Downstream Process Optimization Opportunities Using On-Line and At-Line PAT Instrumentation

Technologies for downstream process applications continue to emerge as the PAT initiative is fully implemented into biotechnology manufacturing.
Jun 01, 2006



Traditional chemical analysis in downstream biotechnology manufacturing operations has been performed in off-line laboratories which are physically and organizationally remote, from the manufacturing site. Results of these assays are often not provided in a timeframe that is useful in controlling and monitoring the downstream process with maximum efficiency. Reports of delays (ranging from hours to days) in obtaining results of analytical monitoring of downstream processes often relegates these functions and the corresponding data to a compilation of historical databases rather than to its intended use as a tool to manage and control the real-time process under observation. Modern manufacturing processes in other industries, such as semiconductor and petrochemical processing, have long recognized and employed the advantages of performing analytical measurements at the production line and have widely used these techniques to enjoy advantages in production efficiency and product quality. The comparison and contrast to the current state of biotechnology manufacturing process efficiency and quality is particularly evident. FDA has long considered application of on-line analytical techniques as credible opportunities to improve product quality and efficiency in pharmaceutical production, including biotechnology and biological production. As a result, FDA began investigating technologies and prospects for application of automation in pharmaceutical, biotechnology, and biological manufacturing processes in ten years ago.

The purpose of the PAT initiative is to move analytical laboratory functions close to the manufacturing process and to improve manufacturing efficiencies and product quality. This would be accomplished by providing real time support and control of manufacturing processes through analysis of the process stream coupled with statistical process control and tight feedback control loops.

The PAT Initiative

The FDA PAT initiative was created formally by the Center for Drug Evaluation and Research (CDER) branch of the FDA in 20021 and sought to provide a framework to employ these techniques for small molecule pharmaceutical production under guidance from FDA. PAT processes2 are becoming an established tool to promote and improve quality and production efficiency in the pharmaceutical manufacturing process. The successes of early implementation in small molecule manufacturing processes led early adopters in the biotech community to explore PAT techniques and processes for potential use in biotechnology applications. It has been demonstrated that the same PAT technology used in traditional pharmaceutical manufacturing can be employed in biotechnology manufacturing with the same positive effect. To that end, FDA is now focusing its PAT initiative on biotechnology and biologicals manufacturing through its Center for Biologics Evaluation and Research (CBER) and PAT offices.

Successful PAT programs are defined by a careful combined application of statistical process control (chemometrics) and use of on-line, at-line, or near-line sensors and instrumentation capable of measuring key parameters of the manufacturing system in real time. These capabilities are arguably most critical and useful in the final stages of biotechnology manufacturing, where the value of the product is at its highest. Downstream processing applications are a specific target for implementation of PAT processes because this production stage is where the desired product of the fermentation or cell culture process is separated from the complex production matrix, then concentrated, identified, quantitated, and collected for final processing and formulation. These operations are particularly suited for use of on-line, at-line, and near-line sensors and analytical instrumentation associated with corresponding chemometric and process control systems.

Statistical process control and chemometric systems are employed across a broad spectrum of industries and are not further explored here. References to general chemometrics and chemometrics specific to biotechnology and biologicals are widely available.3,4,5 The focus of this article is on-line sensors and instrumentation specific to downstream processing.