Applying Mechanistic Models in Bioprocess Development - Measurement, Monitoring, Modelling, and Control of Bioprocesses - page 138

Abbreviations

API Active pharmaceutical ingredient

EMEA European Medicines Agency

FDA Food and Drug Administration

MW Molecular weight

NBE New biological entity

NCE New chemical entity

PAT Process analytical technology

PSE Process systems engineering

QbD Quality by design

RTR Real-time release

OD Optical density

DW (Biomass) Dry weight

Contents

1 Introduction........................................................................................................................ 138

2 Case Study: Aerobic Cultivation of Budding Yeast ........................................................ 140

2.1 Model Formulation ................................................................................................... 141

2.2 Parameter Identifiability Analysis............................................................................ 145

2.3 Parameter Estimation................................................................................................ 149

2.4 Uncertainty Analysis ................................................................................................ 154

2.5 Sensitivity Analysis: Linear Regression of Monte Carlo Simulations ................... 156

3 Discussion .......................................................................................................................... 163

4 Conclusions........................................................................................................................ 164

References................................................................................................................................ 165

1 Introduction

The pharmaceutical industry is changing rapidly nowadays. One important change,
compared with the situation 10 or 20 years ago, is undoubtedly the increased focus
on development of more efficient production processes. The introduction of pro-
cess analytical technology (PAT) by the Food and Drug Administration [ 2 ] forms
an important milestone here, since its publication ended a long period of regulatory
uncertainty. The PAT guidance indeed makes it clear that regulatory bodies are in
favor of more efficient production methods, as long as a safe product can be
guaranteed. This opens up new and exciting possibilities for innovation in phar-
maceutical production processes.
One of the central concepts in PAT is the design space, which is defined as ''the
multi-dimensional combination of critical input variables and critical process