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8 BioPharm International ® Quality and Regulatory Sourcebook eBook March 2024 www.biopharminternational.com Risk Management broad spectrum of products from emergency hospi- tal drugs to over-the-counter remedies. By the end of 2022, drug shortages reached a new peak. This crisis was rooted in various factors, such as an overreliance on foreign sources for active ingredient, a lack of do- mestic manufacturing capacity, and insufficient sup- ply chain visibility into all the companies involved, leading to a misleading appearance of supplier diver- sity. These shortages have profound cascading effects on patient care (7). As a tangible step to help address some of these challenges, a targeted revision of ICH Q 9 was ap- proved. ICH Q 9(R1) was published in Januar y 2023 (8), superseding the original ICH Q9 guidance issued in 2005 (2). This revision narrowly focused on the following four topics deemed critical to advance the competency and effectiveness of the industry in risk management: • high levels of subjectivity in risk assessments and QRM outputs • product availability risks • lack of understanding into what constitutes for- mality in QRM work • lack of clarity on risk-based decision-making. The ICH Q 9(R1) concept paper further suggested risk review and hazard identification as two addi- tional points to be addressed. Considering the topic of subjectivity, the ICH Q9(R1) Concept Paper (1) noted the challenge associated with subjectivity as follows: "High levels of subjectivity in risk assessments and in QRM outputs—the reasons for this can include highly subjective risk scoring methods and differ- ences in how risks are assessed and how hazards, risk, and harms are perceived by different stakeholders. This can lead to var ying levels of effectiveness in the management of risks. While subjectivity cannot be completely eliminated from risk assessment and QRM activities, it may be controlled using well rec- ognized strategies, including addressing bias and behavioral factors." The Concept Paper further went on to describe po- tential benefits of addressing subjectivity and suggests: "Less subjective risk assessments to support man- ufacturing processes should lead to fewer quality de- fects that could present risks to patients. Recalls are required every year to protect patients from the real and/or potential risks presented by defects in medi- cines, leading in some cases to shortages of important medicines. Less subjective risk assessments should also lead to more science-based manufacturing op- erations, control strategies, and validation activities, resulting in the potential for reduced costs and the possibility to free up resources for other necessary activities. ICH Q8, Q10, and Q11 expect science- and risk-based applications, and revising ICH Q 9 to ad- dress subjectivity in QRM more explicitly will help enable/accelerate the continued implementation of Q8, Q10, Q11 (and Q12), because of the foundational relevance of QRM." Drivers to reduce subjectivity are compelling when one considers the opportunity to reduce defects (and, in turn, recalls). Reduced defects will ultimately lead to reduced costs and resources, and further realiza- tion of the goals of a modern PQS. Indeed, one could argue that subjectivity casts a long shadow over many facets of the pharmaceutical business not just QRM. This paper provides an introductory exploration into the topic of subjectivity in QRM by: • reviewing contemporary QRM literature on sub- jectivity • creating a shared understanding of subjectivity for QRM • examining how subjectivity is addressed in the original Q 9 guidance, and comparing it to the revised guidance. Subjectivity: insights from contemporary QRM-related literature The emphasis on subjectivity in ICH Q9(R1) is not sur- prising when one reviews contemporary literature on the topic published since the 2005 release of ICH Q9. Notably, H. Gregg Claycamp, the Regulatory Rappor- teur of the original ICH Q9 guidance document, pub- lished a paper in 2018 entitled "Controlling Subjec- tivity in Risk-based Decision Making: The Benefits of Multi-criteria Decision Analysis" (9). In this paper, in addition to brief discussions on subjectivity inherent in risk assessment and risk management, and linking subjectivity and uncertainty, Claycamp proposed that the problem with subjectivity in QRM stems from two elements as follows: Reduced defects will ultimately lead to reduced costs and resources, and further realization of the goals of a modern PQS.