Regulators Are Exploring with Industry How to Strengthen Quality Risk Management Practices, with Revision of ICH Q9 a Key Focal Point

Regulators and industry are sitting down together to mine their experience and map out some clearer directions and expectations about what is needed to empower quality risk management (QRM) in improving the pharmaceutical quality system (PQS) and the industry/regulatory communication process at the review and inspection levels.

These discussions are taking concrete form in a number of papers and guidances from various agency, industry and academic organizations, including a revision that has begun of ICH’s 15-year-old QRM guideline Q9.

The “business plan” on the Q9 revision effort was endorsed by the ICH Management Committee in late October, 2020. Endorsement of the Q9(R1) “concept paper” followed in November.

The revision plan and paper explain that while ICH was instrumental in advancing industry and regulator understanding of QRM principles and approaches, the benefits envisaged by ICH Q9 “have not yet been fully realized.”

Highlighted are four current QRM problem areas: ● “the high levels of subjectivity in risk assessments and QRM outputs, leading to a lack of good science” ● “challenges in the management of product availability risks, resulting in continued shortages of important medicines for patients” ● “a lack of understanding of what constitutes formality in QRM, and how to apply varying degrees of formality in QRM activities so that a better use of resources can be made,” and ● “a lack of clarity on what constitutes good risk-based decision-making.”

The plan and paper explain how the Q9 revision could help in addressing these issues, leading to “more effective, robust, integrated, and science-based QRM activities within the pharmaceutical environment,” and increased harmonization around QRM’s use and implementation.

In turn, the benefits from more effective QRM strategies would include: ● significant savings in reduced quality defects and product recalls ● efficiencies from better-designed manufacturing processes, more effective control strategies, and validation activities, and ● increased ability to invest in optimizing/modernizing manufacturing processes and technologies.

The timeline included in the business plan calls for a Step 2b draft of the revision to be released in the fall of 2021, with Step 4 adoption of the final revised guideline targeted for June 2022.

The three-part story below explores the current dialogue on QRM and its interrelationship with knowledge and change management, the PQS, and the control strategy across the process and product lifecycle.

As the Q9 revision proposal indicates, the stakes are high in strengthening the effectiveness of QRM in the various roles it needs to play and how this effectiveness is communicated – particularly as the technical complexity of products and processes continues to grow. Shifting the QRM focus from “reactive to proactive,” the proposal stresses, “will enable continual improvement to become a key aspect of the PQS.” 

In turn, central to the dialogue that has taken place in the ICH Q12 context is how to evolve the post-approval change (PAC) regulatory paradigm to empower rather than inhibit this proactive risk and knowledge management approach in order to realize the continual improvement goal. [Editor’s Note: IPQ has closely tracked the QRM/KM/PAC dialogue as it has evolved over the past decade. A chronological bibliography with links to this in-depth IPQ coverage is provided below.]

Part I: ICH Q9 Revision Lead O’Donnell on the Evolution of QRM 

The first part of the story focuses on a presentation at a late February QRM Summit by Ireland HPRA’s Kevin O’Donnell, who is serving as lead on the ICH Q9 revision Expert Working Group (EWG). O’Donnell explored how the principles of quality risk management could be furthered in practice in conjunction with advancements in knowledge management, quality systems, and regulatory communications.

Part II: FDA’s Rick Friedman on Advancing Aseptic Processing through QRM

The second part offers insights on the relevance of current QRM concepts and practice to improving the reliability, compliance and efficiency of aseptic processing, provided by FDA CDER’s Rick Friedman at the 2021 ISPE Aseptic Conference. Friedman is representing FDA on the ICH Q9(R1) EWG, and brings CDER compliance office experience to bear in discussing how to improve aseptic processing risk management and control.

Part III: Industry/Academia Thought Leaders on the Evolving QRM/KM Relationship

The members of the Technical University of Dublin’s Pharmaceutical Regulatory Science Team have been making an important contribution to the QRM/KM dialogue through their cumulative industry experience and ongoing research in conjunction with TUD’s PhD program. The third part focuses on insights offered in March by two of the industry team members, in particular: ● Merck’s Marty Lipa  at the 2021 PDA Annual Meeting, and ● Genentech’s Emma Ramnarine, in an interview conducted through the PDA-Ireland chapter.

IPQ’s 2010-2021 STORIES ON PAC/QRM/KM REGULATORY DIALOGUE

The following is a chronological listing of IPQ stories since 2010 that have covered the pressing issues around post-approval changes and what is needed in conjunction with advancements in risk and knowledge management to make quality regulatory processes across the product lifecycle more cohesive, efficient, process improvement and supply friendly, and internationally harmonized.

2010

● Preparing for and Communicating Manufacturing Changes During Late-Stage Development Smooths Biotech Clearance Process with FDA

● MHRA Has Been Rejecting One-Third of Type IA Variation Notifications Due to Information Shortcomings

2011

● CMC/GMP Procedures and Interpretations Can Pose Challenges for Foreign Firms in ICH Member Japan

● ICH Q11 Draft Gelling on Lifecycle/Change Management and Control Strategy Components

● Europe Asks for Stakeholder Input in Refining and Harmonizing Its Variations Rules Across Member States

● Divergent Global Change Filing Requirements Present Continuous Improvement Roadblocks, Experts Stress at ICH Q10 Conference

2012

● EMA’s Biosimilar Quality Guideline Redraft Sharpens Focus on Target Profiles and Lifecycle Changes of Reference Product

● International Dialogue Should Focus on Harmonizing Control Strategy Filings and CMC Change Requirements, Moheb Nasr’s Industry Experience Confirms

2013

● FDA Draft Guidance on Syringe Connection Problems Reemphasizes Need for Early Agency/Sponsor Dialogue on Combo Products; Post-approval Change Guide Issued

● FDA’s Center for Drugs Redoubles Effort to Achieve 21st Century Quality Vision and Foster Continuous Process Improvement

● Industry Asks FDA to Clarify How Current CMC Submission Paradigm Can Flex to Accommodate Breakthrough Therapy Development Timelines

2014

● Post-Approval Change Regulatory Burden Draws Heat at Japan Biotech CMC Strategy Forum

● Industry Proposals for Addressing Post-Approval Change Burdens Include Harmonizing on Commitments and Classifications

● Global Quality Regulatory Maze Jeopardizes Vaccine Supply, IFPMA is Stressing

● FDA and EMA Finalize Guidances to Help in Post-approval Change Management

● Guides on FDA’s Generic Drug Review Process Continue Apace in July; EU Pilot Pursues Generic Drug Review Streamlining Internationally

● New CMC Submission Approach Needed to Foster Transparency and Continuous Improvement, PhRMA Team Says; Embedding Control Strategy as Regulatory Commitment in QOS Proposed

● ICH’s Lifecycle Management Initiative Q12 is Targeting the Tough Regulatory Issues, With Patient Supply a Driving Concern; Analytical QbD Also on Expanded ICH Agenda

2015

● Asian Agencies Report on Progress in Addressing Emerging Regulatory Challenges at CASSS Biotech CMC Strategy Forum in Japan

● Stress Studies Are Playing Key Role For Roche/Genentech in Assessing Biomanufacturing Process Site Transfers

● Global Change Protocols Proposed as Part of a More Standards-Based Approach to Regulating Life Cycle Management Internationally

● Broad-Based ICH Q12 Expert Working Group Supporting Initiative’s Urgency and Viability, EWG Members Affirm at GPhA Conference

● ICH Q12 EWG Views Established Conditions as Pivotal in Evolving Lifecycle Regulation Internationally; EMA Workshop Provides Input

● More Structured, Interactive Process To Drive Convergence in Latin America Advocated by Biotech Product Regulators and Industry at CMC Strategy Forum in Brasilia

● Industry is Urging Latin American Agencies to Cooperate in Filling Lifecycle Management Regulatory Gaps for Biologics

2016

● Industry/Regulator Dialogue on Knowledge Management is Intensifying in Wake of ICH’s Q12 Initiative

● Impact of Accelerated Pathways on Method Development, Inter-Agency Collaboration Draw Regulator Discussion at Europe Biotech CMC Strategy Forum

2017

● Tension Between Quality Regulatory Paradigm and Pharma’s Innovation, Acceleration and Harmonization Imperatives in Spotlight

● FDA’s Office of Pharmaceutical Quality Advances Review/Inspection Integration

2018

● FDA Inspection Findings Provide Additional Insight on CGMP Expectations for Combination Product Manufacturers

● Pharma is Exploring How to Maximize ICH Q12 Value in Practice; Q12 EWG Encourages Feedback

● CMC Priorities of EFPIA’s European Biopharmaceutical Enterprises Include ADCs, Drug/Device Combos and Statistics

● Role of Established Conditions Drawing Attention in Global Dialogue on ICH Q12’s Potential

● Emergency Preparations Draw Heightened Industry and Regulator Attention as Natural and Man-Made Disasters Proliferate

2019

● KASA and PQ/CMC Initiatives Gain Momentum in FDA’s Efforts to Strengthen Quality Review Process

2020

● Pandemic Stresses Increase FDA Attention on Risk Management Plans for drug Shortage Prevention and Mitigation

2021

● Pandemic Intensifies USP’s Focus on Supply Chain Vulnerabilities and Vaccine Development

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