Rationale for the Revision of Quality Risk Management Guidelines

On August 31, 2023 (Reiwa 5), the Ministry of Health, Labour and Welfare (MHLW) issued a revision of the “Guidelines on Quality Risk Management” through a joint notification from the Director of the Pharmaceutical Evaluation Division and the Director of the Compliance and Narcotics Division (Notification No. Yakuseiyakushin 0831 No. 1 and Yakuseikanma 0831 No. 2). This revision aims to deepen understanding of quality risk management for pharmaceuticals and promote its practical implementation.

Background and Necessity of ICH Q9(R1) Revision

Approximately 15 years have passed since the issuance of the original guideline, during which time the following circumstances were recognized:

First, the original guideline was developed prior to discussions on ICH Q10 (Pharmaceutical Quality System). Consequently, concepts subsequently established in ICH Q10, Q12 (Technical and Regulatory Considerations for Pharmaceutical Product Lifecycle Management), and Q14 (Analytical Procedure Development) were not sufficiently reflected in the original guidance.

Second, it became evident that the benefits of quality risk management anticipated in the original guideline had not been fully realized in practical operations. Specific challenges included inconsistent application of risk management principles, variations in the formality of risk assessments that were not commensurate with the level of risk, and insufficient integration of quality risk management into decision-making processes.

To address these challenges, there was a growing need to establish common understanding regarding quality risk management concepts between regulatory authorities and the pharmaceutical industry, which led to the implementation of this revision. The revised guideline, based on ICH Q9(R1) which was finalized in August 2023, represents an international harmonization effort involving regulatory authorities from the United States, European Union, Japan, and other ICH regions.

Major Newly Added Sections

Chapter 5, “Risk Management Methodology,” introduces three important concepts:

Formality in Quality Risk Management: This concept provides guidance on selecting appropriate approaches commensurate with the degree of risk and the level of documentation required. Formality refers to the rigor, structure, and extent of documentation applied to quality risk management activities. The guideline clarifies that higher-risk situations warrant more formal approaches with comprehensive documentation, while lower-risk scenarios may employ less formal methods. This principle enables efficient resource allocation while maintaining appropriate oversight. The level of formality should be justified and documented, and should be subject to review and adjustment as understanding of the risk evolves.

Risk-Based Decision Making: This establishes a decision-making process based on scientific knowledge and quality risk management principles. Risk-based decisions should consider the level of risk, available scientific evidence, uncertainty, and the potential impact on product quality, safety, and efficacy. The guideline emphasizes that risk-based decisions should be documented, including the rationale, assumptions, and limitations. This approach facilitates more agile and science-based regulatory interactions and supports continuous improvement throughout the product lifecycle.

Management and Minimization of Subjectivity: This addresses measures to control the influence of subjective judgment in risk assessment and enhance objectivity. While some degree of subjectivity is inherent in risk assessment, the guideline provides strategies to manage it, including: using cross-functional teams with diverse expertise, documenting assumptions and rationale, applying structured risk assessment tools, seeking independent review, and calibrating risk assessment approaches through training and examples. The goal is not to eliminate all subjectivity but to ensure it is recognized, controlled, and does not lead to inconsistent or inappropriate conclusions.

Chapter 6, “Integration of Quality Risk Management into Industry and Regulatory Operations,” includes a new section on product supply continuity. This clarifies the role of quality risk management in managing risks that quality or manufacturing issues pose to product supply. The section addresses considerations such as supply chain vulnerability assessment, risk mitigation strategies to prevent or minimize supply disruptions, communication protocols during supply challenges, and the balance between quality requirements and supply continuity. This addition reflects the increasing recognition that quality risk management encompasses not only product quality but also the availability of medicines to patients who need them.

Expansion of Appendices

Appendix II, “Quality Risk Management as Part of Supply Chain Management,” has been newly added. This reflects the importance of risk management in the increasingly globalized pharmaceutical supply chain. The appendix provides guidance on identifying and managing risks associated with: sourcing of starting materials and excipients, selection and qualification of suppliers and contract manufacturers, logistics and distribution, geopolitical factors affecting supply, and counterfeit products. The guidance emphasizes the need for visibility throughout the supply chain and the application of quality risk management principles to ensure continuity of supply while maintaining product quality.

Terminology Revisions and Editorial Improvements

The term “risk identification” has been changed to “hazard identification.” This change clarifies the approach for more accurately identifying and evaluating potential harm factors. Specifically, “hazard identification” focuses on identifying sources of potential harm (hazards), while “risk identification” refers to the broader process of identifying scenarios where hazards could lead to harm. This distinction aligns with international standards such as ISO 14971 (Application of risk management to medical devices) and provides greater clarity in the risk assessment process. The revised terminology emphasizes that the first step in risk assessment is to identify what could cause harm, before evaluating the probability and severity of that harm occurring.

Throughout the document, editorial improvements have been made to create clearer and more practical guidelines. These include: reorganization of content for better logical flow, addition of examples to illustrate key concepts, clarification of relationships between quality risk management and other quality systems elements, and enhanced consistency in terminology and formatting.

Expected Benefits

The following benefits are expected from this revision:

First, improved consistency and effectiveness in the practice of quality risk management. By providing clearer guidance on formality, subjectivity management, and integration with other quality systems, the revised guideline should lead to more uniform and effective application of quality risk management principles across the industry.

Second, promotion of appropriate implementation of risk-based approaches. The enhanced guidance on risk-based decision-making should facilitate more science-driven and efficient regulatory processes, including reduced submission requirements for lower-risk changes and more focused oversight on higher-risk areas.

Third, strengthening of comprehensive quality management systems including the supply chain. The addition of supply chain considerations recognizes that quality risk management extends beyond the manufacturing site to encompass the entire value chain, from raw material suppliers to distribution networks.

Fourth, ensuring stable supply of products. The explicit consideration of supply continuity in quality risk management decisions helps balance quality requirements with the critical need to maintain medicine availability for patients.

Fifth, facilitation of communication between regulatory authorities and industry. By establishing common understanding of quality risk management concepts and terminology, the revised guideline should enhance dialogue and alignment between regulators and pharmaceutical companies, leading to more efficient and effective oversight.

Relationship with Other ICH Guidelines

The revision of ICH Q9(R1) should be understood in the context of the broader ICH quality guideline framework. The revised guideline has been developed to complement and align with:

ICH Q10 (Pharmaceutical Quality System): Q9(R1) provides the risk management foundation that supports the quality system described in Q10, including management responsibility, resource management, and continuous improvement processes.

ICH Q12 (Technical and Regulatory Considerations for Pharmaceutical Product Lifecycle Management): The risk-based decision-making approaches in Q9(R1) directly support the established conditions and post-approval change management concepts in Q12, enabling more flexible lifecycle management.

ICH Q14 (Analytical Procedure Development): Quality risk management principles in Q9(R1) are applied throughout the analytical lifecycle described in Q14, from method development through validation and ongoing performance monitoring.

This integrated approach ensures consistency across quality guidelines and supports a modern, science-based regulatory paradigm.

Implementation Considerations

Organizations implementing the revised guideline should consider the following:

Training programs should be developed to ensure that personnel understand the new concepts, particularly formality, subjectivity management, and risk-based decision-making. Existing quality risk management processes should be reviewed and updated to align with the revised guideline. This may include updating standard operating procedures, templates, and decision-making frameworks. Quality risk management integration should be evaluated across all relevant areas, including product development, manufacturing, supply chain management, change control, deviation management, and regulatory submissions.

Documentation practices should be reviewed to ensure appropriate formality levels, clear documentation of assumptions and rationale, and traceability of risk-based decisions. Governance structures may need adjustment to support cross-functional risk management teams and appropriate escalation of risk-based decisions. Regular review and refinement of quality risk management approaches should be conducted, based on experience and new scientific knowledge.

Conclusion

The revision of the Quality Risk Management Guidelines is positioned as an important measure aimed at achieving both quality assurance and stable supply of pharmaceuticals. The enhanced guidance reflects the evolution of pharmaceutical quality management over the past 15 years and provides a foundation for more effective, science-based approaches to quality risk management. By implementing these principles, the pharmaceutical industry and regulatory authorities can work together to ensure that medicines of appropriate quality reach patients in a timely and reliable manner, while optimizing the use of resources and supporting innovation throughout the product lifecycle.

The success of this revision will depend on the commitment of both industry and regulators to embrace risk-based approaches, invest in training and capability building, and foster open communication based on shared understanding of quality risk management principles. As experience is gained with the revised guideline, continuous learning and refinement of practices will be essential to fully realize the anticipated benefits and to meet the evolving challenges of pharmaceutical quality management in an increasingly complex global environment.

Document Information

• Original Notification: Yakuseiyakushin 0831 No. 1 and Yakuseikanma 0831 No. 2
• Issue Date: August 31, 2023 (Reiwa 5)
• Based on: ICH Q9(R1) – Quality Risk Management
• Issuing Authority: Ministry of Health, Labour and Welfare, Japan