Incorporating CMOs into the clinical trial supply chain

The clinical supply chain involves working with several outsourced partners. Jens Mattuschka, Vice President, CLS Worldwide Operations, Parexel International, looks at core planning to reduce the risk of failure

The clinical trial supply chain is a complex, multistep process with the inherent risk of failure present at every stage in the drug development cycle. It is by no means a simple task to bring all parties together in the correct order to create a coherent, stable flow. A core planning structure must be in place and carefully evaluated to ensure clinical trial success. For clinical logistics to run smoothly, it is important to recognise all dependencies and assess supply chain risks in advance so as to temper them.

One of greatest challenges for contract research organisations (CROs) managing clinical trials and the supply chain is the seamless incorporation of specialised third party suppliers

One of greatest challenges for contract research organisations (CROs) managing clinical trials and the supply chain is the seamless incorporation of specialised third party suppliers, such as manufacturing companies, focused on primary and secondary packaging of investigational medicinal products (IMPs) and other clinical trial materials. Small delays to production timelines are not uncommon and can cause significant overspending. Understandably, when delays occur at one stage in the supply chain, the impact can be felt by every forward link. Costs escalate quickly and the likelihood increases of additional study delays.

Typically, this outcome is due to poorly controlled connections or the absence of a manufacturing supply strategy. Advance planning based on valid trial protocols is essential for avoiding insufficient product quantities or manufacturing capacities.

To develop a successful plan for integrating third parties, it is therefore vital that all links along the chain are considered in advance, especially when implementing best practices to improve information flow among clinical manufacturing, logistics, clinical and IT teams. By collaborating with CMOs from the outset, CROs will be better placed to develop and execute their plans in close cooperation and benefit from a shortened planning cycle time.

The importance of quality

It is important that any manufacturing process that affects the stability of the investigational product, its formulation or packaging, is properly factored. Sometimes good manufacturing practice (GMP) efforts to finish a product are underestimated by clinical R&D personnel, perhaps due to a lack of understanding around the intricacies of the buyer–supplier relationship. CMOs can address this by regularly updating and educating their sponsors and CRO stakeholders.

Recognising the highest impact and importance of quality within the supply chain is a basic but often-neglected element. Without a mindset that embraces quality management, clinical trials face rising costs or, even worse, put patient safety at risk. It is important that operations with the highest standards of quality across the entire platform of R&D services are developed and maintained.

Clinical trial supply chain planning

Limited transparency of demands along the supply chain – from the patient, investigator, clinical monitor, local depot, central distribution centre, CMO or third party vendor involved in pre-production activities – means that last-minute orders, changes or even the misuse of available stock can cause severe delays along the line. This has an impact on trial continuity and inevitably causes huge inventory swings. It can also be damaging for drug safety; if a patient is already enrolled in a trial, they are at risk should they fail to receive the correct medication dosage on time.

Figure 1: CMO – an integral part of supply chain

Having a comprehensive plan in place isn’t always straightforward. Clinical supply planners are required to appraise several elements of the start-up phase, yet they often experience a disconnect from the clinical team. Because CMOs primarily become involved early in the supply chain stage of production, it is essential to embed manufacturing experts into the clinical trial core planning structure. Just as CMOs must be aware of the quantity CROS be aware of the availability of the initial IMP batch and the anticipated delivery time of drugs to sites and patients. Similarly, they should know how long the drug can remain on the shelf. Without this information, expiry management at drug handling sites cannot be properly controlled.

Biopharmaceutical R&D experts and CROs should involve their CMOs in the planning process at the outset and follow a sales and operations planning model from the beginning

Any forward-looking distribution strategy should incorporate key manufacturing elements. It helps to ensure a coherent, logical process is in place far in advance of the completion of packaging. Other aspects that should be incorporated include: expiry date management and distribution schemes, packaging and label design, and the impact of product characteristics – dosage form and temperature conditions.

Given the above, biopharmaceutical R&D experts and CROs should involve their CMOs in the planning process at the outset and follow a sales and operations planning (S&OP) model from the beginning. This is the ‘gold standard’ within the logistics industry, and should be adapted for this special drug market segment with the full involvement of Sponsors, CMOs and CROs in planning. This collaborative method can dramatically reduce planning cycle time and by standardising processes, forecasting accuracy can be improved and stock shortages cut.

Manufacturing

There are many things that can affect the storage, distribution and administration of a product: formulation and stability, as well as IMP kit design, whether that is a study-specific labelled blister, vial or bottle.

For example, a project with relatively large blister packages, shipped under cold chain requirements of 2°C to 8°C lowers the cost of production, particularly for small batches of over-encapsulated drugs. However, this raises transportation costs because the packages must be transported in validated high-volume shippers.

Changing the number of batches produced has a similar outcome. It becomes less expensive to carry out one large production run, but take into account expiry dates, uncertain enrolment numbers and a high volatility in regional distribution demands, and the end product may be quickly rendered unusable. If this happens, the fresh batches needed may be unavailable.

Figure 2: Clinical supply chain journey

Careful planning enables CMOs to foresee deviations before they occur and ensures the best production path is chosen. CMOs can be innovative by optimising manufacturing and implementing better processes. These might include small-batch IMP labelling routines, forecast automation, production planning and resource allocation. Additionally, investments can be made in future logistics areas. Value can be added to clinical trials by supporting the chain through e-labelling, RFID or on-demand/just-in-time labelling approaches.

Project execution

Certain manufacturing aspects can influence distribution, handling and re-supply processes. Although product quantities can be forecasted during the planning phase, the entire chain must continue to be monitored to mitigate the risk of disruption. During the execution phase, planning parameters should be constantly reviewed. This allows adjustments to be made should an external influence threaten product flow. In many ways the planning phase is an ongoing activity, with the core plan constantly being reviewed and updated. However, having a sophisticated plan in place from the start helps simplify the drug development journey.

Technology integration

Considering the discussion above, we must remember the important role that technology plays in this process. Many technical instruments have been introduced by clinical supply chain experts over the years. For example, interactive response technology (IRT) solutions streamline and simplify complex processes. These play a significant role in enabling intelligent and cost-effective in-time supply distribution, a vital function in the global and extremely volatile clinical trial environment.

Efficient planning and the use of optimised technologies prevents product shortages and bottlenecks in the supply chain

The key to success is tightly combining enterprise technology, which brings together manufacturing, storage, distribution, investigational site management and clinical trial management systems – with CMO distribution experts along the clinical supply chain. Meanwhile, the ultimate S&OP tool for any clinical trial logistics organisation is an enterprise resource planning (ERP) solution. Not only does this promote technology integration, but also supports lean process management, allowing for reasonable calculation and more accurate forecasts.

IMP manufacturing can be an uncertain process; complete flexibility is necessary to accommodate the potential for change and CROs and CMOs should build adjustments into initial plans before verifying these along the chain. Regardless, efficient planning and the use of optimised technologies prevents product shortages and bottlenecks in the supply chain, informing decision-making and minimising the need to apply said flexibility. Using enterprise solutions, processes can be streamlined and automated, improving operations and costs.

Future considerations

If CMOs, logistics providers and the wider biopharmaceutical industry can come together to work as trusted partners, a non-disruptive end-to-end clinical supply chain is perfectly achievable. We need only look at other industries with similarly complicated supply chains – the automotive sector, for example – to find the benefits of such teamwork. Bringing a CMO in as a partner at the early stages of development can lead to greater communication and eventually, new and successful approaches to clinical trial logistics. An intelligent supply chain strategy combined with holistic project management will result in a more clear and successful drug development journey.

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