Despite these advantages, there are many considerations that must be taken into account when integrating a flexible plant design into a pharmaceutical development and manufacturing strategy. Even in flexible installations, some aspects of the design and construction are essentially fixed, such as the constraints on HVAC and electrical systems – and, therefore, the physical dimensions of the installations themselves.
This is especially true for organizations that introduce mRNA production into their pharmaceutical development strategy. While this article provides general considerations for designing flexible installations, it is important to keep in mind how certain procedures, such as mRNA production, can limit the flexibility of your flexible installation.
Some mRNA design considerations
Depending on the scale of operation (i.e. preclinical versus commercial manufacturing), a facility can have very different utility, equipment and space requirements. Typically, separate suites are provided for the production of buffer, plasmids, mRNA, lipid nanoparticles (LNP), and filler. These are all generally ISO Grade C cleanroom environments.
In mRNA production, several filtration / concentration and chromatography steps are usually required, and each step may require a unique equipment setup. The entire process may involve five or more Tangential Flow Chromatography / Filtration (TFF) steps and may require a minimal amount of floor space to facilitate these unit operations. Additionally, reverse phase chromatography is common for protein purification and often requires the storage and use of solvents, adding to electrical classification and building code issues.
Additionally, mRNA intermediates require time-consuming analytical / quality testing and mRNA molecules are often unstable at these critical test points in the process. This product instability may require additional equipment in the facility, such as flow-controlled freezers and storage space in ultra-low temperature freezers. The design of facility-based freezer farms requires careful consideration due to the HVAC loads they transmit into their environment and the energy consumption of freezers and HVAC equipment required to reject the heat generated.
The production of lipid nanoparticles also requires the use of 100% ethanol. The use of such a flammable substance calls into question the hazard of the part and the electrical classifications – especially with other generally unclassified equipment used downstream of lipid production. The larger the scale of the process, the greater the challenge of coordinating around these and other design requirements.
Facility design in the COVID era: planning questions
Despite the need for extensive facility planning, the reality of drug research and development during the pandemic underscored the need for faster facility design. Operation Warp Speed notably inaugurated an environment more conducive to a “design-build” partnership in the industry. This is true depending on whether risk versus reward works favorably, because design-build requires some risk mitigation.
Traditionally, a facility is completely designed before construction is undertaken. In a design-build partnership as mentioned above, the project design may, for example, be 60% complete when construction partners are approached. The design work continues more or less in parallel with the construction. While the architect designs the rest of the facility, the building contractors are already on site, studying their construction plan, providing feedback on what has already been done, and recommending placement of the required equipment. This can significantly reduce the time (and, potentially, the cost) to build a facility compared to the traditional method, but it carries a risk if late-stage design changes are requested.
When embarking on the design of your flexible installation, there are four general questions to keep in mind to ensure a successful design outcome:
Are you thinking far enough?
Architects and engineers need to understand what your possible expansion plans may be and how the facility should be constructed. Have you thought about how your facility can be extended?
Understand the limits of your space. Is the available footprint sufficient for expansion? It is usually best to extend within the existing footprint, and this raises its own issues. There may be workarounds available. For example, do you have an atrium area that you could convert relatively quickly to more manufacturing space if needed? If so, does this space have the required ceiling height to accommodate all the ductwork required for the expansion of the facility? (A minimum ceiling height in a suite should be no less than nine feet and should also allow the possibility of high ceiling areas for larger amenities.)
This is a particularly important consideration, even when selecting the site for an existing installation. There isn’t a whole lot of entirely new design in the pharmaceutical industry today. Many installations are being redeveloped in existing “brownfield” type buildings. Understanding how to fit your facility into a footprint that may not have been specifically designed for your particular needs is essential.
What are your actual processing / manufacturing requirements?
Your particular manufacturing plans have requirements that must be fully addressed at the design stage. For example, if you use mRNA and manufacture plasma in the same location, these are usually treated as two separate product facilities. You will need individual dressing spaces and airlocks to support both the plasmid DNA side of the facility and the actual mRNA manufacturing component. All of these considerations are factored into the square footage required for this installation.
How do you organize the storage of materials?
We cannot stress enough the importance of properly considering material storage in facility design. Raw materials, seed cells, drug substance, and drug products may all have different storage requirements, especially with mRNA facilities, but also in general. Equipment storage requirements can typically include 2-8 degree centigrade refrigerators for thawing, -20 degree centigrade freezers for raw materials such as plasmid storage and cryogenic storage for cell banks and products. mRNA. Your plan must meet these requirements. You will also need to assess your material storage against the allowable limits for hazardous areas.
What is your HVAC / Electrical power supply and backup strategy?
We touched on this briefly above, but it bears repeating: CVC isn’t particularly flexible. On the contrary, aspects such as the size of the air handlers and the location of the ducts are essential to the successful design of the installation. Your HVAC infrastructure should not only be sufficient for the installation as you plan to use it today; it must also support plans in five years or more. The same is true for the electrical supply to the installation. Some aspects of the design and construction cannot be easily changed, even in a “flexible” installation.
“Flexible” can be a slightly misleading term for defining expectations and design philosophies. Give the facility the agility to pivot; be reused or extended without significant and unnecessary changes to infrastructure or disruption of ongoing operations is the goal. Flexible or nimble installations 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 design limitations imposed by the planned works; you will create a plan that will give you the agility to move forward quickly and easily in the development of your program and your product.
Jeff Heil, PE is the Discipline Manager of Process Engineering for the DPS Group and has subject matter expertise in the development of mRNA, oligonucleotides and vaccines. Jeff brings over 15 years of process engineering and technical project management expertise to a diverse portfolio of engineering applications with a unique insight into the design challenges associated with processing compressible, multiphase and hazardous materials in applications. brownfields and new. 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 training in hazardous materials, industrial processes and small molecule chemistry. He can be contacted at [email protected]