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Why you should consider manufacturing from the start of the biotech R&D process

by Simon Goldman

One of the most important, yet under-appreciated aspects of biotech commercialisation is the challenge of manufacturing your product at scale. This gained global prominence in the last month as the promise of coronavirus vaccines smashed into the reality of manufacturing bottlenecks and problems with scale-up. This jarring reality-check demonstrated that it’s not enough to come up with a world-changing idea in record-shattering time. It needs to be producible in quantity at a required level of quality.

This week we’re very pleased by news that NovalGen, one of UCLTF’s portfolio companies led by Professor Amit Nathwani, from the UCL Cancer Institute, has announced a strategic partnership with Dutch contract development and manufacturing organisation (CDMO) HALIX for clinical supply of its bispecific antibodies. The NovalGen team have made breathtaking progress getting from bench to bedside in just over two years. In this short space of time, they’ve developed a product to clinical scale in the face of significant challenges – reflecting on their success reveals a number of insights that can provide valuable lessons even for project teams and companies at a much earlier stage of development.

I caught up with Dr Kieran O’Donovan, NovalGen’s Senior Vice President of CMC (Chemistry, Manufacturing and Control) and explored some of these issues at length. While you could probably write a whole PhD on each of them, I’ve outlined some of the finer points here, in roughly chronological order through the translational process. Though our discussion focused mostly on therapeutics, these principles will be useful to anyone working on medical devices or diagnostics as well.

Developability as a basic research consideration

There are practical ‘applicability’ considerations which require some forethought even at the discovery/invention phase (i.e. the ‘R’ of R&D). Kieran highlights that an immediate ‘red flag’ when looking at a new technology – which perhaps has some in vitro or early stage in vivo data – is a situation in which it’s brand-new from a manufacturing perspective. Rather, he says, “in manufacturing you want it boring” with minimal surprises and therefore lower risk of losing money. So, if a new tech can plug into existing manufacturing processes from the get-go (e.g. an IgG1 antibody against a new target), then already it’s going to have a much better chance of being quickly and more efficiently translated to impact – and therefore also getting funded for that translational journey.

From a venture investor’s perspective, it also means that it has an improved chance of being profitable in the long run, which is critical for achieving a capital-efficient exit to an eventual licensee or buyer who has the wherewithal to progress the program to patients. How much profit a particular innovation is actually going to make at some point in the future is not something that is often considered when discovering new ways to improve healthcare in a university lab! But it’s useful to keep in mind right from the start that profit is a function of two things: revenue and cost. Revenue is driven by efficacy in meeting an unmet need – the more efficacious the innovation and the greater the unmet need(s), the higher the potential impact and therefore revenue. Cost is driven by many things, but manufacture is often the most significant. So long as efficacy is very high and the unmet need is very large, then higher revenues can absorb more cost resulting from complex manufacturing processes – autologous CAR-T therapies that can produce complete cancer remission are a case in point. But even these have had a rocky road leading up to their first commercial success in 2017. So, if an early stage innovation looks like it’s going to be very complex to manufacture, then that’s ok – it’s just even more critical to show that it is far more effective than existing or potential alternatives.

It’s never too early to consider developing a potency assay or a reference standard

It seems strange to think about regulators and quality standards when you’re only just demonstrating proof-of-concept in a petri dish. But patient impact is only possible where a product is consistently manufactured to a standard that enables doctors and patients to confidently use it and know that it works. The FDA defines a potency assay as an in vitro or in vivo test (or combination thereof) designed to indicate the specific ability of a product to have a biological effect. Kieran recognises that many biotech ideas might have their first sign of biological effect in an in vivo system, but expresses a preference for a validated, in vitro assay that is strongly correlated with functional efficacy. This is because the assay’s primary purpose in the long run will be to test batches of the manufactured product to ensure safety, purity and potency such that:

(a) sufficient active ingredient can be demonstrated in any given ‘lot’ so as to have the desired biological effect,

(b) sub-par lots can be removed; and

(c) variability in the output of the manufacturing process over time and over a product’s shelf-life can be measured.

They’re also crucial in linking a therapeutic’s clinical efficacy to its dose.

The importance of giving due consideration to potency assays as early as possible in development cannot be overstated. If the only way to measure the specific ability of a product to have a biological effect is in a 6-month-long in vivo model, then this is not going to be particularly scalable or standardisable for something that might be produced and distributed in enormous batches worldwide. Potency assay development is easier where there’s a clearly established mechanism of action linking biological effect in vivo to something that can easily be observed in vitro. Kieran suggests that a fast and inexpensive cellular assay that mimics the mode of action in vivo is the “gold standard” for biologics, or something like a chromatographic assay for a small molecule – but in general the results need to be easily quantifiable.

That doesn’t mean that you’re in an irredeemable situation if mechanism of action hasn’t yet been properly established – at earlier stages of clinical development, regulators have taken a more relaxed view on potency assays. For example, it may be that a panel of different measures that each demonstrate various aspects of the biological function of the technology is acceptable to support a first-in-man trial of a therapeutic, particularly for advanced therapies. But by the time the MHRA, EMA, FDA or indeed any other regulatory authority is ready to approve later-stage trials or indeed licensure for widespread use, they’ll want a formally validated assay (or set of assays) in place that can be easily scaled. Product withdrawals and delays to high-profile late-stage clinical trials have occurred in recent years as regulatory authorities have sought more validation of potency assays. At least thinking about these issues from the start can genuinely enhance the value of a biotech program because it reduces its risk profile the whole way through.

One thing Kieran recommends that academic researchers can practically do from early on is to develop a ‘reference standard’ against which potency can be measured. The first step is to be certain that it represents the product you want, and then characterise it thoroughly and store it securely. Make sure enough is set aside for any cross-comparability exercises in future, as invariably new batches of reference material will need to be made throughout the product’s lifecycle and you want to be able to compare that back to the original. Second, comprehensively document how it was made, what tests were done and what the results would need to be to allow it to be called a ‘reference standard’ (this will be different for every product).

An established reference standard thus provides an ‘anchor’ so that even as processes change or the product evolves towards clinical implementation, they can all be referenced back even years later. This is especially important if the technology is partnered with another company, or handed over to a contract research organisation (CRO) or CDMO for outsourced development and manufacture – it becomes much easier to get the technology into someone else’s hands. Establishing a reference standard should not be too hard or costly to do from even very early stages – after all it often costs several millions to transfer a manufacturing process and produce clinical material, so a few thousands for the reference standard pales into insignificance.

Outsourcing is all about people and trust

As a project or spinout transitions through into a translational pathway, it becomes more likely that external support from CROs or CDMOs will be required in situations where outsourcing makes more sense, is more efficient, or indeed is the only option! Choosing the right partners can make or break a project, and we can learn a lot at the university level from the very structured and strategic approach that a company like NovalGen takes to selecting and working with them:

  • “Look at their inspection track record” – rather than tendering out to three or four organisations and making a decision based simply upon their proposals and costings, it’s worth taking a bit of a deeper dive and looking for any red flags that would immediately rule a potential partner out. Can you speak to anyone who’s used them before?
  • “They actually want you as a partner not a customer – and they’re not paying lip service to this; for some you’re just filling capacity, for others they really mean it” How they treat you right from the start is telling. Are you meeting with their Chief Development Officer and their Chief Business Officer, or is it the B-team? When they suddenly get a request for capacity from a major pharma company (for example) do they speak to you about it straight away, and treat you seriously and help you to plan?
  • “Right from the outset they’re pragmatic on finances and not wanting to ‘nickel-and-dime’ everything” – are their costings reasonable, transparent and importantly complete? Look out for unspecified pass-through costs. And if you can’t tell, then make sure you get some help.
  • “Putting it right: what their plan is to get us back on track?” – problems sometimes do happen in outsourced relationships! Kieran says that the first thing you do when they call you up to say there’s been an issue is to ask them what they plan to do to put it right. In the background, the legal agreement is dusted off just in case. If it’s a straightforward mess-up on their part, then ultimately they’re going to have to reimburse you or make good whatever it is that’s gone wrong. If it’s because you forgot to tell them something or the process is poorly understood, then you will foot the bill – “hence a boring process is best!”. The partner will know that it it’s difficult for you to change providers so it’s a good sign if they’re taking the situation very seriously.

One key decision for many startups is whether to bring manufacturing in-house or whether to engage in a deeper, long-term relationship with a CDMO. The first question to ask is whether an external partner can actually fit your commercial supply needs into their facilities if you’re successful in getting your product out there. Another is to actually forecast how much it would cost to maintain that outsourced commercial manufacturing and over what timeframe, and to compare that to the cost of actually building your own infrastructure – though often it depends on the novelty and complexity of manufacture.

Managing complexity requires really, really good people

NovalGen have progressed from being a UCL lab project to a clinic-ready company in just over two years, and their success in the face of early delays and then the pandemic is a credit to the team they’ve recruited. Do not underestimate the need for a fit-for-purpose team – both in terms of skills/experience, but often more importantly in terms of mindset.

We discussed an interesting balance between domain experience in a team with their passion for the program/drive to achieve results. Some of the team at NovalGen came right out of university when the company was set up (rather than from industry) – “but what they had in spades was enthusiasm and drive, and they would work like demons to get the job done. They were fully engaged. They understood the importance of what they were doing and they're willing to learn.” And this was what enabled them as a team to go “from an idea to a clinical product: developing a process tech, transferring the process and analytics, writing an IMPD and getting that approved; getting clinical drug product manufactured, release-tested and out the door.” And it’s demonstrably this team effort which has got the company to where it is.

I’d also argue that it was some of the early hires that have made an enormous impact on company success over this period. Good science does not translate itself. Getting a highly experienced and motivated leadership team in place very early on is critical – we’re doing this for every project and company we’re funding at UCLTF. Some serious clinical and manufacturing expertise is most important for biotech translation is, alongside viciously good project management and rigorous financial control.

Start thinking ahead early

Clearly we’re not recommending that every early stage university bioscience discovery project needs to have a management team, validated assays and a CRO in place! Rather, there are a few things that can be taken into consideration – and even a couple of easy things that can be directly implemented – from those very initial phases of ‘R’ into ‘D’ that will manufacture a good outcome for patients in the long run.