Table of contents
- Gene therapy manufacturing comes of age: Commercial-scale manufacturing is imminent. Are gene therapy innovators ready?
- Overcoming obstacles in downstream bioprocessing of AAV based gene therapy products
- Overcoming challenges in the development of lentiviral vector manufacturing platforms
- Are modern scalable bioreactors the Cell Culture Strategy needed for Gene & Cell Therapy success?
- Le pouvoir magnétique des nanoparticules triage magnétique cellulaire dépollution des milieux et nano catalyseurs réutilisables
- Développement d’une nouvelle approche préventive pour réduire les infections microbiennes avec les nanoparticules d’oxydes métalliques
- Surveillance numérique de l’environnement : détecter les défaillances avant qu’elles ne se produisent
- Maximizing Sterility Assurance: Sterile Hold Time Testing for Sterilized Items Used in Parenteral Drug Manufacturing
Gene therapy manufacturing comes of age: Commercial-scale manufacturing is imminent. Are gene therapy innovators ready?
Gradually, and then suddenly. When Ernest Hemingway wrote those words in The Sun Also Rises, he couldn’t have known about the gene therapy revolution that would follow nearly a century later and yet he described it perfectly. Sixteen years gradually elapsed between the first draft of the human genome and the first FDA-approved in vivo gene therapy. And now—suddenly—the FDA expects to approve 10 to 20 cell and gene therapy products a year. Decades of research have brought us to this moment, and very soon gene therapies will be a mainstay of commercial-scale biotech manufacturing.
How are today’s gene therapy manufacturers preparing for this step change, and what barriers stand between their breakthrough work at the bench and the patients who need their products at the bedside? Nearly half of all the Horizons survey respondents are at work in this field, so we asked them. Their answers paint the picture of a submarket that’s rapidly maturing as researchers get comfortable pushing boundaries, developing and integrating new technologies, and laying the groundwork for future scalability.
Capital cost/financing
As a whole, the gene therapy submarket raised $10.6B in venture funding last year, marking a 14% year-over-year increase. And yet as Figure 4.1 shows, project owners see financing as a much greater challenge than CMOs. Perhaps this is because CMOs generally operate under a different business framework. They have their own facilities but not their own products; instead of facing pressure to finance clinical trials, build infrastructure, and prepare for commercial launch, they’re focused on delivering scheduled batches and maintaining a full backlog of manufacturing.
Clinical trial results
We were surprised that this challenge didn’t rank higher. Strong trial results generate funding, which pays for manufacturing space, which in turn enables larger production volumes to supply further trials-and so the wheel of gene therapy turns, with clinical trials at its hub. It makes sense that CMOs would worry more than anyone else about this variable, because their manufacturing backlog depends on producing escalating volumes of an owner’s product-which in turn depends on the outcome of clinical trials. Of course, owners are impacted the most, especially in a climate in which regulators approach gene therapies with appropriate caution. To edge toward commercial approval, owners need clinical trial results that will persuade regulators of their product’s safety andunique therapeutic efficacy; if the market already offers a comparable product, approval is unlikely. Perhaps owners consider this such an obvious factor in their success that they chose to focus on other concerns when responding to this question. Though CMOs and owners experience many of these challenges differently, they do share one thing: a dependence on each other. Across the life science industry, but particularly in the nascent space of gene therapy manufacturing, the CMO-owner relationship is often a key to future success-which means it warrants a close examination.
1. How gene therapy manufacturers evaluate potential CMOS
We asked both owners and third-party manufacturers in the gene therapy submarket about the factors they consider most important when selecting or acting as a CMO. As it turns out, nearly everything is important; these “flat” results indicate an intensity of competition at play in today’s gene therapy manufacturing environment (Figure 4.2).
CMOs may find it useful to mine these results for opportunities to differentiate their service offering. In particular:
- Available equipment/process platforms
As the research pipeline matures and owners move closer to product launch, standardized manufacturing platforms with the potential to support rapid gene therapy production at the commercial scale are maturing, too. Contract manufacturers should proactively align their process capabilities with these emerging technologies; this will attract owners who need a manufacturing partner who can accelerate them to market with an effective and scalable platform.
- Supply chain management
This is a shared pain point for everyone. CMOs could distinguish themselves by, say, stocking several months’ worth of single-use components, or by expanding their manufacturing capabilities to include plasmids (more on that later).
- QC testing
Of all the operations along the manufacturing lifecycle, owners very often seek to outsource this one. By expanding their QC testing capabilities, CMOs may find themselves in an advantageous position both as a resource and as a potential turnkey partner for companies.
2. The keys to commercialization: scalable, Next-Gen capabilities
Whether CMO or owner, what are gene therapy innovators doing right now to prepare for the larger scales they’ll need to meet commercial demand in the future? To answer that question, we showed respondents a set of promising capabilities and asked them which ones they’re currently using or planning to use in the near future (Figure 4.3). Each of these capabilities has the potential to dramatically improve the efficiency and scalability of gene therapy manufacturing. To make them work, companies will need to invest heavily in R&D, and they will need to investigate the facility and regulatory implications of integrating these forthcoming capabilities. Despite these hurdles, our survey data shows strong momentum behind each of these capabilities—an encouraging sight for a submarket that’s only just outgrowing its infancy and learning to run.
3. Sterile Filtration
Sterile filtration, a well-established tool in drug substance manufacturing, could unlock huge advantages for gene therapy manufacturers such as smaller and more efficient facilities, lower operating costs, and opportunities for process closure. There’s a significant potential drawback, though: lentiviral and retroviral vectors typically sustain significant yield loss when exposed to a sterile filter.
This is likely why only about a third of owners and even fewer CMOs in our survey are currently using a sterile filter. As long as they’re manufacturing small batches of viral vectors to support pre-clinical or early clinical research, a biosafety cabinet can maintain the necessary sterile processing boundary—without impacting yield. companies would have to meet the regulatory requirements for aseptic processing. That means taking the level of aseptic processing that’s typically reserved for a fill finish step and applying it across the entire process train—an onerous prospect from the perspective of validation, equipment selection, and cost. Even if a manufacturer could somehow justify this approach in the boardroom, they may find it impossible in the plant; many of the technologies used for larger-scale manufacturing, like chromatography systems, were not designed to support aseptic processing. This is likely driving the large segment of owners and CMOs who are planning to incorporate sterile filtration in the future. To make it work, they’ll have to either optimize the process to minimize loss or build that yield loss into their scalability strategy and plan their product train around it. It’s interesting to note that CMOs are less likely than owners to use sterile filtration in their current approach, but slightly more likely to be planning for (or evaluating) its adoption. It could be that CMOs have historically avoided sterile filtration because they’re focused on maximizing their small-batch yields; meanwhile, they’ve seen owners jump ahead with adoption, which may have recently incentivized them to catch up.
4. Moving From Adherent To Suspension Cell Lines
Adherent cell lines, which use an anchor point like tissue or a mesh surface to reproduce, require substantial surface area, a lot of operators to perform cell washing and expansion operations, and the potential for extensive open processing. Many of our respondents have moved away from these challenges by transitioning to suspension cell cultures, which allow for a denser use of operational space while paving the way for closed and automated processing. There is also the advantage of familiarity: gene therapy manufacturers can borrow from the playbook of therapeutic protein manufacturers, who leveraged this approach to leap from benchtop to commercial production 30 years ago.
5. Stable producer cell lines (instead of transient transfection)
Though it’s currently a more established technology than stable producer cell lines, transient transfection is a tricky approach to maintain as production quantities grow. It requires large volumes of raw transgene material, which drives up costs, and it depends on complex chemical dynamics within the bioreactor. If manufacturers pursue transient transfection all the way into commercial production, they’ll find themselves stuck with limited efficiency and high production costs, and they’ll be handcuffed to a transgene supply chain that’s struggling to meet demands. In contrast, a highly productive bank of stable producer cells offers the potential for a more efficient, cost-effective, and scalable process. We haven’t yet seen this technology fully deployed, but the general concept looks a lot like classic biotech: as manufacturers grow a cell line, they can grow the transgene element at the same time. Before this approach becomes a mainstay of gene therapy manufacturing, though, companies need to work out how to engineer cells capable of making the vector without being transfected at scale. CMOs appear to be leading this R&D effort; although owners are currently more likely to have stable cell lines in place already, nearly 90% of CMOs are either planning to adopt this approach or are actively evaluating its potential as a gateway to greater scalability. The small number of CMOs with a stable cell line currently available are ahead of the curve; this is likely a strategic component of their position as a commercial-ready turnkey partner.
6. Plasmids Manufacturing In-House
Only a handful of companies around the world are capable of manufacturing this critical raw material, which has led to a chronic bottleneck in the supply chain.
This is likely why our respondents are showing keen interest in bringing their plasmids source in-house. It’s a complex proposition that will take a lot of R&D to pull off, but the promise of controlling the availability, quality, and cost of such critical materials is a strong incentive. For CMOs, this trend could be game-changing. As the data shows, few are currently manufacturing plasmids, though interest is high. Those who add this capability in the future could find themselves at a great competitive advantage.
7. What does process scalability look like for Gene Therapy Manufacturers?
There’s a reason why the emerging capabilities described above are attracting so much attention among our survey respondents. Change is coming rapidly to this submarket, and gene therapy researchers are under pressure to change with it. Whether well-established or just starting up, most companies with their hand in gene therapy research today are producing the small-scale batches necessary to support pre-clinical or early clinical trials; even early phase cell therapy studies that rely on a gene therapy component aren’t likely to require large batches of critical material.This picture of small-scale benchtop manufacturing speaks to the infancy of the gene therapy industry. But as we can see in Figure 4.8, most respondents expect to increase their production volumes sharply within the next three years. Large biotech companies are especially aspirational in their processing goals, perhaps because they can leverage existing infrastructure to accelerate scale-up—or perhaps they’re more likely to target indications with a large patient population, as opposed to rare or orphan diseases with a smaller market attached. Some of the respondents represented in Figure 4.8 will force their way up that Y-axis using established approaches such as transient transfection, but those who invest early in more innovative and scalable capabilities will find themselves better prepared to enter the commercial marketplace.
8. Compliance with science: how Gene Therapy Manufacturers approach risk?
Commercial-scale gene therapy manufacturing requires careful risk assessment and a production approach that balances efficiency with quality and control. Finding that balance isn’t easy—and maintaining it to the satisfaction of a cautious regulatory body can be even more difficult. From that point of view, we were surprised to see that most respondents reported relatively high comfort with vector production. This could reflect the makeup of our survey audience: as we’ve noted, most respondents are in early R&D and process development roles, which means they’re operating upstream of the stringent quality programs that govern CGMP manufacturing. It’s possible that such high levels of comfort could survive a shift out of the lab and into the commercial-scale plant, though it’s unlikely to happen quickly; manufacturing viral vectors for different products in the same room, while perhaps scientifically possible and ideal in terms of efficient throughput, may be difficult to justify from a regulatory perspective without prohibitively rigorous risk management and a matching quality program in place. Within this big picture, we found two interesting nuances worth noting:
- Isolators are slightly more attractive than single-use technologies (SUTs)
This may come down to the attitude that single-use components mean elevated risk; manufacturers may worry that plastic components could wear down, for example, or that a faulty connection could precipitate a leak. Isolators, on the other hand, are a validated containment system. For high-risk operations, respondents may choose to take on the extra expense of isolator technology. This attitude will likely shift over the coming decade as manufacturers and regulators grow more accustomed to SUTs in gene therapy production, which will enable greater flexibility and faster product changeovers.
- CMOs have a higher risk tolerance than owners.
Because they are familiar with the practice of managing multiple clients within the same facility, CMOs may already have the controls and validation in place to comfortably mitigate the risks of switching between products. This could explain why, on the whole, they responded more favorably than owners in terms of risk tolerance. For patients awaiting a cure and for manufacturers racing to reach the market, the journey to effective and accessible gene therapies may have felt long. In the background, though, a momentous shift is taking place, and quickly. Scalable technologies like stable producer cell lines are emerging; attitudes toward the risks and rewards of efficient gene therapy manufacturing are shifting; innovators are laying the groundwork for tailored commercial approaches that will help them succeed in the marketplace. As a result, today’s gene therapy manufacturers are set to transform the lives of millions of patients—gradually, and then suddenly.
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