Five key manufacturing challenges in autologous commercial cell and gene therapies
PA cell and gene lead Paolo Siciliano, PA pharma supply chain expert Martin Sowden, PA’s US manufacturing lead Shanton Wilcox, and Harry Ustik, a cell and gene therapy manufacturing expert at PA, authored an article for SupplyChainBrain discussing the complex manufacturing challenges of autologous commercial cell and gene therapies.
Cell and gene therapies (CGT) provide highly personalized solutions for previously incurable genetic conditions and chronic diseases. While allogeneic CGT relies on a source of cells from a donor to treat patients, autologous CGT uses a patient's own cells which are processed outside of the body before being reintroduced to the patient, making them fully personalized. Autologous therapies’ personalized nature results in complex manufacturing challenges, driving costs high when transitioning from clinical to commercial scale.
Since 2016, pharmaceutical companies including Novartis, Pfizer, Takeda, Roche, Johnson & Johnson, Gilead, and BMS have invested billions in acquiring autologous and allogeneic CGT assets. This is due, in part, to exorbitant manufacturing costs, and the efficacy that justifies these prices. It’s up to acquirers to shift highly manual, complex clinical processes that achieve successful results to a commercial scale. Here, we describe five of the key challenges associated with more personalized, autologous CGT that contribute to high manufacturing costs and, as a result, the jaw-dropping price tags of these therapies on the market.
1. Batch-of-one, made-to-order
Autologous therapies demand a unique product for each patient, leading to a batch-of-one, made-to-order manufacturing process. This hinders economies of scale. The uniqueness of starting materials (i.e., individual cells) poses hurdles in ensuring quality control during the shift to commercial scale. While batch manufacturing is not possible for autologous CGT, adaptive manufacturing to maintain high bioreactor utilization is critical to keeping costs down.
2. Bioreactor scalability issues
Occupying a bioreactor for an average of 14 days per therapy, autologous CGT processes limit production to 26 therapies per year. To achieve commercial levels, a substantial number of bioreactors is necessary, resulting in a larger facility footprint, increased equipment costs, and higher requirements for trained personnel. This in turn necessitates significant investment from organizations, including complementary upskilling programs to produce at scale.
3. Lack of synchronized planning systems
Inefficient logistics due to geographical and centralized manufacturing, physical ‘cold chain’ actions and equipment, along with digital infrastructure constraints complicate coordination between therapy developers and hospitals. The absence of synchronized systems leads to inefficiencies, delays, and increased risks for patients. These also result in higher costs across the stakeholder landscape. Therefore, effective planning and communication are vital for the smooth movement of materials.
4. Absence of automated processes
The current commercial manufacturing processes for autologous CGT are an adaptation of clinical processes that rely on highly skilled labor, and limited automation. Automation necessitates the vision to step back from current production strategies and re-imagine how scaled manufacturing could unlock current challenges. This requires substantial investments in R&D, technology, staff training, and regulatory compliance.
5. Highly variable forecasts
Forecasting demand for autologous CGT is challenging because of uncertainties in future treatment pathways, and ambiguities around how these therapies will move from ‘last resort’ to an earlier stage of a patient’s treatment journey. Patient eligibility, therapeutic response and alternative treatments contribute to this variability, making investments in manufacturing and research risky. Over-estimating demand leads to under-utilized capacity, while under-estimating demand results in shortages and lost opportunities. It's possible to address this uncertainty through a highly adaptive manufacturing strategy, with multiple CGT assets being produced in the same location.
Autologous CGT offers a promising solution for various diseases, but the transition of these therapies from clinical to commercial scale presents substantial challenges. Addressing these complications will demand the development of highly adaptive supply chains. It will take innovation, collaboration, and investments in technology and infrastructure to ensure the continued success of this ground-breaking field.