Regulatory Science: Risk Management Techniques

Regulatory Science: Risk Management Tools and Techniques

• Regulatory science focuses on risk management tools and techniques.
• The course content includes: Risk Management, ICH Guidelines Q9 Quality Risk Management, definitions, systematic breakdown of risk, risk identification, risk assessment, risk control/reduction, communication, tools and techniques, and a worked example of FMEA.
• Learning outcomes include: Identifying risk, explaining the risk management process in detail, discussing risk management tools, and explaining a case study of risk management.
• Stakeholders in pharmaceuticals include medical practitioners, government, industry, and patients.
• Risk is defined as the combination of the probability of harm and the severity of that harm (ISO/IEC Guide 51).
• Risk Management is a systematic process to assess, control, communicate, and review risks concerning drug quality throughout the product lifecycle.
• Quality risk management is an ongoing process meant for improving scientific based decision making and facilitating action with respect to risks.
• Critical Material Attributes (CMAs) are physical, chemical, biological or microbiological properties of input materials, important for ensuring a desired output material.
• Critical Process Parameters (CPPs) are process parameters whose variability affects critical quality attributes (CQAs). They need to be monitored and controlled for desired quality.
• Risk analysis aims to relate critical process parameters and critical material attributes to critical quality attributes.
• Risk analysis should be evidence-based, and the level of effort/ formality/documentation for quality risk management should be commensurate with the level of risk.

ICH Guidelines Q9 Quality Risk Management

• ICH Q9 provides principles and examples of tools for quality risk management (QRM).
• QRM is applicable to different aspects of pharmaceutical quality, such as development, manufacturing, distribution, inspection and submission/review processes.
• Two primary principles link quality risk management to patient protection: The evaluation of risk to quality should be based on scientific knowledge. The level of effort, formality, and documentation of QRM should be commensurate with the level of risk.

What is Risk?

• A hazard is something that has the potential to harm you.
• Risk is the likelihood of a hazard causing harm.

Definitions

• Risk: The combination of the probability of occurrence of harm and the severity of that harm (ISO/IEC Guide 51).
• Risk Management: A systematic process for the assessment, control, communication, and review of risks to the quality of drug (medicinal) product across the product lifecycle.

Who is Responsible for Risk Management?

• Risk management activities are typically done by interdisciplinary teams.
• Teams should include experts from appropriate areas, such as quality unit, business development, engineering, regulatory affairs, production operations, sales and marketing, legal, statistics, and clinical.

Systematic Approach to Risk Management

• Steps for initiating and planning QRM processes may include defining the problem/risk question, assembling information, identifying a leader and necessary resources, and planning a timeline, deliverables and decision-making level.

Critical Process Parameters and Critical Material Attributes

• Critical Material Attributes (CMAs) are the physical, chemical, biological and microbiological properties of input materials that need to be within appropriate limits. Examples include formulation, excipients, and drug substance.
• Critical Process Parameters (CPPs) are process parameters whose variability affects critical quality attributes. Examples include input materials, equipment, and environmental factors.

Risk Analysis

• The aim of risk analysis is to relate critical process parameters and critical material attributes to critical quality attributes.
• Risk analysis should be based on experience and scientific understanding and link to patient protection.
• Specific questions to consider in risk analysis include: Does this attribute impact the CQA? How does it effect the CQA? How much does it effect the CQA? Can changes be detected? How readily can they be detected? Can it be controlled?

Identifying CQAS

• Critical Quality Attributes (CQAs) are those attributes of the drug that are critical to the performance of the pharmaceutical. Identifying CQAs is an important step in identifying and prioritizing risks. This includes attributes like safety, efficacy, purity, potency, and identity.

Risk Ranking

• Risk ranking (high, medium, and low) facilitates a focus on vital factors concerning cost and time.
• Critical attributes of product and processes affect CQAs, and these need to be monitored and controlled.
• Specifications and limits need to be put in place, and the processes should operate within these limits for CQAs to remain within set limits or unchanged.

How is a Quality Attribute Deemed Critical?

• Severity scale assesses magnitude of impact.
• Criticality only changes when there is a change in severity.
• QTPP (Quality Target Product Profile) potential impacts on safety, efficacy, and quality.

When is a Quality Attribute a CQA?

• A quality attribute becomes a CQA when it has an impact on the patient (efficacy, safety, quality).

Risk Analysis - CMA and CPP Examples

Illustrative tables showing example risk analysis of material and process attributes, using a ranking (low, medium, high) strategy

Quality Risk Management Process

• The process involves identifying what could go wrong, assessing likelihood of problems, severity of consequences, acceptable levels of risk, steps to reduce risk, balancing risk with benefits/resources, and handling new risks.
• A typical quality risk management process includes initiating the process, risk assessment, risk identification, risk analysis, risk evaluation, risk control, risk reduction, risk acceptance, communication, output/result review, risk review events, and continuous improvement.

Risk Assessment Tools

• Tools for basic risk analysis include flowcharts, checksheets, fishbone diagrams, FMEA (Failure Mode and Effects Analysis), FMECA, fault tree analysis, HAZOP analysis and risk ranking tools like Pareto diagrams.

FMEA (Failure Mode and Effects Analysis)

• FMEA is a process analysis tool to evaluate potential failures in processes.
• Uses a systematic approach that breaks down complex processes into manageable steps.
• Teams are needed to identify potential problem areas, estimate probability and consequences of failures, and implement preventive actions.
• FMEA steps involve outlining every step, identifying failures, understanding consequences, determining a Risk Priority Number (RPN), ranking risks, assigning corrective actions, and reviewing the FMEA with implemented controls.

HACCP (Hazard Analysis and Critical Control Points)

• HACCP is a hazard-based preventive approach for the production of quality products. The HACCP system entails seven steps for identifying or preventing any potential safety hazards.

Risk Communication

• Quality risk management depends on effectively communicating risk and risk management information between decision-makers (stakeholders) and others.

Review Risk Management

• Regularly review risk management by monitoring events and processes to account for new information.

• Review should be continuous, applying for adjustments as new knowledge and understanding of the business are identified.