November 6, 2023 PAO-10-23-CL-06
Growth in the biopharmaceutical industry is driving the need for greater capacity facilities. Many manufacturers are seeking to expand their capabilities, whether that means scaling out to treat more patients with autologous therapies or scaling up more traditionally to produce more doses of the same product.
As a new therapy candidate progresses through clinical trials, sponsors must prepare for advancement to the next phase, and ultimately commercial production, on the basis of early and ongoing data generated from those studies. License sponsors are compelled to anticipate study success with proactive patient drug supply planning, which in a “make” (vs. buy) scenario requires considerable capital investment.
As such, ideally the decision to design and construct a new cleanroom often comes in early phase III of the development lifecycle, which is 24–36 months before FDA approval, because of the realities of clinical trials and the complexity of biopharmaceutical projects. As a biopharmaceutical innovator approaches a critical milestone and prepares to move to the next level, they not only need to add more manufacturing space; they need to do so as rapidly as possible.
For cleanroom designers, a comprehensive understanding of where clients are and where they want to get to is critical to the foundation of the design and necessary to ensure that the design and/or integration of a highly regulated aseptic manufacturing facility is conceived and built specifically to meet the drug product processing needs.
A cleanroom project begins with a design concept guided by the biopharmaceutical manufacturer’s goals. Better project parameter inputs yield better outputs, so it is imperative to gather as much information as possible before any drawings are made. The greatest cause of failure for these complex projects is the lack of a robust conceptual design and project planning, which is the foundation for project cost and schedule estimates. Schedule alignment, budget estimate, design compliance, building fit, and FDA review content are all conceptual design outcomes that can be generated in a matter of weeks — well before large capital fund outlays (and risk) are necessitated.
A conceptual design is an imperative and necessary business investment that is often less than 1% (yes, <1%!) of the project finished costs. Factors that impact cleanroom design include the overall size and layout of the manufacturing facility, the number of desired cleanrooms, the type of product and process, the production scale and number of needed operators, and the types of equipment needed. Also important is ensuring that the design complies with current regulatory and industry expectations. Anticipating future needs is also important, as predictions of the likely uses for the cleanroom in the future — whether the current program succeeds or not — will determine the level of flexibility that must be incorporated into the design.
At the start of a project, design firms like AES must ask a lot of questions to gather this information from their clients. Those questions take into consideration the manufacturing process, current compliance, quality controls, and capacities while also thinking of costs, as well as state and local building codes. Biopharmaceutical clients are science based and are not architects, engineers, or builders, and they often do not have a full appreciation of the multitude of cleanroom options that enable speed to market, durability, and flexible facility value.
In our experience, in about half of projects, biopharmaceutical clients have preconceived ideas of what they want — or think they want — for their cleanroom designs. In many cases, owing to regulatory constraints or engineering practicalities, it is not possible or advisable to fulfill those expectations. The best approach is to take a step back and reconsider the overall goals and needs for a project. Then, by leveraging their fundamental expertise, extensive experience gained working on hundreds of previous projects, and proprietary tools, firms like AES can create an optimal, fit-for-purpose design.
There is no substitute for experience in designing and constructing complex cleanroom facilities. It’s often the biggest capital investment in a company’s history. The stakes are high for patients, providers, and shareholders. Project success requires a unique combination of experience, including cleanroom design firms who have team members who have directly been employed with biopharma companies and have held operational roles, comprehending the realities between manufacturing and quality when producing a cGMP drug product.
Prior to selecting a qualified cleanroom design firm, the concept design is the first step in a multiphase cleanroom capital project methodology. Three or four different cleanroom layouts with classification drawings, a preliminary mechanical design, material and people flows, and other details are typically generated. Ideally, cross-contamination assessment is completed for a given design to offer the highest standard of product quality control understanding. The process architect determines the specific square footages and confirms that the cleanroom fit-out is congruent with the greater building envelope. The last step is the provision of specific deliverables, including scheduling and cost estimates associated with each layout, so clients can discuss how the project fits into their strategic plans and their budget. In all, this process takes approximately 8–10 weeks.
However, it cannot be stressed enough that concept design cannot occur without understanding the specific needs and drivers of the project, and gathering that information generally requires conversations with the client’s technical and capital project executive teams. Ergo, the concept design deliverables are only as good at the inputs that go into them.
Scope definition involves understanding what the overall goals of a project are and the client’s preferences for how the project should be executed, including who has what responsibility. AES uses a charter to help define the various aspects, including objectives, in/out scope, key contacts, deliverables, and general concept design timeline. For some projects, clients want an active role in hiring general contractors and managing administrative details, while others want AES to handle the entire project. AES uses additional tools to clearly segregate the roles of a multi-contractor project arrangement.
Team definition relates to which people from the client organization with relevant expertise and experience will work closely with the design firm on a project. Having an effective decision-making body is probably one of the most important contributors to the success of a project, but establishing a good team is often overlooked. The design firm, for instance, may not know the strategic objectives of the client or their approval process for capital projects. Having people with the relevant knowledge to advocate for to the needs of the project across all aspects — from design to GMP manufacturing, quality, and regulatory — is invaluable, especially when considering that this key design information is needed in a product license application (e.g., BLA).
Process definition relates to the manufacturing processes which will be performed in the cleanroom. This includes information about the materials and their key attributes, such as potency; the type of process, such as cell culture or fill/finish, and the protocol; equipment needs; the current development stage and expectations for the next several years; and any other specific constraints that must be considered. This step will also identify key high-risk operational steps that must be quality controlled with the aid of the facility’s design features.
Process definition is only fully realized if the scope of the project is adequately defined and the client’s project team is staffed appropriately and is accessible. If there is a gap in a sponsor’s team experience, this can easily be mitigated with supplemental subject matter expertise via the cleanroom design firm. Cleanroom designers have a vast network of SMEs that can supplement client representation in every modality, process, and product and are invaluable to consult on conceptual design projects.
Often, when constructing cleanrooms, the initial intended use is well understood, but drug makers often have additional products in their pipelines for which the cleanroom might also need to be used at some point in the future. The rate of change in biopharmaceutical technologies and equipment is extremely high, and it is difficult to predict what will be needed in even just five years. A cleanroom design company must be familiar with equipment and technologies that are in development in order to help pharmaceutical manufacturers to prepare for the future. A well-qualified cleanroom design proactively anticipates process change improvements and the facility changes potentially accompanying them. Strategic design planning of placing knockout walls, sizing air-handling units (AHUs), and creating flows that minimally impact ongoing operations when implemented requires design firm experience when interpreting client long-term requirements.
It is important in these instances to take a case-by-case approach, as each project and each client are different. AES follows a process that includes eliciting information from clients about potential future requirements. The key is to first understand the short- and long-term facility needs before trying to establish a potential pathway for reaching them, which requires a structured design approach.
A key difference between constructing a cleanroom in an existing facility and a new site is that, in the former, the cleanroom must fit into a certain stop, while in the latter it is often the heart of the facility. In a greenfield site, it is possible to design an optimal cleanroom that fits well within the overall facility, allowing for the highest levels of efficiency, compliance, and cost-effectiveness.
Fitting a cleanroom into an existing site can be quite challenging. The cleanroom is just one of the areas needed for manufacturing drug products, and designing a cleanroom that will fit into an existing building and also be compliantly situated with respect to the utilities, material receiving, warehousing, waste management, and other key activities often requires sacrificing efficiency, contributing to higher costs.
If an existing site is to be used, it is generally better if clients ask for an optimal cleanroom design and overall layout with associated cost and scheduling estimates and then look to find a suitable existing building. An architectural “test fit” is a short and cost-effective day trip exercise with selected engineers that can be completed when considering different buildings sites for a production facility. This proactive engineering exercise can confirm structural, power grid, and foundational appropriateness, as well as basic flows that could otherwise increase cost if not a good fit for the bioproduction building use. Experts at the design firm can visit potential sites to determine whether they will be a good fit, ensuring a good outcome. When adjustments to the project are needed — and they inevitably are when constructing a cleanroom in an existing building — there is a design basis to work from, and clients can be quickly provided with the necessary changes and their impacts.
Capital project risk assessments based on critical path project schedule analyses help identify the best approaches to implementing a cleanroom design. Such analyses can involve consideration of modular versus traditional approaches to construction and the choice of HVAC system.
Modular design is inherently a fast-track process because the panels are the unit building blocks constructed in a factory while the site is being prepared. There are still risks, however, owing to reliance on the preliminary design. HVAC systems that do not recycle air are more expensive but are an inherent necessity from a compliance and flexibility perspective, and some clients want to consider the risk of not choosing such a system with respect to facility approval. When the client is a CDMO, they may also consider the attractiveness, access, auditability, and exceeding compliance standards for risk-averse clients.
AES has developed matrices for evaluating projects on the basis of the process architecture and preliminary mechanical designs that make it possible to demonstrate the risk relative to the engineering design, process architecture, compliance hurdles, costs, safety considerations for potent compounds, and potential issues for the future. In addition, clients can be shown the consequences of different tradeoffs in space, equipment, and other factors with respect to scheduling and costs. The goal is to facilitate the decision-making process when considering different cleanroom designs.
A methodical approach to cleanroom design and construction is essential to keep projects on track, particularly if no structured client team is provided and the scope and process definitions are slow in coming and less clear than desired.
AES’s approach begins with a proven inquiry approach comprising multiple specific cleanroom design-influencing factors of compliance and costs. The goal is to find out as much needed information as possible and determine which aspects clients do not yet know. When information is not available, a more conservative design is initially adopted. If the client expects to generate the information soon thereafter — such as equipment lists and process flow diagrams, which are part of the CMC requirements for NDA and BLA filings — waiting a day or two is generally the best solution.
If clients push hard to get designs on paper, AES will begin preparing drawings while still gathering the necessary process, equipment, and other information. Running these phases in parallel can help to prevent projects from getting too far ahead of themselves. That should be avoided at all costs, because it often results in large numbers of change orders with negative impacts on schedules and costs.
The best way to ensure that projects stay on the right path is to follow a structured process that begins with collecting all of the necessary information from a team of experts from the client with knowledge about the company’s strategic goals and specific project requirements. Concept designs can then be drawn that take all of the necessary factors into consideration, thereby minimizing the need for changes that can contribute to scheduling delays and higher project costs.
The key to our success has been focusing on the goals and needs of the client’s production process in order to identify the ideal solution. AES is committed to maintaining as balanced an approach as possible to provide the most efficient design that encompasses cost and floor space. We are very flexible. We have experience integrating the AES modular systems in all multi-contractor design/build arrangements. We do what’s best for each client and the client’s patients.
We also are not afraid to have difficult conversations with clients and tell them what they need to hear rather than what they might want to hear. Our team is nimble, highly experienced, and service-oriented. Throughout the cleanroom design process, AES always looks for ways to reduce project timelines and cut costs, providing additional options that help to balance both. We have 30 years of proven designs that are accepted as the standard of excellence by regulatory authorities. A major component of our approach is transparency and open communication to ensure that the client has the information needed to make informed decisions.
AES often builds modular cleanroom systems, and we take the opportunity during the concept design stage to highlight the advantages of modular solutions for clients. These benefits are not only linked to our specific cleanroom system, but to the advantages afforded by pre-piped piping systems and pre-run electrical systems, among other fit-for-purpose cleanroom trademarked products that raise the bar on design compliance, installation speed, and cost effectiveness. The modular approach is the standard of excellence for state-of-the-art advanced medicinal science and patient supply through the application of current technologies and/or methodologies in contact materials, fabrication, and installation of modular cleanroom methods.
The Compass Program at AES is a cleanroom design methodology that combines fit, form, and function objectives by defining the relationship between product, process, and facility requirements — all with transparency about process architecture and compliance aspects.
The objective is to keep the process as simple as possible so that the client only needs to convey the specific project goals and needs and the information that AES requires to confidently develop relevant cleanroom designs. Our experts bring their decades of experience on both the engineering and manufacturing sides to bear on each project. We are thorough in asking experienced cross-functional questions, yielding the optimal cleanroom design. Templates also provide clients with guidance and examples.
AES Compass Program surveys have shown this approach has well received by clients:
AES has completed over 3,000 projects, many of them multi-million-dollar designs that received approval from regulatory authorities and are used today to produce lifesaving and life-changing medications. In the initial years of the COVID-19 pandemic, the vast majority of vaccine product was produced in AES cleanrooms.