Since the release of ICH E6(R2), multiple efforts have been made to interpret the requirements and suggest ways of implementing quality tolerance limits (QTLs) alongside existing risk-based quality management methodologies. While these efforts have contributed positively to developing a common understanding of QTLs, some uncertainty remains regarding implementable approaches. In this article, we review the approaches taken by some leading biopharmaceutical companies, offering recommendations for how to make QTLs most effective, what makes them ineffective, and several case studies to illustrate these concepts. This includes how best to choose QTL parameters and thresholds for a given study, how to differentiate QTLs from key risk indicators, and how QTLs relate to critical-to-quality factors and the statistical design of the trials.