With Tony Hitchcock, Technical Director of Cobra Biologics
Cell and gene therapies would be incredibly difficult to commercialize without disposable manufacturing technology.
Only a small number of cell and gene therapies have been approved to date by the FDA or EMA, but there is a great deal of excitement in the area. Not only are phenomenal advances being seen in science and discovery, but new developments in manufacturing equipment are making the commercial production of the resulting therapies a reality. According to Tony Hitchcock, single-use has been a key enabler of the cell and gene therapy manufacturing industry.
What’s your stance on single-use systems?
I’ve always been a big fan of single-use systems. When they first began to appear on the market, I was working on drugs and manufacturing processes for plasmid DNA to be used in early phase gene therapy clinical trials. One of the biggest issues for us at the time was product segregation and cleaning validation; we were literally buying stainless steel systems and throwing them away after a single production run because we couldn’t validate the cleaning of them.
To that end, single-use systems have been critical to the development of manufacturing process for gene therapy products – I don’t think cell and gene therapies would have taken off without single-use. Consequently, I remain strong advocate of disposable systems.
Initially, there were many industry concerns about single-use; with some people even saying that single-use was not “proper engineering”. The systems were small and when they first emerged, they weren’t suited for commercial production, so it took several years for them to migrate into mainstream manufacture.
What about concerns around extractables and leachables (E&L)?
Patient safety is the number one concern of all regulators, and questions around E&L have been raised within the industry for a number of years. Initially, I don’t think people took single-use systems seriously when they first emerged, and the concerns came in alongside the potential for them to be increasingly used for commercial production. Initially, these concerns came from companies’ internal regulatory groups, who struggled with these approaches, not least because of the lack of clear guidelines relating to the use of plastic-based systems in manufacturing processes, rather than product storage, and the novelty of these approaches.
However, despite this, nearly all biopharma companies have invested heavily over recent years into single-use technologies and in some cases, whole production facilities. In my mind, these decisions were essentially based on the commercial and operational advantages of single-use systems, backed by risk assessments on multiple issues around quality impacts of which E&L was only one factor. From my perspective, I think the issues with E&L is that it has attracted a disproportionate amount of attention in terms of quality risks associated with the use of single-use systems and also detracted from the advantages that these systems can bring in terms of product segregation and cross-contamination.
Overall, I think a huge amount of progress has been made with regards to quality systems through suppliers and end-users working together to address them, and clearly given the number of products which are now either being produced commercially or in clinical trials, there is widespread acceptance of these systems from the regulatory authorities across the world.
It seems to me attention is now moving to other challenges such as disposal and managing plastic waste. Understandably there are environmental concerns and we need to find a way of managing the lifecycle and disposing of these systems appropriately. Recycling will be difficult, but as an industry we need to show that we are managing that waste stream in a professional and responsible manner.
Can you imagine going back to stainless steel?
The early part of my manufacturing career focused on stainless steel. Trying to get products into the clinical phase involved significant plant capital expenditure and there were issues with time and flexibility. Single-use has given the industry flexibility and allowed us to accelerate process development. Today, I think single-use is pretty much the norm for most companies, even for full-scale production. Big Pharma still tends to use stainless steel plants where very large production capacities are required, but there are companies – like Amgen – that have set up newer, smaller facilities that primarily use single-use. One of the issues with going back to stainless steel would be how do you translate backwards from single-use to stainless steel? The industry knows how to move from stainless steel to single-use – there is a lot of experience there – but going back would be difficult, given the infrastructure required for stainless steel facilities.
What developments will the cell and gene therapy area see in the coming years – both in terms of new therapies and manufacturing technologies?
This is a tough question given the rapid amount of development going on both at a technical and at the business level.
In terms of manufacturing technologies, there is clearly a big drive to reduce the costs of vector production and to increase production capacities to allow for products to become more accessible to patients. To achieve this, the focus is currently on switching out of cell culture ware such as cell factories into more scalable technologies such as the iCELLis® bioreactor (Pall’s automated, single-use, fixed-bed bioreactor) or to suspension culture systems. Additionally, there is a drive towards producer cell lines rather than transient production in suspension cultures, which allow for large-scale production in conventional bioreactors.
In terms of new therapies, I think the key developments will be firstly looking at the broader disease areas with significantly larger patient groups than are currently being treated, but this will require significant cost reductions and investment in treatment centers and staff to be achieved. At the other extreme I think the concept of patient specific medicines is likely to become a reality in the coming years. I find this concept really interesting, but it will require a revolution in manufacturing tools and approaches to achieve. I think it offers huge potential benefits for patient in key disease areas such as cancer treatments.
You’re an advocate of single-use. How about other new technologies, such as continuous processing?
Single-use was a game changer because it brought with it such novel benefits. I have less experience with continuous systems, but currently I would say that the benefit is purely commercial, and cost is clearly a critical issue for the industry. I’d like to see the industry exploring what other advantages the technology can bring with regards to different processes and manufacturing strategies.
One of the reasons that single-use ultimately became very successful was that it was very simple and easy to use – workers could put it all together themselves without truly specialized training. If the industry wants continuous biomanufacturing to really take off, then it must be simple and accessible. Right now, many see continuous as a very different type of technology – new and complicated – and adoption is much less likely for therapies with established production platforms, but I think it does have real potential for product areas where there are no established processes.
It is often very hard to change technologies in pharma. The industry does not like change and the implications of change can be severe – in the worst case affecting patient safety so manufacturers and regulators must approach new – even really promising technologies – in a reserved manner. As an industry, I think we need to recognize the gains we’ve had, but we must carry on innovating to see what else we can change. In a way, I think the industry has become stuck. There is a lot of focus on platforms for antibody manufacture and how it can be improved. Indeed, many single-use systems target antibody processing. I think we need to improve platforms so that they can cope with a wider range of drug products.
When it comes to implementing new technologies, what are the considerations for CMOs/CDMOs and how do these differ to biopharma manufacturers?
CMOs, as service providers, cater to a broad range of customers from small biotech to large pharma, who will very often have variable manufacturing needs and experience. When we look to introduce new technologies, compared to directly guiding existing and potential customers from in-house operational groups, CMOs are often better positioned to advise existing and potential customers that any new technology is the right solution for their manufacturing needs, both for clinical supplies and in-market production.
Key issues for our customers are risk and transferability of processes. For these reasons, customers tend to be wary of novel unproven technologies, especially where capital procurement and installation is required that may potentially delay their projects. Additionally, adopting new technologies may also lock them into a specific CMO or process, which may not be acceptable.
On the other hand, customers are also looking for us to provide solutions to their manufacturing needs and see CMOs as “manufacturing experts” especially in areas where they have a proven track record. So when we come to introduce new technologies we need to be able to show that we have expertise in the technology and that it is right solution for the customer’s needs.
What’s the next likely evolution for biopharma manufacturing?
Cell and gene therapy is a key focus for us; it is an exciting field and it is rapidly expanding. We are also reaching a point where we integrate a lot more with point of care users – particularly in the area of cell engineering. In the future, we’ll see a lot more integration with hospitals and how we actually provide these products to the patient. I expect that we’ll need to have some interesting discussions about where we draw the line of biomanufacturing.
A key trend in the biopharma industry as a whole is that many new medicines require small production volumes – either because they are highly potent or target only a niche part of the patient population. We are moving much closer to personalized medicine. Of course, there will always be large stainless steel plants making huge volumes of antibodies, but there will be much more innovation in complex therapeutics that are highly targeted and highly effective for certain patients.
Originally published by The Medicine Maker
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