Many more advanced therapy medicinal products (ATMPs) such as CGTs are now entering the commercialisation stage. Finally, they are set to bring a return on investment and deliver their promises to the patients who need them. As developers embark on this next phase, new pressures emerge.
Organisations must meet ever more stringent compliance standards and ensure the very highest levels of quality and safety, all while consistently driving down costs through efficiency.
As the industry collaborates to make CGTs more accessible and affordable, ATMP platform technology is delivering efficient manufacturing solutions. Through flexibility, modularisation, intensification, automation and digitalisation, the industry is finding solutions for some of the most challenging manufacturing challenges it has ever had to face.
Recouping development costs
The average cost to develop a new therapy stands at $1.3 billion and takes 10–12 years.1 When a CGT gets to the commercialisation stage, there is enormous pressure to recoup this cost. Already, we are seeing gene therapies pass the $1 million per dose mark, a situation that is unreachable for most patients and untenable for the market.2
Manufacturing efficiencies are critical to provide the cost savings that deliver payback without transferring unnecessary cost burdens to payers.
For highly targeted CGTs, reducing manufacturing costs is challenging. Very small batches require single-use fermenters; in the case of autologous treatments such as CAR-T cell therapy, this might be one fermenter per patient and a complete upstream single-use fluid pathway.
Ensuring safety for patients and operators
Contamination is a huge risk in the production of CGTs and the very highest standard of aseptic processing is needed to mitigate this. CGTs are often injected or delivered intravenously straight into extremely vulnerable patients … and sterility must be ensured.
“We have to manage contamination risks at every single step of the process,” says James Drinkwater, Head of GMP Compliance at Franz Ziel GmbH
But contamination is not just a risk to patients. Operators too must be protected against drugs, particularly with the increasing use of biohazardous materials such as genetically modified viral vectors.
The latest revision of GMP Annex 1, the European Union’s requirements for the manufacture of sterile medicinal products, addresses these issues in a standardised mandated way. It requires manufacturers to increase contamination control measures, barrier technology and automation to reduce risk to patients and operators.
Quality without compromise
As new processes evolve, manual tasks are often added to fill gaps in automated workflows; however, with every manual step comes an extra quality risk. Add the challenge of transferring highly sensitive cells between manufacturing stages and it’s easy to see how quality issues emerge and whole batches can be ruined.
Although individually developers are designing quality packages to tackle these challenges, the sharing of good practice is still limited. This lack of cross-industry standardisation makes regulatory approval for CGTs a long-drawn-out process, further adding to the costs and delays in bringing products to market.
Driving safe, compliant and cost-effective manufacturing through efficient ATMP platforms
After more than 10 years of development, the 10% of therapies that make it through regulatory approval should be passed, without delay, into a manufacturing process that is compliant, safe and cost-effective. ATMP manufacturing platforms are ideally placed to fulfil these goals, but they must contain certain key attributes.
Flexibility: CGTs represent a diverse range of therapeutics, so manufacturing platforms need to reflect this. There is strength in standardisation from modular equipment and single-use pathways, but this should not come at the expense of flexibility, which is the only way to ensure the most efficient and effective production.
Platforms need to accommodate different sizes, from clinical production to small batch processes. They should also be suitable for scale-up, which needs to be incorporated into the research and development stages. By using systems that have manufacturing-scale counterparts, small batch production can be easily and predictably upsized for larger allogeneic production.
Modularity: Modular systems that are prevalidated, enclosed and automated address many of the pain points of regulatory compliance, safety, waste reduction and changeover between products. Far from restricting flexibility, these systems are often fully configurable. ATMP filling platforms, for example, can now be configured to process a range of different products — with or without containment.
Modular equipment often brings intensification benefits too. Connecting disparate functions and process steps into one intensified platform can better protect cells that need highly controlled conditions. Different manufacturing functions can be brought together in one integrated system, which can be a game-changer for products with a short shelf-life.
Automation and digitalisation
Removing the “human factor” is central to meeting the contamination control strategy (CCS) element of the new GMP Annex 1 requirements. Human errors are mitigated by automation and human commensal contamination is further reduced by the use of barrier technologies powered by automation.
That said, robotics and barrier technology should always be fully accessible to humans. This means flexibility must be added to the design process so that interventions can be made without compromising the aseptic, Grade A environment or ruining batches.
With automation also comes digitalisation for both control and monitoring. Intensified systems should communicate seamlessly to ensure quality oversight monitoring and establish complete control of the chain of custody.
Robust environmental and process monitoring should also be employed to measure the parameters of viable and non-viable contamination and include trend data for longer-term quality assurance and efficiency improvements.
Tried, tested and prevalidated technology
CGT manufacturing requires an evolution of existing methods, rather than a revolution. It is already known how to safely transfer cells in the biologics sector — using peristaltic pumps with fast, non-shearing processes — and we already use reliable bioreactors and suspension-based culture systems in biologics manufacturing.
Where tried and tested equipment is fit for purpose, it can easily be incorporated into new CGT workflows.
Single-use technology is an obvious choice, giving the option to remove every fluid pathway associated with a batch and replace it with a new prevalidated system. Without clean-in-place or sterilise-in-place requirements, single-use systems can guarantee sterility and meet small-batch and bespoke needs.
Single-use pathways often come prevalidated for regulatory compliance and this is extended into some automated, modular equipment too. Prevalidated, standardised systems bypass bespoke validation and design processes, provide a key part of a robust CCS and can lead to faster regulatory sign-off.
“That's the beauty of single use. It's an ever-evolving, iteration after iteration, sort of product instead of a more in place and dramatically changing later in the future approach that we've seen in the past,” comments Dr Alex Van Hagen, Life Sciences Sector Specialist, Watson-Marlow Fluid Technology Solutions
Investing in people, processing and equipment for a more efficient future
Whether manufacturing occurs in-house or through a CDMO, robust ATMP platforms are critical. With collaboration between academia, developers, CDMOs, NGOs and regulatory bodies, this enabling technology can be used most efficiently and effectively to deliver the best quality products to patients at the lowest possible price.
ATMP platforms require initial capital investment, but the payback is fast and delivers many long-term benefits. Although fit-for-purpose now, many of these platforms are also ready to meet the rapidly changing regulatory and market demands.
Safety, quality and efficacy will continue to be at the heart of all decisions as more CGTs come out of the laboratory, through commercialisation and into the caregiver’s toolbox.
Only through close collaboration and sharing of best-practice and skills will the industry be able to achieve its primary goal: to drive down the cost of treatment so that more and more patients have access to these lifesaving therapies.
Taking a collaborative approach
The challenges of CGT manufacturing are new; however, the knowledge needed to solve them certainly exists. People across different organisations will have experience and expertise in many key areas, but no one group is likely to have them all.
This existing skills shortage will continue to grow as the industry expands, especially in quality assurance and GMP compliance. Wherever skills are held by a few and needed by many, knowledge transfer is key; for CGTs, this will be especially important as developers make the transition to scale-up and scale-out for commercialisation.
“How will we address the talent gap to realise some of these processes and therapeutics?” asks Dr John Milne, Director of Training and Education, National Institute for Bioprocessing Research and Training (NIBRT)
Already, many regions, governments and industry facilitators are recognising this need and initiating plans to foster knowledge transfer and derisk the industry.
Organisations such as the Cell and Gene Therapy Catapult and the National Institute for Bioprocessing Research and Training provide the industry with the connections and tools they need to train teams, establish standards and determine the most efficient and effective way to deliver the CGTs that patients so desperately need.3,4