Demystifying Complex Clinical Trial Kit Preparation

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Developments in biologics and personalized medicines are reshaping the clinical trial landscape. According to Grandview Research, the global biologics market is anticipated to reach $398 billion by 2025, with growth supported by faster drug approval processes (1). Simultaneously, the increasing prevalence of cancer and rare diseases is providing the catalyst for investment in the development of targeted therapies. These precision medicines, which are tailor-made to meet unique patient needs, are expected to reach $85 billion over the next five years, representing a substantial 9.9% compound annual growth rate (2).

The increase in complex, targeted, large-molecule products brings with it disruption to traditional drug development. In an increasingly competitive market, expediting biologic drug development, approval, and commercialization in a bid to achieve timely return on investment is key. As such, clinical trials are shifting from developed nations to emerging countries, including Latin America and Western Europe, which possess greater disease variations (1) and can represent more efficient and cost-effective operations that promote faster completion of key study milestones.

Exploring the conditions for a perfect storm

While developing biologics and personalized medicines present clear opportunities to advance human health, it also makes designing strategic and streamlined supply chains more challenging and risk intensive.

The larger financial investment synonymous with developing and manufacturing biologics makes the existence of waste and inefficiency in the supply chain commercially unviable. This puts pressure on sponsors to optimize supply and minimize waste. This pressure is magnified by the lower product yields associated with biologics. This is largely attributable to the complex manufacturing process, which involves living systems that are sensitive to very minor deviations in the manufacturing process. Short expiration dates are also typical for complex biologics. A lack of stability data means biologics can easily become unstable if not maintained at precise temperature ranges through the process of development to patient delivery.

When combined with the standard study-based challenges of operating global clinical trials—from mid-study protocol amendments or unplanned delays, to navigating multiple country-specific regulatory requirements, to managing bulk drug availability and enrollment changes—the conditions for a perfect storm are evident.

To mitigate these risks to better serve patients and enhance performance, it is necessary to re-examine the approach to and management of the clinical supply chain. As the industry evolves, sponsors should prioritize exploring new ways of conducting and managing clinical supplies geared more toward biologics and personalized medicines. Clinical packaging strategy is a good place to start.

Critical considerations for biologics packaging planning

For supply chains to be flexible and viable, clinical packaging should be planned with the complexities of biologics products in mind, and at the earliest opportunity. There are several critical factors that must be considered to inform a fit-for-purpose packaging strategy that can respond effectively to the complex challenges associated with biologics and personalized medicines.

First, the proposed depots and sites should be checked to establish capacity to appropriately store materials during the last leg of the cold chain. Shipping conditions and processes also need to be scrutinized to ensure product integrity can be upheld. Shipping requirements are often overlooked, yet failure to obtain a firm grasp of the average quantity of material sponsors plan to ship at a time can lead to disruption and delay, while heightening the risk of waste and negative patient impact. At this point, sponsors should consider development of kit designs that will fit within the core of cold-chain shippers. When dealing with high-value biologics, separating products into multiple shipments may increase overhead but mitigates the risk of loss, should temperature be compromised during distribution.

Another crucial factor is assessment of the material-handling capabilities of each step of the process and party involved. This will ensure processes are in place or can be implemented to effectively and safely handle biologics material within the required storage conditions, while prioritizing end-to-end patient safety and product integrity.

Packaging design, materials, and processing options are influenced by a number of product, study, and sponsor-specific requirements. Perhaps the most obvious is clinical trial timelines. If timelines are short, typically it will be harder to use booklet labels and may necessitate use of a previous kit design. Contrastingly, if enough time is provided, a bespoke packaging solution can be designed that meets unique kit requirements and decisions made based on what is best, not what is possible.

It’s also important that sponsors define all packaging and distribution requirements prior to finalizing packaging design, as last-minute changes have the potential to delay the start of a clinical trial.

Although not unique to biologics, blinding can impact packaging strategy and is a prime example of why developing adaptive supply chains is important. For example, when using commercial comparators within a blinded study, the commercial packaging may change throughout the life of the study. Strategies designed to adapt to evolving program requirements will enable sponsors to take additional steps to ensure proper blindness is maintained. Unexpected comparator changes can also have a domino effect on costs, which can be especially detrimental to the performance of programs that involve high-value, low-yield products.

The amount of label text sponsors require can also present challenges when labeling small vials and prefilled syringes. As most biologics-based products are stored within vials, the fragility of the packaging can increase the risk of breakage and require the addition of a bag or pouch into the design of the final unit for shipment or storage. Not only are glass vials more susceptible to breakage during distribution, but the thaw-and-freeze cycle of a product can lead to cracks in glass vials, making plastic vials a better choice in some scenarios.

Fragile packaging components can also limit packaging speed and efficiency if handling requirements prevent the product from spinning, thus removing the option of labeling automation. Biologics product that are sensitivity to light and temperature will further inform handling requirements, options, and limitations for not just packaging design, the types of materials, and production environments, but for storage and shipment, also.

Biologic drugs with special packaging requirements demand a more complex kit design and more time to label or assemble materials. Likewise, if biologics products need to be processed in ultra-low temperature conditions, the choice of materials must be carefully considered. For example, adhesives behave differently based on the application temperature, the storage temperature and duration, and the material to which they are applied. Some adhesives will not hold in ultra-low temperature ranges; cartons may need to be mechanically designed. Products being processed in frozen conditions will require plastic coatings to strengthen the carton and protect from potential moisture damage. Most tamper-evident seals are not effective when applied to plastic; packaging must be adapted to ensure kits that require tamper seals remain both functional and compliant.

Finally, the frequency in which sponsors anticipate updating the expiry dates for biologics products will shape supply chain and packaging approaches. Factoring this into packaging planning at the earliest opportunity will help minimize waste.

Being clear about requirements for packaging and distribution prior to finalizing packaging design will help manage risk and empower sponsors to operate optimized and flexible supply chains that keep timelines on track.

Embracing new tools for new challenges

To respond to the challenges presented by biologics, supply chains need to be nimble and adaptive to change. When it comes to a packaging strategy capable of ensuring costly, temperature-sensitive products remain viable and flexible for wider use across a study’s lifecycle, traditional production models may not deliver in every scenario.

Instead, new approaches are needed to effectively maintain control over high-cost, high-demand clinical supplies, while decreasing waste, increasing product availability, and effectively managing limited stability profiles within the clinical supply chain to meet the specific needs and timelines of biologics trials.

One strategy sponsors can utilize to achieve these goals and inject flexibility and viability into biologics supply chains is just-in-time manufacturing (JTM). Unlike standard batch manufacturing, developed to meet the needs of lower-value, small-molecule products, and less complex program models, JTM offers a more flexible and lower-risk option for sponsors of studies involving biologics and targeted therapeutics.

The production strategy, which can be practiced on its own or as part of a wider LEAN manufacturing initiative, refers to the late-stage customization of clinical kits and is becoming more prevalent across trials involving gene therapies, rare or orphan diseases, oncology, and immunotherapy treatments. It is also becoming increasingly popular for sponsors of targeted therapeutics and patient-centric trials that necessitate patient-specific labeling and kit configuration, for trials operating a pooled supply strategy, and for trials involving drugs with short stability and a need for frequent retesting.

JTM makes it possible for stock materials to be packaged and labeled just prior to shipment to effectively meet varying global need, once demand is known. This approach better supports variable demand typical with biologics programs and patient-specific requirements, while mitigating the risk of high-value investigational medicinal product exceeding its expiry date while awaiting distribution. Implemented appropriately, JTM can reduce the need to pre-package bulk supplies before a study commences and facilitate pooled supply across protocols.

JTM can also reduce over-production leading to enhanced commercial performance. With a recent Tufts study estimating that almost 50% of clinical sites failing to recruit patients in line with estimates (3), significant quantities of seeding stock, produced as part of a batch manufacturing approach, can often remain unused and require destruction and replacement, due to limited expiration.

By combining careful consideration of the critical factors needed to plan a robust biologics packaging strategy with adaptive production methods, sponsors can overcome the challenges of operating complex global trials of biologics and targeted therapies. Through embracing this best practice, sponsors can operate supply chains with the increased flexibility and performance needed to promote timely and successful program completion, all while keeping patients at the heart of operations.

References

1. Grand View Research, Biologics Market Analysis by Source (Microbial, Mammalian), by Products (Monoclonal Antibodies, Vaccines, Recombinant Proteins, Antisense, RNAi), by Disease Category, by Manufacturing, & Segment Forecasts, 2018–2025, Report (2017).
2. Grand View Research, Precision Medicine Market Size, Share & Trends Analysis Report by Application (Genetic Tests, Esoteric Tests, Pharmaceuticals, Medical Devices), by End Use, And Segment Forecasts, 2018–2025), Report (2018).
3. Tufts University Center for the Study of Drug Development, CSDD Impact Report January/February 2020, Report, (2020).

About the authors

Natalie Balanvosky is just-in-time manufacturing solutions manager, and Bryan Thompson is production manager, both with Almac Clinical Services.