At the start of 2021, a crane lifted a shrink-wrapped, elongated structure off a truck flatbed and through a window into an upper floor of Shanghai’s ATLATL Innovation Center. Two months later, that structure was a full-fledged facility for the clinical production of cell therapy products. The idea behind the project was simple: to create a lightweight GMP cell manufacturing unit that is fast to assemble, easy to deliver, and that can be used to scale out production in compliance with regulatory requirements. The outcome was an engineering feat: a plug-and-produce module with connections for clean utilities that houses cell manufacturing in automated, fully enclosed, and sterile systems. A ready-to-go “cell factory”.
Scaling principle: One product for one patient
A significant challenge in bringing promising cell therapies to patients is their time-sensitive and logistics-intensive production. Each cell therapy batch constitutes a single dose for a single patient. This means that commercial-scale expansion cannot be done by conventional volume increase. Instead, each patient-specific batch must be treated as a complete production run and increasing throughput means running several patient-specific runs in parallel. That is, scaling up is really scaling out by parallelization.
That scale-out is simplified by a facility that standardizes production process, environment, and supply in a contained and modular unit. That unit operates as a GMP-compliant cleanroom that integrates the supply of parallel production runs under segregated and controlled flows of people, materials, product, and waste. Growing manufacturing capacity becomes then a de-risked and accelerated process of simply adding one or more units. This is the premise of the CliniMACS Cell Factory®. The facility in Shanghai was a pilot project by Miltenyi Biotec and Exyte to demonstrate its feasibility as a plug-and-produce GMP plant.
Merging process and facility design expertise
Miltenyi Biotec commercializes the ISO 13485–certified CliniMACS Prodigy® Instrument, an integrated device that carries out all process steps in patient-specific cell production. The CliniMACS Prodigy is designed to accommodate different cell manufacturing applications with high process reliability and in a small footprint. Because the complete manufacturing workflow is contained within a closed, single-use, sterile tubing set, a bank of instruments housed in a ballroom-concept cleanroom can perform several runs concurrently. The preconfigured and prefabricated ExyCell module from Exyte integrates elements for air conditioning, lighting, fire protection, power and data cables, sensors, and supply lines that are compatible with CliniMACS Prodigy Instruments. Together, these technologies constitute a GMP facility engineered for fast-tracked construction, streamlined qualification, and modular expansion. In fact, 2 ballrooms of 24 CliniMACS Prodigy Instruments each could achieve routine production of 1,000 batches per year on a combined surface area of about 200 m2.
Going large: A commercial GMP facility
Conceptualizing scale-out as the modular addition of standardized production units simplifies the design, planning, and deployment of large facilities. However, parallelized cell manufacturing comes with challenges. The infrastructure of a modularly expanded GMP plant must arrange supporting services around a core production space that expands or contracts depending on demand. The layout must organize the movement of materials and people to maintain the safety and integrity of processes and products. That includes handling the unique starting material of each batch with electronic tracking systems; coordinating process validation and release testing; and supporting a manufacturing execution system with batch control and real-time data flows. Finally, environment, health, and safety measures must account for larger staffing, materials consumption, and waste generation.
Many requirements for a commercial GMP facility are integral to the CliniMACS Cell Factory concept, ExyCell module, and CliniMACS Prodigy operating principles. The modular unit with instruments processing cells in fully closed systems balances standardization and adaptability to establish optimal operations for different products and throughput levels. Also, the reproducible layout and supply concept makes deployment time and cost-effective. The CliniMACS Cell Factory is not a stepping stone toward but a breakthrough into commercial-scale cell manufacturing.