Drug Product Security

Cell therapy and large-molecule supply chains have traditionally been treated as different entities, but as research around biologics, regenerative medicine, and cell and gene therapies (CGT) has progressed, the gap between these supply chains is quickly closing. Typically, cell therapy products, particularly personalized ones, have needed to be controlled and tracked dose by dose because they need to be delivered to the specific patient for whom they were made. The risk of this process failing within the supply chain could result in the death of a patient, either due to a complication, such as graft versus host disease, or simply because the therapy is no longer being a viable option for a patient who will often have exhausted standard treatment pathways at this point.

This has, over the years that autologous cell therapies have been developing, increasingly pushed therapy developers into utilizing digital eco-systems to support and track the supply and value chains of these therapies from the point where starting material is obtained, through to the final administration of the product. The data that feed into the full Chain of Identity (CoI) and Chain of Custody (CoC) records for these therapies can come from a vast array of systems, potentially operated by different stakeholders in the supply chain such as logistics companies, healthcare sites, and manufacturers. Manually accessing and connecting the information from these systems to create a full CoI and CoC record is time consuming and is prone to error and data duplication. This not only makes it costly, but poses a challenge when production needs to be scaled up and limits the use of the data that are collected in terms of reporting and analysis.

For the sake of both simplicity and scalability, many developers have invested in buying or developing cell orchestration solutions to unite all these disparate systems and pull the relevant information into a central, reportable, and searchable system that can help to drive and control all the steps on a therapy’s journey. These orchestration solutions also have the advantage of acting as a portal into the data that each specific stakeholder within the supply chain needs, ensuring that therapies are handled quickly and efficiently through the various complex steps.

Historically, large-molecule biologics, such as in-vivo gene therapies, have not demanded this level of integration, and tracking as the lack of personalization meant that the supply chain was shorter and did not include the complexity of dealing with patient-specific starting material or patient data. However, the sector has more recently witnessed several new approvals, and drugs with costs of millions of dollars per dose and similar market price estimates are made for more of these therapies in pivotal clinical trials. It is these products that are beginning to change the supply chain needs.

The challenges associated with supporting these drugs through their supply chain are not all entirely new, with many akin to those encountered in cell therapy value chains over the past 10 years, and as a result, large-molecule developers are increasingly looking at the solutions that have been developed to support cell therapy products as challenges begin to align:

• Shipping conditions and chain of custody remain a priority for both therapy types.
• Enhanced reporting and additional product security for high-cost large molecule drugs is desirable to minimize losses in the supply chain.
• High-cost drugs make tracking each patient’s treatment attractive, particularly where dosage is linked to patient specific variables like weight, as it can reduce product waste and loss.
• Reimbursement models that are linked to patient outcome require efficient tracking of individual patient milestones and making these data accessible to the therapy developer.

This article examines how data integrating digital ecosystems are increasingly being deployed to orchestrate cell therapies and could help to address security and traceability challenges throughout the supply chain for the newer, high-cost drug products as more focus shifts to the supply chain post manufacture.

Traceability

Cell orchestration systems historically focused on tracking patient starting material, manufacturing intermediates, and the final drug product. Growth in the sector and increasing numbers of therapies reaching commercialization have made manufacturing scheduling and resources management more significant. Being able to schedule accurately in an industry that potentially has restricted resources is more important now than ever.

As a result, more manufacturing systems are commonly being integrated into the cell orchestration eco-system, such as enterprise resource planning (ERP), manufacturing execution systems (MES), and scheduling management software systems. These integrations make the data that are required for tasks such as detailed batch and raw material tracking easily accessible to the developer in real-time and match it back to specific patient doses.

Additionally, cell orchestration systems already have the functionality to link the large quantities of data relating to shipping and storage conditions (e.g., temperature) to the therapy journey and make this available as part of the CoI record, as well as matching the data with the CoC record to show who was responsible for the material should an excursion become apparent. In addition, high use of digital workflow and data analysis within these eco-systems means that excursions can be proactively flagged to decision makers to try to mitigate loss, reduce costs, and avoid delays. For example, if a supply chain team get advance information about raw materials being delayed or becoming unavailable with enough warning, the manufacture of the product can be rescheduled or rerouted, and the downstream supply chain activities adjusted quickly.

Data compiled to form audit history of a cell therapy within an orchestration system will track all batches/lots/handlers etc. for each patient-specific therapy in a full, time-stamped audit record, facilitating corrective action in the event of an issue or investigation. With many high-cost therapies looking likely to move to patient outcome related reimbursement models, the availability of these data on a patient-by-patient basis could prove invaluable to assist with outcome-related reimbursement.

Manufacturing controls

Where batch sizes are larger and drug product non-specific, there is less of a need for orchestration; however, moving to a patient-specific model where the drug product cost is high makes having finer control to avoid stock build up and minimize storage times advantageous.

The control and visibility that an integrated supply chain offers extends the control and visibility that the drug developer or license holder has over the manufacturing process, allowing them to see and react to the stages within the process if something needs to be altered or a query is raised. With high-cost large molecule drugs often being made in small batches and dispatched on a patient-specific basis, as well as potentially being dispensed on a patient characteristic (e.g., weight), the number of units shipped will be tailored to the patient’s required dose. For this to be done accurately and efficiently, an established and secure way of feeding critical patient data into the supply chain and maintaining a link to the patient’s drug product-specific characteristic for each dose dispatched becomes necessary. It is also important to consider how to produce compliant, patient-specific drug product labelling to preserve the CoI and make it available at key check points where the product is handled, reducing the chance of error.

Offering developer’s supply chain teams visibility into selected data that are held in ERP and MES systems via automated data transfer of specified fields makes it easier for them to deal with short shelf-life, high value products, as they have harmonized access to the information that can drive forecasting and resource availability. Information flow can be two-way through the eco-system, so manufacturer’s planning teams can gain access to the patient schedule from the point where they are approved for the drug. This advance warning and scheduling detail could prove critical in minimizing surplus stocks and predicting both demand and capacity to supply, while offering supply chain teams greater control over the timing, scheduling, partners, and routing used to manufacture and dispatch a product.

Drug product security

Where cost per treatment is high, security concerns within the supply chain may extend beyond ensuring that the product is not tampered with, in addition to the physical condition of the product and the shipping containers. The ability to live track a product to see exactly where it is and who has both physical custody and financial title is important, as is having a full record of the condition of the product at each handover. This information can be fed back to supply chain teams in real-time within an integrated eco-system, with the ‘hub’ system triggering notifications or alerts as required if an event requires a decision or a response.

In addition to traditional drug security concerns, the inclusion of patient data in the supply chain (e.g., in the format of personalized labels) could bring new regulatory risks into the supply chain that traditional pharmaceutical processes do not need to consider. When operating internationally, this can be further complicated by the fact that data protection regulations vary locally, and labelling may need to be managed in multiple languages or over several different templates. Allowing manufacturers to access label formats owned and controlled by the drug developer but printed locally with patient-specific information is another advantage of having a central system which is integrated and accessible to stakeholders throughout the supply chain process.

There are also potential benefits that could be realized from gaining access to detailed shipping data. Broad analysis for various shipping routes, suppliers, or handling centers can identify common points of failure, aid risk analysis, and identify trends that can help inform future route planning and help to minimize time in transit and increase speed to treatment. All of these aspects are likely to be important factors in the commercial modelling of high-cost large molecule drugs, as the need to supply scales up and the incentive to ensure that product moves through the steps of the supply chain swiftly increases.

Post-treatment

Within high-cost treatments, outcome-based reimbursement models appear to be becoming more common, with reimbursement for the product being phased over the recovery period for the patient. Where there is a ‘clock ticking’ from the point of drug product administration, being able to record key post-treatment milestones on a patient-by-patient basis and share the information quickly and efficiently with relevant stakeholders could significantly speed up the reimbursement times for developers, easing the financial burden of supplying these treatments.

This may mean sharing information over several key systems, such as:

1. an orchestration system that records when drug administration has taken place
2. patient hub services or patient management systems that are managing aftercare appointments and follow up
3. invoicing or customer management systems, which could include various user profiles of the stakeholders.

The ability to do this quickly, efficiently, and securely while ensuring that data privacy rules are adhered to is likely to become more pressing, as more drugs fall onto this type of reimbursement model.

Conclusion

As the nature of many of the newly researched large-molecule biologics continues to evolve, and successful medications emerge that cost millions of dollars per dose, it is likely that the supply chain will have to make significant adjustments to manage the increased risk, changing commercial models and the potential of patient-specific data entering the supply chain.

Activities traditionally associated with the cell therapy supply chain, such as real-time tracking and monitoring, patient-specific labelling and dosing, and phased reimbursement from the point of drug administration, are all likely to become more relevant to developers who have products that adhere to this model.

As these challenges have been present in the cell therapy space for the past 10 years, a wealth of digital tools that have been developed to help manage the risk in the supply chain at sufficiently low cost and resource to make scaling up the production and delivery of a therapy sustainable. Manual and paper-based systems have been seen to be prone to weaknesses, labor intensive to manage, and deemed high risk by approving bodies. For example, FDA delayed the approval of the autologous cell therapy Dendreon for several years until the developer could demonstrate that the supply chain was sufficiently well controlled for the product to be approved. This means that when using paper-based traceability at the point of scaling up, large numbers of administrators are required to manage even small increases in patient numbers as these complex supply chains have been seen to have hundreds of manual steps per dose for a patient specific process that is not supported by automation and integration.

As the supply chain environment continues to move toward an integrated digital landscape, vast quantities of data are available for capture and analysis, ensuring that the integrations are robust and secure is critical, which becomes essential when patient data are involved. Utilizing a central system, like a cell orchestration platform that can act as a hub for data that stakeholders and systems within the supply chain can enter/exchange data into directly, helps to minimize data duplication and errors but also restricts data access and ensures that the data controller, or the drug developer, always retains the information from a security and a hosting point of view.

There are a broad variety of solutions and methodologies for creating integrated eco-systems, which will mostly be dependent on the core systems and technologies that are already in place with the various supply chain constituents. However, within the CGT industry, there are already eco-systems and collaborations that have begun to form, and supply chain experts within both developers and supply partners who have amassed experience on how to tackle some of the key challenges that come with designing and implementing integrated solutions. If the large-molecule supply chain continues to produce drugs with extremely high price points, then drawing on the experience collated by those in the cell therapy sector could be invaluable.