Platform Development for the Purification of rAAV Vectors: Interview with Jessica Whelan, University College Dublin

Hello and welcome to this interview for Oxford Global.

Today I'm joined by Jessica Whelan, a lecturer, assistant professor and Head of the School of Chemical Bioprocess Engineering at University College Dublin.

Jessica will be giving a presentation at Cell 2025, and we are very interested to talk about that particular presentation in this interview.

But first, Jessica, thank you very much for joining me today.

Thanks, Tom, and thanks for the invitation to speak at Cell UK.

I'm looking forward to it.

Great.

So could you first talk a bit about your background as a researcher, the kind of industry and academic projects you've been involved with?

Yeah, no problem.

So I started out by studying chemical engineering in UCD here in Dublin, Ireland.

After that, I pursued a PhD and postdoc in the area of upstream processing with a particular interest in monoclonal antibody production.

So there I suppose I developed a skill set or an expertise around the use of process analytical technology, process modelling and control to ultimately streamline and improve the manufacturing processes needed for these sorts of products.

Once I finished the PhD and postdoc, I went out to industry for about 10 years.

So I have worked with companies such as MSD and BMS and an Irish process development company called APC.

And really there I built up experience in I suppose delivering these sorts of products at scale, you know for a commercial manufacture and production.

I returned to the faculty in UCD in 2020 and since then my research group has been focused on really continuing to address the challenges facing the bio manufacture of these products.

So again, continuing to look at the development of platform processes and the use of PAT and modelling so that we can really overcome and accelerate the supply of these types of medicines to the market.

That's great.

Thank you.

Just wanted to ask briefly about your presentation, it's titled Platform development for the purification of rAAV vectors.

Could you tell me a little about how you got involved with AAVs as a delivery vehicle?

Yeah.

So I suppose over the course of the last 20 years of my career in the biopharmaceutical sector, I've seen, the emergence and the development of different modalities.

So monoclonal antibodies have, become very prevalent and are, a standard, widely accepted treatment now, whereas, they had once been novel.

So I suppose I was quite excited to see, a range of new modalities, appearing over the years and AAV is one of those.

I think it shows massive potential to treat, very serious life threatening conditions that, currently there aren't very many treatments on the market, if any for.

So really I saw the emergence of these AAV products as an opportunity to leverage both my academic and industrial experience in this space to be part of a wider community that helps bring these to the patients.

So specifically this project is in collaboration with APC, who are the Irish process development company that I mentioned that I previously worked with.

And really this project is focused on the downstream purification of AAV, looking to develop an approach that will work across all serotypes and accelerate the market or the, I suppose market availability of these drugs by getting it into the clinic and into commercial manufacture as quickly as possible.

Great.

So could you walk me through some of the challenges facing rAAV purification and what AAV characteristics need to be considered in this field?

Yeah, So I suppose there's some unique challenges that face AAV purification that are really derived from the nature of the impurity profile.

So you know, the types of things that you're trying to separate the product from.

So I suppose first up, one of the kind of main impurities if you like are the empty or the partially filled capsids.

And these are particularly challenging to separate while maintaining like a high percentage recovery from the full capsids because they're so similar to that product that you're looking to isolate.

So that's definitely one of the major challenges facing us.

I suppose in addition to that, many AAV processes involve a step where the cell is lysed in order to release capsids, which may be added significant concentration intracellularly.

And this releases a much higher level of impurities when compared with something like a monoclonal antibody.

So we see much higher levels of things like host cell proteins, host cell DNA, cell debris and so on.

So, there is a more, I suppose significant impurity burden or concentration that needs to be removed.

I think in addition to that, uh, depending on the upstream process, the concentration that the AAV is produced at can be quite low.

So there can potentially be the need for very significant concentration steps.

And ultimately, while AAV particles are relatively robust, they're still a very complex biological particle and as such can be impacted by the environmental conditions that they're exposed to.

So, for example, extreme pHs, high shear stresses can all be detrimental to the quality of the product that we're looking to get out.

So, we do need to, I suppose manage the environments that the AAV is exposed to while going through a challenging purification scenario.

And what would some of the benefits be of a GMP ready platform based approach to downstream processing?

So I suppose the benefits of having a platform that would span, a range of serotypes for AAVs is no different to the benefits that we've seen realised in the industry as a result of the platform approach to mAb purification.

So, around, the drug development space, it really accelerates the process development timelines.

It reduces, the cost, the amount of resources needed in that phase.

This allows, a much faster time or reduced time to market, both for the clinic and the commercial stages.

The, I suppose increased level of process knowledge really helps improve risk management through the processes, helps with troubleshooting, once we're actually in commercial manufacturing up and running.

And I suppose ultimately it also aids regulatory review and approval, so if the regulators see, familiar processes coming across their desks for consideration, they will often have, I suppose, like higher levels of comfort or confidence in the process that's being proposed for a manufacturer.

And your presentation's going to outline the development of platform approaches to chromatography process development.

What factors need to be considered when developing a chromatography platform?

Yeah.

So I suppose, again, developing any platform ultimately the challenges that the platform needs to perform both for, the current products that you're interested in, but also for the future products that will be coming down the pipeline.

So it needs to be designed to be robust.

So these products are being produced, via a cell culture.

There is a high inherent level of variability in cell culture processes.

So, typically both within a particular product but also across the portfolio of products, we can expect to see, wide variation in titers, in percentage, full capsids and so on.

So the platform itself has to be robust to be able to manage or accept those high levels of variability as well as being flexible enough to ensure that it can be, optimised or fine-tuned for a particular product.

I think as well, because we're talking about commercial supply, it's really important that any platform developed is highly scalable so that you can produce enough products to supply the market demand for a drug so that it won't impact, patient accessibility to a particular medicine.

High ability to control or automate a process is also desirable.

It typically makes a process, we'll say more robust and less prone to error.

You know, obviously a non-negotiable is that any platform applied will produce product with the required purity and quality attributes.

So again, if you're not hitting those requirements, then you know, you don't have a medicine that's safe and efficacious for the patient.

But these products are particularly expensive to produce.

So, managing yield recovery is also very important.

So you do need to design the platform with a high level of efficiency in mind, and ultimately, one element of that is cost of goods.

So it's also, making choices as you go through that platform development that allows you as much as possible to minimise the cost of goods without compromising on the quality of the medicine that's ultimately produced.

So how can chromatography support the application of viral vectors and other new modalities?

Yeah.

So I think chromatography is really well placed to address lots of the needs around developing a downstream purification platform both for AAVs and other modalities.

So like first up, the sector is extremely familiar with chromatography as a unit operation or a process step because it's really widely adopted in the purification of therapeutic proteins.

So monoclonal antibodies, fusion proteins and so on, through the sector's experience with it there, it's been pro proven to be robust, flexible, scalable.

So you know, it's ticking those boxes for us that we really want to see in a platform.

I think, really over the last five years or so, we've seen really significant innovation both in the academic space and in the vendor space with regard to, kind of new resins or you know, new formats coming to the market that are really expanding the current capability of chromatography and addressing some of the challenges.

So for example, my presentation will refer to a resin AAVX that's produced by Thermo and that is an affinity resin that is again serotype agnostic.

So, that's been a great addition to what's available on the market.

You know, in this space.

I think as well, we've seen very promising reports in the literature with regards to novel modes of operation or you know, more sophisticated modes of operation for chromatography.

So you know, in particular things like multi column continuous approaches to operation of these sorts of steps, which is really, I suppose managing to balance the requirements with regard to quality and you know, maximising percentage full capsids without, taking very significant hits to your percentage recovery or yield through the downstream process.

So I suppose overall I see chromatography as a really critical technology that can satisfy lots of the needs around a downstream platform for these newer modalities.

That's great.

And what about commercial considerations?

Could you talk about some of those considerations involved with such a platform?

Yeah.

So again, I suppose with regard to commercial considerations there, again, no difference at a high level than the considerations that we would have, for any medicine that we're producing, although the specifics, kind of may vary, modality to modality.

So, again, the time to market is extremely important.

So, this will really impact a patient's ability to access these medicines.

So, specifically in an AAV, number of the therapies are targeting paediatric indications.

And I suppose time to market is particularly critical there because you know, you have a relatively small time window where you can intervene and have a very positive impact on those children's lives.

You know, additionally, supply chain is a really important consideration.

So as I was saying, the advent or the emergence of AAVs has really driven a lot of innovation in the vendor space with regard to kind of new resins and so on.

So you know, that in itself is challenging because, some of these resins are, not yet fully understood or, there's not a lot of experience kind of built up with it.

So, considerations around being able to use resins that are available in commercial quantities that are GMP grade, that are sold by qualified vendors or vendors that meet the requirements for qualification with regards to the regulations is also really important.

And I suppose, ultimately then there's also the considerations kind of related to cost of goods.

So, the cost of goods directly impacts the economic viability of these products for companies and their ability to be able to produce them in order to make them available to patients.

So, typically the cost of goods but these drugs are orders of magnitude beyond some of the other modalities on the market and typically they are serving much smaller patient populations as well.

So, I suppose while it's a common consideration across all modalities, it probably has particular significance for AAVs.

Thank you.

And then to bring the conversation back to, as we were saying, the patients, could you discuss some of the outcomes such platform could provide to patients, particularly in the development of, say, vaccines and gene therapy applications?

Yeah, so I suppose I've probably kind of touched on a lot of the points already.

But you know, ultimately having a robust, reliable platform in place improves patient access to the medicines.

So as I said, it'll enable medicines to come to the clinic and to market faster.

It will minimise or reduce the cost of goods so that you know, more of these products are economically viable for pharmaceutical companies to produce, which you know, ultimately is essential for patients to be able to access that.

And I think as I suppose familiarity and experience with platforms builds, it also then will potentially increase the number of products that will come through to the market because you know, just that whole development process, regulatory approval process and so on will be more streamlined and easier to navigate.

That's fantastic, Thank you.

And then just finally, my last question is where do you see this field going in the next five years?

Yeah, so I think this is a really exciting time in this field.

I think, we can expect to see loads of significant advances, exciting innovations.

You know, first up, I think there will be further innovations and improvements in resins in, formats and so on that are available to the market.

I think we will see chromatography and other downstream steps being automated to a much larger extent with integrated process analytical technology and that enhanced automation, and you know, online monitoring will open the door to more sophisticated ways of operating such as the multi column continuous modes of operation that I mentioned.

And I suppose finally, I think that, AI and machine learning will be integrated more routinely into process development, so into accelerating the development of these steps, but also ultimately onto the plant floor into manufacturing in order to ensure that our platform is as robust and as flexible as possible and able to, I suppose, compensate if you like, for maybe unexpected or higher levels of variability than we might originally have anticipated.

Jessica, thank you so much for talking with me today.

And if you were interested in any of the topics that we discussed today, make sure you come to Cell 2025 to see Jessica's presentation and many more at the event.

But yeah, thank you very much, Jessica, for joining me today.

Thanks, Tom.