Chemometrics in bioprocess engineering: process analytical technology (PAT) applications

The production process of an active pharmaceutical ingredient (API) by fermentation in an industrial environment was analysed using process analytical technologies. The Food and Drug Administration's (FDA) process analytical technology (PAT) initiative is intended to be a collaborative effort with industry to promote the integration of new manufacturing technologies into pharmaceutical production [FDA. 2003 "PAT-A Framework for Innovative Pharmaceutical Manufacturing and Quality Assurance (Draft Guideline)." http://www.fda.gov/cder/OPS/PAT.htm]. Within the PAT framework the aim is to design, develop and operate processes consistently to ensure a predefined quality at the end of the manufacturing process. Several case-studies are discussed in which combining chemometrics methods with NIR spectra from samples in different process stages leads to increased process understanding and process control of an API production process. The ab-initio prediction of the expected final titter of an antibiotic fermentation was obtained with raw materials and inoculum quality quantification. NIR reflectance spectroscopy was applied to monitor at-line different quality variables for process samples taken from the fermentation stage of the whole process. Finally, the at-line use of NIR transmittance spectroscopy in one of the API downstream purification steps is described. In this paper the use of PAT as a tool to operate an important shift in quality control efforts is illustrated, showing that quality should not be tested only on final products but in-process to obtain increased quality assurance of final products. (C) 2004 Elsevier B.V. All rights reserved.