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.