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That was a key issue raised at both the Boston Bioprocessing Summit and Boston Biotech Week, and this blog presents some of the views expressed at these events.
The past few years have been incredibly exciting for the field of cell and gene therapy (CGT). We have, at last, witnessed the first market approvals of these potentially curative therapies. Unfortunately, they come at an eye-watering price. For example, Strimvelis—a gene therapy for a very rare immunodeficiency called ADA-SCID—costs an incredible €594,000. Babies born with the disease lack a functioning adenosine deaminase (ADA) gene which results in extremely poor immune function. Strimvelis is an ex vivo gene therapy whereby the patient’s bone marrow cells are modified outside the body with a virus carrying a functional ADA gene and subsequently re-administered. However, as approximately only 15 babies are diagnosed with ACA-SCID in Europe each year, the associated costs are high. Furthermore, Anthony Davies of Dark Horse Consulting argued that these high price points are also a result of high manufacturing costs and not corporate greed as speculated in the media. Therefore, addressing the existing manufacturing constraints could confer significant improvements to CGT affordability.
The manufacturing technologies currently used are sub-optimal, involving open systems and manual pipetting with cell culture flasks instead of bioreactors. The work is very labor-intensive and expensive. And even though viral vector manufacture is more advanced, the current scale is limited. The situation bears resemblance to monoclonal antibodies in the mid-1980s when there was a scramble to expand manufacturing to meet rocketing demand. How rapidly the CGT industry will respond becomes a critical factor.
Large pharma developing CGTs have the ability to acquire manufacturing facilities while smaller biotechs tend to rely on contract manufacturing organizations (CMOs). The problem is that CMOs cannot keep pace with demand – the average waiting time for a CMO to start a new CGT project is 15 months. Furthermore, a CMO’s ability to expand is hampered by a shortage of the necessary skilled staff. Bioprocessing scientists with experience in cell and gene therapy are rare and require significant training once hired. In addition, those with process development experience are particularly hard to find.
Many CGT companies are weighing up the pros and cons of manufacturing in-house versus outsourcing. Devyn Smith of Sigilon Therapeutics discussed the most important questions a CGT company should ask themselves when making this decision:
- Would we be able to manufacture the requisite quality standards in-house?
- Do we have enough capacity in-house or does the CMO?
- How much money would be needed to build internal capacity?
- How many manufacturing sites would be needed for adequate global reach?
- What type of manufacturing is required? Just-in-time, batch, point-of-care?
- What is the net present value (NPV) in either situation?
The product itself will also determine whether internal or external manufacture is more suitable. Key considerations should therefore include:
- Autologous/allogeneic cell therapy and in vivo/ex vivo gene therapy have different manufacturing needs
- How will the cost of goods differ between the two scenarios?
- Would either option be sufficiently scalable for subsequent late-stage clinical trials or commercial manufacturing?
- How easily could the internal manufacturing process later be transferred to a CMO, or vice-versa?
- What is the expected patient experience and does manufacturing location matter?
Anthony Davies predicts that costs to the healthcare system will become untenable unless the cost of goods in manufacturing are optimized. He estimates that labor accounts for 60% of the cost of goods and that this could be improved through automation and enhanced process efficiency. Viral vector manufacturing is also a significant cost that should be optimized and scaled up, as well as improvements in transduction efficiency at a lower multiplicity of infection (MOI).
Both of these conferences provided an exciting forum for undeniably vigorous discussion on how to tackle the issue of costs in CGT manufacturing. While there are still significant challenges to overcome, the future is bright as we see companies emerging with more sophisticated technologies in order to make these therapies commercially viable.