Integrated Processing

To investigate continuous manufacturing (CM), and to streamline and accelerate its drug development process, Vertex Pharmaceuticals, Inc. partnered with GEA to enhance their existing technology and implement primary and backup CM processes. Initially using individual semi-continuous unit operations (a twin screw wet granulator), formulations were first developed and produced in a “discontinuous” mode. A prototype ConsiGma®-25 unit was then purchased to facilitate the production of larger-scale clinical batches. In addition, a multi-product development and launch rig (DLR) was installed to manufacture multiple drug products in a fully continuous mode — starting with the blending of individual excipients, ending with film-coated tablets and incorporating PAT (process analytical technology) to allow real-time release.

Focusing on the integration of separate processing steps into a fully continuous process, as well as ensuring product processing adaptability for multi-product use, the DLR installation had to incorporate continuous wet granulation, fluidized bed drying and tablet compression, as well as initial blending and final film coating of tablets, and include the option of dry granulation and direct compression as an alternative to wet granulation. The rig was also equipped for-real time release, incorporating multiple PAT points to monitor and characterize process intermediates and final product. The scope of the software development alone (to run both the process controls and PAT feedback control loops) was highly complex.

The process starts by blending the API with the excipients, dispensed using loss-in-weight feeders into a continuous in-line blender. After initial blending, the machine can be configured so that the blend flows into a twin-screw wet granulator (wet granulation), a roller compactor (dry granulation) or directly into the second in-line blender (direct compression). For wet granulation, the granules are dried in a segmented fluid bed dryer before being conveyed to the mill. For dry granulation, the milling occurs directly after granulation.

The final blend is then processed in the second in-line blender and compressed with a Courtoy MODUL P press that is equipped with a punch-face lubrication system. This facilitates the production of high drug load tablets with “sticky” APIs while mitigating problems such as tablet picking and sticking. Tablet cores are coated in one of two semi-batch pan film coaters.

The DLR employs ten PAT systems to monitor each unit operation, utilizing NIR, Raman and light scattering for particle sizing. Quality is assured after each unit operation and, ultimately, the process is enabled for real time release testing (RTRt).    

Enhanced Drug Development

CM is ideally suited to the QbD development and manufacture of high quality medicines, with reduced development timelines, which ultimately benefits patients. CM should result in smaller, operationally more efficient and environmentally friendly commercial manufacturing plants, requiring a smaller, highly-skilled labor force.   This makes the return of manufacturing to the USA a more attractive and economically viable option.  Incorporating extensive PAT to allow for RTR provides enhanced efficiency and significantly reduced cycle times, leading to lower inventories, and more flexibility responding to market demands. In addition, real-time monitoring and control reduces the potential for product failures and waste. 

The costs associated with transitioning from traditional batch processes to continuous processes can be offset with API savings during development, particularly for products with high drug load, large commercial volumes, or expensive API.  Using CM for products under development may have a perceived higher risk during this transition period where the manufacturing technology is novel and the regulatory framework is being further defined. However, once this transition period has been successfully navigated and the technology has become established, developing continuous processes will be lower-risk, since scale-up risk will be avoided, and significantly greater process understanding can be achieved at an earlier development phase. CM is therefore not only ideally suited to the QbD development and manufacture of high quality products, but also for breakthrough therapies with reduced development timelines, which ultimately means delivering life-saving medicines faster to patients in need.