ABSTRACT
In the manufacture of therapeutic products, contamination control is of paramount importance to product quality, patient safety, and good manufacturing practice (GMP) compliance. Cleaning processes are the primary line of defense in preventing product adulteration from contaminants such as foreign matter, particulates, product
8.1 Introduction .................................................................................................. 143 8.2 Mechanisms for Cleaning Bioprocess Equipment Systems ......................... 144 8.3 Methods for Monitoring Cleaning Effectiveness ......................................... 144
8.3.1 Traditional Monitoring Approaches ................................................. 144 8.3.2 PAT Monitoring Approaches ............................................................ 145
8.4 Application of PAT for Monitoring and Verifying Equipment System Cleaning ........................................................................................................ 145 8.4.1 On-Line TOC Analysis for Monitoring System Cleaning................ 147
8.5 Application of PAT for Monitoring and Verifying Chromatography Column Cleaning .......................................................................................... 151 8.5.1 Column Integrity Test as a PAT Forward Processing Criterion ....... 153 8.5.2 Column Pressure Drop as a PAT Forward Processing Criterion ...... 155 8.5.3 Product Peak HETP as a PAT Critical Quality Attribute and
Forward Processing Criterion ........................................................... 158 8.5.4 Product Peak Asymmetry Factor as a PAT Critical Quality
Attribute ............................................................................................ 159 8.5.5 Product Peak Retention as a PAT Forward Processing Criterion ..... 160
8.6 Summary of Chromatography Cleaning Process Analysis Technology ...... 161 8.7 Concluding Remarks .................................................................................... 162 References .............................................................................................................. 162
residues, adventitious agents such as viral and microbial organisms, and processing reagents. Despite their critical nature, the control and monitoring of effective cleaning processes can be elusive. A recent survey found that 60% of Food and Drug Administration (FDA) warning letters cited Code of Federal Regulations 21 CFR 211.67 deficiencies relating to inadequate equipment cleaning procedures, monitoring, and documentation (European Compliance Academy 2006). These regulatory, patient safety, and product quality concerns make process analytical technologies (PATs) a powerful tool for enhancing the verification and validation of cleaning processes to ensure that they are well controlled and consistently remove contaminants every time they are used.
