This chapter provides comprehensive guidance for conducting and managing investigations, focusing on systematic approaches to identifying root causes of quality-related incidents. It captures the essential components such as impact assessments, historical reviews, personnel interviews, physical material inspections, equipment and facility evaluations, document reviews, and statistical sampling techniques. Key highlights include a rigorous impact assessment process to evaluate potential effects on critical product attributes, ensuring traceability and regulatory compliance; historical review procedures that analyze deviations over a minimum 12-month period to identify systemic trends; personnel interview protocols designed to gather detailed information; and inspection methodologies using statistically sound sampling plans like ANSI/ASQ Z1.4 and √N + 1. The chapter also provides detailed guidance on investigating OOS results through a phased, scientifically driven approach and strategies for complaint investigations, including reviews of CDMO investigations. By integrating scientific rigor, regulatory compliance, and continuous improvement principles, the approaches support manufacturers in maintaining product quality and patient safety standards.