Cell and Gene Therapies (CGTs) offer promising ways to treat previously devastating and intractable diseases. At the same time, these “living therapies” have one of the most complex supply chains in medicine. The supply chain is most complex for autologous CGTs, where the raw material for the therapy is derived from the person who will receive them. This is in contrast to allogeneic therapies, where the initial biological material is sourced from a donor.
Using biological material from individual donors introduces supply chain challenges such as unreliable sourcing and variability of starting materials. In addition, patients often receive CGTs as an individualised, one-time treatment, so there is no room for error in the CGT’s quality and identity. Changing schedules at any point during collection, manufacturing, shipping and delivery can affect the entire workflow, compromising patient and product safety. In addition to their complexity, the resources and coordination necessary to produce a single therapy make it extremely expensive.
The current cost and complexity of CGT supply chains puts at risk their long-term scalability and affordability. Accordingly, the market success of CGTs depends upon designing supply chains that reduce production cost while mitigating risk, accelerating timelines and positioning drug developers to scale-up for eventual commercialisation, early. At the same time, though, targeting indications with larger patient populations such as heart disease, diabetes or dementia, fundamental questions must be considered about how much room there is in payer budgets to treat large scale populations with CGTs. For this blog, we will review a number of key strategies sponsors can employ to navigate challenges encountered during CGT manufacturing, handling and delivery.
- Engage with regulators early – Regulatory bodies in the US and EU recognise the challenges of CGT development and offer invaluable guidance for navigating chemistry, manufacturing, and controls (CMC) challenges. Additionally, regulators often facilitate accelerated approval pathways for these therapies. Taking advantage of these offerings can help inform strategic and compliant design of the CGT supply chain.
- Implement quality-by-design methodology – Quality-by-design methodology integrates scientific knowledge and risk assessment into system design so that weaknesses in the manufacturing process can be anticipated and avoided. Manufacturing processes that have been developed specifically for variable and living raw materials are essential for ensuring consistent product quality.
- “Close” open systems – Ensuring the speed, quality and consistency of CGT manufacturing is challenged by the unusual number of “open systems,” where the manufacturing workflow is manual and, therefore, at a higher risk of human error and contamination. “Closing” these operations through the use of tubing, welding or connections can help to reduce vulnerabilities during manufacturing. For steps that remain hard to “close,” such as viral transduction and harvesting, formal aseptic processing validation can help assure sterility.
- Pre-freeze critical manufacturing steps – CGTs are extremely sensitive to both time and temperature. So, disruptions during the manufacturing process can compromise the safety of the therapy and, consequently, the patient. Preservation of products throughout these key cell-processing steps via pre-freezing can protect product quality in the case of supply chain failures or delays.
- Enhance downstream yield – One way to reduce the cost of CGT manufacturing is by enhancing downstream yield. Recent estimates show that roughly three quarters of viral vectors are wasted during manufacturing. Using transfection processes and helper viruses, along with selection of high-producing cell lines for viral vectors, can improve overall yield.
- Strategically source supplies and raw materials –Finally, identifying relevant, critical quality attributes of raw materials can help improve reliability of raw material quality.
Handling and delivery
- Implement integrated digital solutions – Frequent handoffs throughout the CGT supply chain introduce many points of potential failure. Digital solutions – including a manufacturing execution system, a laboratory information management system and enterprise resource planning – can help maintain chain of identity for CGT products during manufacturing. Additional systems should also be employed to maintain connections between manufacturers and sites.
- Engage multiple couriers – While most sponsors have a primary courier, establishing secondary and tertiary courier relationships and pre-planning multiple itineraries can help ensure that timelines are not delayed. Establishing relationships with carriers with their own fleets, as opposed to those that rely on commercial flights for transit, can help to reduce the frequency of transit cancellations or delays.
- Train specialised site staff – Formalised training of specialised site staff is key to risk mitigation, especially at sites lacking experience with CGT trials or managing multiple protocols. Staff can be specially trained in the protocol requirements for specific CGTs, and help de-risk the “last 100 yards” of product handling.
- Perform mock runs of protocols – Patients and site schedules are co-dependent and require coordination. Performing mock runs of the end-to-end workflow at clinical sites is one of the most useful ways to troubleshoot the process and reduce the likelihood of human error, especially when site staff resources shift frequently, as was the case during the height of the COVID-19 pandemic.
Perhaps one of the most crucial decisions for sponsors is their choice in CRO. The development of CGTs is case-specific, and best-practices to ensure the reliability, affordability and safety of the CGT supply chain are constantly evolving. In order to optimise the CGT supply chain, sponsors must partner with a CRO that has the experience and the resources necessary to implement the most relevant and up-to-date innovations in manufacturing, delivery, handling and quality control.
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