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Review
. 2023 Jul;57(4):839-848.
doi: 10.1007/s43441-023-00504-6. Epub 2023 Mar 27.

Quality Tolerance Limits' Place in the Quality Management System and Link to the Statistical Trial Design: Case Studies and Recommendations from Early Adopters

Marion Wolfs  1 , Łukasz Bojarski  2 , Steve Young  3 , Lynne Cesario  4 , Marcin Makowski  5 , Linda B Sullivan  6
Affiliations
Review

Quality Tolerance Limits' Place in the Quality Management System and Link to the Statistical Trial Design: Case Studies and Recommendations from Early Adopters

Marion Wolfs et al. Ther Innov Regul Sci. 2023 Jul.

Erratum in

Abstract

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.

Keywords: Case studies; Key risk indicators; Quality tolerance limits; Risk based quality management; Statistical design; Threshold.

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Conflict of interest statement

The author(s) declared no potential conflict of interest with respect to the research, authorship, and/or publication of this article.

Figures

Figure 1
Figure 1
Statistical analysis plan (excerpt)
Figure 2
Figure 2
Percent of Currently Randomized Patients at Risk of Having an Unknown Survival Status at the Final Analysis in Relation to a QTL 4% Threshold for Corrective Action Initiation.
Fig. 3
Fig. 3
The Chart Presents the Completeness of Primary Endpoint Data During the Study. The sss) and secondary (amber) QTL limits.
See this image and copyright information in PMC

References

    1. International Council for Harmonisation (ICH). ICH harmonised guideline: integrated addendum to ICH E6(R1): guideline for good clinical practice E6(R2). https://database.ich.org/sites/default/files/E6_R2_Addendum.pdf; 2016, Accessed 18 July 2022.
    1. European Medicines Agency. Reflection paper on risk based quality management in clinical trials. https://www.ema.europa.eu/en/documents/scientific-guideline/reflection-p...; 2013. Accessed 18 July 2022.
    1. Bhagat R, Bojarski L, Chevalier S, et al. Quality tolerance limits: framework for successful implementation in clinical development. Ther Innov Regul Sci. 2021;55:251–261. doi: 10.1007/s43441-020-00209-0. - DOI - PMC - PubMed
    1. Makowski M, Bhagat R, Chevalier S, et al. Historical benchmarks for quality tolerance limits parameters in clinical trials. Ther Innov Regul Sci. 2021;55:1265–1273. doi: 10.1007/s43441-021-00335-3. - DOI - PMC - PubMed
    1. WCG Metrics Champion Consortium QTL Working Group. Defining quality tolerance limits and key risk indicators that detect risks in a timely manner: reflections from early adopters on emerging best practices (Part 1). Applied Clinical Trials-06-01-2022, Vol. 31, Issue 6. https://www.appliedclinicaltrialsonline.com/view/defining-quality-tolera.... Accessed 18 July 2022.

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