Adeno-Associated Virus (AAV) gene therapy remains remarkably close to its roots in academia despite burgeoning commercial success and prolific investment. That combination of scientific curiosity and capital enables innovation to continue to accelerate, generating potential therapeutics addressing both larger patient populations and ultra-rare diseases previously considered off-limits due to either technological or commercial considerations. As these areas appear more feasible, we are forced as an industry to resolve challenges in manufacturing that have been in some ways left behind by the revolutionary aspect of the results of AAV gene therapy’s first successes.
Our academic roots are showing in the persistence of adherent cell lines, antibiotics, and open processing that are staples of research production but struggle to scale up – they can only scale out.
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This imposes an artificial limit on the reach of our technologies and the access patients across the world have to them by lengthening development times and increasing both development and commercial costs. Ironically, we can reach neither the massive patient populations in cardiac or neurodegenerative diseases nor the multitude of ultra-rare patients treatable with AAV therapies because of this issue: at larger scales, the capacity needs exceed practical facility constraints; for smaller populations, lack of efficient manufacturing keeps development cost-prohibitive. Development and utilization of platform-driven AAV manufacturing can take months or even years off of development timelines and lower bespoke development costs, helping these therapies reach patients faster and with lower cost of goods both in development and on the market. In the midst of continued amazing scientific progress, and in order to allow it to continue, attention must therefore be paid to the perhaps more mundane task of manufacturing process improvement, ideally in the context of establishing robust platforms for AAV manufacturing.
While multiple methodologies exist for AAV production, platform manufacturing is quite a nebulous term, so a bit of time defining it for the purposes of this discussion is perhaps time well spent. At a high level, a manufacturing platform hopes to be a flexible, product- agnostic methodology for producing high quality product at a commercially relevant scale. Regardless of how the elements of AAV’s capsid, the therapeutic transgene, and the enabling mechanisms for viral replication come together, a robust AAV manufacturing platform must be:
- Scalable. While in many cases, the word scalable evokes images of monoclonal antibody-esque stainless steel vats, or even the much- sought-after 2,000L single use bioreactor, it is vital for any platform to scale both up and down. A one to five liter process that can produce a vector for evaluation that is representative of GMP scale is at least as valuable, if not more valuable, than a shiny row of huge bioreactors. Small-scale runs enable decisions to be made quickly, which is paramount, and also cheaply – agile, efficient development at the preclinical stage is vital to being able to get into the clinic as fast as possible. If a manufacturing process requires at-scale productions to be assured of quality and quantity, that time may be better spent developing a downscale model. That model will pay dividends in process validation as well, allowing for data to be generated quickly and accurately to inform specifications and key quality attributes as preparations for commercialization get underway. That being said, a platform must be able to reach clinically and commercially relevant productivity, of course, to be able to achieve successful results at larger scales. This sort of flexibility is much more achievable in suspension systems, as so much work can be leveraged from other biomanufacturing experience.
- Measurable. A platform is only as good as the analytics that support it. Electing to develop and use a platform allows quality control to be focused on that platform, which reduces the challenge of piecing together whether results are significant or not. Being able to focus on the key variables of a platform, regardless of the production methodology, allows for quicker, more confident decision making and increases confidence in the results obtained. Quality control of AAV has enough challenges inherent to the complexity of the therapeutic itself without layering on multiple shifting targets of how that quality is assessed.
- Reproducible. This in some ways is the combination of the two previous points, but a platform, regardless of yield, has to produce similar results at a given scale run-to-run, and normalized results have to be predictable across all scales. Projecting total batch need from a single batch, even a single small-scale batch, is a powerful tool for demand planning. Assessing manufacturability of a construct depends on being able to isolate product specific productivity – something that is extremely challenging when working with multiple production methodologies or even broad variability within a single production method. Tight control of manufacturing parameters and robust analytics are required, and are much more easily developed in a platform context than in product-specific process development. Understanding the impact of process improvements, new technologies, or new scales also relies on a solid foundation of previous consistency to be able to judge cost and benefit appropriately.
Developing a platform enables a more linear development path with fewer variables to examine from the candidate selection and optimization process. In-house capabilities for development that syncs perfectly with later, larger manufacturing enables agility and removes the serious concerns and comparability that have paused several clinical trials of late. Given that AAV production is necessary for development, some version of platform development often moves apace with the lead candidate in a developer’s portfolio, though it can be challenging to balance the focus on clinical entry of that lead candidate with the broader validation of a platform across multiple constructs. Rewards for that investment are often seen in subsequent programs or in improved versions of the initial construct, as well as in the development of intellectual property portfolios in manufacturing technology.
From a regulatory perspective, CMC documentation becomes much quicker, as well as better vetted by the regulatory agencies, even in some cases through mechanisms like Drug Master Files that lighten the burden on regulatory applications and enable innovative development to be adequately protected.
Platform development also holds significant upside for late-stage programs. Validation of a process that has a representative small scale and has been run tens or hundreds of times across various projects is much easier than a bespoke process – especially in AAV where tiny clinical trials mean that just 1-2 batches of a vector can supply all clinical studies. Adapting manufacturing scales to dramatic changes in patient populations, either up or down (as a result of curative therapeutics, competition or additional applications of a therapeutic being possible), is also made significantly easier when a history of scalability and reproducibility has already been established.
Operation of a manufacturing platform comes with its own set of unique challenges and advantages for contract manufacturers. The typical approaches of tech transfer of a client process or development of client-owned processes allow CDMOs to generate revenue from those activities, but inhibit operational optimization of facility design, throughout and quality control. Platform development also enables the CDMO to maintain more effective operator training, safety and development, since staff can gain experience quickly on the platform rather than continually adjusting to variations in client processes. They can also maintain their qualifications more easily with fewer trainings to keep up.
Economically, while the initial costs of platform development must be considered, significant upsides exist especially for a CDMO in the ability to offer quicker access to GMP capacity and avoid burdensome bespoke development costs. Alternatives to the traditional batch pricing model may also be enabled by more dependable results from the platform. Additional revenue streams from potential out- license of the platform also open up to platform-driven CDMOs and therapeutic developers. Many of these conclusions may feel fairly obvious to those familiar with monoclonal antibody production, where CHO-based production has become ubiquitous and cell line development and out-licensing is common, but this approach within the gene therapy space is presently the exception rather than the rule. Given the manufacturing focus inherent in the CDMO business, their position in the industry to clearly see trends and needs, and the resources available to contract manufacturers to devote to platform development, progression towards platform development and utilization leadership within the CDMO community offers benefits to both CDMOs and developers. CDMOs should be expected to lead this effort within the gene therapy industry to provide faster, cheaper manufacturing of these important therapeutics.
A reproducible, measurable and scalable platform is an enormously powerful tool to lower costs and accelerate development timelines, however, it comes with its share of risks and drawbacks. Therapeutic developers are rightly focused on achieving proof of concept of their therapeutics, and platform development takes time, resources and focus from highly skilled and knowledgeable staff that may not show a bottom line return on investment for several years or several therapeutics – something many developers don’t (or can’t) budget for. The strategic choice to develop a platform can also imply some limits to adoption of new technologies while the platform’s baseline is being established. It takes discipline to push through the challenges a project like this will inevitably create, and our field moves so quickly that the next new thing is always hard not to evaluate and incorporate, but that can only be done once a platform is established.
Overall, though, the immutable currency of our industry is time – whether it be patients waiting on potential cures, clinics waiting on doses, or investors waiting on returns. Making good decisions as quickly as possible is paramount, and the time sunk into platform development enables far superior timelines to program-specific process development or continual evaluation of production methodologies. Making a choice, developing expertise in it, and then leveraging that combination of platform and resultant expertise builds operational, regulatory and economic advantages. Ultimately, the ability to help take months or even years off development timelines to deliver potentially life-changing therapeutics to patients that much faster is valuable enough on its own to mandate continued momentum behind platform utilization in AAV gene therapy.