Building Manufacturing Infrastructure for Cell and Gene Therapies
THE PRODUCTION SHORTFALL FOR CELL THERAPIES AND VIRAL VECTORS COULD HAVE A DEVASTATING EFFECT ON THE GROWTH AND SUCCESS OF THE INDUSTRY BUT WHAT ARE THE ROOTS OF THE PROBLEM AND WHO'S GOING TO SOLVE IT?
Cell and gene therapies are closer to becoming the new standard of healthcare. With the potential to treat thousands of patients globally and an estimated market value of $21bn/year worldwide by 2025, there is huge promise both clinically and commercially.
Market approval is just the first step towards a commercially viable product in this maturing and sometimes unpredictable market. There are also some significant bottlenecks relating to pricing and reimbursement, supply chain infrastructure and commercial scale production capacity shortages. To become the new standard of care, treatments have to be accessible, thus, we must strive to reduce the cost per patient from $100,000s to $10,000s. One of the main factors that can influence this is the cost of goods, in particular, manufacturing.
However, the lack of production capacity is a huge potential crisis for our industry and this is occurring at both commercial scale and, more specifically, for viral vector production. This article will examine the contributing factors to the production challenge, how our industry is tackling them and the implications for the long-term commercial success of cell and gene therapy treatments.
The production capacity challenge
There are many factors that have contributed to this manufacturing backlog. Cell and gene therapies are very complex products that require specialised manufacturing facilities and equipment, as well as highly skilled and experienced technical staff and operators. Currently, there is a limited number of CDMOs and academic facilities that are able to cater to this need and most of these CDMOs are at full capacity with waiting lists of months and years. To put it simply, demand is far exceeding supply.
Another layer of complexity lies in the production of viral vectors; a crucial ingredient in many advanced therapies. There is a significant backlog in the manufacture and supply of viral vectors and one of the pressures causing this is high volumes needed per dose, which can require hundreds of litres. The manufacturing processes themselves are also falling short, with low yields, use of technology designed for antibody production and productivity as low as 10%.
Recent case reports from Sarepta tell the scale of the challenge its AAVrh74.MHCK7.micro-dystrophin gene therapy was dosed up to 1014vg/kg and the trial’s dose-escalation plan calls for a highest dose of 2x1014vg/kg; in a 40kg DMD child, this is equivalent to 8x1015 AAV vector genomes. Doses at these levels will require huge production volumes at such low yield rates. However, the average age of patients for Sarepta’s Exondys 51, which is currently 13 years old, is expected to reduce as increasing awareness and expanding coverage helps diagnose younger patients. As such, the average weight of a patient might be more in the region of 20kg rather than 40kg, meaning 4x1015vg is the probable dose.
Tony Hitchcock, Technical Director at Cobra Biologics stated, “If we are to going to be able to treat significant patient populations in key disease areas such as Haemophilia or DMD where treatments require doses sizes in the region >1014 to 1015vg and potential patient numbers are in the thousands, then this equates to production volumes of over 1,000,000L of cell culture, which represents a significant manufacturing challenge to the industry.”
This is understandably a major concern for biotechs and other developers. First, there is the obvious challenge of not being able to manufacture and, therefore, supply your product. Second, investors are becoming increasingly wary of biotechs that lack an available source of vectors or commercial scale manufacturing capacity, but without investment biotechs that don’t have products on the market, i.e. most, cannot continue. Will this stunt the growth and innovation of our industry?
Meeting increased capacity needs
Thankfully, there are several solutions being considered and implemented. One approach is to buy manufacturing slots years in advance; some organisations are even hedging their bets by booking slots with multiple CMOs years in advance. Indeed, both options are very costly in a situation where CoGs need to be tightly controlled. Although, it’s seemingly those with big budgets that can take advantage of this approach; we’ve seen deals struck between Novartis and Oxford Biomedica and between BlueBird Bio and Lonza. However, it’s unlikely that this level of investment is feasible for smaller developers.
An alternative approach to securing manufacturing capacity that is becoming more prevalent, especially when it comes to viral vector manufacturing, is for drug developers to build their own facility illustrated by some recent, high-profile examples. For instance, Spark Therapeutics now have a 48,000 square foot facility at their headquarters in Philadelphia, which includes a state-of-the-art cGMP manufacturing facility and AAV vector GMP manufacturing capabilities. Pfizer is also building a new gene therapy production facility in North Carolina where its recent acquisition, Bamboo Therapeutics, is based. North Carolina has also attracted $55 million investment from Novartis to support their recent gene therapy biotech acquisition, AveXis. A new manufacturing plant will be built in Durham to produce its specialized therapies.
One factor that may be making the ‘in-house’ option a more realistic and sustainable one is a new addition to GE Healthcare’s product line, the KUBio, which is a modular, flexible manufacturing facility. The flexibility, speed to set up and the absence of large capital costs mean owning your manufacturing site is a viable and attractive option for companies of all sizes, provided they have in-house expertise.
Phil Vanek, GE Healthcare Life Sciences’ General Manager of Cell and Gene Therapy Strategy commented “The translation of cell therapies from academic to industrial scale has relied on cherry-picking technologies from the blood processing or bioprocessing industries and integrating them into a largely manual manufacturing process. Rather than looking at any single part of the manufacturing workflow, we try to take a process-level, or enterprise level viewpoint to make sure that every manufactured cell therapy is delivered consistently and safely. To achieve this, our FlexFactory for cell therapy offers a scalable approach enabling companies to add manufacturing capacity through modular suites and equipment and can convert an existing lab or equip a new suite in as little as six months for most applications. GE Healthcare also provides the KUBio for cell therapy; a modular facility that includes multiple FlexFactory equipped suites, each providing capacity of between 150 to 800 doses per year.”
When it comes to plugging the viral vector gap, a combination of both solutions is proving popular. BlueBird Bio has purchased a 125,000-square-foot facility in Durham, North Carolina for manufacturing lentiviral vectors but also has multi-year agreements with Brammer Bio, Novasep and SAFC to produce these vectors.
BioMarin also took the decision to invest in building its own virus-manufacturing plant with no plans to make viruses for anyone but itself. “We don’t want to be in a queue, that’s for sure,” Robert Baffi, head of technical operations at BioMarin to the New York Times. "The new facility also will give the company complete control over manufacturing, he added."
The CDMO community is taking decisive action too with expansion announcements frequently making headlines. As the industry matures and we see more products reaching late phases and gaining market approval, CDMOs are becoming increasingly stretched and wait times are soaring.
"Aldevron’s new 70,000 square-foot manufacturing facility is producing GMP-Source plasmid DNA at the 100-gram scale. We will produce our first full GMP batch next month,” said Michael Chambers, CEO of Aldevron. “We invested in the largest plasmid DNA production operation in the world to support the quality, scale, and throughput needs of our growing industry.” Chambers added that Aldevron uses a single-use 300-litre fermentor with the ability to expand to 2,000 liters and Aldevron’s GMP facility can accommodate nine client projects at the same time.
An overview of current and planned capacity increases is shown in figure 1. Although not an exhaustive list, this graph illustrates the prominent cases of site expansion.
Cell Therapy and Viral Vector Manufacturing Capacity Expansion
Figure 1. Recent and ongoing manufacturing capacity expansions for viral vector and large-scale cell therapies
This graph is not an exhaustive list of manufacturing capacity expansion, rather a snapshot of the data currently available to us. However, it does clearly indicate the trend in increasing manufacturing capacity for viral vector and cell therapy early phase and large-scale production. The table below provides more detail and the locations of these sites, which are mostly situated in the USA, as well as other planned expansions that have not yet publicly announced the level of additional capacity being planned.
Table 1. Locations and volumes recent and ongoing manufacturing capacity expansions for viral vector and large-scale cell therapies in ascending order
|COMPANY||EXPANSION (SQ. FT.)||LOCATION|
|Paragon Bioservices||150,000||Maryland, USA|
|Cell and Gene Therapy Catapult||77,500||Stevenage, UK|
|Aldevron||70,000||North Dakota, USA|
|Brammer Bio||66,000||Massachusetts, USA|
|Cobra Biologics||tbc||Keele, UK and Södertälje, Sweden|
Addressing Brammer Bio’s recent expansion projects, Richard Snyder, CSO, Brammer Bio stated “The partnership we establish with our clients facilitates forecasting of individual viral vector products as well as their pipeline of different products. This insight and contractual commitment from our clientele plus the requests from prospective clients were/are the drivers for Brammer’s expansions in Florida and our two sites in Massachusetts. In 2016, we made the commitment to double the number of cleanrooms in Florida that were completed in 2017 and we are currently doubling the capacity of our process and analytical development laboratories as well as our quality control laboratories. Also, in 2016 we committed to acquiring our Cambridge and Sommerville, MA sites that were converted in 2017 for late phase/commercial viral vector manufacturing. In 2017 we committed to establishing our Lexington, MA site which is now under construction.”
With a clearer understanding of future capacity needs and planned site expansions, can we predict how big the shortfall will be, if any? Not really. The many variables in this equation make it a somewhat futile exercise but we can work together to better plan and develop appropriate strategies to meet demand.
Another important point for consideration is the understanding of the risks associated with the rest of the supply chain as production levels increase and what provisions are needed to ensure the rest of the supply chain infrastructure does not become a bottleneck. A robust supply chain and optimum production capacity across the industry will contribute enormously to reducing CoGs and achieving the bigger picture of developing therapies that are not just clinically efficacious but commercially viable products to change the standard of care globally.