Interview with Hedley Rees on Cell and Gene Therapy Supply Chain
In September 2022, CCP’s CEO, Linda Kim had the pleasure of sitting down with Hedley Rees, Managing Director, PharmaFlow Limited to discuss current Cell and Gene Therapy Supply Chain challenges, and developments in the future.
1. What can you tell us about cell and gene therapies?
Cell therapy refers to the transfer of cells into a patient with the goal of improving a disease. The earliest and most established cell therapy is the blood transfusion. Gene therapy seeks to modify or manipulate the expression of a gene or to alter the biological properties of living cells for therapeutic use. Currently, the most advanced gene therapy is gene-modified cell therapy. This involves removing cells from a patient’s body, to introduce a new gene or correct a faulty gene. The modified cells are then put back into the body. An example of this approach is chimeric antigen receptor (CAR-T) cell therapy. In CAR-T cell therapy, a gene is introduced to the patient’s T cells, which are a kind of immune cell, using a vector (delivery vehicle). The additional gene changes the T-cells in a way that enables them to recognize and attack specific cancer cells.
Cell and gene therapy can be specific to the patient (autologous) or from a donor (allogenic). The supply chain challenges for both allogeneic and autologous therapies are firstly down to them being biologics.
2. What are the main challenges for the management of supply chains for biologics?
Cell and gene therapies are biologics—made from living things. Unfortunately, the foundation of modern-day pharmaceutical supply chains was intended to cater for the simpler and more straight-forward small molecule drugs (made by chemical synthesis). When the needs of the far more variable and complex biologics manufacturing and distribution supply chains, such as monoclonal antibodies, came along, they were made to fit the existing systems, rather than have their special needs catered for. Below is a comparison that should help indicate the differences:
|Small Molecule Drugs||Biologics|
|• Relatively stable||• Sensitive to temperature variation|
|• Long shelf life (2 – 5 years)||• Shelf life measured in months, not years|
|• Store/move @ controlled room temp.||• Store/move @ wide range of temps.|
|• Can identify by chemical analysis||• Identity varies with manuf’g. process|
|• One size fits all patients||• Stratification of product by patient class|
I’ve summarised the main biologics supply chain management challenges below:
Biologics starkly contrast with small molecule compounds, where a particular molecule can be reproduced reasonably accurately, independent of the facility and equipment used to make it. In biologics, the molecules are so large and complex that it is often impossible to define their molecular structures by analysis. All that is known is that a particular process has produced something that has a particular biological effect on a patient. Other manufacturers may not be able to replicate that product and its effect, even if the process appears to be the same. This has led to the industry mantra in biologics, that “the process is the product.” This has been and still is the leading obstacle to biosimilars hitting the market in the same was small molecule generics have. Sponsor companies must prove their product under development will be clinically interchangeable with the reference product. This is a significantly higher and more costly hurdle to jump than for generics and has led to companies steering away from this opportunity area.
A second complication is the sensitivity of biologics to temperature variation and other factors in the environment. A biologic material or product can be lost in the blink of an eye. A moment’s failure in concentration, from an operator or material handler, can mean months of work wasted. A temperature data logger not properly validated, activated, deactivated, or analyzed, can yield the same result—valuable product in the trash.
Supply input materials can also be problematic. They can dramatically affect yield, potency, and quality of output, as the strength (titer) of each new supply of materials can vary widely, depending on factors that are not always obvious to the acquiring company. Getting good pedigree information from suppliers, especially when the upstream supply chain leads to seemingly anonymous donors, can be a nightmare and sometimes even impossible. This is not the end of it. The cost of goods can often make a promising compound commercially nonviable, and lead to catastrophic outcomes for the sponsoring company.
3. What are the additional challenges for cell and gene therapy products?
Allogeneic therapies present the next set of challenges. The most established allogeneic cell therapy is a blood transfusion, and that should help us understand some of the considerations. First, we have cell donors, that must be sourced, screened, and matched to patient categories, or blood groups. Then there is safe storage and transportation, with the associated cold chain management and logistics disciplines applied across the lifecycle of the blood products.
Hopefully this example of the allogeneic blood transfusions and products, will help us get our arms around what is required to counter the challenges. The first point to make is that blood products do not go through the established wholesaler distribution networks that deliver drugs to hospital and community pharmacies for patient and doctor use. Closed networks, such as the Red Cross, take on the task. These networks are embedded into hospital systems to produce the all-important seamless link with the doctors using the blood products.
This should be our baseline as we move on to the most extreme supply chain challenge of all—autologous therapies.
The added complication here is that the patient is the source of the starting material (cGMP applies from here) and the destination of the finished product. See below:
The circular supply chain above adds an extra layer of complexity to the challenge. That extra layer, along with the multiple handovers and actors involved, draws a significant question mark over the feasibility of this approach in delivering safe, effective products to treat patients. We should remember the consequences of any error in the chain of identity with autologous therapies—certain death of the patient.
4.What do you see as the future of cell and gene therapies?
The future of cell and gene therapies will be driven by the commercial opportunities involved. CAR-T therapies are by far the most commercially advanced, as exemplified by Novartis’ Kymriah, which was approved by FDA in August 2017 with a $475,000 price tag. The question we must ask ourselves, however, is this:
“Why do allogeneic blood products utilize a dedicated system seamlessly integrated into hospital systems, when companies developing the more challenging autologous therapies are still trying to make the traditional small molecule system work?”
The supply chain risks and challenges are greater with autologous therapies, yet pharmaceutical companies go on with the small molecule drug model of selling their products into the hospital system, then standing back. This means there is little, if any, meaningful contact with the doctors and other healthcare professionals that will be using them? As we know, the number one rule in advanced manufacturing supply chains in exemplar sectors, is ‘put the end-user of your products front and center.’ The current approach is certainly not doing that.
5. What do you conclude from this?
We need to go back to basics, so that the current disjointed system being applied to cell and gene therapies is joined up and properly integrated into healthcare systems. The current painfully slow progress in commercializing the CAR-T therapies is evidence that investors need to hear.
In a recent article for TrialSite News, titled: Gene therapy—is it really a sound investment prospect?, I explained the issues with commercializing CAR-T based therapies. It is in no one’s interest—product developers, contractors, suppliers, and especially patients, if we go one trying to make a failing system work.
More on the detail of this next time.
About Hedley Rees
Managing Director, PharmaFlow Limited, and author
Hedley Rees is the managing director and lead consultant at PharmaFlow Limited, a UK-based consultancy specialising in the strategic design and management of preclinical, clinical, and commercial supply chains in the pharmaceutical and life science industries. Clients range from large pharmaceutical companies to emerging biotech, investors, lawyers, other consultancies, facility design & build specialists and third-party logistics providers (3PLs). Assignments span preclinical, clinical, and commercial supply chains up to complex multi-product networks covering global territories.
Previous appointments include senior positions at Bayer UK, British Biotech, Vernalis, Ortho Clinical Diagnostics, and OSI Pharmaceuticals. Achievements and Affiliations include:
- Author, Supply Chain Management in the Drug Industry: Delivering Patient Value for Pharmaceuticals and Biologics, Wiley, 2011
- Advisory Board Member, International Institute, Advanced Purchasing & Supply (IIAPS)
- Advisory Board Member GMP Review (GMP = Good Manufacturing Practice)
- Former consultant to Oxford BioMedica on UK Government funding call Advanced Manufacturing Supply Chain Initiative (AMSCI), resulting in funding award of £7.1M
- Former Advisory Board Member to Marken, 2011 - 2012 (now a UPS company)
- Founding Member of Expert Industry Panel for CPhI Worldwide (UBM plc)
- Former member of the UK Bio-Industry Association’s (BIA) Manufacturing Advisory Committee, 2007 – 2011