Cell and Gene 4.0

Unstoppable innovation in numerous fields has driven us to where we are today: Industry 4.0. 

Arguably, the pharmaceutical industry has the opportunity to surpass the efforts of all other sectors with the wonder products being developed in the advanced therapy space; curing illness with a single dose surely represents the imaginable pinnacle of medicine. But the technologies required to manufacture these products – swiftly, accurately, cost effectively, at scale, and under extremely demanding regulatory requirements – must be as advanced as the therapies themselves or stakeholders risk being left behind. 

The cell and gene therapy space may not quite be the final frontier, but it is fascinating to learn that, as we find ourselves quarter of the way through the 21st century, innovators and enablers are still going boldly beyond expectations so that one day, just maybe, we can all live long and prosper. 

In this feature, we gather four experts to help make sense of the varying definitions of Industry 4.0 – and what the fourth industrial revolution has in store for the current and future of cell and gene therapy manufacturing.

How do you define Industry 4.0? 
 

BR: Industry 4.0 is the digitalization of manufacturing; real time manufacturing readouts, real time analysis, and automatic controls. For cell and gene therapies, these technologies can help ensure the product is consistently made the same way every time – regardless of donor variation.

ML: When I think of Industry 4.0, I think of connectivity – and using analytics and data to improve processing. Traditionally, much of the information in drug development has been siloed. Being able to analyze data across the whole value chain is really important. When it comes to Industry 4.0 tech, we also need to think about how we can interact with technology. Right now, the human–technology interface is still in its infancy, but collaboration can push it forward. I don’t think any individual company or service provider can do it alone. 

JF: Industry 4.0 is particularly important for cell and gene therapies. These medicines are inherently variable and don’t lend themselves to GMP as we understand it for more traditional modalities. Having the ability to perform adaptive control, and to build and modify a process around the needs of particular patient cells to create the same outcome, is where we’d all ideally like to be. To achieve this, new sensor technology, real time analytics (and the ability to react to those analytics), IoT devices, and automation will all be a huge help. Right now, we’re somewhere in between Industry 2.0 and 3.0. A lot of paper-based processes are still used for cell and gene therapies, including paper batch records and paper lab notebooks that use disconnected devices or lab-scale tools that aren’t digitized at all.  

JL: I agree with what the others have said. However, I would also add that, before we can truly take advantage of the Industry 4.0 technologies being developed today, we first need to ask, as an industry, how we can become really good at manufacturing cells consistently. Once we really understand the process, we can optimize it even further using Industry 4.0 technology. 

What progress is being made?
 

JF: One of our companies has instituted batch release by exception, through a continuous validation process that uses digital technology. That’s Industry 4.0 stuff right there. 

Batch release is a huge challenge for personalized medicine. With traditional small molecules, a batch can be millions of tablets. For a personalized medicine, each batch is one therapy. No matter how good we get at the rest of the manufacturing process, batch release will always become a bottleneck at scale; you can’t treat 10,000 patients if it takes a day to release two doses.  

BR: Release by exception is our dream and we are trying to implement that too. Every cell and gene product is unique and each partner brings their own unique process, which makes electronic batch records (EBR) difficult. I am very much in favor of some version of standardization to make progress. I also want to see more digital control in the manufacturing process, but we’re still quite far from this being a reality. 

ML: Pharma companies used to be reluctant to have GxP software on cloud-based systems, instead wanting to keep their data on premises. This may work for some modalities, but cell and gene therapies have disparate supply chains with many different stakeholders. Here, cloud-based systems make a huge difference by harmonizing supply chains. Something as simple as sharing information concerning manufacturing capacity with different sets of clinical centers, so that they know when they can schedule starting material collection can be difficult with a siloed approach. The cloud has made data sharing much easier.  

I also believe that these types of technologies are encouraging more companies to add cell and gene therapies to their pipelines because developers can see how manufacturing and supply chains can be effectively managed. Now, we need to focus on scale-up and scale-out so that more patients can be reached. 

JF: Scale up is a key topic. We’re starting to get critical mass with numbers of products, but large numbers of patients remain untreated. It’s time to consider what lessons have been learned and to ask: how do we refashion the infrastructure? Implementation of Industry 4.0 needs to be done carefully. Yes, there are new technologies and standards being developed that help us to talk to each other and help share data, structures, and frameworks, but all of this needs to be put together in a way that makes sense. We must avoid the “cobbled together” approach. Much has been learned over the last six years or so, but it’s time for us to make sure we’re coming together and creating real momentum towards Industry 4.0.

How do we accelerate industry-wide adoption?
 

ML: When you’re thinking about uptake and new solutions, the mantra is “the process is the product.” If you have an approved biologics license application or approved marketing authorization application, there aren’t many incentives to change your process. In fact, making substantial amends to a marketing authorization will probably keep quite a few people up late at night with worry about the consequences! The pharma industry is naturally conservative, so adopting anything new is challenging. This is the mindset we need to somehow overcome. 

BR: Our partner base tends to bring in fairly advanced academic processes; they don’t want to change anything because of their preclinical efficacy data or their phase I data. They are trying to avoid what I (lovingly) call “death by comparability.” Adopting new technologies scares new discovery companies, so reluctance is a real problem. We need a more unified comparability set of standards – a clear path forward so that companies really understand how to demonstrate comparability and easily validate a process change where the product is just as potent. This leads me onto the potency assay, which is, I think, the industry’s Achilles heel in many ways. We need robust – and preferably standard – potency assays.

JF: I would say that we need investor buy-in. Adoption of advanced manufacturing technology and/or digital technologies needs to happen early in the process before reaching the clinic. However, investors have traditionally pushed new therapeutic companies to get into the clinic as fast as possible – leaving little time to focus on digitization and optimization. Incentives in the early development phase need to be aligned. Investors should give their portfolio companies and research partners time to develop a robust process that is repeatable, reliable, and comparable, which is the best foundation for clinical success. 

What role must technology companies play in helping the cell and gene therapy sector move to Industry 4.0?
 

JL: I’m confident that developers and enabling technology companies are working to create common sense manufacturing platform principles. It should help us move faster, and then we can incorporate some of the really cool new stuff that will enable us to analyze blood on the front end and put them into different manufacturing workflows depending on specific cancer mutations. That’s the next drive forward, but we can’t get there unless we simplify. We need to strip away all the needless complexity and just get back to what works, which is delivering oxygen and nutrients to cells, on demand.

JF: The old model of getting great clinical data and getting bought out in phase II no longer applies to advanced therapies. Companies need to prove that their product will be commercially successful, which means thinking about widespread patient access and affordability. We know that Industry 4.0 has benefits, but it’s not easy for drug developers to focus on this area. Drug developers are not software coders nor automation/robotics experts. Technology developers need to do the heavy lifting here and convince scientists in the academic lab to use their technologies to help them achieve scale. We need both flexibility and scalability – not one or the other. Enabling technology companies need to make sure that can happen for the industry.

In cell and gene, we tend to think we’re special – that it’s okay for us to charge up to $4 million for a product. But we are not just competing with other cell and gene products, we are competing with ADCs, small molecules, and biologics, which are also seeing amazing advances. We need to conform to the same rules as every pharmaceutical product – and products need to be affordable and accessible. 

How do you think Industry 4.0 will continue to improve manufacturing? 
 

ML: Although using generative AI in a highly regulated environment may still be a way off, predictive AI is certainly beginning to gather speed in terms of possible use cases. For manufacturing, this could result in more accurate forecasting of drug product demand or more responsive and intelligent scheduling of manufacturing slots, particularly where external factors make these changeable. Using AI in tandem with patient data, supply chain data, and other information could also make it easier to predict which shipping routes or channels hold the lowest chance of delay, which patients might require rearrangement of their treatment date, or make it easier to backfill canceled slots. This has the potential to leverage major efficiency increases. There may even be more that can be done to help mitigate for the varying quality of starting materials within cell and gene to make the production of consistent therapy products less of a challenge.

JL: Venture money, along with pharma deals, will continue to be hard to come by in cell and gene unless we as an industry make meaningful strides to reduce the cost to produce these therapies. Overly complicated manufacturing, which leads to way-too-costly drugs, will continue to be the roadblock in getting more therapies to market. Industry 4.0 could have a major impact on driving down production costs, but only after we first become ruthless in our effort to simplify the manufacturing protocols across the board. 

BR: We are already seeing the benefits of Industry 4.0 in CGT manufacturing by the implementation of electronic batch records, release by exception, and improved sensory process controls. Even so, these digital solutions are challenging to implement for cell therapy manufacturing in its current state, particularly for autologous therapies. Advanced analytics will continue to improve process control and product quality; robotics and automation have the potential to reduce manufacturing errors and labor costs; and advanced engineering, such as nanoparticles, will improve payload delivery to cells for more robust gene editing. 

Industry 4.0 could help turn science fiction into reality. Please present a sci-fi comparison or prediction of what you think the next five years will look like…
 

JL: Imagine a scenario reminiscent of “The Matrix,” where customized therapies are readily available, tailored to individual patients’ needs. Imagine smart factories employing augmented reality with real-time monitoring and intervention, ensuring the highest product quality and efficiency within manufacturing every single time. 

But we must be patient. What we risk by injecting this sci-fi future too soon is baking in overly complex and incredibly expensive processes, and ultimately causing the downfall of otherwise excellent science as viable companies burn cash on complexities rather than focusing on the art of simplification. Our industry cannot perpetuate the current rate, where incredible science and therapies showing great clinical benefit are failing due to the inability of biotech organizations to keep the lights on. The groups focusing on simplification will reap the rewards in the form of added efficiencies (and therefore profit) that Industry 4.0 will bring.

BR: Five years is a short time horizon for the next chapter of cell and gene therapies. The industry is trending toward allogeneic cell therapies, with a goal of highly effective, off-the-shelf, more affordable therapeutics. Perhaps in the next five years a successful allogeneic trial will herald the dawn of the allogeneic era, much like Kymriah brought autologous CAR-T to marketing reality. 

Allogeneic cell therapies are even more dependent than autologous cell therapies on the quality of the starting material, and the cell therapy space still uses primary human tissues as a source. AI may be used to select the optimum donor material for allogeneic therapies that would far exceed our current abilities to screen donors. This is a less frightening and ethically fraught version of the genetic manipulation and selection in movies such as “Gattaca.”

JF: People have nightmares of robots taking control – think of “2001: A Space Odyssey” or “The Terminator” – but the near-term technological advances are going to look a lot more like “Star Trek,” where advanced technologies are omnipresent but frequently behind the scenes, augmenting existing capabilities, automating manual processes, and completing calculations and making inferences that humans cannot. 

In the coming years, we’ll see an ease in demand for highly educated staff to do manual process monitoring. We’ll see improved IoT interconnectivity and data analytics that help us monitor and intervene to improve the quality and safety of individual batches to help us draw deeper insights that will drive the industry toward standardization. 

ML: An old analogy but one that will be familiar to many is the use of the “Star Trek” medical tricorder. It was initially a scanning and analytical diagnosis device, but the intention is what always struck me; in the future, we would have sufficient knowledge and analytical power to offer each patient a treatment specifically tailored to them. This is what we are now seeing in advanced therapies; a field of medicine that can manipulate cells on a patient-by-patient basis to offer hope of a treatment not previously possible. Typically, CAR-T treatments are a therapy of last resort administered once standard of care chemotherapy has failed. 

“Star Trek” storylines were always underwritten by the drive to push the boundaries of scientific discovery. These crews were constantly solving problems that had previously been impossible and making them faster or better than expected. We are privileged to see this in the cell and gene industry every day. Whether a new methodology or a new indication, those frontiers are continually being challenged. Until the point where the equally well-known “Star Trek” replicators and teleporters become a reality, we should all continue to strive to ensure that cell and gene therapies can reach as many patients as possible.