear evidence if a temperature-sensitive medication has been stored in conditions outside the set parameters of the trial. Other chemical or biosensors can be used to determine the chemical and biological integrity of the product and to alert doctors and patients if the drug is unsafe to administer, says Vercruysse.
For biologic drugs, cold-chain storage and transportation are typically crucial parts of the packaging design. Although indicators could warn a patient of potential damage to a product, the aim is to maintain the cold chain with a package that arrives undamaged. Technologies for real-time tracking can monitor conditions such as temperature, humidity, and location and can alert distributors to take action before a package’s conditions are compromised (1). In addition, packaging should be carefully designed for cold temperatures. For example, it is important to consider how the materials and adhesives used in packaging as well as any tamper-evident seals will behave in cold temperatures, reports Almac Clinical Services (2).
“The packaging materials must be able to maintain their structural integrity at low temperatures, protecting the product within from damage,” adds Vercruysse. “Labeling must also be able to withstand low temperatures and moisture to ensure the information they convey remains legible.
Innovation is happening all the time to enhance the properties of packaging materials and inks to achieve these goals.”
The growing pipeline of biologics drugs has increased the need for cold chain capabilities. “We see this trend continuing, not only because of vaccines, but also because of more large-molecule and personalized medicines coming to market,” says Brian Keesee, vice-president and general manager of global clinical operations and supply at PCI Pharma Services.
Another trend is late-stage customization. “Keeping late-stage customization strategies in mind when designing patient kits and labeling helps ensure the end process is successful,” says Keesee.
Late-stage customization strategies are supported by just-in-time manufacturing concepts applied to packaging, which allow materials to be packaged and labeled just before shipping (3).
Labeling is a crucial part of packaging clinical trial materials. “Labels for clinical trial packaging require the same degree of batch-to-batch consistency demanded from drug raw materials,” says Berrón. “Label consistency needs to be maintained across all batches, which could be printed over time and across multiple facilities. Lack of consistency, even in secondary packaging, carries the risk of bias that could inadvertently affect the trial.”
FDA requires serialization of labeling for clinical trial materials, adds Thassu. “The most important consideration for serialization is protecting dose anonymity in a blinded or double-blinded clinical trial. To be truly blinded, a single label lot would be printed with serialization, then individual labels would be randomly assigned from that lot to ‘reference (R)’ or ‘test (T)’ [material]. Only the labeler would hold the unblinding key between a serialized label and R/T treatment.” LGM Pharma uses an automated vision system to ensure conformance of the label to specification.
Thassu notes that automated inspection has been valuable for labeling and for other parts of packaging. “Technical advances in camera vision and verification systems over the past decade have allowed companies to replace manual inspection with an automated equivalent to ensure the uniform presentation of packaging and labeling, at a faster pace,” says Thassu. He says automation can create efficiencies in clinical trial management that can reduce the overall length of clinical trials.
In addition to automating inspection, there are some opportunities for automation in the packaging process. Clinical kitting remains a generally manual process, although automation is used where its benefits can be justified, says Berrón. Automation requires some level of standardization, but clinical kitting has a wide variety of kits and requires flexibility in volumes, which can vary widely at different clinical trial phases, she explains. Benefits of automation include increased productivity and consistency and eliminating ergonomic concerns for workers performing highly repetitive kitting activities. “In 2020, the use of automation certainly picked up another driver when high assembly absenteeism impacted productivity,” notes Berrón. “Efficiency driven by automation provides many benefits, but ultimately it is dependent on the size of the study and standardization of clinical trial kits across multiple studies, [which] limits feeder reconfiguration and retooling [on automated lines].”
Another key consideration for packaging of clinical trial materials is the availability of packaging supplies. Due to the pandemic, the supply chain has been tight across most materials needed for clinical trials, particularly for ancillary items such as swabs, needles, and even gloves, notes Geiger. Existing relationships with suppliers are crucial to being able to source materials when allocations are limited, she points out.
Vercruysse notes that biopharmaceutical manufacturers can consider alternative materials to the traditional glass vials and syringes. Polymers such as polypropylene and cyclic olefin polymer are options. “Careful consideration should be given to the selection of these materials, but also the sourcing to ensure high quality,” he notes.
“Speed and agility became even more evident during the pandemic as we needed to package treatments and vaccines quickly and get them out the door. This meant being creative when sourcing materials as supply route and general availability of supplies was challenged with global shut-downs and reduced travel and logistics routes,” says Keesee.
Material supply partners should have the flexibility to quickly meet changing demand, says Keesee. He also sees a trend toward global, integrated logistics and materials suppliers “Partners that can manage logistics, storage, materials, temperature monitors, and integrated proactive communication globally provide tremendous value to the supply chain ecosystem,” concludes Keesee.
1. J. Markarian, “Tracking Technologies Safeguard Vaccine Cold Chain,” PharmTech.com, April 2, 2021.
2. N. Balanvosky and B. Thompson, Pharm. Tech., Partnering for Bio/Pharma Success Supplement, s26-s28 (February 2021).
3. A. Shanley, Pharm.Tech. 45 (3) 58-62 (2021).
Jennifer Markarian is the manufacturing editor at BioPharm International.
Vol. 34, No. 5
When referring to this article, please cite it as J. Markarian, “Packaging Considerations for Clinical Trial Materials,” BioPharm International 34 (5) 2021.