Cell and gene therapies represent an emerging paradigm, and the future of advanced therapies. As of early 2022, the U.S. Food and Drug Administration (FDA) has approved four gene therapies¹ and six cell-based treatments.² Two additional gene therapies are approved in the EU.

Approvals only tell part of the story, however. More than 1600 gene therapies³ are currently in clinical trials, and the FDA has to date received more than 900 applications to initiate gene-based treatments.⁴ The agency expects that by 2025 it will issue upwards of 200 investigational new drug (IND) applications for advanced therapies per year, with approval of up to 20 such treatments. This unprecedented growth comes with unique challenges for advanced therapy developers and manufacturers, which often center around the three essentials of quality, speed and innovation.

Although contract development and manufacturing organizations (CDMOs) need to establish technical and regulatory competence to succeed in this competitive market, this article will focus less on unit operations and cGMPs than on critical principles that benefit all end users, large and small, from developers with established platform processes to sponsors and CDMOs already involved in the large-scale manufacture of advanced therapies.

The design of a multi-product facility for advanced therapies begins with an assessment of goals and capabilities. Cell and gene therapies are still in their infancy from an industrialization standpoint, and the facilities commissioned today will almost certainly not support future needs. The assessment process might begin with these questions:

• What are the goals of this facility? What is your current and anticipated future strategic focus?
• Which processes, for which therapies and at what capacities, do you project your facility will need to support?
• What are the biosafety and regulatory considerations?
• What are the biosafety and regulatory considerations? Which challenges have you experienced that you would like to avoid?
• How do you tie the complexities together and remain innovative?
• What clinical or commercial phase of products will the facility accommodate?

The Center for Breakthrough Medicines (CBM) is a 700,000 square foot facility that offers end-to-end R&D, cGMP cell and gene therapy development services, cGMP manufacturing and analytical testing. The site’s world-class infrastructure expands CBM’s “Cellicon Valley” footprint and provides capacity, redundant power and utilities to ensure continuous and reliable operation. CBM’s manufacturing facilities will include more than 20 gene therapy suites and more than 20 cell therapy suites with capabilities in adherent and suspension production, drug substance and drug product manufacturing, and formulation development. 

After considering specific mission-based questions, we looked deeper into anticipated needs for this facility. For example, what assets will we offer, what critical adjacencies will be needed and which locations provide the greatest adaptability to accommodate future advanced therapy needs.

As demand and technologies are constantly changing, flexibility is the key to the success of advanced therapy manufacturing facilities. Our design strategy began with process mapping from an end-user perspective. We considered multiple manufacturing scenarios for current and future capabilities to facilitate the seamless transition from clinical to commercial manufacturing. We imagined the optimal way to work and maintain strict segregation and control, a crucial component of any multi-product facility.

Our vision for vector production incorporated large-scale cell culture, which utilizes a wide range of raw materials and which in turn drives larger production volumes. We located cell culture on lower levels near loading docks and modular clean rooms to safeguard capacity. Cell therapy manufacturing has lower requirements for consumables than do gene therapies, but nevertheless requires safe, fast delivery of patient materials and rapid release testing. While this entails less stringent material flow constraints, it does require closer proximity to dedicated docks, co-location of testing suites and higher HVAC requirements.

Nucleic acid production, although a relatively short-duration process, involves intense, short-term material flows. Safety issues arise involving large volumes of flammable liquids. We were concerned that building codes might restrict our use of these materials or require blowout panels. We therefore earmarked anticipated future capabilities with little adjacencies and located production suites near terminal ends of the building where we felt material, personnel and truck traffic would be minimal.

Overall operational consideration for enabling functions were recognized and purpose-built into the design. These considerations include the safe relocation of consumables, transfer lines, waste and other materials, which can make or break a facility design. Also, recognizing the positive effects of equipment diversity with respect to regulatory and manufacturing risk, we selected several different vendors for critical product-contact equipment, e.g., bioreactors, mixers, pumps and tangential flow filtration. This also de-risked our supply chain by allowing a greater variety of consumables.

Equipment diversity provides choices and options with respect to consumables and ancillary equipment, but also gives rise to potential complexities in process characterization, for example how cells expand in one bioreactor type vs. another, or one of a different size. Development labs provide valuable insights into equipment comparability.

Since features of the future supply chain for advanced therapies are uncertain, the ability to adhere to critical product timelines for IND submissions requires a deep appreciation for process understanding that allows for agility and speed without impact. Early investment into process definition on multiple platforms provides the required agility and confidence.

Regulatory considerations

A thorough understanding of manufacturing regulations and safety guidelines is foundational, and critical to achieving quality and safety in the design of any pharmaceutical facility. Particularly for a multi-product facility, an upfront investment into engineering controls for unit operations that require it will pay dividends. Being mindful of these additional factors, which govern mapping out of procedural controls, will help to ensure the optimized flow of personnel, equipment, and waste, whereas an approach that solely considers clinical aspects may result in costly rework. Within the framework of safety and regulatory considerations, we determined that HVAC strategies should incorporate 100% single pass recirculated air. This major decision, combined with additional implementation of critical segregation and contamination control strategies, helped us produce a robust design that supported clinical and commercial manufacturing of many products for many patients.

The age-old question of “build vs. buy” traditionally ignores the third path, namely a hybrid approach that carries its own unique significance regarding facility planning. COVID-19 has forever changed how we work, but supply chains demanding attention today were already under serious strain, long before the pandemic.

Choosing to build hybrid capabilities in-house, which always involves retrofitting and re-deployment of existing infrastructure and equipment, can simplify your supply chain but involves a significantly more substantial capital investment upfront and, long-term, maintenance to keep processes up and running.

Planning for the hybrid option is especially important when considering segregation and contamination control, as these depend on the proximity of equipment to other hardware and people. In this regard vaporized hydrogen peroxide is an incredible tool; the challenge is making it safe and easy to use. A pitfall every designer wants to avoid is that the scheduling of production cycles and related equipment—the key process elements a designer seeks to improve through hybrid designs—themselves become bottlenecks that introduce even greater uncertainty and risk.

Single use bioreactors and supporting equipment has become a no-brainer in a modern bioprocess facilities, to the point where entire facilities are constructed around disposable processing. We sometimes forget, however, the sometimes tortuous return-on-investment and cost-of-goods calculations used to justify the switch from stainless steel to plastic. Designers should therefore examine critically the possibility that, in some circumstances, fixed-tank bioreactors may make more sense, both economically and from the perspective of compliance and risk.

Conclusion

Modern facilities for the manufacture of cell and gene therapies are built upon the foundational systems that connect processes and unit operations. These features, which may be viewed as the glue that holds facilities together in a scientifically valid and regulation-compliant manner, are the basis of a digital roadmap that supports present and future projects: Great facilities are built on great systems.

The supporting cast of systems, which include enterprise resource planning, quality management systems, asset management, security, business management systems, communications tools, manufacturing execution systems, process monitoring and alarming, predictive maintenance, and evidence-based research tools, all become part of a larger manufacturing network that adapts to new technologies and changing needs. In addition to their potential role in new facility designs or retrofits, many of these systems may be implemented in existing facilities with more modest goals and change requirements. 

References

1. https://genetherapynetwork.com/current-therapeutics-research/approved-therapies/
2. https://www.cancer.gov/about-cancer/treatment/research/car-t-cells#:~:text=Since%202017%2C%20six%20CAR%20T,and%20Drug%20Administration%20(FDA)
3. https://www.biospace.com/article/global-cell-therapy-market-clinical-trials-development-patent-insight-2028-/#:~:text=Insight%20On%20More%20than%201600%20Cell%20Therapies%20in%20Clinical%20Trials
4. https://www.thegenehome.com/gene-therapy-process/examples?gclid=CjwKCAjwrqqSBhBbEiwAlQeqGnQcPXqXTCAFh7HDxQwJWvKT2G5cOMsvqXWSc82v1vvMp4el6QVWFxoCI34QAvD_BwE

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Emily Moran is Vice President of Vector Manufacturing at The Center for Breakthrough Medicines, an end-to-end biopharmaceutical CDMO dedicated to the development, manufacturing and approval of cell and gene therapies. She is an experienced leader in cell and gene therapy and biologics manufacturing with a focus on commercial readiness, industrialization and manufacturing stabilization.