Chelsea Stramel, Architectural Designer and Jake Adams, Process Engineer , CRB10.04.19
If you work with oligonucleotides, chances are you’ve felt it: That sense of anticipation, like the moment before the starting pistol in an Olympic sprint. Something exceptional is about to happen. Regulators are now approving therapies designed to overcome the challenges of the body’s annihilating digestive system and successfully reach the target cellular level. Next stop, commercialization. The whole industry is poised in the starting blocks, ready to surge ahead.
What does that surge look like? For many, it’s a new or expanded manufacturing facility. This means thinking about production volumes, equipment sizing, and overall methodologies—the big, mission-critical questions, which require big, mission-critical plans. These are not the only questions, though. Arguably, they aren’t even the most important, because they often overlook a key element: the employee using the process machinery.
As any good coach will tell you, no races are won solely thanks to high-tech gear or trending nutritional regimes. Races are won because of one individual’s singular, well-paced effort over time. That’s true on the track, and it’s true in the oligo manufacturing facility. To win the race—to help more patients manage their genetic disorder—you need a custom training plan, designed by an experienced coach, that addresses particular challenges on the micro level (your individual operators) as well as the macro level (your oligo facility as a whole).
Consider the five questions that follow as the beginning of a training plan to ensure that you enter this race with every advantage.
How is your facility likely to change in the first five years?
Many mature bioscience facilities producing a mature drug type can map their future with relative confidence. Chances are, the drug they’re making today will be the same drug they’re making five years from now. They can make a good guess at that drug’s demand levels over time, and they have years of large-scale manufacturing experience to leverage.
Oligo facilities, though, are less predictable. Think of it in terms of human years. Beyond a receding hairline and a developing interest in birdwatching, a healthy person isn’t likely to change much between 45 and 50. From infancy and age five, though, the changes are cosmic. An oligo facility, like a swaddled newborn, is all sophisticated potential, with few certainties. Your production volume may change enormously. The manufacturing technology you’re using, and the intellectual property you’re protecting, will also evolve in ways you can’t foresee. You may not even be making the same drug in five years.
The planning activities that work so well for legacy manufacturers don't map as neatly to new oligo facilities. You need to detach your growth metrics from production values and find other, more predictable factors to plan around. Headcount is a good option. When other factors are so multifaceted, this projection is an easier commitment.
Let’s say you want to grow your capacity by 40% in five years. If you have 25 people and 500 square feet today, that means 35 people and 700 square feet half a decade from now. Using those numbers, you can plan accordingly. That goes not just for the physical manufacturing space, but also for the amenities (the gym, the café, the staff training facility).
These spaces broadcast an affirmative message to employees, developing their workplace satisfaction and creating a virtuous cycle of productivity and loyalty. This is especially important for oligo facilities, under pressure to meet steeply climbing market demands. In that kind of scenario, change and growth are inevitable. Starting “day one” one with a “year five” vision will ease your path through these changes.
What claims will you make about the product leaving your facility?
For facilities whose manufacturing process ends with a blister pack of pills or a twist-top bottle with a final formulation sloshing inside, this answer is simple: The product is sterile and commercial-ready. The same may not be true at your oligo facility, which could be sending an intermediate or a bulk product elsewhere for sterilization and packaging. You need to ask yourself about the claims you’re making, the potential for those claims to evolve over time, and the consequences of those claims for your facility.
From these central questions branch dozens of others. Some are familiar: How and where will you store your product awaiting shipment? Will it remain stable at room temperature, or does it need to be frozen? Is it photosensitive? What are the ventilation requirements?
Meanwhile, less obvious questions also jostle for attention. How do requirements on product sterility and endotoxin levels impact facility HVAC, material and personnel flow paths, and shipping and receiving functions? What is the pathway between the end product warehouse and the vehicle that will transport it?
How many opportunities for contamination line that pathway and how is that risk controlled? If a custodian towing a cart of trash travels the same hallway as a lab operator rolling a cartful of end product, the impact of contamination is much greater if that end product is sterile (versus a bulk product which will undergo additional purification). Planning for these risks and understanding the impact of your facility’s claims about the end product will help to ensure that your facility is not under (or over) designed.
How secure is your supply chain?
All pharmaceutical facilities have to solve the problem of storing raw, hazardous, and expensive material safely and cost-effectively. For some, the solution is simple: Duplicate a design that exists—and works—at a similar facility. In many cases, this is a perfectly reasonable decision. A warehouse is a warehouse, after all. If engineers have already determined its optimal design for your particular type of material, why return to the drawing board?
For oligo facilities, though, the drawing board is exactly the right place to begin. Synthetic nucleic acids (the major raw materials) are especially expensive, and the solvents used throughout the process are particularly hazardous. These twin qualities—high cost, high danger—clamp oligo facilities in considerable risk.
Smart facility planners loosen that clamp by “designing out” as much risk as possible and ensuring that your materials are both plentiful and securely contained. It starts with a risk-based assessment of your supply chain. How will material arrive at your facility, and from where? If you’re located in an area already densely populated with biopharmaceutical manufacturers and suppliers, you can likely access a well-stocked cache raw material with little risk.
What if you’ve chosen a more remote location? This may place many advantages at your doorstep—cheaper land, more space, less competition for talent and for clients. But disadvantages stalk close behind, including geographic barriers between you and your raw materials.
These barriers increase your need for on-site storage, which has real impact on the design of your facility. Should you store enough material for one more batch, or enough for a month’s worth of production? Or a year? What are the code implications for your new facility in regards to storing additional materials?
Protecting the materials with appropriate warehousing is one thing—protecting your workers is another. How far will those materials have to travel to reach your staging area? Based on that distance, what do you need in place to maintain safety during that journey? Do you need to design segregated corridors for moving raw materials between storage and staging, to protect unsuspecting passersby from exposure? Here, too, lie important design implications.
Have you designed for your downstream purification processes?
What makes oligos so exciting is, in part, their novelty. Thirty years of research and innovation have brought us to the point where these therapies are robust, efficient and reliable, capable of impacting lives at the cellular level.
For most oligo innovators, this excitement converges in the upstream half of the oligo manufacturing process, where the dazzling science of nucleotide drug production puts on its best primetime show. Through a cycle of chemical reactions, individual nucleotide residues are coupled, creating the desired sequence. This requires specialized synthesizers. Scaling up to commercial-level production while maintaining a high yield warrants a lot of attention, but much of the work surrounding the perfection of oligo synthesis (tweaking flow rate and pressure of reagents, reducing water quantity in solvents, etc.) doesn’t actually impact facility design as much as some people expect.
Although the novel chemistry of oligo manufacturing is concentrated upstream where there are seemingly infinite possibilities and variations, that’s not where you’ll find the variations with major impacts on facility design. Those are downstream, where process flows vary significantly, particularly in terms of the purification and final formulation requirements—and that’s where you should swing the beam of your attention if you’d like to ensure product quality.
Start by defining the various purification approaches. Do you need to run the same unit operations twice in the same manufacturing process – once for your crude purification and again as a final pass? If so, are two skids an advantage from an operational, HVAC, material movement, and capacity perspective? Can the purification equipment occupy the same space, or does it need to be segregated to prevent contamination? If this facility will manufacture multiple products, what additional equipment and suite turnaround steps should be considered?
Understanding the design implications of potential downstream variations will ensure smart, controlled growth for your process. Design decisions that accommodate an additional piece of equipment or suite build-out are much different from those that accommodate larger equipment in the same suite. Choosing the correct path will minimize the cost and impact of future work.
Be honest. Do you need process engineering help?
Your answers to the previous four questions will influence the way your facility operates, which in turn will influence your success. Get it right and you’ll likely find yourself smoothly growing as demand soars and more oligo products enter the market. Fantastic, right? But—what then? How can you successfully scale without compromising your process?
If you’re on the verge of expanding, you’ve likely worked out the details of your tech transfer. You’ve done the math on growing the capacity of your synthesizers and the size of your chromatography skids, for example. That’s the most important part, right? Everything else—the minutiae—will sort itself out.
Not necessarily. Think of those Olympians listening for the starting pistol. Think of the double-knot in their laces, the angle of their foot in the starting block, the precision of their breathing. This too is minutiae, isn’t it? Hardly noticeable to anyone. And yet, for those runners, these are the little details that count for everything.
So, too, should the little details matter as you ready your facility to scale. Many of these “little” details have to do with the support functions in your facility, which are so easy to overlook, but can levy significant consequences. For example, a larger batch volume means more small parts to clean. Have you designated a place and a process for that task to be performed efficiently?
It also means heavier loads for operators to carry. You can mitigate this in part by hiring someone with expertise in large-quantity solids dispensing, but without a facility design that’s meant for accommodating growing loads, your operators will end up with sore backs and your productivity will slow. You may be able to overlook this slower process if it’s only once per week, but what if your facility’s growth means that small inefficiencies become a daily drag on operations? Engineered solutions once thought frivolous may become fruitful.
FDA inspectors often look for these details first, knowing that many facilities neglect them as they grow. Attention to detail will do for you what precision does for the Olympian: it will help ensure that all of your hard work and innovation on the mission-critical items has the opportunity to reach its explosive potential instead of being tripped up by an untied shoelace. The one who truly benefits, in the end, is the patient waiting for your products.
Conclusion
It’s an exciting time to be an oligo manufacturer. You’re surrounded by innovators, readying yourself to participate in one of the most anticipated and impactful breakthroughs that pharmaceutical manufacturing has known. Your objectives are Olympian in scale, and to meet them, you need Olympian-scale coaching to help you ask and then answer the most important questions.
Chelsea Stramel is Architectural Designer at CRB, and can be reached at chelsea.stramel@crbusa.com.
Jake Adams is a Process Engineer at CRB, and can be reached at jake.adams@crbusa.com
What does that surge look like? For many, it’s a new or expanded manufacturing facility. This means thinking about production volumes, equipment sizing, and overall methodologies—the big, mission-critical questions, which require big, mission-critical plans. These are not the only questions, though. Arguably, they aren’t even the most important, because they often overlook a key element: the employee using the process machinery.
As any good coach will tell you, no races are won solely thanks to high-tech gear or trending nutritional regimes. Races are won because of one individual’s singular, well-paced effort over time. That’s true on the track, and it’s true in the oligo manufacturing facility. To win the race—to help more patients manage their genetic disorder—you need a custom training plan, designed by an experienced coach, that addresses particular challenges on the micro level (your individual operators) as well as the macro level (your oligo facility as a whole).
Consider the five questions that follow as the beginning of a training plan to ensure that you enter this race with every advantage.
How is your facility likely to change in the first five years?
Many mature bioscience facilities producing a mature drug type can map their future with relative confidence. Chances are, the drug they’re making today will be the same drug they’re making five years from now. They can make a good guess at that drug’s demand levels over time, and they have years of large-scale manufacturing experience to leverage.
Oligo facilities, though, are less predictable. Think of it in terms of human years. Beyond a receding hairline and a developing interest in birdwatching, a healthy person isn’t likely to change much between 45 and 50. From infancy and age five, though, the changes are cosmic. An oligo facility, like a swaddled newborn, is all sophisticated potential, with few certainties. Your production volume may change enormously. The manufacturing technology you’re using, and the intellectual property you’re protecting, will also evolve in ways you can’t foresee. You may not even be making the same drug in five years.
The planning activities that work so well for legacy manufacturers don't map as neatly to new oligo facilities. You need to detach your growth metrics from production values and find other, more predictable factors to plan around. Headcount is a good option. When other factors are so multifaceted, this projection is an easier commitment.
Let’s say you want to grow your capacity by 40% in five years. If you have 25 people and 500 square feet today, that means 35 people and 700 square feet half a decade from now. Using those numbers, you can plan accordingly. That goes not just for the physical manufacturing space, but also for the amenities (the gym, the café, the staff training facility).
These spaces broadcast an affirmative message to employees, developing their workplace satisfaction and creating a virtuous cycle of productivity and loyalty. This is especially important for oligo facilities, under pressure to meet steeply climbing market demands. In that kind of scenario, change and growth are inevitable. Starting “day one” one with a “year five” vision will ease your path through these changes.
What claims will you make about the product leaving your facility?
For facilities whose manufacturing process ends with a blister pack of pills or a twist-top bottle with a final formulation sloshing inside, this answer is simple: The product is sterile and commercial-ready. The same may not be true at your oligo facility, which could be sending an intermediate or a bulk product elsewhere for sterilization and packaging. You need to ask yourself about the claims you’re making, the potential for those claims to evolve over time, and the consequences of those claims for your facility.
From these central questions branch dozens of others. Some are familiar: How and where will you store your product awaiting shipment? Will it remain stable at room temperature, or does it need to be frozen? Is it photosensitive? What are the ventilation requirements?
Meanwhile, less obvious questions also jostle for attention. How do requirements on product sterility and endotoxin levels impact facility HVAC, material and personnel flow paths, and shipping and receiving functions? What is the pathway between the end product warehouse and the vehicle that will transport it?
How many opportunities for contamination line that pathway and how is that risk controlled? If a custodian towing a cart of trash travels the same hallway as a lab operator rolling a cartful of end product, the impact of contamination is much greater if that end product is sterile (versus a bulk product which will undergo additional purification). Planning for these risks and understanding the impact of your facility’s claims about the end product will help to ensure that your facility is not under (or over) designed.
How secure is your supply chain?
All pharmaceutical facilities have to solve the problem of storing raw, hazardous, and expensive material safely and cost-effectively. For some, the solution is simple: Duplicate a design that exists—and works—at a similar facility. In many cases, this is a perfectly reasonable decision. A warehouse is a warehouse, after all. If engineers have already determined its optimal design for your particular type of material, why return to the drawing board?
For oligo facilities, though, the drawing board is exactly the right place to begin. Synthetic nucleic acids (the major raw materials) are especially expensive, and the solvents used throughout the process are particularly hazardous. These twin qualities—high cost, high danger—clamp oligo facilities in considerable risk.
Smart facility planners loosen that clamp by “designing out” as much risk as possible and ensuring that your materials are both plentiful and securely contained. It starts with a risk-based assessment of your supply chain. How will material arrive at your facility, and from where? If you’re located in an area already densely populated with biopharmaceutical manufacturers and suppliers, you can likely access a well-stocked cache raw material with little risk.
What if you’ve chosen a more remote location? This may place many advantages at your doorstep—cheaper land, more space, less competition for talent and for clients. But disadvantages stalk close behind, including geographic barriers between you and your raw materials.
These barriers increase your need for on-site storage, which has real impact on the design of your facility. Should you store enough material for one more batch, or enough for a month’s worth of production? Or a year? What are the code implications for your new facility in regards to storing additional materials?
Protecting the materials with appropriate warehousing is one thing—protecting your workers is another. How far will those materials have to travel to reach your staging area? Based on that distance, what do you need in place to maintain safety during that journey? Do you need to design segregated corridors for moving raw materials between storage and staging, to protect unsuspecting passersby from exposure? Here, too, lie important design implications.
Have you designed for your downstream purification processes?
What makes oligos so exciting is, in part, their novelty. Thirty years of research and innovation have brought us to the point where these therapies are robust, efficient and reliable, capable of impacting lives at the cellular level.
For most oligo innovators, this excitement converges in the upstream half of the oligo manufacturing process, where the dazzling science of nucleotide drug production puts on its best primetime show. Through a cycle of chemical reactions, individual nucleotide residues are coupled, creating the desired sequence. This requires specialized synthesizers. Scaling up to commercial-level production while maintaining a high yield warrants a lot of attention, but much of the work surrounding the perfection of oligo synthesis (tweaking flow rate and pressure of reagents, reducing water quantity in solvents, etc.) doesn’t actually impact facility design as much as some people expect.
Although the novel chemistry of oligo manufacturing is concentrated upstream where there are seemingly infinite possibilities and variations, that’s not where you’ll find the variations with major impacts on facility design. Those are downstream, where process flows vary significantly, particularly in terms of the purification and final formulation requirements—and that’s where you should swing the beam of your attention if you’d like to ensure product quality.
Start by defining the various purification approaches. Do you need to run the same unit operations twice in the same manufacturing process – once for your crude purification and again as a final pass? If so, are two skids an advantage from an operational, HVAC, material movement, and capacity perspective? Can the purification equipment occupy the same space, or does it need to be segregated to prevent contamination? If this facility will manufacture multiple products, what additional equipment and suite turnaround steps should be considered?
Understanding the design implications of potential downstream variations will ensure smart, controlled growth for your process. Design decisions that accommodate an additional piece of equipment or suite build-out are much different from those that accommodate larger equipment in the same suite. Choosing the correct path will minimize the cost and impact of future work.
Be honest. Do you need process engineering help?
Your answers to the previous four questions will influence the way your facility operates, which in turn will influence your success. Get it right and you’ll likely find yourself smoothly growing as demand soars and more oligo products enter the market. Fantastic, right? But—what then? How can you successfully scale without compromising your process?
If you’re on the verge of expanding, you’ve likely worked out the details of your tech transfer. You’ve done the math on growing the capacity of your synthesizers and the size of your chromatography skids, for example. That’s the most important part, right? Everything else—the minutiae—will sort itself out.
Not necessarily. Think of those Olympians listening for the starting pistol. Think of the double-knot in their laces, the angle of their foot in the starting block, the precision of their breathing. This too is minutiae, isn’t it? Hardly noticeable to anyone. And yet, for those runners, these are the little details that count for everything.
So, too, should the little details matter as you ready your facility to scale. Many of these “little” details have to do with the support functions in your facility, which are so easy to overlook, but can levy significant consequences. For example, a larger batch volume means more small parts to clean. Have you designated a place and a process for that task to be performed efficiently?
It also means heavier loads for operators to carry. You can mitigate this in part by hiring someone with expertise in large-quantity solids dispensing, but without a facility design that’s meant for accommodating growing loads, your operators will end up with sore backs and your productivity will slow. You may be able to overlook this slower process if it’s only once per week, but what if your facility’s growth means that small inefficiencies become a daily drag on operations? Engineered solutions once thought frivolous may become fruitful.
FDA inspectors often look for these details first, knowing that many facilities neglect them as they grow. Attention to detail will do for you what precision does for the Olympian: it will help ensure that all of your hard work and innovation on the mission-critical items has the opportunity to reach its explosive potential instead of being tripped up by an untied shoelace. The one who truly benefits, in the end, is the patient waiting for your products.
Conclusion
It’s an exciting time to be an oligo manufacturer. You’re surrounded by innovators, readying yourself to participate in one of the most anticipated and impactful breakthroughs that pharmaceutical manufacturing has known. Your objectives are Olympian in scale, and to meet them, you need Olympian-scale coaching to help you ask and then answer the most important questions.
