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 InitiativeThe 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.