Peter Walters, Lead Process Engineer, CRB USA11.20.19
Cell and gene therapy companies have one major thing in common with other types of biopharmaceutical firms: they need to move fast.
As the first few advanced therapy medicinal products (ATMPs) gain regulatory approval, and as patients with previously incurable diseases find new reasons to hope for effective treatment, the pressure to move quickly can bear down with enormous force. Across every biopharmaceutical area, the years spent progressing through preclinical and clinical studies are years of colossal pre-profit spending. That slender window between the first day of commercial manufacturing and the last day of a patent’s term of protection is often a company’s first and only opportunity to slingshot themselves back into the black. Getting there as soon as possible, while maintaining regulatory compliance and ensuring the safety and care of the patient population, is a central preoccupation.
This is where many of the similarities end. Cell and gene therapy facilities face a unique set of challenges as they scale towards commercial production, and they require equally unique solutions. While other types of biopharmaceutical facilities can follow a template as they grow, calculating their required footprint and equipment capacity based on well-established economies of scale, ATMP facilities have to invent their own way forward.
Nothing is templated. Everything is novel. New generations of technology emerge almost monthly. Open, operator-driven processes are the norm, making up for a limited availability of closed, automated cell and gene therapy technologies on the market today. And because those open processes support the production of highly personalized virus and viral vector products for very small patient populations (as small as just one patient, in the case of autologous production), they can vary greatly even within the same facility, and they require rigorous biosafety design measures. Under these unique and variable conditions, scaling up is very difficult, and scaling out quickly becomes prohibitively expensive.
Many facilities, under pressure to move quickly, put off planning for this transition until well into their Phase II clinical studies. By then, the opportunity to proactively prepare for commercial-scale manufacturing has passed. Facilities are left trying to forcibly stretch small-scale R&D processes to commercial size, leading to immense overhead, lost efficiency, and a strained, unsustainable labor model.
There is a solution: start planning for commercialization as early as the preclinical testing phase. This is a daunting prospect for some; it means siphoning time and money away from today’s priorities in order to prepare for tomorrow’s unknowns. Making room for such an exercise during those pre-profit years is difficult, but it’s necessary. Without the early intervention of a diligent, expert-led plan for commercial scale-out, it won’t matter how fast you get there—you’ll be met with costly, time-consuming challenges that could dismantle all of your early progress.
The Transition from Research to Commercial Manufacturing
As companies work to perfect their process design in the R&D phase, many believe that scaling to commercial production based on current good manufacturing practices (CGMPs) will mean simply transferring that same design into a larger blueprint. The trouble is, the R&D process in ATMP manufacturing isn’t the pliable muscle that some believe it to be; it can’t just extend itself from a small patient population to a large one without risking a lot of integrity and becoming exceedingly inefficient. That’s because the goals of each phase in your product’s development lifecycle aren’t the same.
In the research phase, you’re trying things. You need to carefully parse what works from what doesn’t. You need to test different medias, study the data and draw conclusions about the best way forward. In many facilities, this is achieved through the efforts of human operators, working with open flasks in high-environmental-classification biosafety cabinets. Maybe you have two people doing it all at first, working on developmental lots with a transitional process. As you progress into preclinical testing and early clinical studies, you might scale that model to serve ten people or support a single process equipment train—still manageable, and still largely based on an agenda of investigation and data gathering. Later clinical testing might drive you to ten patients a month. Most companies can manage this scale-up by simply carrying more of their initial process.
In the commercial phase, however, your focus shifts. You need to think about CGMP compliance while growing your throughput as quickly as possible. That means safely scaling that ten-patient process to 100, or 150, or 200 patients a month. It also means scaling your QC testing lab to ensure the integrity of your product and to keep you on the right side of an increasingly active and ever-evolving regulatory body.
Suddenly, the labor model that so beautifully served your R&D activities starts to break down. Where will you find the hundreds of workers required to scale out your operator-driven process? Even if you do find them, where will you put them? Where will they park their cars, eat their lunch, and hold their meetings? Are they skilled? Are they trained? In a field like ATMP manufacturing, where the technology is so new and the processes so variable, will the meteoric growth of your workforce put the quality of your product at risk? Who will scale your SOPs, and who will supervise their application and proactively correct any deviations?
The challenges of finding and onboarding and supervising all of those workers is only the thin end of the wedge. You’ll also need to face the problem of scaling that open process itself. It worked well during your R&D activities, allowing operators to nimbly assess and adjust their materials, but it will be very expensive to scale. First, there’s the cost of adding adequate facility footprint to support your production trains or suite modules—a huge undertaking, especially if you don’t get started until Phase II clinical studies, when it’s difficult to quickly and retroactively right-size your facility for commercialization. Then there’s the cost of constructing, powering and maintaining all those clean rooms to support your open process. Add the cost of building transitional airlocking space as well as QC labs for full-release testing. By the time you’re through, you’re looking at a per-square-foot price tag that could turn even the most well-funded project executives an alarming shade of white.
A labor model and a process that are difficult to scale: these are the linchpin challenges of many cell and gene therapy projects as they mature from clinical testing to commercial manufacturing. Overcoming these challenges by shifting from an open, operator-centric model to one that’s closed, automated, and scalable takes both ingenuity and time. Doing it well means starting the process early, and it requires two key skills: an ability to imagine the future, and a willingness to investigate the best and most efficient way to get there.
Begin with the End in Mind
Start by dropping the words “we’ll figure it out later” from your vocabulary. Instead, develop a company philosophy predicated on flexibility, curiosity, and constant, proactive improvement. That philosophy will get baked into every aspect of your facility as you grow, and will guide you as you set the stage for your future commercial success.
“Setting the stage” means continuously investigating new CGMP-rated technologies, particularly technical models that support automation. Look for opportunities to integrate automated technology into your process right now, while that process is still malleable enough to accommodate it. You may not end up with a fully automated system, but you can come close, if you plan appropriately. This can apply across your entire organization, not just in the production suite. Automation in QC testing, for example, can help reduce bottlenecks and ease the strain of finding more skilled workers and growing your footprint.
Automation in your warehousing process could have enormous impacts too, ensuring that materials are tracked, stored and released with fewer risks and a level of speed and integrity not possible from human workers alone.
Next, you need to assess every purchase decision with a closed, commercial-scale process in mind, even if that process isn’t possible with today’s technology. New technical solutions designed for closed ATMP manufacturing are poised to emerge on the market any day, and when they do, they could have a tremendous impact on process and facility design. Purpose-built isolator technology and other innovations will mean you’ll no longer have to depend quite so heavily on massive clean rooms, transitional airlocks, and unidirectional flow systems to maintain regulatory compliance. This will liberate a large swathe of your facility’s footprint for other, more efficient uses.
You can start planning for that eventuality today by building flexibility into your process design and purchasing decisions. For example, if you need to acquire flasks to support your R&D activities, look for a product design with a correlative that will work in a closed system. You’ll be grateful for this foresight later on, when you begin to transition to a closed process at the commercial scale. Do this with every process-related decision to help future-proof your facility.
You may discover that parts of your process simply can’t be closed, ever. Even that discovery, if made early enough, is useful. It means you can plan around the open elements of your process accordingly. This is how the best facilities make efficient and measurable progress towards profitability: they don’t wait for a magic bullet to strike. Instead, they go looking for one. From day one, they make decisions that promote flexibility and anticipate possible future needs and opportunities.
Find Efficiencies Where You Can
Moving towards commercial manufacturing means taking on larger patient populations, but that doesn’t have to require a much bigger facility. Not if you’ve worked early in your process to adopt systems that integrate vertically, allowing you to expand your pipeline without necessarily expanding your footprint.
Cell and gene therapy facilities with relatively modest biosafety level (BSL) requirements can manage this by designing large ballroom-type operating areas. Each workstation in the ballroom can be equipped with everything needed for a closed, A-to-Z process. Operators aren’t transporting materials from one place to another, risking contamination and losing valuable time; instead, they’re stationary, completing the whole process from start to finish right where they are. This allows for a dense, efficient use of your facility’s footprint; you can stack these stations vertically, reducing overhead costs and supporting a labor model that scales along with your patient population.
Facilities designed to accommodate such a vertical integration strategy from day one have the best chance of succeeding. It’s not impossible to modify your facility later on, but a retrofit is much harder to undertake than a proactive design. It costs more, it may impact your regulatory filings, and it often requires a full-system shut down for the duration of construction work, bringing production to its knees. Proper planning from the outset mitigates against such risks and ensures continual operations as you scale out to commercial manufacturing.
Even facilities whose elevated biosafety levels prevent vertically integration can de-risk their scale-out strategy by scoping future production needs early in the clinical testing process. This means forecasting your requirements for segregated personnel, material and waste flows, and full-room fumigation at a commercial scale. Assess every element closely, right down to the quality of construction materials and door seals. These details, if carefully tended in a facility’s initial design, can mean the difference between a smooth transition to commercialization and a disaster.
A Commercial State of Mind
Your facility represents a new breed of biotechnology company. It looks and operates differently from facilities in more established submarkets, which makes planning for your future scale-out a complex exercise. It’s possible that the technology you’ll be using five years from now hasn’t even been alpha tested today, or that the closed processes you’ll introduce for commercial manufacturing aren’t possible in your present-day research lab. There are no absolutes, and there are no bright lines marking the way forward. But there is this: the possibility of curing a previously incurable disease and dramatically impacting the lives of patients who otherwise face an uncertain future. With that prospect as your talisman, and an expert-driven and proactive approach to planning for a changeable future, you can succeed.
The key is flexibility. By approaching the question of commercial scale-out with a philosophy that embraces (rather than fears) the unknown, you can prepare yourself for whatever comes next.
Peter Walters is Lead Process Engineer with CRB USA. He can be reached at peter.walters@crbusa.com.
As the first few advanced therapy medicinal products (ATMPs) gain regulatory approval, and as patients with previously incurable diseases find new reasons to hope for effective treatment, the pressure to move quickly can bear down with enormous force. Across every biopharmaceutical area, the years spent progressing through preclinical and clinical studies are years of colossal pre-profit spending. That slender window between the first day of commercial manufacturing and the last day of a patent’s term of protection is often a company’s first and only opportunity to slingshot themselves back into the black. Getting there as soon as possible, while maintaining regulatory compliance and ensuring the safety and care of the patient population, is a central preoccupation.
This is where many of the similarities end. Cell and gene therapy facilities face a unique set of challenges as they scale towards commercial production, and they require equally unique solutions. While other types of biopharmaceutical facilities can follow a template as they grow, calculating their required footprint and equipment capacity based on well-established economies of scale, ATMP facilities have to invent their own way forward.
Nothing is templated. Everything is novel. New generations of technology emerge almost monthly. Open, operator-driven processes are the norm, making up for a limited availability of closed, automated cell and gene therapy technologies on the market today. And because those open processes support the production of highly personalized virus and viral vector products for very small patient populations (as small as just one patient, in the case of autologous production), they can vary greatly even within the same facility, and they require rigorous biosafety design measures. Under these unique and variable conditions, scaling up is very difficult, and scaling out quickly becomes prohibitively expensive.
Many facilities, under pressure to move quickly, put off planning for this transition until well into their Phase II clinical studies. By then, the opportunity to proactively prepare for commercial-scale manufacturing has passed. Facilities are left trying to forcibly stretch small-scale R&D processes to commercial size, leading to immense overhead, lost efficiency, and a strained, unsustainable labor model.
There is a solution: start planning for commercialization as early as the preclinical testing phase. This is a daunting prospect for some; it means siphoning time and money away from today’s priorities in order to prepare for tomorrow’s unknowns. Making room for such an exercise during those pre-profit years is difficult, but it’s necessary. Without the early intervention of a diligent, expert-led plan for commercial scale-out, it won’t matter how fast you get there—you’ll be met with costly, time-consuming challenges that could dismantle all of your early progress.
The Transition from Research to Commercial Manufacturing
As companies work to perfect their process design in the R&D phase, many believe that scaling to commercial production based on current good manufacturing practices (CGMPs) will mean simply transferring that same design into a larger blueprint. The trouble is, the R&D process in ATMP manufacturing isn’t the pliable muscle that some believe it to be; it can’t just extend itself from a small patient population to a large one without risking a lot of integrity and becoming exceedingly inefficient. That’s because the goals of each phase in your product’s development lifecycle aren’t the same.
In the research phase, you’re trying things. You need to carefully parse what works from what doesn’t. You need to test different medias, study the data and draw conclusions about the best way forward. In many facilities, this is achieved through the efforts of human operators, working with open flasks in high-environmental-classification biosafety cabinets. Maybe you have two people doing it all at first, working on developmental lots with a transitional process. As you progress into preclinical testing and early clinical studies, you might scale that model to serve ten people or support a single process equipment train—still manageable, and still largely based on an agenda of investigation and data gathering. Later clinical testing might drive you to ten patients a month. Most companies can manage this scale-up by simply carrying more of their initial process.
In the commercial phase, however, your focus shifts. You need to think about CGMP compliance while growing your throughput as quickly as possible. That means safely scaling that ten-patient process to 100, or 150, or 200 patients a month. It also means scaling your QC testing lab to ensure the integrity of your product and to keep you on the right side of an increasingly active and ever-evolving regulatory body.
Suddenly, the labor model that so beautifully served your R&D activities starts to break down. Where will you find the hundreds of workers required to scale out your operator-driven process? Even if you do find them, where will you put them? Where will they park their cars, eat their lunch, and hold their meetings? Are they skilled? Are they trained? In a field like ATMP manufacturing, where the technology is so new and the processes so variable, will the meteoric growth of your workforce put the quality of your product at risk? Who will scale your SOPs, and who will supervise their application and proactively correct any deviations?
The challenges of finding and onboarding and supervising all of those workers is only the thin end of the wedge. You’ll also need to face the problem of scaling that open process itself. It worked well during your R&D activities, allowing operators to nimbly assess and adjust their materials, but it will be very expensive to scale. First, there’s the cost of adding adequate facility footprint to support your production trains or suite modules—a huge undertaking, especially if you don’t get started until Phase II clinical studies, when it’s difficult to quickly and retroactively right-size your facility for commercialization. Then there’s the cost of constructing, powering and maintaining all those clean rooms to support your open process. Add the cost of building transitional airlocking space as well as QC labs for full-release testing. By the time you’re through, you’re looking at a per-square-foot price tag that could turn even the most well-funded project executives an alarming shade of white.
A labor model and a process that are difficult to scale: these are the linchpin challenges of many cell and gene therapy projects as they mature from clinical testing to commercial manufacturing. Overcoming these challenges by shifting from an open, operator-centric model to one that’s closed, automated, and scalable takes both ingenuity and time. Doing it well means starting the process early, and it requires two key skills: an ability to imagine the future, and a willingness to investigate the best and most efficient way to get there.
Begin with the End in Mind
Start by dropping the words “we’ll figure it out later” from your vocabulary. Instead, develop a company philosophy predicated on flexibility, curiosity, and constant, proactive improvement. That philosophy will get baked into every aspect of your facility as you grow, and will guide you as you set the stage for your future commercial success.
“Setting the stage” means continuously investigating new CGMP-rated technologies, particularly technical models that support automation. Look for opportunities to integrate automated technology into your process right now, while that process is still malleable enough to accommodate it. You may not end up with a fully automated system, but you can come close, if you plan appropriately. This can apply across your entire organization, not just in the production suite. Automation in QC testing, for example, can help reduce bottlenecks and ease the strain of finding more skilled workers and growing your footprint.
Automation in your warehousing process could have enormous impacts too, ensuring that materials are tracked, stored and released with fewer risks and a level of speed and integrity not possible from human workers alone.
Next, you need to assess every purchase decision with a closed, commercial-scale process in mind, even if that process isn’t possible with today’s technology. New technical solutions designed for closed ATMP manufacturing are poised to emerge on the market any day, and when they do, they could have a tremendous impact on process and facility design. Purpose-built isolator technology and other innovations will mean you’ll no longer have to depend quite so heavily on massive clean rooms, transitional airlocks, and unidirectional flow systems to maintain regulatory compliance. This will liberate a large swathe of your facility’s footprint for other, more efficient uses.
You can start planning for that eventuality today by building flexibility into your process design and purchasing decisions. For example, if you need to acquire flasks to support your R&D activities, look for a product design with a correlative that will work in a closed system. You’ll be grateful for this foresight later on, when you begin to transition to a closed process at the commercial scale. Do this with every process-related decision to help future-proof your facility.
You may discover that parts of your process simply can’t be closed, ever. Even that discovery, if made early enough, is useful. It means you can plan around the open elements of your process accordingly. This is how the best facilities make efficient and measurable progress towards profitability: they don’t wait for a magic bullet to strike. Instead, they go looking for one. From day one, they make decisions that promote flexibility and anticipate possible future needs and opportunities.
Find Efficiencies Where You Can
Moving towards commercial manufacturing means taking on larger patient populations, but that doesn’t have to require a much bigger facility. Not if you’ve worked early in your process to adopt systems that integrate vertically, allowing you to expand your pipeline without necessarily expanding your footprint.
Cell and gene therapy facilities with relatively modest biosafety level (BSL) requirements can manage this by designing large ballroom-type operating areas. Each workstation in the ballroom can be equipped with everything needed for a closed, A-to-Z process. Operators aren’t transporting materials from one place to another, risking contamination and losing valuable time; instead, they’re stationary, completing the whole process from start to finish right where they are. This allows for a dense, efficient use of your facility’s footprint; you can stack these stations vertically, reducing overhead costs and supporting a labor model that scales along with your patient population.
Facilities designed to accommodate such a vertical integration strategy from day one have the best chance of succeeding. It’s not impossible to modify your facility later on, but a retrofit is much harder to undertake than a proactive design. It costs more, it may impact your regulatory filings, and it often requires a full-system shut down for the duration of construction work, bringing production to its knees. Proper planning from the outset mitigates against such risks and ensures continual operations as you scale out to commercial manufacturing.
Even facilities whose elevated biosafety levels prevent vertically integration can de-risk their scale-out strategy by scoping future production needs early in the clinical testing process. This means forecasting your requirements for segregated personnel, material and waste flows, and full-room fumigation at a commercial scale. Assess every element closely, right down to the quality of construction materials and door seals. These details, if carefully tended in a facility’s initial design, can mean the difference between a smooth transition to commercialization and a disaster.
A Commercial State of Mind
Your facility represents a new breed of biotechnology company. It looks and operates differently from facilities in more established submarkets, which makes planning for your future scale-out a complex exercise. It’s possible that the technology you’ll be using five years from now hasn’t even been alpha tested today, or that the closed processes you’ll introduce for commercial manufacturing aren’t possible in your present-day research lab. There are no absolutes, and there are no bright lines marking the way forward. But there is this: the possibility of curing a previously incurable disease and dramatically impacting the lives of patients who otherwise face an uncertain future. With that prospect as your talisman, and an expert-driven and proactive approach to planning for a changeable future, you can succeed.
The key is flexibility. By approaching the question of commercial scale-out with a philosophy that embraces (rather than fears) the unknown, you can prepare yourself for whatever comes next.
Peter Walters is Lead Process Engineer with CRB USA. He can be reached at peter.walters@crbusa.com.
