The Importance of AAV Process Comparability Throughout Development

Posted: 17 June 2024

Relying on unscalable cell-culture processes during early stages can be fatal for product development.

Markus Hörer, Chief Scientific Officer at Ascend

Process and product development even for well-established modalities such as monoclonal antibodies is not easy. The challenge is all the greater for newer formats such as viral vectors intended for use as gene therapies, gene-modified cell therapies, viral therapies, or vaccines.

Growing pressures to be first to the clinic and then to market only add to the challenges, particularly for smaller companies seeking funding.

It becomes all too easy for speed and cost to drive selection of initial production platforms, often leading to use of solutions not designed with scale-up and commercial production in mind. With this mindset, inevitably there is a need to change the production platform during further product development.

In many cases the high quality and yields obtained at small-scale cannot be maintained after switching to more scalable platforms to meet rising vector demands. Achieving comparable or better quality and the same potency therefore becomes a challenge, and product quality can actually worsen over the course of clinical development, invalidating any efficacy and safety data from earlier studies.

Viral-vector production platforms can theoretically be transferred at any stage of product development, including after IND- enabling studies, Phase I/II, Phase III, or even post-approval. But because making changes can potentially affect product quality and efficacy, there is a need to demonstrate that the new process affords product with the same efficacy and comparable or improved quality/safety profiles. Importantly, even small process changes at the same scale, moving to larger production scales, and manufacturing the product with the same process at two different sites can all lead to a lack of comparability.

Moreover, the requirements for studies and data that support comparability increase as development progresses. Consequently, the risk that comparability cannot be demonstrated using only analytical data also increases. The willingness of regulatory authorities to recognize comparability data is another factor and depends very much on the "medical need" of the patients to be treated, i.e. the risk/benefit profile of the respective indication.

The later the development phase, in fact, the higher the likelihood that agencies will require clinical bridging data/studies in addition to analytical data, particularly if Phase I/II final dose data will be incorporated into the Phase II efficacy read-out to increase the number of evaluable patients. In this case, demonstration of comparability is highly complex if the production platform is switched between the Phase I/II and Phase III studies. In the worst-case scenario, regulators may apply clinical holds until repetition of pre- and early clinical testing of development candidates can be completed, resulting in costly delays for both the drug developer and patients waiting for life-altering treatments.

To avoid these potentially fatal problems, the best approach is to define the target product profile of the product to be commercialized at an early stage, factor them into the choice of production platform, and discuss all aspects with the authorities before the project progresses too far. Not only is the hurdle of translating a candidate from preclinical to clinical development comparatively low in comparison to the challenges associated with Phase III material and commercial product, but regulatory requirements also increase from year to year.

A scalable mindset

Here at Ascend, we are continuously developing our modular AAV production platform, investing a great deal of resources to ensure we offer “state-of the-art" product quality that is comparable across all scales from R&D through commercial manufacturing.

This philosophy lies at the heart of our ongoing Technology Development activities. We are focused on the establishment of next-generation production platforms that minimize the risk of lack of comparability for customers as demand for their AAV vector products increases through clinical development to commercialization. These efforts are supported by ongoing investments in our uniquely broad analytical platform, which has already been successfully applied in analytical comparability studies.

Myself, and my colleagues at Ascend, are very passionate about helping drug developers realize the full potential of AAV-based therapies and vaccines.

Please do not hesitate to reach out to us at business@ascend-adv.com.