By Antony Hitchcock, principal and owner, AGH Bioconsulting

Around five years ago, concerns were raised about the lack of manufacturing capacity for viral vectors and that this would impact the ability to produce late-phase and commercial products. This predicted shortfall in capacity led to significant investments in manufacturing facilities, including acquisitions and the establishment of startups through venture capital funds.

However, over recent years, we have seen significant changes in AAV production processes, with as much as 1 log improvement in process titers being reported as well as up to 2 log improvements in vector potencies, allowing for a significant reduction in vector dosing requirements.

As more products are being licensed, we are also getting data on current sales and uptake of these products. In this article, I will discuss the impact of these process improvements and emerging sales levels on potential manufacturing requirements, especially within the CDMO sector.

Clinical Production Requirements

Material requirements for individual products are highly variable as dose sizes can vary as much as 5 logs and there are wide variations in potential populations, from tens of thousands to fewer than 100. To date, seven gene therapies have been licensed, five of which were in the last two years.

While it is not possible to monitor the exact number of patients treated, companies do report sales, and in all cases high-level price figures are available, making it possible to generate approximate values. Additionally, the dose levels for these products are also reported within regulatory filings.

Let’s Calculate Manufacturing Requirements On The Back Of An Envelope

Let’s look at two of the licensed treatments for what are regarded as higher prevalence diseases, products administered at high doses to children younger than 2 years with spinal muscular atrophy (Zolgensma) and children at least 4 years old with Duchenne muscular dystrophy (Elevidys).

Since the rest of this article is based on my assumptions of demand, I want to take a few moments to explain how I reached my conclusions. Bear with me for a little back-of-the-envelope calculating.

Over the last year, Novartis reported sales of Zolgensma at $1.21 billion, which at a cost of around $2.3 million per patient relates to treating around 526 patients a year. Sarepta reported sales of $181 million last quarter for the DMD treatment Elevidys at a cost of $3.2 million per patient. Assuming no discounts, this relates to the treatment of 56 patients for the reported quarter, which would be 224 over a year if this level of sales is maintained.

In terms of material requirements, Zolgensma is dosed at 1.1 E14vg/kg, and assuming a patient weight of 10 kg, this equates to 1.1 E15vg/kg, so to treat 526 patients, there is a requirement for 5.8 E17vg/pa. Following a similar calculation for Elevidys, which is dosed at 1.33 E14vg/kg, and in this case with older patients, assume a patient weight of 30 kg, which equates to 3.99 E15vg/Kg, there is a requirement of 9.0 E17vg/pa.

If we also assume that productivity of around 1 E17vg can be achieved from an optimized 2,000-L production scale, it suggests requirements of less than 15 x 2,000-L scale production batches to meet current commercial requirements for high-frequency, high-dose products.

Looking at other lower-prevalence diseases, PCT Therapeutics has not reported sales of its AADC therapy Upstaza in the last two financial quarters despite being licensed in the EU since 2022, which suggests low uptake.

While recognizing that these are very much back-of-the-envelope calculations, they give a ballpark indication of the current manufacturing requirements for these types of products in terms of scale and batch numbers.

It should also be recognized that these are first-generation products in terms of manufacturing processes and vector design. As I discussed in a previous article, we are seeing as much as 10-fold improvements in productivity and as much as 1,000-fold improvement in potency, as shown with the recently licensed Beqvex from Pfizer. Additionally, many products, such as ocular and CNS products, are administered locally. All these approaches will result in significantly lower material requirements than those detailed above.

Looking forward, it is not unreasonable that, with current process improvements for products with similar or lower prevalence, it will be possible to meet commercial demands with a single 2,000-L production batch or less for products with similar patient populations and more targeted delivery approaches.

On one hand, this sounds like good news and offers potentially lower product costs. But it also creates a significant challenge for vector producers, both in-house and outsourced, with regard to producing commercial materials. This is something I explore in the rest of the article and discuss the challenges and potential solutions and opportunities in delivering these life-changing medicines.

The Transition From Clinical To Commercial Production

The transition from clinical to commercial production is a significant undertaking for manufacturers, not just regarding process scale and validation but also the operation of the entire facility, including facility designs, control of people/product flows, and segregation of materials. The change is arguably less dramatic for EU facilities where there is a requirement for inspection and licensing to produce clinical material, but the transition is still a significant step requiring more stringent quality management systems.

It is also likely that companies will be inspected and licensed by multiple regulatory agencies, including the FDA and EMA, making significant demands on operational and quality teams in terms of preparation, hosting inspections, and responding to any changes required by inspectors, along with the need to maintain compliance on an ongoing basis.

This in turn reduces operational flexibility and increases operational costs, which is a challenge for multiproduct facilities, especially around product changeover. While facilities are moving toward single-use, there will always be a need to validate facility cleaning, including product removal.

Commercial Manufacturing Process And Analytical Validation

The requirements for the validation of manufacturing processes are laid down in ICH Q8 guidelines. The aim is to establish critical process parameters required to achieve the required critical quality attributes of products and the operational boundaries for these parameters to retain the desired quality attributes and demonstrate that these are at the intended production scale.

Most of this work is achieved through mining development and clinical data and establishing scale-down models of critical process operations. This work culminates in the benchmark performance of three full-scale production batches, which, when successful, can be sold as commercial batches.

Conventionally, the completion of these activities leads to long-term manufacturing operations but as discussed before, demand for some commercial products may require only one large production batch per year. This could mean that facilities and teams go dormant for extended periods. Not only does this situation create issues with low facility occupancy, but it also creates significant challenges around demonstrating continued process compliance and staff training.

The challenge for manufacturing companies going forward will be to establish sustainable business models that can meet commercial requirements in terms of production scales and compliance while having the flexibility to produce clinical materials in the same production facility.

Production scales

As described above, many players have scaled AAV production up to 2,000 L to meet anticipated production requirements. However, given the improvements in process titers and decreased dose levels, it is questionable if this scale will be required for many products. Suppliers may opt for smaller 500 L to 1,000 L facilities. While this approach may require multiple batches to produce the required materials — which is likely to increase the cost of the vectors — it has several advantages for manufacturing groups.

The first is the reduced capital investment and lower operational costs of smaller facilities.

The second is risk. Performing transfection processes at a large scale is challenging, and groups have reported reduced yields and increased batch failures at 2,000 L scale. This leads to a supply continuity issue, which, for commercial products, can obviously have serious financial consequences. Clearly, if it is possible to produce material from a frequently used, well-established process, the risk of batch failures is significantly reduced.

Facility usage

Facility usage is a key issue for manufacturers. Establishing, validating, staffing, and maintaining compliance of large-scale production facilities incur a significant cost; therefore, for such facilities to be financially viable it is essential that they are built at a scale where it is likely that sufficiently high levels of occupancy can be achieved, either within CDMOs or in-house production facilities. Without sufficient occupancy, facilities can rapidly become financially unsustainable even with commercial contracts.

Consequently, if facilities operate as both production and commercial operations, production scales must be suitable for both needs. This gives scope for the production of very low demand commercial products that may otherwise be financially unviable.

Forward Thinking

For the gene therapy sector to be successful, it must be financially sustainable. To be sustainable, the cost of development and production must come down. This is particularly the case for products for small patient populations, where clinical development costs, including process validation, are less easily absorbed.

One key feature of gene therapy products is that the manufacturing processes are largely agnostic of individual products. They are platform processes. This has clear advantages for generating early-stage clinical materials when time and cost are of the essence, but it can also impact late-phase and commercial products. Process standardization clearly reduces cost and time to transition from clinical to commercial activities, especially around areas of validation. Recently, the FDA issued a draft guidance called Platform Technology Designation Program for Drug Development, which applies to vectors and other delivery methods. We have yet to see what elements of these guidelines can be applied to AAVs.

Given the nature of AAVs, it should be possible to establish platform operations for elements of the AAV production process such as cell builds, transfection, and recovery operations as well as serotype-specific DSP and formulation activities, including viral clearance. The same may apply for many of the analytical methods. In doing so, it may be possible to significantly reduce the cost, time, and risk of validating production processes.

CDMO Engagement

CDMOs manufacturing viral vectors and gene therapies currently gain most, if not all of their revenues from the production of clinical rather than commercial material, which is challenging and costly in terms of having to invest heavily in sales and marketing activities. They do so in the hope of clinical projects transitioning to commercial products ensuring long-term revenues. However, given that many of the products they work on may fail or, if successful, be sold to a third party, this business model has significant risk and is compounded by the prospect of limited manufacturing activities.

Therefore, the potential of establishing deeper partnerships with greater long-term commitments with product developers is likely to be attractive to CDMOs and developers alike.  

From the CDMO’s perspective, long-term commitments offer the ability to leverage validated platforms to potential customers, allowing them to accelerate development programs and reduce costs to drug developers. This approach may also be attractive to product developers looking to reduce up-front costs during development and to reduce timelines for product registration, even if it does incur additional long-term costs, including potential royalties.

Always Keep The Patient In Perspective

Finally, and most importantly, we need to look at production approaches that take advantage of technical developments in the field to accelerate the development and commercialization of these products and to increase access to these life-changing products.

Conclusion

It is increasingly apparent that there are significant challenges for AAV producers at present. While some of them relate to the shortfalls in funding from investors, there are deeper issues.

There is a clear need for manufacturers to adapt to changing technology, including improvements in vector design and manufacturing processes. But we must also consider the realistic market demands for these products and establish financially sustainable businesses that can build upon past successes.

About The Author:

Tony Hitchcock is the principal and owner of AGH Bioconsulting. He has spent his decades-long career in the in the biotechnology field, with over 30 years in the production of complex biologics for clinical trials in the European Union and U.S. He has worked in areas of process development and manufacturing with experience in engineering and process systems. He has worked on the development of more than 30 products for clinical trials, including plasmid DNA, viral and bacteriophage products, and recombinant proteins from microbial, mammalian, and insect cell sources. Contact him at tony@aghbioconsulting.com.