The COVID-19 pandemic has turned a spotlight on emerging cell and gene therapeutic platforms. To realize their life-saving potential and move them to market faster, we need advanced facilities that offer improved safety, speed, scalability and flexibility. That means planning for a well-integrated facility layout with high-performing HVAC systems that promote biosafety without compromising future flexibility.
Many of today’s most innovative genetic therapies, including certain highly anticipated SARS-CoV-2 vaccine candidates, rely on select biological agents as their carrier platforms. These therapies offer great curative potential, but they present manufacturers with equally great challenges—particularly when it comes to biosafety.
The CDC’s Federal Select Agent Program lays out clear guidelines that address and mitigate the risks of working with viral vectors and other infectious agents in the lab. To achieve certification, facilities must successfully integrate these guidelines with the well-established tenets of Good Laboratory Practice (GLP), Biosafety in Microbiological and Biomedical Laboratories (BMBL) and/or Good Manufacturing Practice (GMP), ensuring a thoughtful and risk-based approach to biocontainment while maintaining the quality and integrity of their product. It’s a complex undertaking, and its implications for mechanical systems are immense.
Success depends on experience and a proactive approach to facility planning and HVAC design. Working alongside facility planners to identify gaps and develop bespoke biocontainment and decontamination solutions, engineers must answer questions such as:
- Facility layout: How can we rethink an airlock system to facilitate the safe flow of people and materials without compromising future flexibility?
- HVAC zoning: With so many intersecting factors to consider, including containment, segregation, and product protection, how will we recognize the best way forward?
- HVAC systems operations: How can we start up quickly, maintain operational flexibility, and accommodate new decontamination processes as necessary?
Here is a streamlined and proactive approach to answering these and many other complex questions looks like in practice, starting with key considerations and moving through some of the tools and strategies that help project planners and engineers develop a certified, safe, and efficient environment for working with select agents.
Top expectations of a high-performing HVAC strategy
Safety and regulatory compliance
Ensuring safety inside more traditional drug manufacturing facilities is a relatively well-understood and templated undertaking. The frontier work underway in cell and gene therapy manufacturing, on the other hand, hasn’t yet reached that level of standardization, which leaves project teams to determine for themselves how to balance the critical issue of biosafety with established GMP requirements. Such a balance requires a tailored approach to containment, filtration and unit segregation based on the specifics of that facility’s process and the materials it requires. Add highly infectious special agents to that formula and you’ve got quite a job ahead.
Part of that job involves acquiring CDC special agent certification. To qualify, labs must demonstrate that their containment and decontamination strategies are compatible with the BMBL’s agent-specific guidelines. An inactivated virus, for example, might require a BSL2 facility following BSL2 or BSL3 practices, which means that the facility design, including the HVAC systems, must support an elevated degree of physical segregation and biocontainment. When planning a facility, understanding and proactively addressing these requirements in the design phase is key to achieving streamlined approval and protecting the safety of workers inside the facility.
Speed and flexibility
It takes tremendous time and investment to bring a new drug product to market. This is especially true in the field of cell and gene therapy development—a field so new that it can’t yet benefit from the economies of templated and repeatable platforms. To mitigate the cost of failed investigations, many labs pursue multiple drug modalities in parallel, betting that at least one will succeed. It’s a sound strategy from a business point of view, but it requires extreme flexibility inside the facility, where four or five product types might be advancing through the pipeline at the same time. In this context, flexible HVAC systems and decontamination protocols designed to support multi-modal development are essential.
But moving fast isn’t just about the flexibility to pivot between modalities. It’s also about designing a facility that can rapidly scale to large-volume production, which is especially important in pandemic scenarios where shortening the time from drug approval to commercial-scale production is a matter of life and death. Traditional, centrally-located HVAC systems aren’t well-suited for this kind of rapid commercial scale-up or scale-out, and a wholesale retrofit is costly and time-consuming. The pressure is on, in other words, to prepare for potential future demand by introducing customized and scalable solutions early in a facility’s design process.
To address safety concerns, ensure compliance and prepare for fast and flexible product development, some facilities overdesign and oversize their mechanical systems, which inflates capital costs and diminishes operational efficiency. To avoid this fate, a facility’s HVAC system must be custom engineered according to a detailed understanding of the manufacturing process, the operational strategy, and the business objectives in play.
Energy code requirements are becoming another increasingly important influence on HVAC design approaches and overall operational costs. As more cell and gene therapy facilities come online with efficient HVAC zoning strategies and proper filtration systems in place, the industry will correct its outdated perception that these facilities require energy-intensive mechanical installations in order to function safely. With proper design and experience informing their HVAC strategy, they can operate cost-efficiently and with a lower energy load than previously expected.
A new approach to project delivery
When it comes to facility design and construction, there’s one place where safety, speed, flexibility and cost control converge: lean project delivery.
Unlike a traditional design-bid-build approach, in which a project team is siloed across individual scopes of work, lean delivery relies on streamlined collaboration between disciplines from day one. In practical terms, this means that the mechanical engineers responsible for tailoring the facility’s HVAC system have a seat at the planning table alongside facility architects, process engineers, procurement specialists, construction partners, and other project stakeholders. The result is an insightful and well-designed facility layout, featuring an HVAC system that integrates seamlessly with the building’s overall infrastructure and offers both the safety and the flexibility that’s expected of today’s most advanced projects.
To get those advanced projects online successfully, experienced mechanical engineers know how to wield the powerful tools and strategies of lean project delivery. A few of these tools and strategies include:
To get up and running sooner: Modularization and offsite fabrication
The more you’re able to apply a modular and repeatable HVAC design approach across each unit operation or production suite in your facility, the faster you can move from design through construction.
In the context of lean project delivery, all air handling units, energy recovery skids, exhaust fan arrangements and other HVAC components are designed into the overall building plan as early as possible. Those designs are then released to vendors, where they’re fabricated in quality-controlled, offsite manufacturing plants. Once built, these modular HVAC components are delivered whole to the project site and installed in place. This is a key component of lean project delivery and an important strategy for getting a facility up and running on an accelerated timeline.
To prepare for unknown opportunities: An integrated and flexible HVAC system
It’s impossible to know for certain what will be required of a given facility in five or ten years’ time. To prepare for such unknowns, designers must build as much flexibility as possible into every aspect of the facility, giving it the capacity to “flip” from one operation or drug program to another with minimal interruption or redesign required.
For example, imagine a scenario in which a filling room must become a BSL3 space to capitalize on an unexpected spike in demand or to pursue a new and promising program. A traditional facility might need significant redevelopment to make that change. A facility designed for maximum flexibility, on the other hand, has air handling units that can pivot from 85% recirculated air to 100% fresh outside air instantly, and infrastructure that can embrace reverse pressurization and additional decontamination and filtration processes where necessary. In that facility, switching from a filling room to a BSL3 space is no longer a daunting and costly task—it’s simply part of the overall strategy.
To ensure ongoing efficiency: Computer modeling and analysis
Computational fluid dynamics (CFD) modeling gives mechanical teams the opportunity to test proposed HVAC designs before time and money are spent on implementing them.
This is especially useful when planning biocontainment strategies in areas where select agents are present, requiring a thorough risk assessment. Using velocity vectors, experienced engineers can trace simulated particles through the space and evaluate the local mean age of air to identify stagnant regions and improve their proposed design. It can’t replace traditional environmental monitoring and it isn’t a means of certification, but CFD analysis can help determine the safest and most efficient way forward long before construction and HVAC installation begins, potentially saving considerable time and investment.
As the field of cell and gene therapy continues to evolve, the mechanical systems that provide a safe and flexible environment for working with select agents are evolving, too.
At CRB, we know this first-hand. Our full-service approach to lean project delivery includes deep expertise in HVAC design and installation. Our mechanical engineers work alongside a full complement of in-house experts to facilitate CDC certification and provide safe, flexible, and efficient GLP/GMP manufacturing spaces for today’s cell and gene therapy innovators.
To learn more about HVAC’s important role in contamination control, join us on May 26 for a webinar hosted by Pharmaceutical Technology.