Jeff Heil, PE , Novel Therapy SME, DPS Group Global07.08.21
The pharmaceutical industry is increasingly embracing modular facility design when creating spaces for manufacturing treatments, vaccines and other pharma products. Such agile or flexible facilities often promise the capability of modifying design as easily as swapping out building blocks, creating an easier and more cost-conscious way to expand capabilities as the business grows.
Despite these advantages, there are many considerations to take into account when incorporating flexible facility design in a pharmaceutical development and manufacturing strategy. Even in flexible facilities, some aspects of design and construction are essentially fixed, such as constraints regarding HVAC and electrical systems – and, consequently, the physical dimensions of the facilities themselves.
This is particularly true for organizations introducing mRNA production in their pharmaceutical development strategy. While this article will provide general considerations in flexible facility design, it’s important to keep in mind how certain procedures, such as mRNA production, can limit how flexible your flexible facility actually can be.
Some mRNA design considerations
Depending on the scale of the operation (that is, pre-clinical versus commercial manufacturing), a facility may have vastly different utility, equipment and spatial requirements. Typically, separate suites are provided for production of buffer, plasmids, mRNA, Lipid Nanoparticle (LNP), and filling. These are all commonly ISO Grade C clean room environments.
In mRNA production, multiple filtration/concentration and chromatography steps typically are required, and each step may require a unique equipment set-up. The full process may have five or more chromatography/Tangential Flow Filtration (TFF) steps, and may require a minimum amount for floor space to facilitate these unit operations. Additionally, reverse phase chromatography is common for protein purification, and often requires solvent storage and usage, which adds to electrical classification and building code concerns.
What’s more, mRNA product intermediates require analytical/quality testing that takes time to complete and the mRNA molecules are often unstable at these critical testing points in the process. This product instability may call for additional equipment requirements in the facility, such as controlled rate freezers and storage space in ultra-low temperature freezers. Design of freezer farms in facilities requires careful consideration due to the HVAC loads they impart in their surroundings, and energy consumption from both the freezers and HVAC equipment needed to reject their generated heat.
Lipid nano particle production also requires the use of 100% ethanol. Use of such a flammable substance challenges the room hazard and electrical classifications – especially with other typically non-rated equipment used downstream of the lipid production. The greater the process scale, the greater the challenge in coordinating around these and other design requirements.
Facility design in the COVID era: Planning questions
Despite the need for thorough facility planning, the reality of drug research and development during the pandemic has emphasized the need for faster facility design. Operation Warp Speed in particular ushered in an environment that is more conducive to a “design-build” partnership in the industry. This is true depending on whether the risk versus reward yields a favorable outcome, because design-build does require the mitigation of certain risks.
Traditionally, a facility is completely designed before construction is undertaken. In a design-build partnership as mentioned above, project design may, for example, be 60% complete when construction partners are brought in. The design work is continued more or less in parallel with the construction. As the architect is designing the balance of the facility, the construction contractors are already on site, considering their plan for construction, providing input on what has already been done and recommending placement of required equipment. This can substantially reduce the time (and, potentially, the cost) of building a facility over the traditional method, but it carries risk if late-stage changes in the design are requested.
As you embark on your flexible facility design, there are four general questions to keep in mind to ensure a successful design outcome:
Are you thinking far enough ahead?
Architects and engineers need to understand what your possible plans for expansion may be, and how the facility may be have to be built out. Have you considered how your facility can be expanded?
Understand the limitations of your space. Is the available footprint sufficient for expansion? It is generally preferable to expand within the existing footprint, and that raises its own issues. There may be some workarounds available. For example, do you have an atrium area that you could convert relatively quickly into more manufacturing space if needed? If so, does that space have the ceiling height required to accommodate all of the ductwork necessary for the expanded facility? (A minimum ceiling height in a suite should be not less than nine feet, and should also allow for the possibility of bump-up high ceilings areas for larger equipment.)
This is a particularly important consideration even during site selection of an existing facility. There is not a lot of greenfield design in the pharmaceutical industry at the moment. Many facilities are retrofitted into existing, “brownfield” buildings. It’s essential to understand how to accommodate your facility in a footprint that may not have been purpose built for your particular needs.
What are your actual processing/manufacturing requirements?
Your particular manufacturing planshave requirements that must be addressed fully in the design stage. For example, if you are using mRNA, and you’ll be doing plasma manufacturing in the same location, these are typically treated as two separate product facilities. You’ll need individual gowning spaces, and airlocks to support both the plasmid DNA side of the facility and the actual mRNA manufacturing component. All of those considerations factor into the square footage footprint required for that facility.
How are you accommodating materials storage?
We can’t overstate the importance of adequately considering material storage in facility design. Feed stock, seeding cells, drug substance, and drug products may all have different storage requirements – particularly with mRNA facilities, but also in general. Material storage requirements can typically include 2-8 degree Centigrade refrigerators for thawing material, -20 degree Centigrade freezers for feed stock such as plasmid storage, and cryogenic storage for cell banks and for mRNA products. Your plan must address these requirements. You will also need to assess your material storage against the allowable limits for hazard areas.
What is your HVAC/Electrical power and back-up strategy?
We’ve touched on this briefly above, but it bears repeating: HVAC is not particularly flexible. Rather, aspects such as the size of air handlers and placement of duct work are vital to the successful design of the facility. Your HVAC infrastructure must not only be sufficient for the facility as you plan to use it today; it also must support plans five or more years down the road. The same is true for running electrical power through the facility. Some aspects of design and construction cannot be easily changed, even in a “flexible” facility.
“Flexible” can be a slightly misleading term in setting expectations and design philosophies. Giving the facility the agility to pivot; be repurposed or expanded without significant, unnecessary infrastructure changes or interruptions to ongoing operations is the objective. Flexible or agile facilities can be an efficient and cost-effective way to create a design that will accommodate growth and expansion. Flexibility cannot necessarily extend to every design element. By understanding your needs not only now but in the future; as well as the limitations imposed on design by the work being planned; you will create a plan that gives you the agility to move quickly and easily with your program and product development.
Jeff Heil, PE is the Process Engineering Discipline Manager for DPS Group with subject matter expertise in mRNA, oligonucleotide and vaccine development. Jeff brings over 15 years of process engineering and technical project management expertise in a diverse portfolio of engineering applications with unique insight into the design challenges associated with the processing of compressible, multi-phase, and hazardous materials in brownfield and greenfield applications. Jeff is also experienced in the design and validation of process safety systems, providing independent technical assurance of engineering work, and working directly with clients to solve complex engineering problems in a variety of applications. He specializes in leading the execution of process projects with a background in hazardous materials, industrial processes, and small molecule chemistry. He can be reached at Jeffrey.Heil@dpsgroupglobal.com
Despite these advantages, there are many considerations to take into account when incorporating flexible facility design in a pharmaceutical development and manufacturing strategy. Even in flexible facilities, some aspects of design and construction are essentially fixed, such as constraints regarding HVAC and electrical systems – and, consequently, the physical dimensions of the facilities themselves.
This is particularly true for organizations introducing mRNA production in their pharmaceutical development strategy. While this article will provide general considerations in flexible facility design, it’s important to keep in mind how certain procedures, such as mRNA production, can limit how flexible your flexible facility actually can be.
Some mRNA design considerations
Depending on the scale of the operation (that is, pre-clinical versus commercial manufacturing), a facility may have vastly different utility, equipment and spatial requirements. Typically, separate suites are provided for production of buffer, plasmids, mRNA, Lipid Nanoparticle (LNP), and filling. These are all commonly ISO Grade C clean room environments.
In mRNA production, multiple filtration/concentration and chromatography steps typically are required, and each step may require a unique equipment set-up. The full process may have five or more chromatography/Tangential Flow Filtration (TFF) steps, and may require a minimum amount for floor space to facilitate these unit operations. Additionally, reverse phase chromatography is common for protein purification, and often requires solvent storage and usage, which adds to electrical classification and building code concerns.
What’s more, mRNA product intermediates require analytical/quality testing that takes time to complete and the mRNA molecules are often unstable at these critical testing points in the process. This product instability may call for additional equipment requirements in the facility, such as controlled rate freezers and storage space in ultra-low temperature freezers. Design of freezer farms in facilities requires careful consideration due to the HVAC loads they impart in their surroundings, and energy consumption from both the freezers and HVAC equipment needed to reject their generated heat.
Lipid nano particle production also requires the use of 100% ethanol. Use of such a flammable substance challenges the room hazard and electrical classifications – especially with other typically non-rated equipment used downstream of the lipid production. The greater the process scale, the greater the challenge in coordinating around these and other design requirements.
Facility design in the COVID era: Planning questions
Despite the need for thorough facility planning, the reality of drug research and development during the pandemic has emphasized the need for faster facility design. Operation Warp Speed in particular ushered in an environment that is more conducive to a “design-build” partnership in the industry. This is true depending on whether the risk versus reward yields a favorable outcome, because design-build does require the mitigation of certain risks.
Traditionally, a facility is completely designed before construction is undertaken. In a design-build partnership as mentioned above, project design may, for example, be 60% complete when construction partners are brought in. The design work is continued more or less in parallel with the construction. As the architect is designing the balance of the facility, the construction contractors are already on site, considering their plan for construction, providing input on what has already been done and recommending placement of required equipment. This can substantially reduce the time (and, potentially, the cost) of building a facility over the traditional method, but it carries risk if late-stage changes in the design are requested.
As you embark on your flexible facility design, there are four general questions to keep in mind to ensure a successful design outcome:
Are you thinking far enough ahead?
Architects and engineers need to understand what your possible plans for expansion may be, and how the facility may be have to be built out. Have you considered how your facility can be expanded?
Understand the limitations of your space. Is the available footprint sufficient for expansion? It is generally preferable to expand within the existing footprint, and that raises its own issues. There may be some workarounds available. For example, do you have an atrium area that you could convert relatively quickly into more manufacturing space if needed? If so, does that space have the ceiling height required to accommodate all of the ductwork necessary for the expanded facility? (A minimum ceiling height in a suite should be not less than nine feet, and should also allow for the possibility of bump-up high ceilings areas for larger equipment.)
This is a particularly important consideration even during site selection of an existing facility. There is not a lot of greenfield design in the pharmaceutical industry at the moment. Many facilities are retrofitted into existing, “brownfield” buildings. It’s essential to understand how to accommodate your facility in a footprint that may not have been purpose built for your particular needs.
What are your actual processing/manufacturing requirements?
Your particular manufacturing planshave requirements that must be addressed fully in the design stage. For example, if you are using mRNA, and you’ll be doing plasma manufacturing in the same location, these are typically treated as two separate product facilities. You’ll need individual gowning spaces, and airlocks to support both the plasmid DNA side of the facility and the actual mRNA manufacturing component. All of those considerations factor into the square footage footprint required for that facility.
How are you accommodating materials storage?
We can’t overstate the importance of adequately considering material storage in facility design. Feed stock, seeding cells, drug substance, and drug products may all have different storage requirements – particularly with mRNA facilities, but also in general. Material storage requirements can typically include 2-8 degree Centigrade refrigerators for thawing material, -20 degree Centigrade freezers for feed stock such as plasmid storage, and cryogenic storage for cell banks and for mRNA products. Your plan must address these requirements. You will also need to assess your material storage against the allowable limits for hazard areas.
What is your HVAC/Electrical power and back-up strategy?
We’ve touched on this briefly above, but it bears repeating: HVAC is not particularly flexible. Rather, aspects such as the size of air handlers and placement of duct work are vital to the successful design of the facility. Your HVAC infrastructure must not only be sufficient for the facility as you plan to use it today; it also must support plans five or more years down the road. The same is true for running electrical power through the facility. Some aspects of design and construction cannot be easily changed, even in a “flexible” facility.
“Flexible” can be a slightly misleading term in setting expectations and design philosophies. Giving the facility the agility to pivot; be repurposed or expanded without significant, unnecessary infrastructure changes or interruptions to ongoing operations is the objective. Flexible or agile facilities can be an efficient and cost-effective way to create a design that will accommodate growth and expansion. Flexibility cannot necessarily extend to every design element. By understanding your needs not only now but in the future; as well as the limitations imposed on design by the work being planned; you will create a plan that gives you the agility to move quickly and easily with your program and product development.
