Continuous processes

During the past five years, interest in continuous processes for the pharmaceutical industry has increased. FDA is in favor of continuous processes because they are compatible with the agency's quality-by-design (QbD) principles and are amenable to process analytical technologies (PAT). The pharmaceutical industry is interested in continuous processes because they are more efficient, cleaner, and safer than batch processes. They are also less demanding in terms of a manufacturing footprint and manpower. In short, they are more cost effective (5). Because continuous processes are amenable to QbD and PAT, there is less batch-to-batch variability, which results in a lower risk of batch rejection for failure to meet specifications and therefore better process economics. Continuous processes have been used for many decades in other industries. Almost all of the batch-unit operations in pharmaceutical manufacturing can be performed continuously, and these processes can be easily applied to pharmaceutical manufacturing. To successfully implement continuous processes, however, the conventional approach to process development needs to change. Evaluation of the kinetics and mass transfer is required for successful modeling and simulation of any unit operation. This assessment results in a better definition and understanding of the design space. It allows for the identification of critical parameters and their effect on product quality. A better process can be developed and implemented, thereby resulting in a more economical manufacturing process.

To design and operate an SMB unit, it is necessary to understand the process and how its output evolves with changes in flow rates, temperature, or solvent composition (6, 7). Once the critical process parameters are identified and studied, the process can be designed and controlled efficiently. During normal operations, all parameters involved in an SMB operation can be controlled accurately using modern instrumentation and analytical tools. If these parameters are maintained efficiently and accurately within their desired range, the output of the process will consistently be within specifications. Regular sampling or on-line testing is performed to monitor the SMB output and ensure compliance. Recently, the University of Zurich and the equipment manufacturing unit of Novasep (Pompey, France) developed a controller that can automatically adjust the SMB parameters to maintain the product quality and the optimum throughput based on a regular sampling of the SMB output streams (8). This kind of smart automation has not yet been implemented at a commercial scale, but it is an improvement that should find its way to the production floor soon.

Yield improvement. SMB is well established as a binary process that combines the performance of chromatography with the economical benefits of a continuous process. This technique is successfully applied in the pharmaceutical industry for the chiral separation of APIs and intermediates. Chiral separations are only a few of the processes that can benefit from SMB. A few years ago, the purification of crude paclitaxel, a natural high-potency product, was implemented using an SMB process (9). The separation was complex due to a large number of impurities. This process was turned into a binary separation where the troublesome impurities such as impurities not efficiently removed by crystallizations were eluted together in one SMB stream while the purified product was eluted in the other stream. As a result, a crude product with overall purity of approximately 75% was increased to a purity of more than 95% with a recovery greater than 98% before the final crystallization.

Large molecules. The latest application of SMB is the purification of large molecules for the biopharmaceutical industry. Chromatography (i.e., ion exchange and size exclusion) is used to purify the expensive molecules produced from bioreactors and fermenters. These processes usually require large amounts of water-based mobile phases. An increasing number of scientific publications addresses the conversion of these inefficient batch processes into continuous processes (10, 11). Because these batch separations usually require several steps (i.e., loading, elution, and regeneration), the basic set-up of an SMB unit needs to be modified to apply this technique to these separations. SMB units with five zones or more have been designed. These design variations may make the process more complicated, but nevertheless improve throughput and solvent consumption. Other difficult separation problems can also be solved using SMB technology. A few examples, recently developed at AFC, are described below and show how SMB can be efficiently used in API manufacturing.