A peculiar thing happened along the journey of cell and gene therapy: For an industry accustomed to packing years of change inside a single financial quarter, tomorrow’s critical therapies — aimed at thwarting a host of emerging health threats, including a global coronavirus pandemic — remain curiously reliant on the equipment and manufacturing processes of years gone by.
An inaugural CRB Horizons: Cell and Gene Therapy Report — built on the survey responses of nearly 150 advanced therapy medicinal products (ATMP) industry leaders — reveals an alarming dependence on the sort of primitive technology and manual applications that, in their day, made sense for an industry looking to grow quickly and leanly.
A deep dive into an array of important issues confronting the ATMP space finds an industry brimming with optimism for the future, but uncertainty about the path ahead. The pain points of resource and risk are ever-present.
As we enter into the homestretch of this year, where is the cell and gene therapy industry headed in 2021 and beyond? We’ve identified six trends to watch.
- Lack of commercial GMP manufacturing capacity to meet current and future demand
- A need to automate and optimize processes
- Open and manual operations are difficult to scale, driving the need for closed, automated processing at the commercial scale
- A transition from adherent cell culture to suspension cell culture to maximize scalability
- Lack of skilled and available expertise to manage and operate new process equipment
1. The multimodal revolution
Look for exponential growth in this area on the near horizon. Tasked with managing highly complex product pipelines and unsure of which modalities will move successfully through clinical testing, today’s ATMP manufacturers are playing a numbers game by investing in diverse and complex product portfolios.
Nonetheless, almost 60 percent of survey respondents plan to adopt a multimodal solution within two years. We expect this number to dramatically increase over the next five years.
This revolution won’t be easy. Shifting from a dedicated facility to a multimodal facility will challenge how owners, quality departments, regulators, facility designers and others in the industry perceive cell and gene therapy manufacturing. But with this challenge comes improved flexibility, ease of scalability and better cost control.
Like most revolutions, this one will arrive gradually and then all at once. The “gradual” chapter has been underway for some time, with ATMP platforms increasingly accepted in the mainstream clinical environment. This has prompted a recent explosion of mergers, expansions and new enterprises.
Multimodal biotech and ATMP manufacturing is about to take over. ATMP manufacturers who want to own their future by taking control of their present have a narrow window to make their move — but it’s a move destined to pay off for years to come.
2. Gene therapy’s rapid rise and emphasis on stable producer cells
Viral vector manufacturing is on the verge of an extraordinary leap forward. Experts predict that the field will grow by as much as 20 percent per year over the next five years, driven by a surge in regulatory approvals for in-demand cell and gene therapies.
More than 80 percent of survey respondents rely on transient transfection to manufacture viral vectors from packaging cells. Interestingly, however, the stable producer cell line is gaining momentum.
Fully 65 percent of survey respondents are developing (or intend to develop) this type of vector host cell, drawn by the potential for a less expensive, more scalable process. Stable producer cell lines, once an interesting aspiration of a few, are opening the door to compelling new operational models that will shape the future of viral vector production.
For example, what if manufacturers could propagate multiple batches of vector from a single stable producer cell culture? That would eclipse the productivity of the “terminal” triple transfection process and introduce all-new possibilities for the way manufacturers plan and qualify their facilities.
We don’t quite know what the effect of new viral vector manufacturing approaches will be on the industry on the whole. What we do know is that the industry’s innovators will keep finding compelling solutions to manufacture novel, life-sustaining genetic therapies for generations to come.
3. Focus on process and facility optimization
Everyone wants an optimized facility, but there are few clear instructions for getting it. So much depends on the complex science of cell and gene therapy manufacturing, but just as much, or more, depends on how well manufacturers translate that science into facility and process design.
Optimization has now become mission critical. Manufacturers know this. More than 77 percent of survey respondents ranked process development and optimization among their top three commercial manufacturing challenges across both cell and gene therapy platforms. These manufacturers also know that getting optimization right begins with the design of their new facility or manufacturing technology.
Manufacturers need a detailed map to guide them safely across that minefield. That’s the big promise of optimization. It reveals the best possible path from high-level conceptual planning to construction and, finally, to commercial operations. Defining this path from the beginning matters. The further companies move along the path, the more they’ll pay — in budget and in lost time — to accommodate changes and resolve unexpected challenges.
There’s also the progressively higher risk of making a mistake and undermining a design’s synergy late in the project’s development, leading to inefficiencies in construction and in the facility’s ultimate performance. To avoid these roadblocks, manufacturers need to begin with the end in mind, using a facility optimization approach from the start. This will avoid costly wrong turns and dead ends, ultimately delivering what nearly half of survey respondents consider their primary goal of optimization: lower capital and operational spending.
4. Growing interest in turnkey project delivery
Good, fast or affordable: Pick two. If you’ve been part of a traditional design-bid-build (DBB) project in the past, chances are you’ve faced that choice. This is a decade-old paradigm that has plagued a highly complex and technical industry where every project is considered unique. Meanwhile, other complex industries, such as health care, have been early adopters of integrated project delivery models which have proven successful.
This impractical choice has persisted for as long as traditional project delivery has been around — and it hasn’t aged well. Not long ago, 100 percent of survey respondents might have been using DBB. Today, that number has fallen to just 28 percent, while the rest search for more integrative alternatives.
We’re not surprised to see ATMP manufacturers leading this overall migration towards modern and more efficient project delivery methods. They’ve already moved the goalposts in pharmaceutical manufacturing, and now they’re accelerating the adoption of the non-traditional project delivery methods that make those manufacturing goals achievable.
Over the next few years, ATMP manufacturers will continue to propel our industry into a promising era of holistic, turnkey project delivery. The majority of our survey respondents say they would consider turnkey for their next project. We expect this trend to rise dramatically over the coming years.
Of course, not everyone is ready for this evolution. More than a third of our survey respondents say they would not consider a turnkey approach. Keep in mind, however, that a turnkey facility — with a project team that understands your objectives and can balance standardized design with customization — provides exactly what some fear they may be giving up: flexibility and control, simplicity, speed and predictability.
5. Continued reliance on a model which leverages CDMOs and in-house manufacturing
A majority of respondents are uncertain whether they will switch to gene-modifying technology in the near term. Overall, 15 percent of respondents anticipate a technology switch within the next three years.
In the interim, nearly three-quarters of survey respondents work with a CMO or CDMO in some capacity, most often as part of a hybrid in-house/CMO model. This gives manufacturers an opportunity to own the development of their process without huge capital outlay on dedicated facilities and manufacturing talent. It also enables them to completely outsource specific components such as plasmid production.
Partnering has its own costs, though. Despite a recent surge in facility construction and expansion, it’s not unusual for manufacturers to wait a year or more for an opening with a qualified CMO. This accounts for the 27 percent of survey respondents who have chosen to pursue only in-house viral vector manufacturing.
Rather than wait for the industry to catch up with demand, this smaller percentage of respondents are initiating their own solutions and accepting the risks — and potential rewards — that come with going it alone.
6. Regulatory compliance strategies for closed processing
Most ATMP manufacturers surveyed (78 percent) are making products destined for human or veterinary use. Because progress in discovery, developing and evolving therapeutic applications among manufacturers has almost always moved faster than regulation, look for a surge in the development of regulatory compliance strategies — particularly in the area of closed processing and patient specific therapies.
In many cases, regulators are familiar with ATMP technologies. In others, the emerging technologies and process platforms for ATMP production are so novel that they may not be fully compatible with current GMP regulations. Making a wrong decision — or a decision that works for small-batch production but will not scale to commercial-volume GMP production — could result in significant regulatory delays. With so much depending on speed-to-market, avoiding these risks is paramount.
In 2013, the International Society of Pharmaceutical Engineers (ISPE) introduced the concept of closed bioprocessing, laying out the rationale and criteria for what is closed and what is not. Soon after, regulators began recommending the use of closed bioprocessing. They saw it as the safest way to make biologics with the least risk of contamination, including for vaccines and therapeutic proteins. These concepts must now continue to be implemented for novel therapies. For manufacturers, this translates into lower cost to patients, lower operating costs, lower facility costs, and a smaller overall footprint.
To take advantage of these benefits, therefore, pharmaceutical manufacturers need a regulatory strategy. This means understanding ATMP regulations, communicating with regulatory agencies and industry peers and embracing closed bioprocessing.
A sound regulatory strategy will help with the initial design of the bioprocess used during commercial production, and in turn will reduce contamination risk and operating costs, ensure reliable production and smooth the regulatory approval process.
Preparing for the future
The pharma manufacturing industry is poised for some large-scale changes as early as the coming year. In some cases it may have been prompted by facing the hard realities of drug development and discovery in the COVID era; in others it’s simply an extension of the groundwork laid over past years of diligent effort.
Regardless of what has motivated these changes, the next five years will be interesting. Companies that acknowledge these trends will be best prepared for a sound and successful future.
ATMP startups that are new to therapeutic manufacturing might not be fully aware of the challenges they’ll face as they move from the lab to the cleanroom. More mature companies with a history of dedicated, stick-built manufacturing sites and rigid procurement processes might have reservations about initiating a non-traditional capital development project.
For both types of companies and everyone in between, the first step in navigating this opportunity and unlocking its advantages is knowing which questions to ask. For example:
- Scheduling and cost control: How can you balance the pressure to get up and running as quickly as possible with the need to manage your costs, particularly while your products are in the early investigational stage?
- Compliance and closed processing: What will it take to ensure end-to-end regulatory approval when the concept of a multimodal facility is so new?
- Partnership: Should you invest in the necessary infrastructure to keep all your operations in-house, or find a CDMO to support some or all of your manufacturing and testing needs?
- Supply chain: Should you rely on a third-party supplier for your raw materials? What are the risks and potential payoffs of using your multimodal facility to manufacture plasmids, viral vectors and other necessary materials in-house?
- Location: Where should you put your multimodal facility? Near an urban center, where you’re more likely to find top talent? Near a transport hub, which would simplify logistics? Next to a hospital or point-of-care facility?
- Construction approach: Traditional construction methods are falling out of favor as leaner, more flexible alternatives become available. What’s the best option for your multimodal project? Should you take advantage of the speed of a prefab solution, despite its higher price tag? Or is the extremely popular approach of combining modular and stick-built systems best for your unique circumstances?