Amin Adibi is a biomedical engineer and a research assistant at the University of British Columbia. His areas of interest include cell manufacturing and bioprocess optimization, clinical translation of cellular therapies, health outcomes and cost-effectiveness modelling. Amin has an MSc degree from University of Calgary, where he focused on developing adjuvant MSC-based therapies for brain aneurysms. Follow him on twitter at @aminadibi
Last month, CCRM hosted the Cell and Gene Therapies Workshop (CGTW16) in Whistler, BC. The one-day workshop focused on large scale cell manufacturing, clinical trials, regulatory issues and health economics. CCRM’s Chief Technology Officer, Dr. Kim Warren, was the keynote speaker at a dinner the night before and provided a glance into best practices in developing a manufacturing strategy for any given cell or gene therapy product. As she pointed out, raw materials play a key role in successful cell manufacturing, and it is essential to have verified alternate sourcing available to safeguard against potential disruptions in the supply chain. She also touched upon potential differences between development stage and GMP manufacturing: “GMP manufacturing usually takes longer; it is therefore important to ask whether the product is going to remain the same, and whether there are assays in place to test for that.”
The key theme in Kim Warren’s talk was the need for good and detailed characterization of the product, which she says is often an incremental process, and to define identity, purity and potency with as much detail as possible. Establishing the potency and testing for it has been one of the major challenges in manufacturing cell and gene therapies. In Dr. Warren’s experience, the way to go about it is to find and use surrogate markers. “Start looking [for surrogate markers] early, cast a wide net, and then focus in,” she says. She also mentioned that when establishing stability, it is important to consider not only the final product, but also raw materials and intermediates. Equally important is the stability of the final product as it is being shipped, stored or administered in clinical settings.
The need to pay enough attention to ancillary materials was something that Lee Buckler, the CEO of Vancouver-based cell therapy startup RepliCel, also emphasized: “Your product is only as good as your ancillaries and your delivery mechanism.” Variations and imprecision in intradermal injection of cells was one of the challenges that Lee Buckler and his colleagues identified early-on in developing their dermal sheath cup cell therapy for hair regeneration. This led to the development of RepliCel’s innovative Dermatology Injector Device, a device that allows for automated and controlled injection of a multitude of dermatological products into the skin. Interestingly, the dermatology injector is expected to be the very first RepliCel product to hit the market.
Another interesting talk was Dr. Nick Timmins’ take on the state of cell and gene therapies in 2016 and engineering challenges in cell manufacturing. CCRM’s Dr. Timmins, VP Technology and Director BridGE@CCRM, opened his talk by mentioning a few cell therapy success stories, including the cases of Emma Whitehead, the first child whose leukemia was successfully cured by a CAR T cell therapy, and Darek Fidyka, the Polish firefighter who regained the ability to walk after a surgery involving olfactory ensheathing cell therapy helped his severed spinal cord regenerate. While advances like these are truly amazing, the question remains as to how can we produce large amounts of cells at minimum cost, so we can make cell therapies available to a large number of patients?
To answer this question, we must first understand the required number of cells. As Dr. Timmins pointed out, a quick back-of-the-envelope calculation will show that the demand for a CAR T cell therapy for acute lymphoblastic leukemia and chronic lymphocytic leukemia may very well exceed 25,000 doses per year in North America alone, with each dose requiring as much as one to 10 billion cells. That would translate to 25,000 annual batches in the case of an autologous therapy, which would be exceedingly difficult and costly to manufacture, or approximately 13 x 2000L batches/year in the case of an allogeneic therapy.
But what does it take to produce this many doses every year in a reliable and cost-effective manner? According to Dr. Timmins, it is extremely important to define what the product is. The first step towards such a Quality by Design (QbD) approach is to develop a Quality Target Product Profile (QTPP): “QTPP is a living document for describing what your envisioned product is, and it evolves as your knowledge increases,” says Dr. Timmins. At minimum, QTPP defines quantitative criteria for identity, purity and potency, which leads to critical quality attributes, a set of product characteristics that guarantees its safety and efficacy. Critical quality attributes are in turn controlled by critical process parameters, raw material attributes and their interaction. A design of experiments (DOE) approach can then be pursued to optimize process inputs within the design space, in order to yield sufficient number of clinical-grade quality cells.
I thought the speakers shared valuable insights into manufacturing challenges for cell and gene therapies, but I’ve just given you a taste of what I learned. Tune in next week for part 2 on scale-up challenges, closed systems and more!