In this interview, Jason King, Associate Business Development Director at OXGENE, a WuXi Advanced Therapies company, describes how end-to-end solutions can help in overcoming bottlenecks associated with plasmid manufacture, as well as how to prepare for scaling up.
Could you please introduce yourself and tell us a bit about your role?
My name is Jason King, I’m in business development for OXGENE, a WuXi Advanced Therapies company. My role is to interest clients in our cell and gene therapy platforms.
How is WuXi Advanced Therapies operating as an end-to-end solution provider?
Describing ourselves as an end-to-end provider means that we now fulfil the whole range of activities for our clients. Right from the earliest stages where we’re cloning their genes of interest into our viral vector systems and then optimizing them to get the best productivity, to process development work and handing over to our colleagues in Philadelphia to carry out the clinical grade manufacturing as well as the testing that goes with that, means that we can now do the whole process. We can take clients right from the beginning to the end. We do everything except the clinical trials themselves.
What do partners gain from having that end-to-end service provision?
Mainly it’s about tech transfer, as a technology transfer is something which can be quite complex. If you’ve already done the small skill work with our plasmid systems, for example, then when you transfer it to the clinical manufacturing stage, it’s the same materials, the same cells and you’re sure that things are going to work, so it de-risks the situation.
What range of plasmid scales and qualities are you able to deliver?
In terms of qualities, we do research-grade ‘clinical GMP’ and ‘commercial GMP’. The clinical and commercial GMP are both produced in the same GMP facility, but the commercial GMP has more quality assays associated with it. Scale-wise, we can go right from small-scale 1 milligram for customers who want to just evaluate or test out the plasmids initially, right up to 50 gram scales, and we can do that for research grade all the way through to commercial GMP.
What are your lead times for plasmids?
So for research-grade plasmids, we actually have all of the packaging plasmids for lentivirus vector production and AAV vector production in-stock, so lead times are about 2 weeks. We also have stocks of clinical GMP plasmids, so again, 2 weeks. For GMP plasmids, we’re looking at around 3 months.
What benefits do OXGENE’s AAV and lenti plasmids have?
So both the lentiviral and AAV plasmids have been created and optimized by OXGENE. By optimization, we mean codon optimization and plasmid size reduction, which means that the transfection efficiencies are much higher. As a result, the productivity for AAV and LV production are much higher and industry leading, in fact.
The nice thing is that WuXi Advanced Therapies in Philadelphia carries out the clinical grade manufacturing of these vectors using exactly the same reagents, using the same vector systems in the same cells. So again, if it works in small scale preclinical, it should work as well in clinical grade manufacturing
How can larger viral vector batches be accommodated as systems scale?
The plasmid system is really good for preclinical and early stage clinical work and gives you great flexibility. When you are moving towards Phase III clinical trials and on to commercial manufacturing, more scalable solutions can be useful.
OXGENE has developed two different scalable systems – TESSA™ for AAV manufacture, and LentiVEX™ stable producer lines for lentiviral vector manufacture. These are really interesting for later stages as the components of the stable systems are exactly the same as in the transient system, so if you want to move from the plasmid-based system to this scalable system later, the reproducibility of production should be greater.
What else needs to be considered when assessing scalability?
It’s more to do with reproducibility and with scaling, it’s important. A plasmid system scales up well to 200 litre bioreactors, but beyond that it becomes quite difficult and challenging. The scalable systems don’t rely on plasmid transfection, and therefore are more scalable.
From an operator point of view, it’s a much simpler process to add a biochemical to induce expression of vectors rather than to try and transfect 3 or 4 plasmids into all of those cells.
How can plasmid manufacture become a bottleneck for clinical grade viral vector manufacture?
People talk about the bottleneck quite a lot and this is really an issue. When you have lead times for clinical production slots for viral vector manufacture that are 6 or 7 months, you need to ensure that the plasmid produced is supplied in a shorter time frame than that. This is why we aim for 3-month time frames for the GMP plasmid so you can be sure in knowing that your plasmids are going to be available for the manufacturer to do the viral vector manufacturing with them.