ICH Q9: Quality Risk Management CDER ADVISORY COMMITTEE FOR PHARMACEUTICAL SCIENCE (ACPS) October 5-6, 2006 Rockville, MD H. Gregg Claycamp, Ph.D. Office of New Animal Drug Evaluation gregg.claycamp@fda.hhs.gov

Why was ICH Q9 needed? To ensure a common understanding of Quality Risk Management (QRM) by both industry and regulators To facilitate moving to the “Desired State” To facilitate communication and transparency To move from ‘fire fighting’ to management of risk ICH Q9 explains A common language and process Potential methodologies for QRM Where QRM can add value

What’s in Quality Risk Management? Q9 has broad risk concepts and principles Principles for implementation Elements of Risk Assessment/Management Processes Does not discuss a single tool, but “The Right Tool for the Job” approach Risk Management Tools High-level (Ideas and Concepts) Mid-Level (Quantitative and Qualitative) Low-Level (Real numbers and real time)

What’s not in ICH Q9 … A “cookbook” for risk management A specific prescription for your risk management program An exhaustive treatment of theory An exhaustive list of methods and tools

Q9’s Sample Process Risk Communication Risk Management Tools Initiate Risk Review Risk Assessment Risk Evaluation unacceptable Risk Control Risk Analysis Risk Reduction Risk Identification Review Events Risk Acceptance Initiate Quality Risk Management Process Output / Result of the Risk Communication Risk Management Tools

QRM is not a Single Process Start Process- step Risk identification Decision Feedback procedure Risk analysis Sub-Sub- process Sub- process Start End Start End Etc. End

Different Meanings of “Risk” Individual: Risk is a cognitive and emotional response to expected loss. Society: Risk is a societal expression of expected harm tempered by expected benefits. Organizations: Risk is a combination of the probability of occurrence and severity of selected harms. Technical: Risk is usually based on the expected value of the conditional probability of the event occurring times the consequence of the event given that it has occurred.

Q9 Overarching Principles “The evaluation of the risk to quality should be based on scientific knowledge and ultimately link back to the protection of the patient; and The level of effort, formality, and documentation of the quality risk management process should be commensurate with the level of risk.”

Concept: Link Back to Patient Risk Opportunities to impact risk using quality risk management Design Process Materials Manufacturing Facilities Distribution Patient

QRM and the Design Space Risk analysts estimate probabilities of being outside (or inside!) of design limits, given various scenarios. v2 design space v1 v3 What is the chance (probability) of “falling outside” of the design space per unit time? Design parameters and their intersection in a “design space” concept

QRM: Another Systems Approach A systematic process for the assessment, control, communication and review of risks to the quality of the drug product across the product lifecyle. “Systems” thinking and methods!

“Risk Management” is Universal Company Strategic Risks Operational Risks Financial Risks Compliance Risks Competitor Advantage Company Viability Shareholder Harm Patient Harm ICH Q9 Impact

Severity and Probability  Risk High Risk Increasing Probability of Occurrence Medium Risk Low Risk Increasing Severity of Harm/Consequence

Tools for Risk Management ICH Q9 Includes an Annex of Tools

“High-Level” Tools Often rely mixed kinds of information: Quantitative Qualitative Expert judgment Focus on systematic thinking: Define the risk question Organize information under categories, attributes Build decision making paths

Examples of implementation: FDA CDER/ORA Site Selection process for GMP inspections CVM pre-approval decision support system (PAIDSS) Other efforts in progress

Qualitative Risk Estimation SAMPLE TABLE ONLY Health Severity Scale Probability of Occurrence Very Low Low Medium High Very High Death Hospitalization Acute Illness Worry Low Risk Medium Risk High Risk A B C

Risk Ranking –High Level Facility (Risk Ranking) Site M Site T Site C Site D Site X Site A Scored and Prioritized Under Multiple Criteria Process Product SAMPLE CHART

Mid-Level: Combinations of Methods More formula-driven than High-level tools and approaches Expert-driven qualitative with some data FME(C)A Decision analytic methods Limitations Which experts? Risk-analytical methods Sorting value- and perception-driven assessments with quantitative variables

FME(C)A 10 9 8 7 6 5 4 3 2 1 10 9 8 7 6 5 4 3 2 1 Severity of Effect Criticality S x O 10 9 8 7 6 5 4 3 2 1 10 9 8 7 6 5 4 3 2 1 1 2 3 4 5 6 7 8 9 10 “SOD” or “Risk Number” S x O x D Severity of Effect S O Occurrence Probability Detection* *Higher detection ability lowers risk score.

FME(C)A—Intermediate Tool SAMPLE CHART

Present Status of the Guideline Published as US Guidance, June 2006 http://www.fda.gov/cder/guidance/7153fnl.htm Judging by industry and regulatory conferences, workshops, publications: interest in Q9 remains high Some members of the ICH EWG compiled presentations for information. Now available on ICH website: http://www.ich.org/cache/compo/276-254-1.html

Next Steps? From great ideas to practice—how? Both industry and regulators want to know Which risks firsts? Which tools are best? How will I know “good” from “bad” risk management? Do we need dept./divisions of risk managers?

Examples of Implementation: Industry Many presentations at conferences showing examples of: Failure modes and effects analysis (FMEAs) Multivariate models (QC/QA integration) Systems design, modeling and application are readily adaptable to QRM approaches

Keys to Implementation Key to implementation: the systems approaches in Q8-Q9-Q10 leverage the best parts of existing knowledge bases and expertise for systematic control of risks to pharmaceutical quality. Gregg’s Pareto principle for QRM: “More than 80% of the expertise for a Quality Risk Management program exists among the domain --i.e., not risk-- experts.”